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Gatekeeper, provider, HCP: The slow degradation of the doctor title
What’s in a name? A lot, if you’re a doctor.
"Doctor" is our formal title, although technically it means anyone with a higher educational degree. We’re also called physicians, or healers. In other times, we may have been medicine men, witch doctors, or shamans. Or we may prefer a more specific name based on our chosen field: neurologist, internist, or surgeon, for example.
Recently, though, we’ve had specific (and less flattering) names hung on us – health care providers, primary care physicians, gatekeepers – not to mention the alphabet soup that longer names bring (HCP, PCP).
It kind of puts us in a semantic identity crisis. Especially with all the HCPs out there who aren’t MDs or DOs.
But no matter what title they hang on me, I know what I do. I care for people who need me. I provide treatment for those I can help and support to those I can’t. I hold hands. I write prescriptions. I discuss test results. I talk, and I listen. I fill out forms. I argue with insurance companies. I go home each night and in the morning come back and do it all over again.
Somehow saying I’m an HCP doesn’t seem to do the job description justice.
I remember a residency meeting I attended in the mid-90s. I was in training, and the meeting was held to introduce all the residents to the hospital’s new health plan. The insurance lady running it told us not to use the word "patients" but instead call them "lives." Doctors, in her doublespeak, were "providers" unless you were in internal medicine or family practice, in which case you had the even less flattering name of "gatekeeper."
The meeting got increasingly acrimonious, and the insurance lady looked more and more uncomfortable. Finally, a family practice resident named Barb stood up and said, "You can change words all you want, but here’s the truth. We are not providers, or PCPs, or gatekeepers. We are doctors. And we do our best to care for people, even when your company won’t."
Barb stood up, turned on her heel, and walked out with her long skirt swirling. The insurance company lady was obviously angry and left through the exit behind her.
It’s now 20 years later, Barb, and I don’t think anyone could have said it better, then or now. It still holds true.
Dr. Block has a solo neurology practice in Scottsdale, Ariz.
What’s in a name? A lot, if you’re a doctor.
"Doctor" is our formal title, although technically it means anyone with a higher educational degree. We’re also called physicians, or healers. In other times, we may have been medicine men, witch doctors, or shamans. Or we may prefer a more specific name based on our chosen field: neurologist, internist, or surgeon, for example.
Recently, though, we’ve had specific (and less flattering) names hung on us – health care providers, primary care physicians, gatekeepers – not to mention the alphabet soup that longer names bring (HCP, PCP).
It kind of puts us in a semantic identity crisis. Especially with all the HCPs out there who aren’t MDs or DOs.
But no matter what title they hang on me, I know what I do. I care for people who need me. I provide treatment for those I can help and support to those I can’t. I hold hands. I write prescriptions. I discuss test results. I talk, and I listen. I fill out forms. I argue with insurance companies. I go home each night and in the morning come back and do it all over again.
Somehow saying I’m an HCP doesn’t seem to do the job description justice.
I remember a residency meeting I attended in the mid-90s. I was in training, and the meeting was held to introduce all the residents to the hospital’s new health plan. The insurance lady running it told us not to use the word "patients" but instead call them "lives." Doctors, in her doublespeak, were "providers" unless you were in internal medicine or family practice, in which case you had the even less flattering name of "gatekeeper."
The meeting got increasingly acrimonious, and the insurance lady looked more and more uncomfortable. Finally, a family practice resident named Barb stood up and said, "You can change words all you want, but here’s the truth. We are not providers, or PCPs, or gatekeepers. We are doctors. And we do our best to care for people, even when your company won’t."
Barb stood up, turned on her heel, and walked out with her long skirt swirling. The insurance company lady was obviously angry and left through the exit behind her.
It’s now 20 years later, Barb, and I don’t think anyone could have said it better, then or now. It still holds true.
Dr. Block has a solo neurology practice in Scottsdale, Ariz.
What’s in a name? A lot, if you’re a doctor.
"Doctor" is our formal title, although technically it means anyone with a higher educational degree. We’re also called physicians, or healers. In other times, we may have been medicine men, witch doctors, or shamans. Or we may prefer a more specific name based on our chosen field: neurologist, internist, or surgeon, for example.
Recently, though, we’ve had specific (and less flattering) names hung on us – health care providers, primary care physicians, gatekeepers – not to mention the alphabet soup that longer names bring (HCP, PCP).
It kind of puts us in a semantic identity crisis. Especially with all the HCPs out there who aren’t MDs or DOs.
But no matter what title they hang on me, I know what I do. I care for people who need me. I provide treatment for those I can help and support to those I can’t. I hold hands. I write prescriptions. I discuss test results. I talk, and I listen. I fill out forms. I argue with insurance companies. I go home each night and in the morning come back and do it all over again.
Somehow saying I’m an HCP doesn’t seem to do the job description justice.
I remember a residency meeting I attended in the mid-90s. I was in training, and the meeting was held to introduce all the residents to the hospital’s new health plan. The insurance lady running it told us not to use the word "patients" but instead call them "lives." Doctors, in her doublespeak, were "providers" unless you were in internal medicine or family practice, in which case you had the even less flattering name of "gatekeeper."
The meeting got increasingly acrimonious, and the insurance lady looked more and more uncomfortable. Finally, a family practice resident named Barb stood up and said, "You can change words all you want, but here’s the truth. We are not providers, or PCPs, or gatekeepers. We are doctors. And we do our best to care for people, even when your company won’t."
Barb stood up, turned on her heel, and walked out with her long skirt swirling. The insurance company lady was obviously angry and left through the exit behind her.
It’s now 20 years later, Barb, and I don’t think anyone could have said it better, then or now. It still holds true.
Dr. Block has a solo neurology practice in Scottsdale, Ariz.
The Medical Roundtable: Current and Future Strategies for Overcoming Diuretic Resistance in Acute Heart Failure
It is well recognized that diuretic therapy remains the main approach to volume management in heart failure patients and carries a first-line recommendation according to the American College of Cardiology/American Heart Association (ACC/AHA) guidelines.1 However, in more advanced patients and those who have been on chronic diuretic therapy, many fail to respond to escalating doses of intermittent loop diuretics, a common clinical scenario referred to as “diuretic resistance.”
In patients exhibiting diuretic resistance, several approaches have been utilized. This includes increasing the frequency of administration or initiating a continuous infusion of the loop diuretic, changing to a more potent (on a milligram per milligram basis) loop, or combining a loop diuretic with a thiazide agent. Other approaches to enhancing fluid removal such as ultrafiltration and the addition of other intravenous (IV) vasoactive agents have also been considered. Only a few studies have evaluated the individual efficacy and safety of these different approaches.
There is a paucity of head-to-head studies to guide our approach, with most of the comparative data being limited to the comparison of intermittent bolus to continuous infusion loop diuretic administration. In those studies the results have been somewhat conflicting. In addition, all these data have inherent limitations and are open to interpretation. Thus there continues to be a debate as to the best method for volume management in acute heart failure. In the future we may have new pharmacologic therapies and the role of ultrafiltration and other nonpharmacologic approaches may be clarified.
I thought we could start with the issue of continuous infusion and what is the role of continuous infusion compared to intermittent bolus loop diuretic administration. Perhaps Dr. Mehra could start us off by giving us his impressions on this issue.
DR. MEHRA: Let me first begin by amplifying one important item on the clinical definition of diuretic resistance. We tend to think of a patient with advanced heart failure or heart failure with decompensation as having evidence of diuretic resistance if a certain threshold of exposure to incremental IV diuretic bolus therapy does not evoke an adequate diuretic response. Clinicians consider unresponsiveness to 160 mg or 200 mg of IV furosemide administered as a bolus evokes an anemic urine output response in the subsequent two to three hours as demonstrating clinical diuretic resistance.
It is important to note also that many of these trials did not in fact include just diuretic resistance or diuretic refractory patients. Most of the recent clinical trials, such as Diuretic Optimization Strategies Evaluation (DOSE) looked at patients with congestion in the setting of decompensated heart failure who were being treated with a diuretic regimen with the idea of testing two very specific strategies of diuretic use. First, a low dose compared to a high dose strategy, and the second a continuous infusion strategy compated to a bolus dosing strategy.2 These are clinically useful strategies, which until now have not been subjected to randomized control trials. In that sense the DOSE trial has helped us move forward in a clinical direction.
To summarize the DOSE trial,2 this study suggested that neither of these specific clinical strategies were superior to the other ones, including a low dose/ high dose or bolus dose/continuous dosing with a diuretic. The study found some signals that suggested that the higher dose strategy was associated with less dyspnea but at a risk of a greater incidence of worsening of renal function, at least in the short-term. Thus, the appropriate interpretation of the DOSE trial is that it has shown us evidence of the reasonable safety and effectiveness of all of these strategies when used early in the course of decompensated heart failure. Would you agree with that, Tien and Jo Ellen?
DR. RODGERS: I definitely agree that the DOSE trial demonstrated, in a broad population of patients presenting with acute decompensated heart failure and requiring diuretic therapy ,that there is no difference between IV bolus and continuous diuretic administration, but that there is some benefit with high dose, specifically 2.5 times the oral dose, compared to a low dose. In addition to a reduced area under the curve for dyspnea at 72 hours, patients receiving high dose therapy also experienced a significant reduction in weight and net fluid loss at 72 hours. As Dr. Mehra pointed out, this benefit may be at the expense of temporary worsening of renal function. And thus, in practice, we need to be mindful of patient selection and which patients need more aggressive diuretic response compared to those patients in whom you are not willing to tolerate worsening renal function to gain the additional diuretic response. The former may be the patient who needs more aggressive relief of dyspnea—perhaps the patient in the emergency room with poor oxygen saturation. This patient should be managed with the high dose diuretic strategy. The latter may be the patient with acute or chronic renal failure in whom the risk of worsening renal function does not outweigh the benefit of more aggressive diuresis.
The issue that is critical to emphasize is that the DOSE trial assessed diuretic effectiveness of various diuretic strategies in patients who were requiring diuretic therapy, but may or may not be truly diuretic resistant. And thus, the patients enrolled were simply in decompensated heart failure secondary to fluid overload. Looking at the demographic characteristics of the trial population including baseline systolic blood pressure, serum urea nitrogen and serum creatinine as well as serum sodium, it would be anticipated that these patients would have fairly low in-hospital mortality rates compared to patients with systolic blood pressures less than 115 mm Hg, serum urea nitrogen greater than 43, and serum creatinine >3.75 mg/dL, as demonstrated by prior Acute Decompensated Heart Failure National Registry (ADHERE) data. Patients who are developing diuretic resistance are more apt to be in this latter group. Such patients may be more prone to renal dysfunction and other adverse outcomes with aggressive diuretic therapy. Diuretic response in this patient population has not been assessed.
DR. NG: Yes, I have to agree with both of you. Overall, the trial does give us some sense of the safety and the efficacy of the high versus the low dose. However, one important caveat when it comes to the interpretation of the continuous infusion compared to the intermittent infusion results was that the dosing was fixed in these two arms for the first 48 hours of the study, but then from 48 to 72 hours it became open label. There definitely was a suggestion that the continuous infusion arm had a lower dose requirement overall and required less dose escalation.
In terms of the interpretation of the DOSE trial for the continuous infusion versus intermittent infusion comparison, the lack of difference in overall urine output is in agreement with the recently published study by Dr. O’Connor’s group showing absolutely no difference between continuous infusion and intermittent bolus infusions using the same daily dose.3 On the surface it seems in contrast to the Thompson study,4 which found a trend toward an increase in urine output with continuous infusion. However, it is consistent if one considers that in the latter study the actual dose received over 24 hours was not the same. I still have some issue with the amount of diuretic that was received in the DOSE study for the intermittent versus continuous infusion comparison when the take home message of the study was that there was no difference between the two regimens.
DR. MEHRA: The fundamental issue relates to the application of these findings to clinical practice. Does it not affect clinical practice at all, or do we take comfort in the finding from the DOSE trial that, hey, the continuous high-dose diuretic strategy is reasonably safe and one should not run away from it if you deem as a clinician that that is the appropriate strategy to use by a particular patient? For example, someone with chronic long-standing heart failure with exposure to chronic high dose diuretic therapy, and some renal dysfunction at the time of inception of continuous IV diuretic therapy may be more suitable for chronic infusion therapy. At that point in time I think that my clinician gestalt would be to use a higher dose continuous infusion strategy, not simply because I am worried about the amount of urine output, but perhaps also because of the toxicity associated with the higher dose diuretic bolus regimens that one may encounter. The DOSE trial did not look at toxicity, particularly oto-toxicity; it mainly focused its safety endpoints on renal function.
DR. NG: I think the issue of other safety signals not addressed in the DOSE trial have come up in some of the other studies. A Cochrane Review,5 which was completed prior to the three latest trials, looked at all the smaller studies and found continuous infusion was associated with a lower incidence of ototoxicity compared to intermittent bolus therapy.
DR. MEHRA: That’s correct. In fact, much of that information comes from the chronic renal failure literature as well, where continuous infusions with drugs like bumetanide have been shown to result in a lower incidence of cochlear toxicity.
DR. NG: Okay, so Dr. Rodgers, I think we’re all in agreement that the DOSE trial allows us to feel better about using higher doses of loop diuretics in select acute heart failure patients. But based on the data from the most recent trials by Thompson, Allen, and the DOSE trial, do you believe there is still a strong rationale for using continuous infusion as opposed to intermittent bolus.
Any time a clinician is starting to push to higher diuretic doses with no response or is starting to consider additional therapies, one should be cognizant of the risk of additional electrolyte wasting and worsening renal function and assured that these safety parameters are closely monitored. This is when patient selection for more aggressive diuretic regimens must be carefully considered. In addition, there remain many unanswered questions about appropriate alternative therapies and the role of such in further increasing or perhaps mitigating these risks. Alternative therapies studied to date include low dose dopamine, low dose nesiritide, and other vasoactive agents.
With regard specifically to ototoxicity, this is an adverse effect that is probably very underappreciated and perhaps it’s because clinicians rarely monitor it. Most clinicians are very aware that if you administer a large, single, IV bolus dose of 180 mg of furosemide too rapidly (for example, greater than 4 mg per minute), the risk of ototoxicity is increased, but I’m less certain at what precise dose of a furosemide continuous infusion a clinician should avoid or more assertively monitor for ototoxicity. Perhaps the focus of future research should include assessing the role of these additional or alternative therapies in minimizing toxicities including ototoxicity. Do you have any suggestions, Dr. Mehra?
DR. MEHRA: I think that the data suggest that cochlear toxicity or ototoxicity is related to the peak effects and not the trough effect, so the higher the bolus dosing, the more the chance that one could have cochlear toxicity, particularly if there are other ototoxic agents being administered concomitantly. For example, if someone is receiving a drug like a gentamycin-type analog, for instance, along with a diuretic infusion or a diuretic bolus, I think there’s magnification of that ototoxicity. Frankly that isn’t the overriding concern of most clinicians, and in fact we do not systematically study it, as you’ve pointed out. I often am more concerned in the diuretic resistant patients with the best dosing strategy. I know that, Tien, you have done some work in that regard and I wonder if we could turn the conversation toward discussing what kind of combination diuretic strategies really work in reducing fluid overload.
DR. NG: Clearly another option which is commonly used in practice is the combination of diuretic agents, specifically a loop diuretic added to a thiazide agent, a thiazide which is still effective even in the setting of poor renal perfusion. There are a lot of observational and small studies that have evaluated whether or not the addition of a thiazide, such as metolazone, to a loop diuretic, such as furosemide or bumetanide, augments sodium excretion and urine output. A paper that was published in the Journal of the American College of Cardiology summarized some of these data found a signal for increased urine output.6 Our group recently evaluated the addition of metolazone to furosemide, compared to just a continuous infusion of furosemide, and found a statistically significant greater increase in mean hourly urine output with the combination compared to furosemide used by itself.
What was interesting about our data, which are consistent with some of the existing data, is there was actually no signal for worsening renal function in our patients who received the combination, although there was a signal for an increased risk of electrolyte disturbances. So the conclusion of our study, since it was an observational study, was because of potential differences in clinical efficacy and safety, there is a great need for further study in prospective trials of these alternative strategies, such as combining agents, to truly understand whether these therapies are more effective while remaining relatively safe.
DR. RODGERS: These studies have made important contributions to the literature, but as Tien explains, are not optimally designed trials. Thus, there is need for prospective evaluations to address these unanswered questions. When conducting these future prospective studies, it will be important to include endpoints such as 30-day rehospitalization. If these alternative regimens more effectively diurese, then length of hospital stay may even be reduced by a day or two. With that said, I would be concerned that patients might subsequently suffer other adverse consequences such as continued unwanted diuresis and related adverse effects post-discharge. This is an important question to address with agents such as metolazone, given the long half-life and considerable intra- and inter-patient variability in onset of action with this agent. Future prospective trials need to address outcomes, such as length of stay and rehospitalization at 30 days, for these very reasons.
There are many reasons these trials have not been prospectively conducted in the past, and one major rate-limiting factor is the uniqueness of the population of patients with refractory fluid overload. When clinicians are faced with these patients, they often start to inquire about the appropriateness of a right heart catheter and inotropic therapy simply because diuretic refractoriness may be an indicator of low cardiac output. Patient characteristics such as concomitant inotropic therapy was most often an exclusion criteria for the previously discussed trials.
DR. MEHRA: So let me respond to that, Jo Ellen. First of all, I was taught to use a lot of metolazone, and frankly, as I matured clinically, I became less enamored by that drug as I realized how tough a drug it was on the kidneys and on electrolyte balance. There is this notion of what is the appropriate clinical endpoint, and I think you alluded to it. The endpoint needs to be clinically relevant. The endpoint should focus on the patient and not be one where the clinician feels better. Essentially we have been a bit swayed by how much urine output can be evoked and how much fluid can be removed. We have a large number of papers and data emerging that tell us that there may be a significant disconnect between the amount of fluid removal and clinical outcomes. As an example, studies like the Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study with Tolvaptan (EVEREST)7 with a vasopressin receptor antagonist showed effectiveness of the drug tolvaptan in improving hyponatremia, and in reducing weight in patients significantly, compared to placebo, but was no better than placebo in influencing 24 month outcomes from a cardiovascular endpoint. So we have to fundamentally ask the question, do any of these strategies actually make a real difference in patients?
The other issue is that we need to do a better job of discriminating among the distinct patient groups that present with diuretic resistance syndrome. So, for example, it would be clinically less useful to start using incremental diuretic strategies and multiple drug regimens in a patient who has a clear low output state causing diuretic resistance. In such a patient, perhaps, a strategy that improves cardiac output with or without the need for mechanical circulatory support might be the appropriate one to overcome diuretic resistance.
In another situation where you have acute pulmonary edema, for instance, in the setting of severe hypertension or acute ischemic syndromes, I think the treatment ought to be very different. In such situations, step number one from a clinical standpoint is to segregate the patients into classifications of why the diuretic resistance has occurred and what is the relationship of that diuretic resistance to pump function. As an example, most of the multiple drug use strategies that work do so in the setting where true renal causes of diuretic resistance have occurred. This is manifested pathologically by the development of tubular hypertrophy, which determines classical diuretic resistance. In those situations, even considering a “renal rest” such as with ultrafiltration for a few days in some series has shown to be of benefit. It is in those situations where using multiple agents may be beneficial from a fluid removal standpoint. You’re right, Jo Ellen, we have to ask ourselves to what end we are actually making patients better. And our definitions of how we make patients better are equally critical.
Tien, do you have some thoughts about that?
DR. NG: Yes, I have to agree. I think an issue has always been, what is the appropriate endpoint for our acute heart failure patients? This has been debated for years and years now, and when you look at the safety signals or the safety endpoints that are currently being used and the efficacy endpoints, we really don’t know whether these are the optimal safety and efficacy endpoints. In one sense we’re using urine output, and as you’ve pointed out there are clearly data showing that urine output isn’t necessarily the greatest indicator of an improved prognosis in these patients. At the same time, looking at serum creatinine changes as a measure of renal function obviously has its limitations as well. With serum creatinine one wouldn’t expect large changes in these relatively short-term trials, as it is a delayed marker of renal injury. So in the future, to look at the renal safety of these agents it will be important to incorporate some novel, more accurate and early markers of acute kidney injury. I think that will help us understand whether or not we are actually doing something beneficial for these patients or whether we are just treating ourselves.
DR. RODGERS: I completely agree, Dr. Ng. I think that many of our future trials are focusing on either the right population or the right endpoint. Some good examples, Dr. Mehra just mentioned ultrafiltration and the Cardiorenal Rescue Study in Acute Decompensated Heart Failure (CARRESS) trial,8 which is currently recruiting patients, and this study is specifically enrolling patients who are congested and fluid overloaded, but who have experienced renal insufficiency. The primary endpoint is a combination of weight and renal function changes. I am optimistic that any follow-up studies to CARRESS will assess endpoints such as mortality and rehospitalization. Other trials such as the Phosphodiesterase-5 Inhibition to Improve Clinical Status and Exercise Capacity in Diastolic Heart Failure (RELAX) trial9 with the agent relaxin, also are enrolling patients with mild to moderate renal insufficiency. This trial is designed to assess clinically meaningful endpoints such as worsening heart failure associated with longer length of stay, as well as 60-day outcomes. It is great that these trials are addressing how to manage the patients that clinicians most struggle with.
DR. NG: Would either of you like to comment on some of the novel pharmacologic approaches which are currently being evaluated? This includes low dose nesiritide compared to low dose dopamine, the Renal Optimization Strategies Evaluation in Acute Heart Failure (ROSE) trial,10 designer natriuretic peptides such as CDNP or CUNP. Thus far agents such as vasopressin antagonists and adenosine receptor antagonists haven’t been associated with positive results from a cardiorenal standpoint; however, I was wondering if you believe these agents may still have a potential role?
DR. RODGERS: The ROSE trial, again alludes to what we previously discussed regarding the addition of other agents in an attempt to minimize toxicity of diuretic therapy. This trial is assessing our ability to effectively manage the fluid overload without causing renal injury. Similar to RELAX,9 the ROSE trial is enrolling patients with impaired renal function as defined by a creatinine clearance between 15 and 60 mL/min. As Dr. Ng had suggested, they are utilizing a new marker for renal dysfunction in this trial. Their primary endpoint is change in cystatin C. Cystatin C is an excellent marker of kidney function because it is devoid of some of the limitations or inaccuracies of measuring serum creatinine, specifically it may more readily detect milder forms of renal impairment. Also, it is more reliable in patients with varying muscle mass or protein intake, which is commonly a problem in our heart failure patients who have cachexia due to low cardiac output or fluid overload.
DR. MEHRA: I think that the future is clearly in many of these trials that are being undertaken. I’m particularly optimistic about the combined use of diuretic infusions with low dose dopamine, for instance. That has been a strategy that’s been used in the past, but it’s very controversial. I understand that one of the components of the ROSE trial that is testing these various strategies includes low dose dopamine. It should be an interesting facet to investigate to see what is the role of an old drug that’s easily available and won’t cost us incremental dollars in a cost-restrained system.
I actually do think that agents need to continue to be investigated, but I have been very disappointed with the way the current field of agents looks. As you look at the vasopressin receptor antagonists, they’ve all come out fairly short in enhancing clinical outcomes. My suspicion is that there will be sub-populations that benefit and sub-populations that are harmed by these therapies. That is the uniform outcome in almost all situations where you have high morbidity and mortality, such as in acute decompensated heart failure. My personal feeling is that we need to do a better job of finding which populations are most likely to benefit and our attention ought to be focused there. I still think that there will be selective roles for these agents in the appropriately defined groups of patients.
The problem with any such study that looks either at surrogate biomarkers like cystatin C or looks at just patient derived global assessment scales or renal function, is the very small study size, often with a small number of patients in each group. It is therefore very difficult to pull out the groups of patients in whom harm occurred and distinguish them very clearly from the groups of patients in whom clear benefit was observed. I suspect that one of the studies from which we ought to get more information in this regard is the large Acute Study of Clinical Effectiveness of Nesiritide in Decompensated Heart Failure Trial (ASCEND), with more than 7000 patients.11 I think the value of that particular trial is probably confined to developing a very clear interface of investigations that will guide us to pick out those particular subgroups of patients in whom we should use targeted approaches for incremental diuretic or fluid removing strategies. What do you guys think?
DR. NG: I fully agree with both of your previous sentiments. Clearly the general sense is loop diuretics, regardless of how they’re administered or dosed, represents a suboptimal method to affect fluid removal from our volume overloaded patients. There remains hope that in the future new therapies that are more sparing from a pathophysiology standpoint will be developed so that we can effectively manage volume status in our patients while also having a positive effect on their outcomes.
So, yes, I hold hope that different combinations of pharmacologic agents as well as device therapies will be developed, and we’ll gain a greater appreciation of how to optimally select between these therapeutic options for individual patients.
Before concluding, I want to get your thoughts on one last issue. In the past we’ve approached diuresis as being a consequence of hypoperfusion. More recently, data focusing on venous congestion and how that influences diuretic responsiveness has emerged. My feeling is that as we understand the contribution of venous congestion to renal function in acute heart failure, new physiologic targets may be identified.
DR. MEHRA: Let me make a few comments about that. If you just think about the person who is most likely to develop diuretic resistance, it would be a person who has low blood pressure, chronic renal insufficiency, and very high right sided pressures. I think we’re learning now that the frequency of cardiorenal syndrome in patients with chronic heart failure is singularly linked to the severity of right heart function. And right heart failure is probably the closest correlate. Small observational studies have addressed the issue of intra-abdominal pressure as a surrogate marker for worsening renal function and improvements following release of intra-abdominal pressure, by removal of ascitic fluid or by decongesting these patients to reduce right atrial pressure, these have all shown some signals towards reduction in serum creatinine and recovery from cardiorenal syndrome.
So I think we are beginning to move in the direction that congestion is bad, that right-sided heart failure is probably the focus of our therapy, and that one surrogate for right heart failure other than the jugular venous pressure is intra-abdominal pressure, which can be very easily measured by placing a Foley in the bladders of these patients and attaching that to a pressure manometer.
DR. NG: Jo Ellen, did you have anything to add there?
DR. RODGERS: No.
DR. NG: Okay, in that case I would like to thank you all for your participation. To conclude I’ll provide a brief summary of what we’ve discussed. We began with a discussion of the role of continuous infusion and high-dose compared to low-dose loop diuretics as a method for overcoming clinical diuretic resistance. We all agree that, although the data are not airtight, they do suggest that there doesn’t seem to be large differences in terms of efficacy and in safety using high versus low or intermittent versus continuous infusion. The actual selection of the strategy should take into account the clinical status and characteristics of the individual patient.
We then moved to the issue of different diuretic strategies. We are hopeful that the addition of other agents which help augment overall diuresis will allow for a loop diuretic sparing effect, and may represent a better approach. Some of the current trials will help clarify that issue. We ended with just a very brief discussion on the need in future studies to identify optimal patients and optimal endpoints, as well as looking at the overall model of congestion, right-sided failure, and its contribution to the cardiorenal syndrome that we manage daily in our acute heart failure patients.
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It is well recognized that diuretic therapy remains the main approach to volume management in heart failure patients and carries a first-line recommendation according to the American College of Cardiology/American Heart Association (ACC/AHA) guidelines.1 However, in more advanced patients and those who have been on chronic diuretic therapy, many fail to respond to escalating doses of intermittent loop diuretics, a common clinical scenario referred to as “diuretic resistance.”
In patients exhibiting diuretic resistance, several approaches have been utilized. This includes increasing the frequency of administration or initiating a continuous infusion of the loop diuretic, changing to a more potent (on a milligram per milligram basis) loop, or combining a loop diuretic with a thiazide agent. Other approaches to enhancing fluid removal such as ultrafiltration and the addition of other intravenous (IV) vasoactive agents have also been considered. Only a few studies have evaluated the individual efficacy and safety of these different approaches.
There is a paucity of head-to-head studies to guide our approach, with most of the comparative data being limited to the comparison of intermittent bolus to continuous infusion loop diuretic administration. In those studies the results have been somewhat conflicting. In addition, all these data have inherent limitations and are open to interpretation. Thus there continues to be a debate as to the best method for volume management in acute heart failure. In the future we may have new pharmacologic therapies and the role of ultrafiltration and other nonpharmacologic approaches may be clarified.
I thought we could start with the issue of continuous infusion and what is the role of continuous infusion compared to intermittent bolus loop diuretic administration. Perhaps Dr. Mehra could start us off by giving us his impressions on this issue.
DR. MEHRA: Let me first begin by amplifying one important item on the clinical definition of diuretic resistance. We tend to think of a patient with advanced heart failure or heart failure with decompensation as having evidence of diuretic resistance if a certain threshold of exposure to incremental IV diuretic bolus therapy does not evoke an adequate diuretic response. Clinicians consider unresponsiveness to 160 mg or 200 mg of IV furosemide administered as a bolus evokes an anemic urine output response in the subsequent two to three hours as demonstrating clinical diuretic resistance.
It is important to note also that many of these trials did not in fact include just diuretic resistance or diuretic refractory patients. Most of the recent clinical trials, such as Diuretic Optimization Strategies Evaluation (DOSE) looked at patients with congestion in the setting of decompensated heart failure who were being treated with a diuretic regimen with the idea of testing two very specific strategies of diuretic use. First, a low dose compared to a high dose strategy, and the second a continuous infusion strategy compated to a bolus dosing strategy.2 These are clinically useful strategies, which until now have not been subjected to randomized control trials. In that sense the DOSE trial has helped us move forward in a clinical direction.
To summarize the DOSE trial,2 this study suggested that neither of these specific clinical strategies were superior to the other ones, including a low dose/ high dose or bolus dose/continuous dosing with a diuretic. The study found some signals that suggested that the higher dose strategy was associated with less dyspnea but at a risk of a greater incidence of worsening of renal function, at least in the short-term. Thus, the appropriate interpretation of the DOSE trial is that it has shown us evidence of the reasonable safety and effectiveness of all of these strategies when used early in the course of decompensated heart failure. Would you agree with that, Tien and Jo Ellen?
DR. RODGERS: I definitely agree that the DOSE trial demonstrated, in a broad population of patients presenting with acute decompensated heart failure and requiring diuretic therapy ,that there is no difference between IV bolus and continuous diuretic administration, but that there is some benefit with high dose, specifically 2.5 times the oral dose, compared to a low dose. In addition to a reduced area under the curve for dyspnea at 72 hours, patients receiving high dose therapy also experienced a significant reduction in weight and net fluid loss at 72 hours. As Dr. Mehra pointed out, this benefit may be at the expense of temporary worsening of renal function. And thus, in practice, we need to be mindful of patient selection and which patients need more aggressive diuretic response compared to those patients in whom you are not willing to tolerate worsening renal function to gain the additional diuretic response. The former may be the patient who needs more aggressive relief of dyspnea—perhaps the patient in the emergency room with poor oxygen saturation. This patient should be managed with the high dose diuretic strategy. The latter may be the patient with acute or chronic renal failure in whom the risk of worsening renal function does not outweigh the benefit of more aggressive diuresis.
The issue that is critical to emphasize is that the DOSE trial assessed diuretic effectiveness of various diuretic strategies in patients who were requiring diuretic therapy, but may or may not be truly diuretic resistant. And thus, the patients enrolled were simply in decompensated heart failure secondary to fluid overload. Looking at the demographic characteristics of the trial population including baseline systolic blood pressure, serum urea nitrogen and serum creatinine as well as serum sodium, it would be anticipated that these patients would have fairly low in-hospital mortality rates compared to patients with systolic blood pressures less than 115 mm Hg, serum urea nitrogen greater than 43, and serum creatinine >3.75 mg/dL, as demonstrated by prior Acute Decompensated Heart Failure National Registry (ADHERE) data. Patients who are developing diuretic resistance are more apt to be in this latter group. Such patients may be more prone to renal dysfunction and other adverse outcomes with aggressive diuretic therapy. Diuretic response in this patient population has not been assessed.
DR. NG: Yes, I have to agree with both of you. Overall, the trial does give us some sense of the safety and the efficacy of the high versus the low dose. However, one important caveat when it comes to the interpretation of the continuous infusion compared to the intermittent infusion results was that the dosing was fixed in these two arms for the first 48 hours of the study, but then from 48 to 72 hours it became open label. There definitely was a suggestion that the continuous infusion arm had a lower dose requirement overall and required less dose escalation.
In terms of the interpretation of the DOSE trial for the continuous infusion versus intermittent infusion comparison, the lack of difference in overall urine output is in agreement with the recently published study by Dr. O’Connor’s group showing absolutely no difference between continuous infusion and intermittent bolus infusions using the same daily dose.3 On the surface it seems in contrast to the Thompson study,4 which found a trend toward an increase in urine output with continuous infusion. However, it is consistent if one considers that in the latter study the actual dose received over 24 hours was not the same. I still have some issue with the amount of diuretic that was received in the DOSE study for the intermittent versus continuous infusion comparison when the take home message of the study was that there was no difference between the two regimens.
DR. MEHRA: The fundamental issue relates to the application of these findings to clinical practice. Does it not affect clinical practice at all, or do we take comfort in the finding from the DOSE trial that, hey, the continuous high-dose diuretic strategy is reasonably safe and one should not run away from it if you deem as a clinician that that is the appropriate strategy to use by a particular patient? For example, someone with chronic long-standing heart failure with exposure to chronic high dose diuretic therapy, and some renal dysfunction at the time of inception of continuous IV diuretic therapy may be more suitable for chronic infusion therapy. At that point in time I think that my clinician gestalt would be to use a higher dose continuous infusion strategy, not simply because I am worried about the amount of urine output, but perhaps also because of the toxicity associated with the higher dose diuretic bolus regimens that one may encounter. The DOSE trial did not look at toxicity, particularly oto-toxicity; it mainly focused its safety endpoints on renal function.
DR. NG: I think the issue of other safety signals not addressed in the DOSE trial have come up in some of the other studies. A Cochrane Review,5 which was completed prior to the three latest trials, looked at all the smaller studies and found continuous infusion was associated with a lower incidence of ototoxicity compared to intermittent bolus therapy.
DR. MEHRA: That’s correct. In fact, much of that information comes from the chronic renal failure literature as well, where continuous infusions with drugs like bumetanide have been shown to result in a lower incidence of cochlear toxicity.
DR. NG: Okay, so Dr. Rodgers, I think we’re all in agreement that the DOSE trial allows us to feel better about using higher doses of loop diuretics in select acute heart failure patients. But based on the data from the most recent trials by Thompson, Allen, and the DOSE trial, do you believe there is still a strong rationale for using continuous infusion as opposed to intermittent bolus.
Any time a clinician is starting to push to higher diuretic doses with no response or is starting to consider additional therapies, one should be cognizant of the risk of additional electrolyte wasting and worsening renal function and assured that these safety parameters are closely monitored. This is when patient selection for more aggressive diuretic regimens must be carefully considered. In addition, there remain many unanswered questions about appropriate alternative therapies and the role of such in further increasing or perhaps mitigating these risks. Alternative therapies studied to date include low dose dopamine, low dose nesiritide, and other vasoactive agents.
