Emergency Medicine

Higher baseline cardiorespiratory fitness (CRF) is associated with better outcomes after atrial fibrillation (AFib) ablation, according to new research.

In a single-center, retrospective cohort study, patients with the highest level of baseline CRF had significantly lower rates of arrhythmia recurrence and death than did patients with lower levels of CRF.

“It is stunning how just a simple measure, in this case walking on a treadmill, can predict whether atrial fibrillation ablation will be a successful endeavor or if it will fail,” senior author Wael A. Jaber, MD, professor of medicine, Cleveland Clinic, said in an interview.

“We found that ablation was not successful in most patients who had poor functional class and, conversely, that it was successful in most patients who were in tip-top shape when they walked on the treadmill. Our results can help clinicians inform patients about what they can expect after the procedure, depending on the baseline fitness level,” Dr. Jaber said.

The study was published online Aug. 2 in Heart Rhythm.

Several studies have shown a reduction in AFib incidence among individuals who report a physically active lifestyle, but the extent to which baseline CRF influences arrhythmia rates after AFib ablation is unknown, the authors note.

For the study, Dr. Jaber and colleagues analyzed results in 591 consecutive patients (mean age, 66.5 years; 75% male) with symptomatic paroxysmal or persistent AFib who underwent de novo AFib ablation at their institution. Only patients who had undergone an exercise stress test in the 12 months before AFib ablation (average, 4.5 months) were included.

Age- and sex-specific predicted metabolic equivalents (METs) were calculated using the St. James model for women and the Veterans Affairs referral model for men. The number of METs achieved was then divided by the predicted METs, and the patients were categorized into low (<85% predicted; n = 152), adequate (85%-100% predicted; n = 115), and high (>100% predicted; n = 324) CRF groups. Functional capacity was characterized as poor in 56 patients (9.5%), fair in 94 (16.0%), average in 225 (38.1%), good in 169 (28.6%), and high in 47 (8.0%).

During a mean follow-up of 32 months, arrhythmia recurrence was observed in 79% of patients in the low-CRF group, 54% of patients in the adequate-CRF group, and 27.5% of patients in the high-CRF group (P < .0001). Rates of repeat arrhythmia-related hospitalization, repeat rhythm-control procedures, and the need for ongoing antiarrhythmic therapy (ATT) were significantly lower in the high-CRF group. Specifically, ATT was stopped in 56% of patients in the high-CRF group, compared with 24% in the adequate-CRF group and 11% in the low-CRF group (P < .0001). Rehospitalization for arrhythmia was required in 18.5%, 38.0%, and 60.5% of cases, respectively, and repeat direct-current cardioversion or ablation was performed in 26.0%, 49.0%, and 65.0%, respectively (P < .0001 for both).

Death occurred in 11% of the low-CRF group, compared with 4% in the adequate-CRF group and 2.5% in the high-CRF group. Most (70%) of the deaths were caused by cardiovascular events, including heart failure, cardiac arrest, and coronary artery disease. The most common cause of noncardiac death was respiratory failure (13%), followed by sepsis (10%), malignancy (3%), and complications of Parkinson’s disease (3%).

“Although there was a statistically significant association between higher CRF and lower mortality in this cohort, the findings are to be viewed through the prism of a small sample size and relatively low death rate,” the authors wrote.


 

Don’t “overpromise” results

“The important message for clinicians is that when, you are discussing what to expect after atrial fibrillation ablation with your patients, do not overpromise the results. You can inform them that the success of the procedure depends more on how they perform on the baseline exercise test, and less on the ablation itself,” Dr. Jaber said.

Clinicians might want to consider advising their patients to become more active and increase their fitness level before undergoing the procedure, but whether doing so will improve outcomes is still unknown.

“This is what we don’t know. It makes sense. Hopefully, our results will encourage people to be more active before they arrive here for the procedure,” he said. “Our study is retrospective and is hypothesis generating, but we are planning a prospective study where patients will be referred to cardiac rehab prior to having ablation to try to improve their functional class to see if this will improve outcomes.”

Survival of the fittest

In an accompanying editorial commentary, Eric Black-Maier, MD, and Jonathan P. Piccini Sr, MD, from Duke University Medical Center, Durham, N.C., wrote that the findings have “important implications for clinical practice and raise important additional questions.”

They note that catheter ablation as a first-line rhythm-control strategy, per current recommendations, “seems reasonable” in individuals with high baseline cardiorespiratory fitness, but that the benefit is less clear for patients with poor baseline CRF and uncontrolled risk factors.

“Significant limitations in functional status may be at least partially attributable to uncontrolled [AFib], and patients with limited exercise capacity may stand to gain most from successful catheter ablation,” the editorialists wrote.

“Furthermore, because shorter time from [AFib] diagnosis to catheter ablation has been associated with improved outcomes, the decision to postpone ablation in favor of lifestyle modification is not without potential adverse consequences,” they added.

Dr. Black-Maier and Dr. Piccini agree with the need for additional prospective randomized clinical trials to confirm that exercise training to improve cardiorespiratory fitness before AFib ablation is practical and effective for reducing arrhythmia recurrence.

“Over the past 50-plus years, our understanding of cardiorespiratory fitness, exercise capacity, and arrhythmia occurrence in patients with [AFib] continues to evolve,” the editorialists concluded. Data from the study “clearly demonstrate that arrhythmia-free survival is indeed survival of the fittest. Time will tell if exercise training and improvements in cardiorespiratory fitness can change outcomes after ablation.”

The study was sponsored by the Cleveland Clinic. Dr. Jaber and Dr. Black-Maier report no relevant financial relationships. Dr. Piccini receives grants for clinical research from Abbott, the American Heart Association, the Association for the Advancement of Medical Instrumentation, Bayer, Boston Scientific, and Philips and serves as a consultant to Abbott, Allergan, ARCA Biopharma, Biotronik, Boston Scientific, LivaNova, Medtronic, Milestone, MyoKardia, Sanofi, Philips, and UpToDate.
 

A version of this story originally appeared on Medscape.com.

Higher baseline cardiorespiratory fitness (CRF) is associated with better outcomes after atrial fibrillation (AFib) ablation, according to new research.

In a single-center, retrospective cohort study, patients with the highest level of baseline CRF had significantly lower rates of arrhythmia recurrence and death than did patients with lower levels of CRF.

“It is stunning how just a simple measure, in this case walking on a treadmill, can predict whether atrial fibrillation ablation will be a successful endeavor or if it will fail,” senior author Wael A. Jaber, MD, professor of medicine, Cleveland Clinic, said in an interview.

“We found that ablation was not successful in most patients who had poor functional class and, conversely, that it was successful in most patients who were in tip-top shape when they walked on the treadmill. Our results can help clinicians inform patients about what they can expect after the procedure, depending on the baseline fitness level,” Dr. Jaber said.

The study was published online Aug. 2 in Heart Rhythm.

Several studies have shown a reduction in AFib incidence among individuals who report a physically active lifestyle, but the extent to which baseline CRF influences arrhythmia rates after AFib ablation is unknown, the authors note.

For the study, Dr. Jaber and colleagues analyzed results in 591 consecutive patients (mean age, 66.5 years; 75% male) with symptomatic paroxysmal or persistent AFib who underwent de novo AFib ablation at their institution. Only patients who had undergone an exercise stress test in the 12 months before AFib ablation (average, 4.5 months) were included.

Age- and sex-specific predicted metabolic equivalents (METs) were calculated using the St. James model for women and the Veterans Affairs referral model for men. The number of METs achieved was then divided by the predicted METs, and the patients were categorized into low (<85% predicted; n = 152), adequate (85%-100% predicted; n = 115), and high (>100% predicted; n = 324) CRF groups. Functional capacity was characterized as poor in 56 patients (9.5%), fair in 94 (16.0%), average in 225 (38.1%), good in 169 (28.6%), and high in 47 (8.0%).

During a mean follow-up of 32 months, arrhythmia recurrence was observed in 79% of patients in the low-CRF group, 54% of patients in the adequate-CRF group, and 27.5% of patients in the high-CRF group (P < .0001). Rates of repeat arrhythmia-related hospitalization, repeat rhythm-control procedures, and the need for ongoing antiarrhythmic therapy (ATT) were significantly lower in the high-CRF group. Specifically, ATT was stopped in 56% of patients in the high-CRF group, compared with 24% in the adequate-CRF group and 11% in the low-CRF group (P < .0001). Rehospitalization for arrhythmia was required in 18.5%, 38.0%, and 60.5% of cases, respectively, and repeat direct-current cardioversion or ablation was performed in 26.0%, 49.0%, and 65.0%, respectively (P < .0001 for both).

Death occurred in 11% of the low-CRF group, compared with 4% in the adequate-CRF group and 2.5% in the high-CRF group. Most (70%) of the deaths were caused by cardiovascular events, including heart failure, cardiac arrest, and coronary artery disease. The most common cause of noncardiac death was respiratory failure (13%), followed by sepsis (10%), malignancy (3%), and complications of Parkinson’s disease (3%).

“Although there was a statistically significant association between higher CRF and lower mortality in this cohort, the findings are to be viewed through the prism of a small sample size and relatively low death rate,” the authors wrote.


 

Don’t “overpromise” results

“The important message for clinicians is that when, you are discussing what to expect after atrial fibrillation ablation with your patients, do not overpromise the results. You can inform them that the success of the procedure depends more on how they perform on the baseline exercise test, and less on the ablation itself,” Dr. Jaber said.

Clinicians might want to consider advising their patients to become more active and increase their fitness level before undergoing the procedure, but whether doing so will improve outcomes is still unknown.

“This is what we don’t know. It makes sense. Hopefully, our results will encourage people to be more active before they arrive here for the procedure,” he said. “Our study is retrospective and is hypothesis generating, but we are planning a prospective study where patients will be referred to cardiac rehab prior to having ablation to try to improve their functional class to see if this will improve outcomes.”

Survival of the fittest

In an accompanying editorial commentary, Eric Black-Maier, MD, and Jonathan P. Piccini Sr, MD, from Duke University Medical Center, Durham, N.C., wrote that the findings have “important implications for clinical practice and raise important additional questions.”

They note that catheter ablation as a first-line rhythm-control strategy, per current recommendations, “seems reasonable” in individuals with high baseline cardiorespiratory fitness, but that the benefit is less clear for patients with poor baseline CRF and uncontrolled risk factors.

“Significant limitations in functional status may be at least partially attributable to uncontrolled [AFib], and patients with limited exercise capacity may stand to gain most from successful catheter ablation,” the editorialists wrote.

“Furthermore, because shorter time from [AFib] diagnosis to catheter ablation has been associated with improved outcomes, the decision to postpone ablation in favor of lifestyle modification is not without potential adverse consequences,” they added.

Dr. Black-Maier and Dr. Piccini agree with the need for additional prospective randomized clinical trials to confirm that exercise training to improve cardiorespiratory fitness before AFib ablation is practical and effective for reducing arrhythmia recurrence.

“Over the past 50-plus years, our understanding of cardiorespiratory fitness, exercise capacity, and arrhythmia occurrence in patients with [AFib] continues to evolve,” the editorialists concluded. Data from the study “clearly demonstrate that arrhythmia-free survival is indeed survival of the fittest. Time will tell if exercise training and improvements in cardiorespiratory fitness can change outcomes after ablation.”

The study was sponsored by the Cleveland Clinic. Dr. Jaber and Dr. Black-Maier report no relevant financial relationships. Dr. Piccini receives grants for clinical research from Abbott, the American Heart Association, the Association for the Advancement of Medical Instrumentation, Bayer, Boston Scientific, and Philips and serves as a consultant to Abbott, Allergan, ARCA Biopharma, Biotronik, Boston Scientific, LivaNova, Medtronic, Milestone, MyoKardia, Sanofi, Philips, and UpToDate.
 

A version of this story originally appeared on Medscape.com.

Higher baseline cardiorespiratory fitness (CRF) is associated with better outcomes after atrial fibrillation (AFib) ablation, according to new research.

In a single-center, retrospective cohort study, patients with the highest level of baseline CRF had significantly lower rates of arrhythmia recurrence and death than did patients with lower levels of CRF.

“It is stunning how just a simple measure, in this case walking on a treadmill, can predict whether atrial fibrillation ablation will be a successful endeavor or if it will fail,” senior author Wael A. Jaber, MD, professor of medicine, Cleveland Clinic, said in an interview.

“We found that ablation was not successful in most patients who had poor functional class and, conversely, that it was successful in most patients who were in tip-top shape when they walked on the treadmill. Our results can help clinicians inform patients about what they can expect after the procedure, depending on the baseline fitness level,” Dr. Jaber said.

The study was published online Aug. 2 in Heart Rhythm.

Several studies have shown a reduction in AFib incidence among individuals who report a physically active lifestyle, but the extent to which baseline CRF influences arrhythmia rates after AFib ablation is unknown, the authors note.

For the study, Dr. Jaber and colleagues analyzed results in 591 consecutive patients (mean age, 66.5 years; 75% male) with symptomatic paroxysmal or persistent AFib who underwent de novo AFib ablation at their institution. Only patients who had undergone an exercise stress test in the 12 months before AFib ablation (average, 4.5 months) were included.

Age- and sex-specific predicted metabolic equivalents (METs) were calculated using the St. James model for women and the Veterans Affairs referral model for men. The number of METs achieved was then divided by the predicted METs, and the patients were categorized into low (<85% predicted; n = 152), adequate (85%-100% predicted; n = 115), and high (>100% predicted; n = 324) CRF groups. Functional capacity was characterized as poor in 56 patients (9.5%), fair in 94 (16.0%), average in 225 (38.1%), good in 169 (28.6%), and high in 47 (8.0%).

During a mean follow-up of 32 months, arrhythmia recurrence was observed in 79% of patients in the low-CRF group, 54% of patients in the adequate-CRF group, and 27.5% of patients in the high-CRF group (P < .0001). Rates of repeat arrhythmia-related hospitalization, repeat rhythm-control procedures, and the need for ongoing antiarrhythmic therapy (ATT) were significantly lower in the high-CRF group. Specifically, ATT was stopped in 56% of patients in the high-CRF group, compared with 24% in the adequate-CRF group and 11% in the low-CRF group (P < .0001). Rehospitalization for arrhythmia was required in 18.5%, 38.0%, and 60.5% of cases, respectively, and repeat direct-current cardioversion or ablation was performed in 26.0%, 49.0%, and 65.0%, respectively (P < .0001 for both).

Death occurred in 11% of the low-CRF group, compared with 4% in the adequate-CRF group and 2.5% in the high-CRF group. Most (70%) of the deaths were caused by cardiovascular events, including heart failure, cardiac arrest, and coronary artery disease. The most common cause of noncardiac death was respiratory failure (13%), followed by sepsis (10%), malignancy (3%), and complications of Parkinson’s disease (3%).

“Although there was a statistically significant association between higher CRF and lower mortality in this cohort, the findings are to be viewed through the prism of a small sample size and relatively low death rate,” the authors wrote.


 

Don’t “overpromise” results

“The important message for clinicians is that when, you are discussing what to expect after atrial fibrillation ablation with your patients, do not overpromise the results. You can inform them that the success of the procedure depends more on how they perform on the baseline exercise test, and less on the ablation itself,” Dr. Jaber said.

Clinicians might want to consider advising their patients to become more active and increase their fitness level before undergoing the procedure, but whether doing so will improve outcomes is still unknown.

“This is what we don’t know. It makes sense. Hopefully, our results will encourage people to be more active before they arrive here for the procedure,” he said. “Our study is retrospective and is hypothesis generating, but we are planning a prospective study where patients will be referred to cardiac rehab prior to having ablation to try to improve their functional class to see if this will improve outcomes.”

Survival of the fittest

In an accompanying editorial commentary, Eric Black-Maier, MD, and Jonathan P. Piccini Sr, MD, from Duke University Medical Center, Durham, N.C., wrote that the findings have “important implications for clinical practice and raise important additional questions.”

They note that catheter ablation as a first-line rhythm-control strategy, per current recommendations, “seems reasonable” in individuals with high baseline cardiorespiratory fitness, but that the benefit is less clear for patients with poor baseline CRF and uncontrolled risk factors.

“Significant limitations in functional status may be at least partially attributable to uncontrolled [AFib], and patients with limited exercise capacity may stand to gain most from successful catheter ablation,” the editorialists wrote.

“Furthermore, because shorter time from [AFib] diagnosis to catheter ablation has been associated with improved outcomes, the decision to postpone ablation in favor of lifestyle modification is not without potential adverse consequences,” they added.

Dr. Black-Maier and Dr. Piccini agree with the need for additional prospective randomized clinical trials to confirm that exercise training to improve cardiorespiratory fitness before AFib ablation is practical and effective for reducing arrhythmia recurrence.

“Over the past 50-plus years, our understanding of cardiorespiratory fitness, exercise capacity, and arrhythmia occurrence in patients with [AFib] continues to evolve,” the editorialists concluded. Data from the study “clearly demonstrate that arrhythmia-free survival is indeed survival of the fittest. Time will tell if exercise training and improvements in cardiorespiratory fitness can change outcomes after ablation.”

The study was sponsored by the Cleveland Clinic. Dr. Jaber and Dr. Black-Maier report no relevant financial relationships. Dr. Piccini receives grants for clinical research from Abbott, the American Heart Association, the Association for the Advancement of Medical Instrumentation, Bayer, Boston Scientific, and Philips and serves as a consultant to Abbott, Allergan, ARCA Biopharma, Biotronik, Boston Scientific, LivaNova, Medtronic, Milestone, MyoKardia, Sanofi, Philips, and UpToDate.
 

A version of this story originally appeared on Medscape.com.

The benefits from sodium-glucose cotransporter 2 inhibitor drugs proven during the past year for cutting heart failure hospitalization rates substantially in patients with heart failure with reduced ejection fraction and slowing progression of chronic kidney disease, all regardless of diabetes status, have thrust this drug class into the top tier of agents for potentially treating millions of patients with cardiac or renal disease.

The sodium-glucose cotransporter 2 (SGLT2) inhibitors, first licensed for U.S. marketing in 2013 purely for glycemic control, have, during the 5 years since the first cardiovascular outcome trial results for the class came out, shown benefits in a range of patients reminiscent of what’s been established for ACE inhibitors and angiotensin receptor blockers (ARBs).

The wide-reaching benefits of SGLT2 inhibitors have recently become even more relevant by showing clinically meaningful effects in patients without type 2 diabetes (T2D). And in an uncanny coincidence, the SGLT2 inhibitors appear to act in complementary harmony with the ACE inhibitors and ARBs for preserving heart and renal function. These properties have made the SGLT2 inhibitors especially attractive as a new weapon for controlling the ascendant disorder of cardiorenal syndrome.

“SGLT2 inhibitors have a relatively greater impact on cardiovascular outcomes, compared with ACE inhibitors and ARBs, but the effects [of the two classes] are synergistic and ideally patients receive both,” said Peter McCullough, MD, a specialist in treating cardiorenal syndrome and other cardiovascular and renal disorders at Baylor, Scott, and White Heart and Vascular Hospital in Dallas. The SGLT2 inhibitors are among the drugs best suited to both treating and preventing cardiorenal syndrome by targeting both ends of the disorder, said Dr. McCullough, who chaired an American Heart Association panel that last year issued a scientific statement on cardiorenal syndrome (Circulation. 2019 Apr 16;139[16]:e840-78).

Although data on the SGLT2 inhibitors “are evolving,” the drug class is “going in the direction” of being “reasonably compared” with the ACE inhibitors and ARBs, said Javed Butler, MD, professor and chair of medicine at the University of Mississippi Medical Center, Jackson. “There are certainly complementary benefits that we see for both cardiovascular and renal outcomes.”

“We’ll think more and more about the SGLT2 inhibitors like renin-angiotensin system [RAS] inhibitors,” said David Z. Cherney, MD, referring to the drug class that includes ACE inhibitors and ARBs. “We should start to approach SGLT2 inhibitors like RAS inhibitors, with pleiotropic effects that go beyond glucose,” said Dr. Cherney, a nephrologist and professor of medicine at the University of Toronto, during the virtual annual scientific sessions of the American Diabetes Association in June 2020.
 

Working together in the nephron

One of the clearest complementary interactions between the SGLT2 inhibitors and the RAS inhibitors is their ability to reduce intraglomerular pressure, a key mechanism that slows nephron loss and progression of chronic kidney disease. SGLT2 inhibitors reduce sodium absorption in the proximal tubule that causes, through tubuloglomerular feedback, afferent arteriole constriction that lowers intraglomerular pressure, while the RAS inhibitors inhibit efferent arteriole constriction mediated by angiotensin II, also cutting intraglomerular pressure. Together, “they almost work in tandem,” explained Janani Rangaswami, MD, a nephrologist at Einstein Medical Center in Philadelphia, vice chair of the Kidney Council of the AHA, and first author of the 2019 cardiorenal syndrome AHA statement.

“Many had worried that if we target both the afferent and efferent arterioles simultaneously, it might increase the risk for acute kidney injury. What has been reassuring in both the recent data from the DAPA-HF trial and in recent meta-analysis was no evidence of increased risk for acute kidney injury with use of the SGLT2 inhibitor,” Dr. Rangaswami said in an interview. For example, a recent report on more than 39,000 Canadian patients with T2D who were at least 66 years old and newly begun on either an SGLT2 inhibitor or a different oral diabetes drug (a dipeptidyl peptidase–4 inhibitor), found a statistically significant 21% lower rate of acute kidney injury during the first 90 days on treatment with an SGLT2 inhibitor in a propensity score–matched analysis (CMAJ. 2020 Apr 6;192: e351-60).

Sara Freeman/MDedge News

Much of the concern about possible acute kidney injury stemmed from a property that the SGLT2 inhibitors share with RAS inhibitors: They cause an initial, reversible decline in glomerular filtration rate (GFR), followed by longer-term nephron preservation, a pattern attributable to reduced intraglomerular pressure. The question early on was: “ ‘Does this harm the kidney?’ But what we’ve seen is that patients do better over time, even with this initial hit. Whenever you offload the glomerulus you cut barotrauma and protect renal function,” explained Silvio E. Inzucchi, MD, professor of medicine at Yale University, New Haven, Conn., and director of the Yale Medicine Diabetes Center.

Dr. Inzucchi cautioned, however, that a small number of patients starting treatment with an SGLT2 inhibitor may have their GFR drop too sharply, especially if their GFR was low to start with. “You need to be careful, especially at the lower end of the GFR range. I recheck renal function after 1 month” after a patient starts an SGLT2. Patients whose level falls too low may need to discontinue. He added that it’s hard to set a uniform threshold for alarm, and instead assess patients on a case-by-case basis, but “you need some threshold in mind, where you will stop” treatment.
 

