Can patients with atrial fibrillation  undergo a percutaneous procedure to reduce their risk of stroke, thereby eliminating the need for lifelong treatment with an oral anticoagulant drug? The data are preliminary, but this is an emerging option that physicians should be aware of.

We review here the current evidence and techniques aimed at isolating the left atrial appendage to prevent stroke, and we emphasize the need for continued systematic comparisons between oral anticoagulation and percutaneous treatment options.

NOVEL TREATMENTS ARE NEEDED

Atrial fibrillation is the most common cardiac arrhythmia,¹ affecting an estimated 1% to 2% of people worldwide. In 2001, an estimated 2.3 million persons in the United States had atrial fibrillation, and that number is expected to more than double by 2050.²

Atrial fibrillation independently increases the risk of stroke by a factor of 4 to 5.³ The American Heart Association ranks stroke as the fourth most common cause of death and the leading cause of disability in the United States.⁴ Atrial fibrillation accounts for 15% of strokes in people of all ages and 30% in those over age 80.⁵ Untreated, 2% to 5% of patients with atrial fibrillation suffer a stroke in any given year.⁶ Most of these strokes are cardioembolic, with thrombi originating in the left atrial appendage.⁷ Furthermore, it has been estimated^8,9 that patients with atrial fibrillation who have already had a stroke and cannot tolerate oral anticoagulants have an annual risk of stroke close to 12% and a relative risk of approximately 3.0 compared with those with atrial fibrillation and prior stroke who can tolerate anticoagulation.

Oral anticoagulation effectively prevents thromboembolic events associated with atrial fibrillation,¹⁰ but several factors limit its efficacy and applicability. The risk of bleeding complications, the need for frequent monitoring, and challenges with compliance create a large population of patients who would benefit from alternative approaches. Consequently, physicians have looked for other ways to prevent stroke—especially surgical and transcatheter procedures—that are not associated with an ongoing risk of hemorrhage and a lifelong need to take an anticoagulant.

THE LEFT ATRIAL APPENDAGE: A SITE OF CLOT FORMATION

The left atrial appendage is the most common site of thrombus formation, particularly in patients with nonvalvular atrial fibrillation. Nearly 90% of thrombi discovered in the left atrium form in the appendage.⁷ A study of 233 patients not on long-term anticoagulation revealed that after 48 hours of atrial fibrillation, 15% had a left atrial thrombus, and all but one of the thrombi were in the appendage.¹¹

Atrial fibrillation increases the risk of stroke by a factor of 4 to 5

Believed to function as a decompression chamber during left ventricular systole, the left atrial appendage is embryologically derived from the left wall of the primary atrium. It is in close proximity to the free wall of the left ventricle, and therefore its flow can vary with left ventricular function. Relative stasis due to its location and extensive trabeculations, especially in times of poor forward flow, make it a high-risk site for clot formation.¹²

ANTICOAGULATION: EFFECTIVE BUT IMPERFECT

In deciding whether a patient with atrial fibrillation should be prescribed anticoagulation therapy, the physician must balance the risk of stroke against the risk of bleeding. Several tools for assessing these two risks have been developed. Of note, some of the risk factors for stroke are the same as some of the risk factors for bleeding.

Calculating the risk of stroke

CHADS₂ and CHA2DS₂-VASc are the two most commonly used tools for assessing the risk of stroke, but only the newer CHA₂DS₂-VASc has received a class I recommendation (the highest) from the European Society of Cardiology (ESC).¹³

CHADS₂ risk factors are Congestive heart failure (1 point), Hypertension (1 point), Age 75 or older (1 point), Diabetes (1 point), and  Stroke or transient ischemic attack (2 points). Risk of stroke is considered low with a score of 0, intermediate with a score of 1, and high with a score of 2 or more. 

CHA₂DS₂-VASc risk factors are Congestive heart failure or left ventricular ejection fraction ≤ 40% (1 point), Hypertension (1 point), Age ≥ 75 (2 points), Age 65–74 (1 point), Diabetes mellitus (1 point), Stroke, transient ischemic attack, or thromboembolism (2 points), Vascular disease (1 point), and female Sex (1 point). Low risk is defined as a score of 0 for a man or, for a woman with no other risk factors, a score of 1. A score of 1 for a man indicates moderate risk, and a score of 2 or more is high risk.

Calculating the risk of bleeding

Tools for assessing bleeding risk include ATRIA2 and HAS-BLED,¹⁴ the latter carrying a class I recommendation from the ESC.¹³

HAS-BLED risk factors are Hypertension (1 point), Abnormal renal or liver function (1 point each), Stroke (1 point), Bleeding (1 point), Labile international normalized ratio (INR) (1 point), Elderly (age > 65) (1 point), and Drug or alcohol use (1 point each). The risk of bleeding is considered high with a score of 3 or higher.

Disadvantages of oral anticoagulation

Oral anticoagulation is the standard treatment for preventing stroke in patients with atrial fibrillation, and the vitamin K antagonist warfarin remains the foundation.

Though highly effective, warfarin requires close monitoring and frequent dose adjustments because of its numerous food and drug interactions. Bleeding risk and the challenge of frequent monitoring rule out treatment with warfarin in 14% to 44% of patients with atrial fibrillation.¹⁵ Even in “ideal” candidates, warfarin is underused, with one study reporting that only 38% of those with clinical indications for it had been prescribed warfarin, and of those for whom it had not been prescribed, 63% were also not taking aspirin.¹⁶ Moreover, a meta-analysis suggested that the average patient treated with warfarin has his or her INR in the therapeutic range only about 55% of the time.¹⁷

Newer, target-specific oral anticoagulants such as dabigatran (a direct thrombin inhibitor) and rivaroxaban and apixaban (both factor Xa inhibitors) do not require monitoring and have fewer drug interactions. But like warfarin, they also confer a risk of serious bleeding.^18–20 Most of the studies of these newer drugs have compared them with warfarin, with the preponderance of evidence showing them to be either noninferior or superior to warfarin for stroke reduction. But bleeding complication rates remain significant, apixaban having lower rates of major bleeding than dabigatran and rivaroxaban.

Untreated, 2%–5% of patients with atrial fibrillation will suffer a stroke in any given year

In a meta-analysis, Ruff et al²¹ concluded that the target-specific oral anticoagulants provide a favorable balance of risk and benefit. Compared with warfarin, these new drugs reduced the rate of stroke or systemic embolic events by 19%. There was also a significant reduction in rates of intracranial hemorrhage and all-cause mortality. The risk of major bleeding was similar to that with warfarin, though there was a higher risk of gastrointestinal bleeding with target-specific agents. These effects were consistent across a wide range of patients.

Given the difficulties, risks, and serious side effects of anticoagulant therapy, many patients stop taking these drugs soon after starting them, either on their own or on their physician’s recommendation. In the RE-LY trial (Dabigatran vs Warfarin in Patients With Atrial Fibrillation), 10% of patients receiving dabigatran and 17% of those receiving warfarin stopped the treatment within 1 to 2 years.²² In a similar trial of rivaroxaban vs warfarin in nonvalvular atrial fibrillation (the ROCKET-AF trial), 24% of those treated with rivaroxaban and 22% of those treated with warfarin stopped treatment during the study.¹⁹ In the ARISTOTLE trial (Apixaban vs Warfarin in Patients With Atrial Fibrillation), 25% of patients discontinued apixaban and 28% discontinued warfarin.²⁰

The results of these trials show a clear need for treatments without high attrition rates, since patients with atrial fibrillation need protection from stroke for the rest of their life.

SURGICAL CLOSURE AS AN ADD-ON TO OTHER PROCEDURES

If the patient is undergoing cardiac surgery for another reason, the surgeon can excise, suture, staple, or clip the left atrial appendage shut at the same time. Closure is recommended as part of valve replacement.⁸ In a 2008 retrospective study, left atrial appendage closure was successfully performed in 40% of those undergoing the procedure during cardiac surgery, and complete closure occurred more often with excision than with suture exclusion and stapler exclusion.²³ A study of patients who underwent ligation of the left atrial appendage during mitral value replacement found that 35% demonstrated incomplete closure as determined by transesophageal echocardiography.²⁴

Newer devices have shown more success. The AtriClip (AtriCure Inc., West Chester, OH) is a self-closing, implantable clip applied epicardially by either an open surgical or a minimally invasive technique.²⁵ Successful closure was confirmed in 60 of 61 patients at 90 days as determined by computed tomography or transesophageal echocardiography, and there were no adverse events related to implantation of the device.²⁵ The TigerPaw system (Terumo Cardiovascular Systems, Ann Arbor, MI)²⁶ is a fastener delivered surgically around the base of the ostium of the left atrial appendage. In an initial trial, 90 days after the procedure, transesophageal echocardiography showed no leaks in any of those who were examined (54 of 60 patients).