With regard specifically to ototoxicity, this is an adverse effect that is probably very underappreciated and perhaps it’s because clinicians rarely monitor it. Most clinicians are very aware that if you administer a large, single, IV bolus dose of 180 mg of furosemide too rapidly (for example, greater than 4 mg per minute), the risk of ototoxicity is increased, but I’m less certain at what precise dose of a furosemide continuous infusion a clinician should avoid or more assertively monitor for ototoxicity. Perhaps the focus of future research should include assessing the role of these additional or alternative therapies in minimizing toxicities including ototoxicity. Do you have any suggestions, Dr. Mehra?
DR. MEHRA: I think that the data suggest that cochlear toxicity or ototoxicity is related to the peak effects and not the trough effect, so the higher the bolus dosing, the more the chance that one could have cochlear toxicity, particularly if there are other ototoxic agents being administered concomitantly. For example, if someone is receiving a drug like a gentamycin-type analog, for instance, along with a diuretic infusion or a diuretic bolus, I think there’s magnification of that ototoxicity. Frankly that isn’t the overriding concern of most clinicians, and in fact we do not systematically study it, as you’ve pointed out. I often am more concerned in the diuretic resistant patients with the best dosing strategy. I know that, Tien, you have done some work in that regard and I wonder if we could turn the conversation toward discussing what kind of combination diuretic strategies really work in reducing fluid overload.
DR. NG: Clearly another option which is commonly used in practice is the combination of diuretic agents, specifically a loop diuretic added to a thiazide agent, a thiazide which is still effective even in the setting of poor renal perfusion. There are a lot of observational and small studies that have evaluated whether or not the addition of a thiazide, such as metolazone, to a loop diuretic, such as furosemide or bumetanide, augments sodium excretion and urine output. A paper that was published in the Journal of the American College of Cardiology summarized some of these data found a signal for increased urine output.6 Our group recently evaluated the addition of metolazone to furosemide, compared to just a continuous infusion of furosemide, and found a statistically significant greater increase in mean hourly urine output with the combination compared to furosemide used by itself.
What was interesting about our data, which are consistent with some of the existing data, is there was actually no signal for worsening renal function in our patients who received the combination, although there was a signal for an increased risk of electrolyte disturbances. So the conclusion of our study, since it was an observational study, was because of potential differences in clinical efficacy and safety, there is a great need for further study in prospective trials of these alternative strategies, such as combining agents, to truly understand whether these therapies are more effective while remaining relatively safe.
DR. RODGERS: These studies have made important contributions to the literature, but as Tien explains, are not optimally designed trials. Thus, there is need for prospective evaluations to address these unanswered questions. When conducting these future prospective studies, it will be important to include endpoints such as 30-day rehospitalization. If these alternative regimens more effectively diurese, then length of hospital stay may even be reduced by a day or two. With that said, I would be concerned that patients might subsequently suffer other adverse consequences such as continued unwanted diuresis and related adverse effects post-discharge. This is an important question to address with agents such as metolazone, given the long half-life and considerable intra- and inter-patient variability in onset of action with this agent. Future prospective trials need to address outcomes, such as length of stay and rehospitalization at 30 days, for these very reasons.
There are many reasons these trials have not been prospectively conducted in the past, and one major rate-limiting factor is the uniqueness of the population of patients with refractory fluid overload. When clinicians are faced with these patients, they often start to inquire about the appropriateness of a right heart catheter and inotropic therapy simply because diuretic refractoriness may be an indicator of low cardiac output. Patient characteristics such as concomitant inotropic therapy was most often an exclusion criteria for the previously discussed trials.
DR. MEHRA: So let me respond to that, Jo Ellen. First of all, I was taught to use a lot of metolazone, and frankly, as I matured clinically, I became less enamored by that drug as I realized how tough a drug it was on the kidneys and on electrolyte balance. There is this notion of what is the appropriate clinical endpoint, and I think you alluded to it. The endpoint needs to be clinically relevant. The endpoint should focus on the patient and not be one where the clinician feels better. Essentially we have been a bit swayed by how much urine output can be evoked and how much fluid can be removed. We have a large number of papers and data emerging that tell us that there may be a significant disconnect between the amount of fluid removal and clinical outcomes. As an example, studies like the Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study with Tolvaptan (EVEREST)7 with a vasopressin receptor antagonist showed effectiveness of the drug tolvaptan in improving hyponatremia, and in reducing weight in patients significantly, compared to placebo, but was no better than placebo in influencing 24 month outcomes from a cardiovascular endpoint. So we have to fundamentally ask the question, do any of these strategies actually make a real difference in patients?
The other issue is that we need to do a better job of discriminating among the distinct patient groups that present with diuretic resistance syndrome. So, for example, it would be clinically less useful to start using incremental diuretic strategies and multiple drug regimens in a patient who has a clear low output state causing diuretic resistance. In such a patient, perhaps, a strategy that improves cardiac output with or without the need for mechanical circulatory support might be the appropriate one to overcome diuretic resistance.
In another situation where you have acute pulmonary edema, for instance, in the setting of severe hypertension or acute ischemic syndromes, I think the treatment ought to be very different. In such situations, step number one from a clinical standpoint is to segregate the patients into classifications of why the diuretic resistance has occurred and what is the relationship of that diuretic resistance to pump function. As an example, most of the multiple drug use strategies that work do so in the setting where true renal causes of diuretic resistance have occurred. This is manifested pathologically by the development of tubular hypertrophy, which determines classical diuretic resistance. In those situations, even considering a “renal rest” such as with ultrafiltration for a few days in some series has shown to be of benefit. It is in those situations where using multiple agents may be beneficial from a fluid removal standpoint. You’re right, Jo Ellen, we have to ask ourselves to what end we are actually making patients better. And our definitions of how we make patients better are equally critical.
Tien, do you have some thoughts about that?
DR. NG: Yes, I have to agree. I think an issue has always been, what is the appropriate endpoint for our acute heart failure patients? This has been debated for years and years now, and when you look at the safety signals or the safety endpoints that are currently being used and the efficacy endpoints, we really don’t know whether these are the optimal safety and efficacy endpoints. In one sense we’re using urine output, and as you’ve pointed out there are clearly data showing that urine output isn’t necessarily the greatest indicator of an improved prognosis in these patients. At the same time, looking at serum creatinine changes as a measure of renal function obviously has its limitations as well. With serum creatinine one wouldn’t expect large changes in these relatively short-term trials, as it is a delayed marker of renal injury. So in the future, to look at the renal safety of these agents it will be important to incorporate some novel, more accurate and early markers of acute kidney injury. I think that will help us understand whether or not we are actually doing something beneficial for these patients or whether we are just treating ourselves.
DR. RODGERS: I completely agree, Dr. Ng. I think that many of our future trials are focusing on either the right population or the right endpoint. Some good examples, Dr. Mehra just mentioned ultrafiltration and the Cardiorenal Rescue Study in Acute Decompensated Heart Failure (CARRESS) trial,8 which is currently recruiting patients, and this study is specifically enrolling patients who are congested and fluid overloaded, but who have experienced renal insufficiency. The primary endpoint is a combination of weight and renal function changes. I am optimistic that any follow-up studies to CARRESS will assess endpoints such as mortality and rehospitalization. Other trials such as the Phosphodiesterase-5 Inhibition to Improve Clinical Status and Exercise Capacity in Diastolic Heart Failure (RELAX) trial9 with the agent relaxin, also are enrolling patients with mild to moderate renal insufficiency. This trial is designed to assess clinically meaningful endpoints such as worsening heart failure associated with longer length of stay, as well as 60-day outcomes. It is great that these trials are addressing how to manage the patients that clinicians most struggle with.
DR. NG: Would either of you like to comment on some of the novel pharmacologic approaches which are currently being evaluated? This includes low dose nesiritide compared to low dose dopamine, the Renal Optimization Strategies Evaluation in Acute Heart Failure (ROSE) trial,10 designer natriuretic peptides such as CDNP or CUNP. Thus far agents such as vasopressin antagonists and adenosine receptor antagonists haven’t been associated with positive results from a cardiorenal standpoint; however, I was wondering if you believe these agents may still have a potential role?
DR. RODGERS: The ROSE trial, again alludes to what we previously discussed regarding the addition of other agents in an attempt to minimize toxicity of diuretic therapy. This trial is assessing our ability to effectively manage the fluid overload without causing renal injury. Similar to RELAX,9 the ROSE trial is enrolling patients with impaired renal function as defined by a creatinine clearance between 15 and 60 mL/min. As Dr. Ng had suggested, they are utilizing a new marker for renal dysfunction in this trial. Their primary endpoint is change in cystatin C. Cystatin C is an excellent marker of kidney function because it is devoid of some of the limitations or inaccuracies of measuring serum creatinine, specifically it may more readily detect milder forms of renal impairment. Also, it is more reliable in patients with varying muscle mass or protein intake, which is commonly a problem in our heart failure patients who have cachexia due to low cardiac output or fluid overload.
DR. MEHRA: I think that the future is clearly in many of these trials that are being undertaken. I’m particularly optimistic about the combined use of diuretic infusions with low dose dopamine, for instance. That has been a strategy that’s been used in the past, but it’s very controversial. I understand that one of the components of the ROSE trial that is testing these various strategies includes low dose dopamine. It should be an interesting facet to investigate to see what is the role of an old drug that’s easily available and won’t cost us incremental dollars in a cost-restrained system.
I actually do think that agents need to continue to be investigated, but I have been very disappointed with the way the current field of agents looks. As you look at the vasopressin receptor antagonists, they’ve all come out fairly short in enhancing clinical outcomes. My suspicion is that there will be sub-populations that benefit and sub-populations that are harmed by these therapies. That is the uniform outcome in almost all situations where you have high morbidity and mortality, such as in acute decompensated heart failure. My personal feeling is that we need to do a better job of finding which populations are most likely to benefit and our attention ought to be focused there. I still think that there will be selective roles for these agents in the appropriately defined groups of patients.
The problem with any such study that looks either at surrogate biomarkers like cystatin C or looks at just patient derived global assessment scales or renal function, is the very small study size, often with a small number of patients in each group. It is therefore very difficult to pull out the groups of patients in whom harm occurred and distinguish them very clearly from the groups of patients in whom clear benefit was observed. I suspect that one of the studies from which we ought to get more information in this regard is the large Acute Study of Clinical Effectiveness of Nesiritide in Decompensated Heart Failure Trial (ASCEND), with more than 7000 patients.11 I think the value of that particular trial is probably confined to developing a very clear interface of investigations that will guide us to pick out those particular subgroups of patients in whom we should use targeted approaches for incremental diuretic or fluid removing strategies. What do you guys think?
DR. NG: I fully agree with both of your previous sentiments. Clearly the general sense is loop diuretics, regardless of how they’re administered or dosed, represents a suboptimal method to affect fluid removal from our volume overloaded patients. There remains hope that in the future new therapies that are more sparing from a pathophysiology standpoint will be developed so that we can effectively manage volume status in our patients while also having a positive effect on their outcomes.
So, yes, I hold hope that different combinations of pharmacologic agents as well as device therapies will be developed, and we’ll gain a greater appreciation of how to optimally select between these therapeutic options for individual patients.
Before concluding, I want to get your thoughts on one last issue. In the past we’ve approached diuresis as being a consequence of hypoperfusion. More recently, data focusing on venous congestion and how that influences diuretic responsiveness has emerged. My feeling is that as we understand the contribution of venous congestion to renal function in acute heart failure, new physiologic targets may be identified.
DR. MEHRA: Let me make a few comments about that. If you just think about the person who is most likely to develop diuretic resistance, it would be a person who has low blood pressure, chronic renal insufficiency, and very high right sided pressures. I think we’re learning now that the frequency of cardiorenal syndrome in patients with chronic heart failure is singularly linked to the severity of right heart function. And right heart failure is probably the closest correlate. Small observational studies have addressed the issue of intra-abdominal pressure as a surrogate marker for worsening renal function and improvements following release of intra-abdominal pressure, by removal of ascitic fluid or by decongesting these patients to reduce right atrial pressure, these have all shown some signals towards reduction in serum creatinine and recovery from cardiorenal syndrome.
So I think we are beginning to move in the direction that congestion is bad, that right-sided heart failure is probably the focus of our therapy, and that one surrogate for right heart failure other than the jugular venous pressure is intra-abdominal pressure, which can be very easily measured by placing a Foley in the bladders of these patients and attaching that to a pressure manometer.
DR. NG: Jo Ellen, did you have anything to add there?
DR. RODGERS: No.
DR. NG: Okay, in that case I would like to thank you all for your participation. To conclude I’ll provide a brief summary of what we’ve discussed. We began with a discussion of the role of continuous infusion and high-dose compared to low-dose loop diuretics as a method for overcoming clinical diuretic resistance. We all agree that, although the data are not airtight, they do suggest that there doesn’t seem to be large differences in terms of efficacy and in safety using high versus low or intermittent versus continuous infusion. The actual selection of the strategy should take into account the clinical status and characteristics of the individual patient.
We then moved to the issue of different diuretic strategies. We are hopeful that the addition of other agents which help augment overall diuresis will allow for a loop diuretic sparing effect, and may represent a better approach. Some of the current trials will help clarify that issue. We ended with just a very brief discussion on the need in future studies to identify optimal patients and optimal endpoints, as well as looking at the overall model of congestion, right-sided failure, and its contribution to the cardiorenal syndrome that we manage daily in our acute heart failure patients.
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It is well recognized that diuretic therapy remains the main approach to volume management in heart failure patients and carries a first-line recommendation according to the American College of Cardiology/American Heart Association (ACC/AHA) guidelines.1 However, in more advanced patients and those who have been on chronic diuretic therapy, many fail to respond to escalating doses of intermittent loop diuretics, a common clinical scenario referred to as “diuretic resistance.”
In patients exhibiting diuretic resistance, several approaches have been utilized. This includes increasing the frequency of administration or initiating a continuous infusion of the loop diuretic, changing to a more potent (on a milligram per milligram basis) loop, or combining a loop diuretic with a thiazide agent. Other approaches to enhancing fluid removal such as ultrafiltration and the addition of other intravenous (IV) vasoactive agents have also been considered. Only a few studies have evaluated the individual efficacy and safety of these different approaches.
There is a paucity of head-to-head studies to guide our approach, with most of the comparative data being limited to the comparison of intermittent bolus to continuous infusion loop diuretic administration. In those studies the results have been somewhat conflicting. In addition, all these data have inherent limitations and are open to interpretation. Thus there continues to be a debate as to the best method for volume management in acute heart failure. In the future we may have new pharmacologic therapies and the role of ultrafiltration and other nonpharmacologic approaches may be clarified.
I thought we could start with the issue of continuous infusion and what is the role of continuous infusion compared to intermittent bolus loop diuretic administration. Perhaps Dr. Mehra could start us off by giving us his impressions on this issue.
DR. MEHRA: Let me first begin by amplifying one important item on the clinical definition of diuretic resistance. We tend to think of a patient with advanced heart failure or heart failure with decompensation as having evidence of diuretic resistance if a certain threshold of exposure to incremental IV diuretic bolus therapy does not evoke an adequate diuretic response. Clinicians consider unresponsiveness to 160 mg or 200 mg of IV furosemide administered as a bolus evokes an anemic urine output response in the subsequent two to three hours as demonstrating clinical diuretic resistance.
It is important to note also that many of these trials did not in fact include just diuretic resistance or diuretic refractory patients. Most of the recent clinical trials, such as Diuretic Optimization Strategies Evaluation (DOSE) looked at patients with congestion in the setting of decompensated heart failure who were being treated with a diuretic regimen with the idea of testing two very specific strategies of diuretic use. First, a low dose compared to a high dose strategy, and the second a continuous infusion strategy compated to a bolus dosing strategy.2 These are clinically useful strategies, which until now have not been subjected to randomized control trials. In that sense the DOSE trial has helped us move forward in a clinical direction.
To summarize the DOSE trial,2 this study suggested that neither of these specific clinical strategies were superior to the other ones, including a low dose/ high dose or bolus dose/continuous dosing with a diuretic. The study found some signals that suggested that the higher dose strategy was associated with less dyspnea but at a risk of a greater incidence of worsening of renal function, at least in the short-term. Thus, the appropriate interpretation of the DOSE trial is that it has shown us evidence of the reasonable safety and effectiveness of all of these strategies when used early in the course of decompensated heart failure. Would you agree with that, Tien and Jo Ellen?
DR. RODGERS: I definitely agree that the DOSE trial demonstrated, in a broad population of patients presenting with acute decompensated heart failure and requiring diuretic therapy ,that there is no difference between IV bolus and continuous diuretic administration, but that there is some benefit with high dose, specifically 2.5 times the oral dose, compared to a low dose. In addition to a reduced area under the curve for dyspnea at 72 hours, patients receiving high dose therapy also experienced a significant reduction in weight and net fluid loss at 72 hours. As Dr. Mehra pointed out, this benefit may be at the expense of temporary worsening of renal function. And thus, in practice, we need to be mindful of patient selection and which patients need more aggressive diuretic response compared to those patients in whom you are not willing to tolerate worsening renal function to gain the additional diuretic response. The former may be the patient who needs more aggressive relief of dyspnea—perhaps the patient in the emergency room with poor oxygen saturation. This patient should be managed with the high dose diuretic strategy. The latter may be the patient with acute or chronic renal failure in whom the risk of worsening renal function does not outweigh the benefit of more aggressive diuresis.
The issue that is critical to emphasize is that the DOSE trial assessed diuretic effectiveness of various diuretic strategies in patients who were requiring diuretic therapy, but may or may not be truly diuretic resistant. And thus, the patients enrolled were simply in decompensated heart failure secondary to fluid overload. Looking at the demographic characteristics of the trial population including baseline systolic blood pressure, serum urea nitrogen and serum creatinine as well as serum sodium, it would be anticipated that these patients would have fairly low in-hospital mortality rates compared to patients with systolic blood pressures less than 115 mm Hg, serum urea nitrogen greater than 43, and serum creatinine >3.75 mg/dL, as demonstrated by prior Acute Decompensated Heart Failure National Registry (ADHERE) data. Patients who are developing diuretic resistance are more apt to be in this latter group. Such patients may be more prone to renal dysfunction and other adverse outcomes with aggressive diuretic therapy. Diuretic response in this patient population has not been assessed.
DR. NG: Yes, I have to agree with both of you. Overall, the trial does give us some sense of the safety and the efficacy of the high versus the low dose. However, one important caveat when it comes to the interpretation of the continuous infusion compared to the intermittent infusion results was that the dosing was fixed in these two arms for the first 48 hours of the study, but then from 48 to 72 hours it became open label. There definitely was a suggestion that the continuous infusion arm had a lower dose requirement overall and required less dose escalation.
In terms of the interpretation of the DOSE trial for the continuous infusion versus intermittent infusion comparison, the lack of difference in overall urine output is in agreement with the recently published study by Dr. O’Connor’s group showing absolutely no difference between continuous infusion and intermittent bolus infusions using the same daily dose.3 On the surface it seems in contrast to the Thompson study,4 which found a trend toward an increase in urine output with continuous infusion. However, it is consistent if one considers that in the latter study the actual dose received over 24 hours was not the same. I still have some issue with the amount of diuretic that was received in the DOSE study for the intermittent versus continuous infusion comparison when the take home message of the study was that there was no difference between the two regimens.
DR. MEHRA: The fundamental issue relates to the application of these findings to clinical practice. Does it not affect clinical practice at all, or do we take comfort in the finding from the DOSE trial that, hey, the continuous high-dose diuretic strategy is reasonably safe and one should not run away from it if you deem as a clinician that that is the appropriate strategy to use by a particular patient? For example, someone with chronic long-standing heart failure with exposure to chronic high dose diuretic therapy, and some renal dysfunction at the time of inception of continuous IV diuretic therapy may be more suitable for chronic infusion therapy. At that point in time I think that my clinician gestalt would be to use a higher dose continuous infusion strategy, not simply because I am worried about the amount of urine output, but perhaps also because of the toxicity associated with the higher dose diuretic bolus regimens that one may encounter. The DOSE trial did not look at toxicity, particularly oto-toxicity; it mainly focused its safety endpoints on renal function.
DR. NG: I think the issue of other safety signals not addressed in the DOSE trial have come up in some of the other studies. A Cochrane Review,5 which was completed prior to the three latest trials, looked at all the smaller studies and found continuous infusion was associated with a lower incidence of ototoxicity compared to intermittent bolus therapy.
DR. MEHRA: That’s correct. In fact, much of that information comes from the chronic renal failure literature as well, where continuous infusions with drugs like bumetanide have been shown to result in a lower incidence of cochlear toxicity.
DR. NG: Okay, so Dr. Rodgers, I think we’re all in agreement that the DOSE trial allows us to feel better about using higher doses of loop diuretics in select acute heart failure patients. But based on the data from the most recent trials by Thompson, Allen, and the DOSE trial, do you believe there is still a strong rationale for using continuous infusion as opposed to intermittent bolus.
Any time a clinician is starting to push to higher diuretic doses with no response or is starting to consider additional therapies, one should be cognizant of the risk of additional electrolyte wasting and worsening renal function and assured that these safety parameters are closely monitored. This is when patient selection for more aggressive diuretic regimens must be carefully considered. In addition, there remain many unanswered questions about appropriate alternative therapies and the role of such in further increasing or perhaps mitigating these risks. Alternative therapies studied to date include low dose dopamine, low dose nesiritide, and other vasoactive agents.
With regard specifically to ototoxicity, this is an adverse effect that is probably very underappreciated and perhaps it’s because clinicians rarely monitor it. Most clinicians are very aware that if you administer a large, single, IV bolus dose of 180 mg of furosemide too rapidly (for example, greater than 4 mg per minute), the risk of ototoxicity is increased, but I’m less certain at what precise dose of a furosemide continuous infusion a clinician should avoid or more assertively monitor for ototoxicity. Perhaps the focus of future research should include assessing the role of these additional or alternative therapies in minimizing toxicities including ototoxicity. Do you have any suggestions, Dr. Mehra?
DR. MEHRA: I think that the data suggest that cochlear toxicity or ototoxicity is related to the peak effects and not the trough effect, so the higher the bolus dosing, the more the chance that one could have cochlear toxicity, particularly if there are other ototoxic agents being administered concomitantly. For example, if someone is receiving a drug like a gentamycin-type analog, for instance, along with a diuretic infusion or a diuretic bolus, I think there’s magnification of that ototoxicity. Frankly that isn’t the overriding concern of most clinicians, and in fact we do not systematically study it, as you’ve pointed out. I often am more concerned in the diuretic resistant patients with the best dosing strategy. I know that, Tien, you have done some work in that regard and I wonder if we could turn the conversation toward discussing what kind of combination diuretic strategies really work in reducing fluid overload.
DR. NG: Clearly another option which is commonly used in practice is the combination of diuretic agents, specifically a loop diuretic added to a thiazide agent, a thiazide which is still effective even in the setting of poor renal perfusion. There are a lot of observational and small studies that have evaluated whether or not the addition of a thiazide, such as metolazone, to a loop diuretic, such as furosemide or bumetanide, augments sodium excretion and urine output. A paper that was published in the Journal of the American College of Cardiology summarized some of these data found a signal for increased urine output.6 Our group recently evaluated the addition of metolazone to furosemide, compared to just a continuous infusion of furosemide, and found a statistically significant greater increase in mean hourly urine output with the combination compared to furosemide used by itself.
What was interesting about our data, which are consistent with some of the existing data, is there was actually no signal for worsening renal function in our patients who received the combination, although there was a signal for an increased risk of electrolyte disturbances. So the conclusion of our study, since it was an observational study, was because of potential differences in clinical efficacy and safety, there is a great need for further study in prospective trials of these alternative strategies, such as combining agents, to truly understand whether these therapies are more effective while remaining relatively safe.
DR. RODGERS: These studies have made important contributions to the literature, but as Tien explains, are not optimally designed trials. Thus, there is need for prospective evaluations to address these unanswered questions. When conducting these future prospective studies, it will be important to include endpoints such as 30-day rehospitalization. If these alternative regimens more effectively diurese, then length of hospital stay may even be reduced by a day or two. With that said, I would be concerned that patients might subsequently suffer other adverse consequences such as continued unwanted diuresis and related adverse effects post-discharge. This is an important question to address with agents such as metolazone, given the long half-life and considerable intra- and inter-patient variability in onset of action with this agent. Future prospective trials need to address outcomes, such as length of stay and rehospitalization at 30 days, for these very reasons.
There are many reasons these trials have not been prospectively conducted in the past, and one major rate-limiting factor is the uniqueness of the population of patients with refractory fluid overload. When clinicians are faced with these patients, they often start to inquire about the appropriateness of a right heart catheter and inotropic therapy simply because diuretic refractoriness may be an indicator of low cardiac output. Patient characteristics such as concomitant inotropic therapy was most often an exclusion criteria for the previously discussed trials.
DR. MEHRA: So let me respond to that, Jo Ellen. First of all, I was taught to use a lot of metolazone, and frankly, as I matured clinically, I became less enamored by that drug as I realized how tough a drug it was on the kidneys and on electrolyte balance. There is this notion of what is the appropriate clinical endpoint, and I think you alluded to it. The endpoint needs to be clinically relevant. The endpoint should focus on the patient and not be one where the clinician feels better. Essentially we have been a bit swayed by how much urine output can be evoked and how much fluid can be removed. We have a large number of papers and data emerging that tell us that there may be a significant disconnect between the amount of fluid removal and clinical outcomes. As an example, studies like the Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study with Tolvaptan (EVEREST)7 with a vasopressin receptor antagonist showed effectiveness of the drug tolvaptan in improving hyponatremia, and in reducing weight in patients significantly, compared to placebo, but was no better than placebo in influencing 24 month outcomes from a cardiovascular endpoint. So we have to fundamentally ask the question, do any of these strategies actually make a real difference in patients?
The other issue is that we need to do a better job of discriminating among the distinct patient groups that present with diuretic resistance syndrome. So, for example, it would be clinically less useful to start using incremental diuretic strategies and multiple drug regimens in a patient who has a clear low output state causing diuretic resistance. In such a patient, perhaps, a strategy that improves cardiac output with or without the need for mechanical circulatory support might be the appropriate one to overcome diuretic resistance.
In another situation where you have acute pulmonary edema, for instance, in the setting of severe hypertension or acute ischemic syndromes, I think the treatment ought to be very different. In such situations, step number one from a clinical standpoint is to segregate the patients into classifications of why the diuretic resistance has occurred and what is the relationship of that diuretic resistance to pump function. As an example, most of the multiple drug use strategies that work do so in the setting where true renal causes of diuretic resistance have occurred. This is manifested pathologically by the development of tubular hypertrophy, which determines classical diuretic resistance. In those situations, even considering a “renal rest” such as with ultrafiltration for a few days in some series has shown to be of benefit. It is in those situations where using multiple agents may be beneficial from a fluid removal standpoint. You’re right, Jo Ellen, we have to ask ourselves to what end we are actually making patients better. And our definitions of how we make patients better are equally critical.
Tien, do you have some thoughts about that?
DR. NG: Yes, I have to agree. I think an issue has always been, what is the appropriate endpoint for our acute heart failure patients? This has been debated for years and years now, and when you look at the safety signals or the safety endpoints that are currently being used and the efficacy endpoints, we really don’t know whether these are the optimal safety and efficacy endpoints. In one sense we’re using urine output, and as you’ve pointed out there are clearly data showing that urine output isn’t necessarily the greatest indicator of an improved prognosis in these patients. At the same time, looking at serum creatinine changes as a measure of renal function obviously has its limitations as well. With serum creatinine one wouldn’t expect large changes in these relatively short-term trials, as it is a delayed marker of renal injury. So in the future, to look at the renal safety of these agents it will be important to incorporate some novel, more accurate and early markers of acute kidney injury. I think that will help us understand whether or not we are actually doing something beneficial for these patients or whether we are just treating ourselves.
DR. RODGERS: I completely agree, Dr. Ng. I think that many of our future trials are focusing on either the right population or the right endpoint. Some good examples, Dr. Mehra just mentioned ultrafiltration and the Cardiorenal Rescue Study in Acute Decompensated Heart Failure (CARRESS) trial,8 which is currently recruiting patients, and this study is specifically enrolling patients who are congested and fluid overloaded, but who have experienced renal insufficiency. The primary endpoint is a combination of weight and renal function changes. I am optimistic that any follow-up studies to CARRESS will assess endpoints such as mortality and rehospitalization. Other trials such as the Phosphodiesterase-5 Inhibition to Improve Clinical Status and Exercise Capacity in Diastolic Heart Failure (RELAX) trial9 with the agent relaxin, also are enrolling patients with mild to moderate renal insufficiency. This trial is designed to assess clinically meaningful endpoints such as worsening heart failure associated with longer length of stay, as well as 60-day outcomes. It is great that these trials are addressing how to manage the patients that clinicians most struggle with.
DR. NG: Would either of you like to comment on some of the novel pharmacologic approaches which are currently being evaluated? This includes low dose nesiritide compared to low dose dopamine, the Renal Optimization Strategies Evaluation in Acute Heart Failure (ROSE) trial,10 designer natriuretic peptides such as CDNP or CUNP. Thus far agents such as vasopressin antagonists and adenosine receptor antagonists haven’t been associated with positive results from a cardiorenal standpoint; however, I was wondering if you believe these agents may still have a potential role?
DR. RODGERS: The ROSE trial, again alludes to what we previously discussed regarding the addition of other agents in an attempt to minimize toxicity of diuretic therapy. This trial is assessing our ability to effectively manage the fluid overload without causing renal injury. Similar to RELAX,9 the ROSE trial is enrolling patients with impaired renal function as defined by a creatinine clearance between 15 and 60 mL/min. As Dr. Ng had suggested, they are utilizing a new marker for renal dysfunction in this trial. Their primary endpoint is change in cystatin C. Cystatin C is an excellent marker of kidney function because it is devoid of some of the limitations or inaccuracies of measuring serum creatinine, specifically it may more readily detect milder forms of renal impairment. Also, it is more reliable in patients with varying muscle mass or protein intake, which is commonly a problem in our heart failure patients who have cachexia due to low cardiac output or fluid overload.
DR. MEHRA: I think that the future is clearly in many of these trials that are being undertaken. I’m particularly optimistic about the combined use of diuretic infusions with low dose dopamine, for instance. That has been a strategy that’s been used in the past, but it’s very controversial. I understand that one of the components of the ROSE trial that is testing these various strategies includes low dose dopamine. It should be an interesting facet to investigate to see what is the role of an old drug that’s easily available and won’t cost us incremental dollars in a cost-restrained system.
I actually do think that agents need to continue to be investigated, but I have been very disappointed with the way the current field of agents looks. As you look at the vasopressin receptor antagonists, they’ve all come out fairly short in enhancing clinical outcomes. My suspicion is that there will be sub-populations that benefit and sub-populations that are harmed by these therapies. That is the uniform outcome in almost all situations where you have high morbidity and mortality, such as in acute decompensated heart failure. My personal feeling is that we need to do a better job of finding which populations are most likely to benefit and our attention ought to be focused there. I still think that there will be selective roles for these agents in the appropriately defined groups of patients.
The problem with any such study that looks either at surrogate biomarkers like cystatin C or looks at just patient derived global assessment scales or renal function, is the very small study size, often with a small number of patients in each group. It is therefore very difficult to pull out the groups of patients in whom harm occurred and distinguish them very clearly from the groups of patients in whom clear benefit was observed. I suspect that one of the studies from which we ought to get more information in this regard is the large Acute Study of Clinical Effectiveness of Nesiritide in Decompensated Heart Failure Trial (ASCEND), with more than 7000 patients.11 I think the value of that particular trial is probably confined to developing a very clear interface of investigations that will guide us to pick out those particular subgroups of patients in whom we should use targeted approaches for incremental diuretic or fluid removing strategies. What do you guys think?
DR. NG: I fully agree with both of your previous sentiments. Clearly the general sense is loop diuretics, regardless of how they’re administered or dosed, represents a suboptimal method to affect fluid removal from our volume overloaded patients. There remains hope that in the future new therapies that are more sparing from a pathophysiology standpoint will be developed so that we can effectively manage volume status in our patients while also having a positive effect on their outcomes.
So, yes, I hold hope that different combinations of pharmacologic agents as well as device therapies will be developed, and we’ll gain a greater appreciation of how to optimally select between these therapeutic options for individual patients.
Before concluding, I want to get your thoughts on one last issue. In the past we’ve approached diuresis as being a consequence of hypoperfusion. More recently, data focusing on venous congestion and how that influences diuretic responsiveness has emerged. My feeling is that as we understand the contribution of venous congestion to renal function in acute heart failure, new physiologic targets may be identified.
DR. MEHRA: Let me make a few comments about that. If you just think about the person who is most likely to develop diuretic resistance, it would be a person who has low blood pressure, chronic renal insufficiency, and very high right sided pressures. I think we’re learning now that the frequency of cardiorenal syndrome in patients with chronic heart failure is singularly linked to the severity of right heart function. And right heart failure is probably the closest correlate. Small observational studies have addressed the issue of intra-abdominal pressure as a surrogate marker for worsening renal function and improvements following release of intra-abdominal pressure, by removal of ascitic fluid or by decongesting these patients to reduce right atrial pressure, these have all shown some signals towards reduction in serum creatinine and recovery from cardiorenal syndrome.
So I think we are beginning to move in the direction that congestion is bad, that right-sided heart failure is probably the focus of our therapy, and that one surrogate for right heart failure other than the jugular venous pressure is intra-abdominal pressure, which can be very easily measured by placing a Foley in the bladders of these patients and attaching that to a pressure manometer.
DR. NG: Jo Ellen, did you have anything to add there?
DR. RODGERS: No.
DR. NG: Okay, in that case I would like to thank you all for your participation. To conclude I’ll provide a brief summary of what we’ve discussed. We began with a discussion of the role of continuous infusion and high-dose compared to low-dose loop diuretics as a method for overcoming clinical diuretic resistance. We all agree that, although the data are not airtight, they do suggest that there doesn’t seem to be large differences in terms of efficacy and in safety using high versus low or intermittent versus continuous infusion. The actual selection of the strategy should take into account the clinical status and characteristics of the individual patient.
We then moved to the issue of different diuretic strategies. We are hopeful that the addition of other agents which help augment overall diuresis will allow for a loop diuretic sparing effect, and may represent a better approach. Some of the current trials will help clarify that issue. We ended with just a very brief discussion on the need in future studies to identify optimal patients and optimal endpoints, as well as looking at the overall model of congestion, right-sided failure, and its contribution to the cardiorenal syndrome that we manage daily in our acute heart failure patients.
FoxP2 Media LLC is the publisher of The Medical Roundtable.
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BVS and renal denervation fuel a continental divide
It’s no secret that the Food and Drug Administration and the European Commission take very different approaches to how they allow medical devices onto the market. Their different tacks have produced a profound disconnect in how cardiologists on the two continents use two of the newest technologies in their specialty: bioabsorbable vascular scaffolds for coronary disease and renal denervation for controlling treatment-resistant hypertension.