A smarter diuretic

One of the most intriguing renal effects of SGLT2 inhibitors is their diuretic action. During a talk at the virtual ADA scientific sessions, cardiologist Jeffrey Testani, MD, called them “smart” diuretics, because their effect on diuresis is relatively modest but comes without the neurohormonal price paid when patients take conventional loop diuretics.

”Loop diuretics are particularly bad,” causing neurohormonal activation that includes norepinephrine, renin, and vasopressin, said Dr. Testani, director of heart failure research at Yale. They also fail to produce a meaningful drop in blood volume despite causing substantial natriuresis.

In contrast, SGLT2 inhibitors cause “moderate” natriuresis while producing a significant cut in blood volume. “The body seems content with this lower plasma volume without activating catecholamines or renin, and that’s how the SGLT2 inhibitors differ from other diuretics,” said Dr. Inzucchi.

The class also maintains serum levels of potassium and magnesium, produces significant improvements in serum uric acid levels, and avoids the electrolyte abnormalities, volume depletion, and acute kidney injury that can occur with conventional distal diuretics, Dr. Testani said.

In short, the SGLT2 inhibitors “are safe and easy-to-use diuretics,” which allows them to fill a “huge unmet need for patients with heart failure.” As evidence accumulates for the benefits of the drug class in patients with heart failure and renal disease, “uptake will be extensive,” Dr. Testani predicted, driven in part by how easy it is to add the class to existing cardiorenal drug regimens.

Other standard therapies for patients with heart failure with reduced ejection fraction (HFrEF) risk electrolyte abnormalities, renal dysfunction, significantly lower blood pressure, often make patients feel worse, and involve a slow and laborious titration process, Dr. Testani noted. The SGLT2 inhibitor agents avoid these issues, a property that has played out in quality of life assessments of patients with HFrEF who received a drug from this class.
 

Outcomes met in trial after trial

In the DAPA-HF trial, with 4,443 patients with HFrEF and divided roughly equally between those with or without T2D, treatment with dapagliflozin (Farxiga) linked with significant improvements in health status and quality of life measured by the Kansas City Cardiomyopathy Questionnaire (Circulation. 2020 Jan 14;141[2]:90-9). “Not all treatments for HFrEF improve symptoms,” but in this study the SGTL2 inhibitor dapagliflozin did, boosting the Kansas City Cardiomyopathy Questionnaire score by about the same magnitude as treatment with a cardiac resynchronization device in patients with HFrEF, said Mikhail N. Kosiborod, MD, director of Cardiometabolic Research at Saint Luke’s Mid America Heart Institute in Kansas City, Mo., speaking at the virtual ADA scientific sessions.

Two more recent renal observations have further solidified the growing role of these drugs for kidney protection. Results from the CREDENCE trial that looked at canagliflozin (Invokana) treatment in 4,401 patients with T2D and albuminuria and chronic kidney disease showed canagliflozin treatment cut the primary, composite renal endpoint by a statistically significant 30%, compared with placebo (N Engl J Med. 2019 Jun 13;380[24]:2295-306). The study stopped earlier than planned because of how effective canagliflozin appeared.

Sara Freeman/Frontline Medical News

“Never before has a renal protection clinical trial stopped for overwhelming efficacy,” noted nephrologist Katherine R. Tuttle, MD, executive director for research at Providence Health Care in Spokane, Wash. “It’s very exciting to have a treatment that works on both the heart and kidney, given their interrelationship,” she said during the ADA sessions. Dr. Tuttle called the cardiorenal effects from the SGLT2 inhibitors “amazing.”

Just as the DAPA-HF trial’s primary outcome showed the ability of at least one drug from the class, dapagliflozin, to improve outcomes in HFrEF patients without T2D, topline results recently reported from the DAPA-CDK trial showed for the first time renal protection by an SGLT2 inhibitor in patients with chronic kidney disease but no T2D, in a study with about 4,300 patients.

Although detailed results from DAPA-CKD are not yet available, so far the outcomes seem consistent with the CREDENCE findings, and the cumulative renal findings for the class show the SGLT2 inhibitors have “potential for a profound impact on the patients we see in every nephrology clinic, and with dual cardiorenal disease,” said Dr. Rangaswami. The class is now established as “standard of care for patients with chronic kidney disease. The CREDENCE results made that clear.”

The DAPA-CKD findings in patients with chronic kidney disease regardless of their diabetes status “are very important. We really have not had any advances in this space for some time, and chronic kidney disease patients have very poor outcomes, both cardiovascular and renal,” commented Dr. Butler. The advantage from using this drug class in these patients “is huge.”

The DAPA-CKD findings are a “major advance,” agreed Dr. McCullough.
 

SGLT2 inhibitor use needs to grow

Experts lament that although the evidence favoring the class has been very bullish, prescribing uptake has been slow, perhaps partly explained by the retail U.S. cost for most of these agents, generally about $17/day.

Cost is, unfortunately, an issue right now for these drugs, said Dr. Butler. Generic formulations are imminent, “but we cannot accept waiting. Providing this therapy when insurance coverage is available,” is essential.

The FDA has already granted tentative approval to some generic formulations, although resolution of patent issues can delay generics actually reaching the market. “Generic dapagliflozin will have a major impact; the marketplace for these drugs will shift very quickly,” predicted Dr. McCullough.

But price may not be the sole barrier, cautioned Dr. Rangaswami. “I don’t think it’s just a cost issue. Several factors explain the slow uptake,” of the SGLT2 inhibitors. “The biggest barrier is that this is a new drug class, and understanding how to use the class is not yet where it needs to be in the physician community.” One of the biggest problems is that the SGLT2 inhibitors are still primarily regarded as drugs to treat hyperglycemia.

Physicians who treat patients with heart or renal disease “need to wrap their head around the idea that a drug with antihyperglycemic effects is now in their practice territory, and something they need to prescribe,” she noted. Currently “there is a reluctance to prescribe these drugs given the perception that they are antihyperglycemic agents, and usually get deferred to primary care physicians or endocrinologists. This results in huge missed opportunities by cardiologists and nephrologists in initiating these agents that have major cardiorenal risk reduction effects.”

The key role that cardiologists need to play in prescribing the SGLT2 inhibitors was brought home in a recent study of two representative U.S. health systems that showed patients with T2D were far more likely to see a cardiologist than an endocrinologist (Cardiovasc Endocrinol Metab. 2020 Jun;9[2]:56-9).

“The SGLT2 inhibitors are definitely a game-changing drug class,” summed up Dr. Rangaswami. “We’re going to see a lot of use in patients with heart and kidney disease.”

Dr. Cherney has been a consultant to or has received honoraria from AstraZeneca, Boehringer Ingelheim, Janssen, Lilly, Merck, Mitsubishi Tanabe Pharma, and Sanofi. Dr. Butler has had financial relationships with numerous pharmaceutical companies. Dr. McCullough and Dr. Rangaswami had no disclosures. Dr. Inzucchi has been a consultant to or helped run trials for Abbott, AstraZeneca, Boehringer Ingelheim, Merck, Novo Nordisk, Sanofi/Lexicon, and vTv Therapeutics. Dr. Testani has been a consultant to AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, cardionomic, FIRE1 Magenta Med, Novartis, Reprieve, Sanofi, and W.L. Gore. Dr. Kosiborod has been a consultant to or led trials for Amarin, Amgen, Applied Therapeutics, AstraZeneca, Bayer, Boehringer Ingelheim, Glytec, Janssen, Eli Lilly, Merck, Novartis, Novo Nordisk, Sanofi, and Vifor. Dr. Tuttle has been a consultant to AstraZeneca, Boehringer Ingelheim, Gilead, Goldfinch Bio, Eli Lilly, and Novo Nordisk.

[email protected]

The benefits from sodium-glucose cotransporter 2 inhibitor drugs proven during the past year for cutting heart failure hospitalization rates substantially in patients with heart failure with reduced ejection fraction and slowing progression of chronic kidney disease, all regardless of diabetes status, have thrust this drug class into the top tier of agents for potentially treating millions of patients with cardiac or renal disease.

The sodium-glucose cotransporter 2 (SGLT2) inhibitors, first licensed for U.S. marketing in 2013 purely for glycemic control, have, during the 5 years since the first cardiovascular outcome trial results for the class came out, shown benefits in a range of patients reminiscent of what’s been established for ACE inhibitors and angiotensin receptor blockers (ARBs).

The wide-reaching benefits of SGLT2 inhibitors have recently become even more relevant by showing clinically meaningful effects in patients without type 2 diabetes (T2D). And in an uncanny coincidence, the SGLT2 inhibitors appear to act in complementary harmony with the ACE inhibitors and ARBs for preserving heart and renal function. These properties have made the SGLT2 inhibitors especially attractive as a new weapon for controlling the ascendant disorder of cardiorenal syndrome.

“SGLT2 inhibitors have a relatively greater impact on cardiovascular outcomes, compared with ACE inhibitors and ARBs, but the effects [of the two classes] are synergistic and ideally patients receive both,” said Peter McCullough, MD, a specialist in treating cardiorenal syndrome and other cardiovascular and renal disorders at Baylor, Scott, and White Heart and Vascular Hospital in Dallas. The SGLT2 inhibitors are among the drugs best suited to both treating and preventing cardiorenal syndrome by targeting both ends of the disorder, said Dr. McCullough, who chaired an American Heart Association panel that last year issued a scientific statement on cardiorenal syndrome (Circulation. 2019 Apr 16;139[16]:e840-78).

Although data on the SGLT2 inhibitors “are evolving,” the drug class is “going in the direction” of being “reasonably compared” with the ACE inhibitors and ARBs, said Javed Butler, MD, professor and chair of medicine at the University of Mississippi Medical Center, Jackson. “There are certainly complementary benefits that we see for both cardiovascular and renal outcomes.”

“We’ll think more and more about the SGLT2 inhibitors like renin-angiotensin system [RAS] inhibitors,” said David Z. Cherney, MD, referring to the drug class that includes ACE inhibitors and ARBs. “We should start to approach SGLT2 inhibitors like RAS inhibitors, with pleiotropic effects that go beyond glucose,” said Dr. Cherney, a nephrologist and professor of medicine at the University of Toronto, during the virtual annual scientific sessions of the American Diabetes Association in June 2020.
 

Working together in the nephron

One of the clearest complementary interactions between the SGLT2 inhibitors and the RAS inhibitors is their ability to reduce intraglomerular pressure, a key mechanism that slows nephron loss and progression of chronic kidney disease. SGLT2 inhibitors reduce sodium absorption in the proximal tubule that causes, through tubuloglomerular feedback, afferent arteriole constriction that lowers intraglomerular pressure, while the RAS inhibitors inhibit efferent arteriole constriction mediated by angiotensin II, also cutting intraglomerular pressure. Together, “they almost work in tandem,” explained Janani Rangaswami, MD, a nephrologist at Einstein Medical Center in Philadelphia, vice chair of the Kidney Council of the AHA, and first author of the 2019 cardiorenal syndrome AHA statement.

“Many had worried that if we target both the afferent and efferent arterioles simultaneously, it might increase the risk for acute kidney injury. What has been reassuring in both the recent data from the DAPA-HF trial and in recent meta-analysis was no evidence of increased risk for acute kidney injury with use of the SGLT2 inhibitor,” Dr. Rangaswami said in an interview. For example, a recent report on more than 39,000 Canadian patients with T2D who were at least 66 years old and newly begun on either an SGLT2 inhibitor or a different oral diabetes drug (a dipeptidyl peptidase–4 inhibitor), found a statistically significant 21% lower rate of acute kidney injury during the first 90 days on treatment with an SGLT2 inhibitor in a propensity score–matched analysis (CMAJ. 2020 Apr 6;192: e351-60).

Sara Freeman/MDedge News

Much of the concern about possible acute kidney injury stemmed from a property that the SGLT2 inhibitors share with RAS inhibitors: They cause an initial, reversible decline in glomerular filtration rate (GFR), followed by longer-term nephron preservation, a pattern attributable to reduced intraglomerular pressure. The question early on was: “ ‘Does this harm the kidney?’ But what we’ve seen is that patients do better over time, even with this initial hit. Whenever you offload the glomerulus you cut barotrauma and protect renal function,” explained Silvio E. Inzucchi, MD, professor of medicine at Yale University, New Haven, Conn., and director of the Yale Medicine Diabetes Center.

Dr. Inzucchi cautioned, however, that a small number of patients starting treatment with an SGLT2 inhibitor may have their GFR drop too sharply, especially if their GFR was low to start with. “You need to be careful, especially at the lower end of the GFR range. I recheck renal function after 1 month” after a patient starts an SGLT2. Patients whose level falls too low may need to discontinue. He added that it’s hard to set a uniform threshold for alarm, and instead assess patients on a case-by-case basis, but “you need some threshold in mind, where you will stop” treatment.
 

A smarter diuretic

One of the most intriguing renal effects of SGLT2 inhibitors is their diuretic action. During a talk at the virtual ADA scientific sessions, cardiologist Jeffrey Testani, MD, called them “smart” diuretics, because their effect on diuresis is relatively modest but comes without the neurohormonal price paid when patients take conventional loop diuretics.

”Loop diuretics are particularly bad,” causing neurohormonal activation that includes norepinephrine, renin, and vasopressin, said Dr. Testani, director of heart failure research at Yale. They also fail to produce a meaningful drop in blood volume despite causing substantial natriuresis.

In contrast, SGLT2 inhibitors cause “moderate” natriuresis while producing a significant cut in blood volume. “The body seems content with this lower plasma volume without activating catecholamines or renin, and that’s how the SGLT2 inhibitors differ from other diuretics,” said Dr. Inzucchi.

The class also maintains serum levels of potassium and magnesium, produces significant improvements in serum uric acid levels, and avoids the electrolyte abnormalities, volume depletion, and acute kidney injury that can occur with conventional distal diuretics, Dr. Testani said.

In short, the SGLT2 inhibitors “are safe and easy-to-use diuretics,” which allows them to fill a “huge unmet need for patients with heart failure.” As evidence accumulates for the benefits of the drug class in patients with heart failure and renal disease, “uptake will be extensive,” Dr. Testani predicted, driven in part by how easy it is to add the class to existing cardiorenal drug regimens.

Other standard therapies for patients with heart failure with reduced ejection fraction (HFrEF) risk electrolyte abnormalities, renal dysfunction, significantly lower blood pressure, often make patients feel worse, and involve a slow and laborious titration process, Dr. Testani noted. The SGLT2 inhibitor agents avoid these issues, a property that has played out in quality of life assessments of patients with HFrEF who received a drug from this class.
 

Outcomes met in trial after trial

In the DAPA-HF trial, with 4,443 patients with HFrEF and divided roughly equally between those with or without T2D, treatment with dapagliflozin (Farxiga) linked with significant improvements in health status and quality of life measured by the Kansas City Cardiomyopathy Questionnaire (Circulation. 2020 Jan 14;141[2]:90-9). “Not all treatments for HFrEF improve symptoms,” but in this study the SGTL2 inhibitor dapagliflozin did, boosting the Kansas City Cardiomyopathy Questionnaire score by about the same magnitude as treatment with a cardiac resynchronization device in patients with HFrEF, said Mikhail N. Kosiborod, MD, director of Cardiometabolic Research at Saint Luke’s Mid America Heart Institute in Kansas City, Mo., speaking at the virtual ADA scientific sessions.

Two more recent renal observations have further solidified the growing role of these drugs for kidney protection. Results from the CREDENCE trial that looked at canagliflozin (Invokana) treatment in 4,401 patients with T2D and albuminuria and chronic kidney disease showed canagliflozin treatment cut the primary, composite renal endpoint by a statistically significant 30%, compared with placebo (N Engl J Med. 2019 Jun 13;380[24]:2295-306). The study stopped earlier than planned because of how effective canagliflozin appeared.

Sara Freeman/Frontline Medical News

“Never before has a renal protection clinical trial stopped for overwhelming efficacy,” noted nephrologist Katherine R. Tuttle, MD, executive director for research at Providence Health Care in Spokane, Wash. “It’s very exciting to have a treatment that works on both the heart and kidney, given their interrelationship,” she said during the ADA sessions. Dr. Tuttle called the cardiorenal effects from the SGLT2 inhibitors “amazing.”

Just as the DAPA-HF trial’s primary outcome showed the ability of at least one drug from the class, dapagliflozin, to improve outcomes in HFrEF patients without T2D, topline results recently reported from the DAPA-CDK trial showed for the first time renal protection by an SGLT2 inhibitor in patients with chronic kidney disease but no T2D, in a study with about 4,300 patients.

Although detailed results from DAPA-CKD are not yet available, so far the outcomes seem consistent with the CREDENCE findings, and the cumulative renal findings for the class show the SGLT2 inhibitors have “potential for a profound impact on the patients we see in every nephrology clinic, and with dual cardiorenal disease,” said Dr. Rangaswami. The class is now established as “standard of care for patients with chronic kidney disease. The CREDENCE results made that clear.”

The DAPA-CKD findings in patients with chronic kidney disease regardless of their diabetes status “are very important. We really have not had any advances in this space for some time, and chronic kidney disease patients have very poor outcomes, both cardiovascular and renal,” commented Dr. Butler. The advantage from using this drug class in these patients “is huge.”

The DAPA-CKD findings are a “major advance,” agreed Dr. McCullough.
 

SGLT2 inhibitor use needs to grow

Experts lament that although the evidence favoring the class has been very bullish, prescribing uptake has been slow, perhaps partly explained by the retail U.S. cost for most of these agents, generally about $17/day.

Cost is, unfortunately, an issue right now for these drugs, said Dr. Butler. Generic formulations are imminent, “but we cannot accept waiting. Providing this therapy when insurance coverage is available,” is essential.

The FDA has already granted tentative approval to some generic formulations, although resolution of patent issues can delay generics actually reaching the market. “Generic dapagliflozin will have a major impact; the marketplace for these drugs will shift very quickly,” predicted Dr. McCullough.

But price may not be the sole barrier, cautioned Dr. Rangaswami. “I don’t think it’s just a cost issue. Several factors explain the slow uptake,” of the SGLT2 inhibitors. “The biggest barrier is that this is a new drug class, and understanding how to use the class is not yet where it needs to be in the physician community.” One of the biggest problems is that the SGLT2 inhibitors are still primarily regarded as drugs to treat hyperglycemia.

Physicians who treat patients with heart or renal disease “need to wrap their head around the idea that a drug with antihyperglycemic effects is now in their practice territory, and something they need to prescribe,” she noted. Currently “there is a reluctance to prescribe these drugs given the perception that they are antihyperglycemic agents, and usually get deferred to primary care physicians or endocrinologists. This results in huge missed opportunities by cardiologists and nephrologists in initiating these agents that have major cardiorenal risk reduction effects.”

The key role that cardiologists need to play in prescribing the SGLT2 inhibitors was brought home in a recent study of two representative U.S. health systems that showed patients with T2D were far more likely to see a cardiologist than an endocrinologist (Cardiovasc Endocrinol Metab. 2020 Jun;9[2]:56-9).

“The SGLT2 inhibitors are definitely a game-changing drug class,” summed up Dr. Rangaswami. “We’re going to see a lot of use in patients with heart and kidney disease.”

Dr. Cherney has been a consultant to or has received honoraria from AstraZeneca, Boehringer Ingelheim, Janssen, Lilly, Merck, Mitsubishi Tanabe Pharma, and Sanofi. Dr. Butler has had financial relationships with numerous pharmaceutical companies. Dr. McCullough and Dr. Rangaswami had no disclosures. Dr. Inzucchi has been a consultant to or helped run trials for Abbott, AstraZeneca, Boehringer Ingelheim, Merck, Novo Nordisk, Sanofi/Lexicon, and vTv Therapeutics. Dr. Testani has been a consultant to AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, cardionomic, FIRE1 Magenta Med, Novartis, Reprieve, Sanofi, and W.L. Gore. Dr. Kosiborod has been a consultant to or led trials for Amarin, Amgen, Applied Therapeutics, AstraZeneca, Bayer, Boehringer Ingelheim, Glytec, Janssen, Eli Lilly, Merck, Novartis, Novo Nordisk, Sanofi, and Vifor. Dr. Tuttle has been a consultant to AstraZeneca, Boehringer Ingelheim, Gilead, Goldfinch Bio, Eli Lilly, and Novo Nordisk.

[email protected]

The benefits from sodium-glucose cotransporter 2 inhibitor drugs proven during the past year for cutting heart failure hospitalization rates substantially in patients with heart failure with reduced ejection fraction and slowing progression of chronic kidney disease, all regardless of diabetes status, have thrust this drug class into the top tier of agents for potentially treating millions of patients with cardiac or renal disease.

The sodium-glucose cotransporter 2 (SGLT2) inhibitors, first licensed for U.S. marketing in 2013 purely for glycemic control, have, during the 5 years since the first cardiovascular outcome trial results for the class came out, shown benefits in a range of patients reminiscent of what’s been established for ACE inhibitors and angiotensin receptor blockers (ARBs).

The wide-reaching benefits of SGLT2 inhibitors have recently become even more relevant by showing clinically meaningful effects in patients without type 2 diabetes (T2D). And in an uncanny coincidence, the SGLT2 inhibitors appear to act in complementary harmony with the ACE inhibitors and ARBs for preserving heart and renal function. These properties have made the SGLT2 inhibitors especially attractive as a new weapon for controlling the ascendant disorder of cardiorenal syndrome.

“SGLT2 inhibitors have a relatively greater impact on cardiovascular outcomes, compared with ACE inhibitors and ARBs, but the effects [of the two classes] are synergistic and ideally patients receive both,” said Peter McCullough, MD, a specialist in treating cardiorenal syndrome and other cardiovascular and renal disorders at Baylor, Scott, and White Heart and Vascular Hospital in Dallas. The SGLT2 inhibitors are among the drugs best suited to both treating and preventing cardiorenal syndrome by targeting both ends of the disorder, said Dr. McCullough, who chaired an American Heart Association panel that last year issued a scientific statement on cardiorenal syndrome (Circulation. 2019 Apr 16;139[16]:e840-78).

Although data on the SGLT2 inhibitors “are evolving,” the drug class is “going in the direction” of being “reasonably compared” with the ACE inhibitors and ARBs, said Javed Butler, MD, professor and chair of medicine at the University of Mississippi Medical Center, Jackson. “There are certainly complementary benefits that we see for both cardiovascular and renal outcomes.”