Amputation of the left atrial appendage is also considered part of the maze procedure for atrial fibrillation, in which the operator creates multiple small scars in the atria to prevent irregular impulses from being conducted.²⁷

Results of these surgical approaches have been mixed, as incomplete closure or clipping actually increases the risk of left atrial thrombus formation and embolization.²⁸ Moreover, these invasive surgical techniques are associated with significant periprocedural morbidity.²⁹ Because of the high risk of surgical complications, cardiac specialists have sought less invasive percutaneous procedures to manage stroke risk in patients with atrial fibrillation.

PERCUTANEOUS OCCLUSION

One option for closing the left atrial appendage is a percutaneous transseptal approach in which a plug is placed in the opening connecting the appendage to the rest of the atrium.

The PLAATO device

The Percutaneous LAA Transcatheter Occlusion (PLAATO) device (Appriva Medical Inc., Sunnyvale, CA) contains an expandable nitinol-covered cage designed to be placed in the orifice of the left atrial appendage. Over time, tissue grows into the device, entirely isolating the appendage from the rest of the atrium.

In 2002, Sievert et al³⁰ reported using this device in 15 patients. Subsequently, in a nonrandomized trial in patients with contraindications to lifelong anticoagulation, total occlusion was achieved in 108 of 111 patients, with no thrombosis or migration of the device at 6 months. The annual risk of stroke was 2.2%, a reduction in relative risk of 65% based on the CHADS₂ score.³¹

But despite this apparent success, the PLAATO device was discontinued for unspecified commercial reasons.

Amplatzer cardiac plug

Modeled after an atrial septal occluder, the Amplatzer cardiac plug (St. Jude Medical, St. Paul, MN) consists of a lobe and a disk connected by a central waist.

In 2011, Park et al³² published their initial experience implanting this device in patients who either could not tolerate or did not desire long-term anticoagulation. They reported a 96% closure rate (137 of 143 patients), but there were serious complications in 10 patients: 3 with ischemic stroke, 2 with device embolism, and 5 with pericardial effusions.

Warfarin remains the foundation of stroke prevention in atrial fibrillation

Urena et al³³ reported similar results in 52 patients with absolute contraindications to warfarin, with a 98.1% implantation rate. Patients were then maintained on either single or dual antiplatelet therapy at the discretion of the operator. At 20-month follow-up, there had been one stroke, one transient ischemic attack, and one major bleeding event. The leakage rate was 16.2% as determined by transesophageal echocardiography.

While initial results were promising, a clinical trial comparing this device and optimal medical treatment is currently on hold. Thus, there are no clear data comparing the Amplatzer device with oral anticoagulation.³⁴

The Watchman device

The Watchman device (Boston Scientific, Marlborough, MA), an evolution of the PLAATO device, is a self-expanding nitinol structure with fixation barbs and a polyethylene membrane to protect the atrium-facing side of the device (Figure 1).

A pilot trial reported successful implantation in 66 of 75 patients, though the device was found to migrate after placement in 5 of the first 16 patients using the original device and delivery system. The device was modified, and no further embolization of the device occurred.³⁵

The PROTECT-AF trial (Protection in Patients With Atrial Fibrillation)³⁶ was the first completed and published randomized controlled trial evaluating left atrial appendage closure using a device vs long-term warfarin therapy. This study randomized 707 people with nonvalvular atrial fibrillation from 59 centers worldwide to receive the Watchman device or a control treatment. The study included patients age 18 or older with nonvalvular atrial fibrillation who were able to tolerate warfarin therapy. Patients in the control group received warfarin for the duration of the study and were monitored every 2 weeks for a goal INR of 2 to 3, achieving a therapeutic INR 66% of the time. The device group was also treated with warfarin for 45 days to allow device endothelialization. Warfarin was discontinued if transesophageal echocardiography showed complete closure or significantly decreased flow around the device. Patients in the device group were then treated with aspirin and clopidogrel for 6 months, and then with aspirin indefinitely.

Incomplete closure or clipping actually increases the risk of thrombosis and embolization

At 1,065 patient-years of follow-up, PROTECT-AF showed that in patients with atrial fibrillation who were candidates for warfarin therapy, percutaneous left atrial appendage closure using the Watchman device reduced the rate of hemorrhagic stroke compared with warfarin and was noninferior to warfarin in terms of all-cause mortality and stroke. A 4-year follow-up to the PROTECT-AF trial found that receiving the Watchman was better than taking warfarin in terms of risk of cardiovascular death, stroke and other systemic embolization, and all-cause mortality. The adverse event rates were 2.3% in the device group and 3.8% in the control group, a 40% relative risk reduction in the Watchman group.³⁷

The PREVAIL trial (Prospective Randomized Evaluation of the WATCHMAN LAA Closure Device in Patients With Atrial Fibrillation vs Long-Term Warfarin Therapy) aimed to confirm the safety and efficacy of the Watchman device compared with long-term warfarin therapy.³⁸ The event rate (defined as 7-day occurrence of death, ischemic stroke, systemic embolism, and procedure- or device-related complications requiring major cardiovascular or endovascular intervention) was 2.2%. But the PREVAIL trial was unable to show that the device was noninferior to warfarin in terms of its second primary end point of stroke, systemic embolism, and cardiovascular or unexplained death at 18 months. When performed by physicians who were new to the procedure, the procedure was successful (ie, the device was successfully implanted) in 93.2%; the rate was slightly higher (96.3%) when performed by experienced implanters.

Safety data gathered in PREVAIL in conjunction with demonstrated efficacy from PROTECT-AF suggest that the Watchman device may be a safe and effective alternative to long-term oral anticoagulation in patients with nonvalvular atrial fibrillation.

In patients with contraindications to warfarin

Most of the published data have been about the efficacy of occlusion devices compared with long-term warfarin therapy. Unfortunately, the population that has not been studied extensively is patients who have contraindications to long-term oral anticoagulation, who would benefit the most from an occlusive device.

The ASA Plavix Feasibility Study (ASAP) focused on this population, specifically those who had a CHADS₂ score of 1 or higher and who were considered ineligible for warfarin, to determine whether closure using the Watchman device could be safely performed without a transition period with warfarin.³⁹ After device implantation, trial participants were given clopidogrel for 6 months and aspirin indefinitely. The trial enrolled 150 patients and followed them for a mean of 14.4 (± 8.6) months. In that time, there were four strokes, five pericardial effusions, and six instances of device-related thrombus by transesophageal echocardiography. Three of the strokes were ischemic (1.7% per year), which is a 77% reduction from the expected rate of 7.3% based on the CHADS₂ scores of the patient cohort.

These data suggest that implantation of the Watchman device may be appropriate for those who cannot tolerate warfarin even in the short term.

The Lariat system

The Lariat suture delivery device (SentreHeart, Inc., Redwood City, CA) is approved by the US Food and Drug Administration (FDA) for soft-tissue closure and has been used for percutaneous left atrial appendage closure. It uses a magnet-tipped wire that is passed to the epicardial side of the left atrial appendage via pericardial access to meet a second magnet-tipped wire introduced into the appendage via transseptal access. A “lasso” is then advanced over the epicardial guide wire and tightened down around the ostium of the left atrial appendage. This tool facilitates deployment of a nonabsorbable polyester suture, which effectively ligates off the appendage from the rest of the left atrium (Figure 2).⁴⁰ In theory, the Lariat’s epicardial approach could eliminate the need for short- and long-term anticoagulation, as there would be no foreign body left within the heart.

In an initial cohort of 89 patients in Poland,41 the investigators reported a 96% closure rate as determined by transesophageal echocardiography immediately after the procedure. At 1-year follow-up, there was 98% complete closure, including cases of incomplete closure detected earlier.41 Adverse events were limited, with only two cases of severe pericarditis, two strokes, and one pericardial effusion. These results were replicated in the United States in a cohort of 25 patients, with a 100% closure rate and no stroke events.⁴²

There have been three published case reports of left atrial clot formation after successful left atrial appendage ligation using the Lariat device.^43–45 These experiences further emphasize that closure does not necessarily confer instant stroke prevention, and there remains a need to investigate the need for routine imaging and possibly periprocedural anticoagulation after ligation.