The European Commission granted a CE mark to the first bioabsorbable vascular stent (BVS), Abbott’s Absorb, in 2011, and Abbott announced the launch of international marketing in September 2012. By last May, an Absorb BVS had been placed in more than 50,000 patients worldwide, according to a company spokesperson.
In contrast, the U.S. total of patients who received a BVS is much lower, and is limited to those randomized to receive a BVS in one of the two ongoing U.S. pivotal trials comparing its performance with a second-generation, drug-eluting metallic stent. One of those trials, with 2,000 total patients, completed enrollment in April 2014, but a second slated to have 3,000 total continues to enroll, so the soonest a BVS might come onto the U.S. market is at least 3 years off.
Not only does Europe have tens of thousands of BVS-treated patients, but several established interventional programs there, such as the Thoraxcenter in Rotterdam (the Netherlands), and others in Italy, Spain, Poland, and the Czech Republic, have adopted the BVS as their default approach for treating patients with percutaneous coronary intervention (PCI). For now, a BVS-first approach does not translate into universal use because only about a fifth of all PCI patients have anatomy suitable for BVS placement. But these BVS-first centers are using them in any PCI patient with anatomy that’s appropriate regardless of the severity of their coronary disease or the complexity of their coronary lesion. This means that BVSs have been placed in growing numbers of European patients with myocardial infarctions, acute coronary syndrome, and bifurcations, as well as in other types of clinically advanced PCI patients.
For renal denervation the numbers are not as disparate, but the prevailing attitudes of many thought leaders are. In Europe, Asia, and a few other parts of the world, interventionalists have used the Symplicity catheter, the first renal denervation device on the world market starting in 2010, in more than 5,500 patients as of this August, according to a spokesperson for Medtronic, the company that sells this device.
The consensus among many European interventional cardiologists and hypertension specialists at the annual EuroPCR meeting was that renal denervation is an effective and valuable option for managing otherwise uncontrolled hypertension, when performed carefully and thoroughly in well-selected patients with true drug-resistant hypertension. They stuck with that opinion despite the report in March that renal denervation failed to produce a significant blood pressure reduction compared with a sham procedure in the pivotal U.S. trial, SYMPLICITY HTN 3 (New Engl. J. Med. 2014;370:1393-1401).
A statement from three leading European cardiologists issued under the auspices of the EuroPCR meeting last May spelled out that despite the negative trial findings, "renal denervation is an option in patients with difficult-to-control hypertension, in whom other treatments have failed."
In the United States, the failed pivotal trial seems to have temporarily put U.S. testing of renal denervation on hold as companies and their consultants scramble to figure out how to avoid the problems that doomed SYMPLICITY HTN 3.
U.S. and European cardiologists show agreement in several other new areas of practice, but for BVS and renal denervation the transatlantic divide is stark.
On Twitter @mitchelzoler
It’s no secret that the Food and Drug Administration and the European Commission take very different approaches to how they allow medical devices onto the market. Their different tacks have produced a profound disconnect in how cardiologists on the two continents use two of the newest technologies in their specialty: bioabsorbable vascular scaffolds for coronary disease and renal denervation for controlling treatment-resistant hypertension.
The European Commission granted a CE mark to the first bioabsorbable vascular stent (BVS), Abbott’s Absorb, in 2011, and Abbott announced the launch of international marketing in September 2012. By last May, an Absorb BVS had been placed in more than 50,000 patients worldwide, according to a company spokesperson.
In contrast, the U.S. total of patients who received a BVS is much lower, and is limited to those randomized to receive a BVS in one of the two ongoing U.S. pivotal trials comparing its performance with a second-generation, drug-eluting metallic stent. One of those trials, with 2,000 total patients, completed enrollment in April 2014, but a second slated to have 3,000 total continues to enroll, so the soonest a BVS might come onto the U.S. market is at least 3 years off.
Not only does Europe have tens of thousands of BVS-treated patients, but several established interventional programs there, such as the Thoraxcenter in Rotterdam (the Netherlands), and others in Italy, Spain, Poland, and the Czech Republic, have adopted the BVS as their default approach for treating patients with percutaneous coronary intervention (PCI). For now, a BVS-first approach does not translate into universal use because only about a fifth of all PCI patients have anatomy suitable for BVS placement. But these BVS-first centers are using them in any PCI patient with anatomy that’s appropriate regardless of the severity of their coronary disease or the complexity of their coronary lesion. This means that BVSs have been placed in growing numbers of European patients with myocardial infarctions, acute coronary syndrome, and bifurcations, as well as in other types of clinically advanced PCI patients.
For renal denervation the numbers are not as disparate, but the prevailing attitudes of many thought leaders are. In Europe, Asia, and a few other parts of the world, interventionalists have used the Symplicity catheter, the first renal denervation device on the world market starting in 2010, in more than 5,500 patients as of this August, according to a spokesperson for Medtronic, the company that sells this device.
The consensus among many European interventional cardiologists and hypertension specialists at the annual EuroPCR meeting was that renal denervation is an effective and valuable option for managing otherwise uncontrolled hypertension, when performed carefully and thoroughly in well-selected patients with true drug-resistant hypertension. They stuck with that opinion despite the report in March that renal denervation failed to produce a significant blood pressure reduction compared with a sham procedure in the pivotal U.S. trial, SYMPLICITY HTN 3 (New Engl. J. Med. 2014;370:1393-1401).
A statement from three leading European cardiologists issued under the auspices of the EuroPCR meeting last May spelled out that despite the negative trial findings, "renal denervation is an option in patients with difficult-to-control hypertension, in whom other treatments have failed."
In the United States, the failed pivotal trial seems to have temporarily put U.S. testing of renal denervation on hold as companies and their consultants scramble to figure out how to avoid the problems that doomed SYMPLICITY HTN 3.
U.S. and European cardiologists show agreement in several other new areas of practice, but for BVS and renal denervation the transatlantic divide is stark.
On Twitter @mitchelzoler
It’s no secret that the Food and Drug Administration and the European Commission take very different approaches to how they allow medical devices onto the market. Their different tacks have produced a profound disconnect in how cardiologists on the two continents use two of the newest technologies in their specialty: bioabsorbable vascular scaffolds for coronary disease and renal denervation for controlling treatment-resistant hypertension.
The European Commission granted a CE mark to the first bioabsorbable vascular stent (BVS), Abbott’s Absorb, in 2011, and Abbott announced the launch of international marketing in September 2012. By last May, an Absorb BVS had been placed in more than 50,000 patients worldwide, according to a company spokesperson.
In contrast, the U.S. total of patients who received a BVS is much lower, and is limited to those randomized to receive a BVS in one of the two ongoing U.S. pivotal trials comparing its performance with a second-generation, drug-eluting metallic stent. One of those trials, with 2,000 total patients, completed enrollment in April 2014, but a second slated to have 3,000 total continues to enroll, so the soonest a BVS might come onto the U.S. market is at least 3 years off.
Not only does Europe have tens of thousands of BVS-treated patients, but several established interventional programs there, such as the Thoraxcenter in Rotterdam (the Netherlands), and others in Italy, Spain, Poland, and the Czech Republic, have adopted the BVS as their default approach for treating patients with percutaneous coronary intervention (PCI). For now, a BVS-first approach does not translate into universal use because only about a fifth of all PCI patients have anatomy suitable for BVS placement. But these BVS-first centers are using them in any PCI patient with anatomy that’s appropriate regardless of the severity of their coronary disease or the complexity of their coronary lesion. This means that BVSs have been placed in growing numbers of European patients with myocardial infarctions, acute coronary syndrome, and bifurcations, as well as in other types of clinically advanced PCI patients.
For renal denervation the numbers are not as disparate, but the prevailing attitudes of many thought leaders are. In Europe, Asia, and a few other parts of the world, interventionalists have used the Symplicity catheter, the first renal denervation device on the world market starting in 2010, in more than 5,500 patients as of this August, according to a spokesperson for Medtronic, the company that sells this device.
The consensus among many European interventional cardiologists and hypertension specialists at the annual EuroPCR meeting was that renal denervation is an effective and valuable option for managing otherwise uncontrolled hypertension, when performed carefully and thoroughly in well-selected patients with true drug-resistant hypertension. They stuck with that opinion despite the report in March that renal denervation failed to produce a significant blood pressure reduction compared with a sham procedure in the pivotal U.S. trial, SYMPLICITY HTN 3 (New Engl. J. Med. 2014;370:1393-1401).
A statement from three leading European cardiologists issued under the auspices of the EuroPCR meeting last May spelled out that despite the negative trial findings, "renal denervation is an option in patients with difficult-to-control hypertension, in whom other treatments have failed."
In the United States, the failed pivotal trial seems to have temporarily put U.S. testing of renal denervation on hold as companies and their consultants scramble to figure out how to avoid the problems that doomed SYMPLICITY HTN 3.
U.S. and European cardiologists show agreement in several other new areas of practice, but for BVS and renal denervation the transatlantic divide is stark.
On Twitter @mitchelzoler
Responding to the heroin epidemic one patient at a time
Once regarded as a curse of the urban poor, heroin now has a stronghold on many suburban, middle class communities.I was stunned to learn that heroin use is so prevalent in the quiet Baltimore suburb where I work that our local police officers carry Narcan kits. Use has become so ubiquitous in our country that U.S. Attorney General Eric Holder has said law enforcement officials should consider carrying heroin’s antidote. From Smalltown U.S.A. to booming metropolises, this inexpensive narcotic is wreaking havoc on individuals and their families.
Sure, I admit an occasional patient with "a history of heroin abuse" who takes methadone. Rarely, I may see physical evidence of heroin use. But in most cases, patients who use heroin present as overdose cases in the ED, where they are discharged home when they are stable or admitted directly to the intensive care unit. Sadly, I recently received from the ICU a transfer of a heroin overdose patient – a handsome young man in his 20s, his entire life ahead of him, loving parents and siblings at his bedside. He was completely oblivious to everything around him – comatose, on hospice, dying before he had a real chance to live.
There was nothing I could do for him or his family other than to provide comfort. But perhaps I can do more for future potential overdose victims. You know, the heroin users admitted for a skin abscess after missing a vein or for DKA because they were too high to remember to take their insulin. Yes, we are busy; but we need to take 5-10 minutes to address the issue, to listen to the user’s story and encourage them, uplift them. Substance abuse counselors are invaluable, but by taking the time to care about our patients as individuals, hospitalists might just be the straw to break the camel’s back of heroin use for someone. Considering that most heroin addicts these days are young adults, a 10 minute investment of our time now may help buy those patients back another 40 or 50 years of their lives.
Dr. Hester is a hospitalist at Baltimore-Washington Medical Center in Glen Burnie, Md. She is the creator of the Patient Whiz, a patient-engagement app for iOS. Reach her at [email protected].
Once regarded as a curse of the urban poor, heroin now has a stronghold on many suburban, middle class communities.I was stunned to learn that heroin use is so prevalent in the quiet Baltimore suburb where I work that our local police officers carry Narcan kits. Use has become so ubiquitous in our country that U.S. Attorney General Eric Holder has said law enforcement officials should consider carrying heroin’s antidote. From Smalltown U.S.A. to booming metropolises, this inexpensive narcotic is wreaking havoc on individuals and their families.
Sure, I admit an occasional patient with "a history of heroin abuse" who takes methadone. Rarely, I may see physical evidence of heroin use. But in most cases, patients who use heroin present as overdose cases in the ED, where they are discharged home when they are stable or admitted directly to the intensive care unit. Sadly, I recently received from the ICU a transfer of a heroin overdose patient – a handsome young man in his 20s, his entire life ahead of him, loving parents and siblings at his bedside. He was completely oblivious to everything around him – comatose, on hospice, dying before he had a real chance to live.
There was nothing I could do for him or his family other than to provide comfort. But perhaps I can do more for future potential overdose victims. You know, the heroin users admitted for a skin abscess after missing a vein or for DKA because they were too high to remember to take their insulin. Yes, we are busy; but we need to take 5-10 minutes to address the issue, to listen to the user’s story and encourage them, uplift them. Substance abuse counselors are invaluable, but by taking the time to care about our patients as individuals, hospitalists might just be the straw to break the camel’s back of heroin use for someone. Considering that most heroin addicts these days are young adults, a 10 minute investment of our time now may help buy those patients back another 40 or 50 years of their lives.
Dr. Hester is a hospitalist at Baltimore-Washington Medical Center in Glen Burnie, Md. She is the creator of the Patient Whiz, a patient-engagement app for iOS. Reach her at [email protected].
Once regarded as a curse of the urban poor, heroin now has a stronghold on many suburban, middle class communities.I was stunned to learn that heroin use is so prevalent in the quiet Baltimore suburb where I work that our local police officers carry Narcan kits. Use has become so ubiquitous in our country that U.S. Attorney General Eric Holder has said law enforcement officials should consider carrying heroin’s antidote. From Smalltown U.S.A. to booming metropolises, this inexpensive narcotic is wreaking havoc on individuals and their families.
Sure, I admit an occasional patient with "a history of heroin abuse" who takes methadone. Rarely, I may see physical evidence of heroin use. But in most cases, patients who use heroin present as overdose cases in the ED, where they are discharged home when they are stable or admitted directly to the intensive care unit. Sadly, I recently received from the ICU a transfer of a heroin overdose patient – a handsome young man in his 20s, his entire life ahead of him, loving parents and siblings at his bedside. He was completely oblivious to everything around him – comatose, on hospice, dying before he had a real chance to live.
There was nothing I could do for him or his family other than to provide comfort. But perhaps I can do more for future potential overdose victims. You know, the heroin users admitted for a skin abscess after missing a vein or for DKA because they were too high to remember to take their insulin. Yes, we are busy; but we need to take 5-10 minutes to address the issue, to listen to the user’s story and encourage them, uplift them. Substance abuse counselors are invaluable, but by taking the time to care about our patients as individuals, hospitalists might just be the straw to break the camel’s back of heroin use for someone. Considering that most heroin addicts these days are young adults, a 10 minute investment of our time now may help buy those patients back another 40 or 50 years of their lives.
Dr. Hester is a hospitalist at Baltimore-Washington Medical Center in Glen Burnie, Md. She is the creator of the Patient Whiz, a patient-engagement app for iOS. Reach her at [email protected].
PTSD ‘updates’ in DSM-5 concerning
As a seasoned psychiatrist, I try to take most events in stride. My main reaction to unsettling events is to flatten down and take my own pulse.
However, when I saw the article in the Lancet Psychiatry (2014 Aug. 14 [doi:10.1016/S2215-0366(14)70235-4]) by my longtime colleague, Col. (Ret.) Charles W. Hoge, M.D., and his coauthors, my pulse went way up, and "Oh, my God" was my very unscientific reaction.
As readers may recall, the new definition of posttraumatic stress disorder raises the number of symptoms from 17 to 20, and 8 of those original symptoms were substantially reworded. In addition, PTSD was moved in the new manual from an anxiety disorder to disorders related to trauma and stressors.
In their study, Dr. Hoge and his coauthors administered surveys to soldiers looking at DSM-IV-TR and DSM-5 criteria. In brief, about a third of soldiers who met DSM-IV-TR criteria for PTSD did not meet DSM-5 criteria. Almost a third were in the opposite camp, meeting DSM-5 but not the older criteria, wrote Dr. Hoge of the Center for Psychiatry and Neuroscience at the Walter Reed Army Institute of Research in Silver Spring, Md. The main issue is about criterion C and the splitting up of avoidance symptoms from depressive symptoms.
Why was my reaction so strong? I had thought that the new criteria would widen those eligible for the diagnosis. Instead, it eliminates almost a third of them, mainly because they did not meet the avoidant criteria. (Please read the article for the full complex details.)
In the disability system in the military and Veterans Affairs system, the diagnosis of PTSD carries major weight. So what will happen if the criteria exclude them?
The good news is that both Veterans Affairs and the Department of Defense have made it clear that service members and veterans who already have the diagnosis according to the DSM-IV will not have it changed as a result of DSM-5, so the new definition mostly pertains to those newly seeking care or benefits now. It remains unclear what diagnosis should be used for those veterans who clearly would have met the previous definition (which has been used for more than 25 years), but not the new one. The DSM-5 recommends the use of adjustment disorder in this case, but some experts are concerned that the use of this diagnosis for this purpose will have negative effects. A major issue is that service members can be separated without benefits for an adjustment disorder. Questions also remain about whether adjustment disorder should have even been paired with PTSD in the same chapter in the new DSM-5.
In the accompanying commentary, Dr. Alexander C. McFarlane, of the Centre for Traumatic Studies at the University of Adelaide, Australia, warns about the negative consequences of the change in definition (Lancet Psychiatry 2014 Aug. 14 [doi:10.1016/S2215-0366(14)70321-9]. He also urges caution when the new diagnosis is used in forensic or disability evaluations.
I recommend that readers review this important article and commentary, and that the military and the VA also take a cautious approach.
Dr. Ritchie is former chief of psychiatry for the U.S. Army and current chief clinical officer in the behavioral health department for the District of Columbia.
As a seasoned psychiatrist, I try to take most events in stride. My main reaction to unsettling events is to flatten down and take my own pulse.
However, when I saw the article in the Lancet Psychiatry (2014 Aug. 14 [doi:10.1016/S2215-0366(14)70235-4]) by my longtime colleague, Col. (Ret.) Charles W. Hoge, M.D., and his coauthors, my pulse went way up, and "Oh, my God" was my very unscientific reaction.
As readers may recall, the new definition of posttraumatic stress disorder raises the number of symptoms from 17 to 20, and 8 of those original symptoms were substantially reworded. In addition, PTSD was moved in the new manual from an anxiety disorder to disorders related to trauma and stressors.
In their study, Dr. Hoge and his coauthors administered surveys to soldiers looking at DSM-IV-TR and DSM-5 criteria. In brief, about a third of soldiers who met DSM-IV-TR criteria for PTSD did not meet DSM-5 criteria. Almost a third were in the opposite camp, meeting DSM-5 but not the older criteria, wrote Dr. Hoge of the Center for Psychiatry and Neuroscience at the Walter Reed Army Institute of Research in Silver Spring, Md. The main issue is about criterion C and the splitting up of avoidance symptoms from depressive symptoms.
Why was my reaction so strong? I had thought that the new criteria would widen those eligible for the diagnosis. Instead, it eliminates almost a third of them, mainly because they did not meet the avoidant criteria. (Please read the article for the full complex details.)
In the disability system in the military and Veterans Affairs system, the diagnosis of PTSD carries major weight. So what will happen if the criteria exclude them?
The good news is that both Veterans Affairs and the Department of Defense have made it clear that service members and veterans who already have the diagnosis according to the DSM-IV will not have it changed as a result of DSM-5, so the new definition mostly pertains to those newly seeking care or benefits now. It remains unclear what diagnosis should be used for those veterans who clearly would have met the previous definition (which has been used for more than 25 years), but not the new one. The DSM-5 recommends the use of adjustment disorder in this case, but some experts are concerned that the use of this diagnosis for this purpose will have negative effects. A major issue is that service members can be separated without benefits for an adjustment disorder. Questions also remain about whether adjustment disorder should have even been paired with PTSD in the same chapter in the new DSM-5.
In the accompanying commentary, Dr. Alexander C. McFarlane, of the Centre for Traumatic Studies at the University of Adelaide, Australia, warns about the negative consequences of the change in definition (Lancet Psychiatry 2014 Aug. 14 [doi:10.1016/S2215-0366(14)70321-9]. He also urges caution when the new diagnosis is used in forensic or disability evaluations.
I recommend that readers review this important article and commentary, and that the military and the VA also take a cautious approach.
Dr. Ritchie is former chief of psychiatry for the U.S. Army and current chief clinical officer in the behavioral health department for the District of Columbia.
As a seasoned psychiatrist, I try to take most events in stride. My main reaction to unsettling events is to flatten down and take my own pulse.
However, when I saw the article in the Lancet Psychiatry (2014 Aug. 14 [doi:10.1016/S2215-0366(14)70235-4]) by my longtime colleague, Col. (Ret.) Charles W. Hoge, M.D., and his coauthors, my pulse went way up, and "Oh, my God" was my very unscientific reaction.
As readers may recall, the new definition of posttraumatic stress disorder raises the number of symptoms from 17 to 20, and 8 of those original symptoms were substantially reworded. In addition, PTSD was moved in the new manual from an anxiety disorder to disorders related to trauma and stressors.
In their study, Dr. Hoge and his coauthors administered surveys to soldiers looking at DSM-IV-TR and DSM-5 criteria. In brief, about a third of soldiers who met DSM-IV-TR criteria for PTSD did not meet DSM-5 criteria. Almost a third were in the opposite camp, meeting DSM-5 but not the older criteria, wrote Dr. Hoge of the Center for Psychiatry and Neuroscience at the Walter Reed Army Institute of Research in Silver Spring, Md. The main issue is about criterion C and the splitting up of avoidance symptoms from depressive symptoms.
Why was my reaction so strong? I had thought that the new criteria would widen those eligible for the diagnosis. Instead, it eliminates almost a third of them, mainly because they did not meet the avoidant criteria. (Please read the article for the full complex details.)
In the disability system in the military and Veterans Affairs system, the diagnosis of PTSD carries major weight. So what will happen if the criteria exclude them?
The good news is that both Veterans Affairs and the Department of Defense have made it clear that service members and veterans who already have the diagnosis according to the DSM-IV will not have it changed as a result of DSM-5, so the new definition mostly pertains to those newly seeking care or benefits now. It remains unclear what diagnosis should be used for those veterans who clearly would have met the previous definition (which has been used for more than 25 years), but not the new one. The DSM-5 recommends the use of adjustment disorder in this case, but some experts are concerned that the use of this diagnosis for this purpose will have negative effects. A major issue is that service members can be separated without benefits for an adjustment disorder. Questions also remain about whether adjustment disorder should have even been paired with PTSD in the same chapter in the new DSM-5.
In the accompanying commentary, Dr. Alexander C. McFarlane, of the Centre for Traumatic Studies at the University of Adelaide, Australia, warns about the negative consequences of the change in definition (Lancet Psychiatry 2014 Aug. 14 [doi:10.1016/S2215-0366(14)70321-9]. He also urges caution when the new diagnosis is used in forensic or disability evaluations.
I recommend that readers review this important article and commentary, and that the military and the VA also take a cautious approach.
Dr. Ritchie is former chief of psychiatry for the U.S. Army and current chief clinical officer in the behavioral health department for the District of Columbia.
The Medical Roundtable: New Marker of Heart Failure Outcomes: Galectin-3
With me is Dr. Rudolf de Boer, from University Medical Center, Groningen, The Netherlands, who has done some of the basic science work; Dr. Salvatore Di Somma, who is an emergency physician at San Andrea Hospital at the University Sapienza in Rome; and Dr. Alan Maisel, a world-renowned biomarker researcher from the University of California San Diego at the Veterans Administration. I am Frank Peacock, a Professor in Emergency Medicine and the Director of Research at the Baylor College of Medicine.
Welcome, gentlemen. I’d like to open this up with Dr. Boer, starting with some discussion on what he knows about this marker.
Dr. de Boer: Yes, thank you, Dr. Peacock, for your introduction. I will briefly introduce galectin-3 to you, although I’m sure most of you have become familiar with it to some extent. It was actually not so long ago that galectin-3 was scientifically discovered in the 1980s. When it was discovered, its function was not fully recognized. It was only 8 years ago that galectin-3 was associated with heart failure development and cardiac remodeling.1
Galectin-3 is a member of the galectin family, which is a large family comprising about 20 galectins. Galectin-3 is unique because it’s a so-called chimera-type galectin, meaning that upon lectin binding, it forms multidimers, shaping a mesh, which is thought to add to the stiffness of the interstitial matrix, and in the case of heart failure, it adds stiffness to the extracellular myocardial matrix.2 Galectin-3 can be activated by all kinds of lectins, and in the normal heart, these ligands are believed to be major cellular proteins such as laminin and collagens. In damaged organs in general, and in heart failure in particular, galectin-3 is predominantly released by macrophages and the activating lectins are clearly more abundant, and this is generally thought to be the mechanism of galectin-3 activation in heart failure.
As I mentioned, a first seminal paper1 on the potential role of galectin-3 in heart failure was published in 2004. In a rat model with transition from compensated to decompensated heart failure, galectin-3 was the most strongly differentially expressed gene in this transitional phase. With further experimentation, the investigators showed that adding galectin-3 into the pericardial sac rendered superphysiological levels of galectin-3, and with this perturbation, they were able to provoke adverse cardiac remodeling with collagen deposition and left ventricular dysfunction. So, not only does galectin-3 seem to be associated with heart failure development, but may also be a part of the pathophysiology of cardiac remodeling and heart failure. This, of course, is very interesting.
Furthermore, galectin-3 seems to be a factor that is very dominant in the matrix: it does not predominantly act on cardiomyocytes, but on fibroblasts and the matrix compartment of the heart. It is strictly colocalized with sites of fibrosis where injury occurs, and it was shown that the primary source of galectin-3 in the heart includes all kinds of inflammatory cells, mainly macrophages, at the site of injury, for example, post-myocardial infarction or in hypertensive models. However, some other cells also produce galectin-3 including cardiac fibroblasts and mast cells. Mast cells are clearly less abundant, and fibroblasts are very abundant but produce a rather low amount of galectin-3. So overall, the primary source of galectin-3 is believed to be macrophages. As it is currently understood, when galectin-3 is produced, it turns cardiac fibroblasts into matrix-producing myofibroblasts, which then adds to the remodeling, specifically extracellular matrix production and fibrogenesis, not so much left ventricular hypertrophy, and this may contribute to the ultimate culmination into overt heart failure.
This is a general scheme of how we think of galectin-3 right now. As said before, interestingly, galectin-3 is associated with the disease process, but when activated, it has also been shown to add to the pathophysiology. Besides the naturally occurring binding lectins, investigators have developed neutralizing lectins that may bind to galectin-3 and render it inactive. This approach may actually downregulate galectin-3 activity with the aim to attenuate the galectin-3—driven progress of cardiac remodeling and to halt heart failure development. Recently, these neutralizing lectins have been tested in several animal models of hypertension, and it was shown that galectin-3 can be inhibited; this is associated with the attenuation of end-organ damage.3,4
Besides cardiac fibrosis, it has been observed that galectin-3 is also activated in liver fibrosis,5 kidney fibrosis,6 and lung fibrosis.7 Experimental studies using pharmacological compounds specifically targeting galectin-3 in non-cardiac disease have also been quite successful in attenuating tissue fibrosis.7 I think this adds an extra level of interest to this protein—that is, it’s not only a marker of disease severity, but also some kind of culprit biomarker, suggesting that it is part of the pathophysiology of heart failure, and can be a target of specific therapy.
Dr. Peacock: Perfect, Dr. Boer, that’s a really nice review of what we know up to this point about galectin-3. I think the next question is—is it ready for the clinical world? And if so, how would we be using it? Dr. Di Somma, what do you think about this and the use of galectin-3 in the emergency department?
Dr. Di Somma: That’s a very important question, because for patients presenting to an emergency department for shortness of breath due to acute heart failure, the physician has 3 main important jobs to do. First, a quick diagnosis is needed to start immediately with treatment because from papers in the literature,8 it is very clear that how fast you are in making the diagnosis and starting the treatment is going to have an important impact on both the patient’s outcome and length of stay. So, the first job is to give an appropriate diagnosis, but of no less importance is to immediately perform a risk specification, which is very important in terms of determining how aggressive your treatment must be, as well as the disposition based on this certification analysis of your patients with acute heart failure.
It seems possible now to discriminate between patients arriving in the Emergency Department with signs and symptoms of acute heart failure with galectin-3 levels of <17.8 pg/mL compared to patients with a galectin-3 level greater than this cutoff. Patients with a galectin-3 level of <17.8 pg/mL have a better prognosis after 30 days on follow-up examination, which, from the emergency physician’s point of view, is of great importance in immediately understanding the severity of the patient’s condition, because the disposition for these patients should be different.
Galectin-3 levels could be influenced by age and the kidney function. So if the patient is very old (> 75 years) and his estimated glomerular filtration rate is below 30 mL/min, the galectin-3 levels could be higher than expected. This could be related to the ongoing fibrotic process in the kidney that galectin-3 is mirroring. Moreover, in patients presenting with concomitant oncologic disease, galectin levels could be also higher.
For acute heart failure treatment, we now have many options, but in majority of the cases, the therapy is based on the use of intravenous diuretics. The current guidelines recommend high doses of intravenous diuretics, but also consider the possibility that, if immediately after a patient presents to the emergency department, you are able to make a correct diagnosis and determine the treatment and the following disposition based on biomarkers, the dosage of diuretic should also be based on appropriate patient risk stratification. A galectin-3 level of >17.8 pg/mL for instance indicates that a patient is at high risk for hospitalization, so you must be more cautious with this patient, possibly with a more aggressive intravenous diuretic treatment. Furthermore, the emergency department physician could also decide on the basis of a galectin-3 level of >17.8 pg/mL whether or not to discharge these patients only after infusion or to admit this patient to the hospital. On the contrary, since the job of the emergency department physician is mostly to rule out less severe cases, a galectin-3 level of <17.8 pg/mL (indicating less heart fibrosis) would probably indicate that it is safe to discharge a patient after just a small increase in the diuretic treatment dosage.
The use of galectin-3 will also have an important impact on the problem of overcrowding in the emergency department. In the recertification of patients coming to the emergency department with acute heart failure, there is an important possibility that adding the opportunity to measure galectin-3 can positively impact treatment from the emergency department physician.
Dr. Peacock: I think you brought up some extremely important points. You have to make a diagnosis first. Galectin-3 does not diagnose heart failure, but as you said, once you’ve established the probability that the patient has heart failure, galectin-3 is an outstanding prognostic agent. As Dr. de Boer said, it reflects generalized fibrosis, and there is a lack of specificity in that situation. However, once you’ve decided that the diagnosis is heart failure, then it’s an excellent prognostic, and if you define the cutoff point as 17.8 pg/mL, it identifies patients who would be at lower or higher risk for adverse outcomes subsequent to discharge.
This is really important for emergency medicine because we really don’t have anything that tells us what the future will look like in heart failure, except for B-type natriuretic peptide (BNP), which is really poor at predicting the next 2 weeks, and troponin, which is excellent, but is only elevated in a very small minority of cases using the contemporary assays available in the United States at this time.
Dr. Maisel: You can also make a case that once a diagnosis of heart failure is made—it’s sort of a moderate or mild-to-moderate heart failure, the BNP level is just a little above the grey zone, maybe 500 or 600 pg/mL, and the patient responds well to the diuretic—this isn’t like a troponin-positive acute coronary syndrome patient where, even if it’s just slightly positive, you’re still going to admit them. But, if you could show a propensity to have fibrosis in the short term and long term in this case of heart failure, and especially, if the patient is new to the system, then you may want to admit the patient to make sure this person gets on excellent therapy—and I’ll be talking about the role of mineralocorticoid receptor antagonists in a few minutes.
I think it’s significant to say, “Maybe this guy should not go home.” His level is above 17.8 pg/mL, and he has mild heart failure. He’s prone to just go downhill with each recurrent heart failure admission, and we need to take a closer look. If, in fact, you don’t admit him, then this is a person I would bring back within probably the first week to keep a close eye on.
Dr. Peacock: Dr. Maisel, what are you going to do when Dr. Di Somma sees a patient in the emergency department, their galectin-3 level is 27 pg/mL, and he sends the patient upstairs? Now, you’re at the receiving end.
It’s not a complete answer, but I think that as we go forward with research, we know this is a high-risk patient. Not only for short- and long-term prognosis, but at a high risk even to be readmitted in the next 30 days. Data from the Coordinating Study Evaluating Outcomes of Advising and Counseling in Heart Failure (COACH) clearly show this.9 We need to cut into the vicious cycle of heart failure, which we used to think of as just neural hormones. You give renin and blockers—angiotensin blockers and beta blockers—and you reduce that vicious cycle of vasoconstriction and increased afterload.
Now, we know there are other events that occur in acute heart failure. Some of these are inflammatory, some are ischemic, and some may easily link to activation of fibroblasts via galectin. We want to cut into this vicious cycle, if we can.
Dr. Peacock: What about aldosterone antagonists?
Dr. Maisel: Why don’t I take a few minutes and just give an overview on heart failure and how I see as a cardiologist that galectin-3 should perhaps have a role. Amongst ourselves, we know how common heart failure is: 6 million people in the United States, and almost 15 million people in Europe. The burden is more than all cancers combined, and what we’re finding out is that you don’t just say nowadays that a person has heart failure. They don’t all funnel into this one specific pathway, so they all look alike. In fact, heart failure is not necessarily a disease as much as a heterogeneous group of conditions that cannot meet the body’s demand for work.
So, you could probably look at the general heart failure population and pull out a number of things. You could pull out some genetic disorders. You could pull out endocrine disorders. You could also pull out people who had drug problems, and that’s often what we try to do. But, I think galectin-3 also gives us a window into another category that I will call galectin-3–mediated heart failure, which is an active scarring or fibrosis process. It’s progressive, and these patients are at higher risk for adverse outcomes.
Why is this important? Because these patients may respond to a drug differently than do other groups. In fact, early on, they may respond to drugs that we normally don’t give early, like aldosterone blockade, and later on, when they have very severe heart failure and high galectin-3 levels, they may be burned out enough to no longer respond to the treatment as we expect.
As a biomarker researcher, I also believe that we need multiple biomarkers to separate complex patients, and heart failure patients certainly are complex in the way they present with concomitant kidney disease, lung disease, diabetes, etc. So, the one biomarker that we all use is the natriuretic peptides. I like the fact that galectin-3 and the natriuretic peptides seem to be synergistic. You have a marker for fibrosis: the natriuretic peptides, markers of cardiac stress, and the fibrosis marker galectin-3 are relatively stable. BNP, to an extent, then tells you how much volume you need to remove to get back to baseline, dry BNP levels. When you look at prognosis, galectin-3 clearly adds to what you get from BNP. Galectin-3 can identify between 10% and 20% more patients at additional risk for adverse events.
One really interesting facet of galectin-3 is in preventing heart failure. To try to prevent heart failure, we need to get patients at the stage-A and stage-B level. That is why we went from New York Heart Association class to the American College of Cardiology/American Heart Association stages of heart failure, stage A being that of high risk but without structural disease and stage B, with structural disease but no signs or symptoms of heart failure yet.
As part of the Framingham Offspring Study, the researchers evaluated about 3500 subjects based on galectin-3 quartiles.10 First, they found that galectin-3 seemed to correlate with other risk factors including age, blood pressure, and other factors like diabetes, renal dysfunction, etc.
But, when they followed these patients for 8 years, for those who were otherwise normal, you could show very good gradation of risk for quartiles 1 to 4, not just for the development of heart failure, but also for the development of death. The hazard ratios were about 1:4, which is very significant.10
So what does this suggest? There’s a group of people who perhaps just have diabetes and slight hypertension, and what I’m going to do, as soon as I get the assay, is start measuring galectin-3 levels. If it’s high, I’m going to sit these patients down and say, “What this tells me is that you are going to have big problems if we don’t control things.” That’s very important.