“We’ll think more and more about the SGLT2 inhibitors like renin-angiotensin system [RAS] inhibitors,” said David Z. Cherney, MD, referring to the drug class that includes ACE inhibitors and ARBs. “We should start to approach SGLT2 inhibitors like RAS inhibitors, with pleiotropic effects that go beyond glucose,” said Dr. Cherney, a nephrologist and professor of medicine at the University of Toronto, during the virtual annual scientific sessions of the American Diabetes Association in June 2020.
 

Working together in the nephron

One of the clearest complementary interactions between the SGLT2 inhibitors and the RAS inhibitors is their ability to reduce intraglomerular pressure, a key mechanism that slows nephron loss and progression of chronic kidney disease. SGLT2 inhibitors reduce sodium absorption in the proximal tubule that causes, through tubuloglomerular feedback, afferent arteriole constriction that lowers intraglomerular pressure, while the RAS inhibitors inhibit efferent arteriole constriction mediated by angiotensin II, also cutting intraglomerular pressure. Together, “they almost work in tandem,” explained Janani Rangaswami, MD, a nephrologist at Einstein Medical Center in Philadelphia, vice chair of the Kidney Council of the AHA, and first author of the 2019 cardiorenal syndrome AHA statement.

“Many had worried that if we target both the afferent and efferent arterioles simultaneously, it might increase the risk for acute kidney injury. What has been reassuring in both the recent data from the DAPA-HF trial and in recent meta-analysis was no evidence of increased risk for acute kidney injury with use of the SGLT2 inhibitor,” Dr. Rangaswami said in an interview. For example, a recent report on more than 39,000 Canadian patients with T2D who were at least 66 years old and newly begun on either an SGLT2 inhibitor or a different oral diabetes drug (a dipeptidyl peptidase–4 inhibitor), found a statistically significant 21% lower rate of acute kidney injury during the first 90 days on treatment with an SGLT2 inhibitor in a propensity score–matched analysis (CMAJ. 2020 Apr 6;192: e351-60).

Sara Freeman/MDedge News

Much of the concern about possible acute kidney injury stemmed from a property that the SGLT2 inhibitors share with RAS inhibitors: They cause an initial, reversible decline in glomerular filtration rate (GFR), followed by longer-term nephron preservation, a pattern attributable to reduced intraglomerular pressure. The question early on was: “ ‘Does this harm the kidney?’ But what we’ve seen is that patients do better over time, even with this initial hit. Whenever you offload the glomerulus you cut barotrauma and protect renal function,” explained Silvio E. Inzucchi, MD, professor of medicine at Yale University, New Haven, Conn., and director of the Yale Medicine Diabetes Center.

Dr. Inzucchi cautioned, however, that a small number of patients starting treatment with an SGLT2 inhibitor may have their GFR drop too sharply, especially if their GFR was low to start with. “You need to be careful, especially at the lower end of the GFR range. I recheck renal function after 1 month” after a patient starts an SGLT2. Patients whose level falls too low may need to discontinue. He added that it’s hard to set a uniform threshold for alarm, and instead assess patients on a case-by-case basis, but “you need some threshold in mind, where you will stop” treatment.
 

A smarter diuretic

One of the most intriguing renal effects of SGLT2 inhibitors is their diuretic action. During a talk at the virtual ADA scientific sessions, cardiologist Jeffrey Testani, MD, called them “smart” diuretics, because their effect on diuresis is relatively modest but comes without the neurohormonal price paid when patients take conventional loop diuretics.

”Loop diuretics are particularly bad,” causing neurohormonal activation that includes norepinephrine, renin, and vasopressin, said Dr. Testani, director of heart failure research at Yale. They also fail to produce a meaningful drop in blood volume despite causing substantial natriuresis.

In contrast, SGLT2 inhibitors cause “moderate” natriuresis while producing a significant cut in blood volume. “The body seems content with this lower plasma volume without activating catecholamines or renin, and that’s how the SGLT2 inhibitors differ from other diuretics,” said Dr. Inzucchi.

The class also maintains serum levels of potassium and magnesium, produces significant improvements in serum uric acid levels, and avoids the electrolyte abnormalities, volume depletion, and acute kidney injury that can occur with conventional distal diuretics, Dr. Testani said.

In short, the SGLT2 inhibitors “are safe and easy-to-use diuretics,” which allows them to fill a “huge unmet need for patients with heart failure.” As evidence accumulates for the benefits of the drug class in patients with heart failure and renal disease, “uptake will be extensive,” Dr. Testani predicted, driven in part by how easy it is to add the class to existing cardiorenal drug regimens.

Other standard therapies for patients with heart failure with reduced ejection fraction (HFrEF) risk electrolyte abnormalities, renal dysfunction, significantly lower blood pressure, often make patients feel worse, and involve a slow and laborious titration process, Dr. Testani noted. The SGLT2 inhibitor agents avoid these issues, a property that has played out in quality of life assessments of patients with HFrEF who received a drug from this class.
 

Outcomes met in trial after trial

In the DAPA-HF trial, with 4,443 patients with HFrEF and divided roughly equally between those with or without T2D, treatment with dapagliflozin (Farxiga) linked with significant improvements in health status and quality of life measured by the Kansas City Cardiomyopathy Questionnaire (Circulation. 2020 Jan 14;141[2]:90-9). “Not all treatments for HFrEF improve symptoms,” but in this study the SGTL2 inhibitor dapagliflozin did, boosting the Kansas City Cardiomyopathy Questionnaire score by about the same magnitude as treatment with a cardiac resynchronization device in patients with HFrEF, said Mikhail N. Kosiborod, MD, director of Cardiometabolic Research at Saint Luke’s Mid America Heart Institute in Kansas City, Mo., speaking at the virtual ADA scientific sessions.

Two more recent renal observations have further solidified the growing role of these drugs for kidney protection. Results from the CREDENCE trial that looked at canagliflozin (Invokana) treatment in 4,401 patients with T2D and albuminuria and chronic kidney disease showed canagliflozin treatment cut the primary, composite renal endpoint by a statistically significant 30%, compared with placebo (N Engl J Med. 2019 Jun 13;380[24]:2295-306). The study stopped earlier than planned because of how effective canagliflozin appeared.

Sara Freeman/Frontline Medical News

“Never before has a renal protection clinical trial stopped for overwhelming efficacy,” noted nephrologist Katherine R. Tuttle, MD, executive director for research at Providence Health Care in Spokane, Wash. “It’s very exciting to have a treatment that works on both the heart and kidney, given their interrelationship,” she said during the ADA sessions. Dr. Tuttle called the cardiorenal effects from the SGLT2 inhibitors “amazing.”

Just as the DAPA-HF trial’s primary outcome showed the ability of at least one drug from the class, dapagliflozin, to improve outcomes in HFrEF patients without T2D, topline results recently reported from the DAPA-CDK trial showed for the first time renal protection by an SGLT2 inhibitor in patients with chronic kidney disease but no T2D, in a study with about 4,300 patients.

Although detailed results from DAPA-CKD are not yet available, so far the outcomes seem consistent with the CREDENCE findings, and the cumulative renal findings for the class show the SGLT2 inhibitors have “potential for a profound impact on the patients we see in every nephrology clinic, and with dual cardiorenal disease,” said Dr. Rangaswami. The class is now established as “standard of care for patients with chronic kidney disease. The CREDENCE results made that clear.”

The DAPA-CKD findings in patients with chronic kidney disease regardless of their diabetes status “are very important. We really have not had any advances in this space for some time, and chronic kidney disease patients have very poor outcomes, both cardiovascular and renal,” commented Dr. Butler. The advantage from using this drug class in these patients “is huge.”

The DAPA-CKD findings are a “major advance,” agreed Dr. McCullough.
 

SGLT2 inhibitor use needs to grow

Experts lament that although the evidence favoring the class has been very bullish, prescribing uptake has been slow, perhaps partly explained by the retail U.S. cost for most of these agents, generally about $17/day.

Cost is, unfortunately, an issue right now for these drugs, said Dr. Butler. Generic formulations are imminent, “but we cannot accept waiting. Providing this therapy when insurance coverage is available,” is essential.

The FDA has already granted tentative approval to some generic formulations, although resolution of patent issues can delay generics actually reaching the market. “Generic dapagliflozin will have a major impact; the marketplace for these drugs will shift very quickly,” predicted Dr. McCullough.

But price may not be the sole barrier, cautioned Dr. Rangaswami. “I don’t think it’s just a cost issue. Several factors explain the slow uptake,” of the SGLT2 inhibitors. “The biggest barrier is that this is a new drug class, and understanding how to use the class is not yet where it needs to be in the physician community.” One of the biggest problems is that the SGLT2 inhibitors are still primarily regarded as drugs to treat hyperglycemia.

Physicians who treat patients with heart or renal disease “need to wrap their head around the idea that a drug with antihyperglycemic effects is now in their practice territory, and something they need to prescribe,” she noted. Currently “there is a reluctance to prescribe these drugs given the perception that they are antihyperglycemic agents, and usually get deferred to primary care physicians or endocrinologists. This results in huge missed opportunities by cardiologists and nephrologists in initiating these agents that have major cardiorenal risk reduction effects.”

The key role that cardiologists need to play in prescribing the SGLT2 inhibitors was brought home in a recent study of two representative U.S. health systems that showed patients with T2D were far more likely to see a cardiologist than an endocrinologist (Cardiovasc Endocrinol Metab. 2020 Jun;9[2]:56-9).

“The SGLT2 inhibitors are definitely a game-changing drug class,” summed up Dr. Rangaswami. “We’re going to see a lot of use in patients with heart and kidney disease.”

Dr. Cherney has been a consultant to or has received honoraria from AstraZeneca, Boehringer Ingelheim, Janssen, Lilly, Merck, Mitsubishi Tanabe Pharma, and Sanofi. Dr. Butler has had financial relationships with numerous pharmaceutical companies. Dr. McCullough and Dr. Rangaswami had no disclosures. Dr. Inzucchi has been a consultant to or helped run trials for Abbott, AstraZeneca, Boehringer Ingelheim, Merck, Novo Nordisk, Sanofi/Lexicon, and vTv Therapeutics. Dr. Testani has been a consultant to AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, cardionomic, FIRE1 Magenta Med, Novartis, Reprieve, Sanofi, and W.L. Gore. Dr. Kosiborod has been a consultant to or led trials for Amarin, Amgen, Applied Therapeutics, AstraZeneca, Bayer, Boehringer Ingelheim, Glytec, Janssen, Eli Lilly, Merck, Novartis, Novo Nordisk, Sanofi, and Vifor. Dr. Tuttle has been a consultant to AstraZeneca, Boehringer Ingelheim, Gilead, Goldfinch Bio, Eli Lilly, and Novo Nordisk.

[email protected]

Evidence for a link between cannabis use and cardiovascular health remains unsupported, and the potential risks outweigh any potential benefits, according to a scientific statement from the American Heart Association.

American Heart Association

The increased legalization of cannabis and cannabis products in the United States has driven medical professionals to evaluate the safety and efficacy of cannabis in relation to health conditions, wrote Robert L. Page II, PharmD, of the University of Colorado, Aurora, and colleagues.

In a statement published in Circulation, the researchers noted that although cannabis has been shown to relieve pain and other symptoms in certain conditions, clinicians in the United States have been limited from studying its health effects because of federal law restrictions. “Cannabis remains a schedule I controlled substance, deeming no accepted medical use, a high potential for abuse, and an unacceptable safety profile,” the researchers wrote.

The statement addresses issues with the use of cannabis by individuals with cardiovascular disease or those at increased risk. Observational studies have shown no cardiovascular benefits associated with cannabis, the writers noted. The most common chemicals in cannabis include THC (tetrahydrocannabinolic acid) and CBD (cannabidiol).

Some research has shown associations between CBD cardiovascular features including lower blood pressure and reduced inflammation, the writers noted. However, THC, the component of cannabis associated with a “high” or intoxication, has been associated with heart rhythm abnormalities. The writers cited data suggesting an increased risk of heart attacks, atrial fibrillation and heart failure, although more research is needed.

The statement outlines common cannabis formulations including plant-based, extracts, crystalline forms, edible products, and tinctures. In addition, the statement notes that synthetic cannabis products are marketed and used in the United States without subject to regulation.

“Over the past 5 years, we have seen a surge in cannabis use, particularly during the COVID-19 pandemic here in Colorado, especially among adolescents and young adults,” Dr. Page said in an interview. Because of the surge, health care practitioners need to familiarize themselves with not only the benefits, but risks associated with cannabis use regardless of the formulation,” he said. As heart disease remains a leading cause of death in the United States, understanding the cardiovascular risks associated with cannabis is crucial at this time.

Dr. Page noted that popular attitudes about cannabis could pose risks to users’ cardiovascular health. “One leading misconception about cannabis is because it is ‘natural’ it must be safe,” Dr. Page said. “As with all medications, cannabis has side effects, some of which can be cardiovascular in nature,” he said. “Significant drug-drug interactions can occur as CBD and THC, both found in cannabis, inhibit CYP3A4, which metabolizes a large number of medications used to treat many cardiovascular conditions,” he noted.

“Unfortunately, much of the published data is observational in nature due to the federal restrictions on cannabis as a schedule I drug,” said Dr. Page. “Nonetheless, safety signals have emerged regarding cannabis use and adverse cardiovascular outcomes, including myocardial infarction, heart failure, and atrial fibrillation. Carefully designed prospective short- and long-term studies regarding cannabis use and cardiovascular safety are needed,” he emphasized.

Areas in particular need of additional research include the cardiovascular effects of cannabis in several vulnerable populations such as adolescents, older adults, pregnant women, transplant recipients, and those with underlying cardiovascular disease, said Dr. Page.

“Nonetheless, based on the safety signals described within this Clinical Science Statement, an open discussion regarding the risks of using cannabis needs to occur between patient and health care providers,” he said. “Furthermore, patients must be transparent regarding their cannabis use with their cardiologist and primary care provider. The cannabis story will continue to evolve and is a rapidly moving/changing target,” he said.

“Whether cannabis use is a definitive risk factor for cardiovascular disease as with tobacco use is still unknown, and both acute and long-term studies are desperately needed to address this issue,” he said.

Dr. Page had no relevant financial conflicts to disclose.

SOURCE: Page et al. Circulation. 2020 Aug 5. doi: 10.1161/CIR.0000000000000883.

Evidence for a link between cannabis use and cardiovascular health remains unsupported, and the potential risks outweigh any potential benefits, according to a scientific statement from the American Heart Association.

American Heart Association

The increased legalization of cannabis and cannabis products in the United States has driven medical professionals to evaluate the safety and efficacy of cannabis in relation to health conditions, wrote Robert L. Page II, PharmD, of the University of Colorado, Aurora, and colleagues.

In a statement published in Circulation, the researchers noted that although cannabis has been shown to relieve pain and other symptoms in certain conditions, clinicians in the United States have been limited from studying its health effects because of federal law restrictions. “Cannabis remains a schedule I controlled substance, deeming no accepted medical use, a high potential for abuse, and an unacceptable safety profile,” the researchers wrote.

The statement addresses issues with the use of cannabis by individuals with cardiovascular disease or those at increased risk. Observational studies have shown no cardiovascular benefits associated with cannabis, the writers noted. The most common chemicals in cannabis include THC (tetrahydrocannabinolic acid) and CBD (cannabidiol).

Some research has shown associations between CBD cardiovascular features including lower blood pressure and reduced inflammation, the writers noted. However, THC, the component of cannabis associated with a “high” or intoxication, has been associated with heart rhythm abnormalities. The writers cited data suggesting an increased risk of heart attacks, atrial fibrillation and heart failure, although more research is needed.

The statement outlines common cannabis formulations including plant-based, extracts, crystalline forms, edible products, and tinctures. In addition, the statement notes that synthetic cannabis products are marketed and used in the United States without subject to regulation.

“Over the past 5 years, we have seen a surge in cannabis use, particularly during the COVID-19 pandemic here in Colorado, especially among adolescents and young adults,” Dr. Page said in an interview. Because of the surge, health care practitioners need to familiarize themselves with not only the benefits, but risks associated with cannabis use regardless of the formulation,” he said. As heart disease remains a leading cause of death in the United States, understanding the cardiovascular risks associated with cannabis is crucial at this time.

Dr. Page noted that popular attitudes about cannabis could pose risks to users’ cardiovascular health. “One leading misconception about cannabis is because it is ‘natural’ it must be safe,” Dr. Page said. “As with all medications, cannabis has side effects, some of which can be cardiovascular in nature,” he said. “Significant drug-drug interactions can occur as CBD and THC, both found in cannabis, inhibit CYP3A4, which metabolizes a large number of medications used to treat many cardiovascular conditions,” he noted.

“Unfortunately, much of the published data is observational in nature due to the federal restrictions on cannabis as a schedule I drug,” said Dr. Page. “Nonetheless, safety signals have emerged regarding cannabis use and adverse cardiovascular outcomes, including myocardial infarction, heart failure, and atrial fibrillation. Carefully designed prospective short- and long-term studies regarding cannabis use and cardiovascular safety are needed,” he emphasized.

Areas in particular need of additional research include the cardiovascular effects of cannabis in several vulnerable populations such as adolescents, older adults, pregnant women, transplant recipients, and those with underlying cardiovascular disease, said Dr. Page.

“Nonetheless, based on the safety signals described within this Clinical Science Statement, an open discussion regarding the risks of using cannabis needs to occur between patient and health care providers,” he said. “Furthermore, patients must be transparent regarding their cannabis use with their cardiologist and primary care provider. The cannabis story will continue to evolve and is a rapidly moving/changing target,” he said.

“Whether cannabis use is a definitive risk factor for cardiovascular disease as with tobacco use is still unknown, and both acute and long-term studies are desperately needed to address this issue,” he said.

Dr. Page had no relevant financial conflicts to disclose.

SOURCE: Page et al. Circulation. 2020 Aug 5. doi: 10.1161/CIR.0000000000000883.

Evidence for a link between cannabis use and cardiovascular health remains unsupported, and the potential risks outweigh any potential benefits, according to a scientific statement from the American Heart Association.

American Heart Association

The increased legalization of cannabis and cannabis products in the United States has driven medical professionals to evaluate the safety and efficacy of cannabis in relation to health conditions, wrote Robert L. Page II, PharmD, of the University of Colorado, Aurora, and colleagues.

In a statement published in Circulation, the researchers noted that although cannabis has been shown to relieve pain and other symptoms in certain conditions, clinicians in the United States have been limited from studying its health effects because of federal law restrictions. “Cannabis remains a schedule I controlled substance, deeming no accepted medical use, a high potential for abuse, and an unacceptable safety profile,” the researchers wrote.

The statement addresses issues with the use of cannabis by individuals with cardiovascular disease or those at increased risk. Observational studies have shown no cardiovascular benefits associated with cannabis, the writers noted. The most common chemicals in cannabis include THC (tetrahydrocannabinolic acid) and CBD (cannabidiol).

Some research has shown associations between CBD cardiovascular features including lower blood pressure and reduced inflammation, the writers noted. However, THC, the component of cannabis associated with a “high” or intoxication, has been associated with heart rhythm abnormalities. The writers cited data suggesting an increased risk of heart attacks, atrial fibrillation and heart failure, although more research is needed.

The statement outlines common cannabis formulations including plant-based, extracts, crystalline forms, edible products, and tinctures. In addition, the statement notes that synthetic cannabis products are marketed and used in the United States without subject to regulation.

“Over the past 5 years, we have seen a surge in cannabis use, particularly during the COVID-19 pandemic here in Colorado, especially among adolescents and young adults,” Dr. Page said in an interview. Because of the surge, health care practitioners need to familiarize themselves with not only the benefits, but risks associated with cannabis use regardless of the formulation,” he said. As heart disease remains a leading cause of death in the United States, understanding the cardiovascular risks associated with cannabis is crucial at this time.

Dr. Page noted that popular attitudes about cannabis could pose risks to users’ cardiovascular health. “One leading misconception about cannabis is because it is ‘natural’ it must be safe,” Dr. Page said. “As with all medications, cannabis has side effects, some of which can be cardiovascular in nature,” he said. “Significant drug-drug interactions can occur as CBD and THC, both found in cannabis, inhibit CYP3A4, which metabolizes a large number of medications used to treat many cardiovascular conditions,” he noted.

“Unfortunately, much of the published data is observational in nature due to the federal restrictions on cannabis as a schedule I drug,” said Dr. Page. “Nonetheless, safety signals have emerged regarding cannabis use and adverse cardiovascular outcomes, including myocardial infarction, heart failure, and atrial fibrillation. Carefully designed prospective short- and long-term studies regarding cannabis use and cardiovascular safety are needed,” he emphasized.

Areas in particular need of additional research include the cardiovascular effects of cannabis in several vulnerable populations such as adolescents, older adults, pregnant women, transplant recipients, and those with underlying cardiovascular disease, said Dr. Page.

“Nonetheless, based on the safety signals described within this Clinical Science Statement, an open discussion regarding the risks of using cannabis needs to occur between patient and health care providers,” he said. “Furthermore, patients must be transparent regarding their cannabis use with their cardiologist and primary care provider. The cannabis story will continue to evolve and is a rapidly moving/changing target,” he said.

“Whether cannabis use is a definitive risk factor for cardiovascular disease as with tobacco use is still unknown, and both acute and long-term studies are desperately needed to address this issue,” he said.

Dr. Page had no relevant financial conflicts to disclose.

SOURCE: Page et al. Circulation. 2020 Aug 5. doi: 10.1161/CIR.0000000000000883.

Patients on antithrombotics after an acute MI will face a greater risk for bleeding and secondary cardiovascular (CV) events if they start taking any nonaspirin NSAID, confirms a large observational study.

Like other research before it, the new study suggests those risks will be much lower for some nonaspirin NSAIDs than others. But it may also challenge at least some conventional thinking about the safety of these drugs, and is based solely on a large cohort in South Korea, a group for which such NSAID data has been in short supply.

“It was intriguing that our study presented better safety profiles with celecoxib and meloxicam versus other subtypes of NSAIDs,” noted the report, published online July 27 in the Journal of the American College of Cardiology.

Most of the NSAIDs included in the analysis, “including naproxen, conferred a significantly higher risk for cardiovascular and bleeding events, compared with celecoxib and meloxicam,” wrote the authors, led by Dong Oh Kang, MD, Korea University Guro Hospital, Seoul, South Korea.