More recently, Pillai et al⁴⁶ published their initial experience following 71 patients with echocardiograms 3 months after left atrial appendage closure using the Lariat device. They reported leaks in 6 of the 71 patients; five of the leaks were successfully closed using the Amplatzer Septal Occluder, and one was closed with a repeat Lariat procedure.

Although the Lariat system has been used in more than 2,000 patients worldwide (SentreHeart, personal communication), there has been no published systematic comparison between it and oral anticoagulation to date.

AN EMERGING OPTION

Established guidelines help determine which patients with atrial fibrillation should receive oral anticoagulant therapy. For patients who have absolute contraindications to oral anticoagulants or who are undergoing cardiac surgery, surgical ligation of the left atrial appendage is an option. But for those with contraindications to oral anticoagulation in both the short term and the long term, there is a growing body of evidence suggesting that a percutaneous intervention is at least noninferior to—and in some cases is superior to—warfarin. Figure 3 shows our recommendations for the steps to determine which patients would be most appropriate to consider for left atrial appendage closure.

Holmes et al⁴⁷ propose that we may now have enough evidence to support an expedited regulatory approval process of these occlusion devices. But there are still a number of areas in which further investigation is clearly needed before left atrial appendage occlusion devices can be widely adopted.

The trials discussed above had specific inclusion and exclusion criteria, and therefore, although they support percutaneous intervention, the generalizability of their results remains in question. Indeed, the patients in PROTECT-AF³⁶ had an average CHADS₂ score of only 2.2. This study also included only patients who were able to tolerate both aspirin and clopidogrel simultaneously for a significant amount of time. Hence, one cannot assume the results would be the same in patients who have strict contraindications to warfarin or any target-specific oral anticoagulant. Concern regarding the generalizability of the conclusions from PROTECT-AF and PREVAIL has led to mixed votes (three assessments to date) from the FDA Circulatory Device Panel.⁴⁸

In an encouraging review of cases, Gafoor et al⁴⁹ reported safe and efficacious occlusion in octogenarians using the devices mentioned above. These patients often pose the greatest challenge in initiating long-term anticoagulation because of the many drug-drug interactions and the risk of intracranial hemorrhage secondary to falls.

Further, while occlusion devices would clearly be useful for patients in whom traditional oral anticoagulation is not an option, the newer oral anticoagulants might complicate the picture somewhat. As shown by Ruff et al,²¹ the risk-benefit ratio of these target-specific oral anticoagulants is quite favorable and by some measurements is superior to that of warfarin. Could there be a group of patients who cannot take warfarin but could instead do well on one of the newer anticoagulants, thus alleviating the need for percutaneous intervention? As the newer oral anticoagulants become more commonly used, the cost-benefit analysis of implanting an occlusion device could shift.

We expect that percutaneous closure will someday be a viable and equal option for stroke prevention

Lastly, in this era of high-value medical care, one must consider the cost-effectiveness of these novel interventions. As with any new technology, the up-front cost of implantation is certainly greater than that of warfarin therapy. If device implantation can prevent a hospitalization from a major bleed secondary to warfarin use or prevent a catastrophic stroke due to untreated atrial fibrillation, then the cost-benefit analysis may be tipped in the other direction. As these devices become more widely available and physicians have more experience implanting them, the costs will likely decrease.

As with oral anticoagulation therapy, all interventions, whether surgical or percutaneous, carry a risk of bleeding and stroke. There remains no substitute for frank and clear discussions between the physician and patient regarding the risks and benefits of each approach.

While a growing body of evidence surrounds left atrial appendage occlusion devices, many questions remain. Notably, could these devices be used in patients who can tolerate oral anticoagulants? And if so, which subgroups would benefit most? Does occlusion or ligation of the left atrial appendage affect electrical connections between it and the left atrium, thereby lowering the burden of atrial fibrillation?

We expect that continued investigation of and experience with left atrial appendage closure devices will position them one day as a viable and equal option for preventing stroke in patients with atrial fibrillation.

Can patients with atrial fibrillation  undergo a percutaneous procedure to reduce their risk of stroke, thereby eliminating the need for lifelong treatment with an oral anticoagulant drug? The data are preliminary, but this is an emerging option that physicians should be aware of.

We review here the current evidence and techniques aimed at isolating the left atrial appendage to prevent stroke, and we emphasize the need for continued systematic comparisons between oral anticoagulation and percutaneous treatment options.

NOVEL TREATMENTS ARE NEEDED

Atrial fibrillation is the most common cardiac arrhythmia,¹ affecting an estimated 1% to 2% of people worldwide. In 2001, an estimated 2.3 million persons in the United States had atrial fibrillation, and that number is expected to more than double by 2050.²

Atrial fibrillation independently increases the risk of stroke by a factor of 4 to 5.³ The American Heart Association ranks stroke as the fourth most common cause of death and the leading cause of disability in the United States.⁴ Atrial fibrillation accounts for 15% of strokes in people of all ages and 30% in those over age 80.⁵ Untreated, 2% to 5% of patients with atrial fibrillation suffer a stroke in any given year.⁶ Most of these strokes are cardioembolic, with thrombi originating in the left atrial appendage.⁷ Furthermore, it has been estimated^8,9 that patients with atrial fibrillation who have already had a stroke and cannot tolerate oral anticoagulants have an annual risk of stroke close to 12% and a relative risk of approximately 3.0 compared with those with atrial fibrillation and prior stroke who can tolerate anticoagulation.

Oral anticoagulation effectively prevents thromboembolic events associated with atrial fibrillation,¹⁰ but several factors limit its efficacy and applicability. The risk of bleeding complications, the need for frequent monitoring, and challenges with compliance create a large population of patients who would benefit from alternative approaches. Consequently, physicians have looked for other ways to prevent stroke—especially surgical and transcatheter procedures—that are not associated with an ongoing risk of hemorrhage and a lifelong need to take an anticoagulant.

THE LEFT ATRIAL APPENDAGE: A SITE OF CLOT FORMATION

The left atrial appendage is the most common site of thrombus formation, particularly in patients with nonvalvular atrial fibrillation. Nearly 90% of thrombi discovered in the left atrium form in the appendage.⁷ A study of 233 patients not on long-term anticoagulation revealed that after 48 hours of atrial fibrillation, 15% had a left atrial thrombus, and all but one of the thrombi were in the appendage.¹¹

Atrial fibrillation increases the risk of stroke by a factor of 4 to 5

Believed to function as a decompression chamber during left ventricular systole, the left atrial appendage is embryologically derived from the left wall of the primary atrium. It is in close proximity to the free wall of the left ventricle, and therefore its flow can vary with left ventricular function. Relative stasis due to its location and extensive trabeculations, especially in times of poor forward flow, make it a high-risk site for clot formation.¹²

ANTICOAGULATION: EFFECTIVE BUT IMPERFECT

In deciding whether a patient with atrial fibrillation should be prescribed anticoagulation therapy, the physician must balance the risk of stroke against the risk of bleeding. Several tools for assessing these two risks have been developed. Of note, some of the risk factors for stroke are the same as some of the risk factors for bleeding.

Calculating the risk of stroke

CHADS₂ and CHA2DS₂-VASc are the two most commonly used tools for assessing the risk of stroke, but only the newer CHA₂DS₂-VASc has received a class I recommendation (the highest) from the European Society of Cardiology (ESC).¹³

CHADS₂ risk factors are Congestive heart failure (1 point), Hypertension (1 point), Age 75 or older (1 point), Diabetes (1 point), and  Stroke or transient ischemic attack (2 points). Risk of stroke is considered low with a score of 0, intermediate with a score of 1, and high with a score of 2 or more. 

CHA₂DS₂-VASc risk factors are Congestive heart failure or left ventricular ejection fraction ≤ 40% (1 point), Hypertension (1 point), Age ≥ 75 (2 points), Age 65–74 (1 point), Diabetes mellitus (1 point), Stroke, transient ischemic attack, or thromboembolism (2 points), Vascular disease (1 point), and female Sex (1 point). Low risk is defined as a score of 0 for a man or, for a woman with no other risk factors, a score of 1. A score of 1 for a man indicates moderate risk, and a score of 2 or more is high risk.