As Dr. Di Somma mentioned, we now have a number: 17.8 pg/mL has been substantiated in a number of studies as a fairly robust cutoff point, below which you do well, and above which, you don’t do well. As a heart-failure doctor, a biomarker researcher, and an associate editor for the Journal of the American College of Cardiology, I see a lot of biomarker papers. We don’t like prognostic papers anymore unless you can do something about it. What do you do with this biomarker? We talk about pre-heart failure, but when you have heart failure, what do we do with it?
Well, a lot of the markers that we study (BNPs, troponins, etc) are death markers. We don’t know if we can do something about the marker levels increasing, but at least in my opinion, galectin-3 gives us an opportunity early in the disease to prevent progressive fibrosis.
So, let’s say you have 2 patients, one has a galectin-3 level of 8, and the other has a galectin-3 level of 35. They both have diabetes and both have slight heart failure. The one with the high galectin-3 is going to progress at a much steeper descent, because with each episode, you’re activating myofibroblasts to release galectin and deposit collagen. Well, galectin-3 gives us opportunities to use a biomarker to potentially guide treatment, so that we can personalize medicine. The guidelines for heart failure medications say that everybody should be given the same dose of everything, and we know that’s not usually what really works in practice.
One of the things that we’ve been talking about at some of our galectin-3 meetings is whether we could use this to guide therapy, and where the unmet need is. Well, one of the unmet needs is in acute decompensated heart failure. In the United States, with the “Obamacare” situation, we’re not paying hospitals—and maybe physicians, because of this, won’t get paid—if a patient is sent home and then readmitted within 30 days. And, that readmission rate around the country is 20% or higher.
We know molecules like BNP, troponin, and galectin-3 are related. They’re biomarkers that are related to readmission, which gives us an opportunity to treat a patient. Well, what other treatment do we use? Normally, we use diuretics or vasodilators. People often withhold angiotensin-converting enzyme (ACE) inhibitors if there’s any kidney dysfunction present. Aldosterone blockade is never given acutely in the hospital. I think this is mostly because physicians are afraid of hypercalcemia, an interaction with ACE inhibitors, etc. But, we know in other forms of heart failure, way back to the Randomized Aldactone Evaluation Study (RALES)11 and then the Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS),12 which is actually a trial of in-house acute heart failure after a myocardial infarction, and then more recently, the Eplerenone in Mild Patients Hospitalization and Survival Study in Heart Failure (EMPHASIS-HF)13 has basically begun to switch guidelines toward giving aldosterone blockers earlier in the course of chronic heart failure.4
What about acute heart failure? We don’t have good strategies, as I mentioned, to prevent readmissions. Nothing we have done has really worked. The idea behind aldosterone 3 was really formulated in a large part by Bert Pitt in an article a few years ago,12 which talked about the possibility of using mineralocorticoid receptor antagonists in acute heart failure, and makes a lot of sense. Aldosterone levels are so high in acute heart failure that it is left relatively unchecked by ACE and angiotensin receptor blockers and does everything to promote a vicious cycle of vasoconstriction, salt and water retention, ischemia, arrhythmias, etc, and yet, nothing is recommended. Even in the guidelines, which the European Society of Cardiology is just coming out with, regarding earlier treatment of patients with aldosterone blockers, there’s nothing about in-hospitalization treatment.
Using an aldosterone blocker in the acute treatment of heart failure may be an unmet need. We are going to be starting a study to try this. This will be the second biomarker-guided heart failure trial, the first one was called ACAT Intravascular Atherosclerosis Treatment Evaluation (ACTIVATE),14 which will use copeptin to put the patients on a copeptin antagonist, called tolvaptan. This study will be called the Reduction in Events with Galectin-3 and Aldosterone Blockade in Acute Heart Failure (REGAL) trial. It will be a multicenter study in Europe and the United States; Dr. Boer will be very involved in this, I know. In the case of patients with acute heart failure, if they don’t have a contraindication and are not on an aldosterone blocker, their galectin-3 levels will be measured. If the levels are high, they will be placed on spironolactone or placebo, and the follow-up is looking for 90-day events.
Now, the interesting thing about this study, which is what a lot of people were worried about, is how you can keep a patient on a placebo for 90 days, since aldosterone blockers are indicated in those with ejection fractions under 35%? The answer is that we will include patients with ejection fractions over 35%. In other words, we will take mild systolic dysfunction and heart failure with preserved ejection fraction and enroll those patients.
Some others can comment, but there’s some decent data. I think Dr. Boer has some data on this, and some other scientists have data suggesting that diastolic dysfunction is, in part, associated with fibrosis and that galectin-3 may be a very important signal.15 We will get a chance to look at this. It will be a relatively easy study to do. For the primary endpoint, we’re going to look at a decrease in events compared to the placebo. So, I’m very excited about that as a heart-failure researcher.
The other question I am excited about answering is whether we can use galectin-3 as a predictor for a response to cardiac resynchronization therapy (CRT) and implantable cardioverter-defibrillator, especially these resynchronization devices that are undergoing a lot of change. They’re very expensive. We have a moving target for which patients we’re being reimbursed. The latest is that, if a patient has heart failure and a wide QRS, but not a left bundle branch block, he/she may no longer qualify for CRT or implantable cardioverter-defibrillator. Earlier, it was used for any patient with a wide QRS. Now, it’s just basically moving to the left bundle.
So, there are probably people in between who will do better, and there’s some early unpublished data, which we could talk about a little bit, from Boston Scientific, arising from the Multicenter Automatic Defibrillator Implantation Trial with Cardiac Resynchronization Therapy (MADIT-CRT) study,16 which showed that galectin-3 predicted adverse outcomes in patients despite optimal therapy. In a small number of patients thus far, it has been seen that if a high galectin-3 level was observed at the time of implantation, there was more of a reduction of events than that observed if a patient had low galectin-3 levels. This observation needs to be substantiated, but it certainly is very exciting.
Again, as a heart-failure and biomarker researcher, I’m very excited to try to integrate new biomarkers into panels that will complement each other, but in ways that allow us to separate patients out, guide institute treatment, and then bio-monitor those patients with the biomarker. So far, we haven’t seen a robust change in galectin-3 levels with treatment, but we’ll need to see as we go on. In any event, a high level puts you in a very important category that I think that we can address right now.
It’s not a complete answer, but I think that as we go forward with research, we know this is a high-risk patient. Not only for short- and long-term prognosis, but at a high risk even to be readmitted in the next 30 days. Data from the Coordinating Study Evaluating Outcomes of Advising and Counseling in Heart Failure (COACH) clearly show this.9 We need to cut into the vicious cycle of heart failure, which we used to think of as just neural hormones. You give renin and blockers—angiotensin blockers and beta blockers—and you reduce that vicious cycle of vasoconstriction and increased afterload.
Now, we know there are other events that occur in acute heart failure. Some of these are inflammatory, some are ischemic, and some may easily link to activation of fibroblasts via galectin. We want to cut into this vicious cycle, if we can.
Dr. Peacock: What about aldosterone antagonists?
Dr. Maisel: Why don’t I take a few minutes and just give an overview on heart failure and how I see as a cardiologist that galectin-3 should perhaps have a role. Amongst ourselves, we know how common heart failure is: 6 million people in the United States, and almost 15 million people in Europe. The burden is more than all cancers combined, and what we’re finding out is that you don’t just say nowadays that a person has heart failure. They don’t all funnel into this one specific pathway, so they all look alike. In fact, heart failure is not necessarily a disease as much as a heterogeneous group of conditions that cannot meet the body’s demand for work.
So, you could probably look at the general heart failure population and pull out a number of things. You could pull out some genetic disorders. You could pull out endocrine disorders. You could also pull out people who had drug problems, and that’s often what we try to do. But, I think galectin-3 also gives us a window into another category that I will call galectin-3–mediated heart failure, which is an active scarring or fibrosis process. It’s progressive, and these patients are at higher risk for adverse outcomes.
Why is this important? Because these patients may respond to a drug differently than do other groups. In fact, early on, they may respond to drugs that we normally don’t give early, like aldosterone blockade, and later on, when they have very severe heart failure and high galectin-3 levels, they may be burned out enough to no longer respond to the treatment as we expect.
As a biomarker researcher, I also believe that we need multiple biomarkers to separate complex patients, and heart failure patients certainly are complex in the way they present with concomitant kidney disease, lung disease, diabetes, etc. So, the one biomarker that we all use is the natriuretic peptides. I like the fact that galectin-3 and the natriuretic peptides seem to be synergistic. You have a marker for fibrosis: the natriuretic peptides, markers of cardiac stress, and the fibrosis marker galectin-3 are relatively stable. BNP, to an extent, then tells you how much volume you need to remove to get back to baseline, dry BNP levels. When you look at prognosis, galectin-3 clearly adds to what you get from BNP. Galectin-3 can identify between 10% and 20% more patients at additional risk for adverse events.
One really interesting facet of galectin-3 is in preventing heart failure. To try to prevent heart failure, we need to get patients at the stage-A and stage-B level. That is why we went from New York Heart Association class to the American College of Cardiology/American Heart Association stages of heart failure, stage A being that of high risk but without structural disease and stage B, with structural disease but no signs or symptoms of heart failure yet.
As part of the Framingham Offspring Study, the researchers evaluated about 3500 subjects based on galectin-3 quartiles.10 First, they found that galectin-3 seemed to correlate with other risk factors including age, blood pressure, and other factors like diabetes, renal dysfunction, etc.
But, when they followed these patients for 8 years, for those who were otherwise normal, you could show very good gradation of risk for quartiles 1 to 4, not just for the development of heart failure, but also for the development of death. The hazard ratios were about 1:4, which is very significant.10
So what does this suggest? There’s a group of people who perhaps just have diabetes and slight hypertension, and what I’m going to do, as soon as I get the assay, is start measuring galectin-3 levels. If it’s high, I’m going to sit these patients down and say, “What this tells me is that you are going to have big problems if we don’t control things.” That’s very important.
As Dr. Di Somma mentioned, we now have a number: 17.8 pg/mL has been substantiated in a number of studies as a fairly robust cutoff point, below which you do well, and above which, you don’t do well. As a heart-failure doctor, a biomarker researcher, and an associate editor for the Journal of the American College of Cardiology, I see a lot of biomarker papers. We don’t like prognostic papers anymore unless you can do something about it. What do you do with this biomarker? We talk about pre-heart failure, but when you have heart failure, what do we do with it?
Well, a lot of the markers that we study (BNPs, troponins, etc) are death markers. We don’t know if we can do something about the marker levels increasing, but at least in my opinion, galectin-3 gives us an opportunity early in the disease to prevent progressive fibrosis.
So, let’s say you have 2 patients, one has a galectin-3 level of 8, and the other has a galectin-3 level of 35. They both have diabetes and both have slight heart failure. The one with the high galectin-3 is going to progress at a much steeper descent, because with each episode, you’re activating myofibroblasts to release galectin and deposit collagen. Well, galectin-3 gives us opportunities to use a biomarker to potentially guide treatment, so that we can personalize medicine. The guidelines for heart failure medications say that everybody should be given the same dose of everything, and we know that’s not usually what really works in practice.
One of the things that we’ve been talking about at some of our galectin-3 meetings is whether we could use this to guide therapy, and where the unmet need is. Well, one of the unmet needs is in acute decompensated heart failure. In the United States, with the “Obamacare” situation, we’re not paying hospitals—and maybe physicians, because of this, won’t get paid—if a patient is sent home and then readmitted within 30 days. And, that readmission rate around the country is 20% or higher.
We know molecules like BNP, troponin, and galectin-3 are related. They’re biomarkers that are related to readmission, which gives us an opportunity to treat a patient. Well, what other treatment do we use? Normally, we use diuretics or vasodilators. People often withhold angiotensin-converting enzyme (ACE) inhibitors if there’s any kidney dysfunction present. Aldosterone blockade is never given acutely in the hospital. I think this is mostly because physicians are afraid of hypercalcemia, an interaction with ACE inhibitors, etc. But, we know in other forms of heart failure, way back to the Randomized Aldactone Evaluation Study (RALES)11 and then the Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS),12 which is actually a trial of in-house acute heart failure after a myocardial infarction, and then more recently, the Eplerenone in Mild Patients Hospitalization and Survival Study in Heart Failure (EMPHASIS-HF)13 has basically begun to switch guidelines toward giving aldosterone blockers earlier in the course of chronic heart failure.4
What about acute heart failure? We don’t have good strategies, as I mentioned, to prevent readmissions. Nothing we have done has really worked. The idea behind aldosterone 3 was really formulated in a large part by Bert Pitt in an article a few years ago,12 which talked about the possibility of using mineralocorticoid receptor antagonists in acute heart failure, and makes a lot of sense. Aldosterone levels are so high in acute heart failure that it is left relatively unchecked by ACE and angiotensin receptor blockers and does everything to promote a vicious cycle of vasoconstriction, salt and water retention, ischemia, arrhythmias, etc, and yet, nothing is recommended. Even in the guidelines, which the European Society of Cardiology is just coming out with, regarding earlier treatment of patients with aldosterone blockers, there’s nothing about in-hospitalization treatment.
Using an aldosterone blocker in the acute treatment of heart failure may be an unmet need. We are going to be starting a study to try this. This will be the second biomarker-guided heart failure trial, the first one was called ACAT Intravascular Atherosclerosis Treatment Evaluation (ACTIVATE),14 which will use copeptin to put the patients on a copeptin antagonist, called tolvaptan. This study will be called the Reduction in Events with Galectin-3 and Aldosterone Blockade in Acute Heart Failure (REGAL) trial. It will be a multicenter study in Europe and the United States; Dr. Boer will be very involved in this, I know. In the case of patients with acute heart failure, if they don’t have a contraindication and are not on an aldosterone blocker, their galectin-3 levels will be measured. If the levels are high, they will be placed on spironolactone or placebo, and the follow-up is looking for 90-day events.
Now, the interesting thing about this study, which is what a lot of people were worried about, is how you can keep a patient on a placebo for 90 days, since aldosterone blockers are indicated in those with ejection fractions under 35%? The answer is that we will include patients with ejection fractions over 35%. In other words, we will take mild systolic dysfunction and heart failure with preserved ejection fraction and enroll those patients.
Some others can comment, but there’s some decent data. I think Dr. Boer has some data on this, and some other scientists have data suggesting that diastolic dysfunction is, in part, associated with fibrosis and that galectin-3 may be a very important signal.15 We will get a chance to look at this. It will be a relatively easy study to do. For the primary endpoint, we’re going to look at a decrease in events compared to the placebo. So, I’m very excited about that as a heart-failure researcher.
The other question I am excited about answering is whether we can use galectin-3 as a predictor for a response to cardiac resynchronization therapy (CRT) and implantable cardioverter-defibrillator, especially these resynchronization devices that are undergoing a lot of change. They’re very expensive. We have a moving target for which patients we’re being reimbursed. The latest is that, if a patient has heart failure and a wide QRS, but not a left bundle branch block, he/she may no longer qualify for CRT or implantable cardioverter-defibrillator. Earlier, it was used for any patient with a wide QRS. Now, it’s just basically moving to the left bundle.
So, there are probably people in between who will do better, and there’s some early unpublished data, which we could talk about a little bit, from Boston Scientific, arising from the Multicenter Automatic Defibrillator Implantation Trial with Cardiac Resynchronization Therapy (MADIT-CRT) study,16 which showed that galectin-3 predicted adverse outcomes in patients despite optimal therapy. In a small number of patients thus far, it has been seen that if a high galectin-3 level was observed at the time of implantation, there was more of a reduction of events than that observed if a patient had low galectin-3 levels. This observation needs to be substantiated, but it certainly is very exciting.
Again, as a heart-failure and biomarker researcher, I’m very excited to try to integrate new biomarkers into panels that will complement each other, but in ways that allow us to separate patients out, guide institute treatment, and then bio-monitor those patients with the biomarker. So far, we haven’t seen a robust change in galectin-3 levels with treatment, but we’ll need to see as we go on. In any event, a high level puts you in a very important category that I think that we can address right now.
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With me is Dr. Rudolf de Boer, from University Medical Center, Groningen, The Netherlands, who has done some of the basic science work; Dr. Salvatore Di Somma, who is an emergency physician at San Andrea Hospital at the University Sapienza in Rome; and Dr. Alan Maisel, a world-renowned biomarker researcher from the University of California San Diego at the Veterans Administration. I am Frank Peacock, a Professor in Emergency Medicine and the Director of Research at the Baylor College of Medicine.
Welcome, gentlemen. I’d like to open this up with Dr. Boer, starting with some discussion on what he knows about this marker.
Dr. de Boer: Yes, thank you, Dr. Peacock, for your introduction. I will briefly introduce galectin-3 to you, although I’m sure most of you have become familiar with it to some extent. It was actually not so long ago that galectin-3 was scientifically discovered in the 1980s. When it was discovered, its function was not fully recognized. It was only 8 years ago that galectin-3 was associated with heart failure development and cardiac remodeling.1
Galectin-3 is a member of the galectin family, which is a large family comprising about 20 galectins. Galectin-3 is unique because it’s a so-called chimera-type galectin, meaning that upon lectin binding, it forms multidimers, shaping a mesh, which is thought to add to the stiffness of the interstitial matrix, and in the case of heart failure, it adds stiffness to the extracellular myocardial matrix.2 Galectin-3 can be activated by all kinds of lectins, and in the normal heart, these ligands are believed to be major cellular proteins such as laminin and collagens. In damaged organs in general, and in heart failure in particular, galectin-3 is predominantly released by macrophages and the activating lectins are clearly more abundant, and this is generally thought to be the mechanism of galectin-3 activation in heart failure.
As I mentioned, a first seminal paper1 on the potential role of galectin-3 in heart failure was published in 2004. In a rat model with transition from compensated to decompensated heart failure, galectin-3 was the most strongly differentially expressed gene in this transitional phase. With further experimentation, the investigators showed that adding galectin-3 into the pericardial sac rendered superphysiological levels of galectin-3, and with this perturbation, they were able to provoke adverse cardiac remodeling with collagen deposition and left ventricular dysfunction. So, not only does galectin-3 seem to be associated with heart failure development, but may also be a part of the pathophysiology of cardiac remodeling and heart failure. This, of course, is very interesting.
Furthermore, galectin-3 seems to be a factor that is very dominant in the matrix: it does not predominantly act on cardiomyocytes, but on fibroblasts and the matrix compartment of the heart. It is strictly colocalized with sites of fibrosis where injury occurs, and it was shown that the primary source of galectin-3 in the heart includes all kinds of inflammatory cells, mainly macrophages, at the site of injury, for example, post-myocardial infarction or in hypertensive models. However, some other cells also produce galectin-3 including cardiac fibroblasts and mast cells. Mast cells are clearly less abundant, and fibroblasts are very abundant but produce a rather low amount of galectin-3. So overall, the primary source of galectin-3 is believed to be macrophages. As it is currently understood, when galectin-3 is produced, it turns cardiac fibroblasts into matrix-producing myofibroblasts, which then adds to the remodeling, specifically extracellular matrix production and fibrogenesis, not so much left ventricular hypertrophy, and this may contribute to the ultimate culmination into overt heart failure.
This is a general scheme of how we think of galectin-3 right now. As said before, interestingly, galectin-3 is associated with the disease process, but when activated, it has also been shown to add to the pathophysiology. Besides the naturally occurring binding lectins, investigators have developed neutralizing lectins that may bind to galectin-3 and render it inactive. This approach may actually downregulate galectin-3 activity with the aim to attenuate the galectin-3—driven progress of cardiac remodeling and to halt heart failure development. Recently, these neutralizing lectins have been tested in several animal models of hypertension, and it was shown that galectin-3 can be inhibited; this is associated with the attenuation of end-organ damage.3,4
Besides cardiac fibrosis, it has been observed that galectin-3 is also activated in liver fibrosis,5 kidney fibrosis,6 and lung fibrosis.7 Experimental studies using pharmacological compounds specifically targeting galectin-3 in non-cardiac disease have also been quite successful in attenuating tissue fibrosis.7 I think this adds an extra level of interest to this protein—that is, it’s not only a marker of disease severity, but also some kind of culprit biomarker, suggesting that it is part of the pathophysiology of heart failure, and can be a target of specific therapy.
Dr. Peacock: Perfect, Dr. Boer, that’s a really nice review of what we know up to this point about galectin-3. I think the next question is—is it ready for the clinical world? And if so, how would we be using it? Dr. Di Somma, what do you think about this and the use of galectin-3 in the emergency department?
Dr. Di Somma: That’s a very important question, because for patients presenting to an emergency department for shortness of breath due to acute heart failure, the physician has 3 main important jobs to do. First, a quick diagnosis is needed to start immediately with treatment because from papers in the literature,8 it is very clear that how fast you are in making the diagnosis and starting the treatment is going to have an important impact on both the patient’s outcome and length of stay. So, the first job is to give an appropriate diagnosis, but of no less importance is to immediately perform a risk specification, which is very important in terms of determining how aggressive your treatment must be, as well as the disposition based on this certification analysis of your patients with acute heart failure.
It seems possible now to discriminate between patients arriving in the Emergency Department with signs and symptoms of acute heart failure with galectin-3 levels of <17.8 pg/mL compared to patients with a galectin-3 level greater than this cutoff. Patients with a galectin-3 level of <17.8 pg/mL have a better prognosis after 30 days on follow-up examination, which, from the emergency physician’s point of view, is of great importance in immediately understanding the severity of the patient’s condition, because the disposition for these patients should be different.
Galectin-3 levels could be influenced by age and the kidney function. So if the patient is very old (> 75 years) and his estimated glomerular filtration rate is below 30 mL/min, the galectin-3 levels could be higher than expected. This could be related to the ongoing fibrotic process in the kidney that galectin-3 is mirroring. Moreover, in patients presenting with concomitant oncologic disease, galectin levels could be also higher.
For acute heart failure treatment, we now have many options, but in majority of the cases, the therapy is based on the use of intravenous diuretics. The current guidelines recommend high doses of intravenous diuretics, but also consider the possibility that, if immediately after a patient presents to the emergency department, you are able to make a correct diagnosis and determine the treatment and the following disposition based on biomarkers, the dosage of diuretic should also be based on appropriate patient risk stratification. A galectin-3 level of >17.8 pg/mL for instance indicates that a patient is at high risk for hospitalization, so you must be more cautious with this patient, possibly with a more aggressive intravenous diuretic treatment. Furthermore, the emergency department physician could also decide on the basis of a galectin-3 level of >17.8 pg/mL whether or not to discharge these patients only after infusion or to admit this patient to the hospital. On the contrary, since the job of the emergency department physician is mostly to rule out less severe cases, a galectin-3 level of <17.8 pg/mL (indicating less heart fibrosis) would probably indicate that it is safe to discharge a patient after just a small increase in the diuretic treatment dosage.
The use of galectin-3 will also have an important impact on the problem of overcrowding in the emergency department. In the recertification of patients coming to the emergency department with acute heart failure, there is an important possibility that adding the opportunity to measure galectin-3 can positively impact treatment from the emergency department physician.
Dr. Peacock: I think you brought up some extremely important points. You have to make a diagnosis first. Galectin-3 does not diagnose heart failure, but as you said, once you’ve established the probability that the patient has heart failure, galectin-3 is an outstanding prognostic agent. As Dr. de Boer said, it reflects generalized fibrosis, and there is a lack of specificity in that situation. However, once you’ve decided that the diagnosis is heart failure, then it’s an excellent prognostic, and if you define the cutoff point as 17.8 pg/mL, it identifies patients who would be at lower or higher risk for adverse outcomes subsequent to discharge.
This is really important for emergency medicine because we really don’t have anything that tells us what the future will look like in heart failure, except for B-type natriuretic peptide (BNP), which is really poor at predicting the next 2 weeks, and troponin, which is excellent, but is only elevated in a very small minority of cases using the contemporary assays available in the United States at this time.
Dr. Maisel: You can also make a case that once a diagnosis of heart failure is made—it’s sort of a moderate or mild-to-moderate heart failure, the BNP level is just a little above the grey zone, maybe 500 or 600 pg/mL, and the patient responds well to the diuretic—this isn’t like a troponin-positive acute coronary syndrome patient where, even if it’s just slightly positive, you’re still going to admit them. But, if you could show a propensity to have fibrosis in the short term and long term in this case of heart failure, and especially, if the patient is new to the system, then you may want to admit the patient to make sure this person gets on excellent therapy—and I’ll be talking about the role of mineralocorticoid receptor antagonists in a few minutes.
I think it’s significant to say, “Maybe this guy should not go home.” His level is above 17.8 pg/mL, and he has mild heart failure. He’s prone to just go downhill with each recurrent heart failure admission, and we need to take a closer look. If, in fact, you don’t admit him, then this is a person I would bring back within probably the first week to keep a close eye on.
Dr. Peacock: Dr. Maisel, what are you going to do when Dr. Di Somma sees a patient in the emergency department, their galectin-3 level is 27 pg/mL, and he sends the patient upstairs? Now, you’re at the receiving end.
It’s not a complete answer, but I think that as we go forward with research, we know this is a high-risk patient. Not only for short- and long-term prognosis, but at a high risk even to be readmitted in the next 30 days. Data from the Coordinating Study Evaluating Outcomes of Advising and Counseling in Heart Failure (COACH) clearly show this.9 We need to cut into the vicious cycle of heart failure, which we used to think of as just neural hormones. You give renin and blockers—angiotensin blockers and beta blockers—and you reduce that vicious cycle of vasoconstriction and increased afterload.
Now, we know there are other events that occur in acute heart failure. Some of these are inflammatory, some are ischemic, and some may easily link to activation of fibroblasts via galectin. We want to cut into this vicious cycle, if we can.
Dr. Peacock: What about aldosterone antagonists?
Dr. Maisel: Why don’t I take a few minutes and just give an overview on heart failure and how I see as a cardiologist that galectin-3 should perhaps have a role. Amongst ourselves, we know how common heart failure is: 6 million people in the United States, and almost 15 million people in Europe. The burden is more than all cancers combined, and what we’re finding out is that you don’t just say nowadays that a person has heart failure. They don’t all funnel into this one specific pathway, so they all look alike. In fact, heart failure is not necessarily a disease as much as a heterogeneous group of conditions that cannot meet the body’s demand for work.
So, you could probably look at the general heart failure population and pull out a number of things. You could pull out some genetic disorders. You could pull out endocrine disorders. You could also pull out people who had drug problems, and that’s often what we try to do. But, I think galectin-3 also gives us a window into another category that I will call galectin-3–mediated heart failure, which is an active scarring or fibrosis process. It’s progressive, and these patients are at higher risk for adverse outcomes.
Why is this important? Because these patients may respond to a drug differently than do other groups. In fact, early on, they may respond to drugs that we normally don’t give early, like aldosterone blockade, and later on, when they have very severe heart failure and high galectin-3 levels, they may be burned out enough to no longer respond to the treatment as we expect.
As a biomarker researcher, I also believe that we need multiple biomarkers to separate complex patients, and heart failure patients certainly are complex in the way they present with concomitant kidney disease, lung disease, diabetes, etc. So, the one biomarker that we all use is the natriuretic peptides. I like the fact that galectin-3 and the natriuretic peptides seem to be synergistic. You have a marker for fibrosis: the natriuretic peptides, markers of cardiac stress, and the fibrosis marker galectin-3 are relatively stable. BNP, to an extent, then tells you how much volume you need to remove to get back to baseline, dry BNP levels. When you look at prognosis, galectin-3 clearly adds to what you get from BNP. Galectin-3 can identify between 10% and 20% more patients at additional risk for adverse events.
One really interesting facet of galectin-3 is in preventing heart failure. To try to prevent heart failure, we need to get patients at the stage-A and stage-B level. That is why we went from New York Heart Association class to the American College of Cardiology/American Heart Association stages of heart failure, stage A being that of high risk but without structural disease and stage B, with structural disease but no signs or symptoms of heart failure yet.
As part of the Framingham Offspring Study, the researchers evaluated about 3500 subjects based on galectin-3 quartiles.10 First, they found that galectin-3 seemed to correlate with other risk factors including age, blood pressure, and other factors like diabetes, renal dysfunction, etc.
But, when they followed these patients for 8 years, for those who were otherwise normal, you could show very good gradation of risk for quartiles 1 to 4, not just for the development of heart failure, but also for the development of death. The hazard ratios were about 1:4, which is very significant.10
So what does this suggest? There’s a group of people who perhaps just have diabetes and slight hypertension, and what I’m going to do, as soon as I get the assay, is start measuring galectin-3 levels. If it’s high, I’m going to sit these patients down and say, “What this tells me is that you are going to have big problems if we don’t control things.” That’s very important.
As Dr. Di Somma mentioned, we now have a number: 17.8 pg/mL has been substantiated in a number of studies as a fairly robust cutoff point, below which you do well, and above which, you don’t do well. As a heart-failure doctor, a biomarker researcher, and an associate editor for the Journal of the American College of Cardiology, I see a lot of biomarker papers. We don’t like prognostic papers anymore unless you can do something about it. What do you do with this biomarker? We talk about pre-heart failure, but when you have heart failure, what do we do with it?
Well, a lot of the markers that we study (BNPs, troponins, etc) are death markers. We don’t know if we can do something about the marker levels increasing, but at least in my opinion, galectin-3 gives us an opportunity early in the disease to prevent progressive fibrosis.
So, let’s say you have 2 patients, one has a galectin-3 level of 8, and the other has a galectin-3 level of 35. They both have diabetes and both have slight heart failure. The one with the high galectin-3 is going to progress at a much steeper descent, because with each episode, you’re activating myofibroblasts to release galectin and deposit collagen. Well, galectin-3 gives us opportunities to use a biomarker to potentially guide treatment, so that we can personalize medicine. The guidelines for heart failure medications say that everybody should be given the same dose of everything, and we know that’s not usually what really works in practice.
One of the things that we’ve been talking about at some of our galectin-3 meetings is whether we could use this to guide therapy, and where the unmet need is. Well, one of the unmet needs is in acute decompensated heart failure. In the United States, with the “Obamacare” situation, we’re not paying hospitals—and maybe physicians, because of this, won’t get paid—if a patient is sent home and then readmitted within 30 days. And, that readmission rate around the country is 20% or higher.
We know molecules like BNP, troponin, and galectin-3 are related. They’re biomarkers that are related to readmission, which gives us an opportunity to treat a patient. Well, what other treatment do we use? Normally, we use diuretics or vasodilators. People often withhold angiotensin-converting enzyme (ACE) inhibitors if there’s any kidney dysfunction present. Aldosterone blockade is never given acutely in the hospital. I think this is mostly because physicians are afraid of hypercalcemia, an interaction with ACE inhibitors, etc. But, we know in other forms of heart failure, way back to the Randomized Aldactone Evaluation Study (RALES)11 and then the Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS),12 which is actually a trial of in-house acute heart failure after a myocardial infarction, and then more recently, the Eplerenone in Mild Patients Hospitalization and Survival Study in Heart Failure (EMPHASIS-HF)13 has basically begun to switch guidelines toward giving aldosterone blockers earlier in the course of chronic heart failure.4
What about acute heart failure? We don’t have good strategies, as I mentioned, to prevent readmissions. Nothing we have done has really worked. The idea behind aldosterone 3 was really formulated in a large part by Bert Pitt in an article a few years ago,12 which talked about the possibility of using mineralocorticoid receptor antagonists in acute heart failure, and makes a lot of sense. Aldosterone levels are so high in acute heart failure that it is left relatively unchecked by ACE and angiotensin receptor blockers and does everything to promote a vicious cycle of vasoconstriction, salt and water retention, ischemia, arrhythmias, etc, and yet, nothing is recommended. Even in the guidelines, which the European Society of Cardiology is just coming out with, regarding earlier treatment of patients with aldosterone blockers, there’s nothing about in-hospitalization treatment.
Using an aldosterone blocker in the acute treatment of heart failure may be an unmet need. We are going to be starting a study to try this. This will be the second biomarker-guided heart failure trial, the first one was called ACAT Intravascular Atherosclerosis Treatment Evaluation (ACTIVATE),14 which will use copeptin to put the patients on a copeptin antagonist, called tolvaptan. This study will be called the Reduction in Events with Galectin-3 and Aldosterone Blockade in Acute Heart Failure (REGAL) trial. It will be a multicenter study in Europe and the United States; Dr. Boer will be very involved in this, I know. In the case of patients with acute heart failure, if they don’t have a contraindication and are not on an aldosterone blocker, their galectin-3 levels will be measured. If the levels are high, they will be placed on spironolactone or placebo, and the follow-up is looking for 90-day events.
Now, the interesting thing about this study, which is what a lot of people were worried about, is how you can keep a patient on a placebo for 90 days, since aldosterone blockers are indicated in those with ejection fractions under 35%? The answer is that we will include patients with ejection fractions over 35%. In other words, we will take mild systolic dysfunction and heart failure with preserved ejection fraction and enroll those patients.
Some others can comment, but there’s some decent data. I think Dr. Boer has some data on this, and some other scientists have data suggesting that diastolic dysfunction is, in part, associated with fibrosis and that galectin-3 may be a very important signal.15 We will get a chance to look at this. It will be a relatively easy study to do. For the primary endpoint, we’re going to look at a decrease in events compared to the placebo. So, I’m very excited about that as a heart-failure researcher.
The other question I am excited about answering is whether we can use galectin-3 as a predictor for a response to cardiac resynchronization therapy (CRT) and implantable cardioverter-defibrillator, especially these resynchronization devices that are undergoing a lot of change. They’re very expensive. We have a moving target for which patients we’re being reimbursed. The latest is that, if a patient has heart failure and a wide QRS, but not a left bundle branch block, he/she may no longer qualify for CRT or implantable cardioverter-defibrillator. Earlier, it was used for any patient with a wide QRS. Now, it’s just basically moving to the left bundle.
So, there are probably people in between who will do better, and there’s some early unpublished data, which we could talk about a little bit, from Boston Scientific, arising from the Multicenter Automatic Defibrillator Implantation Trial with Cardiac Resynchronization Therapy (MADIT-CRT) study,16 which showed that galectin-3 predicted adverse outcomes in patients despite optimal therapy. In a small number of patients thus far, it has been seen that if a high galectin-3 level was observed at the time of implantation, there was more of a reduction of events than that observed if a patient had low galectin-3 levels. This observation needs to be substantiated, but it certainly is very exciting.
Again, as a heart-failure and biomarker researcher, I’m very excited to try to integrate new biomarkers into panels that will complement each other, but in ways that allow us to separate patients out, guide institute treatment, and then bio-monitor those patients with the biomarker. So far, we haven’t seen a robust change in galectin-3 levels with treatment, but we’ll need to see as we go on. In any event, a high level puts you in a very important category that I think that we can address right now.
It’s not a complete answer, but I think that as we go forward with research, we know this is a high-risk patient. Not only for short- and long-term prognosis, but at a high risk even to be readmitted in the next 30 days. Data from the Coordinating Study Evaluating Outcomes of Advising and Counseling in Heart Failure (COACH) clearly show this.9 We need to cut into the vicious cycle of heart failure, which we used to think of as just neural hormones. You give renin and blockers—angiotensin blockers and beta blockers—and you reduce that vicious cycle of vasoconstriction and increased afterload.