A main contribution of the study “is the thorough and comprehensive evaluation of the Korean population by use of the nationwide prescription claims database that reflects real-world clinical practice,” senior author Cheol Ung Choi, MD, PhD, of the same institution, said in an interview.

“Because we included the largest number of patients of any comparable clinical studies on NSAID treatment after MI thus far, our study may allow the generalizability of the adverse events of NSAIDs to all patients by constituting global evidence encompassing different population groups,” Dr. Choi said.

The analysis has limitations along with its strengths, the authors acknowledged, including its observational design and potential for confounding not addressed in statistical adjustments.

Observers of the study concurred, but some cited evidence pointing to such confounding that is serious enough to question the entire study’s validity.

Among the cohort of more than 100,000 patients followed for an average of about 2.3 years after their MI, the adjusted risk of thromboembolic CV events went up almost 7 times for those who took any NSAID for at least 4 consecutive weeks, compared with those who didn’t take NSAIDs, based on prescription records.

Their adjusted risk of bleeding events – which included gastrointestinal, intracranial, respiratory, or urinary tract bleeding or posthemorrhagic anemia, the group writes – was increased 300%.

There was wide variance in the adjusted hazard ratios for outcomes by type of NSAID. The risk of CV events climbed from a low of about 3 with meloxicam and almost 5 for celecoxib to more than 10 and 12 for naproxen and dexibuprofen, respectively.

The hazard ratios for bleeding ranged from about 3 for both meloxicam and celecoxib to more than 6 for naproxen.

Of note, celecoxib and meloxicam both preferentially target the cyclooxygenase type 2 (COX-2) pathway, and naproxen among NSAIDs once had a reputation for relative cardiac safety, although subsequent studies have challenged that notion.

“On the basis of the contemporary guidelines, NSAID treatment should be limited as much as possible after MI; however, our data suggest that celecoxib and meloxicam could be considered possible alternative choices in patients with MI when NSAID prescription is unavoidable,” the group wrote.

They acknowledged some limitations of the analysis, including an observational design and the possibility of unidentified confounders; that mortality outcomes were not available from the National Health Insurance Service database used in the study; and that the 2009-2013 span for the data didn’t allow consideration of more contemporary antiplatelet agents and direct oral anticoagulants.

Also, NSAID use was based on prescriptions without regard to over-the-counter usage. Although use of over-the-counter NSAIDs is common in Korea, “most MI patients in Korea are prescribed most medications, including NSAIDs, in the hospital. So I think that usage of over-the-counter NSAIDs did not change the results,” Dr. Choi said.

“This study breaks new ground by demonstrating cardiovascular safety of meloxicam (and not only of celecoxib), probably because of its higher COX-2 selectivity,” wrote the authors of an accompanying editorial, Juan J. Badimon, PhD, and Carlos G. Santos-Gallego, MD, both of the Icahn School of Medicine at Mount Sinai, New York.

Notably, “this paper rejects the cardiovascular safety of naproxen, which had been suggested classically and in the previous Danish data, but that was not evident in this study.” The finding is consistent with the PRECISION trial, in which both bleeding and CV risk were increased with naproxen versus other NSAIDs, observed Dr. Badimon and Dr. Santos-Gallego.

They agreed with the authors in recommending that, “although NSAID treatment should be avoided in patients with MI, if the use of NSAIDs is inevitable due to comorbidities, the prescription of celecoxib and meloxicam could be considered as alternative options.”

But, “as no study is perfect, this article also presents some limitations,” the editorial agreed, citing some of the same issues noted by Dr. Kang and associates, along with potential confounding by indication and the lack of “clinical information to adjust (e.g., angiographic features, left ventricular function).”

“There’s undoubtedly residual confounding,” James M. Brophy, MD, PhD, a pharmacoepidemiologist at McGill University, Montreal, said in an interview.

The 400%-900% relative risks for CV events “are just too far in left field, compared to everything else we know,” he said. “There has never been a class of drugs that have shown this sort of magnitude of effect for adverse events.”

Even in PRECISION with its more than 24,000 high-coronary-risk patients randomized and followed for 5 years, Dr. Brophy observed, relative risks for the different NSAIDs varied by an order of magnitude of only 1-2.

“You should be interpreting things in the context of what is already known,” Dr. Brophy said. “The only conclusion I would draw is the paper is fatally flawed.”

The registry included 108,232 primarily male patients followed from their first diagnosed MI for CV and bleeding events. About 1.9% were prescribed at least one NSAID for 4 or more consecutive weeks during the follow-up period averaging 2.3 years, the group reported.

The most frequently prescribed NSAID was diclofenac, at about 72% of prescribed NSAIDs in the analysis for CV events and about 69% in the bleeding-event analysis.

Adding any NSAID to post-MI antithrombotic therapy led to an adjusted HR of 6.96 (P < .001) for CV events and 4.08 (P < .001) for bleeding events, compared with no NSAID treatment.

The 88% of the cohort who were on dual-antiplatelet therapy with aspirin and clopidogrel showed very nearly the same risk increases for both endpoints.

Further studies are needed to confirm the results “and ensure their generalizability to other populations,” Dr. Choi said. They should be validated especially using the claims data bases of countries near Korea, “such as Japan and Taiwan, to examine the reproducibility of the results in similar ethnic populations.”

That the study focused on a cohort in Korea is a strength, contended the authors as well as Dr. Badimon and Dr. Santos-Gallego, given “that most data about NSAIDs were extracted from Western populations, but the risk of thrombosis/bleeding post-MI varies according to ethnicity,” according to the editorial

Dr. Brophy agreed, but doubted that ethnic differences are responsible for variation in relative risks between the current results and other studies. “There are pharmacogenomic differences between different ethnicities as to how they activate these drugs. But I suspect that sort of difference is really minor. Maybe it leads to a 2% or a 5% difference in risks.”

Dr. Kang and associates, Dr. Badimon, Dr. Santos-Gallego, and Dr. Brophy disclosed no relevant financial relationships.

A version of this article originally appeared on Medscape.com.

Patients on antithrombotics after an acute MI will face a greater risk for bleeding and secondary cardiovascular (CV) events if they start taking any nonaspirin NSAID, confirms a large observational study.

Like other research before it, the new study suggests those risks will be much lower for some nonaspirin NSAIDs than others. But it may also challenge at least some conventional thinking about the safety of these drugs, and is based solely on a large cohort in South Korea, a group for which such NSAID data has been in short supply.

“It was intriguing that our study presented better safety profiles with celecoxib and meloxicam versus other subtypes of NSAIDs,” noted the report, published online July 27 in the Journal of the American College of Cardiology.

Most of the NSAIDs included in the analysis, “including naproxen, conferred a significantly higher risk for cardiovascular and bleeding events, compared with celecoxib and meloxicam,” wrote the authors, led by Dong Oh Kang, MD, Korea University Guro Hospital, Seoul, South Korea.

A main contribution of the study “is the thorough and comprehensive evaluation of the Korean population by use of the nationwide prescription claims database that reflects real-world clinical practice,” senior author Cheol Ung Choi, MD, PhD, of the same institution, said in an interview.

“Because we included the largest number of patients of any comparable clinical studies on NSAID treatment after MI thus far, our study may allow the generalizability of the adverse events of NSAIDs to all patients by constituting global evidence encompassing different population groups,” Dr. Choi said.

The analysis has limitations along with its strengths, the authors acknowledged, including its observational design and potential for confounding not addressed in statistical adjustments.

Observers of the study concurred, but some cited evidence pointing to such confounding that is serious enough to question the entire study’s validity.

Among the cohort of more than 100,000 patients followed for an average of about 2.3 years after their MI, the adjusted risk of thromboembolic CV events went up almost 7 times for those who took any NSAID for at least 4 consecutive weeks, compared with those who didn’t take NSAIDs, based on prescription records.

Their adjusted risk of bleeding events – which included gastrointestinal, intracranial, respiratory, or urinary tract bleeding or posthemorrhagic anemia, the group writes – was increased 300%.

There was wide variance in the adjusted hazard ratios for outcomes by type of NSAID. The risk of CV events climbed from a low of about 3 with meloxicam and almost 5 for celecoxib to more than 10 and 12 for naproxen and dexibuprofen, respectively.

The hazard ratios for bleeding ranged from about 3 for both meloxicam and celecoxib to more than 6 for naproxen.

Of note, celecoxib and meloxicam both preferentially target the cyclooxygenase type 2 (COX-2) pathway, and naproxen among NSAIDs once had a reputation for relative cardiac safety, although subsequent studies have challenged that notion.

“On the basis of the contemporary guidelines, NSAID treatment should be limited as much as possible after MI; however, our data suggest that celecoxib and meloxicam could be considered possible alternative choices in patients with MI when NSAID prescription is unavoidable,” the group wrote.

They acknowledged some limitations of the analysis, including an observational design and the possibility of unidentified confounders; that mortality outcomes were not available from the National Health Insurance Service database used in the study; and that the 2009-2013 span for the data didn’t allow consideration of more contemporary antiplatelet agents and direct oral anticoagulants.

Also, NSAID use was based on prescriptions without regard to over-the-counter usage. Although use of over-the-counter NSAIDs is common in Korea, “most MI patients in Korea are prescribed most medications, including NSAIDs, in the hospital. So I think that usage of over-the-counter NSAIDs did not change the results,” Dr. Choi said.

“This study breaks new ground by demonstrating cardiovascular safety of meloxicam (and not only of celecoxib), probably because of its higher COX-2 selectivity,” wrote the authors of an accompanying editorial, Juan J. Badimon, PhD, and Carlos G. Santos-Gallego, MD, both of the Icahn School of Medicine at Mount Sinai, New York.

Notably, “this paper rejects the cardiovascular safety of naproxen, which had been suggested classically and in the previous Danish data, but that was not evident in this study.” The finding is consistent with the PRECISION trial, in which both bleeding and CV risk were increased with naproxen versus other NSAIDs, observed Dr. Badimon and Dr. Santos-Gallego.

They agreed with the authors in recommending that, “although NSAID treatment should be avoided in patients with MI, if the use of NSAIDs is inevitable due to comorbidities, the prescription of celecoxib and meloxicam could be considered as alternative options.”

But, “as no study is perfect, this article also presents some limitations,” the editorial agreed, citing some of the same issues noted by Dr. Kang and associates, along with potential confounding by indication and the lack of “clinical information to adjust (e.g., angiographic features, left ventricular function).”

“There’s undoubtedly residual confounding,” James M. Brophy, MD, PhD, a pharmacoepidemiologist at McGill University, Montreal, said in an interview.

The 400%-900% relative risks for CV events “are just too far in left field, compared to everything else we know,” he said. “There has never been a class of drugs that have shown this sort of magnitude of effect for adverse events.”

Even in PRECISION with its more than 24,000 high-coronary-risk patients randomized and followed for 5 years, Dr. Brophy observed, relative risks for the different NSAIDs varied by an order of magnitude of only 1-2.

“You should be interpreting things in the context of what is already known,” Dr. Brophy said. “The only conclusion I would draw is the paper is fatally flawed.”

The registry included 108,232 primarily male patients followed from their first diagnosed MI for CV and bleeding events. About 1.9% were prescribed at least one NSAID for 4 or more consecutive weeks during the follow-up period averaging 2.3 years, the group reported.

The most frequently prescribed NSAID was diclofenac, at about 72% of prescribed NSAIDs in the analysis for CV events and about 69% in the bleeding-event analysis.

Adding any NSAID to post-MI antithrombotic therapy led to an adjusted HR of 6.96 (P < .001) for CV events and 4.08 (P < .001) for bleeding events, compared with no NSAID treatment.

The 88% of the cohort who were on dual-antiplatelet therapy with aspirin and clopidogrel showed very nearly the same risk increases for both endpoints.

Further studies are needed to confirm the results “and ensure their generalizability to other populations,” Dr. Choi said. They should be validated especially using the claims data bases of countries near Korea, “such as Japan and Taiwan, to examine the reproducibility of the results in similar ethnic populations.”

That the study focused on a cohort in Korea is a strength, contended the authors as well as Dr. Badimon and Dr. Santos-Gallego, given “that most data about NSAIDs were extracted from Western populations, but the risk of thrombosis/bleeding post-MI varies according to ethnicity,” according to the editorial

Dr. Brophy agreed, but doubted that ethnic differences are responsible for variation in relative risks between the current results and other studies. “There are pharmacogenomic differences between different ethnicities as to how they activate these drugs. But I suspect that sort of difference is really minor. Maybe it leads to a 2% or a 5% difference in risks.”

Dr. Kang and associates, Dr. Badimon, Dr. Santos-Gallego, and Dr. Brophy disclosed no relevant financial relationships.

A version of this article originally appeared on Medscape.com.

Patients on antithrombotics after an acute MI will face a greater risk for bleeding and secondary cardiovascular (CV) events if they start taking any nonaspirin NSAID, confirms a large observational study.

Like other research before it, the new study suggests those risks will be much lower for some nonaspirin NSAIDs than others. But it may also challenge at least some conventional thinking about the safety of these drugs, and is based solely on a large cohort in South Korea, a group for which such NSAID data has been in short supply.

“It was intriguing that our study presented better safety profiles with celecoxib and meloxicam versus other subtypes of NSAIDs,” noted the report, published online July 27 in the Journal of the American College of Cardiology.

Most of the NSAIDs included in the analysis, “including naproxen, conferred a significantly higher risk for cardiovascular and bleeding events, compared with celecoxib and meloxicam,” wrote the authors, led by Dong Oh Kang, MD, Korea University Guro Hospital, Seoul, South Korea.

A main contribution of the study “is the thorough and comprehensive evaluation of the Korean population by use of the nationwide prescription claims database that reflects real-world clinical practice,” senior author Cheol Ung Choi, MD, PhD, of the same institution, said in an interview.

“Because we included the largest number of patients of any comparable clinical studies on NSAID treatment after MI thus far, our study may allow the generalizability of the adverse events of NSAIDs to all patients by constituting global evidence encompassing different population groups,” Dr. Choi said.

The analysis has limitations along with its strengths, the authors acknowledged, including its observational design and potential for confounding not addressed in statistical adjustments.

Observers of the study concurred, but some cited evidence pointing to such confounding that is serious enough to question the entire study’s validity.

Among the cohort of more than 100,000 patients followed for an average of about 2.3 years after their MI, the adjusted risk of thromboembolic CV events went up almost 7 times for those who took any NSAID for at least 4 consecutive weeks, compared with those who didn’t take NSAIDs, based on prescription records.

Their adjusted risk of bleeding events – which included gastrointestinal, intracranial, respiratory, or urinary tract bleeding or posthemorrhagic anemia, the group writes – was increased 300%.

There was wide variance in the adjusted hazard ratios for outcomes by type of NSAID. The risk of CV events climbed from a low of about 3 with meloxicam and almost 5 for celecoxib to more than 10 and 12 for naproxen and dexibuprofen, respectively.

The hazard ratios for bleeding ranged from about 3 for both meloxicam and celecoxib to more than 6 for naproxen.

Of note, celecoxib and meloxicam both preferentially target the cyclooxygenase type 2 (COX-2) pathway, and naproxen among NSAIDs once had a reputation for relative cardiac safety, although subsequent studies have challenged that notion.

“On the basis of the contemporary guidelines, NSAID treatment should be limited as much as possible after MI; however, our data suggest that celecoxib and meloxicam could be considered possible alternative choices in patients with MI when NSAID prescription is unavoidable,” the group wrote.

They acknowledged some limitations of the analysis, including an observational design and the possibility of unidentified confounders; that mortality outcomes were not available from the National Health Insurance Service database used in the study; and that the 2009-2013 span for the data didn’t allow consideration of more contemporary antiplatelet agents and direct oral anticoagulants.

Also, NSAID use was based on prescriptions without regard to over-the-counter usage. Although use of over-the-counter NSAIDs is common in Korea, “most MI patients in Korea are prescribed most medications, including NSAIDs, in the hospital. So I think that usage of over-the-counter NSAIDs did not change the results,” Dr. Choi said.

“This study breaks new ground by demonstrating cardiovascular safety of meloxicam (and not only of celecoxib), probably because of its higher COX-2 selectivity,” wrote the authors of an accompanying editorial, Juan J. Badimon, PhD, and Carlos G. Santos-Gallego, MD, both of the Icahn School of Medicine at Mount Sinai, New York.

Notably, “this paper rejects the cardiovascular safety of naproxen, which had been suggested classically and in the previous Danish data, but that was not evident in this study.” The finding is consistent with the PRECISION trial, in which both bleeding and CV risk were increased with naproxen versus other NSAIDs, observed Dr. Badimon and Dr. Santos-Gallego.

They agreed with the authors in recommending that, “although NSAID treatment should be avoided in patients with MI, if the use of NSAIDs is inevitable due to comorbidities, the prescription of celecoxib and meloxicam could be considered as alternative options.”

But, “as no study is perfect, this article also presents some limitations,” the editorial agreed, citing some of the same issues noted by Dr. Kang and associates, along with potential confounding by indication and the lack of “clinical information to adjust (e.g., angiographic features, left ventricular function).”

“There’s undoubtedly residual confounding,” James M. Brophy, MD, PhD, a pharmacoepidemiologist at McGill University, Montreal, said in an interview.

The 400%-900% relative risks for CV events “are just too far in left field, compared to everything else we know,” he said. “There has never been a class of drugs that have shown this sort of magnitude of effect for adverse events.”

Even in PRECISION with its more than 24,000 high-coronary-risk patients randomized and followed for 5 years, Dr. Brophy observed, relative risks for the different NSAIDs varied by an order of magnitude of only 1-2.

“You should be interpreting things in the context of what is already known,” Dr. Brophy said. “The only conclusion I would draw is the paper is fatally flawed.”

The registry included 108,232 primarily male patients followed from their first diagnosed MI for CV and bleeding events. About 1.9% were prescribed at least one NSAID for 4 or more consecutive weeks during the follow-up period averaging 2.3 years, the group reported.

The most frequently prescribed NSAID was diclofenac, at about 72% of prescribed NSAIDs in the analysis for CV events and about 69% in the bleeding-event analysis.

Adding any NSAID to post-MI antithrombotic therapy led to an adjusted HR of 6.96 (P < .001) for CV events and 4.08 (P < .001) for bleeding events, compared with no NSAID treatment.

The 88% of the cohort who were on dual-antiplatelet therapy with aspirin and clopidogrel showed very nearly the same risk increases for both endpoints.

Further studies are needed to confirm the results “and ensure their generalizability to other populations,” Dr. Choi said. They should be validated especially using the claims data bases of countries near Korea, “such as Japan and Taiwan, to examine the reproducibility of the results in similar ethnic populations.”

That the study focused on a cohort in Korea is a strength, contended the authors as well as Dr. Badimon and Dr. Santos-Gallego, given “that most data about NSAIDs were extracted from Western populations, but the risk of thrombosis/bleeding post-MI varies according to ethnicity,” according to the editorial

Dr. Brophy agreed, but doubted that ethnic differences are responsible for variation in relative risks between the current results and other studies. “There are pharmacogenomic differences between different ethnicities as to how they activate these drugs. But I suspect that sort of difference is really minor. Maybe it leads to a 2% or a 5% difference in risks.”

Dr. Kang and associates, Dr. Badimon, Dr. Santos-Gallego, and Dr. Brophy disclosed no relevant financial relationships.

A version of this article originally appeared on Medscape.com.

Most interventional cardiologists still rely solely upon angiography in making revascularization decisions about intermediate stenoses in the setting of stable coronary artery disease – and in doing so they end up making the wrong call nearly 40% of the time, according to the results of an international survey presented at the virtual annual meeting of the European Association of Percutaneous Cardiovascular Interventions.

“We saw a strong tendency to visually overestimate the percent diameter stenosis,” reported Gabor G. Toth, MD, an interventional cardiologist at the Medical University of Graz (Austria).

The same tendency has been highlighted in numerous randomized trials and observational studies. That’s why both European and U.S. guidelines now strongly recommend invasive functional assessment, such as fractional-flow reserve (FFR) testing, in evaluating the significance of intermediate stenoses in the absence of noninvasive evidence of ischemia. The new survey findings point to an important disconnect between these guideline recommendations and current clinical practice, he noted.

Dr. Toth presented the results of the second web-based, international survey on interventional decision-making strategy sponsored by the European Association of Percutaneous Cardiovascular Interventions. He contrasted the findings with those of the previously reported first international online survey, conducted 6 years earlier, for which he was first author (Circ Cardiovasc Interv. 2014 Dec;7[6]:751-9).

The two surveys were identically designed. In both, participants answered questions that enabled investigators to place them into one of four categories based upon the extent of their experience in interventional cardiology. The participants were also presented with 5 angiograms of focal intermediate stenoses and asked to determine the stenosis significance of each lesion. No information on the functional significance of the stenoses was included; however, the respondents could request additional diagnostic information by “ordering” adjunctive invasive functional assessment tests, including FFR, quantitative coronary angiography, intravascular ultrasound, or optical coherence tomography. Importantly, participating cardiologists were asked to make their decisions based upon best possible clinical practice in a hypothetical scenario where financial constraints had no role.

The second international survey was conducted during the latter half of 2019. The 334 interventional cardiologists who responded performed a total of 978 case evaluations including 2,054 coronary lesion assessments.

About 59% of all decisions were made solely on the basis of angiographic appearance without any information as to the functional significance of a given stenosis: Indeed, 13% of all stenoses were thereby declared to be “certainly” nonsignificant, and 46% were deemed “certainly” significant. In total, that figure was down significantly from the 71% rate in the first survey. In the first survey, 47% of decisions based upon angiographic appearance alone were discordant with FFR results known to the investigators, compared with a 39% discordance rate in the second survey.

Of the physician decisions made in the second survey, 10% involved a request for intravascular imaging, essentially unchanged from the 9% rate in the first survey. However, there was a significant increase over time in requests for invasive functional assessment tests: 25% in the first survey, rising to 31% in the second. This increase was entirely driven by additional requests for data on nonhyperemic pressure ratios; there was no difference in requests for FFR testing between the 2013 and 2019 surveys.

Clinician experience played an interesting role in decision-making: “Experience does not have an impact on the accuracy of angiographically based decisions, but experience does have an impact on understanding the need for adjunctive functional diagnostic testing,” Dr. Toth explained.

Indeed, 21% of decisions made by the least-experienced interventional cardiologists involved a request for adjunctive invasive functional assessment, compared with 24% of decisions by physicians in the third quartile of experience, 32% in the second, and 37% of decisions made by the most experienced clinicians.