Calculating the risk of bleeding

Tools for assessing bleeding risk include ATRIA2 and HAS-BLED,¹⁴ the latter carrying a class I recommendation from the ESC.¹³

HAS-BLED risk factors are Hypertension (1 point), Abnormal renal or liver function (1 point each), Stroke (1 point), Bleeding (1 point), Labile international normalized ratio (INR) (1 point), Elderly (age > 65) (1 point), and Drug or alcohol use (1 point each). The risk of bleeding is considered high with a score of 3 or higher.

Disadvantages of oral anticoagulation

Oral anticoagulation is the standard treatment for preventing stroke in patients with atrial fibrillation, and the vitamin K antagonist warfarin remains the foundation.

Though highly effective, warfarin requires close monitoring and frequent dose adjustments because of its numerous food and drug interactions. Bleeding risk and the challenge of frequent monitoring rule out treatment with warfarin in 14% to 44% of patients with atrial fibrillation.¹⁵ Even in “ideal” candidates, warfarin is underused, with one study reporting that only 38% of those with clinical indications for it had been prescribed warfarin, and of those for whom it had not been prescribed, 63% were also not taking aspirin.¹⁶ Moreover, a meta-analysis suggested that the average patient treated with warfarin has his or her INR in the therapeutic range only about 55% of the time.¹⁷

Newer, target-specific oral anticoagulants such as dabigatran (a direct thrombin inhibitor) and rivaroxaban and apixaban (both factor Xa inhibitors) do not require monitoring and have fewer drug interactions. But like warfarin, they also confer a risk of serious bleeding.^18–20 Most of the studies of these newer drugs have compared them with warfarin, with the preponderance of evidence showing them to be either noninferior or superior to warfarin for stroke reduction. But bleeding complication rates remain significant, apixaban having lower rates of major bleeding than dabigatran and rivaroxaban.

Untreated, 2%–5% of patients with atrial fibrillation will suffer a stroke in any given year

In a meta-analysis, Ruff et al²¹ concluded that the target-specific oral anticoagulants provide a favorable balance of risk and benefit. Compared with warfarin, these new drugs reduced the rate of stroke or systemic embolic events by 19%. There was also a significant reduction in rates of intracranial hemorrhage and all-cause mortality. The risk of major bleeding was similar to that with warfarin, though there was a higher risk of gastrointestinal bleeding with target-specific agents. These effects were consistent across a wide range of patients.

Given the difficulties, risks, and serious side effects of anticoagulant therapy, many patients stop taking these drugs soon after starting them, either on their own or on their physician’s recommendation. In the RE-LY trial (Dabigatran vs Warfarin in Patients With Atrial Fibrillation), 10% of patients receiving dabigatran and 17% of those receiving warfarin stopped the treatment within 1 to 2 years.²² In a similar trial of rivaroxaban vs warfarin in nonvalvular atrial fibrillation (the ROCKET-AF trial), 24% of those treated with rivaroxaban and 22% of those treated with warfarin stopped treatment during the study.¹⁹ In the ARISTOTLE trial (Apixaban vs Warfarin in Patients With Atrial Fibrillation), 25% of patients discontinued apixaban and 28% discontinued warfarin.²⁰

The results of these trials show a clear need for treatments without high attrition rates, since patients with atrial fibrillation need protection from stroke for the rest of their life.

SURGICAL CLOSURE AS AN ADD-ON TO OTHER PROCEDURES

If the patient is undergoing cardiac surgery for another reason, the surgeon can excise, suture, staple, or clip the left atrial appendage shut at the same time. Closure is recommended as part of valve replacement.⁸ In a 2008 retrospective study, left atrial appendage closure was successfully performed in 40% of those undergoing the procedure during cardiac surgery, and complete closure occurred more often with excision than with suture exclusion and stapler exclusion.²³ A study of patients who underwent ligation of the left atrial appendage during mitral value replacement found that 35% demonstrated incomplete closure as determined by transesophageal echocardiography.²⁴

Newer devices have shown more success. The AtriClip (AtriCure Inc., West Chester, OH) is a self-closing, implantable clip applied epicardially by either an open surgical or a minimally invasive technique.²⁵ Successful closure was confirmed in 60 of 61 patients at 90 days as determined by computed tomography or transesophageal echocardiography, and there were no adverse events related to implantation of the device.²⁵ The TigerPaw system (Terumo Cardiovascular Systems, Ann Arbor, MI)²⁶ is a fastener delivered surgically around the base of the ostium of the left atrial appendage. In an initial trial, 90 days after the procedure, transesophageal echocardiography showed no leaks in any of those who were examined (54 of 60 patients).

Amputation of the left atrial appendage is also considered part of the maze procedure for atrial fibrillation, in which the operator creates multiple small scars in the atria to prevent irregular impulses from being conducted.²⁷

Results of these surgical approaches have been mixed, as incomplete closure or clipping actually increases the risk of left atrial thrombus formation and embolization.²⁸ Moreover, these invasive surgical techniques are associated with significant periprocedural morbidity.²⁹ Because of the high risk of surgical complications, cardiac specialists have sought less invasive percutaneous procedures to manage stroke risk in patients with atrial fibrillation.

PERCUTANEOUS OCCLUSION

One option for closing the left atrial appendage is a percutaneous transseptal approach in which a plug is placed in the opening connecting the appendage to the rest of the atrium.

The PLAATO device

The Percutaneous LAA Transcatheter Occlusion (PLAATO) device (Appriva Medical Inc., Sunnyvale, CA) contains an expandable nitinol-covered cage designed to be placed in the orifice of the left atrial appendage. Over time, tissue grows into the device, entirely isolating the appendage from the rest of the atrium.

In 2002, Sievert et al³⁰ reported using this device in 15 patients. Subsequently, in a nonrandomized trial in patients with contraindications to lifelong anticoagulation, total occlusion was achieved in 108 of 111 patients, with no thrombosis or migration of the device at 6 months. The annual risk of stroke was 2.2%, a reduction in relative risk of 65% based on the CHADS₂ score.³¹

But despite this apparent success, the PLAATO device was discontinued for unspecified commercial reasons.

Amplatzer cardiac plug

Modeled after an atrial septal occluder, the Amplatzer cardiac plug (St. Jude Medical, St. Paul, MN) consists of a lobe and a disk connected by a central waist.

In 2011, Park et al³² published their initial experience implanting this device in patients who either could not tolerate or did not desire long-term anticoagulation. They reported a 96% closure rate (137 of 143 patients), but there were serious complications in 10 patients: 3 with ischemic stroke, 2 with device embolism, and 5 with pericardial effusions.

Warfarin remains the foundation of stroke prevention in atrial fibrillation

Urena et al³³ reported similar results in 52 patients with absolute contraindications to warfarin, with a 98.1% implantation rate. Patients were then maintained on either single or dual antiplatelet therapy at the discretion of the operator. At 20-month follow-up, there had been one stroke, one transient ischemic attack, and one major bleeding event. The leakage rate was 16.2% as determined by transesophageal echocardiography.

While initial results were promising, a clinical trial comparing this device and optimal medical treatment is currently on hold. Thus, there are no clear data comparing the Amplatzer device with oral anticoagulation.³⁴

The Watchman device

The Watchman device (Boston Scientific, Marlborough, MA), an evolution of the PLAATO device, is a self-expanding nitinol structure with fixation barbs and a polyethylene membrane to protect the atrium-facing side of the device (Figure 1).

A pilot trial reported successful implantation in 66 of 75 patients, though the device was found to migrate after placement in 5 of the first 16 patients using the original device and delivery system. The device was modified, and no further embolization of the device occurred.³⁵

The PROTECT-AF trial (Protection in Patients With Atrial Fibrillation)³⁶ was the first completed and published randomized controlled trial evaluating left atrial appendage closure using a device vs long-term warfarin therapy. This study randomized 707 people with nonvalvular atrial fibrillation from 59 centers worldwide to receive the Watchman device or a control treatment. The study included patients age 18 or older with nonvalvular atrial fibrillation who were able to tolerate warfarin therapy. Patients in the control group received warfarin for the duration of the study and were monitored every 2 weeks for a goal INR of 2 to 3, achieving a therapeutic INR 66% of the time. The device group was also treated with warfarin for 45 days to allow device endothelialization. Warfarin was discontinued if transesophageal echocardiography showed complete closure or significantly decreased flow around the device. Patients in the device group were then treated with aspirin and clopidogrel for 6 months, and then with aspirin indefinitely.