Now, we know there are other events that occur in acute heart failure. Some of these are inflammatory, some are ischemic, and some may easily link to activation of fibroblasts via galectin. We want to cut into this vicious cycle, if we can.
Dr. Peacock: What about aldosterone antagonists?
Dr. Maisel: Why don’t I take a few minutes and just give an overview on heart failure and how I see as a cardiologist that galectin-3 should perhaps have a role. Amongst ourselves, we know how common heart failure is: 6 million people in the United States, and almost 15 million people in Europe. The burden is more than all cancers combined, and what we’re finding out is that you don’t just say nowadays that a person has heart failure. They don’t all funnel into this one specific pathway, so they all look alike. In fact, heart failure is not necessarily a disease as much as a heterogeneous group of conditions that cannot meet the body’s demand for work.
So, you could probably look at the general heart failure population and pull out a number of things. You could pull out some genetic disorders. You could pull out endocrine disorders. You could also pull out people who had drug problems, and that’s often what we try to do. But, I think galectin-3 also gives us a window into another category that I will call galectin-3–mediated heart failure, which is an active scarring or fibrosis process. It’s progressive, and these patients are at higher risk for adverse outcomes.
Why is this important? Because these patients may respond to a drug differently than do other groups. In fact, early on, they may respond to drugs that we normally don’t give early, like aldosterone blockade, and later on, when they have very severe heart failure and high galectin-3 levels, they may be burned out enough to no longer respond to the treatment as we expect.
As a biomarker researcher, I also believe that we need multiple biomarkers to separate complex patients, and heart failure patients certainly are complex in the way they present with concomitant kidney disease, lung disease, diabetes, etc. So, the one biomarker that we all use is the natriuretic peptides. I like the fact that galectin-3 and the natriuretic peptides seem to be synergistic. You have a marker for fibrosis: the natriuretic peptides, markers of cardiac stress, and the fibrosis marker galectin-3 are relatively stable. BNP, to an extent, then tells you how much volume you need to remove to get back to baseline, dry BNP levels. When you look at prognosis, galectin-3 clearly adds to what you get from BNP. Galectin-3 can identify between 10% and 20% more patients at additional risk for adverse events.
One really interesting facet of galectin-3 is in preventing heart failure. To try to prevent heart failure, we need to get patients at the stage-A and stage-B level. That is why we went from New York Heart Association class to the American College of Cardiology/American Heart Association stages of heart failure, stage A being that of high risk but without structural disease and stage B, with structural disease but no signs or symptoms of heart failure yet.
As part of the Framingham Offspring Study, the researchers evaluated about 3500 subjects based on galectin-3 quartiles.10 First, they found that galectin-3 seemed to correlate with other risk factors including age, blood pressure, and other factors like diabetes, renal dysfunction, etc.
But, when they followed these patients for 8 years, for those who were otherwise normal, you could show very good gradation of risk for quartiles 1 to 4, not just for the development of heart failure, but also for the development of death. The hazard ratios were about 1:4, which is very significant.10
So what does this suggest? There’s a group of people who perhaps just have diabetes and slight hypertension, and what I’m going to do, as soon as I get the assay, is start measuring galectin-3 levels. If it’s high, I’m going to sit these patients down and say, “What this tells me is that you are going to have big problems if we don’t control things.” That’s very important.
As Dr. Di Somma mentioned, we now have a number: 17.8 pg/mL has been substantiated in a number of studies as a fairly robust cutoff point, below which you do well, and above which, you don’t do well. As a heart-failure doctor, a biomarker researcher, and an associate editor for the Journal of the American College of Cardiology, I see a lot of biomarker papers. We don’t like prognostic papers anymore unless you can do something about it. What do you do with this biomarker? We talk about pre-heart failure, but when you have heart failure, what do we do with it?
Well, a lot of the markers that we study (BNPs, troponins, etc) are death markers. We don’t know if we can do something about the marker levels increasing, but at least in my opinion, galectin-3 gives us an opportunity early in the disease to prevent progressive fibrosis.
So, let’s say you have 2 patients, one has a galectin-3 level of 8, and the other has a galectin-3 level of 35. They both have diabetes and both have slight heart failure. The one with the high galectin-3 is going to progress at a much steeper descent, because with each episode, you’re activating myofibroblasts to release galectin and deposit collagen. Well, galectin-3 gives us opportunities to use a biomarker to potentially guide treatment, so that we can personalize medicine. The guidelines for heart failure medications say that everybody should be given the same dose of everything, and we know that’s not usually what really works in practice.
One of the things that we’ve been talking about at some of our galectin-3 meetings is whether we could use this to guide therapy, and where the unmet need is. Well, one of the unmet needs is in acute decompensated heart failure. In the United States, with the “Obamacare” situation, we’re not paying hospitals—and maybe physicians, because of this, won’t get paid—if a patient is sent home and then readmitted within 30 days. And, that readmission rate around the country is 20% or higher.
We know molecules like BNP, troponin, and galectin-3 are related. They’re biomarkers that are related to readmission, which gives us an opportunity to treat a patient. Well, what other treatment do we use? Normally, we use diuretics or vasodilators. People often withhold angiotensin-converting enzyme (ACE) inhibitors if there’s any kidney dysfunction present. Aldosterone blockade is never given acutely in the hospital. I think this is mostly because physicians are afraid of hypercalcemia, an interaction with ACE inhibitors, etc. But, we know in other forms of heart failure, way back to the Randomized Aldactone Evaluation Study (RALES)11 and then the Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS),12 which is actually a trial of in-house acute heart failure after a myocardial infarction, and then more recently, the Eplerenone in Mild Patients Hospitalization and Survival Study in Heart Failure (EMPHASIS-HF)13 has basically begun to switch guidelines toward giving aldosterone blockers earlier in the course of chronic heart failure.4
What about acute heart failure? We don’t have good strategies, as I mentioned, to prevent readmissions. Nothing we have done has really worked. The idea behind aldosterone 3 was really formulated in a large part by Bert Pitt in an article a few years ago,12 which talked about the possibility of using mineralocorticoid receptor antagonists in acute heart failure, and makes a lot of sense. Aldosterone levels are so high in acute heart failure that it is left relatively unchecked by ACE and angiotensin receptor blockers and does everything to promote a vicious cycle of vasoconstriction, salt and water retention, ischemia, arrhythmias, etc, and yet, nothing is recommended. Even in the guidelines, which the European Society of Cardiology is just coming out with, regarding earlier treatment of patients with aldosterone blockers, there’s nothing about in-hospitalization treatment.
Using an aldosterone blocker in the acute treatment of heart failure may be an unmet need. We are going to be starting a study to try this. This will be the second biomarker-guided heart failure trial, the first one was called ACAT Intravascular Atherosclerosis Treatment Evaluation (ACTIVATE),14 which will use copeptin to put the patients on a copeptin antagonist, called tolvaptan. This study will be called the Reduction in Events with Galectin-3 and Aldosterone Blockade in Acute Heart Failure (REGAL) trial. It will be a multicenter study in Europe and the United States; Dr. Boer will be very involved in this, I know. In the case of patients with acute heart failure, if they don’t have a contraindication and are not on an aldosterone blocker, their galectin-3 levels will be measured. If the levels are high, they will be placed on spironolactone or placebo, and the follow-up is looking for 90-day events.
Now, the interesting thing about this study, which is what a lot of people were worried about, is how you can keep a patient on a placebo for 90 days, since aldosterone blockers are indicated in those with ejection fractions under 35%? The answer is that we will include patients with ejection fractions over 35%. In other words, we will take mild systolic dysfunction and heart failure with preserved ejection fraction and enroll those patients.
Some others can comment, but there’s some decent data. I think Dr. Boer has some data on this, and some other scientists have data suggesting that diastolic dysfunction is, in part, associated with fibrosis and that galectin-3 may be a very important signal.15 We will get a chance to look at this. It will be a relatively easy study to do. For the primary endpoint, we’re going to look at a decrease in events compared to the placebo. So, I’m very excited about that as a heart-failure researcher.
The other question I am excited about answering is whether we can use galectin-3 as a predictor for a response to cardiac resynchronization therapy (CRT) and implantable cardioverter-defibrillator, especially these resynchronization devices that are undergoing a lot of change. They’re very expensive. We have a moving target for which patients we’re being reimbursed. The latest is that, if a patient has heart failure and a wide QRS, but not a left bundle branch block, he/she may no longer qualify for CRT or implantable cardioverter-defibrillator. Earlier, it was used for any patient with a wide QRS. Now, it’s just basically moving to the left bundle.
So, there are probably people in between who will do better, and there’s some early unpublished data, which we could talk about a little bit, from Boston Scientific, arising from the Multicenter Automatic Defibrillator Implantation Trial with Cardiac Resynchronization Therapy (MADIT-CRT) study,16 which showed that galectin-3 predicted adverse outcomes in patients despite optimal therapy. In a small number of patients thus far, it has been seen that if a high galectin-3 level was observed at the time of implantation, there was more of a reduction of events than that observed if a patient had low galectin-3 levels. This observation needs to be substantiated, but it certainly is very exciting.
Again, as a heart-failure and biomarker researcher, I’m very excited to try to integrate new biomarkers into panels that will complement each other, but in ways that allow us to separate patients out, guide institute treatment, and then bio-monitor those patients with the biomarker. So far, we haven’t seen a robust change in galectin-3 levels with treatment, but we’ll need to see as we go on. In any event, a high level puts you in a very important category that I think that we can address right now.
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With me is Dr. Rudolf de Boer, from University Medical Center, Groningen, The Netherlands, who has done some of the basic science work; Dr. Salvatore Di Somma, who is an emergency physician at San Andrea Hospital at the University Sapienza in Rome; and Dr. Alan Maisel, a world-renowned biomarker researcher from the University of California San Diego at the Veterans Administration. I am Frank Peacock, a Professor in Emergency Medicine and the Director of Research at the Baylor College of Medicine.
Welcome, gentlemen. I’d like to open this up with Dr. Boer, starting with some discussion on what he knows about this marker.
Dr. de Boer: Yes, thank you, Dr. Peacock, for your introduction. I will briefly introduce galectin-3 to you, although I’m sure most of you have become familiar with it to some extent. It was actually not so long ago that galectin-3 was scientifically discovered in the 1980s. When it was discovered, its function was not fully recognized. It was only 8 years ago that galectin-3 was associated with heart failure development and cardiac remodeling.1
Galectin-3 is a member of the galectin family, which is a large family comprising about 20 galectins. Galectin-3 is unique because it’s a so-called chimera-type galectin, meaning that upon lectin binding, it forms multidimers, shaping a mesh, which is thought to add to the stiffness of the interstitial matrix, and in the case of heart failure, it adds stiffness to the extracellular myocardial matrix.2 Galectin-3 can be activated by all kinds of lectins, and in the normal heart, these ligands are believed to be major cellular proteins such as laminin and collagens. In damaged organs in general, and in heart failure in particular, galectin-3 is predominantly released by macrophages and the activating lectins are clearly more abundant, and this is generally thought to be the mechanism of galectin-3 activation in heart failure.
As I mentioned, a first seminal paper1 on the potential role of galectin-3 in heart failure was published in 2004. In a rat model with transition from compensated to decompensated heart failure, galectin-3 was the most strongly differentially expressed gene in this transitional phase. With further experimentation, the investigators showed that adding galectin-3 into the pericardial sac rendered superphysiological levels of galectin-3, and with this perturbation, they were able to provoke adverse cardiac remodeling with collagen deposition and left ventricular dysfunction. So, not only does galectin-3 seem to be associated with heart failure development, but may also be a part of the pathophysiology of cardiac remodeling and heart failure. This, of course, is very interesting.
Furthermore, galectin-3 seems to be a factor that is very dominant in the matrix: it does not predominantly act on cardiomyocytes, but on fibroblasts and the matrix compartment of the heart. It is strictly colocalized with sites of fibrosis where injury occurs, and it was shown that the primary source of galectin-3 in the heart includes all kinds of inflammatory cells, mainly macrophages, at the site of injury, for example, post-myocardial infarction or in hypertensive models. However, some other cells also produce galectin-3 including cardiac fibroblasts and mast cells. Mast cells are clearly less abundant, and fibroblasts are very abundant but produce a rather low amount of galectin-3. So overall, the primary source of galectin-3 is believed to be macrophages. As it is currently understood, when galectin-3 is produced, it turns cardiac fibroblasts into matrix-producing myofibroblasts, which then adds to the remodeling, specifically extracellular matrix production and fibrogenesis, not so much left ventricular hypertrophy, and this may contribute to the ultimate culmination into overt heart failure.
This is a general scheme of how we think of galectin-3 right now. As said before, interestingly, galectin-3 is associated with the disease process, but when activated, it has also been shown to add to the pathophysiology. Besides the naturally occurring binding lectins, investigators have developed neutralizing lectins that may bind to galectin-3 and render it inactive. This approach may actually downregulate galectin-3 activity with the aim to attenuate the galectin-3—driven progress of cardiac remodeling and to halt heart failure development. Recently, these neutralizing lectins have been tested in several animal models of hypertension, and it was shown that galectin-3 can be inhibited; this is associated with the attenuation of end-organ damage.3,4
Besides cardiac fibrosis, it has been observed that galectin-3 is also activated in liver fibrosis,5 kidney fibrosis,6 and lung fibrosis.7 Experimental studies using pharmacological compounds specifically targeting galectin-3 in non-cardiac disease have also been quite successful in attenuating tissue fibrosis.7 I think this adds an extra level of interest to this protein—that is, it’s not only a marker of disease severity, but also some kind of culprit biomarker, suggesting that it is part of the pathophysiology of heart failure, and can be a target of specific therapy.
Dr. Peacock: Perfect, Dr. Boer, that’s a really nice review of what we know up to this point about galectin-3. I think the next question is—is it ready for the clinical world? And if so, how would we be using it? Dr. Di Somma, what do you think about this and the use of galectin-3 in the emergency department?
Dr. Di Somma: That’s a very important question, because for patients presenting to an emergency department for shortness of breath due to acute heart failure, the physician has 3 main important jobs to do. First, a quick diagnosis is needed to start immediately with treatment because from papers in the literature,8 it is very clear that how fast you are in making the diagnosis and starting the treatment is going to have an important impact on both the patient’s outcome and length of stay. So, the first job is to give an appropriate diagnosis, but of no less importance is to immediately perform a risk specification, which is very important in terms of determining how aggressive your treatment must be, as well as the disposition based on this certification analysis of your patients with acute heart failure.
It seems possible now to discriminate between patients arriving in the Emergency Department with signs and symptoms of acute heart failure with galectin-3 levels of <17.8 pg/mL compared to patients with a galectin-3 level greater than this cutoff. Patients with a galectin-3 level of <17.8 pg/mL have a better prognosis after 30 days on follow-up examination, which, from the emergency physician’s point of view, is of great importance in immediately understanding the severity of the patient’s condition, because the disposition for these patients should be different.
Galectin-3 levels could be influenced by age and the kidney function. So if the patient is very old (> 75 years) and his estimated glomerular filtration rate is below 30 mL/min, the galectin-3 levels could be higher than expected. This could be related to the ongoing fibrotic process in the kidney that galectin-3 is mirroring. Moreover, in patients presenting with concomitant oncologic disease, galectin levels could be also higher.
For acute heart failure treatment, we now have many options, but in majority of the cases, the therapy is based on the use of intravenous diuretics. The current guidelines recommend high doses of intravenous diuretics, but also consider the possibility that, if immediately after a patient presents to the emergency department, you are able to make a correct diagnosis and determine the treatment and the following disposition based on biomarkers, the dosage of diuretic should also be based on appropriate patient risk stratification. A galectin-3 level of >17.8 pg/mL for instance indicates that a patient is at high risk for hospitalization, so you must be more cautious with this patient, possibly with a more aggressive intravenous diuretic treatment. Furthermore, the emergency department physician could also decide on the basis of a galectin-3 level of >17.8 pg/mL whether or not to discharge these patients only after infusion or to admit this patient to the hospital. On the contrary, since the job of the emergency department physician is mostly to rule out less severe cases, a galectin-3 level of <17.8 pg/mL (indicating less heart fibrosis) would probably indicate that it is safe to discharge a patient after just a small increase in the diuretic treatment dosage.
The use of galectin-3 will also have an important impact on the problem of overcrowding in the emergency department. In the recertification of patients coming to the emergency department with acute heart failure, there is an important possibility that adding the opportunity to measure galectin-3 can positively impact treatment from the emergency department physician.
Dr. Peacock: I think you brought up some extremely important points. You have to make a diagnosis first. Galectin-3 does not diagnose heart failure, but as you said, once you’ve established the probability that the patient has heart failure, galectin-3 is an outstanding prognostic agent. As Dr. de Boer said, it reflects generalized fibrosis, and there is a lack of specificity in that situation. However, once you’ve decided that the diagnosis is heart failure, then it’s an excellent prognostic, and if you define the cutoff point as 17.8 pg/mL, it identifies patients who would be at lower or higher risk for adverse outcomes subsequent to discharge.
This is really important for emergency medicine because we really don’t have anything that tells us what the future will look like in heart failure, except for B-type natriuretic peptide (BNP), which is really poor at predicting the next 2 weeks, and troponin, which is excellent, but is only elevated in a very small minority of cases using the contemporary assays available in the United States at this time.
Dr. Maisel: You can also make a case that once a diagnosis of heart failure is made—it’s sort of a moderate or mild-to-moderate heart failure, the BNP level is just a little above the grey zone, maybe 500 or 600 pg/mL, and the patient responds well to the diuretic—this isn’t like a troponin-positive acute coronary syndrome patient where, even if it’s just slightly positive, you’re still going to admit them. But, if you could show a propensity to have fibrosis in the short term and long term in this case of heart failure, and especially, if the patient is new to the system, then you may want to admit the patient to make sure this person gets on excellent therapy—and I’ll be talking about the role of mineralocorticoid receptor antagonists in a few minutes.
I think it’s significant to say, “Maybe this guy should not go home.” His level is above 17.8 pg/mL, and he has mild heart failure. He’s prone to just go downhill with each recurrent heart failure admission, and we need to take a closer look. If, in fact, you don’t admit him, then this is a person I would bring back within probably the first week to keep a close eye on.
Dr. Peacock: Dr. Maisel, what are you going to do when Dr. Di Somma sees a patient in the emergency department, their galectin-3 level is 27 pg/mL, and he sends the patient upstairs? Now, you’re at the receiving end.
It’s not a complete answer, but I think that as we go forward with research, we know this is a high-risk patient. Not only for short- and long-term prognosis, but at a high risk even to be readmitted in the next 30 days. Data from the Coordinating Study Evaluating Outcomes of Advising and Counseling in Heart Failure (COACH) clearly show this.9 We need to cut into the vicious cycle of heart failure, which we used to think of as just neural hormones. You give renin and blockers—angiotensin blockers and beta blockers—and you reduce that vicious cycle of vasoconstriction and increased afterload.
Now, we know there are other events that occur in acute heart failure. Some of these are inflammatory, some are ischemic, and some may easily link to activation of fibroblasts via galectin. We want to cut into this vicious cycle, if we can.
Dr. Peacock: What about aldosterone antagonists?
Dr. Maisel: Why don’t I take a few minutes and just give an overview on heart failure and how I see as a cardiologist that galectin-3 should perhaps have a role. Amongst ourselves, we know how common heart failure is: 6 million people in the United States, and almost 15 million people in Europe. The burden is more than all cancers combined, and what we’re finding out is that you don’t just say nowadays that a person has heart failure. They don’t all funnel into this one specific pathway, so they all look alike. In fact, heart failure is not necessarily a disease as much as a heterogeneous group of conditions that cannot meet the body’s demand for work.
So, you could probably look at the general heart failure population and pull out a number of things. You could pull out some genetic disorders. You could pull out endocrine disorders. You could also pull out people who had drug problems, and that’s often what we try to do. But, I think galectin-3 also gives us a window into another category that I will call galectin-3–mediated heart failure, which is an active scarring or fibrosis process. It’s progressive, and these patients are at higher risk for adverse outcomes.
Why is this important? Because these patients may respond to a drug differently than do other groups. In fact, early on, they may respond to drugs that we normally don’t give early, like aldosterone blockade, and later on, when they have very severe heart failure and high galectin-3 levels, they may be burned out enough to no longer respond to the treatment as we expect.
As a biomarker researcher, I also believe that we need multiple biomarkers to separate complex patients, and heart failure patients certainly are complex in the way they present with concomitant kidney disease, lung disease, diabetes, etc. So, the one biomarker that we all use is the natriuretic peptides. I like the fact that galectin-3 and the natriuretic peptides seem to be synergistic. You have a marker for fibrosis: the natriuretic peptides, markers of cardiac stress, and the fibrosis marker galectin-3 are relatively stable. BNP, to an extent, then tells you how much volume you need to remove to get back to baseline, dry BNP levels. When you look at prognosis, galectin-3 clearly adds to what you get from BNP. Galectin-3 can identify between 10% and 20% more patients at additional risk for adverse events.
One really interesting facet of galectin-3 is in preventing heart failure. To try to prevent heart failure, we need to get patients at the stage-A and stage-B level. That is why we went from New York Heart Association class to the American College of Cardiology/American Heart Association stages of heart failure, stage A being that of high risk but without structural disease and stage B, with structural disease but no signs or symptoms of heart failure yet.
As part of the Framingham Offspring Study, the researchers evaluated about 3500 subjects based on galectin-3 quartiles.10 First, they found that galectin-3 seemed to correlate with other risk factors including age, blood pressure, and other factors like diabetes, renal dysfunction, etc.
But, when they followed these patients for 8 years, for those who were otherwise normal, you could show very good gradation of risk for quartiles 1 to 4, not just for the development of heart failure, but also for the development of death. The hazard ratios were about 1:4, which is very significant.10
So what does this suggest? There’s a group of people who perhaps just have diabetes and slight hypertension, and what I’m going to do, as soon as I get the assay, is start measuring galectin-3 levels. If it’s high, I’m going to sit these patients down and say, “What this tells me is that you are going to have big problems if we don’t control things.” That’s very important.
As Dr. Di Somma mentioned, we now have a number: 17.8 pg/mL has been substantiated in a number of studies as a fairly robust cutoff point, below which you do well, and above which, you don’t do well. As a heart-failure doctor, a biomarker researcher, and an associate editor for the Journal of the American College of Cardiology, I see a lot of biomarker papers. We don’t like prognostic papers anymore unless you can do something about it. What do you do with this biomarker? We talk about pre-heart failure, but when you have heart failure, what do we do with it?
Well, a lot of the markers that we study (BNPs, troponins, etc) are death markers. We don’t know if we can do something about the marker levels increasing, but at least in my opinion, galectin-3 gives us an opportunity early in the disease to prevent progressive fibrosis.
So, let’s say you have 2 patients, one has a galectin-3 level of 8, and the other has a galectin-3 level of 35. They both have diabetes and both have slight heart failure. The one with the high galectin-3 is going to progress at a much steeper descent, because with each episode, you’re activating myofibroblasts to release galectin and deposit collagen. Well, galectin-3 gives us opportunities to use a biomarker to potentially guide treatment, so that we can personalize medicine. The guidelines for heart failure medications say that everybody should be given the same dose of everything, and we know that’s not usually what really works in practice.
One of the things that we’ve been talking about at some of our galectin-3 meetings is whether we could use this to guide therapy, and where the unmet need is. Well, one of the unmet needs is in acute decompensated heart failure. In the United States, with the “Obamacare” situation, we’re not paying hospitals—and maybe physicians, because of this, won’t get paid—if a patient is sent home and then readmitted within 30 days. And, that readmission rate around the country is 20% or higher.
We know molecules like BNP, troponin, and galectin-3 are related. They’re biomarkers that are related to readmission, which gives us an opportunity to treat a patient. Well, what other treatment do we use? Normally, we use diuretics or vasodilators. People often withhold angiotensin-converting enzyme (ACE) inhibitors if there’s any kidney dysfunction present. Aldosterone blockade is never given acutely in the hospital. I think this is mostly because physicians are afraid of hypercalcemia, an interaction with ACE inhibitors, etc. But, we know in other forms of heart failure, way back to the Randomized Aldactone Evaluation Study (RALES)11 and then the Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS),12 which is actually a trial of in-house acute heart failure after a myocardial infarction, and then more recently, the Eplerenone in Mild Patients Hospitalization and Survival Study in Heart Failure (EMPHASIS-HF)13 has basically begun to switch guidelines toward giving aldosterone blockers earlier in the course of chronic heart failure.4
What about acute heart failure? We don’t have good strategies, as I mentioned, to prevent readmissions. Nothing we have done has really worked. The idea behind aldosterone 3 was really formulated in a large part by Bert Pitt in an article a few years ago,12 which talked about the possibility of using mineralocorticoid receptor antagonists in acute heart failure, and makes a lot of sense. Aldosterone levels are so high in acute heart failure that it is left relatively unchecked by ACE and angiotensin receptor blockers and does everything to promote a vicious cycle of vasoconstriction, salt and water retention, ischemia, arrhythmias, etc, and yet, nothing is recommended. Even in the guidelines, which the European Society of Cardiology is just coming out with, regarding earlier treatment of patients with aldosterone blockers, there’s nothing about in-hospitalization treatment.
Using an aldosterone blocker in the acute treatment of heart failure may be an unmet need. We are going to be starting a study to try this. This will be the second biomarker-guided heart failure trial, the first one was called ACAT Intravascular Atherosclerosis Treatment Evaluation (ACTIVATE),14 which will use copeptin to put the patients on a copeptin antagonist, called tolvaptan. This study will be called the Reduction in Events with Galectin-3 and Aldosterone Blockade in Acute Heart Failure (REGAL) trial. It will be a multicenter study in Europe and the United States; Dr. Boer will be very involved in this, I know. In the case of patients with acute heart failure, if they don’t have a contraindication and are not on an aldosterone blocker, their galectin-3 levels will be measured. If the levels are high, they will be placed on spironolactone or placebo, and the follow-up is looking for 90-day events.
Now, the interesting thing about this study, which is what a lot of people were worried about, is how you can keep a patient on a placebo for 90 days, since aldosterone blockers are indicated in those with ejection fractions under 35%? The answer is that we will include patients with ejection fractions over 35%. In other words, we will take mild systolic dysfunction and heart failure with preserved ejection fraction and enroll those patients.
Some others can comment, but there’s some decent data. I think Dr. Boer has some data on this, and some other scientists have data suggesting that diastolic dysfunction is, in part, associated with fibrosis and that galectin-3 may be a very important signal.15 We will get a chance to look at this. It will be a relatively easy study to do. For the primary endpoint, we’re going to look at a decrease in events compared to the placebo. So, I’m very excited about that as a heart-failure researcher.
The other question I am excited about answering is whether we can use galectin-3 as a predictor for a response to cardiac resynchronization therapy (CRT) and implantable cardioverter-defibrillator, especially these resynchronization devices that are undergoing a lot of change. They’re very expensive. We have a moving target for which patients we’re being reimbursed. The latest is that, if a patient has heart failure and a wide QRS, but not a left bundle branch block, he/she may no longer qualify for CRT or implantable cardioverter-defibrillator. Earlier, it was used for any patient with a wide QRS. Now, it’s just basically moving to the left bundle.
So, there are probably people in between who will do better, and there’s some early unpublished data, which we could talk about a little bit, from Boston Scientific, arising from the Multicenter Automatic Defibrillator Implantation Trial with Cardiac Resynchronization Therapy (MADIT-CRT) study,16 which showed that galectin-3 predicted adverse outcomes in patients despite optimal therapy. In a small number of patients thus far, it has been seen that if a high galectin-3 level was observed at the time of implantation, there was more of a reduction of events than that observed if a patient had low galectin-3 levels. This observation needs to be substantiated, but it certainly is very exciting.
Again, as a heart-failure and biomarker researcher, I’m very excited to try to integrate new biomarkers into panels that will complement each other, but in ways that allow us to separate patients out, guide institute treatment, and then bio-monitor those patients with the biomarker. So far, we haven’t seen a robust change in galectin-3 levels with treatment, but we’ll need to see as we go on. In any event, a high level puts you in a very important category that I think that we can address right now.
It’s not a complete answer, but I think that as we go forward with research, we know this is a high-risk patient. Not only for short- and long-term prognosis, but at a high risk even to be readmitted in the next 30 days. Data from the Coordinating Study Evaluating Outcomes of Advising and Counseling in Heart Failure (COACH) clearly show this.9 We need to cut into the vicious cycle of heart failure, which we used to think of as just neural hormones. You give renin and blockers—angiotensin blockers and beta blockers—and you reduce that vicious cycle of vasoconstriction and increased afterload.
Now, we know there are other events that occur in acute heart failure. Some of these are inflammatory, some are ischemic, and some may easily link to activation of fibroblasts via galectin. We want to cut into this vicious cycle, if we can.
Dr. Peacock: What about aldosterone antagonists?
Dr. Maisel: Why don’t I take a few minutes and just give an overview on heart failure and how I see as a cardiologist that galectin-3 should perhaps have a role. Amongst ourselves, we know how common heart failure is: 6 million people in the United States, and almost 15 million people in Europe. The burden is more than all cancers combined, and what we’re finding out is that you don’t just say nowadays that a person has heart failure. They don’t all funnel into this one specific pathway, so they all look alike. In fact, heart failure is not necessarily a disease as much as a heterogeneous group of conditions that cannot meet the body’s demand for work.
So, you could probably look at the general heart failure population and pull out a number of things. You could pull out some genetic disorders. You could pull out endocrine disorders. You could also pull out people who had drug problems, and that’s often what we try to do. But, I think galectin-3 also gives us a window into another category that I will call galectin-3–mediated heart failure, which is an active scarring or fibrosis process. It’s progressive, and these patients are at higher risk for adverse outcomes.
Why is this important? Because these patients may respond to a drug differently than do other groups. In fact, early on, they may respond to drugs that we normally don’t give early, like aldosterone blockade, and later on, when they have very severe heart failure and high galectin-3 levels, they may be burned out enough to no longer respond to the treatment as we expect.
As a biomarker researcher, I also believe that we need multiple biomarkers to separate complex patients, and heart failure patients certainly are complex in the way they present with concomitant kidney disease, lung disease, diabetes, etc. So, the one biomarker that we all use is the natriuretic peptides. I like the fact that galectin-3 and the natriuretic peptides seem to be synergistic. You have a marker for fibrosis: the natriuretic peptides, markers of cardiac stress, and the fibrosis marker galectin-3 are relatively stable. BNP, to an extent, then tells you how much volume you need to remove to get back to baseline, dry BNP levels. When you look at prognosis, galectin-3 clearly adds to what you get from BNP. Galectin-3 can identify between 10% and 20% more patients at additional risk for adverse events.
One really interesting facet of galectin-3 is in preventing heart failure. To try to prevent heart failure, we need to get patients at the stage-A and stage-B level. That is why we went from New York Heart Association class to the American College of Cardiology/American Heart Association stages of heart failure, stage A being that of high risk but without structural disease and stage B, with structural disease but no signs or symptoms of heart failure yet.
As part of the Framingham Offspring Study, the researchers evaluated about 3500 subjects based on galectin-3 quartiles.10 First, they found that galectin-3 seemed to correlate with other risk factors including age, blood pressure, and other factors like diabetes, renal dysfunction, etc.
But, when they followed these patients for 8 years, for those who were otherwise normal, you could show very good gradation of risk for quartiles 1 to 4, not just for the development of heart failure, but also for the development of death. The hazard ratios were about 1:4, which is very significant.10
So what does this suggest? There’s a group of people who perhaps just have diabetes and slight hypertension, and what I’m going to do, as soon as I get the assay, is start measuring galectin-3 levels. If it’s high, I’m going to sit these patients down and say, “What this tells me is that you are going to have big problems if we don’t control things.” That’s very important.
As Dr. Di Somma mentioned, we now have a number: 17.8 pg/mL has been substantiated in a number of studies as a fairly robust cutoff point, below which you do well, and above which, you don’t do well. As a heart-failure doctor, a biomarker researcher, and an associate editor for the Journal of the American College of Cardiology, I see a lot of biomarker papers. We don’t like prognostic papers anymore unless you can do something about it. What do you do with this biomarker? We talk about pre-heart failure, but when you have heart failure, what do we do with it?
Well, a lot of the markers that we study (BNPs, troponins, etc) are death markers. We don’t know if we can do something about the marker levels increasing, but at least in my opinion, galectin-3 gives us an opportunity early in the disease to prevent progressive fibrosis.
So, let’s say you have 2 patients, one has a galectin-3 level of 8, and the other has a galectin-3 level of 35. They both have diabetes and both have slight heart failure. The one with the high galectin-3 is going to progress at a much steeper descent, because with each episode, you’re activating myofibroblasts to release galectin and deposit collagen. Well, galectin-3 gives us opportunities to use a biomarker to potentially guide treatment, so that we can personalize medicine. The guidelines for heart failure medications say that everybody should be given the same dose of everything, and we know that’s not usually what really works in practice.
One of the things that we’ve been talking about at some of our galectin-3 meetings is whether we could use this to guide therapy, and where the unmet need is. Well, one of the unmet needs is in acute decompensated heart failure. In the United States, with the “Obamacare” situation, we’re not paying hospitals—and maybe physicians, because of this, won’t get paid—if a patient is sent home and then readmitted within 30 days. And, that readmission rate around the country is 20% or higher.
We know molecules like BNP, troponin, and galectin-3 are related. They’re biomarkers that are related to readmission, which gives us an opportunity to treat a patient. Well, what other treatment do we use? Normally, we use diuretics or vasodilators. People often withhold angiotensin-converting enzyme (ACE) inhibitors if there’s any kidney dysfunction present. Aldosterone blockade is never given acutely in the hospital. I think this is mostly because physicians are afraid of hypercalcemia, an interaction with ACE inhibitors, etc. But, we know in other forms of heart failure, way back to the Randomized Aldactone Evaluation Study (RALES)11 and then the Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS),12 which is actually a trial of in-house acute heart failure after a myocardial infarction, and then more recently, the Eplerenone in Mild Patients Hospitalization and Survival Study in Heart Failure (EMPHASIS-HF)13 has basically begun to switch guidelines toward giving aldosterone blockers earlier in the course of chronic heart failure.4
What about acute heart failure? We don’t have good strategies, as I mentioned, to prevent readmissions. Nothing we have done has really worked. The idea behind aldosterone 3 was really formulated in a large part by Bert Pitt in an article a few years ago,12 which talked about the possibility of using mineralocorticoid receptor antagonists in acute heart failure, and makes a lot of sense. Aldosterone levels are so high in acute heart failure that it is left relatively unchecked by ACE and angiotensin receptor blockers and does everything to promote a vicious cycle of vasoconstriction, salt and water retention, ischemia, arrhythmias, etc, and yet, nothing is recommended. Even in the guidelines, which the European Society of Cardiology is just coming out with, regarding earlier treatment of patients with aldosterone blockers, there’s nothing about in-hospitalization treatment.