Discussant Michael Haude, MD, PhD, said that “these results clearly show that eyeball angioguidance is still the dominant tool used in decision-making, and that this eyeball angioguidance continuously overestimates the stenosis when you compare the results to quantitative coronary angiography.

“These results, surprisingly for me, show a quite low uptake of the invasive functional assessments despite overwhelming scientific data leading to clear guideline-based recommendations. Why is this the case, even after financial constraints are ruled out? Probably because FFR is still a complex invasive procedure. Maybe, in the future, quantitative flow-ratio angiography [which requires no pressure wire] or CT-based FFR will be more popular,” said Dr. Haude, an interventional cardiologist at the Rheinland Clinic in Neuss, Germany.

He reported receiving research grants from Biotronik and serving as a paid consultant to that company as well as Cardiac Dimensions, Orbus Neich, and Philips. Dr. Toth reported having no financial conflicts regarding the international survey.

[email protected]

Most interventional cardiologists still rely solely upon angiography in making revascularization decisions about intermediate stenoses in the setting of stable coronary artery disease – and in doing so they end up making the wrong call nearly 40% of the time, according to the results of an international survey presented at the virtual annual meeting of the European Association of Percutaneous Cardiovascular Interventions.

“We saw a strong tendency to visually overestimate the percent diameter stenosis,” reported Gabor G. Toth, MD, an interventional cardiologist at the Medical University of Graz (Austria).

The same tendency has been highlighted in numerous randomized trials and observational studies. That’s why both European and U.S. guidelines now strongly recommend invasive functional assessment, such as fractional-flow reserve (FFR) testing, in evaluating the significance of intermediate stenoses in the absence of noninvasive evidence of ischemia. The new survey findings point to an important disconnect between these guideline recommendations and current clinical practice, he noted.

Dr. Toth presented the results of the second web-based, international survey on interventional decision-making strategy sponsored by the European Association of Percutaneous Cardiovascular Interventions. He contrasted the findings with those of the previously reported first international online survey, conducted 6 years earlier, for which he was first author (Circ Cardiovasc Interv. 2014 Dec;7[6]:751-9).

The two surveys were identically designed. In both, participants answered questions that enabled investigators to place them into one of four categories based upon the extent of their experience in interventional cardiology. The participants were also presented with 5 angiograms of focal intermediate stenoses and asked to determine the stenosis significance of each lesion. No information on the functional significance of the stenoses was included; however, the respondents could request additional diagnostic information by “ordering” adjunctive invasive functional assessment tests, including FFR, quantitative coronary angiography, intravascular ultrasound, or optical coherence tomography. Importantly, participating cardiologists were asked to make their decisions based upon best possible clinical practice in a hypothetical scenario where financial constraints had no role.

The second international survey was conducted during the latter half of 2019. The 334 interventional cardiologists who responded performed a total of 978 case evaluations including 2,054 coronary lesion assessments.

About 59% of all decisions were made solely on the basis of angiographic appearance without any information as to the functional significance of a given stenosis: Indeed, 13% of all stenoses were thereby declared to be “certainly” nonsignificant, and 46% were deemed “certainly” significant. In total, that figure was down significantly from the 71% rate in the first survey. In the first survey, 47% of decisions based upon angiographic appearance alone were discordant with FFR results known to the investigators, compared with a 39% discordance rate in the second survey.

Of the physician decisions made in the second survey, 10% involved a request for intravascular imaging, essentially unchanged from the 9% rate in the first survey. However, there was a significant increase over time in requests for invasive functional assessment tests: 25% in the first survey, rising to 31% in the second. This increase was entirely driven by additional requests for data on nonhyperemic pressure ratios; there was no difference in requests for FFR testing between the 2013 and 2019 surveys.

Clinician experience played an interesting role in decision-making: “Experience does not have an impact on the accuracy of angiographically based decisions, but experience does have an impact on understanding the need for adjunctive functional diagnostic testing,” Dr. Toth explained.

Indeed, 21% of decisions made by the least-experienced interventional cardiologists involved a request for adjunctive invasive functional assessment, compared with 24% of decisions by physicians in the third quartile of experience, 32% in the second, and 37% of decisions made by the most experienced clinicians.

Discussant Michael Haude, MD, PhD, said that “these results clearly show that eyeball angioguidance is still the dominant tool used in decision-making, and that this eyeball angioguidance continuously overestimates the stenosis when you compare the results to quantitative coronary angiography.

“These results, surprisingly for me, show a quite low uptake of the invasive functional assessments despite overwhelming scientific data leading to clear guideline-based recommendations. Why is this the case, even after financial constraints are ruled out? Probably because FFR is still a complex invasive procedure. Maybe, in the future, quantitative flow-ratio angiography [which requires no pressure wire] or CT-based FFR will be more popular,” said Dr. Haude, an interventional cardiologist at the Rheinland Clinic in Neuss, Germany.

He reported receiving research grants from Biotronik and serving as a paid consultant to that company as well as Cardiac Dimensions, Orbus Neich, and Philips. Dr. Toth reported having no financial conflicts regarding the international survey.

[email protected]

Most interventional cardiologists still rely solely upon angiography in making revascularization decisions about intermediate stenoses in the setting of stable coronary artery disease – and in doing so they end up making the wrong call nearly 40% of the time, according to the results of an international survey presented at the virtual annual meeting of the European Association of Percutaneous Cardiovascular Interventions.

“We saw a strong tendency to visually overestimate the percent diameter stenosis,” reported Gabor G. Toth, MD, an interventional cardiologist at the Medical University of Graz (Austria).

The same tendency has been highlighted in numerous randomized trials and observational studies. That’s why both European and U.S. guidelines now strongly recommend invasive functional assessment, such as fractional-flow reserve (FFR) testing, in evaluating the significance of intermediate stenoses in the absence of noninvasive evidence of ischemia. The new survey findings point to an important disconnect between these guideline recommendations and current clinical practice, he noted.

Dr. Toth presented the results of the second web-based, international survey on interventional decision-making strategy sponsored by the European Association of Percutaneous Cardiovascular Interventions. He contrasted the findings with those of the previously reported first international online survey, conducted 6 years earlier, for which he was first author (Circ Cardiovasc Interv. 2014 Dec;7[6]:751-9).

The two surveys were identically designed. In both, participants answered questions that enabled investigators to place them into one of four categories based upon the extent of their experience in interventional cardiology. The participants were also presented with 5 angiograms of focal intermediate stenoses and asked to determine the stenosis significance of each lesion. No information on the functional significance of the stenoses was included; however, the respondents could request additional diagnostic information by “ordering” adjunctive invasive functional assessment tests, including FFR, quantitative coronary angiography, intravascular ultrasound, or optical coherence tomography. Importantly, participating cardiologists were asked to make their decisions based upon best possible clinical practice in a hypothetical scenario where financial constraints had no role.

The second international survey was conducted during the latter half of 2019. The 334 interventional cardiologists who responded performed a total of 978 case evaluations including 2,054 coronary lesion assessments.

About 59% of all decisions were made solely on the basis of angiographic appearance without any information as to the functional significance of a given stenosis: Indeed, 13% of all stenoses were thereby declared to be “certainly” nonsignificant, and 46% were deemed “certainly” significant. In total, that figure was down significantly from the 71% rate in the first survey. In the first survey, 47% of decisions based upon angiographic appearance alone were discordant with FFR results known to the investigators, compared with a 39% discordance rate in the second survey.

Of the physician decisions made in the second survey, 10% involved a request for intravascular imaging, essentially unchanged from the 9% rate in the first survey. However, there was a significant increase over time in requests for invasive functional assessment tests: 25% in the first survey, rising to 31% in the second. This increase was entirely driven by additional requests for data on nonhyperemic pressure ratios; there was no difference in requests for FFR testing between the 2013 and 2019 surveys.

Clinician experience played an interesting role in decision-making: “Experience does not have an impact on the accuracy of angiographically based decisions, but experience does have an impact on understanding the need for adjunctive functional diagnostic testing,” Dr. Toth explained.

Indeed, 21% of decisions made by the least-experienced interventional cardiologists involved a request for adjunctive invasive functional assessment, compared with 24% of decisions by physicians in the third quartile of experience, 32% in the second, and 37% of decisions made by the most experienced clinicians.

Discussant Michael Haude, MD, PhD, said that “these results clearly show that eyeball angioguidance is still the dominant tool used in decision-making, and that this eyeball angioguidance continuously overestimates the stenosis when you compare the results to quantitative coronary angiography.

“These results, surprisingly for me, show a quite low uptake of the invasive functional assessments despite overwhelming scientific data leading to clear guideline-based recommendations. Why is this the case, even after financial constraints are ruled out? Probably because FFR is still a complex invasive procedure. Maybe, in the future, quantitative flow-ratio angiography [which requires no pressure wire] or CT-based FFR will be more popular,” said Dr. Haude, an interventional cardiologist at the Rheinland Clinic in Neuss, Germany.

He reported receiving research grants from Biotronik and serving as a paid consultant to that company as well as Cardiac Dimensions, Orbus Neich, and Philips. Dr. Toth reported having no financial conflicts regarding the international survey.

[email protected]

Because heart failure patients with recovered ejection fraction are a complex and diverse group, little consensus has emerged on how to define, diagnose, and manage this growing population.

To provide some clarity for identifying and treating these patients, a Journal of the American College of Cardiology scientific expert panel has issued a consensus document. Published Aug. 3 in the Journal of the American College of Cardiology, it provides a working definition of heart failure with recovered ejection fraction (HFrecEF) and recommends approaches for treatment and follow-up.
 

Defining a new class of HF

“Part of the impetus of this was to bring attention to what we think is a new class of heart failure, and it requires different treatment modalities and different ways of thinking about it,” expert panel member Douglas L. Mann, MD, cardiologist-in-chief at Barnes Jewish Hospital in St. Louis, said in an interview. “It’s a newly discovered HF biology about which we know very little and it’s very confusing to just go on the ejection fraction alone.”

The panel, led by Jane E. Wilcox, MD, of Northwestern University, Chicago, recommends three components for a working definition of HFrecEF: 1) documentation of a decreased left ventricle ejection fraction (LVEF) of less than 40% at baseline; 2) a 10% or greater absolute improvement in LVEF; and 3) a second measurement of LVEF >40%.

“We try to give it a nomenclature that clearly indicates what it is,” Dr. Mann said. “There has been a lot of confusing terminology.” Among the terms the panel calls out in the lexicon of modestly recovered EF, in addition to HFrecEF, are HF improved EF, HF with preserved EF (HFpEF), borderline HFpEF and HF with mid-range EF (HFmrEF).

The panel also recommends that guideline-based medical and device therapies for HFrecEF should continue indefinitely until there’s a better understanding of the biology and clinical epidemiology of HFrecEF, and that these patients should have close clinical follow-up because of the high risk of HF relapse.

Determining EF’s ‘trajectory’

The findings presented in the statement should help cardiologists distinguish HFrecEF from HFpEF, Dr. Mann noted. “Because EF is moving, we also have to emphasize the importance of following the trajectory of EF,” he said. “It’s not enough to know where the EF is; you have to know where it came from – if it had been from a higher number or a lower number – because that will help inform you about the patient’s disease.”

In that regard, the panel states that the level of change in LVEF – the “trajectory” – will provide clues to the nature and extent of myocardial injury, degree and duration of LV remodeling, and the type of therapy that’s indicated. Clinicians should consider HFmrEF, a description the European Society of Cardiology has endorsed, as an entity different from HFrecEF without data on LVEF trajectory.

The statement delves into the biology of HFrecEF, defining reverse LV remodeling as the restoration of some normalization to cardiac myocyte size and LV chamber geometry that results in a leftward shift toward normalization of end-diastolic pressure volume. The panel also noted that cardiac remodeling in reverse LV remodeling and recovery of LV function is bidirectional and involves multiple molecular and cellular changes that contribute to changes in the heart’s size, shape and function, and explains the role gene expression has in HF-related LV changes.

The statement explores the recovery of LV function, noting that spontaneous recovery often occurs when the cause of the myocardial dysfunction resolves. Common causes are chronic tachycardia and thyroid disease.

That panel noted that “super responders” to cardiac resynchronization therapy can provide insight into HFrecEF. Favorable responders include women, patients with nonischemic HF, very wide ECG ventricular depolarization wavelength with left-bundle branch block morphology, and dyssynchrony on ECG.

Bruce Jancin/MDedge News

The panel states that, “regardless of the definition of HFrecEF,” the evidence suggests that younger patients, women, and those with nonischemic disease, shorter disease duration, and relatively few comorbidities are more likely to recover LVEF – and their outcomes are typically better than those of patients with HF reduced EF (HFrEF) and HFpEF.

Clinicians should bear in mind, however, that patients on guideline-directed medical therapy (GDMT) who achieve complete normalization of LV structure and function are prone to recurrent LV dysfunction and HF. The panel explored the role of potential treatment for three different etiologies of HF. Little is known about Takotsubo cardiomyopathy, considered a transient form of LV dysfunction, in terms of how many of these patients will develop HFrEF or if they’ll benefit from GDMT. Alcohol-induced cardiomyopathy patients should continue on medical therapy even if they have HFrecEF, as should patients with fulminant and nonfulminant myocarditis.
 

Managing HFrecEF

Management should include assessment of jugular vein distention and signs of volume overload – “particularly concerning in HFrecEF” – the panel noted. ECG is cost effective, and signs of left-bundle branch block are predictors of low success with GDMT alone. The panel also recommended a family history going back three generations and consideration of genetic testing to determine the risk for sudden cardiac death. Two-dimensional ECG can help predict GDMT response and cardiovascular magnetic resonance imaging can provide information about myocardial substrate at the time of diagnosis of HFrEF.

The panel suggested four areas for future research: 1) improved phenotyping of HFrEF; 2) use of inception cohorts to better understand the natural history of HFrecEF; 3) clinical trials to better define those clinical care components most effective at maintaining remission; and 4) basic studies to better define the biology of HFrecEF. “The goal,” wrote Dr. Wilcox and colleagues, “is to develop new therapeutic targets that will enable patients with HFrecEF to experience a durable remission from HF.”

Dr. Wilcox reported receiving funding from the National Institutes of Health and the American Heart Association, and financial relationships with Abbott, Medtronic, and Cytokinetics. Dr. Mann has received funding from NIH and reports financial relationships with MyoKardia and Novartis. Coauthors reported funding from NIH and AHA and financial relationships with Novartis, Amgen, AstraZeneca, Thoratec Corporation (Abbott), Sanofi, Pfizer, MyoKardia and American Regent.

SOURCE: Wilcox JE et al. J Am Coll Cardiol. 2020;76:719-34.

Because heart failure patients with recovered ejection fraction are a complex and diverse group, little consensus has emerged on how to define, diagnose, and manage this growing population.

To provide some clarity for identifying and treating these patients, a Journal of the American College of Cardiology scientific expert panel has issued a consensus document. Published Aug. 3 in the Journal of the American College of Cardiology, it provides a working definition of heart failure with recovered ejection fraction (HFrecEF) and recommends approaches for treatment and follow-up.
 

Defining a new class of HF

“Part of the impetus of this was to bring attention to what we think is a new class of heart failure, and it requires different treatment modalities and different ways of thinking about it,” expert panel member Douglas L. Mann, MD, cardiologist-in-chief at Barnes Jewish Hospital in St. Louis, said in an interview. “It’s a newly discovered HF biology about which we know very little and it’s very confusing to just go on the ejection fraction alone.”

The panel, led by Jane E. Wilcox, MD, of Northwestern University, Chicago, recommends three components for a working definition of HFrecEF: 1) documentation of a decreased left ventricle ejection fraction (LVEF) of less than 40% at baseline; 2) a 10% or greater absolute improvement in LVEF; and 3) a second measurement of LVEF >40%.

“We try to give it a nomenclature that clearly indicates what it is,” Dr. Mann said. “There has been a lot of confusing terminology.” Among the terms the panel calls out in the lexicon of modestly recovered EF, in addition to HFrecEF, are HF improved EF, HF with preserved EF (HFpEF), borderline HFpEF and HF with mid-range EF (HFmrEF).

The panel also recommends that guideline-based medical and device therapies for HFrecEF should continue indefinitely until there’s a better understanding of the biology and clinical epidemiology of HFrecEF, and that these patients should have close clinical follow-up because of the high risk of HF relapse.

Determining EF’s ‘trajectory’

The findings presented in the statement should help cardiologists distinguish HFrecEF from HFpEF, Dr. Mann noted. “Because EF is moving, we also have to emphasize the importance of following the trajectory of EF,” he said. “It’s not enough to know where the EF is; you have to know where it came from – if it had been from a higher number or a lower number – because that will help inform you about the patient’s disease.”

In that regard, the panel states that the level of change in LVEF – the “trajectory” – will provide clues to the nature and extent of myocardial injury, degree and duration of LV remodeling, and the type of therapy that’s indicated. Clinicians should consider HFmrEF, a description the European Society of Cardiology has endorsed, as an entity different from HFrecEF without data on LVEF trajectory.

The statement delves into the biology of HFrecEF, defining reverse LV remodeling as the restoration of some normalization to cardiac myocyte size and LV chamber geometry that results in a leftward shift toward normalization of end-diastolic pressure volume. The panel also noted that cardiac remodeling in reverse LV remodeling and recovery of LV function is bidirectional and involves multiple molecular and cellular changes that contribute to changes in the heart’s size, shape and function, and explains the role gene expression has in HF-related LV changes.

The statement explores the recovery of LV function, noting that spontaneous recovery often occurs when the cause of the myocardial dysfunction resolves. Common causes are chronic tachycardia and thyroid disease.

That panel noted that “super responders” to cardiac resynchronization therapy can provide insight into HFrecEF. Favorable responders include women, patients with nonischemic HF, very wide ECG ventricular depolarization wavelength with left-bundle branch block morphology, and dyssynchrony on ECG.

Bruce Jancin/MDedge News

The panel states that, “regardless of the definition of HFrecEF,” the evidence suggests that younger patients, women, and those with nonischemic disease, shorter disease duration, and relatively few comorbidities are more likely to recover LVEF – and their outcomes are typically better than those of patients with HF reduced EF (HFrEF) and HFpEF.

Clinicians should bear in mind, however, that patients on guideline-directed medical therapy (GDMT) who achieve complete normalization of LV structure and function are prone to recurrent LV dysfunction and HF. The panel explored the role of potential treatment for three different etiologies of HF. Little is known about Takotsubo cardiomyopathy, considered a transient form of LV dysfunction, in terms of how many of these patients will develop HFrEF or if they’ll benefit from GDMT. Alcohol-induced cardiomyopathy patients should continue on medical therapy even if they have HFrecEF, as should patients with fulminant and nonfulminant myocarditis.
 

Managing HFrecEF

Management should include assessment of jugular vein distention and signs of volume overload – “particularly concerning in HFrecEF” – the panel noted. ECG is cost effective, and signs of left-bundle branch block are predictors of low success with GDMT alone. The panel also recommended a family history going back three generations and consideration of genetic testing to determine the risk for sudden cardiac death. Two-dimensional ECG can help predict GDMT response and cardiovascular magnetic resonance imaging can provide information about myocardial substrate at the time of diagnosis of HFrEF.

The panel suggested four areas for future research: 1) improved phenotyping of HFrEF; 2) use of inception cohorts to better understand the natural history of HFrecEF; 3) clinical trials to better define those clinical care components most effective at maintaining remission; and 4) basic studies to better define the biology of HFrecEF. “The goal,” wrote Dr. Wilcox and colleagues, “is to develop new therapeutic targets that will enable patients with HFrecEF to experience a durable remission from HF.”

Dr. Wilcox reported receiving funding from the National Institutes of Health and the American Heart Association, and financial relationships with Abbott, Medtronic, and Cytokinetics. Dr. Mann has received funding from NIH and reports financial relationships with MyoKardia and Novartis. Coauthors reported funding from NIH and AHA and financial relationships with Novartis, Amgen, AstraZeneca, Thoratec Corporation (Abbott), Sanofi, Pfizer, MyoKardia and American Regent.

SOURCE: Wilcox JE et al. J Am Coll Cardiol. 2020;76:719-34.

Because heart failure patients with recovered ejection fraction are a complex and diverse group, little consensus has emerged on how to define, diagnose, and manage this growing population.

To provide some clarity for identifying and treating these patients, a Journal of the American College of Cardiology scientific expert panel has issued a consensus document. Published Aug. 3 in the Journal of the American College of Cardiology, it provides a working definition of heart failure with recovered ejection fraction (HFrecEF) and recommends approaches for treatment and follow-up.
 

Defining a new class of HF

“Part of the impetus of this was to bring attention to what we think is a new class of heart failure, and it requires different treatment modalities and different ways of thinking about it,” expert panel member Douglas L. Mann, MD, cardiologist-in-chief at Barnes Jewish Hospital in St. Louis, said in an interview. “It’s a newly discovered HF biology about which we know very little and it’s very confusing to just go on the ejection fraction alone.”

The panel, led by Jane E. Wilcox, MD, of Northwestern University, Chicago, recommends three components for a working definition of HFrecEF: 1) documentation of a decreased left ventricle ejection fraction (LVEF) of less than 40% at baseline; 2) a 10% or greater absolute improvement in LVEF; and 3) a second measurement of LVEF >40%.

“We try to give it a nomenclature that clearly indicates what it is,” Dr. Mann said. “There has been a lot of confusing terminology.” Among the terms the panel calls out in the lexicon of modestly recovered EF, in addition to HFrecEF, are HF improved EF, HF with preserved EF (HFpEF), borderline HFpEF and HF with mid-range EF (HFmrEF).

The panel also recommends that guideline-based medical and device therapies for HFrecEF should continue indefinitely until there’s a better understanding of the biology and clinical epidemiology of HFrecEF, and that these patients should have close clinical follow-up because of the high risk of HF relapse.

Determining EF’s ‘trajectory’

The findings presented in the statement should help cardiologists distinguish HFrecEF from HFpEF, Dr. Mann noted. “Because EF is moving, we also have to emphasize the importance of following the trajectory of EF,” he said. “It’s not enough to know where the EF is; you have to know where it came from – if it had been from a higher number or a lower number – because that will help inform you about the patient’s disease.”

In that regard, the panel states that the level of change in LVEF – the “trajectory” – will provide clues to the nature and extent of myocardial injury, degree and duration of LV remodeling, and the type of therapy that’s indicated. Clinicians should consider HFmrEF, a description the European Society of Cardiology has endorsed, as an entity different from HFrecEF without data on LVEF trajectory.