Incomplete closure or clipping actually increases the risk of thrombosis and embolization

At 1,065 patient-years of follow-up, PROTECT-AF showed that in patients with atrial fibrillation who were candidates for warfarin therapy, percutaneous left atrial appendage closure using the Watchman device reduced the rate of hemorrhagic stroke compared with warfarin and was noninferior to warfarin in terms of all-cause mortality and stroke. A 4-year follow-up to the PROTECT-AF trial found that receiving the Watchman was better than taking warfarin in terms of risk of cardiovascular death, stroke and other systemic embolization, and all-cause mortality. The adverse event rates were 2.3% in the device group and 3.8% in the control group, a 40% relative risk reduction in the Watchman group.³⁷

The PREVAIL trial (Prospective Randomized Evaluation of the WATCHMAN LAA Closure Device in Patients With Atrial Fibrillation vs Long-Term Warfarin Therapy) aimed to confirm the safety and efficacy of the Watchman device compared with long-term warfarin therapy.³⁸ The event rate (defined as 7-day occurrence of death, ischemic stroke, systemic embolism, and procedure- or device-related complications requiring major cardiovascular or endovascular intervention) was 2.2%. But the PREVAIL trial was unable to show that the device was noninferior to warfarin in terms of its second primary end point of stroke, systemic embolism, and cardiovascular or unexplained death at 18 months. When performed by physicians who were new to the procedure, the procedure was successful (ie, the device was successfully implanted) in 93.2%; the rate was slightly higher (96.3%) when performed by experienced implanters.

Safety data gathered in PREVAIL in conjunction with demonstrated efficacy from PROTECT-AF suggest that the Watchman device may be a safe and effective alternative to long-term oral anticoagulation in patients with nonvalvular atrial fibrillation.

In patients with contraindications to warfarin

Most of the published data have been about the efficacy of occlusion devices compared with long-term warfarin therapy. Unfortunately, the population that has not been studied extensively is patients who have contraindications to long-term oral anticoagulation, who would benefit the most from an occlusive device.

The ASA Plavix Feasibility Study (ASAP) focused on this population, specifically those who had a CHADS₂ score of 1 or higher and who were considered ineligible for warfarin, to determine whether closure using the Watchman device could be safely performed without a transition period with warfarin.³⁹ After device implantation, trial participants were given clopidogrel for 6 months and aspirin indefinitely. The trial enrolled 150 patients and followed them for a mean of 14.4 (± 8.6) months. In that time, there were four strokes, five pericardial effusions, and six instances of device-related thrombus by transesophageal echocardiography. Three of the strokes were ischemic (1.7% per year), which is a 77% reduction from the expected rate of 7.3% based on the CHADS₂ scores of the patient cohort.

These data suggest that implantation of the Watchman device may be appropriate for those who cannot tolerate warfarin even in the short term.

The Lariat system

The Lariat suture delivery device (SentreHeart, Inc., Redwood City, CA) is approved by the US Food and Drug Administration (FDA) for soft-tissue closure and has been used for percutaneous left atrial appendage closure. It uses a magnet-tipped wire that is passed to the epicardial side of the left atrial appendage via pericardial access to meet a second magnet-tipped wire introduced into the appendage via transseptal access. A “lasso” is then advanced over the epicardial guide wire and tightened down around the ostium of the left atrial appendage. This tool facilitates deployment of a nonabsorbable polyester suture, which effectively ligates off the appendage from the rest of the left atrium (Figure 2).⁴⁰ In theory, the Lariat’s epicardial approach could eliminate the need for short- and long-term anticoagulation, as there would be no foreign body left within the heart.

In an initial cohort of 89 patients in Poland,41 the investigators reported a 96% closure rate as determined by transesophageal echocardiography immediately after the procedure. At 1-year follow-up, there was 98% complete closure, including cases of incomplete closure detected earlier.41 Adverse events were limited, with only two cases of severe pericarditis, two strokes, and one pericardial effusion. These results were replicated in the United States in a cohort of 25 patients, with a 100% closure rate and no stroke events.⁴²

There have been three published case reports of left atrial clot formation after successful left atrial appendage ligation using the Lariat device.^43–45 These experiences further emphasize that closure does not necessarily confer instant stroke prevention, and there remains a need to investigate the need for routine imaging and possibly periprocedural anticoagulation after ligation.

More recently, Pillai et al⁴⁶ published their initial experience following 71 patients with echocardiograms 3 months after left atrial appendage closure using the Lariat device. They reported leaks in 6 of the 71 patients; five of the leaks were successfully closed using the Amplatzer Septal Occluder, and one was closed with a repeat Lariat procedure.

Although the Lariat system has been used in more than 2,000 patients worldwide (SentreHeart, personal communication), there has been no published systematic comparison between it and oral anticoagulation to date.

AN EMERGING OPTION

Established guidelines help determine which patients with atrial fibrillation should receive oral anticoagulant therapy. For patients who have absolute contraindications to oral anticoagulants or who are undergoing cardiac surgery, surgical ligation of the left atrial appendage is an option. But for those with contraindications to oral anticoagulation in both the short term and the long term, there is a growing body of evidence suggesting that a percutaneous intervention is at least noninferior to—and in some cases is superior to—warfarin. Figure 3 shows our recommendations for the steps to determine which patients would be most appropriate to consider for left atrial appendage closure.

Holmes et al⁴⁷ propose that we may now have enough evidence to support an expedited regulatory approval process of these occlusion devices. But there are still a number of areas in which further investigation is clearly needed before left atrial appendage occlusion devices can be widely adopted.

The trials discussed above had specific inclusion and exclusion criteria, and therefore, although they support percutaneous intervention, the generalizability of their results remains in question. Indeed, the patients in PROTECT-AF³⁶ had an average CHADS₂ score of only 2.2. This study also included only patients who were able to tolerate both aspirin and clopidogrel simultaneously for a significant amount of time. Hence, one cannot assume the results would be the same in patients who have strict contraindications to warfarin or any target-specific oral anticoagulant. Concern regarding the generalizability of the conclusions from PROTECT-AF and PREVAIL has led to mixed votes (three assessments to date) from the FDA Circulatory Device Panel.⁴⁸

In an encouraging review of cases, Gafoor et al⁴⁹ reported safe and efficacious occlusion in octogenarians using the devices mentioned above. These patients often pose the greatest challenge in initiating long-term anticoagulation because of the many drug-drug interactions and the risk of intracranial hemorrhage secondary to falls.

Further, while occlusion devices would clearly be useful for patients in whom traditional oral anticoagulation is not an option, the newer oral anticoagulants might complicate the picture somewhat. As shown by Ruff et al,²¹ the risk-benefit ratio of these target-specific oral anticoagulants is quite favorable and by some measurements is superior to that of warfarin. Could there be a group of patients who cannot take warfarin but could instead do well on one of the newer anticoagulants, thus alleviating the need for percutaneous intervention? As the newer oral anticoagulants become more commonly used, the cost-benefit analysis of implanting an occlusion device could shift.

We expect that percutaneous closure will someday be a viable and equal option for stroke prevention

Lastly, in this era of high-value medical care, one must consider the cost-effectiveness of these novel interventions. As with any new technology, the up-front cost of implantation is certainly greater than that of warfarin therapy. If device implantation can prevent a hospitalization from a major bleed secondary to warfarin use or prevent a catastrophic stroke due to untreated atrial fibrillation, then the cost-benefit analysis may be tipped in the other direction. As these devices become more widely available and physicians have more experience implanting them, the costs will likely decrease.

As with oral anticoagulation therapy, all interventions, whether surgical or percutaneous, carry a risk of bleeding and stroke. There remains no substitute for frank and clear discussions between the physician and patient regarding the risks and benefits of each approach.

While a growing body of evidence surrounds left atrial appendage occlusion devices, many questions remain. Notably, could these devices be used in patients who can tolerate oral anticoagulants? And if so, which subgroups would benefit most? Does occlusion or ligation of the left atrial appendage affect electrical connections between it and the left atrium, thereby lowering the burden of atrial fibrillation?

We expect that continued investigation of and experience with left atrial appendage closure devices will position them one day as a viable and equal option for preventing stroke in patients with atrial fibrillation.