Using an aldosterone blocker in the acute treatment of heart failure may be an unmet need. We are going to be starting a study to try this. This will be the second biomarker-guided heart failure trial, the first one was called ACAT Intravascular Atherosclerosis Treatment Evaluation (ACTIVATE),14 which will use copeptin to put the patients on a copeptin antagonist, called tolvaptan. This study will be called the Reduction in Events with Galectin-3 and Aldosterone Blockade in Acute Heart Failure (REGAL) trial. It will be a multicenter study in Europe and the United States; Dr. Boer will be very involved in this, I know. In the case of patients with acute heart failure, if they don’t have a contraindication and are not on an aldosterone blocker, their galectin-3 levels will be measured. If the levels are high, they will be placed on spironolactone or placebo, and the follow-up is looking for 90-day events.
Now, the interesting thing about this study, which is what a lot of people were worried about, is how you can keep a patient on a placebo for 90 days, since aldosterone blockers are indicated in those with ejection fractions under 35%? The answer is that we will include patients with ejection fractions over 35%. In other words, we will take mild systolic dysfunction and heart failure with preserved ejection fraction and enroll those patients.
Some others can comment, but there’s some decent data. I think Dr. Boer has some data on this, and some other scientists have data suggesting that diastolic dysfunction is, in part, associated with fibrosis and that galectin-3 may be a very important signal.15 We will get a chance to look at this. It will be a relatively easy study to do. For the primary endpoint, we’re going to look at a decrease in events compared to the placebo. So, I’m very excited about that as a heart-failure researcher.
The other question I am excited about answering is whether we can use galectin-3 as a predictor for a response to cardiac resynchronization therapy (CRT) and implantable cardioverter-defibrillator, especially these resynchronization devices that are undergoing a lot of change. They’re very expensive. We have a moving target for which patients we’re being reimbursed. The latest is that, if a patient has heart failure and a wide QRS, but not a left bundle branch block, he/she may no longer qualify for CRT or implantable cardioverter-defibrillator. Earlier, it was used for any patient with a wide QRS. Now, it’s just basically moving to the left bundle.
So, there are probably people in between who will do better, and there’s some early unpublished data, which we could talk about a little bit, from Boston Scientific, arising from the Multicenter Automatic Defibrillator Implantation Trial with Cardiac Resynchronization Therapy (MADIT-CRT) study,16 which showed that galectin-3 predicted adverse outcomes in patients despite optimal therapy. In a small number of patients thus far, it has been seen that if a high galectin-3 level was observed at the time of implantation, there was more of a reduction of events than that observed if a patient had low galectin-3 levels. This observation needs to be substantiated, but it certainly is very exciting.
Again, as a heart-failure and biomarker researcher, I’m very excited to try to integrate new biomarkers into panels that will complement each other, but in ways that allow us to separate patients out, guide institute treatment, and then bio-monitor those patients with the biomarker. So far, we haven’t seen a robust change in galectin-3 levels with treatment, but we’ll need to see as we go on. In any event, a high level puts you in a very important category that I think that we can address right now.
FoxP2 Media LLC is the publisher of The Medical Roundtable.
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A deadly chain reaction, on one condition
Story
DM was a 60-year-old woman with a history of granulomatosis polyangiitis controlled with cyclophosphamide. She was sent to the hospital as a direct admission by her nephrologist because of worsening renal function and the possibility that DM was suffering from uncontrolled vasculitis. DM was admitted to the hospital by Dr. Hospitalist 1. The history and physical documented that DM was generally weak, but otherwise without specific complaints.
The serum creatinine was 3.89 mg/dL, and coagulation studies were normal. DM’s comorbidities were numerous, including hypertension, coronary artery disease, peripheral vascular disease, and paroxysmal atrial fibrillation. The referring nephrologist had already written orders for a pulsed steroid protocol (Solu-Medrol intravenously for 3 days), in addition to arranging for a renal biopsy by interventional radiology (IR) the following day.
Dr. Hospitalist 1 wrote standard admission orders and made DM nothing per os after midnight. For venous thromboembolism (VTE) prophylaxis, Dr. Hospitalist 1 also wrote for DM to receive mechanical compression to her legs and to begin Lovenox 30 mg subcutaneously daily after the biopsy, only when OK with IR.
The next day, DM was seen in the morning by her nephrologist and Dr. Hospitalist 2 on rounds. Later that afternoon, DM underwent a right renal biopsy under CT guidance by IR. A small hematoma was noted immediately following the procedure. At 8 p.m. that night, DM received 30 mg of Lovenox subcutaneously.
Overnight, DM became tachycardic and complained of right flank pain. Her morning labs drawn at 5 a.m. found a significant drop in her blood count (Hgb, 6.1 mg/dL) and decline in her renal function (serum creatinine, 4.46 mg/dL). A repeat CT of the abdomen and pelvis found an enlarging perinephric hematoma. Dr. Hospitalist 2 immediately moved DM to the ICU and began supportive transfusions.
DM’s blood counts and renal function stabilized over the next 24-36 hrs. However, on the evening of hospital day 4 (ICU day 2), DM experienced shortness of breath followed quickly by a ventricular fibrillation arrest. Telemetry strips before the code demonstrated ST-elevation myocardial infarction. It took almost 45minutes of resuscitation, but DM regained her pulse. At this point, she was now intubated and critically ill. Cardiology was consulted, but given DM’s recent perinephric hematoma, it was felt that she would not tolerate antiplatelet or antithrombotic therapies. Subsequent echocardiogram demonstrated a severely damaged left ventricle from her MI. Even worse, DM went into acute renal failure and shock liver with coagulopathy.
After multiple discussions with the family in the ensuing week, care was ultimately withdrawn and DM passed away.
Complaint
The family understood the bleeding risk of a renal biopsy, but they were upset to learn that DM received blood thinners around the time of her procedure. DM had a previous bleed on Coumadin years earlier, and she even had a "Coumadin allergy" documented in the chart. A lawsuit was filed and both the hospital (employer of the nurses) and Dr. Hospitalist 1 were named in the suit. The complaint alleged that it was substandard for DM to have received Lovenox in this case and that the Lovenox caused the hemorrhage, which in turn led to a myocardial infarction and death.
Scientific principles
Granulomatosis polyangiitis increases the risk for venous and arterial thrombosis. Patients at risk for thrombosis benefit from prophylactic anticoagulation. However, bleeding is the primary complication of renal biopsy and anticoagulation increases that risk. Postbiopsy bleeding can occur into one of three sites: 1) the collecting system (leading to microscopic or gross hematuria); 2) underneath the renal capsule (leading to pressure tamponade and pain); or 3) into the perinephric space (leading to hematoma formation and a possibly large drop in hemoglobin). Most clinically significant bleeding is recognized within 12-24 hours of the biopsy, but bleeding may occur up to several days after the procedure. Anticoagulation should not be used for at least 12-24 hours postbiopsy, and if possible, withholding anticoagulants for a more prolonged period of up to 1 week may be preferable.
Complaint rebuttal and discussion
Discovery in this case confirmed that the original order by Dr. Hospitalist 1 was not transcribed into the medical administration record with any conditions, and IR was not contacted to approve the Lovenox prior to administration. The nurse who gave the Lovenox was simply following the incomplete order that existed on the administration record.
As a result, the hospital settled with the plaintiff early in the process; yet the plaintiff continued to assert that the order itself (whether it was followed properly or not) was substandard and Dr. Hospitalist 1 was also negligent. Dr. Hospitalist 1 defended her Lovenox order as being appropriate and reasonable because DM was at risk for VTE, the dose prescribed was reduced for renal impairment, and it was a conditional order that required approval by interventional radiology prior to medication administration. Dr. Hospitalist 1 was resolute that if her order had just been followed, DM would never have received the medication.
Conclusion
Hospitalists write conditional orders every day. In fact, all "PRN" orders are conditional and presume the use of nursing clinical judgment. However, some conditional orders are directed at other physicians or services (for example, "Discharge the patient if OK with surgery" or "Resume Coumadin if OK with orthopedics").
Often these orders are expedient and typically replace direct communication. But hospitalists should remember that such conditional orders trigger a potential act of commission with nursing as the communication "go-between." There was nothing unreasonable about the conditional order for Lovenox in this case per se. Yet, had this order not been written at all – the chain reaction that subsequently occurred may have been avoided altogether. The jury in this case returned a defense verdict in favor of the hospitalist.
Dr. Michota is director of academic affairs in the hospital medicine department at the Cleveland Clinic and medical editor of Hospitalist News. He has been involved in peer review both within and outside the legal system. Read past columns at ehospitalistnews.com/Lessons.
Story
DM was a 60-year-old woman with a history of granulomatosis polyangiitis controlled with cyclophosphamide. She was sent to the hospital as a direct admission by her nephrologist because of worsening renal function and the possibility that DM was suffering from uncontrolled vasculitis. DM was admitted to the hospital by Dr. Hospitalist 1. The history and physical documented that DM was generally weak, but otherwise without specific complaints.
The serum creatinine was 3.89 mg/dL, and coagulation studies were normal. DM’s comorbidities were numerous, including hypertension, coronary artery disease, peripheral vascular disease, and paroxysmal atrial fibrillation. The referring nephrologist had already written orders for a pulsed steroid protocol (Solu-Medrol intravenously for 3 days), in addition to arranging for a renal biopsy by interventional radiology (IR) the following day.
Dr. Hospitalist 1 wrote standard admission orders and made DM nothing per os after midnight. For venous thromboembolism (VTE) prophylaxis, Dr. Hospitalist 1 also wrote for DM to receive mechanical compression to her legs and to begin Lovenox 30 mg subcutaneously daily after the biopsy, only when OK with IR.
The next day, DM was seen in the morning by her nephrologist and Dr. Hospitalist 2 on rounds. Later that afternoon, DM underwent a right renal biopsy under CT guidance by IR. A small hematoma was noted immediately following the procedure. At 8 p.m. that night, DM received 30 mg of Lovenox subcutaneously.
Overnight, DM became tachycardic and complained of right flank pain. Her morning labs drawn at 5 a.m. found a significant drop in her blood count (Hgb, 6.1 mg/dL) and decline in her renal function (serum creatinine, 4.46 mg/dL). A repeat CT of the abdomen and pelvis found an enlarging perinephric hematoma. Dr. Hospitalist 2 immediately moved DM to the ICU and began supportive transfusions.
DM’s blood counts and renal function stabilized over the next 24-36 hrs. However, on the evening of hospital day 4 (ICU day 2), DM experienced shortness of breath followed quickly by a ventricular fibrillation arrest. Telemetry strips before the code demonstrated ST-elevation myocardial infarction. It took almost 45minutes of resuscitation, but DM regained her pulse. At this point, she was now intubated and critically ill. Cardiology was consulted, but given DM’s recent perinephric hematoma, it was felt that she would not tolerate antiplatelet or antithrombotic therapies. Subsequent echocardiogram demonstrated a severely damaged left ventricle from her MI. Even worse, DM went into acute renal failure and shock liver with coagulopathy.
After multiple discussions with the family in the ensuing week, care was ultimately withdrawn and DM passed away.
Complaint
The family understood the bleeding risk of a renal biopsy, but they were upset to learn that DM received blood thinners around the time of her procedure. DM had a previous bleed on Coumadin years earlier, and she even had a "Coumadin allergy" documented in the chart. A lawsuit was filed and both the hospital (employer of the nurses) and Dr. Hospitalist 1 were named in the suit. The complaint alleged that it was substandard for DM to have received Lovenox in this case and that the Lovenox caused the hemorrhage, which in turn led to a myocardial infarction and death.
Scientific principles
Granulomatosis polyangiitis increases the risk for venous and arterial thrombosis. Patients at risk for thrombosis benefit from prophylactic anticoagulation. However, bleeding is the primary complication of renal biopsy and anticoagulation increases that risk. Postbiopsy bleeding can occur into one of three sites: 1) the collecting system (leading to microscopic or gross hematuria); 2) underneath the renal capsule (leading to pressure tamponade and pain); or 3) into the perinephric space (leading to hematoma formation and a possibly large drop in hemoglobin). Most clinically significant bleeding is recognized within 12-24 hours of the biopsy, but bleeding may occur up to several days after the procedure. Anticoagulation should not be used for at least 12-24 hours postbiopsy, and if possible, withholding anticoagulants for a more prolonged period of up to 1 week may be preferable.
Complaint rebuttal and discussion
Discovery in this case confirmed that the original order by Dr. Hospitalist 1 was not transcribed into the medical administration record with any conditions, and IR was not contacted to approve the Lovenox prior to administration. The nurse who gave the Lovenox was simply following the incomplete order that existed on the administration record.
As a result, the hospital settled with the plaintiff early in the process; yet the plaintiff continued to assert that the order itself (whether it was followed properly or not) was substandard and Dr. Hospitalist 1 was also negligent. Dr. Hospitalist 1 defended her Lovenox order as being appropriate and reasonable because DM was at risk for VTE, the dose prescribed was reduced for renal impairment, and it was a conditional order that required approval by interventional radiology prior to medication administration. Dr. Hospitalist 1 was resolute that if her order had just been followed, DM would never have received the medication.
Conclusion
Hospitalists write conditional orders every day. In fact, all "PRN" orders are conditional and presume the use of nursing clinical judgment. However, some conditional orders are directed at other physicians or services (for example, "Discharge the patient if OK with surgery" or "Resume Coumadin if OK with orthopedics").
Often these orders are expedient and typically replace direct communication. But hospitalists should remember that such conditional orders trigger a potential act of commission with nursing as the communication "go-between." There was nothing unreasonable about the conditional order for Lovenox in this case per se. Yet, had this order not been written at all – the chain reaction that subsequently occurred may have been avoided altogether. The jury in this case returned a defense verdict in favor of the hospitalist.
Dr. Michota is director of academic affairs in the hospital medicine department at the Cleveland Clinic and medical editor of Hospitalist News. He has been involved in peer review both within and outside the legal system. Read past columns at ehospitalistnews.com/Lessons.
Story
DM was a 60-year-old woman with a history of granulomatosis polyangiitis controlled with cyclophosphamide. She was sent to the hospital as a direct admission by her nephrologist because of worsening renal function and the possibility that DM was suffering from uncontrolled vasculitis. DM was admitted to the hospital by Dr. Hospitalist 1. The history and physical documented that DM was generally weak, but otherwise without specific complaints.
The serum creatinine was 3.89 mg/dL, and coagulation studies were normal. DM’s comorbidities were numerous, including hypertension, coronary artery disease, peripheral vascular disease, and paroxysmal atrial fibrillation. The referring nephrologist had already written orders for a pulsed steroid protocol (Solu-Medrol intravenously for 3 days), in addition to arranging for a renal biopsy by interventional radiology (IR) the following day.
Dr. Hospitalist 1 wrote standard admission orders and made DM nothing per os after midnight. For venous thromboembolism (VTE) prophylaxis, Dr. Hospitalist 1 also wrote for DM to receive mechanical compression to her legs and to begin Lovenox 30 mg subcutaneously daily after the biopsy, only when OK with IR.
The next day, DM was seen in the morning by her nephrologist and Dr. Hospitalist 2 on rounds. Later that afternoon, DM underwent a right renal biopsy under CT guidance by IR. A small hematoma was noted immediately following the procedure. At 8 p.m. that night, DM received 30 mg of Lovenox subcutaneously.
Overnight, DM became tachycardic and complained of right flank pain. Her morning labs drawn at 5 a.m. found a significant drop in her blood count (Hgb, 6.1 mg/dL) and decline in her renal function (serum creatinine, 4.46 mg/dL). A repeat CT of the abdomen and pelvis found an enlarging perinephric hematoma. Dr. Hospitalist 2 immediately moved DM to the ICU and began supportive transfusions.
DM’s blood counts and renal function stabilized over the next 24-36 hrs. However, on the evening of hospital day 4 (ICU day 2), DM experienced shortness of breath followed quickly by a ventricular fibrillation arrest. Telemetry strips before the code demonstrated ST-elevation myocardial infarction. It took almost 45minutes of resuscitation, but DM regained her pulse. At this point, she was now intubated and critically ill. Cardiology was consulted, but given DM’s recent perinephric hematoma, it was felt that she would not tolerate antiplatelet or antithrombotic therapies. Subsequent echocardiogram demonstrated a severely damaged left ventricle from her MI. Even worse, DM went into acute renal failure and shock liver with coagulopathy.
After multiple discussions with the family in the ensuing week, care was ultimately withdrawn and DM passed away.
Complaint
The family understood the bleeding risk of a renal biopsy, but they were upset to learn that DM received blood thinners around the time of her procedure. DM had a previous bleed on Coumadin years earlier, and she even had a "Coumadin allergy" documented in the chart. A lawsuit was filed and both the hospital (employer of the nurses) and Dr. Hospitalist 1 were named in the suit. The complaint alleged that it was substandard for DM to have received Lovenox in this case and that the Lovenox caused the hemorrhage, which in turn led to a myocardial infarction and death.
Scientific principles
Granulomatosis polyangiitis increases the risk for venous and arterial thrombosis. Patients at risk for thrombosis benefit from prophylactic anticoagulation. However, bleeding is the primary complication of renal biopsy and anticoagulation increases that risk. Postbiopsy bleeding can occur into one of three sites: 1) the collecting system (leading to microscopic or gross hematuria); 2) underneath the renal capsule (leading to pressure tamponade and pain); or 3) into the perinephric space (leading to hematoma formation and a possibly large drop in hemoglobin). Most clinically significant bleeding is recognized within 12-24 hours of the biopsy, but bleeding may occur up to several days after the procedure. Anticoagulation should not be used for at least 12-24 hours postbiopsy, and if possible, withholding anticoagulants for a more prolonged period of up to 1 week may be preferable.
Complaint rebuttal and discussion
Discovery in this case confirmed that the original order by Dr. Hospitalist 1 was not transcribed into the medical administration record with any conditions, and IR was not contacted to approve the Lovenox prior to administration. The nurse who gave the Lovenox was simply following the incomplete order that existed on the administration record.
As a result, the hospital settled with the plaintiff early in the process; yet the plaintiff continued to assert that the order itself (whether it was followed properly or not) was substandard and Dr. Hospitalist 1 was also negligent. Dr. Hospitalist 1 defended her Lovenox order as being appropriate and reasonable because DM was at risk for VTE, the dose prescribed was reduced for renal impairment, and it was a conditional order that required approval by interventional radiology prior to medication administration. Dr. Hospitalist 1 was resolute that if her order had just been followed, DM would never have received the medication.
Conclusion
Hospitalists write conditional orders every day. In fact, all "PRN" orders are conditional and presume the use of nursing clinical judgment. However, some conditional orders are directed at other physicians or services (for example, "Discharge the patient if OK with surgery" or "Resume Coumadin if OK with orthopedics").
Often these orders are expedient and typically replace direct communication. But hospitalists should remember that such conditional orders trigger a potential act of commission with nursing as the communication "go-between." There was nothing unreasonable about the conditional order for Lovenox in this case per se. Yet, had this order not been written at all – the chain reaction that subsequently occurred may have been avoided altogether. The jury in this case returned a defense verdict in favor of the hospitalist.
Dr. Michota is director of academic affairs in the hospital medicine department at the Cleveland Clinic and medical editor of Hospitalist News. He has been involved in peer review both within and outside the legal system. Read past columns at ehospitalistnews.com/Lessons.
App use increased physical activity
People who used a smartphone pedometer app walked 22% more steps (or about half a mile) per day after 8 weeks than did people in a control group in a small, randomized, open-label study.
The 90 participants in rural western Ireland were older than 16 years and owned an Android smartphone, which they were asked to keep charged and to carry during waking hours. Investigators downloaded the app to all phones and calibrated it to each individual to record step counts accurately. All participants were given physical activity goals and information on the benefits of exercise.
In the first week, the app display was not visible while it recorded baseline activity data. Mean step counts in the first week were 5,138 steps/day in the control group and 4,365/day in the intervention group. That difference was not statistically significant, but the investigators still adjusted for it in final analyses, Dr. Liam G. Glynn and his associates reported in the British Journal of General Practice.
The intervention group was then showed the app’s features and settings and encouraged to interact with the app to help meet activity goals. The control group’s app continued to track steps without any interaction.
Among 40 people in the control group and 37 in the intervention group with follow-up data 7 weeks later, the daily counts decreased by 386 steps in the control group and increased by 1,631 steps in the intervention group (Br. J. Gen. Pract. 2014;64:e384-91).
Participants in both groups increased their walking initially, but only the intervention group maintained the increased activity, accounting for the step count difference between groups at 8 weeks, said Dr. Glynn, a general practice physician at the National University of Ireland, Galway.
The study used the Accupedo-Pro pedometer app because it included preestablished, desirable features such as automatic feedback and tracking of step counts and calories burned, visually appealing graphics of step count history, the ability to input goals, and feedback on goal achievement. The Accupedo-Pro app is available for iPhones and Android devices for $3.99. Hundreds of other activity-tracking apps of varying quality are available for free or for sale.
After researchers adjusted for factors unrelated to the study that may have increased step counts during the study period, they found that the mean daily count at baseline for the intervention group was 4,771 steps/day. The difference between the intervention and control groups by the end of 8 weeks was a mean increase of 1,029 steps/day favoring the app use, a 22% gain, compared with the intervention group’s baseline, Dr. Glynn reported.
That’s enough of a change to be clinically meaningful if it’s maintained, based on a large body of literature on exercise and health, he said. Dr. Glynn and his associates now are following app users in several European countries to monitor long-term health outcomes.
The current study was too small to show a difference in health measures such as blood pressure, weight, or body mass index. And it was too short to show whether or not apps embedded in phones can overcome one of the weak points of separate devices used solely as pedometers or activity trackers – namely, the tendency for many people to stop using them over time.
One in three people who owned a fitness tracker stopped using the device in the past year, mainly because they lost interest in tracking their activity level, according to a survey by International Data Corp.
Nonetheless, pedometers and other small hardware-based fitness trackers remain popular. Florida insurer AvMed recently announced that it will cover the cost of the Fitlinxx Pebble activity meter for Medicare Advantage members enrolled in the Walkadoo pedometer-based walking program run by MeYou Health.
Separate data suggest that, among mobile phone customers, 60% in the United States and 57% in Ireland have a smartphone, Dr. Glynn said, and that 90% of U.S. mobile phone users have their phone with them 24 hours a day. Theoretically, a smartphone pedometer app might get more use than a conventional pedometer because it doesn’t require carrying a separate piece of technology.
"This intervention is now firmly on my list (as a clinician) of options for patients to whom I am recommending increased physical activity," Dr. Glynn said in an interview.
He reported having no financial disclosures.
On Twitter @sherryboschert
People who used a smartphone pedometer app walked 22% more steps (or about half a mile) per day after 8 weeks than did people in a control group in a small, randomized, open-label study.
The 90 participants in rural western Ireland were older than 16 years and owned an Android smartphone, which they were asked to keep charged and to carry during waking hours. Investigators downloaded the app to all phones and calibrated it to each individual to record step counts accurately. All participants were given physical activity goals and information on the benefits of exercise.
In the first week, the app display was not visible while it recorded baseline activity data. Mean step counts in the first week were 5,138 steps/day in the control group and 4,365/day in the intervention group. That difference was not statistically significant, but the investigators still adjusted for it in final analyses, Dr. Liam G. Glynn and his associates reported in the British Journal of General Practice.
The intervention group was then showed the app’s features and settings and encouraged to interact with the app to help meet activity goals. The control group’s app continued to track steps without any interaction.
Among 40 people in the control group and 37 in the intervention group with follow-up data 7 weeks later, the daily counts decreased by 386 steps in the control group and increased by 1,631 steps in the intervention group (Br. J. Gen. Pract. 2014;64:e384-91).
Participants in both groups increased their walking initially, but only the intervention group maintained the increased activity, accounting for the step count difference between groups at 8 weeks, said Dr. Glynn, a general practice physician at the National University of Ireland, Galway.
The study used the Accupedo-Pro pedometer app because it included preestablished, desirable features such as automatic feedback and tracking of step counts and calories burned, visually appealing graphics of step count history, the ability to input goals, and feedback on goal achievement. The Accupedo-Pro app is available for iPhones and Android devices for $3.99. Hundreds of other activity-tracking apps of varying quality are available for free or for sale.
After researchers adjusted for factors unrelated to the study that may have increased step counts during the study period, they found that the mean daily count at baseline for the intervention group was 4,771 steps/day. The difference between the intervention and control groups by the end of 8 weeks was a mean increase of 1,029 steps/day favoring the app use, a 22% gain, compared with the intervention group’s baseline, Dr. Glynn reported.
That’s enough of a change to be clinically meaningful if it’s maintained, based on a large body of literature on exercise and health, he said. Dr. Glynn and his associates now are following app users in several European countries to monitor long-term health outcomes.
The current study was too small to show a difference in health measures such as blood pressure, weight, or body mass index. And it was too short to show whether or not apps embedded in phones can overcome one of the weak points of separate devices used solely as pedometers or activity trackers – namely, the tendency for many people to stop using them over time.
One in three people who owned a fitness tracker stopped using the device in the past year, mainly because they lost interest in tracking their activity level, according to a survey by International Data Corp.
Nonetheless, pedometers and other small hardware-based fitness trackers remain popular. Florida insurer AvMed recently announced that it will cover the cost of the Fitlinxx Pebble activity meter for Medicare Advantage members enrolled in the Walkadoo pedometer-based walking program run by MeYou Health.
Separate data suggest that, among mobile phone customers, 60% in the United States and 57% in Ireland have a smartphone, Dr. Glynn said, and that 90% of U.S. mobile phone users have their phone with them 24 hours a day. Theoretically, a smartphone pedometer app might get more use than a conventional pedometer because it doesn’t require carrying a separate piece of technology.
"This intervention is now firmly on my list (as a clinician) of options for patients to whom I am recommending increased physical activity," Dr. Glynn said in an interview.
He reported having no financial disclosures.
On Twitter @sherryboschert
People who used a smartphone pedometer app walked 22% more steps (or about half a mile) per day after 8 weeks than did people in a control group in a small, randomized, open-label study.
The 90 participants in rural western Ireland were older than 16 years and owned an Android smartphone, which they were asked to keep charged and to carry during waking hours. Investigators downloaded the app to all phones and calibrated it to each individual to record step counts accurately. All participants were given physical activity goals and information on the benefits of exercise.
In the first week, the app display was not visible while it recorded baseline activity data. Mean step counts in the first week were 5,138 steps/day in the control group and 4,365/day in the intervention group. That difference was not statistically significant, but the investigators still adjusted for it in final analyses, Dr. Liam G. Glynn and his associates reported in the British Journal of General Practice.
The intervention group was then showed the app’s features and settings and encouraged to interact with the app to help meet activity goals. The control group’s app continued to track steps without any interaction.
Among 40 people in the control group and 37 in the intervention group with follow-up data 7 weeks later, the daily counts decreased by 386 steps in the control group and increased by 1,631 steps in the intervention group (Br. J. Gen. Pract. 2014;64:e384-91).
Participants in both groups increased their walking initially, but only the intervention group maintained the increased activity, accounting for the step count difference between groups at 8 weeks, said Dr. Glynn, a general practice physician at the National University of Ireland, Galway.
The study used the Accupedo-Pro pedometer app because it included preestablished, desirable features such as automatic feedback and tracking of step counts and calories burned, visually appealing graphics of step count history, the ability to input goals, and feedback on goal achievement. The Accupedo-Pro app is available for iPhones and Android devices for $3.99. Hundreds of other activity-tracking apps of varying quality are available for free or for sale.
After researchers adjusted for factors unrelated to the study that may have increased step counts during the study period, they found that the mean daily count at baseline for the intervention group was 4,771 steps/day. The difference between the intervention and control groups by the end of 8 weeks was a mean increase of 1,029 steps/day favoring the app use, a 22% gain, compared with the intervention group’s baseline, Dr. Glynn reported.
That’s enough of a change to be clinically meaningful if it’s maintained, based on a large body of literature on exercise and health, he said. Dr. Glynn and his associates now are following app users in several European countries to monitor long-term health outcomes.
The current study was too small to show a difference in health measures such as blood pressure, weight, or body mass index. And it was too short to show whether or not apps embedded in phones can overcome one of the weak points of separate devices used solely as pedometers or activity trackers – namely, the tendency for many people to stop using them over time.
One in three people who owned a fitness tracker stopped using the device in the past year, mainly because they lost interest in tracking their activity level, according to a survey by International Data Corp.
Nonetheless, pedometers and other small hardware-based fitness trackers remain popular. Florida insurer AvMed recently announced that it will cover the cost of the Fitlinxx Pebble activity meter for Medicare Advantage members enrolled in the Walkadoo pedometer-based walking program run by MeYou Health.
Separate data suggest that, among mobile phone customers, 60% in the United States and 57% in Ireland have a smartphone, Dr. Glynn said, and that 90% of U.S. mobile phone users have their phone with them 24 hours a day. Theoretically, a smartphone pedometer app might get more use than a conventional pedometer because it doesn’t require carrying a separate piece of technology.
"This intervention is now firmly on my list (as a clinician) of options for patients to whom I am recommending increased physical activity," Dr. Glynn said in an interview.
He reported having no financial disclosures.
On Twitter @sherryboschert
ALS ice bucket challenge: It’s hard to argue with success
The ALS ice bucket challenge has taken the social media world by storm and surprised many by how fast and far it has spread. People simply make a video of themselves dumping a bucket of ice water on their heads and then post it on a social media site and challenge others to do the same within 24 hours or make a donation to ALS research (or both).
The stunt, which began early in the summer as a challenge unrelated to amyotrophic lateral sclerosis, has resonated with many people in the dog days of summer and has been helped by many celebrities taking up the challenge. It became linked to ALS when Peter Frates, a 29-year-old man with the disease, took the challenge – albeit by nodding his head to the song "Ice Ice Baby" instead of having ice water dumped on him – and asked others to do the same.
According to the ALS Association, as of Aug. 19, existing donors and more than 450,000 new donors have contributed $22.9 million since July 29, compared with $1.9 million during the same period last year. The ALS has a four-out-of-four stars rating on Charity Navigator, and an overall score of 90.73 out of 100. Overall, 72% of its expenses are spent on the programs and services it delivers, 11% on administration, and 17% on fundraising.
Some critics have suggested that the stunt promotes click and post activism, keeping people from doing real activism, or is "narcissism masked as altruism," but most people have embraced it as fun for a good cause.
I asked a few Clinical Neurology News editorial advisory board members to weigh in:
• Dr. Richard J. Caselli, professor of neurology at the Mayo Clinic, Scottsdale, Ariz.: "If it is raising money for ALS research, what’s not to like? Not everyone was destined to be a molecular biologist or clinical trialist, and this gives people a way to contribute that seems to be culturally in synch with the ‘social media’ community. ... The ice water is an interesting twist in that it implies that if you turn a blind eye to this cause you should punish yourself, and I suspect many people harbor feelings of at least slight guilt when they feel they are not contributing to worthwhile needs."
• Matthew Huentelman, Ph.D., associate professor of neurogenomics at the Translational Genomics Research Institute, Phoenix: "If a campaign works (and doesn’t harm) then it is hard to argue against. I think that any awareness campaign that actually gets a response from the White House has probably been a useful one. President Obama confirmed he would be donating but not doing the ice bucket thing. ... I suspect that a lot of research foundations are going to be having ‘tough’ conversations at this month’s board meetings as they compare their awareness and fundraising attempts to the simple ALS ice bucket challenge. It just demonstrates to all of us again that social media is relevant for both spreading the word and getting results. There are a few keys from this too: (1) visual "stuff" matters – short video clips is now how the world communicates; (2) challenging your friends/colleagues by name is important, too – it sort of forces a response from them; and (3) celebs are still key to pushing something viral in a truly short period of time."
(While you contemplate taking the ice bucket challenge, you might as well visit Dr. Huentelman’s social media project, MindCrowd, a site leveraging social media to recruit participants into a brain research study.)
The ALS ice bucket challenge has taken the social media world by storm and surprised many by how fast and far it has spread. People simply make a video of themselves dumping a bucket of ice water on their heads and then post it on a social media site and challenge others to do the same within 24 hours or make a donation to ALS research (or both).
The stunt, which began early in the summer as a challenge unrelated to amyotrophic lateral sclerosis, has resonated with many people in the dog days of summer and has been helped by many celebrities taking up the challenge. It became linked to ALS when Peter Frates, a 29-year-old man with the disease, took the challenge – albeit by nodding his head to the song "Ice Ice Baby" instead of having ice water dumped on him – and asked others to do the same.
According to the ALS Association, as of Aug. 19, existing donors and more than 450,000 new donors have contributed $22.9 million since July 29, compared with $1.9 million during the same period last year. The ALS has a four-out-of-four stars rating on Charity Navigator, and an overall score of 90.73 out of 100. Overall, 72% of its expenses are spent on the programs and services it delivers, 11% on administration, and 17% on fundraising.
Some critics have suggested that the stunt promotes click and post activism, keeping people from doing real activism, or is "narcissism masked as altruism," but most people have embraced it as fun for a good cause.
I asked a few Clinical Neurology News editorial advisory board members to weigh in:
• Dr. Richard J. Caselli, professor of neurology at the Mayo Clinic, Scottsdale, Ariz.: "If it is raising money for ALS research, what’s not to like? Not everyone was destined to be a molecular biologist or clinical trialist, and this gives people a way to contribute that seems to be culturally in synch with the ‘social media’ community. ... The ice water is an interesting twist in that it implies that if you turn a blind eye to this cause you should punish yourself, and I suspect many people harbor feelings of at least slight guilt when they feel they are not contributing to worthwhile needs."
• Matthew Huentelman, Ph.D., associate professor of neurogenomics at the Translational Genomics Research Institute, Phoenix: "If a campaign works (and doesn’t harm) then it is hard to argue against. I think that any awareness campaign that actually gets a response from the White House has probably been a useful one. President Obama confirmed he would be donating but not doing the ice bucket thing. ... I suspect that a lot of research foundations are going to be having ‘tough’ conversations at this month’s board meetings as they compare their awareness and fundraising attempts to the simple ALS ice bucket challenge. It just demonstrates to all of us again that social media is relevant for both spreading the word and getting results. There are a few keys from this too: (1) visual "stuff" matters – short video clips is now how the world communicates; (2) challenging your friends/colleagues by name is important, too – it sort of forces a response from them; and (3) celebs are still key to pushing something viral in a truly short period of time."
(While you contemplate taking the ice bucket challenge, you might as well visit Dr. Huentelman’s social media project, MindCrowd, a site leveraging social media to recruit participants into a brain research study.)
The ALS ice bucket challenge has taken the social media world by storm and surprised many by how fast and far it has spread. People simply make a video of themselves dumping a bucket of ice water on their heads and then post it on a social media site and challenge others to do the same within 24 hours or make a donation to ALS research (or both).
The stunt, which began early in the summer as a challenge unrelated to amyotrophic lateral sclerosis, has resonated with many people in the dog days of summer and has been helped by many celebrities taking up the challenge. It became linked to ALS when Peter Frates, a 29-year-old man with the disease, took the challenge – albeit by nodding his head to the song "Ice Ice Baby" instead of having ice water dumped on him – and asked others to do the same.