The statement delves into the biology of HFrecEF, defining reverse LV remodeling as the restoration of some normalization to cardiac myocyte size and LV chamber geometry that results in a leftward shift toward normalization of end-diastolic pressure volume. The panel also noted that cardiac remodeling in reverse LV remodeling and recovery of LV function is bidirectional and involves multiple molecular and cellular changes that contribute to changes in the heart’s size, shape and function, and explains the role gene expression has in HF-related LV changes.

The statement explores the recovery of LV function, noting that spontaneous recovery often occurs when the cause of the myocardial dysfunction resolves. Common causes are chronic tachycardia and thyroid disease.

That panel noted that “super responders” to cardiac resynchronization therapy can provide insight into HFrecEF. Favorable responders include women, patients with nonischemic HF, very wide ECG ventricular depolarization wavelength with left-bundle branch block morphology, and dyssynchrony on ECG.

Bruce Jancin/MDedge News

The panel states that, “regardless of the definition of HFrecEF,” the evidence suggests that younger patients, women, and those with nonischemic disease, shorter disease duration, and relatively few comorbidities are more likely to recover LVEF – and their outcomes are typically better than those of patients with HF reduced EF (HFrEF) and HFpEF.

Clinicians should bear in mind, however, that patients on guideline-directed medical therapy (GDMT) who achieve complete normalization of LV structure and function are prone to recurrent LV dysfunction and HF. The panel explored the role of potential treatment for three different etiologies of HF. Little is known about Takotsubo cardiomyopathy, considered a transient form of LV dysfunction, in terms of how many of these patients will develop HFrEF or if they’ll benefit from GDMT. Alcohol-induced cardiomyopathy patients should continue on medical therapy even if they have HFrecEF, as should patients with fulminant and nonfulminant myocarditis.
 

Managing HFrecEF

Management should include assessment of jugular vein distention and signs of volume overload – “particularly concerning in HFrecEF” – the panel noted. ECG is cost effective, and signs of left-bundle branch block are predictors of low success with GDMT alone. The panel also recommended a family history going back three generations and consideration of genetic testing to determine the risk for sudden cardiac death. Two-dimensional ECG can help predict GDMT response and cardiovascular magnetic resonance imaging can provide information about myocardial substrate at the time of diagnosis of HFrEF.

The panel suggested four areas for future research: 1) improved phenotyping of HFrEF; 2) use of inception cohorts to better understand the natural history of HFrecEF; 3) clinical trials to better define those clinical care components most effective at maintaining remission; and 4) basic studies to better define the biology of HFrecEF. “The goal,” wrote Dr. Wilcox and colleagues, “is to develop new therapeutic targets that will enable patients with HFrecEF to experience a durable remission from HF.”

Dr. Wilcox reported receiving funding from the National Institutes of Health and the American Heart Association, and financial relationships with Abbott, Medtronic, and Cytokinetics. Dr. Mann has received funding from NIH and reports financial relationships with MyoKardia and Novartis. Coauthors reported funding from NIH and AHA and financial relationships with Novartis, Amgen, AstraZeneca, Thoratec Corporation (Abbott), Sanofi, Pfizer, MyoKardia and American Regent.

SOURCE: Wilcox JE et al. J Am Coll Cardiol. 2020;76:719-34.

A 76-year-old woman presented recently to a Toronto-area hospital with acute onset muscle pain, limb weakness, difficulty walking, and rhabdomyolysis associated with a sharp spike in her plasma level of rosuvastatin – a drug she had been on uneventfully for more than 5 years, within days of starting for the first time treatment with the SGLT2 inhibitor canagliflozin (Invokana).

The patient’s Canadian clinicians stopped her treatment with both rosuvastatin and canagliflozin, administered intravenous crystalloid fluids, and within days her pain subsided and her limb weakness gradually improved, allowing her discharge 10 days later while she was ambulating with a walker.

“To our knowledge this is the first published report of a drug interaction between rosuvastatin and canagliflozin,” wrote the authors of the case report (Ann Intern Med. 2020 Aug 3. doi: 10.7326/L20-0549). They cited the importance of the observation given the widespread use today of rosuvastatin for lowering low density lipoprotein cholesterol and exerting pleiotropic effects; and canagliflozin for its modest effects for reducing hyperglycemia, as well as its important role in reducing adverse cardiovascular outcomes, slowing progression of chronic kidney disease, and having a mild but important diuretic effect. “We encourage clinicians to remain vigilant for features of myotoxicity when canagliflozin and rosuvastatin are coprescribed,” they wrote, avoiding discussion of whether this may represent class or drug-specific effects.

“It’s reasonable to be mindful of this risk, but this is not a reason to not use rosuvastatin and canagliflozin in a patient,” nor for the time being to avoid any other combination of a statin and SGLT2 (sodium-glucose cotransporter 2) inhibitor, said David Juurlink, MD, head of the division of clinical pharmacology and toxicology at Sunnybrook Health Sciences Centre in Toronto and lead author of the report. “Few drug interactions have absolute contraindications. The admonition is just to be careful. It’s premature to say they shouldn’t be used together,” he said in an interview.

“We don’t know how much of an outlier this patient is. But it would be important to tell patients” on this or a similar combination to alert their clinicians if they start to have muscle aches, which should be a “red flag” to stop the statin, the SGLT2 inhibitor, or both until the situation can be fully assessed, Dr. Juurlink advised.
 

Sky high rosuvastatin levels

The linchpin of the observed adverse effects appeared to be a startlingly high elevation of the patient’s plasma rosuvastatin level when she was hospitalized 15 days after starting canagliflozin and 12 days after the onset of her thigh pain and weakness. Testing showed a plasma rosuvastatin concentration of 176 ng/mL, “more than 15-fold higher than the mean value expected” in patients taking 40 mg rosuvastatin daily, the maximum labeled dosage for the drug and what the affected patient had been taking without prior incident for more than 5 years. The patient’s canagliflozin dosage was 100 mg/day, the standard starting dosage according to the drug’s label.

The report’s authors noted that genetic assessment of the patient, a woman originally from the Philippines who was “high functioning,” and diagnosed with type 2 diabetes, showed she was heterozygous for a polymorphism, c.421C>A, which is linked with increased rosuvastatin plasma levels in the plasma. They also cited a report that canagliflozin can interact with proteins involved in hepatic drug uptake.

“We speculate that, in our patient, the addition of canagliflozin enhanced intestinal rosuvastatin absorption, inhibited its hepatocellular uptake, and impaired its excretion into bile canaliculi and the proximal tubule, resulting in rosuvastatin accumulation and leading to hepatotoxicity and myotoxicity,” the clinicians wrote in their report.

“There is little doubt this was a drug interaction, but it does not apply uniformly to everyone.” The severity of the interaction would depend on the dosages, the comorbidities a patient has, and their genetic profile, Dr. Juurlink said.
 

Concern and skepticism

Other clinicians who regularly prescribe these drugs expressed concern about the observation as well as skepticism about the prevalence of patients who could potentially experience similar effects.

Catherine Hackett/MDedge News

“We don’t know how common are these genetic abnormalities. If this is extremely rare, then it doesn’t have many clinical implications, but if a large portion of the population has this [genetic] abnormality, it’s something we’d need to pay attention to,” Steven E. Nissen, MD, chair of cardiovascular medicine at the Cleveland Clinic Foundation, said in an interview. “It will be important to know the prevalence” of the genetic polymorphism carried by the reported patient, said Dr. Nissen, who has done research on lipid-lowering medications and drug safety.

“This could be important, or a very rare one-off. I can’t say which,” based on what’s currently known, he said. “There are many unanswered questions that make it hard to know how important this will be. It requires further investigation. There is a lot of uncertainty.”

Dr. Nissen particularly endorsed studies that approach this issue by looking at the prevalence rates of the implicated genetic polymorphism rather than pharmacovigilance studies that make epidemiologic assessments of adverse-effect prevalence. Studies that look for adverse-effect associations in large patient populations are “sloppy, and unless the interaction is incredibly intense they are not very sensitive,” he said.

But Dr. Juurlink, a pharmacoepidemiologist whose specialty includes studies of this sort, said that they could be useful if carefully designed. He suggested, for example, comparing in large patient databases the observed incidence of rhabdomyolysis among patients on an SGLT2 inhibitor and also on rosuvastatin with those on pravastatin, a statin with a different metabolic profile. Another approach to further examining the observation would be dosage studies with rosuvastatin and canagliflozin in healthy volunteers, he said.

Dr. Nissen noted that rosuvastatin is a key agent from the statin class because it’s the “most effective” for lowering low density lipoprotein cholesterol. “Rosuvastatin is a go-to drug,” he declared. On the other hand, canagliflozin is “a little less used” than other drugs in the SGLT2 inhibitor class, specifically dapagliflozin (Farxiga) and empagliflozin (Jardiance), he said.

One in a million?

“This was a freak accident. I don’t find it at all concerning. It was definitely one in a million,” Yehuda Handelsman, MD, an endocrinologist and diabetes specialist who is medical director of The Metabolic Institute of America in Tarzana, Calif., said in an interview. “None of us have seen it” in either the several cardiovascular outcome trials now run on multiple drugs in the SGLT2 inhibitor class that included many patients also taking a statin, or in routine practice, he said. Dr. Handelsman noted that in his practice he had never seen a similar case despite treating “hundreds if not thousands of patients” with type 2 diabetes, virtually all of whom were on a statin and were also treated with an SGLT2 inhibitor, including many with canagliflozin.

Dr. Handelsman cited the notably low estimated glomerular filtration rate in the reported patient, who was described as having a serum creatinine level of 150 mcmol/L (1.7 mg/dL) prior to canagliflozin treatment that then rose to 194 mcmol/L (2.19 mg/dL) at the time of hospitalization, which corresponds to estimated glomerular filtration rates of 29-31 and 21-23 mL/min per 1.73 m², respectively, depending on the calculator used, rates that were possibly below the labeled minimum rate of 30 mL/min per 1.73 m² for patients starting canagliflozin treatment. The case report cited the patient as having stage 3B chronic kidney disease, which corresponds to a eGFR of 30-44* mL/min per 1.73 m².

“I think the patient had acute kidney injury” on starting canagliflozin “that may have affected the [rosuvastatin] metabolism,” Dr. Handelsman suggested. “She had severe kidney dysfunction to start with that fell further with SGLT2 inhibitor treatment,” a well described and usually transient effect of starting drugs in this class because of changes the SGLT2 inhibitors cause in renal blood flow. He noted that the patient had not been receiving an angiotensin-converting enzyme inhibitor or angiotensin-receptor blocker, which may have contributed to her acute problems with fluid balance. Most similar patients with type 2 diabetes, cardiovascular disease risk, and chronic kidney disease would be on stable treatment with a drug that inhibits the renin-angiotensin system before starting an SGLT2 inhibitor, and not already having a RAS inhibitor on board before starting canagliflozin may have somehow contributed to the observed adverse effects, Dr. Handelsman said.

Dr. Juurlink was skeptical that the kidneys played a major role. “An abrupt change in renal function can influence statin clearance, but this was a 15-fold increase. You can’t explain such a dramatic increase by a transient reduction in renal function,” he said.

Dr. Juurlink and coauthors had no disclosures. Dr. Nissen had no relevant disclosures. Dr. Handelsman has been a consultant to companies that market drugs in the SGLT2 inhibitor class.

[email protected]

SOURCE: Brailovski E et al. Ann Intern Med. 2020 Aug 3. doi: 10.7326/L20-0549.

*Correction: This value was missing from the original article.

A 76-year-old woman presented recently to a Toronto-area hospital with acute onset muscle pain, limb weakness, difficulty walking, and rhabdomyolysis associated with a sharp spike in her plasma level of rosuvastatin – a drug she had been on uneventfully for more than 5 years, within days of starting for the first time treatment with the SGLT2 inhibitor canagliflozin (Invokana).

The patient’s Canadian clinicians stopped her treatment with both rosuvastatin and canagliflozin, administered intravenous crystalloid fluids, and within days her pain subsided and her limb weakness gradually improved, allowing her discharge 10 days later while she was ambulating with a walker.

“To our knowledge this is the first published report of a drug interaction between rosuvastatin and canagliflozin,” wrote the authors of the case report (Ann Intern Med. 2020 Aug 3. doi: 10.7326/L20-0549). They cited the importance of the observation given the widespread use today of rosuvastatin for lowering low density lipoprotein cholesterol and exerting pleiotropic effects; and canagliflozin for its modest effects for reducing hyperglycemia, as well as its important role in reducing adverse cardiovascular outcomes, slowing progression of chronic kidney disease, and having a mild but important diuretic effect. “We encourage clinicians to remain vigilant for features of myotoxicity when canagliflozin and rosuvastatin are coprescribed,” they wrote, avoiding discussion of whether this may represent class or drug-specific effects.

“It’s reasonable to be mindful of this risk, but this is not a reason to not use rosuvastatin and canagliflozin in a patient,” nor for the time being to avoid any other combination of a statin and SGLT2 (sodium-glucose cotransporter 2) inhibitor, said David Juurlink, MD, head of the division of clinical pharmacology and toxicology at Sunnybrook Health Sciences Centre in Toronto and lead author of the report. “Few drug interactions have absolute contraindications. The admonition is just to be careful. It’s premature to say they shouldn’t be used together,” he said in an interview.

“We don’t know how much of an outlier this patient is. But it would be important to tell patients” on this or a similar combination to alert their clinicians if they start to have muscle aches, which should be a “red flag” to stop the statin, the SGLT2 inhibitor, or both until the situation can be fully assessed, Dr. Juurlink advised.
 

Sky high rosuvastatin levels

The linchpin of the observed adverse effects appeared to be a startlingly high elevation of the patient’s plasma rosuvastatin level when she was hospitalized 15 days after starting canagliflozin and 12 days after the onset of her thigh pain and weakness. Testing showed a plasma rosuvastatin concentration of 176 ng/mL, “more than 15-fold higher than the mean value expected” in patients taking 40 mg rosuvastatin daily, the maximum labeled dosage for the drug and what the affected patient had been taking without prior incident for more than 5 years. The patient’s canagliflozin dosage was 100 mg/day, the standard starting dosage according to the drug’s label.

The report’s authors noted that genetic assessment of the patient, a woman originally from the Philippines who was “high functioning,” and diagnosed with type 2 diabetes, showed she was heterozygous for a polymorphism, c.421C>A, which is linked with increased rosuvastatin plasma levels in the plasma. They also cited a report that canagliflozin can interact with proteins involved in hepatic drug uptake.

“We speculate that, in our patient, the addition of canagliflozin enhanced intestinal rosuvastatin absorption, inhibited its hepatocellular uptake, and impaired its excretion into bile canaliculi and the proximal tubule, resulting in rosuvastatin accumulation and leading to hepatotoxicity and myotoxicity,” the clinicians wrote in their report.

“There is little doubt this was a drug interaction, but it does not apply uniformly to everyone.” The severity of the interaction would depend on the dosages, the comorbidities a patient has, and their genetic profile, Dr. Juurlink said.
 

Concern and skepticism

Other clinicians who regularly prescribe these drugs expressed concern about the observation as well as skepticism about the prevalence of patients who could potentially experience similar effects.

Catherine Hackett/MDedge News

“We don’t know how common are these genetic abnormalities. If this is extremely rare, then it doesn’t have many clinical implications, but if a large portion of the population has this [genetic] abnormality, it’s something we’d need to pay attention to,” Steven E. Nissen, MD, chair of cardiovascular medicine at the Cleveland Clinic Foundation, said in an interview. “It will be important to know the prevalence” of the genetic polymorphism carried by the reported patient, said Dr. Nissen, who has done research on lipid-lowering medications and drug safety.

“This could be important, or a very rare one-off. I can’t say which,” based on what’s currently known, he said. “There are many unanswered questions that make it hard to know how important this will be. It requires further investigation. There is a lot of uncertainty.”

Dr. Nissen particularly endorsed studies that approach this issue by looking at the prevalence rates of the implicated genetic polymorphism rather than pharmacovigilance studies that make epidemiologic assessments of adverse-effect prevalence. Studies that look for adverse-effect associations in large patient populations are “sloppy, and unless the interaction is incredibly intense they are not very sensitive,” he said.

But Dr. Juurlink, a pharmacoepidemiologist whose specialty includes studies of this sort, said that they could be useful if carefully designed. He suggested, for example, comparing in large patient databases the observed incidence of rhabdomyolysis among patients on an SGLT2 inhibitor and also on rosuvastatin with those on pravastatin, a statin with a different metabolic profile. Another approach to further examining the observation would be dosage studies with rosuvastatin and canagliflozin in healthy volunteers, he said.

Dr. Nissen noted that rosuvastatin is a key agent from the statin class because it’s the “most effective” for lowering low density lipoprotein cholesterol. “Rosuvastatin is a go-to drug,” he declared. On the other hand, canagliflozin is “a little less used” than other drugs in the SGLT2 inhibitor class, specifically dapagliflozin (Farxiga) and empagliflozin (Jardiance), he said.

One in a million?

“This was a freak accident. I don’t find it at all concerning. It was definitely one in a million,” Yehuda Handelsman, MD, an endocrinologist and diabetes specialist who is medical director of The Metabolic Institute of America in Tarzana, Calif., said in an interview. “None of us have seen it” in either the several cardiovascular outcome trials now run on multiple drugs in the SGLT2 inhibitor class that included many patients also taking a statin, or in routine practice, he said. Dr. Handelsman noted that in his practice he had never seen a similar case despite treating “hundreds if not thousands of patients” with type 2 diabetes, virtually all of whom were on a statin and were also treated with an SGLT2 inhibitor, including many with canagliflozin.

Dr. Handelsman cited the notably low estimated glomerular filtration rate in the reported patient, who was described as having a serum creatinine level of 150 mcmol/L (1.7 mg/dL) prior to canagliflozin treatment that then rose to 194 mcmol/L (2.19 mg/dL) at the time of hospitalization, which corresponds to estimated glomerular filtration rates of 29-31 and 21-23 mL/min per 1.73 m², respectively, depending on the calculator used, rates that were possibly below the labeled minimum rate of 30 mL/min per 1.73 m² for patients starting canagliflozin treatment. The case report cited the patient as having stage 3B chronic kidney disease, which corresponds to a eGFR of 30-44* mL/min per 1.73 m².

“I think the patient had acute kidney injury” on starting canagliflozin “that may have affected the [rosuvastatin] metabolism,” Dr. Handelsman suggested. “She had severe kidney dysfunction to start with that fell further with SGLT2 inhibitor treatment,” a well described and usually transient effect of starting drugs in this class because of changes the SGLT2 inhibitors cause in renal blood flow. He noted that the patient had not been receiving an angiotensin-converting enzyme inhibitor or angiotensin-receptor blocker, which may have contributed to her acute problems with fluid balance. Most similar patients with type 2 diabetes, cardiovascular disease risk, and chronic kidney disease would be on stable treatment with a drug that inhibits the renin-angiotensin system before starting an SGLT2 inhibitor, and not already having a RAS inhibitor on board before starting canagliflozin may have somehow contributed to the observed adverse effects, Dr. Handelsman said.

Dr. Juurlink was skeptical that the kidneys played a major role. “An abrupt change in renal function can influence statin clearance, but this was a 15-fold increase. You can’t explain such a dramatic increase by a transient reduction in renal function,” he said.

Dr. Juurlink and coauthors had no disclosures. Dr. Nissen had no relevant disclosures. Dr. Handelsman has been a consultant to companies that market drugs in the SGLT2 inhibitor class.

[email protected]

SOURCE: Brailovski E et al. Ann Intern Med. 2020 Aug 3. doi: 10.7326/L20-0549.

*Correction: This value was missing from the original article.

A 76-year-old woman presented recently to a Toronto-area hospital with acute onset muscle pain, limb weakness, difficulty walking, and rhabdomyolysis associated with a sharp spike in her plasma level of rosuvastatin – a drug she had been on uneventfully for more than 5 years, within days of starting for the first time treatment with the SGLT2 inhibitor canagliflozin (Invokana).

The patient’s Canadian clinicians stopped her treatment with both rosuvastatin and canagliflozin, administered intravenous crystalloid fluids, and within days her pain subsided and her limb weakness gradually improved, allowing her discharge 10 days later while she was ambulating with a walker.

“To our knowledge this is the first published report of a drug interaction between rosuvastatin and canagliflozin,” wrote the authors of the case report (Ann Intern Med. 2020 Aug 3. doi: 10.7326/L20-0549). They cited the importance of the observation given the widespread use today of rosuvastatin for lowering low density lipoprotein cholesterol and exerting pleiotropic effects; and canagliflozin for its modest effects for reducing hyperglycemia, as well as its important role in reducing adverse cardiovascular outcomes, slowing progression of chronic kidney disease, and having a mild but important diuretic effect. “We encourage clinicians to remain vigilant for features of myotoxicity when canagliflozin and rosuvastatin are coprescribed,” they wrote, avoiding discussion of whether this may represent class or drug-specific effects.

“It’s reasonable to be mindful of this risk, but this is not a reason to not use rosuvastatin and canagliflozin in a patient,” nor for the time being to avoid any other combination of a statin and SGLT2 (sodium-glucose cotransporter 2) inhibitor, said David Juurlink, MD, head of the division of clinical pharmacology and toxicology at Sunnybrook Health Sciences Centre in Toronto and lead author of the report. “Few drug interactions have absolute contraindications. The admonition is just to be careful. It’s premature to say they shouldn’t be used together,” he said in an interview.

“We don’t know how much of an outlier this patient is. But it would be important to tell patients” on this or a similar combination to alert their clinicians if they start to have muscle aches, which should be a “red flag” to stop the statin, the SGLT2 inhibitor, or both until the situation can be fully assessed, Dr. Juurlink advised.
 

Sky high rosuvastatin levels

The linchpin of the observed adverse effects appeared to be a startlingly high elevation of the patient’s plasma rosuvastatin level when she was hospitalized 15 days after starting canagliflozin and 12 days after the onset of her thigh pain and weakness. Testing showed a plasma rosuvastatin concentration of 176 ng/mL, “more than 15-fold higher than the mean value expected” in patients taking 40 mg rosuvastatin daily, the maximum labeled dosage for the drug and what the affected patient had been taking without prior incident for more than 5 years. The patient’s canagliflozin dosage was 100 mg/day, the standard starting dosage according to the drug’s label.

The report’s authors noted that genetic assessment of the patient, a woman originally from the Philippines who was “high functioning,” and diagnosed with type 2 diabetes, showed she was heterozygous for a polymorphism, c.421C>A, which is linked with increased rosuvastatin plasma levels in the plasma. They also cited a report that canagliflozin can interact with proteins involved in hepatic drug uptake.