Can patients with atrial fibrillation  undergo a percutaneous procedure to reduce their risk of stroke, thereby eliminating the need for lifelong treatment with an oral anticoagulant drug? The data are preliminary, but this is an emerging option that physicians should be aware of.

We review here the current evidence and techniques aimed at isolating the left atrial appendage to prevent stroke, and we emphasize the need for continued systematic comparisons between oral anticoagulation and percutaneous treatment options.

NOVEL TREATMENTS ARE NEEDED

Atrial fibrillation is the most common cardiac arrhythmia,¹ affecting an estimated 1% to 2% of people worldwide. In 2001, an estimated 2.3 million persons in the United States had atrial fibrillation, and that number is expected to more than double by 2050.²

Atrial fibrillation independently increases the risk of stroke by a factor of 4 to 5.³ The American Heart Association ranks stroke as the fourth most common cause of death and the leading cause of disability in the United States.⁴ Atrial fibrillation accounts for 15% of strokes in people of all ages and 30% in those over age 80.⁵ Untreated, 2% to 5% of patients with atrial fibrillation suffer a stroke in any given year.⁶ Most of these strokes are cardioembolic, with thrombi originating in the left atrial appendage.⁷ Furthermore, it has been estimated^8,9 that patients with atrial fibrillation who have already had a stroke and cannot tolerate oral anticoagulants have an annual risk of stroke close to 12% and a relative risk of approximately 3.0 compared with those with atrial fibrillation and prior stroke who can tolerate anticoagulation.

Oral anticoagulation effectively prevents thromboembolic events associated with atrial fibrillation,¹⁰ but several factors limit its efficacy and applicability. The risk of bleeding complications, the need for frequent monitoring, and challenges with compliance create a large population of patients who would benefit from alternative approaches. Consequently, physicians have looked for other ways to prevent stroke—especially surgical and transcatheter procedures—that are not associated with an ongoing risk of hemorrhage and a lifelong need to take an anticoagulant.

THE LEFT ATRIAL APPENDAGE: A SITE OF CLOT FORMATION

The left atrial appendage is the most common site of thrombus formation, particularly in patients with nonvalvular atrial fibrillation. Nearly 90% of thrombi discovered in the left atrium form in the appendage.⁷ A study of 233 patients not on long-term anticoagulation revealed that after 48 hours of atrial fibrillation, 15% had a left atrial thrombus, and all but one of the thrombi were in the appendage.¹¹

Atrial fibrillation increases the risk of stroke by a factor of 4 to 5

Believed to function as a decompression chamber during left ventricular systole, the left atrial appendage is embryologically derived from the left wall of the primary atrium. It is in close proximity to the free wall of the left ventricle, and therefore its flow can vary with left ventricular function. Relative stasis due to its location and extensive trabeculations, especially in times of poor forward flow, make it a high-risk site for clot formation.¹²

ANTICOAGULATION: EFFECTIVE BUT IMPERFECT

In deciding whether a patient with atrial fibrillation should be prescribed anticoagulation therapy, the physician must balance the risk of stroke against the risk of bleeding. Several tools for assessing these two risks have been developed. Of note, some of the risk factors for stroke are the same as some of the risk factors for bleeding.

Calculating the risk of stroke

CHADS₂ and CHA2DS₂-VASc are the two most commonly used tools for assessing the risk of stroke, but only the newer CHA₂DS₂-VASc has received a class I recommendation (the highest) from the European Society of Cardiology (ESC).¹³

CHADS₂ risk factors are Congestive heart failure (1 point), Hypertension (1 point), Age 75 or older (1 point), Diabetes (1 point), and  Stroke or transient ischemic attack (2 points). Risk of stroke is considered low with a score of 0, intermediate with a score of 1, and high with a score of 2 or more. 

CHA₂DS₂-VASc risk factors are Congestive heart failure or left ventricular ejection fraction ≤ 40% (1 point), Hypertension (1 point), Age ≥ 75 (2 points), Age 65–74 (1 point), Diabetes mellitus (1 point), Stroke, transient ischemic attack, or thromboembolism (2 points), Vascular disease (1 point), and female Sex (1 point). Low risk is defined as a score of 0 for a man or, for a woman with no other risk factors, a score of 1. A score of 1 for a man indicates moderate risk, and a score of 2 or more is high risk.

Calculating the risk of bleeding

Tools for assessing bleeding risk include ATRIA2 and HAS-BLED,¹⁴ the latter carrying a class I recommendation from the ESC.¹³

HAS-BLED risk factors are Hypertension (1 point), Abnormal renal or liver function (1 point each), Stroke (1 point), Bleeding (1 point), Labile international normalized ratio (INR) (1 point), Elderly (age > 65) (1 point), and Drug or alcohol use (1 point each). The risk of bleeding is considered high with a score of 3 or higher.

Disadvantages of oral anticoagulation

Oral anticoagulation is the standard treatment for preventing stroke in patients with atrial fibrillation, and the vitamin K antagonist warfarin remains the foundation.

Though highly effective, warfarin requires close monitoring and frequent dose adjustments because of its numerous food and drug interactions. Bleeding risk and the challenge of frequent monitoring rule out treatment with warfarin in 14% to 44% of patients with atrial fibrillation.¹⁵ Even in “ideal” candidates, warfarin is underused, with one study reporting that only 38% of those with clinical indications for it had been prescribed warfarin, and of those for whom it had not been prescribed, 63% were also not taking aspirin.¹⁶ Moreover, a meta-analysis suggested that the average patient treated with warfarin has his or her INR in the therapeutic range only about 55% of the time.¹⁷

Newer, target-specific oral anticoagulants such as dabigatran (a direct thrombin inhibitor) and rivaroxaban and apixaban (both factor Xa inhibitors) do not require monitoring and have fewer drug interactions. But like warfarin, they also confer a risk of serious bleeding.^18–20 Most of the studies of these newer drugs have compared them with warfarin, with the preponderance of evidence showing them to be either noninferior or superior to warfarin for stroke reduction. But bleeding complication rates remain significant, apixaban having lower rates of major bleeding than dabigatran and rivaroxaban.

Untreated, 2%–5% of patients with atrial fibrillation will suffer a stroke in any given year

In a meta-analysis, Ruff et al²¹ concluded that the target-specific oral anticoagulants provide a favorable balance of risk and benefit. Compared with warfarin, these new drugs reduced the rate of stroke or systemic embolic events by 19%. There was also a significant reduction in rates of intracranial hemorrhage and all-cause mortality. The risk of major bleeding was similar to that with warfarin, though there was a higher risk of gastrointestinal bleeding with target-specific agents. These effects were consistent across a wide range of patients.

Given the difficulties, risks, and serious side effects of anticoagulant therapy, many patients stop taking these drugs soon after starting them, either on their own or on their physician’s recommendation. In the RE-LY trial (Dabigatran vs Warfarin in Patients With Atrial Fibrillation), 10% of patients receiving dabigatran and 17% of those receiving warfarin stopped the treatment within 1 to 2 years.²² In a similar trial of rivaroxaban vs warfarin in nonvalvular atrial fibrillation (the ROCKET-AF trial), 24% of those treated with rivaroxaban and 22% of those treated with warfarin stopped treatment during the study.¹⁹ In the ARISTOTLE trial (Apixaban vs Warfarin in Patients With Atrial Fibrillation), 25% of patients discontinued apixaban and 28% discontinued warfarin.²⁰

The results of these trials show a clear need for treatments without high attrition rates, since patients with atrial fibrillation need protection from stroke for the rest of their life.

SURGICAL CLOSURE AS AN ADD-ON TO OTHER PROCEDURES

If the patient is undergoing cardiac surgery for another reason, the surgeon can excise, suture, staple, or clip the left atrial appendage shut at the same time. Closure is recommended as part of valve replacement.⁸ In a 2008 retrospective study, left atrial appendage closure was successfully performed in 40% of those undergoing the procedure during cardiac surgery, and complete closure occurred more often with excision than with suture exclusion and stapler exclusion.²³ A study of patients who underwent ligation of the left atrial appendage during mitral value replacement found that 35% demonstrated incomplete closure as determined by transesophageal echocardiography.²⁴

Newer devices have shown more success. The AtriClip (AtriCure Inc., West Chester, OH) is a self-closing, implantable clip applied epicardially by either an open surgical or a minimally invasive technique.²⁵ Successful closure was confirmed in 60 of 61 patients at 90 days as determined by computed tomography or transesophageal echocardiography, and there were no adverse events related to implantation of the device.²⁵ The TigerPaw system (Terumo Cardiovascular Systems, Ann Arbor, MI)²⁶ is a fastener delivered surgically around the base of the ostium of the left atrial appendage. In an initial trial, 90 days after the procedure, transesophageal echocardiography showed no leaks in any of those who were examined (54 of 60 patients).