According to the ALS Association, as of Aug. 19, existing donors and more than 450,000 new donors have contributed $22.9 million since July 29, compared with $1.9 million during the same period last year. The ALS has a four-out-of-four stars rating on Charity Navigator, and an overall score of 90.73 out of 100. Overall, 72% of its expenses are spent on the programs and services it delivers, 11% on administration, and 17% on fundraising.
Some critics have suggested that the stunt promotes click and post activism, keeping people from doing real activism, or is "narcissism masked as altruism," but most people have embraced it as fun for a good cause.
I asked a few Clinical Neurology News editorial advisory board members to weigh in:
• Dr. Richard J. Caselli, professor of neurology at the Mayo Clinic, Scottsdale, Ariz.: "If it is raising money for ALS research, what’s not to like? Not everyone was destined to be a molecular biologist or clinical trialist, and this gives people a way to contribute that seems to be culturally in synch with the ‘social media’ community. ... The ice water is an interesting twist in that it implies that if you turn a blind eye to this cause you should punish yourself, and I suspect many people harbor feelings of at least slight guilt when they feel they are not contributing to worthwhile needs."
• Matthew Huentelman, Ph.D., associate professor of neurogenomics at the Translational Genomics Research Institute, Phoenix: "If a campaign works (and doesn’t harm) then it is hard to argue against. I think that any awareness campaign that actually gets a response from the White House has probably been a useful one. President Obama confirmed he would be donating but not doing the ice bucket thing. ... I suspect that a lot of research foundations are going to be having ‘tough’ conversations at this month’s board meetings as they compare their awareness and fundraising attempts to the simple ALS ice bucket challenge. It just demonstrates to all of us again that social media is relevant for both spreading the word and getting results. There are a few keys from this too: (1) visual "stuff" matters – short video clips is now how the world communicates; (2) challenging your friends/colleagues by name is important, too – it sort of forces a response from them; and (3) celebs are still key to pushing something viral in a truly short period of time."
(While you contemplate taking the ice bucket challenge, you might as well visit Dr. Huentelman’s social media project, MindCrowd, a site leveraging social media to recruit participants into a brain research study.)
The Medical Roundtable: Hypertension in Pregnancy
That’s one of the reasons we’re having this conversation. One of the more controversial issues in medicine has been that of hypertension in pregnant women. The guidelines have not changed much in the last 50 years, although some effort to update these guidelines has been made recently. Today, we discuss the following: (1) The definition of elevated BP in pregnancy: is it too complicated? (2) Indications for therapy; should you wait until the BP increases to levels of 160/105 to 110 mm Hg? Is there any danger in allowing the systolic BP to remain elevated for a few months in a pregnant woman? (3) The indications for interruption of pregnancy; should we begin treatment earlier and continue to use the drugs that have been suggested over the years? During pregnancy, hypertension is typically classified as chronic hypertension (pre-existing or onset prior to 20 weeks gestation), gestational hypertension, preeclampsia, or preeclampsia superimposed on chronic hypertension.
I’m Dr. Marvin Moser, Clinical Professor of Medicine at Yale. We have with us Dr. Phyllis August, Professor of Research and Medicine and OB/GYN at Cornell Weill Medical College; Vesna Garovic, a Professor of Medicine at the Mayo Clinic who has done a great deal of work on hypertension in pregnancy; and Dr. Carl Rose, Associate Professor of Maternal-Fetal Medicine at the Mayo Clinic, to discuss this controversial subject.
Dr. August, let’s start with you. What about the definition of hypertension? We have a very complicated list of definitions of hypertension in pregnancy; do you want to review some of those? Should we simplify the criteria for clinicians?
Dr. August: I think we need to distinguish between the diagnostic category and the definition of hypertension. The definition of hypertension for the general, non-pregnant population is not very different from that for pregnant women. Obstetricians speak about mild hypertension in pregnancy, which they define as a systolic pressure of 140 to 150 mm Hg and diastolic pressure of 90 to 109 mm Hg, and then severe hypertension. There are 2 categories for hypertension: severe hypertension is a pressure of 160/110 mm Hg and above, and mild to moderate hypertension is a pressure below that level. The diagnosis of hypertension is made at a pressure of 140/90 mm Hg and above, so really, it’s not very different from Stages 1 and 2 of essential hypertension outlined in the last Joint National Committee report.1
Preeclampsia, preeclampsia superimposed on chronic hypertension, chronic hypertension alone, and gestational hypertension are the diagnostic categories within which you can have either mild to moderate or severe hypertension.
Dr. Moser: Do we need all these designations? I know that the pathophysiology of preeclampsia is different from that of essential hypertension, but are the definitions helpful for the clinician? What’s the difference, for example, if you have someone with chronic hypertension who becomes pregnant? What if you have someone with pre-eclampsia superimposed on chronic hypertension, and you have these 4 categories. Are they helpful? Does this definition affect therapy?
Dr. August: They are helpful because what we really need to identify is the condition of the woman who, because of the pregnancy, is either developing new hypertension, or that of a woman who had hypertension before, but because of the pregnancy, her hypertension is worsening. That situation can change quickly, leading to serious maternal vmorbidity and fetal morbidity. This also helps to identify women who really need to be watched closely and addressed in a different way from someone who, at the beginning of pregnancy, had a pressure of 150/100 mm Hg and has the same pressure even at mid-pregnancy. I think the diagnostic categories are useful, and the fact that they’ve been used for many decades supports their effectiveness. They’re not perfect, but they are useful.
Dr. Moser: Dr. Rose, do you want to add to that?
Dr. Rose: As an obstetrician, I would suggest that these categories allow us to communicate with one another using common terminology that we collectively understand. It also influences the obstetric management of these patients.
Dr. Garovic: It is likely that young women who don’t see a physician and present with a BP of 150/100 mm Hg when they are pregnant, have had hypertension for a longer period, which has been asymptomatic and subclinical and that it has been brought to the attention of the clinician only due to the pregnancy.
Having said that, I’m not sure that it helps that much with respect to treatment because target levels at which BP treatment is started are decreasing, especially in the tertiary centers. My approach is to treat a pregnant woman with a documented systolic BP of 150 mm Hg on at least 2 occasions, whether symptomatic or asymptomatic and at risk for preeclampsia or not.
Dr. Moser: In the last American Society of Hypertension recommendations,2 it was clearly stated that the level of the BP should guide treatment and the decision of when to interrupt or deliver the pregnancy. So, if it is the level of BP that the clinician is following, why do we need sub-designations? In other words, if the woman has chronic hypertension to start with, you’re obviously going to try and keep the systolic BP below 140 mm Hg. If she develops hypertension in the first trimester or second trimester, which is a rare occurrence, you’re going to reduce the BP. If she develops hypertension in the third trimester with or without proteinuria, for example, you’re going to treat it. So, why don’t we simplify this and treat the BP without 4 or 5 definitions? Of course, if the BP rises and there is proteinuria in the third trimester, other options will also need to be considered. Also, proteinuria in the second trimester is an indication of preeclampsia.
Dr. August: In my experience, if you have a patient who has a BP reading of 120/80 mm Hg at the start of pregnancy, and then at 20 weeks, the BP is 150/100 mm Hg, even with no proteinuria, you have to be very worried about the patient because she’s developing either superimposed preeclampsia or gestational hypertension, until proven otherwise. That’s different from a BP of 150/100 mm Hg that was stable and started out that way at 8 weeks of pregnancy, and then at 20 weeks, it still is 150/100 mm Hg. There has been no change, and no evidence for an evolving process that is potentially dangerous to the mother and fetus, so I would disagree that it’s just a number.
Dr. Moser: How would you treat the patient differently, Dr. August?
Dr. August: If a woman had a clear, well-documented pressure of 110 to 120/70 to 80 mm Hg early in pregnancy and then in the second trimester and developed mild to moderate or Stage 1 hypertension, I would make sure to check all her laboratory data and rule out preeclampsia, but I would be very worried that she was developing a pregnancy-related disorder like pre-eclampsia or gestational hypertension, and I would examine her very frequently.
Dr. Moser: But would you treat her BP?
Dr. August: I would probably treat her BP if it was 150/95 to 99 mm Hg. Even though the guidelines say 160 mm Hg, 150 mm Hg is close to 160 mm Hg and since the patient’s pressure is currently at 150 mm Hg, it may increase to 160 mm Hg in an hour from now when the patient is a little more stressed and uncomfortable; therefore, 150 mm Hg is my cutoff.
Dr. Moser: Consider this: the normal systolic pressure of a pregnant woman is 110 mm Hg, 120 mm Hg, or even lower sometimes, and even in the second and third trimester, it shouldn’t be more than 120 mm Hg, and 130 mm Hg at the most. Now, if a woman’s pressure exceeds the 140/90 mm Hg cutoff of hypertension, why do obstetricians wait until the level increases to 150 mm Hg, or as you said, 160 mm Hg?
Dr. August: They wait because they think lowering the BP too much might compromise the placental perfusion.
Dr. Moser: Dr. Garovic or Dr. Rose, can you comment on the concept that an elevated systolic pressure for a couple of months in pregnancy isn’t going to do any harm?
Dr. Rose: I agree with Dr. August that the pathophysiology of the processes is different. In other words, I do not believe that we should simply treat hypertension and categorize all the accompanying processes as a similar prenatal complication. If a mother develops new-onset hypertension late in pregnancy, certainly this represents a different clinical scenario from one who develops hypertension at 18 weeks of gestation, although implications for the pregnancy may ultimately be similar.
Dr. August: But I would argue that a woman who develops hypertension at 18 weeks and didn’t have it at 12 weeks is at a more serious risk for preterm birth than the woman who develops hypertension in the third trimester.
Dr. Moser: Let me argue on the other side again. Such patients are at risk, but what are you going to do about the risk? You’re going to check some enzymes and chemistries, etc, but what is the only thing that you might do to reduce the risk of progression of hypertension or a small placenta, which may be a result of infarcts from elevated BP? I’m trying to determine whether just lowering the BP, even though the pathophysiology is different, might prevent progression of hypertension. I know it may not prevent the progression of preeclampsia, but early treatment might prevent or delay interruption of pregnancy, based upon the criteria of an elevated BP.
Dr. Garovic: I just want to clarify the point that I was discussing earlier. A BP of 150/100 mm Hg at 21 weeks’ gestation may represent a significantly elevated BP, as the patient’s BP, at that time of pregnancy, should be even lower than her pre-pregnancy levels. I would not treat somebody with a BP of 150/100 mm Hg based on a single office reading for the same reason that we may not treat hypertension based on a single office reading in the general population. However, if I have enough evidence that a patient has sustained hypertension, especially in the second trimester when the BP should be lower than non-pregnant levels, I will treat that patient. Treatment is given after a 6-hour BP reading or nurse-monitored BP readings over a 30-minute to 1-hour period to generate enough evidence to show that BP is certainly steadily elevated.
I would like to discuss a recent patient: she was a 36-year-old woman with a BP of 150/100 mm Hg. It was her first pregnancy, and she was approximately 12 weeks pregnant. She was referred to us from one of the regional clinics close to Rochester. She underwent a retroperitoneal ultrasound, which showed bilateral renal artery stenosis/fibromuscular secondary to fibromuscular dysplasia. So, she had a BP of 150/100 mm Hg, but by the time she saw us, her systolic pressure was 160 to 170 mm Hg and diastolic pressure was in the 100s range. Dr. Rose and I aggressively treated her with 300 mg labetalol twice a day and nifedipine once a day; her BP effectively was reduced to 120 to 130 mm Hg systolic pressure and 70 to 80 mm Hg diastolic pressure, and she delivered a full-term baby boy at 38 gestational weeks.
Dr. August: Let me ask you a question: did she really have renovascular hypertension? Was she successfully revascularized and did her blood pressure normalize after revascularization?
Dr. Garovic: At 6 months post-partum, she underwent a renal angiogram with bilateral angioplasties with a subsequent normalization of her BP. She remains normotensive, when off BP medications.
Dr. Moser: Do you believe that if we treat elevated BP early, we might delay or prevent iatrogenic preterm deliveries?
Dr. August: Yes, I think your point is that if somebody in the third trimester has preeclampsia or gestational hypertension and severe hypertension, and you lower their BP and, if all other parameters are normal, the baby is fine, and the mother’s platelet count is normal, you can prevent her from having a preterm birth. You can extend the pregnancy by preventing the BP from reaching levels that are too dangerous and thus require delivery.
Dr. August: I don’t think there’s any such strong evidence, but there are several issues to consider. One is that you need to weigh the risks and benefits. We don’t have convincing data on the effects, except the hemodynamic effects, of the drugs on the baby’s neurologic development and organ development. We have certain drugs that we think are safe, but have they been rigorously evaluated? Can we say with a 100% certainty that these drugs have absolutely no adverse effects on fetal growth and development? No, we can’t.
During pregnancy, we avoid exposure to any drug. The question is “what are the risks of treating mild hypertension and what are the benefits?” The treatment benefits to the mother maybe fairly small at 140/90 mm Hg. The risks to the baby are not fully known yet. Hemodynamically, we don’t know that the placental blood flow is being compromised. The data that suggest that smaller babies are a result of lowering the BP are very poor. However, you have to think that it’s probably better to use as few medications as possible during pregnancy for those reasons. Dr. Rose, I’d like to hear your opinion on this.
Dr. Rose: I would concur with Dr. August. Although Peter von Dadelszen’s 2002 metaanalysis3 suggests an association between BP control and fetal growth restriction, the more recent systematic review from Abalos4 suggests that treatment of chronic hypertension during pregnancy for lowering the BPs to thresholds lower than historically considered for therapy, should have a very small effect on neonatal birth weight.4
Dr. Moser: Maybe, some newborns born of hypertensive women are smaller because of the placental infarcts.
Dr. August: It is entirely plausible that hypertension contributes to placental pathology; The question of which is worse—mild hypertension or antihypertensive therapy—has simply not been adequately studied either. It’s just the general principle of whether you can avoid using a medication during pregnancy; if you can, you avoid it, whatever be the medication.
Dr. Garovic: I don’t know whether Dr. Rose and Dr. August would agree, but that meta-analysis3 has one important limitation that is hardly ever addressed. It was published in 2002; so, basically, it included studies published before 2000 when doctors were even more reluctant to treat hypertension. Who was getting treated then? It was likely severely hypertensive women and those with diabetes and other risk factors that are associated with an increased risk for intrauterine growth restriction from the beginning of their pregnancies. So, there may have been an initial selection bias about whom to treat. Therefore, intrauterine growth restriction in these women is likely, at least in part, related to their underlying comorbidities.
Dr. August: I completely agree with Dr. Garovic about that, and yes, I think you make a very good point.
Dr. Moser: To summarize this particular part of the discussion, all of you would agree that treating a patient with a BP > 140/90 mm Hg, even though that’s the definition of hypertension, may not be a good idea because the use of any medication in pregnancy is to be avoided, if possible. I believe that 140/90 mm Hg is an abnormal BP in a pregnant woman, whether it’s at the beginning of pregnancy or later on at 20 weeks or 30 weeks of gestation. I would favor treatment and lowering of BP slowly, because I don’t think the evidence showing fetal harm is very strong. The general consensus, however, of the experts thus far is that they are reluctant to treat a patient until the pressure reaches 150/100 or 155/100 mm Hg.
Dr. August: Well, it’s toward 150 mm Hg. One thing I can say with certainty is that we don’t have good data. We don’t have data to indicate that that treating a pressure of 140/90 mm Hg is harmful, nor do we have good data to show that treating mild hypertension is beneficial.
Dr. Garovic: I don’t know whether current theories would agree with that, but if a young patient (say about 28 years old) without any risk factors has a steady elevation of BP above 140/90 mm Hg, and I see her when she is 12 weeks pregnant, ie, early in pregnancy, I will treat her and follow-up her BP closely.
Dr. August: I agree with that.
Dr. Garovic: Again, I don’t think that it is a wise decision to treat hypertension based on a single BP reading. For me, a steady BP above 140/90 mm Hg in a young patient is an indication for treatment. We are trying to identify these patients very early and keep their BPs at 130/80 mm Hg throughout their pregnancies.
Dr. August: I would agree with that.
Dr. Moser: Would all of you agree that if a woman came in pregnant with chronic hypertension on medication, the medication should be continued, except for agents that effect the renin-angiotensin system, with the caveat that in the first trimester, you might have to lower the dosage because the pressures may be lower?
Dr. August: Most of the time, we do that. We don’t stop all the medications. We follow-up the patients closely. We see if the pregnancy has caused a decrease in BP. If the patient’s BP is 110/70, we would consider reducing the BP medications; we keep many women on medications during pregnancy, as long as they’re safe under them.
Dr. Moser: But you’d keep them on a diuretic or calcium channel blocker?
Dr. August: I would choose nifedipine because there’s more data about nifedipine.
Dr. Garovic: I agree with that.
Dr. August: I think amlodipine is safe, but unfortunately, there aren’t a lot of data on it. I have used verapamil; there are some data on it, although not comparable to the data on nifedipine.
Dr. Garovic: Verapamil also acts faster than amlodipine: it starts working earlier.
Dr. Moser: What about the continual use of diuretics, for example?
Dr. August: I continue administering them, particularly in patients with salt-sensitive hypertension. It is often possible to lower the dose during pregnancy if blood pressure decreases. I stop spironolactone but not hydrochlorothiazide. I don’t think there are a lot of data on chlorthalidone in pregnancy.
Dr. Moser: Dr. Rose, would you agree that if a person with known hypertension came in on medication, you tend to continue it, with the caveat, as Dr. August said, that if the pressure reduced, which it does in the first trimester, you might have to adjust the dosage downward, and, of course, never continue an angiotensin-converting-enzyme inhibitor, angiotensin receptor blocker, or renin inhibitor because of damage to the fetus?
Dr. Rose: Absolutely. During the second trimester, when the physiologic fall in BP occurs, one may need to discontinue medications in some patients, anticipating that therapy will be resumed later in gestation during the third trimester when BPs begin to rise.
Dr. Garovic: We are now trying to conduct a population-based study and see the effects of that “short” duration of hypertension in pregnancy with respect to cardiovascular risk later in life. Chances are that hypertension of any duration may induce vascular damage. For example, magnetic resonance imaging studies of the brain in women with eclampsia showed vasogenic edema involving the posterior circulation, which, with neurological signs and symptoms, was consistent with the diagnosis of posterior reversible encephalopathy syndrome. Follow-up studies of these patients have suggested that permanent cerebrovascular damage of the brain may occur in some of them.5,6 These changes may have some long-term effects on their neurological health and cognitive functioning later in life.
Dr. Moser: So, you’re convinced that a BP of 150 or 160 mm Hg, even for just 4 or 5 months in a young woman, might produce some long-term vascular changes?
Dr. Garovic: I think that there is a high possibility for that. Again, we don’t have data to support it, but the absence of evidence is not the evidence of absence. I would be delighted to see a study following up these women after their affected pregnancies. A paper published in the Journal of American College of Obstetrics and Gynecology7 indicated that women with a history of eclampsia have self-reported poor cognitive functioning years after their pregnancies. So, preeclampsia and brain neurological deficit are concerning conditions, and we don’t know whether they are related to only the BP or some other mechanisms. For example, endothelial dysfunction, which is a systemic condition in pre-eclamptic pregnancy, may actually facilitate any kind of vascular damage induced by high BPs.
Dr. Moser: There is evidence of endothelial dysfunction in hypertension too. Drs. August and Rose, would you agree or disagree that systolic BPs of 150 or 160 mm Hg for 4 or 5 months can produce permanent vascular changes?
Dr. August: I wouldn’t rule it out. It could happen in some people, and maybe there’s some heterogeneity; some might be able to tolerate it with impunity, but it may be more dangerous in people with other vascular risk factors or older individuals. High BP for 4 to 6 months is not very good.
Dr. Rose: I would agree. I think that at this point, we don’t have substantive data that speak one way or the other. But, it certainly seems very reasonable.
Dr. Moser: Yes, in some of the hypertension studies done in pregnant women, it would appear that if you treat early, the benefit is greater. But as you say, the data are certainly not compelling.
Since we don’t completely agree on when you should start treatment, although I think there’s a tendency toward earlier intervention, perhaps we should discuss what medicines should be used now. Obstetricians have been using alpha methyldopa and hydralazine for many years, because they’re comfortable with them and because studies have shown that they’re well tolerated. All of us in the hypertension field, however, know that these may not be the most effective drugs, and if you use them and the pressure keeps increasing, there’s a tendency for pregnancy interruption. What about changing the treatment algorithms, even though, as Dr. August has pointed out many times, there is little evidence of long-term outcomes with some of the newer drugs. Except for the angiotensin-converting–enzyme inhibitors and the angiotensin receptor blockers, there is very little evidence of fetal problems with beta blockers, although there is a report of smaller babies, but that was questionable as obstetricians are reluctant to use beta blockers, calcium channel blockers, or diuretics, partly because of lack of experience and possible litigation.
Dr. Rose: We are a relatively conservative group.
Dr. August: We use labetalol a lot. I think everybody’s happy with labetalol, which is an alpha-beta blocker. It’s reasonably effective, so I think that’s become the drug that everybody reaches for first, to treat hypertension in pregnancy, and I would say the next is nifedipine. I just got an E-mail today from a patient who I started administering nifedipine to, and she’s already complaining of swollen ankles and headache. You tend to get more side effects from nifedipine than labetalol, even though it may be more effective. Methyldopa is not the best drug, but it does work in pregnancy. There’s some evidence that sympathetic nervous system activity is part of the pathogenesis of preeclampsia, and I’ve seen methyldopa work. It makes people tired, which means that they don’t do much and spend a lot of time resting which is not necessarily bad.
Dr. Moser: Oh, yes, and depressed.
Dr. August: But, I’ve written a few prescriptions for methyldopa in the last 12 months. It’s not my first choice; I’d say it’s my third. I don’t initiate diuretics for preeclampsia or gestational hypertension. However, I might start somebody with chronic hypertension on a diuretic.
Dr. Moser: What about the effect or concern for litigation? You deliver babies, and those who deliver babies are very concerned about this because any drug, as Dr. August mentioned, has a potential for doing something, and some lawyer somewhere is going to find a reason to say it’s a terrible drug to use. Do you think that plays a role in obstetricians’ activities?
Dr. August: I think the legal profession has ruined the field of OB/GYN. They’ve decimated it. They’ve made it impossible; I don’t know what Dr. Rose has to say about it, but I think it’s one of the great tragedies of the last 30 years in medicine.
Dr. Rose is a hero for persisting in this environment and actually taking the risks to be involved in the process of delivering babies when it is such a hostile environment. I feel strongly about it because I’ve seen it, and I’m sure Dr. Rose does too.
Dr. Rose: Additionally, dosing frequency perhaps should be a consideration in the treatment of hypertension, with any type of medication requiring more frequent dosing intervals, the subsequent compliance rates are much lower. Thus, when I consider any type of medication that I'm prescribing more than twice a day, I'm not sure how realistic it is to expect good compliance.
Dr. Moser: I’m going to ask each of you to imagine that you were the chairperson of a new committee and summarize the definitions of hypertension and decide when to treat and how to treat. Would you make any major suggestions that are different from the present guidelines that have been used for so many years?
Dr. Rose: Currently, the American Congress of Obstetricians and Gynecologists recommends instituting medical therapy for patients with chronic hypertension at threshold values of 150–160/100–110 mm Hg and at diastolic values of 105–110 mm Hg for patients with preeclampsia.8
Dr. Moser: What about the drugs that we use? Would you expand the recommendations, as Dr. August mentioned, to include calcium channel blockers, drugs like labetalol, and diuretics?
Dr. Rose: Yes.
Dr. Garovic: With respect to medications, I completely agree with what other speakers have said. In general, young women, especially those with either severe hypertension in the absence of a family history or with features of secondary hypertension (such as an abdominal bruit) should be ruled out for secondary hypertension, optimally before pregnancy.
Dr. August: I would argue for a clinical trial similar to, but not exactly the same as, the Systolic Blood Pressure Intervention Trial (SPRINT), in non-pregnant people, where you could at least establish the safety of lowering BP to a normal BP (eg, 120/80 mm Hg) in women with chronic hypertension. I think one of the problems with studies like Action to Control Cardiovascular Risk in Diabetes (ACCORD), and maybe SPRINT, is that there are certain patients in whom you should not force the BP to 120/80 mm Hg. If you have to combine 3 or 4 drugs, it’s probably not worth it. So, I think the design of such a study would have to be carefully considered. But, I would like to know whether it’s safe; should we keep women at approximately normal BPs during pregnancy and look at the outcomes that are more pregnancy-related as well as maternal?
Dr. Moser: Is it advisable not to wait until their pressure gets as high as presently supported by guideline committees, just because there is no evidence and no definitive studies to prove otherwise?
Dr. August: Yes. But a large, cooperative, collaborative, multi-center study would need to be conducted to prove this.
Dr. Moser: I thank you all very much.
FoxP2 Media LLC is the publisher of The Medical Roundtable.
That’s one of the reasons we’re having this conversation. One of the more controversial issues in medicine has been that of hypertension in pregnant women. The guidelines have not changed much in the last 50 years, although some effort to update these guidelines has been made recently. Today, we discuss the following: (1) The definition of elevated BP in pregnancy: is it too complicated? (2) Indications for therapy; should you wait until the BP increases to levels of 160/105 to 110 mm Hg? Is there any danger in allowing the systolic BP to remain elevated for a few months in a pregnant woman? (3) The indications for interruption of pregnancy; should we begin treatment earlier and continue to use the drugs that have been suggested over the years? During pregnancy, hypertension is typically classified as chronic hypertension (pre-existing or onset prior to 20 weeks gestation), gestational hypertension, preeclampsia, or preeclampsia superimposed on chronic hypertension.
I’m Dr. Marvin Moser, Clinical Professor of Medicine at Yale. We have with us Dr. Phyllis August, Professor of Research and Medicine and OB/GYN at Cornell Weill Medical College; Vesna Garovic, a Professor of Medicine at the Mayo Clinic who has done a great deal of work on hypertension in pregnancy; and Dr. Carl Rose, Associate Professor of Maternal-Fetal Medicine at the Mayo Clinic, to discuss this controversial subject.
Dr. August, let’s start with you. What about the definition of hypertension? We have a very complicated list of definitions of hypertension in pregnancy; do you want to review some of those? Should we simplify the criteria for clinicians?
Dr. August: I think we need to distinguish between the diagnostic category and the definition of hypertension. The definition of hypertension for the general, non-pregnant population is not very different from that for pregnant women. Obstetricians speak about mild hypertension in pregnancy, which they define as a systolic pressure of 140 to 150 mm Hg and diastolic pressure of 90 to 109 mm Hg, and then severe hypertension. There are 2 categories for hypertension: severe hypertension is a pressure of 160/110 mm Hg and above, and mild to moderate hypertension is a pressure below that level. The diagnosis of hypertension is made at a pressure of 140/90 mm Hg and above, so really, it’s not very different from Stages 1 and 2 of essential hypertension outlined in the last Joint National Committee report.1
Preeclampsia, preeclampsia superimposed on chronic hypertension, chronic hypertension alone, and gestational hypertension are the diagnostic categories within which you can have either mild to moderate or severe hypertension.
Dr. Moser: Do we need all these designations? I know that the pathophysiology of preeclampsia is different from that of essential hypertension, but are the definitions helpful for the clinician? What’s the difference, for example, if you have someone with chronic hypertension who becomes pregnant? What if you have someone with pre-eclampsia superimposed on chronic hypertension, and you have these 4 categories. Are they helpful? Does this definition affect therapy?
Dr. August: They are helpful because what we really need to identify is the condition of the woman who, because of the pregnancy, is either developing new hypertension, or that of a woman who had hypertension before, but because of the pregnancy, her hypertension is worsening. That situation can change quickly, leading to serious maternal vmorbidity and fetal morbidity. This also helps to identify women who really need to be watched closely and addressed in a different way from someone who, at the beginning of pregnancy, had a pressure of 150/100 mm Hg and has the same pressure even at mid-pregnancy. I think the diagnostic categories are useful, and the fact that they’ve been used for many decades supports their effectiveness. They’re not perfect, but they are useful.
Dr. Moser: Dr. Rose, do you want to add to that?
Dr. Rose: As an obstetrician, I would suggest that these categories allow us to communicate with one another using common terminology that we collectively understand. It also influences the obstetric management of these patients.
Dr. Garovic: It is likely that young women who don’t see a physician and present with a BP of 150/100 mm Hg when they are pregnant, have had hypertension for a longer period, which has been asymptomatic and subclinical and that it has been brought to the attention of the clinician only due to the pregnancy.
Having said that, I’m not sure that it helps that much with respect to treatment because target levels at which BP treatment is started are decreasing, especially in the tertiary centers. My approach is to treat a pregnant woman with a documented systolic BP of 150 mm Hg on at least 2 occasions, whether symptomatic or asymptomatic and at risk for preeclampsia or not.
Dr. Moser: In the last American Society of Hypertension recommendations,2 it was clearly stated that the level of the BP should guide treatment and the decision of when to interrupt or deliver the pregnancy. So, if it is the level of BP that the clinician is following, why do we need sub-designations? In other words, if the woman has chronic hypertension to start with, you’re obviously going to try and keep the systolic BP below 140 mm Hg. If she develops hypertension in the first trimester or second trimester, which is a rare occurrence, you’re going to reduce the BP. If she develops hypertension in the third trimester with or without proteinuria, for example, you’re going to treat it. So, why don’t we simplify this and treat the BP without 4 or 5 definitions? Of course, if the BP rises and there is proteinuria in the third trimester, other options will also need to be considered. Also, proteinuria in the second trimester is an indication of preeclampsia.
Dr. August: In my experience, if you have a patient who has a BP reading of 120/80 mm Hg at the start of pregnancy, and then at 20 weeks, the BP is 150/100 mm Hg, even with no proteinuria, you have to be very worried about the patient because she’s developing either superimposed preeclampsia or gestational hypertension, until proven otherwise. That’s different from a BP of 150/100 mm Hg that was stable and started out that way at 8 weeks of pregnancy, and then at 20 weeks, it still is 150/100 mm Hg. There has been no change, and no evidence for an evolving process that is potentially dangerous to the mother and fetus, so I would disagree that it’s just a number.
Dr. Moser: How would you treat the patient differently, Dr. August?
Dr. August: If a woman had a clear, well-documented pressure of 110 to 120/70 to 80 mm Hg early in pregnancy and then in the second trimester and developed mild to moderate or Stage 1 hypertension, I would make sure to check all her laboratory data and rule out preeclampsia, but I would be very worried that she was developing a pregnancy-related disorder like pre-eclampsia or gestational hypertension, and I would examine her very frequently.
Dr. Moser: But would you treat her BP?
Dr. August: I would probably treat her BP if it was 150/95 to 99 mm Hg. Even though the guidelines say 160 mm Hg, 150 mm Hg is close to 160 mm Hg and since the patient’s pressure is currently at 150 mm Hg, it may increase to 160 mm Hg in an hour from now when the patient is a little more stressed and uncomfortable; therefore, 150 mm Hg is my cutoff.
Dr. Moser: Consider this: the normal systolic pressure of a pregnant woman is 110 mm Hg, 120 mm Hg, or even lower sometimes, and even in the second and third trimester, it shouldn’t be more than 120 mm Hg, and 130 mm Hg at the most. Now, if a woman’s pressure exceeds the 140/90 mm Hg cutoff of hypertension, why do obstetricians wait until the level increases to 150 mm Hg, or as you said, 160 mm Hg?
Dr. August: They wait because they think lowering the BP too much might compromise the placental perfusion.
Dr. Moser: Dr. Garovic or Dr. Rose, can you comment on the concept that an elevated systolic pressure for a couple of months in pregnancy isn’t going to do any harm?
Dr. Rose: I agree with Dr. August that the pathophysiology of the processes is different. In other words, I do not believe that we should simply treat hypertension and categorize all the accompanying processes as a similar prenatal complication. If a mother develops new-onset hypertension late in pregnancy, certainly this represents a different clinical scenario from one who develops hypertension at 18 weeks of gestation, although implications for the pregnancy may ultimately be similar.
Dr. August: But I would argue that a woman who develops hypertension at 18 weeks and didn’t have it at 12 weeks is at a more serious risk for preterm birth than the woman who develops hypertension in the third trimester.
Dr. Moser: Let me argue on the other side again. Such patients are at risk, but what are you going to do about the risk? You’re going to check some enzymes and chemistries, etc, but what is the only thing that you might do to reduce the risk of progression of hypertension or a small placenta, which may be a result of infarcts from elevated BP? I’m trying to determine whether just lowering the BP, even though the pathophysiology is different, might prevent progression of hypertension. I know it may not prevent the progression of preeclampsia, but early treatment might prevent or delay interruption of pregnancy, based upon the criteria of an elevated BP.
Dr. Garovic: I just want to clarify the point that I was discussing earlier. A BP of 150/100 mm Hg at 21 weeks’ gestation may represent a significantly elevated BP, as the patient’s BP, at that time of pregnancy, should be even lower than her pre-pregnancy levels. I would not treat somebody with a BP of 150/100 mm Hg based on a single office reading for the same reason that we may not treat hypertension based on a single office reading in the general population. However, if I have enough evidence that a patient has sustained hypertension, especially in the second trimester when the BP should be lower than non-pregnant levels, I will treat that patient. Treatment is given after a 6-hour BP reading or nurse-monitored BP readings over a 30-minute to 1-hour period to generate enough evidence to show that BP is certainly steadily elevated.
I would like to discuss a recent patient: she was a 36-year-old woman with a BP of 150/100 mm Hg. It was her first pregnancy, and she was approximately 12 weeks pregnant. She was referred to us from one of the regional clinics close to Rochester. She underwent a retroperitoneal ultrasound, which showed bilateral renal artery stenosis/fibromuscular secondary to fibromuscular dysplasia. So, she had a BP of 150/100 mm Hg, but by the time she saw us, her systolic pressure was 160 to 170 mm Hg and diastolic pressure was in the 100s range. Dr. Rose and I aggressively treated her with 300 mg labetalol twice a day and nifedipine once a day; her BP effectively was reduced to 120 to 130 mm Hg systolic pressure and 70 to 80 mm Hg diastolic pressure, and she delivered a full-term baby boy at 38 gestational weeks.
Dr. August: Let me ask you a question: did she really have renovascular hypertension? Was she successfully revascularized and did her blood pressure normalize after revascularization?
Dr. Garovic: At 6 months post-partum, she underwent a renal angiogram with bilateral angioplasties with a subsequent normalization of her BP. She remains normotensive, when off BP medications.
Dr. Moser: Do you believe that if we treat elevated BP early, we might delay or prevent iatrogenic preterm deliveries?
Dr. August: Yes, I think your point is that if somebody in the third trimester has preeclampsia or gestational hypertension and severe hypertension, and you lower their BP and, if all other parameters are normal, the baby is fine, and the mother’s platelet count is normal, you can prevent her from having a preterm birth. You can extend the pregnancy by preventing the BP from reaching levels that are too dangerous and thus require delivery.
Dr. August: I don’t think there’s any such strong evidence, but there are several issues to consider. One is that you need to weigh the risks and benefits. We don’t have convincing data on the effects, except the hemodynamic effects, of the drugs on the baby’s neurologic development and organ development. We have certain drugs that we think are safe, but have they been rigorously evaluated? Can we say with a 100% certainty that these drugs have absolutely no adverse effects on fetal growth and development? No, we can’t.