“We speculate that, in our patient, the addition of canagliflozin enhanced intestinal rosuvastatin absorption, inhibited its hepatocellular uptake, and impaired its excretion into bile canaliculi and the proximal tubule, resulting in rosuvastatin accumulation and leading to hepatotoxicity and myotoxicity,” the clinicians wrote in their report.

“There is little doubt this was a drug interaction, but it does not apply uniformly to everyone.” The severity of the interaction would depend on the dosages, the comorbidities a patient has, and their genetic profile, Dr. Juurlink said.
 

Concern and skepticism

Other clinicians who regularly prescribe these drugs expressed concern about the observation as well as skepticism about the prevalence of patients who could potentially experience similar effects.

Catherine Hackett/MDedge News

“We don’t know how common are these genetic abnormalities. If this is extremely rare, then it doesn’t have many clinical implications, but if a large portion of the population has this [genetic] abnormality, it’s something we’d need to pay attention to,” Steven E. Nissen, MD, chair of cardiovascular medicine at the Cleveland Clinic Foundation, said in an interview. “It will be important to know the prevalence” of the genetic polymorphism carried by the reported patient, said Dr. Nissen, who has done research on lipid-lowering medications and drug safety.

“This could be important, or a very rare one-off. I can’t say which,” based on what’s currently known, he said. “There are many unanswered questions that make it hard to know how important this will be. It requires further investigation. There is a lot of uncertainty.”

Dr. Nissen particularly endorsed studies that approach this issue by looking at the prevalence rates of the implicated genetic polymorphism rather than pharmacovigilance studies that make epidemiologic assessments of adverse-effect prevalence. Studies that look for adverse-effect associations in large patient populations are “sloppy, and unless the interaction is incredibly intense they are not very sensitive,” he said.

But Dr. Juurlink, a pharmacoepidemiologist whose specialty includes studies of this sort, said that they could be useful if carefully designed. He suggested, for example, comparing in large patient databases the observed incidence of rhabdomyolysis among patients on an SGLT2 inhibitor and also on rosuvastatin with those on pravastatin, a statin with a different metabolic profile. Another approach to further examining the observation would be dosage studies with rosuvastatin and canagliflozin in healthy volunteers, he said.

Dr. Nissen noted that rosuvastatin is a key agent from the statin class because it’s the “most effective” for lowering low density lipoprotein cholesterol. “Rosuvastatin is a go-to drug,” he declared. On the other hand, canagliflozin is “a little less used” than other drugs in the SGLT2 inhibitor class, specifically dapagliflozin (Farxiga) and empagliflozin (Jardiance), he said.

One in a million?

“This was a freak accident. I don’t find it at all concerning. It was definitely one in a million,” Yehuda Handelsman, MD, an endocrinologist and diabetes specialist who is medical director of The Metabolic Institute of America in Tarzana, Calif., said in an interview. “None of us have seen it” in either the several cardiovascular outcome trials now run on multiple drugs in the SGLT2 inhibitor class that included many patients also taking a statin, or in routine practice, he said. Dr. Handelsman noted that in his practice he had never seen a similar case despite treating “hundreds if not thousands of patients” with type 2 diabetes, virtually all of whom were on a statin and were also treated with an SGLT2 inhibitor, including many with canagliflozin.

Dr. Handelsman cited the notably low estimated glomerular filtration rate in the reported patient, who was described as having a serum creatinine level of 150 mcmol/L (1.7 mg/dL) prior to canagliflozin treatment that then rose to 194 mcmol/L (2.19 mg/dL) at the time of hospitalization, which corresponds to estimated glomerular filtration rates of 29-31 and 21-23 mL/min per 1.73 m², respectively, depending on the calculator used, rates that were possibly below the labeled minimum rate of 30 mL/min per 1.73 m² for patients starting canagliflozin treatment. The case report cited the patient as having stage 3B chronic kidney disease, which corresponds to a eGFR of 30-44* mL/min per 1.73 m².

“I think the patient had acute kidney injury” on starting canagliflozin “that may have affected the [rosuvastatin] metabolism,” Dr. Handelsman suggested. “She had severe kidney dysfunction to start with that fell further with SGLT2 inhibitor treatment,” a well described and usually transient effect of starting drugs in this class because of changes the SGLT2 inhibitors cause in renal blood flow. He noted that the patient had not been receiving an angiotensin-converting enzyme inhibitor or angiotensin-receptor blocker, which may have contributed to her acute problems with fluid balance. Most similar patients with type 2 diabetes, cardiovascular disease risk, and chronic kidney disease would be on stable treatment with a drug that inhibits the renin-angiotensin system before starting an SGLT2 inhibitor, and not already having a RAS inhibitor on board before starting canagliflozin may have somehow contributed to the observed adverse effects, Dr. Handelsman said.

Dr. Juurlink was skeptical that the kidneys played a major role. “An abrupt change in renal function can influence statin clearance, but this was a 15-fold increase. You can’t explain such a dramatic increase by a transient reduction in renal function,” he said.

Dr. Juurlink and coauthors had no disclosures. Dr. Nissen had no relevant disclosures. Dr. Handelsman has been a consultant to companies that market drugs in the SGLT2 inhibitor class.

[email protected]

SOURCE: Brailovski E et al. Ann Intern Med. 2020 Aug 3. doi: 10.7326/L20-0549.

*Correction: This value was missing from the original article.

Clinical guidelines for cholesterol management may have two blind spots when it comes to heart attack prevention: Most younger adults with premature coronary artery disease who’ve had a myocardial infarction don’t meet guideline criteria for preventative statin therapy, and survivors under age 55 don’t meet the criteria for continuing nonstatin lipid-lowering treatments, a large single-center retrospective study has shown.

“The classic approach we’ve taken to identifying young adults for prevention is inadequate in younger adults,” corresponding author Ann Marie Navar, MD, PhD, of Duke University, Durham, N.C., said in an interview. “While awaiting more definitive research we should at minimum be using all the tools at our disposal, including broader use of coronary artery calcium [CAC] scoring, to identify young people who may benefit from statin therapy.”

The retrospective observational study analyzed records of 6,639 adults who had cardiac catheterization at Duke University Medical Center from 1995 to 2012 for a first myocardial infarction with obstructive coronary artery disease. The study considered those under age 55 years as “younger” patients, comprising 41% of the study group (2,733); 35% were “middle-aged” at 55-65 years (2,324) and 24% were “older,” at 66-75 years (1,582).

The report, published online Aug. 3 in the Journal of the American College of Cardiology, noted that most of the adults with premature CAD did not meet criteria for preventative statin therapy before their first MI based on ACC/American Heart Association clinical guidelines from 2013 and 2018. It also noted that younger MI survivors are also less frequently eligible for secondary prevention with intensive nonstatin lipid-lowering therapies than are older adults despite a much longer potential life span – and opportunity for another MI – for the former.

The researchers sought to evaluate the real-world implications of changes made in the 2018 guideline for adults who develop premature ischemic heart disease, and found that fewer younger patients qualify for preventative statin therapy under the 2018 guidelines.

“Younger individuals with very high-risk criteria are at higher risk of major adverse cardiovascular events, a finding supporting the appropriate implementation of intensive lipid-lowering therapies in these patients,” wrote lead author Michel Zeitouni, MD, MSc, and colleagues.
 

Key findings

The investigators reported that younger adults were significantly less likely to meet a class I recommendation for statins under the 2013 guideline (42.9%), compared with their middle-aged (70%) and older (82.5%) counterparts; and under the 2018 guideline, at 39.4%, 59.5%, and 77.4%, respectively (both P < .001).

Similarly, when both class I and class IIa recommendations were accounted for, younger patients were significantly less likely than were middle-aged and older patients to be eligible for statins before their index MI under both the 2013 (56.7%, 79.5%, and 85.2%, respectively and 2018 guidelines (46.4%, 73.5%, and 88.2%, respectively (both P < .01).

After their first MI, one in four younger patients (28.3%) met the very high-risk criteria compared with 40% of middle-aged and 81.4% of older patients (P trend < .001). In 8 years of follow-up, patients with very high-risk criteria based on the 2018 guideline had twice the rate of death, nonfatal MI, or stroke (hazard ratio [HR]: 2.15; 95% confidence interval, 1.98-2.33; P < .001).

The researchers acknowledged that the 2018 guideline took the important step of implementing risk enhancers – patient characteristics such as obesity and metabolic syndrome – along with the 10-year atherosclerotic cardiovascular disease (ASCVD) risk score to better identify high-risk young individuals who need statins. However, they also noted that the ability of the guidelines to identify young adults before their first MI “remains suboptimal.”

How to protect younger patients

“The 2018 guidelines will be most effective if we as providers do our best to identify risk enhancers and if we can use CAC scoring more broadly,” Dr. Navar said, noting that although CAC scoring has been shown to improve risk prediction, insurance coverage can be problematic.

“We also need to be careful to screen for the presence of the risk enhancers, such as inflammatory disease, family history, and women-specific risk factors, to make sure we aren’t missing an important high-risk group,” she added.

Other solutions to better identify at-risk younger adults include considering upgrades to the guidelines’ class IIb recommendation to class IIa to emphasize the importance of recognizing lower-risk younger adults, and recommending statins for patients at higher lifetime risk than age- and sex-matched peers, the researchers noted. “In our cohort, young individuals admitted for a first MI had a higher lifetime ASCVD risk score than did patients in the older age categories,” Dr. Zeitouni and colleagues wrote.

Dr. Navar said that these findings are a reminder that guidelines aren’t mandates. “Guidelines are meant to be a starting point for patients and physicians,” she said. “The absence of a recommendation doesn’t mean something isn’t recommended, but that there is not enough data to say one way or another.” 

The study “provides important evidence” that the 2018 guidelines exempted about half of the younger adults who had a first MI from preventative statin therapy, Ron Blankstein, MD, and Avinainder Singh, MD, MMSc, noted in an editorial (J Am Coll Cardiol. 2020;76:665-8).

Brigham and Women&#039;s Hospital

“Data from both the Duke and Young-MI registries should force us to reexamine how we allocate statin use among young individuals,” they noted. Dr. Blankstein is with Brigham and Women’s Hospital, Harvard Medical School, Boston. Dr. Singh is with Yale University, New Haven, Conn.

Dr. Zeitouni reported receiving lecture fees from Bristol-Myers Squibb/Pfizer. Dr. Navar reported financial relationships with Amarin, Janssen, Amgen, Sanofi and Regeneron Pharmaceuticals, AstraZeneca, Esperion, Novo Nordisk, Novartis, The Medicine Company, New Amsterdam, Cerner and Pfizer. Dr. Blankstein reported receiving research support from Amgen. Dr. Singh has no relevant financial relationships to report.

SOURCE: M. Zeitouni et al. J Am Coll Cardiol 2020 Aug 3;76:653-64.

Clinical guidelines for cholesterol management may have two blind spots when it comes to heart attack prevention: Most younger adults with premature coronary artery disease who’ve had a myocardial infarction don’t meet guideline criteria for preventative statin therapy, and survivors under age 55 don’t meet the criteria for continuing nonstatin lipid-lowering treatments, a large single-center retrospective study has shown.

“The classic approach we’ve taken to identifying young adults for prevention is inadequate in younger adults,” corresponding author Ann Marie Navar, MD, PhD, of Duke University, Durham, N.C., said in an interview. “While awaiting more definitive research we should at minimum be using all the tools at our disposal, including broader use of coronary artery calcium [CAC] scoring, to identify young people who may benefit from statin therapy.”

The retrospective observational study analyzed records of 6,639 adults who had cardiac catheterization at Duke University Medical Center from 1995 to 2012 for a first myocardial infarction with obstructive coronary artery disease. The study considered those under age 55 years as “younger” patients, comprising 41% of the study group (2,733); 35% were “middle-aged” at 55-65 years (2,324) and 24% were “older,” at 66-75 years (1,582).

The report, published online Aug. 3 in the Journal of the American College of Cardiology, noted that most of the adults with premature CAD did not meet criteria for preventative statin therapy before their first MI based on ACC/American Heart Association clinical guidelines from 2013 and 2018. It also noted that younger MI survivors are also less frequently eligible for secondary prevention with intensive nonstatin lipid-lowering therapies than are older adults despite a much longer potential life span – and opportunity for another MI – for the former.

The researchers sought to evaluate the real-world implications of changes made in the 2018 guideline for adults who develop premature ischemic heart disease, and found that fewer younger patients qualify for preventative statin therapy under the 2018 guidelines.

“Younger individuals with very high-risk criteria are at higher risk of major adverse cardiovascular events, a finding supporting the appropriate implementation of intensive lipid-lowering therapies in these patients,” wrote lead author Michel Zeitouni, MD, MSc, and colleagues.
 

Key findings

The investigators reported that younger adults were significantly less likely to meet a class I recommendation for statins under the 2013 guideline (42.9%), compared with their middle-aged (70%) and older (82.5%) counterparts; and under the 2018 guideline, at 39.4%, 59.5%, and 77.4%, respectively (both P < .001).

Similarly, when both class I and class IIa recommendations were accounted for, younger patients were significantly less likely than were middle-aged and older patients to be eligible for statins before their index MI under both the 2013 (56.7%, 79.5%, and 85.2%, respectively and 2018 guidelines (46.4%, 73.5%, and 88.2%, respectively (both P < .01).

After their first MI, one in four younger patients (28.3%) met the very high-risk criteria compared with 40% of middle-aged and 81.4% of older patients (P trend < .001). In 8 years of follow-up, patients with very high-risk criteria based on the 2018 guideline had twice the rate of death, nonfatal MI, or stroke (hazard ratio [HR]: 2.15; 95% confidence interval, 1.98-2.33; P < .001).

The researchers acknowledged that the 2018 guideline took the important step of implementing risk enhancers – patient characteristics such as obesity and metabolic syndrome – along with the 10-year atherosclerotic cardiovascular disease (ASCVD) risk score to better identify high-risk young individuals who need statins. However, they also noted that the ability of the guidelines to identify young adults before their first MI “remains suboptimal.”

How to protect younger patients

“The 2018 guidelines will be most effective if we as providers do our best to identify risk enhancers and if we can use CAC scoring more broadly,” Dr. Navar said, noting that although CAC scoring has been shown to improve risk prediction, insurance coverage can be problematic.

“We also need to be careful to screen for the presence of the risk enhancers, such as inflammatory disease, family history, and women-specific risk factors, to make sure we aren’t missing an important high-risk group,” she added.

Other solutions to better identify at-risk younger adults include considering upgrades to the guidelines’ class IIb recommendation to class IIa to emphasize the importance of recognizing lower-risk younger adults, and recommending statins for patients at higher lifetime risk than age- and sex-matched peers, the researchers noted. “In our cohort, young individuals admitted for a first MI had a higher lifetime ASCVD risk score than did patients in the older age categories,” Dr. Zeitouni and colleagues wrote.

Dr. Navar said that these findings are a reminder that guidelines aren’t mandates. “Guidelines are meant to be a starting point for patients and physicians,” she said. “The absence of a recommendation doesn’t mean something isn’t recommended, but that there is not enough data to say one way or another.” 

The study “provides important evidence” that the 2018 guidelines exempted about half of the younger adults who had a first MI from preventative statin therapy, Ron Blankstein, MD, and Avinainder Singh, MD, MMSc, noted in an editorial (J Am Coll Cardiol. 2020;76:665-8).

Brigham and Women&#039;s Hospital

“Data from both the Duke and Young-MI registries should force us to reexamine how we allocate statin use among young individuals,” they noted. Dr. Blankstein is with Brigham and Women’s Hospital, Harvard Medical School, Boston. Dr. Singh is with Yale University, New Haven, Conn.

Dr. Zeitouni reported receiving lecture fees from Bristol-Myers Squibb/Pfizer. Dr. Navar reported financial relationships with Amarin, Janssen, Amgen, Sanofi and Regeneron Pharmaceuticals, AstraZeneca, Esperion, Novo Nordisk, Novartis, The Medicine Company, New Amsterdam, Cerner and Pfizer. Dr. Blankstein reported receiving research support from Amgen. Dr. Singh has no relevant financial relationships to report.

SOURCE: M. Zeitouni et al. J Am Coll Cardiol 2020 Aug 3;76:653-64.

Clinical guidelines for cholesterol management may have two blind spots when it comes to heart attack prevention: Most younger adults with premature coronary artery disease who’ve had a myocardial infarction don’t meet guideline criteria for preventative statin therapy, and survivors under age 55 don’t meet the criteria for continuing nonstatin lipid-lowering treatments, a large single-center retrospective study has shown.

“The classic approach we’ve taken to identifying young adults for prevention is inadequate in younger adults,” corresponding author Ann Marie Navar, MD, PhD, of Duke University, Durham, N.C., said in an interview. “While awaiting more definitive research we should at minimum be using all the tools at our disposal, including broader use of coronary artery calcium [CAC] scoring, to identify young people who may benefit from statin therapy.”

The retrospective observational study analyzed records of 6,639 adults who had cardiac catheterization at Duke University Medical Center from 1995 to 2012 for a first myocardial infarction with obstructive coronary artery disease. The study considered those under age 55 years as “younger” patients, comprising 41% of the study group (2,733); 35% were “middle-aged” at 55-65 years (2,324) and 24% were “older,” at 66-75 years (1,582).

The report, published online Aug. 3 in the Journal of the American College of Cardiology, noted that most of the adults with premature CAD did not meet criteria for preventative statin therapy before their first MI based on ACC/American Heart Association clinical guidelines from 2013 and 2018. It also noted that younger MI survivors are also less frequently eligible for secondary prevention with intensive nonstatin lipid-lowering therapies than are older adults despite a much longer potential life span – and opportunity for another MI – for the former.

The researchers sought to evaluate the real-world implications of changes made in the 2018 guideline for adults who develop premature ischemic heart disease, and found that fewer younger patients qualify for preventative statin therapy under the 2018 guidelines.

“Younger individuals with very high-risk criteria are at higher risk of major adverse cardiovascular events, a finding supporting the appropriate implementation of intensive lipid-lowering therapies in these patients,” wrote lead author Michel Zeitouni, MD, MSc, and colleagues.
 

Key findings

The investigators reported that younger adults were significantly less likely to meet a class I recommendation for statins under the 2013 guideline (42.9%), compared with their middle-aged (70%) and older (82.5%) counterparts; and under the 2018 guideline, at 39.4%, 59.5%, and 77.4%, respectively (both P < .001).

Similarly, when both class I and class IIa recommendations were accounted for, younger patients were significantly less likely than were middle-aged and older patients to be eligible for statins before their index MI under both the 2013 (56.7%, 79.5%, and 85.2%, respectively and 2018 guidelines (46.4%, 73.5%, and 88.2%, respectively (both P < .01).

After their first MI, one in four younger patients (28.3%) met the very high-risk criteria compared with 40% of middle-aged and 81.4% of older patients (P trend < .001). In 8 years of follow-up, patients with very high-risk criteria based on the 2018 guideline had twice the rate of death, nonfatal MI, or stroke (hazard ratio [HR]: 2.15; 95% confidence interval, 1.98-2.33; P < .001).

The researchers acknowledged that the 2018 guideline took the important step of implementing risk enhancers – patient characteristics such as obesity and metabolic syndrome – along with the 10-year atherosclerotic cardiovascular disease (ASCVD) risk score to better identify high-risk young individuals who need statins. However, they also noted that the ability of the guidelines to identify young adults before their first MI “remains suboptimal.”

How to protect younger patients

“The 2018 guidelines will be most effective if we as providers do our best to identify risk enhancers and if we can use CAC scoring more broadly,” Dr. Navar said, noting that although CAC scoring has been shown to improve risk prediction, insurance coverage can be problematic.

“We also need to be careful to screen for the presence of the risk enhancers, such as inflammatory disease, family history, and women-specific risk factors, to make sure we aren’t missing an important high-risk group,” she added.

Other solutions to better identify at-risk younger adults include considering upgrades to the guidelines’ class IIb recommendation to class IIa to emphasize the importance of recognizing lower-risk younger adults, and recommending statins for patients at higher lifetime risk than age- and sex-matched peers, the researchers noted. “In our cohort, young individuals admitted for a first MI had a higher lifetime ASCVD risk score than did patients in the older age categories,” Dr. Zeitouni and colleagues wrote.

Dr. Navar said that these findings are a reminder that guidelines aren’t mandates. “Guidelines are meant to be a starting point for patients and physicians,” she said. “The absence of a recommendation doesn’t mean something isn’t recommended, but that there is not enough data to say one way or another.” 

The study “provides important evidence” that the 2018 guidelines exempted about half of the younger adults who had a first MI from preventative statin therapy, Ron Blankstein, MD, and Avinainder Singh, MD, MMSc, noted in an editorial (J Am Coll Cardiol. 2020;76:665-8).

Brigham and Women&#039;s Hospital

“Data from both the Duke and Young-MI registries should force us to reexamine how we allocate statin use among young individuals,” they noted. Dr. Blankstein is with Brigham and Women’s Hospital, Harvard Medical School, Boston. Dr. Singh is with Yale University, New Haven, Conn.

Dr. Zeitouni reported receiving lecture fees from Bristol-Myers Squibb/Pfizer. Dr. Navar reported financial relationships with Amarin, Janssen, Amgen, Sanofi and Regeneron Pharmaceuticals, AstraZeneca, Esperion, Novo Nordisk, Novartis, The Medicine Company, New Amsterdam, Cerner and Pfizer. Dr. Blankstein reported receiving research support from Amgen. Dr. Singh has no relevant financial relationships to report.

SOURCE: M. Zeitouni et al. J Am Coll Cardiol 2020 Aug 3;76:653-64.

The COVID-19 pandemic is taking a particularly severe financial toll on people with diabetes, new research from the United States suggests.

Results from a national online survey of 5,000 people with diabetes conducted between June 26 and July 1, 2020, were posted July 29 on the American Diabetes Association website.

The survey, conducted by the diabetes research company dQ&A in association with the ADA, revealed that Americans with diabetes are experiencing extreme financial pressures, leading to medication and supply rationing.

A high proportion of respondents had either lost income or are working in jobs that place them at risk for catching the novel coronavirus.

“These new numbers show the urgency needed to adopt measures to protect and assist the millions of people with diabetes who are suffering through this pandemic,” Tracey D. Brown, CEO of the ADA, said in a statement.

She called for states to extend health care coverage to people who have lost their jobs, for the eradication of insulin copays during the pandemic, and for increased COVID-19 testing capacity in high-risk communities.