Amputation of the left atrial appendage is also considered part of the maze procedure for atrial fibrillation, in which the operator creates multiple small scars in the atria to prevent irregular impulses from being conducted.²⁷

Results of these surgical approaches have been mixed, as incomplete closure or clipping actually increases the risk of left atrial thrombus formation and embolization.²⁸ Moreover, these invasive surgical techniques are associated with significant periprocedural morbidity.²⁹ Because of the high risk of surgical complications, cardiac specialists have sought less invasive percutaneous procedures to manage stroke risk in patients with atrial fibrillation.

PERCUTANEOUS OCCLUSION

One option for closing the left atrial appendage is a percutaneous transseptal approach in which a plug is placed in the opening connecting the appendage to the rest of the atrium.

The PLAATO device

The Percutaneous LAA Transcatheter Occlusion (PLAATO) device (Appriva Medical Inc., Sunnyvale, CA) contains an expandable nitinol-covered cage designed to be placed in the orifice of the left atrial appendage. Over time, tissue grows into the device, entirely isolating the appendage from the rest of the atrium.

In 2002, Sievert et al³⁰ reported using this device in 15 patients. Subsequently, in a nonrandomized trial in patients with contraindications to lifelong anticoagulation, total occlusion was achieved in 108 of 111 patients, with no thrombosis or migration of the device at 6 months. The annual risk of stroke was 2.2%, a reduction in relative risk of 65% based on the CHADS₂ score.³¹

But despite this apparent success, the PLAATO device was discontinued for unspecified commercial reasons.

Amplatzer cardiac plug

Modeled after an atrial septal occluder, the Amplatzer cardiac plug (St. Jude Medical, St. Paul, MN) consists of a lobe and a disk connected by a central waist.

In 2011, Park et al³² published their initial experience implanting this device in patients who either could not tolerate or did not desire long-term anticoagulation. They reported a 96% closure rate (137 of 143 patients), but there were serious complications in 10 patients: 3 with ischemic stroke, 2 with device embolism, and 5 with pericardial effusions.

Warfarin remains the foundation of stroke prevention in atrial fibrillation

Urena et al³³ reported similar results in 52 patients with absolute contraindications to warfarin, with a 98.1% implantation rate. Patients were then maintained on either single or dual antiplatelet therapy at the discretion of the operator. At 20-month follow-up, there had been one stroke, one transient ischemic attack, and one major bleeding event. The leakage rate was 16.2% as determined by transesophageal echocardiography.

While initial results were promising, a clinical trial comparing this device and optimal medical treatment is currently on hold. Thus, there are no clear data comparing the Amplatzer device with oral anticoagulation.³⁴

The Watchman device

The Watchman device (Boston Scientific, Marlborough, MA), an evolution of the PLAATO device, is a self-expanding nitinol structure with fixation barbs and a polyethylene membrane to protect the atrium-facing side of the device (Figure 1).

A pilot trial reported successful implantation in 66 of 75 patients, though the device was found to migrate after placement in 5 of the first 16 patients using the original device and delivery system. The device was modified, and no further embolization of the device occurred.³⁵

The PROTECT-AF trial (Protection in Patients With Atrial Fibrillation)³⁶ was the first completed and published randomized controlled trial evaluating left atrial appendage closure using a device vs long-term warfarin therapy. This study randomized 707 people with nonvalvular atrial fibrillation from 59 centers worldwide to receive the Watchman device or a control treatment. The study included patients age 18 or older with nonvalvular atrial fibrillation who were able to tolerate warfarin therapy. Patients in the control group received warfarin for the duration of the study and were monitored every 2 weeks for a goal INR of 2 to 3, achieving a therapeutic INR 66% of the time. The device group was also treated with warfarin for 45 days to allow device endothelialization. Warfarin was discontinued if transesophageal echocardiography showed complete closure or significantly decreased flow around the device. Patients in the device group were then treated with aspirin and clopidogrel for 6 months, and then with aspirin indefinitely.

Incomplete closure or clipping actually increases the risk of thrombosis and embolization

At 1,065 patient-years of follow-up, PROTECT-AF showed that in patients with atrial fibrillation who were candidates for warfarin therapy, percutaneous left atrial appendage closure using the Watchman device reduced the rate of hemorrhagic stroke compared with warfarin and was noninferior to warfarin in terms of all-cause mortality and stroke. A 4-year follow-up to the PROTECT-AF trial found that receiving the Watchman was better than taking warfarin in terms of risk of cardiovascular death, stroke and other systemic embolization, and all-cause mortality. The adverse event rates were 2.3% in the device group and 3.8% in the control group, a 40% relative risk reduction in the Watchman group.³⁷

The PREVAIL trial (Prospective Randomized Evaluation of the WATCHMAN LAA Closure Device in Patients With Atrial Fibrillation vs Long-Term Warfarin Therapy) aimed to confirm the safety and efficacy of the Watchman device compared with long-term warfarin therapy.³⁸ The event rate (defined as 7-day occurrence of death, ischemic stroke, systemic embolism, and procedure- or device-related complications requiring major cardiovascular or endovascular intervention) was 2.2%. But the PREVAIL trial was unable to show that the device was noninferior to warfarin in terms of its second primary end point of stroke, systemic embolism, and cardiovascular or unexplained death at 18 months. When performed by physicians who were new to the procedure, the procedure was successful (ie, the device was successfully implanted) in 93.2%; the rate was slightly higher (96.3%) when performed by experienced implanters.

Safety data gathered in PREVAIL in conjunction with demonstrated efficacy from PROTECT-AF suggest that the Watchman device may be a safe and effective alternative to long-term oral anticoagulation in patients with nonvalvular atrial fibrillation.

In patients with contraindications to warfarin

Most of the published data have been about the efficacy of occlusion devices compared with long-term warfarin therapy. Unfortunately, the population that has not been studied extensively is patients who have contraindications to long-term oral anticoagulation, who would benefit the most from an occlusive device.

The ASA Plavix Feasibility Study (ASAP) focused on this population, specifically those who had a CHADS₂ score of 1 or higher and who were considered ineligible for warfarin, to determine whether closure using the Watchman device could be safely performed without a transition period with warfarin.³⁹ After device implantation, trial participants were given clopidogrel for 6 months and aspirin indefinitely. The trial enrolled 150 patients and followed them for a mean of 14.4 (± 8.6) months. In that time, there were four strokes, five pericardial effusions, and six instances of device-related thrombus by transesophageal echocardiography. Three of the strokes were ischemic (1.7% per year), which is a 77% reduction from the expected rate of 7.3% based on the CHADS₂ scores of the patient cohort.

These data suggest that implantation of the Watchman device may be appropriate for those who cannot tolerate warfarin even in the short term.

The Lariat system

The Lariat suture delivery device (SentreHeart, Inc., Redwood City, CA) is approved by the US Food and Drug Administration (FDA) for soft-tissue closure and has been used for percutaneous left atrial appendage closure. It uses a magnet-tipped wire that is passed to the epicardial side of the left atrial appendage via pericardial access to meet a second magnet-tipped wire introduced into the appendage via transseptal access. A “lasso” is then advanced over the epicardial guide wire and tightened down around the ostium of the left atrial appendage. This tool facilitates deployment of a nonabsorbable polyester suture, which effectively ligates off the appendage from the rest of the left atrium (Figure 2).⁴⁰ In theory, the Lariat’s epicardial approach could eliminate the need for short- and long-term anticoagulation, as there would be no foreign body left within the heart.

In an initial cohort of 89 patients in Poland,41 the investigators reported a 96% closure rate as determined by transesophageal echocardiography immediately after the procedure. At 1-year follow-up, there was 98% complete closure, including cases of incomplete closure detected earlier.41 Adverse events were limited, with only two cases of severe pericarditis, two strokes, and one pericardial effusion. These results were replicated in the United States in a cohort of 25 patients, with a 100% closure rate and no stroke events.⁴²

There have been three published case reports of left atrial clot formation after successful left atrial appendage ligation using the Lariat device.^43–45 These experiences further emphasize that closure does not necessarily confer instant stroke prevention, and there remains a need to investigate the need for routine imaging and possibly periprocedural anticoagulation after ligation.