During pregnancy, we avoid exposure to any drug. The question is “what are the risks of treating mild hypertension and what are the benefits?” The treatment benefits to the mother maybe fairly small at 140/90 mm Hg. The risks to the baby are not fully known yet. Hemodynamically, we don’t know that the placental blood flow is being compromised. The data that suggest that smaller babies are a result of lowering the BP are very poor. However, you have to think that it’s probably better to use as few medications as possible during pregnancy for those reasons. Dr. Rose, I’d like to hear your opinion on this.
Dr. Rose: I would concur with Dr. August. Although Peter von Dadelszen’s 2002 metaanalysis3 suggests an association between BP control and fetal growth restriction, the more recent systematic review from Abalos4 suggests that treatment of chronic hypertension during pregnancy for lowering the BPs to thresholds lower than historically considered for therapy, should have a very small effect on neonatal birth weight.4
Dr. Moser: Maybe, some newborns born of hypertensive women are smaller because of the placental infarcts.
Dr. August: It is entirely plausible that hypertension contributes to placental pathology; The question of which is worse—mild hypertension or antihypertensive therapy—has simply not been adequately studied either. It’s just the general principle of whether you can avoid using a medication during pregnancy; if you can, you avoid it, whatever be the medication.
Dr. Garovic: I don’t know whether Dr. Rose and Dr. August would agree, but that meta-analysis3 has one important limitation that is hardly ever addressed. It was published in 2002; so, basically, it included studies published before 2000 when doctors were even more reluctant to treat hypertension. Who was getting treated then? It was likely severely hypertensive women and those with diabetes and other risk factors that are associated with an increased risk for intrauterine growth restriction from the beginning of their pregnancies. So, there may have been an initial selection bias about whom to treat. Therefore, intrauterine growth restriction in these women is likely, at least in part, related to their underlying comorbidities.
Dr. August: I completely agree with Dr. Garovic about that, and yes, I think you make a very good point.
Dr. Moser: To summarize this particular part of the discussion, all of you would agree that treating a patient with a BP > 140/90 mm Hg, even though that’s the definition of hypertension, may not be a good idea because the use of any medication in pregnancy is to be avoided, if possible. I believe that 140/90 mm Hg is an abnormal BP in a pregnant woman, whether it’s at the beginning of pregnancy or later on at 20 weeks or 30 weeks of gestation. I would favor treatment and lowering of BP slowly, because I don’t think the evidence showing fetal harm is very strong. The general consensus, however, of the experts thus far is that they are reluctant to treat a patient until the pressure reaches 150/100 or 155/100 mm Hg.
Dr. August: Well, it’s toward 150 mm Hg. One thing I can say with certainty is that we don’t have good data. We don’t have data to indicate that that treating a pressure of 140/90 mm Hg is harmful, nor do we have good data to show that treating mild hypertension is beneficial.
Dr. Garovic: I don’t know whether current theories would agree with that, but if a young patient (say about 28 years old) without any risk factors has a steady elevation of BP above 140/90 mm Hg, and I see her when she is 12 weeks pregnant, ie, early in pregnancy, I will treat her and follow-up her BP closely.
Dr. August: I agree with that.
Dr. Garovic: Again, I don’t think that it is a wise decision to treat hypertension based on a single BP reading. For me, a steady BP above 140/90 mm Hg in a young patient is an indication for treatment. We are trying to identify these patients very early and keep their BPs at 130/80 mm Hg throughout their pregnancies.
Dr. August: I would agree with that.
Dr. Moser: Would all of you agree that if a woman came in pregnant with chronic hypertension on medication, the medication should be continued, except for agents that effect the renin-angiotensin system, with the caveat that in the first trimester, you might have to lower the dosage because the pressures may be lower?
Dr. August: Most of the time, we do that. We don’t stop all the medications. We follow-up the patients closely. We see if the pregnancy has caused a decrease in BP. If the patient’s BP is 110/70, we would consider reducing the BP medications; we keep many women on medications during pregnancy, as long as they’re safe under them.
Dr. Moser: But you’d keep them on a diuretic or calcium channel blocker?
Dr. August: I would choose nifedipine because there’s more data about nifedipine.
Dr. Garovic: I agree with that.
Dr. August: I think amlodipine is safe, but unfortunately, there aren’t a lot of data on it. I have used verapamil; there are some data on it, although not comparable to the data on nifedipine.
Dr. Garovic: Verapamil also acts faster than amlodipine: it starts working earlier.
Dr. Moser: What about the continual use of diuretics, for example?
Dr. August: I continue administering them, particularly in patients with salt-sensitive hypertension. It is often possible to lower the dose during pregnancy if blood pressure decreases. I stop spironolactone but not hydrochlorothiazide. I don’t think there are a lot of data on chlorthalidone in pregnancy.
Dr. Moser: Dr. Rose, would you agree that if a person with known hypertension came in on medication, you tend to continue it, with the caveat, as Dr. August said, that if the pressure reduced, which it does in the first trimester, you might have to adjust the dosage downward, and, of course, never continue an angiotensin-converting-enzyme inhibitor, angiotensin receptor blocker, or renin inhibitor because of damage to the fetus?
Dr. Rose: Absolutely. During the second trimester, when the physiologic fall in BP occurs, one may need to discontinue medications in some patients, anticipating that therapy will be resumed later in gestation during the third trimester when BPs begin to rise.
Dr. Garovic: We are now trying to conduct a population-based study and see the effects of that “short” duration of hypertension in pregnancy with respect to cardiovascular risk later in life. Chances are that hypertension of any duration may induce vascular damage. For example, magnetic resonance imaging studies of the brain in women with eclampsia showed vasogenic edema involving the posterior circulation, which, with neurological signs and symptoms, was consistent with the diagnosis of posterior reversible encephalopathy syndrome. Follow-up studies of these patients have suggested that permanent cerebrovascular damage of the brain may occur in some of them.5,6 These changes may have some long-term effects on their neurological health and cognitive functioning later in life.
Dr. Moser: So, you’re convinced that a BP of 150 or 160 mm Hg, even for just 4 or 5 months in a young woman, might produce some long-term vascular changes?
Dr. Garovic: I think that there is a high possibility for that. Again, we don’t have data to support it, but the absence of evidence is not the evidence of absence. I would be delighted to see a study following up these women after their affected pregnancies. A paper published in the Journal of American College of Obstetrics and Gynecology7 indicated that women with a history of eclampsia have self-reported poor cognitive functioning years after their pregnancies. So, preeclampsia and brain neurological deficit are concerning conditions, and we don’t know whether they are related to only the BP or some other mechanisms. For example, endothelial dysfunction, which is a systemic condition in pre-eclamptic pregnancy, may actually facilitate any kind of vascular damage induced by high BPs.
Dr. Moser: There is evidence of endothelial dysfunction in hypertension too. Drs. August and Rose, would you agree or disagree that systolic BPs of 150 or 160 mm Hg for 4 or 5 months can produce permanent vascular changes?
Dr. August: I wouldn’t rule it out. It could happen in some people, and maybe there’s some heterogeneity; some might be able to tolerate it with impunity, but it may be more dangerous in people with other vascular risk factors or older individuals. High BP for 4 to 6 months is not very good.
Dr. Rose: I would agree. I think that at this point, we don’t have substantive data that speak one way or the other. But, it certainly seems very reasonable.
Dr. Moser: Yes, in some of the hypertension studies done in pregnant women, it would appear that if you treat early, the benefit is greater. But as you say, the data are certainly not compelling.
Since we don’t completely agree on when you should start treatment, although I think there’s a tendency toward earlier intervention, perhaps we should discuss what medicines should be used now. Obstetricians have been using alpha methyldopa and hydralazine for many years, because they’re comfortable with them and because studies have shown that they’re well tolerated. All of us in the hypertension field, however, know that these may not be the most effective drugs, and if you use them and the pressure keeps increasing, there’s a tendency for pregnancy interruption. What about changing the treatment algorithms, even though, as Dr. August has pointed out many times, there is little evidence of long-term outcomes with some of the newer drugs. Except for the angiotensin-converting–enzyme inhibitors and the angiotensin receptor blockers, there is very little evidence of fetal problems with beta blockers, although there is a report of smaller babies, but that was questionable as obstetricians are reluctant to use beta blockers, calcium channel blockers, or diuretics, partly because of lack of experience and possible litigation.
Dr. Rose: We are a relatively conservative group.
Dr. August: We use labetalol a lot. I think everybody’s happy with labetalol, which is an alpha-beta blocker. It’s reasonably effective, so I think that’s become the drug that everybody reaches for first, to treat hypertension in pregnancy, and I would say the next is nifedipine. I just got an E-mail today from a patient who I started administering nifedipine to, and she’s already complaining of swollen ankles and headache. You tend to get more side effects from nifedipine than labetalol, even though it may be more effective. Methyldopa is not the best drug, but it does work in pregnancy. There’s some evidence that sympathetic nervous system activity is part of the pathogenesis of preeclampsia, and I’ve seen methyldopa work. It makes people tired, which means that they don’t do much and spend a lot of time resting which is not necessarily bad.
Dr. Moser: Oh, yes, and depressed.
Dr. August: But, I’ve written a few prescriptions for methyldopa in the last 12 months. It’s not my first choice; I’d say it’s my third. I don’t initiate diuretics for preeclampsia or gestational hypertension. However, I might start somebody with chronic hypertension on a diuretic.
Dr. Moser: What about the effect or concern for litigation? You deliver babies, and those who deliver babies are very concerned about this because any drug, as Dr. August mentioned, has a potential for doing something, and some lawyer somewhere is going to find a reason to say it’s a terrible drug to use. Do you think that plays a role in obstetricians’ activities?
Dr. August: I think the legal profession has ruined the field of OB/GYN. They’ve decimated it. They’ve made it impossible; I don’t know what Dr. Rose has to say about it, but I think it’s one of the great tragedies of the last 30 years in medicine.
Dr. Rose is a hero for persisting in this environment and actually taking the risks to be involved in the process of delivering babies when it is such a hostile environment. I feel strongly about it because I’ve seen it, and I’m sure Dr. Rose does too.
Dr. Rose: Additionally, dosing frequency perhaps should be a consideration in the treatment of hypertension, with any type of medication requiring more frequent dosing intervals, the subsequent compliance rates are much lower. Thus, when I consider any type of medication that I'm prescribing more than twice a day, I'm not sure how realistic it is to expect good compliance.
Dr. Moser: I’m going to ask each of you to imagine that you were the chairperson of a new committee and summarize the definitions of hypertension and decide when to treat and how to treat. Would you make any major suggestions that are different from the present guidelines that have been used for so many years?
Dr. Rose: Currently, the American Congress of Obstetricians and Gynecologists recommends instituting medical therapy for patients with chronic hypertension at threshold values of 150–160/100–110 mm Hg and at diastolic values of 105–110 mm Hg for patients with preeclampsia.8
Dr. Moser: What about the drugs that we use? Would you expand the recommendations, as Dr. August mentioned, to include calcium channel blockers, drugs like labetalol, and diuretics?
Dr. Rose: Yes.
Dr. Garovic: With respect to medications, I completely agree with what other speakers have said. In general, young women, especially those with either severe hypertension in the absence of a family history or with features of secondary hypertension (such as an abdominal bruit) should be ruled out for secondary hypertension, optimally before pregnancy.
Dr. August: I would argue for a clinical trial similar to, but not exactly the same as, the Systolic Blood Pressure Intervention Trial (SPRINT), in non-pregnant people, where you could at least establish the safety of lowering BP to a normal BP (eg, 120/80 mm Hg) in women with chronic hypertension. I think one of the problems with studies like Action to Control Cardiovascular Risk in Diabetes (ACCORD), and maybe SPRINT, is that there are certain patients in whom you should not force the BP to 120/80 mm Hg. If you have to combine 3 or 4 drugs, it’s probably not worth it. So, I think the design of such a study would have to be carefully considered. But, I would like to know whether it’s safe; should we keep women at approximately normal BPs during pregnancy and look at the outcomes that are more pregnancy-related as well as maternal?
Dr. Moser: Is it advisable not to wait until their pressure gets as high as presently supported by guideline committees, just because there is no evidence and no definitive studies to prove otherwise?
Dr. August: Yes. But a large, cooperative, collaborative, multi-center study would need to be conducted to prove this.
Dr. Moser: I thank you all very much.
FoxP2 Media LLC is the publisher of The Medical Roundtable.
That’s one of the reasons we’re having this conversation. One of the more controversial issues in medicine has been that of hypertension in pregnant women. The guidelines have not changed much in the last 50 years, although some effort to update these guidelines has been made recently. Today, we discuss the following: (1) The definition of elevated BP in pregnancy: is it too complicated? (2) Indications for therapy; should you wait until the BP increases to levels of 160/105 to 110 mm Hg? Is there any danger in allowing the systolic BP to remain elevated for a few months in a pregnant woman? (3) The indications for interruption of pregnancy; should we begin treatment earlier and continue to use the drugs that have been suggested over the years? During pregnancy, hypertension is typically classified as chronic hypertension (pre-existing or onset prior to 20 weeks gestation), gestational hypertension, preeclampsia, or preeclampsia superimposed on chronic hypertension.
I’m Dr. Marvin Moser, Clinical Professor of Medicine at Yale. We have with us Dr. Phyllis August, Professor of Research and Medicine and OB/GYN at Cornell Weill Medical College; Vesna Garovic, a Professor of Medicine at the Mayo Clinic who has done a great deal of work on hypertension in pregnancy; and Dr. Carl Rose, Associate Professor of Maternal-Fetal Medicine at the Mayo Clinic, to discuss this controversial subject.
Dr. August, let’s start with you. What about the definition of hypertension? We have a very complicated list of definitions of hypertension in pregnancy; do you want to review some of those? Should we simplify the criteria for clinicians?
Dr. August: I think we need to distinguish between the diagnostic category and the definition of hypertension. The definition of hypertension for the general, non-pregnant population is not very different from that for pregnant women. Obstetricians speak about mild hypertension in pregnancy, which they define as a systolic pressure of 140 to 150 mm Hg and diastolic pressure of 90 to 109 mm Hg, and then severe hypertension. There are 2 categories for hypertension: severe hypertension is a pressure of 160/110 mm Hg and above, and mild to moderate hypertension is a pressure below that level. The diagnosis of hypertension is made at a pressure of 140/90 mm Hg and above, so really, it’s not very different from Stages 1 and 2 of essential hypertension outlined in the last Joint National Committee report.1
Preeclampsia, preeclampsia superimposed on chronic hypertension, chronic hypertension alone, and gestational hypertension are the diagnostic categories within which you can have either mild to moderate or severe hypertension.
Dr. Moser: Do we need all these designations? I know that the pathophysiology of preeclampsia is different from that of essential hypertension, but are the definitions helpful for the clinician? What’s the difference, for example, if you have someone with chronic hypertension who becomes pregnant? What if you have someone with pre-eclampsia superimposed on chronic hypertension, and you have these 4 categories. Are they helpful? Does this definition affect therapy?
Dr. August: They are helpful because what we really need to identify is the condition of the woman who, because of the pregnancy, is either developing new hypertension, or that of a woman who had hypertension before, but because of the pregnancy, her hypertension is worsening. That situation can change quickly, leading to serious maternal vmorbidity and fetal morbidity. This also helps to identify women who really need to be watched closely and addressed in a different way from someone who, at the beginning of pregnancy, had a pressure of 150/100 mm Hg and has the same pressure even at mid-pregnancy. I think the diagnostic categories are useful, and the fact that they’ve been used for many decades supports their effectiveness. They’re not perfect, but they are useful.
Dr. Moser: Dr. Rose, do you want to add to that?
Dr. Rose: As an obstetrician, I would suggest that these categories allow us to communicate with one another using common terminology that we collectively understand. It also influences the obstetric management of these patients.
Dr. Garovic: It is likely that young women who don’t see a physician and present with a BP of 150/100 mm Hg when they are pregnant, have had hypertension for a longer period, which has been asymptomatic and subclinical and that it has been brought to the attention of the clinician only due to the pregnancy.
Having said that, I’m not sure that it helps that much with respect to treatment because target levels at which BP treatment is started are decreasing, especially in the tertiary centers. My approach is to treat a pregnant woman with a documented systolic BP of 150 mm Hg on at least 2 occasions, whether symptomatic or asymptomatic and at risk for preeclampsia or not.
Dr. Moser: In the last American Society of Hypertension recommendations,2 it was clearly stated that the level of the BP should guide treatment and the decision of when to interrupt or deliver the pregnancy. So, if it is the level of BP that the clinician is following, why do we need sub-designations? In other words, if the woman has chronic hypertension to start with, you’re obviously going to try and keep the systolic BP below 140 mm Hg. If she develops hypertension in the first trimester or second trimester, which is a rare occurrence, you’re going to reduce the BP. If she develops hypertension in the third trimester with or without proteinuria, for example, you’re going to treat it. So, why don’t we simplify this and treat the BP without 4 or 5 definitions? Of course, if the BP rises and there is proteinuria in the third trimester, other options will also need to be considered. Also, proteinuria in the second trimester is an indication of preeclampsia.
Dr. August: In my experience, if you have a patient who has a BP reading of 120/80 mm Hg at the start of pregnancy, and then at 20 weeks, the BP is 150/100 mm Hg, even with no proteinuria, you have to be very worried about the patient because she’s developing either superimposed preeclampsia or gestational hypertension, until proven otherwise. That’s different from a BP of 150/100 mm Hg that was stable and started out that way at 8 weeks of pregnancy, and then at 20 weeks, it still is 150/100 mm Hg. There has been no change, and no evidence for an evolving process that is potentially dangerous to the mother and fetus, so I would disagree that it’s just a number.
Dr. Moser: How would you treat the patient differently, Dr. August?
Dr. August: If a woman had a clear, well-documented pressure of 110 to 120/70 to 80 mm Hg early in pregnancy and then in the second trimester and developed mild to moderate or Stage 1 hypertension, I would make sure to check all her laboratory data and rule out preeclampsia, but I would be very worried that she was developing a pregnancy-related disorder like pre-eclampsia or gestational hypertension, and I would examine her very frequently.
Dr. Moser: But would you treat her BP?
Dr. August: I would probably treat her BP if it was 150/95 to 99 mm Hg. Even though the guidelines say 160 mm Hg, 150 mm Hg is close to 160 mm Hg and since the patient’s pressure is currently at 150 mm Hg, it may increase to 160 mm Hg in an hour from now when the patient is a little more stressed and uncomfortable; therefore, 150 mm Hg is my cutoff.
Dr. Moser: Consider this: the normal systolic pressure of a pregnant woman is 110 mm Hg, 120 mm Hg, or even lower sometimes, and even in the second and third trimester, it shouldn’t be more than 120 mm Hg, and 130 mm Hg at the most. Now, if a woman’s pressure exceeds the 140/90 mm Hg cutoff of hypertension, why do obstetricians wait until the level increases to 150 mm Hg, or as you said, 160 mm Hg?
Dr. August: They wait because they think lowering the BP too much might compromise the placental perfusion.
Dr. Moser: Dr. Garovic or Dr. Rose, can you comment on the concept that an elevated systolic pressure for a couple of months in pregnancy isn’t going to do any harm?
Dr. Rose: I agree with Dr. August that the pathophysiology of the processes is different. In other words, I do not believe that we should simply treat hypertension and categorize all the accompanying processes as a similar prenatal complication. If a mother develops new-onset hypertension late in pregnancy, certainly this represents a different clinical scenario from one who develops hypertension at 18 weeks of gestation, although implications for the pregnancy may ultimately be similar.
Dr. August: But I would argue that a woman who develops hypertension at 18 weeks and didn’t have it at 12 weeks is at a more serious risk for preterm birth than the woman who develops hypertension in the third trimester.
Dr. Moser: Let me argue on the other side again. Such patients are at risk, but what are you going to do about the risk? You’re going to check some enzymes and chemistries, etc, but what is the only thing that you might do to reduce the risk of progression of hypertension or a small placenta, which may be a result of infarcts from elevated BP? I’m trying to determine whether just lowering the BP, even though the pathophysiology is different, might prevent progression of hypertension. I know it may not prevent the progression of preeclampsia, but early treatment might prevent or delay interruption of pregnancy, based upon the criteria of an elevated BP.
Dr. Garovic: I just want to clarify the point that I was discussing earlier. A BP of 150/100 mm Hg at 21 weeks’ gestation may represent a significantly elevated BP, as the patient’s BP, at that time of pregnancy, should be even lower than her pre-pregnancy levels. I would not treat somebody with a BP of 150/100 mm Hg based on a single office reading for the same reason that we may not treat hypertension based on a single office reading in the general population. However, if I have enough evidence that a patient has sustained hypertension, especially in the second trimester when the BP should be lower than non-pregnant levels, I will treat that patient. Treatment is given after a 6-hour BP reading or nurse-monitored BP readings over a 30-minute to 1-hour period to generate enough evidence to show that BP is certainly steadily elevated.
I would like to discuss a recent patient: she was a 36-year-old woman with a BP of 150/100 mm Hg. It was her first pregnancy, and she was approximately 12 weeks pregnant. She was referred to us from one of the regional clinics close to Rochester. She underwent a retroperitoneal ultrasound, which showed bilateral renal artery stenosis/fibromuscular secondary to fibromuscular dysplasia. So, she had a BP of 150/100 mm Hg, but by the time she saw us, her systolic pressure was 160 to 170 mm Hg and diastolic pressure was in the 100s range. Dr. Rose and I aggressively treated her with 300 mg labetalol twice a day and nifedipine once a day; her BP effectively was reduced to 120 to 130 mm Hg systolic pressure and 70 to 80 mm Hg diastolic pressure, and she delivered a full-term baby boy at 38 gestational weeks.
Dr. August: Let me ask you a question: did she really have renovascular hypertension? Was she successfully revascularized and did her blood pressure normalize after revascularization?
Dr. Garovic: At 6 months post-partum, she underwent a renal angiogram with bilateral angioplasties with a subsequent normalization of her BP. She remains normotensive, when off BP medications.
Dr. Moser: Do you believe that if we treat elevated BP early, we might delay or prevent iatrogenic preterm deliveries?
Dr. August: Yes, I think your point is that if somebody in the third trimester has preeclampsia or gestational hypertension and severe hypertension, and you lower their BP and, if all other parameters are normal, the baby is fine, and the mother’s platelet count is normal, you can prevent her from having a preterm birth. You can extend the pregnancy by preventing the BP from reaching levels that are too dangerous and thus require delivery.
Dr. August: I don’t think there’s any such strong evidence, but there are several issues to consider. One is that you need to weigh the risks and benefits. We don’t have convincing data on the effects, except the hemodynamic effects, of the drugs on the baby’s neurologic development and organ development. We have certain drugs that we think are safe, but have they been rigorously evaluated? Can we say with a 100% certainty that these drugs have absolutely no adverse effects on fetal growth and development? No, we can’t.
During pregnancy, we avoid exposure to any drug. The question is “what are the risks of treating mild hypertension and what are the benefits?” The treatment benefits to the mother maybe fairly small at 140/90 mm Hg. The risks to the baby are not fully known yet. Hemodynamically, we don’t know that the placental blood flow is being compromised. The data that suggest that smaller babies are a result of lowering the BP are very poor. However, you have to think that it’s probably better to use as few medications as possible during pregnancy for those reasons. Dr. Rose, I’d like to hear your opinion on this.
Dr. Rose: I would concur with Dr. August. Although Peter von Dadelszen’s 2002 metaanalysis3 suggests an association between BP control and fetal growth restriction, the more recent systematic review from Abalos4 suggests that treatment of chronic hypertension during pregnancy for lowering the BPs to thresholds lower than historically considered for therapy, should have a very small effect on neonatal birth weight.4
Dr. Moser: Maybe, some newborns born of hypertensive women are smaller because of the placental infarcts.
Dr. August: It is entirely plausible that hypertension contributes to placental pathology; The question of which is worse—mild hypertension or antihypertensive therapy—has simply not been adequately studied either. It’s just the general principle of whether you can avoid using a medication during pregnancy; if you can, you avoid it, whatever be the medication.
Dr. Garovic: I don’t know whether Dr. Rose and Dr. August would agree, but that meta-analysis3 has one important limitation that is hardly ever addressed. It was published in 2002; so, basically, it included studies published before 2000 when doctors were even more reluctant to treat hypertension. Who was getting treated then? It was likely severely hypertensive women and those with diabetes and other risk factors that are associated with an increased risk for intrauterine growth restriction from the beginning of their pregnancies. So, there may have been an initial selection bias about whom to treat. Therefore, intrauterine growth restriction in these women is likely, at least in part, related to their underlying comorbidities.
Dr. August: I completely agree with Dr. Garovic about that, and yes, I think you make a very good point.
Dr. Moser: To summarize this particular part of the discussion, all of you would agree that treating a patient with a BP > 140/90 mm Hg, even though that’s the definition of hypertension, may not be a good idea because the use of any medication in pregnancy is to be avoided, if possible. I believe that 140/90 mm Hg is an abnormal BP in a pregnant woman, whether it’s at the beginning of pregnancy or later on at 20 weeks or 30 weeks of gestation. I would favor treatment and lowering of BP slowly, because I don’t think the evidence showing fetal harm is very strong. The general consensus, however, of the experts thus far is that they are reluctant to treat a patient until the pressure reaches 150/100 or 155/100 mm Hg.
Dr. August: Well, it’s toward 150 mm Hg. One thing I can say with certainty is that we don’t have good data. We don’t have data to indicate that that treating a pressure of 140/90 mm Hg is harmful, nor do we have good data to show that treating mild hypertension is beneficial.
Dr. Garovic: I don’t know whether current theories would agree with that, but if a young patient (say about 28 years old) without any risk factors has a steady elevation of BP above 140/90 mm Hg, and I see her when she is 12 weeks pregnant, ie, early in pregnancy, I will treat her and follow-up her BP closely.
Dr. August: I agree with that.
Dr. Garovic: Again, I don’t think that it is a wise decision to treat hypertension based on a single BP reading. For me, a steady BP above 140/90 mm Hg in a young patient is an indication for treatment. We are trying to identify these patients very early and keep their BPs at 130/80 mm Hg throughout their pregnancies.
Dr. August: I would agree with that.
Dr. Moser: Would all of you agree that if a woman came in pregnant with chronic hypertension on medication, the medication should be continued, except for agents that effect the renin-angiotensin system, with the caveat that in the first trimester, you might have to lower the dosage because the pressures may be lower?
Dr. August: Most of the time, we do that. We don’t stop all the medications. We follow-up the patients closely. We see if the pregnancy has caused a decrease in BP. If the patient’s BP is 110/70, we would consider reducing the BP medications; we keep many women on medications during pregnancy, as long as they’re safe under them.
Dr. Moser: But you’d keep them on a diuretic or calcium channel blocker?
Dr. August: I would choose nifedipine because there’s more data about nifedipine.
Dr. Garovic: I agree with that.
Dr. August: I think amlodipine is safe, but unfortunately, there aren’t a lot of data on it. I have used verapamil; there are some data on it, although not comparable to the data on nifedipine.
Dr. Garovic: Verapamil also acts faster than amlodipine: it starts working earlier.
Dr. Moser: What about the continual use of diuretics, for example?
Dr. August: I continue administering them, particularly in patients with salt-sensitive hypertension. It is often possible to lower the dose during pregnancy if blood pressure decreases. I stop spironolactone but not hydrochlorothiazide. I don’t think there are a lot of data on chlorthalidone in pregnancy.
Dr. Moser: Dr. Rose, would you agree that if a person with known hypertension came in on medication, you tend to continue it, with the caveat, as Dr. August said, that if the pressure reduced, which it does in the first trimester, you might have to adjust the dosage downward, and, of course, never continue an angiotensin-converting-enzyme inhibitor, angiotensin receptor blocker, or renin inhibitor because of damage to the fetus?
Dr. Rose: Absolutely. During the second trimester, when the physiologic fall in BP occurs, one may need to discontinue medications in some patients, anticipating that therapy will be resumed later in gestation during the third trimester when BPs begin to rise.
Dr. Garovic: We are now trying to conduct a population-based study and see the effects of that “short” duration of hypertension in pregnancy with respect to cardiovascular risk later in life. Chances are that hypertension of any duration may induce vascular damage. For example, magnetic resonance imaging studies of the brain in women with eclampsia showed vasogenic edema involving the posterior circulation, which, with neurological signs and symptoms, was consistent with the diagnosis of posterior reversible encephalopathy syndrome. Follow-up studies of these patients have suggested that permanent cerebrovascular damage of the brain may occur in some of them.5,6 These changes may have some long-term effects on their neurological health and cognitive functioning later in life.
Dr. Moser: So, you’re convinced that a BP of 150 or 160 mm Hg, even for just 4 or 5 months in a young woman, might produce some long-term vascular changes?
Dr. Garovic: I think that there is a high possibility for that. Again, we don’t have data to support it, but the absence of evidence is not the evidence of absence. I would be delighted to see a study following up these women after their affected pregnancies. A paper published in the Journal of American College of Obstetrics and Gynecology7 indicated that women with a history of eclampsia have self-reported poor cognitive functioning years after their pregnancies. So, preeclampsia and brain neurological deficit are concerning conditions, and we don’t know whether they are related to only the BP or some other mechanisms. For example, endothelial dysfunction, which is a systemic condition in pre-eclamptic pregnancy, may actually facilitate any kind of vascular damage induced by high BPs.
Dr. Moser: There is evidence of endothelial dysfunction in hypertension too. Drs. August and Rose, would you agree or disagree that systolic BPs of 150 or 160 mm Hg for 4 or 5 months can produce permanent vascular changes?
Dr. August: I wouldn’t rule it out. It could happen in some people, and maybe there’s some heterogeneity; some might be able to tolerate it with impunity, but it may be more dangerous in people with other vascular risk factors or older individuals. High BP for 4 to 6 months is not very good.
Dr. Rose: I would agree. I think that at this point, we don’t have substantive data that speak one way or the other. But, it certainly seems very reasonable.
Dr. Moser: Yes, in some of the hypertension studies done in pregnant women, it would appear that if you treat early, the benefit is greater. But as you say, the data are certainly not compelling.
Since we don’t completely agree on when you should start treatment, although I think there’s a tendency toward earlier intervention, perhaps we should discuss what medicines should be used now. Obstetricians have been using alpha methyldopa and hydralazine for many years, because they’re comfortable with them and because studies have shown that they’re well tolerated. All of us in the hypertension field, however, know that these may not be the most effective drugs, and if you use them and the pressure keeps increasing, there’s a tendency for pregnancy interruption. What about changing the treatment algorithms, even though, as Dr. August has pointed out many times, there is little evidence of long-term outcomes with some of the newer drugs. Except for the angiotensin-converting–enzyme inhibitors and the angiotensin receptor blockers, there is very little evidence of fetal problems with beta blockers, although there is a report of smaller babies, but that was questionable as obstetricians are reluctant to use beta blockers, calcium channel blockers, or diuretics, partly because of lack of experience and possible litigation.
Dr. Rose: We are a relatively conservative group.
Dr. August: We use labetalol a lot. I think everybody’s happy with labetalol, which is an alpha-beta blocker. It’s reasonably effective, so I think that’s become the drug that everybody reaches for first, to treat hypertension in pregnancy, and I would say the next is nifedipine. I just got an E-mail today from a patient who I started administering nifedipine to, and she’s already complaining of swollen ankles and headache. You tend to get more side effects from nifedipine than labetalol, even though it may be more effective. Methyldopa is not the best drug, but it does work in pregnancy. There’s some evidence that sympathetic nervous system activity is part of the pathogenesis of preeclampsia, and I’ve seen methyldopa work. It makes people tired, which means that they don’t do much and spend a lot of time resting which is not necessarily bad.
Dr. Moser: Oh, yes, and depressed.
Dr. August: But, I’ve written a few prescriptions for methyldopa in the last 12 months. It’s not my first choice; I’d say it’s my third. I don’t initiate diuretics for preeclampsia or gestational hypertension. However, I might start somebody with chronic hypertension on a diuretic.
Dr. Moser: What about the effect or concern for litigation? You deliver babies, and those who deliver babies are very concerned about this because any drug, as Dr. August mentioned, has a potential for doing something, and some lawyer somewhere is going to find a reason to say it’s a terrible drug to use. Do you think that plays a role in obstetricians’ activities?
Dr. August: I think the legal profession has ruined the field of OB/GYN. They’ve decimated it. They’ve made it impossible; I don’t know what Dr. Rose has to say about it, but I think it’s one of the great tragedies of the last 30 years in medicine.
Dr. Rose is a hero for persisting in this environment and actually taking the risks to be involved in the process of delivering babies when it is such a hostile environment. I feel strongly about it because I’ve seen it, and I’m sure Dr. Rose does too.
Dr. Rose: Additionally, dosing frequency perhaps should be a consideration in the treatment of hypertension, with any type of medication requiring more frequent dosing intervals, the subsequent compliance rates are much lower. Thus, when I consider any type of medication that I'm prescribing more than twice a day, I'm not sure how realistic it is to expect good compliance.
Dr. Moser: I’m going to ask each of you to imagine that you were the chairperson of a new committee and summarize the definitions of hypertension and decide when to treat and how to treat. Would you make any major suggestions that are different from the present guidelines that have been used for so many years?
Dr. Rose: Currently, the American Congress of Obstetricians and Gynecologists recommends instituting medical therapy for patients with chronic hypertension at threshold values of 150–160/100–110 mm Hg and at diastolic values of 105–110 mm Hg for patients with preeclampsia.8
Dr. Moser: What about the drugs that we use? Would you expand the recommendations, as Dr. August mentioned, to include calcium channel blockers, drugs like labetalol, and diuretics?
Dr. Rose: Yes.
Dr. Garovic: With respect to medications, I completely agree with what other speakers have said. In general, young women, especially those with either severe hypertension in the absence of a family history or with features of secondary hypertension (such as an abdominal bruit) should be ruled out for secondary hypertension, optimally before pregnancy.
Dr. August: I would argue for a clinical trial similar to, but not exactly the same as, the Systolic Blood Pressure Intervention Trial (SPRINT), in non-pregnant people, where you could at least establish the safety of lowering BP to a normal BP (eg, 120/80 mm Hg) in women with chronic hypertension. I think one of the problems with studies like Action to Control Cardiovascular Risk in Diabetes (ACCORD), and maybe SPRINT, is that there are certain patients in whom you should not force the BP to 120/80 mm Hg. If you have to combine 3 or 4 drugs, it’s probably not worth it. So, I think the design of such a study would have to be carefully considered. But, I would like to know whether it’s safe; should we keep women at approximately normal BPs during pregnancy and look at the outcomes that are more pregnancy-related as well as maternal?
Dr. Moser: Is it advisable not to wait until their pressure gets as high as presently supported by guideline committees, just because there is no evidence and no definitive studies to prove otherwise?
Dr. August: Yes. But a large, cooperative, collaborative, multi-center study would need to be conducted to prove this.
Dr. Moser: I thank you all very much.
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