“If these actions aren’t taken immediately, we will continue to see devastating impacts and outcomes for millions of vulnerable Americans,” Ms. Brown stressed.
 

COVID-19 has worsened financial pressures for people with diabetes

In the survey, 24% of respondents reported having used savings, loans, or stimulus check money to pay for diabetes care in the past 3 months. Among those who have lost income, half are using savings or stimulus money.

A quarter of respondents said they have been self-rationing supplies to cut costs.

Extrapolating to the entire U.S. population with diabetes, dQ&A estimated that roughly 650,000 are skipping insulin doses or taking less than prescribed, and 3 million are skipping blood glucose tests.

In June, the unemployment rate for people with diabetes was 18%, higher than the national rate of 12%.

Also higher is the proportion of those working prior to the pandemic who have since lost income: 33%, compared with 29% for the general population.

Among those who are self-employed, 7 in 10 of those with diabetes have lost some or all of their income.
 

Many with diabetes who are employed are vulnerable to exposure

Of those who remain employed, half said they can’t work from home.

Of those, 60% work in essential industries, with 22% in health care. A large majority, 90%, reported lack of social distancing at work and nearly a third work in places that don’t require masks.

“People with diabetes are helping to provide the services we all depend on during this pandemic, even as it puts their own well-being at risk,” the report said.

It concluded that “these numbers represent a conservative estimate of the pandemic’s impact. They are generated from an ongoing online study of the diabetes population amongst people who have opted in to participate.”

A version of this article originally appeared on Medscape.com.

The COVID-19 pandemic is taking a particularly severe financial toll on people with diabetes, new research from the United States suggests.

Results from a national online survey of 5,000 people with diabetes conducted between June 26 and July 1, 2020, were posted July 29 on the American Diabetes Association website.

The survey, conducted by the diabetes research company dQ&A in association with the ADA, revealed that Americans with diabetes are experiencing extreme financial pressures, leading to medication and supply rationing.

A high proportion of respondents had either lost income or are working in jobs that place them at risk for catching the novel coronavirus.

“These new numbers show the urgency needed to adopt measures to protect and assist the millions of people with diabetes who are suffering through this pandemic,” Tracey D. Brown, CEO of the ADA, said in a statement.

She called for states to extend health care coverage to people who have lost their jobs, for the eradication of insulin copays during the pandemic, and for increased COVID-19 testing capacity in high-risk communities.

“If these actions aren’t taken immediately, we will continue to see devastating impacts and outcomes for millions of vulnerable Americans,” Ms. Brown stressed.
 

COVID-19 has worsened financial pressures for people with diabetes

In the survey, 24% of respondents reported having used savings, loans, or stimulus check money to pay for diabetes care in the past 3 months. Among those who have lost income, half are using savings or stimulus money.

A quarter of respondents said they have been self-rationing supplies to cut costs.

Extrapolating to the entire U.S. population with diabetes, dQ&A estimated that roughly 650,000 are skipping insulin doses or taking less than prescribed, and 3 million are skipping blood glucose tests.

In June, the unemployment rate for people with diabetes was 18%, higher than the national rate of 12%.

Also higher is the proportion of those working prior to the pandemic who have since lost income: 33%, compared with 29% for the general population.

Among those who are self-employed, 7 in 10 of those with diabetes have lost some or all of their income.
 

Many with diabetes who are employed are vulnerable to exposure

Of those who remain employed, half said they can’t work from home.

Of those, 60% work in essential industries, with 22% in health care. A large majority, 90%, reported lack of social distancing at work and nearly a third work in places that don’t require masks.

“People with diabetes are helping to provide the services we all depend on during this pandemic, even as it puts their own well-being at risk,” the report said.

It concluded that “these numbers represent a conservative estimate of the pandemic’s impact. They are generated from an ongoing online study of the diabetes population amongst people who have opted in to participate.”

A version of this article originally appeared on Medscape.com.

The COVID-19 pandemic is taking a particularly severe financial toll on people with diabetes, new research from the United States suggests.

Results from a national online survey of 5,000 people with diabetes conducted between June 26 and July 1, 2020, were posted July 29 on the American Diabetes Association website.

The survey, conducted by the diabetes research company dQ&A in association with the ADA, revealed that Americans with diabetes are experiencing extreme financial pressures, leading to medication and supply rationing.

A high proportion of respondents had either lost income or are working in jobs that place them at risk for catching the novel coronavirus.

“These new numbers show the urgency needed to adopt measures to protect and assist the millions of people with diabetes who are suffering through this pandemic,” Tracey D. Brown, CEO of the ADA, said in a statement.

She called for states to extend health care coverage to people who have lost their jobs, for the eradication of insulin copays during the pandemic, and for increased COVID-19 testing capacity in high-risk communities.

“If these actions aren’t taken immediately, we will continue to see devastating impacts and outcomes for millions of vulnerable Americans,” Ms. Brown stressed.
 

COVID-19 has worsened financial pressures for people with diabetes

In the survey, 24% of respondents reported having used savings, loans, or stimulus check money to pay for diabetes care in the past 3 months. Among those who have lost income, half are using savings or stimulus money.

A quarter of respondents said they have been self-rationing supplies to cut costs.

Extrapolating to the entire U.S. population with diabetes, dQ&A estimated that roughly 650,000 are skipping insulin doses or taking less than prescribed, and 3 million are skipping blood glucose tests.

In June, the unemployment rate for people with diabetes was 18%, higher than the national rate of 12%.

Also higher is the proportion of those working prior to the pandemic who have since lost income: 33%, compared with 29% for the general population.

Among those who are self-employed, 7 in 10 of those with diabetes have lost some or all of their income.
 

Many with diabetes who are employed are vulnerable to exposure

Of those who remain employed, half said they can’t work from home.

Of those, 60% work in essential industries, with 22% in health care. A large majority, 90%, reported lack of social distancing at work and nearly a third work in places that don’t require masks.

“People with diabetes are helping to provide the services we all depend on during this pandemic, even as it puts their own well-being at risk,” the report said.

It concluded that “these numbers represent a conservative estimate of the pandemic’s impact. They are generated from an ongoing online study of the diabetes population amongst people who have opted in to participate.”

A version of this article originally appeared on Medscape.com.

A new palliative care intervention for U.S. patients with advanced heart failure did not improve quality of life or mood after 16 weeks of participation in a randomized trial.

“Future analyses and studies will examine both the patient factors and intervention components to find the right palliative care dose, for the right patient, at the right time,” wrote Marie A. Bakitas, DNSc, of the University of Alabama at Birmingham, and coauthors. The study was published in JAMA Internal Medicine.

“My first reaction is disappointment,” Larry Allen, MD, of the University of Colorado in Denver, said in an interview. “We had hoped to see the ENABLE program, which had been successful in cancer, translate to the heart failure setting.”
 

Improvement of palliative care in heart failure patients might rest on who needs it most

“One thing to note,” Dr. Allen added in an interview, “is that, in this population of patients, some of the measures they were trying to improve were already relatively mild to start with. It may not be that the intervention didn’t help but that they picked a patient population that wasn’t particularly in need. If you treat someone who doesn’t have a problem, it’s hard to make them better.”

In a separate interview, Dr. Bakitas acknowledged a similar sentiment. “We were a little surprised until we looked at our sample,” she said. “We realized that we had recruited all these very high-functioning, good quality-of-life patients. What we then did was look at a subsample of patients who had low quality of life at baseline. Low and behold, the intervention had an effect. The patients who started with a poor quality of life had a statistically and clinically significant benefit. Their KCCQ score increased by over 5 points.”

As for next steps. Dr. Bakitas noted that they’re twofold: “One is refining the patient population who can benefit, and the second is working on the intervention and figuring out which pieces are the ones that provide the most benefit.

“Because of logistics and practical issues, not everyone in the study got all the intervention that they should have. Think of it like a drug trial; if someone misses a pill, they don’t get the full dose that we thought would work. We need to make sure our interventions have the right pieces in place. We don’t want to develop a great intervention that’s not practical for patients.”

Study design and outcomes

To determine the benefits of early palliative care for patients with heart failure, the researchers developed the ENABLE CHF-PC (Educate, Nurture, Advise, Before Life Ends Comprehensive Heartcare for Patients and Caregivers) intervention. This nurse-led program includes an in-person consultant followed by six telehealth nurse coaching sessions lasting 30-40 minutes and then monthly follow-up calls through either 48 weeks or the patient’s death.

To test the effectiveness of their intervention after 16 weeks, the researchers launched a two-site, single-blind randomized clinical trial made up of 415 patients who were 50 years or older with advanced heart failure. Among the patients, 53% were men and the mean age was 64 years; 55% were African American, 26% lived in a rural area, and 46% had a high school education or less. The average length of time since heart failure diagnosis was 5.1 years.

Patients were randomized evenly to receive either the ENABLE CHF-PC intervention (208) or usual care. The primary outcomes were quality of life (QOL), which was measured by the heart failure–specific 23-item Kansas City Cardiomyopathy Questionnaire (KCCQ) and the 14-item Functional Assessment of Chronic Illness Therapy–Palliative-14 (FACIT Pal-14), and mood, which was measured by the 14-item Hospital Anxiety and Depression Scale (HADS). Pain was measured via 3-item pain intensity and 2-item pain interference scales.

Effect size was measured as Cohen d or d-equivalent, where a small effect is 0.2, medium is 0.5, and large is about 0.854.

At baseline, the mean KCCQ score of 52.6 at baseline indicated a “fairly good” QOL across all patients. After 16 weeks, the mean KCCQ score improved 3.9 points in the intervention group, compared with 2.3 points in the usual care group (d = 0.07; [95% confidence interval, –0.09-0.24]). In addition, the mean FACIT-Pal-14 score improved 1.4 points in the intervention group compared to 0.2 points in the usual care group (d = 0.12 [95% CI, –0.03-0.28]). Only small differences were observed between groups regarding anxiety and depression, but pain intensity (difference, –2.8; SE, 0.9; d = –0.26 [95% CI, –0.43-0.09]) and pain interference (difference, –2.3; SE, 1; d = –0.21 [95% CI, –0.40 to –0.02]) demonstrated a statistically significant and clinically important decrease.
 

As heart failure care evolves, so must palliative care

Though the study and intervention developed by Dr. Bakitas and colleagues is commendable, it is only somewhat surprising that it did not drastically improve patients’ quality of life, Nathan E. Goldstein, MD, of the Icahn School of Medicine at Mount Sinai in New York, wrote in an accompanying editorial.

He noted several reasons for the lack of improvement, including a large proportion of patients still being in the early stages of the disease. Ultimately, however, he wonders if innovation in heart failure care ultimately impacted the study while it was occurring. Medications and technological advancements evolve rapidly in this field, he said, especially over the course of a 3-year study period.

To continue this work and produce real benefits in patients with advanced heart failure, Dr. Goldstein emphasized the need for “dynamic palliative care interventions that can adapt to the constantly changing landscape of the patient’s needs caused by the underlying nature of the disease, as well as the innovations in the field of cardiology.”

The authors acknowledged their study’s limitations, including data attrition at 16 weeks that was higher than expected – a turn of events they attributed to “unique socioeconomic factors … and lack of regular health care appointments” among some participants. In addition, a minority of patients were unable to stick to the study protocol, which has led the researchers to begin investigating video alternatives to in-person consultation.

The study was supported by the National Institutes of Health/National Institutes of Nursing Research. Four of the authors reported received grants from the National Institutes of Nursing Research outside the submitted work or during the study. Dr. Goldstein reported no conflicts of interest.

SOURCE: Bakitas MA et al. JAMA Intern Med. 2020 July 27. doi: 10.1001/jamainternmed.2020.2861.

A new palliative care intervention for U.S. patients with advanced heart failure did not improve quality of life or mood after 16 weeks of participation in a randomized trial.

“Future analyses and studies will examine both the patient factors and intervention components to find the right palliative care dose, for the right patient, at the right time,” wrote Marie A. Bakitas, DNSc, of the University of Alabama at Birmingham, and coauthors. The study was published in JAMA Internal Medicine.

“My first reaction is disappointment,” Larry Allen, MD, of the University of Colorado in Denver, said in an interview. “We had hoped to see the ENABLE program, which had been successful in cancer, translate to the heart failure setting.”
 

Improvement of palliative care in heart failure patients might rest on who needs it most

“One thing to note,” Dr. Allen added in an interview, “is that, in this population of patients, some of the measures they were trying to improve were already relatively mild to start with. It may not be that the intervention didn’t help but that they picked a patient population that wasn’t particularly in need. If you treat someone who doesn’t have a problem, it’s hard to make them better.”

In a separate interview, Dr. Bakitas acknowledged a similar sentiment. “We were a little surprised until we looked at our sample,” she said. “We realized that we had recruited all these very high-functioning, good quality-of-life patients. What we then did was look at a subsample of patients who had low quality of life at baseline. Low and behold, the intervention had an effect. The patients who started with a poor quality of life had a statistically and clinically significant benefit. Their KCCQ score increased by over 5 points.”

As for next steps. Dr. Bakitas noted that they’re twofold: “One is refining the patient population who can benefit, and the second is working on the intervention and figuring out which pieces are the ones that provide the most benefit.

“Because of logistics and practical issues, not everyone in the study got all the intervention that they should have. Think of it like a drug trial; if someone misses a pill, they don’t get the full dose that we thought would work. We need to make sure our interventions have the right pieces in place. We don’t want to develop a great intervention that’s not practical for patients.”

Study design and outcomes

To determine the benefits of early palliative care for patients with heart failure, the researchers developed the ENABLE CHF-PC (Educate, Nurture, Advise, Before Life Ends Comprehensive Heartcare for Patients and Caregivers) intervention. This nurse-led program includes an in-person consultant followed by six telehealth nurse coaching sessions lasting 30-40 minutes and then monthly follow-up calls through either 48 weeks or the patient’s death.

To test the effectiveness of their intervention after 16 weeks, the researchers launched a two-site, single-blind randomized clinical trial made up of 415 patients who were 50 years or older with advanced heart failure. Among the patients, 53% were men and the mean age was 64 years; 55% were African American, 26% lived in a rural area, and 46% had a high school education or less. The average length of time since heart failure diagnosis was 5.1 years.

Patients were randomized evenly to receive either the ENABLE CHF-PC intervention (208) or usual care. The primary outcomes were quality of life (QOL), which was measured by the heart failure–specific 23-item Kansas City Cardiomyopathy Questionnaire (KCCQ) and the 14-item Functional Assessment of Chronic Illness Therapy–Palliative-14 (FACIT Pal-14), and mood, which was measured by the 14-item Hospital Anxiety and Depression Scale (HADS). Pain was measured via 3-item pain intensity and 2-item pain interference scales.

Effect size was measured as Cohen d or d-equivalent, where a small effect is 0.2, medium is 0.5, and large is about 0.854.

At baseline, the mean KCCQ score of 52.6 at baseline indicated a “fairly good” QOL across all patients. After 16 weeks, the mean KCCQ score improved 3.9 points in the intervention group, compared with 2.3 points in the usual care group (d = 0.07; [95% confidence interval, –0.09-0.24]). In addition, the mean FACIT-Pal-14 score improved 1.4 points in the intervention group compared to 0.2 points in the usual care group (d = 0.12 [95% CI, –0.03-0.28]). Only small differences were observed between groups regarding anxiety and depression, but pain intensity (difference, –2.8; SE, 0.9; d = –0.26 [95% CI, –0.43-0.09]) and pain interference (difference, –2.3; SE, 1; d = –0.21 [95% CI, –0.40 to –0.02]) demonstrated a statistically significant and clinically important decrease.
 

As heart failure care evolves, so must palliative care

Though the study and intervention developed by Dr. Bakitas and colleagues is commendable, it is only somewhat surprising that it did not drastically improve patients’ quality of life, Nathan E. Goldstein, MD, of the Icahn School of Medicine at Mount Sinai in New York, wrote in an accompanying editorial.

He noted several reasons for the lack of improvement, including a large proportion of patients still being in the early stages of the disease. Ultimately, however, he wonders if innovation in heart failure care ultimately impacted the study while it was occurring. Medications and technological advancements evolve rapidly in this field, he said, especially over the course of a 3-year study period.

To continue this work and produce real benefits in patients with advanced heart failure, Dr. Goldstein emphasized the need for “dynamic palliative care interventions that can adapt to the constantly changing landscape of the patient’s needs caused by the underlying nature of the disease, as well as the innovations in the field of cardiology.”

The authors acknowledged their study’s limitations, including data attrition at 16 weeks that was higher than expected – a turn of events they attributed to “unique socioeconomic factors … and lack of regular health care appointments” among some participants. In addition, a minority of patients were unable to stick to the study protocol, which has led the researchers to begin investigating video alternatives to in-person consultation.

The study was supported by the National Institutes of Health/National Institutes of Nursing Research. Four of the authors reported received grants from the National Institutes of Nursing Research outside the submitted work or during the study. Dr. Goldstein reported no conflicts of interest.

SOURCE: Bakitas MA et al. JAMA Intern Med. 2020 July 27. doi: 10.1001/jamainternmed.2020.2861.

A new palliative care intervention for U.S. patients with advanced heart failure did not improve quality of life or mood after 16 weeks of participation in a randomized trial.

“Future analyses and studies will examine both the patient factors and intervention components to find the right palliative care dose, for the right patient, at the right time,” wrote Marie A. Bakitas, DNSc, of the University of Alabama at Birmingham, and coauthors. The study was published in JAMA Internal Medicine.

“My first reaction is disappointment,” Larry Allen, MD, of the University of Colorado in Denver, said in an interview. “We had hoped to see the ENABLE program, which had been successful in cancer, translate to the heart failure setting.”
 

Improvement of palliative care in heart failure patients might rest on who needs it most

“One thing to note,” Dr. Allen added in an interview, “is that, in this population of patients, some of the measures they were trying to improve were already relatively mild to start with. It may not be that the intervention didn’t help but that they picked a patient population that wasn’t particularly in need. If you treat someone who doesn’t have a problem, it’s hard to make them better.”

In a separate interview, Dr. Bakitas acknowledged a similar sentiment. “We were a little surprised until we looked at our sample,” she said. “We realized that we had recruited all these very high-functioning, good quality-of-life patients. What we then did was look at a subsample of patients who had low quality of life at baseline. Low and behold, the intervention had an effect. The patients who started with a poor quality of life had a statistically and clinically significant benefit. Their KCCQ score increased by over 5 points.”

As for next steps. Dr. Bakitas noted that they’re twofold: “One is refining the patient population who can benefit, and the second is working on the intervention and figuring out which pieces are the ones that provide the most benefit.

“Because of logistics and practical issues, not everyone in the study got all the intervention that they should have. Think of it like a drug trial; if someone misses a pill, they don’t get the full dose that we thought would work. We need to make sure our interventions have the right pieces in place. We don’t want to develop a great intervention that’s not practical for patients.”

Study design and outcomes

To determine the benefits of early palliative care for patients with heart failure, the researchers developed the ENABLE CHF-PC (Educate, Nurture, Advise, Before Life Ends Comprehensive Heartcare for Patients and Caregivers) intervention. This nurse-led program includes an in-person consultant followed by six telehealth nurse coaching sessions lasting 30-40 minutes and then monthly follow-up calls through either 48 weeks or the patient’s death.

To test the effectiveness of their intervention after 16 weeks, the researchers launched a two-site, single-blind randomized clinical trial made up of 415 patients who were 50 years or older with advanced heart failure. Among the patients, 53% were men and the mean age was 64 years; 55% were African American, 26% lived in a rural area, and 46% had a high school education or less. The average length of time since heart failure diagnosis was 5.1 years.

Patients were randomized evenly to receive either the ENABLE CHF-PC intervention (208) or usual care. The primary outcomes were quality of life (QOL), which was measured by the heart failure–specific 23-item Kansas City Cardiomyopathy Questionnaire (KCCQ) and the 14-item Functional Assessment of Chronic Illness Therapy–Palliative-14 (FACIT Pal-14), and mood, which was measured by the 14-item Hospital Anxiety and Depression Scale (HADS). Pain was measured via 3-item pain intensity and 2-item pain interference scales.

Effect size was measured as Cohen d or d-equivalent, where a small effect is 0.2, medium is 0.5, and large is about 0.854.

At baseline, the mean KCCQ score of 52.6 at baseline indicated a “fairly good” QOL across all patients. After 16 weeks, the mean KCCQ score improved 3.9 points in the intervention group, compared with 2.3 points in the usual care group (d = 0.07; [95% confidence interval, –0.09-0.24]). In addition, the mean FACIT-Pal-14 score improved 1.4 points in the intervention group compared to 0.2 points in the usual care group (d = 0.12 [95% CI, –0.03-0.28]). Only small differences were observed between groups regarding anxiety and depression, but pain intensity (difference, –2.8; SE, 0.9; d = –0.26 [95% CI, –0.43-0.09]) and pain interference (difference, –2.3; SE, 1; d = –0.21 [95% CI, –0.40 to –0.02]) demonstrated a statistically significant and clinically important decrease.
 

As heart failure care evolves, so must palliative care

Though the study and intervention developed by Dr. Bakitas and colleagues is commendable, it is only somewhat surprising that it did not drastically improve patients’ quality of life, Nathan E. Goldstein, MD, of the Icahn School of Medicine at Mount Sinai in New York, wrote in an accompanying editorial.

He noted several reasons for the lack of improvement, including a large proportion of patients still being in the early stages of the disease. Ultimately, however, he wonders if innovation in heart failure care ultimately impacted the study while it was occurring. Medications and technological advancements evolve rapidly in this field, he said, especially over the course of a 3-year study period.

To continue this work and produce real benefits in patients with advanced heart failure, Dr. Goldstein emphasized the need for “dynamic palliative care interventions that can adapt to the constantly changing landscape of the patient’s needs caused by the underlying nature of the disease, as well as the innovations in the field of cardiology.”

The authors acknowledged their study’s limitations, including data attrition at 16 weeks that was higher than expected – a turn of events they attributed to “unique socioeconomic factors … and lack of regular health care appointments” among some participants. In addition, a minority of patients were unable to stick to the study protocol, which has led the researchers to begin investigating video alternatives to in-person consultation.

The study was supported by the National Institutes of Health/National Institutes of Nursing Research. Four of the authors reported received grants from the National Institutes of Nursing Research outside the submitted work or during the study. Dr. Goldstein reported no conflicts of interest.

SOURCE: Bakitas MA et al. JAMA Intern Med. 2020 July 27. doi: 10.1001/jamainternmed.2020.2861.