More recently, Pillai et al⁴⁶ published their initial experience following 71 patients with echocardiograms 3 months after left atrial appendage closure using the Lariat device. They reported leaks in 6 of the 71 patients; five of the leaks were successfully closed using the Amplatzer Septal Occluder, and one was closed with a repeat Lariat procedure.

Although the Lariat system has been used in more than 2,000 patients worldwide (SentreHeart, personal communication), there has been no published systematic comparison between it and oral anticoagulation to date.

AN EMERGING OPTION

Established guidelines help determine which patients with atrial fibrillation should receive oral anticoagulant therapy. For patients who have absolute contraindications to oral anticoagulants or who are undergoing cardiac surgery, surgical ligation of the left atrial appendage is an option. But for those with contraindications to oral anticoagulation in both the short term and the long term, there is a growing body of evidence suggesting that a percutaneous intervention is at least noninferior to—and in some cases is superior to—warfarin. Figure 3 shows our recommendations for the steps to determine which patients would be most appropriate to consider for left atrial appendage closure.

Holmes et al⁴⁷ propose that we may now have enough evidence to support an expedited regulatory approval process of these occlusion devices. But there are still a number of areas in which further investigation is clearly needed before left atrial appendage occlusion devices can be widely adopted.

The trials discussed above had specific inclusion and exclusion criteria, and therefore, although they support percutaneous intervention, the generalizability of their results remains in question. Indeed, the patients in PROTECT-AF³⁶ had an average CHADS₂ score of only 2.2. This study also included only patients who were able to tolerate both aspirin and clopidogrel simultaneously for a significant amount of time. Hence, one cannot assume the results would be the same in patients who have strict contraindications to warfarin or any target-specific oral anticoagulant. Concern regarding the generalizability of the conclusions from PROTECT-AF and PREVAIL has led to mixed votes (three assessments to date) from the FDA Circulatory Device Panel.⁴⁸

In an encouraging review of cases, Gafoor et al⁴⁹ reported safe and efficacious occlusion in octogenarians using the devices mentioned above. These patients often pose the greatest challenge in initiating long-term anticoagulation because of the many drug-drug interactions and the risk of intracranial hemorrhage secondary to falls.

Further, while occlusion devices would clearly be useful for patients in whom traditional oral anticoagulation is not an option, the newer oral anticoagulants might complicate the picture somewhat. As shown by Ruff et al,²¹ the risk-benefit ratio of these target-specific oral anticoagulants is quite favorable and by some measurements is superior to that of warfarin. Could there be a group of patients who cannot take warfarin but could instead do well on one of the newer anticoagulants, thus alleviating the need for percutaneous intervention? As the newer oral anticoagulants become more commonly used, the cost-benefit analysis of implanting an occlusion device could shift.

We expect that percutaneous closure will someday be a viable and equal option for stroke prevention

Lastly, in this era of high-value medical care, one must consider the cost-effectiveness of these novel interventions. As with any new technology, the up-front cost of implantation is certainly greater than that of warfarin therapy. If device implantation can prevent a hospitalization from a major bleed secondary to warfarin use or prevent a catastrophic stroke due to untreated atrial fibrillation, then the cost-benefit analysis may be tipped in the other direction. As these devices become more widely available and physicians have more experience implanting them, the costs will likely decrease.

As with oral anticoagulation therapy, all interventions, whether surgical or percutaneous, carry a risk of bleeding and stroke. There remains no substitute for frank and clear discussions between the physician and patient regarding the risks and benefits of each approach.

While a growing body of evidence surrounds left atrial appendage occlusion devices, many questions remain. Notably, could these devices be used in patients who can tolerate oral anticoagulants? And if so, which subgroups would benefit most? Does occlusion or ligation of the left atrial appendage affect electrical connections between it and the left atrium, thereby lowering the burden of atrial fibrillation?

We expect that continued investigation of and experience with left atrial appendage closure devices will position them one day as a viable and equal option for preventing stroke in patients with atrial fibrillation.

A 48-year-old woman presented to the emergency department after 2 days of nonproductive cough, chest discomfort, worsening shortness of breath, and subjective fever. She had a history of systemic sclerosis. She was currently taking prednisone 20 mg daily and aspirin 81 mg daily.

Physical examination revealed tachypnea (28 breaths per minute), and bronchial breath sounds in the left lower chest posteriorly.

The initial laboratory workup revealed:

• Hemoglobin 106 g/L (reference range 115–155)
• Mean corpuscular volume 84 fL (80–100)
• White blood cell count 29.4 × 10⁹/L (3.70–11.0), with 85% neutrophils
• Platelet count 180 × 10⁹/L (150–350)
• Lactate dehydrogenase 312 U/L (100–220).

Chest radiography showed opacification of the lower lobe of the left lung.

She was admitted to the hospital and started treatment with intravenous azithromycin and ceftriaxone for presumed community-acquired pneumonia, based on the clinical presentation and findings on chest radiography. Because of her immunosuppression (due to chronic prednisone therapy) and her high lactate dehydrogenase level, Pneumocystis jirovecii pneumonia was suspected, and because she had a history of allergy to trimethoprim-sulfamethoxazole and pentamidine, she was started on dapsone.

During the next 24 hours, she developed worsening dyspnea, hypoxia, and cyanosis. She was placed on an air-entrainment mask, with a fraction of inspired oxygen of 0.5. Pulse oximetry showed an oxygen saturation of 85%, but arterial blood gas analysis indicated an oxyhemoglobin concentration of 95%.

THE ‘SATURATION GAP’

1. Which is most likely to have caused the discrepancy between the oxyhemoglobin concentration and the oxygen saturation by pulse oximetry in this patient?

• Methemoglobinemia
• Carbon monoxide poisoning
• Inappropriate placement of the pulse oximeter probe
• Pulmonary embolism

Methemoglobinemia is the most likely cause of the discrepancy between the oxyhemoglobin levels and the oxygen saturation by pulse oximetry, a phenomenon also known as the “saturation gap.” Other common causes are cyanide poisoning and carbon monoxide poisoning.

P jirovecii pneumonia was suspected, and dapsone was started in light of her allergy to trimethoprim-sulfamethoxazole and pentamidine

Carbon monoxide poisoning, however, does not explain our patient’s cyanosis. On the contrary, carbon monoxide poisoning can actually cause the patient’s lips and mucous membranes to appear unnaturally bright pink. Also, carbon monoxide poisoning raises the blood concentration of carboxyhemoglobin (which has a high affinity for oxygen), and this usually causes pulse oximetry to read inappropriately high, whereas in our patient it read low.

Incorrect placement of the pulse oximeter probe can result in an inaccurate measurement of oxygen saturation. Visualization of the waveform on the plethysmograph or the signal quality index can be used to assess adequate placement of the pulse oximeter probe. However, inadequate probe placement does not explain our patient’s dyspnea and cyanosis.

Pulmonary embolism can lead to hypoxia as a result of ventilation-perfusion mismatch. However, pulmonary embolism leading to low oxygen saturation on pulse oximetry will also lead to concomitantly low oxyhemoglobin levels as measured by arterial blood gas analysis, and this was not seen in our patient.

BACK TO OUR PATIENT

Because there was a discrepancy between our patient’s pulse oximetry reading and oxyhemoglobin concentration by arterial blood gas measurement, her methemoglobin level was checked and was found to be 30%, thus confirming the diagnosis of methemoglobinemia.

WHAT IS METHEMOGLOBINEMIA, AND WHAT CAUSES IT?

Oxygen is normally bound to iron in its ferrous (Fe²⁺) form in hemoglobin to form oxyhemoglobin. Oxidative stress in the body can cause iron to change from the ferrous to the ferric (Fe³⁺) state, forming methemoglobin. Methemoglobin is normally present in the blood in low levels (< 1% of the total hemoglobin), and ferric iron is reduced and recycled back to the ferrous form by NADH-cytochrome b5 reductase, an enzyme present in red blood cells. This protective mechanism maintains methemoglobin levels within safe limits. But increased production can lead to accumulation of methemoglobin, resulting in dyspnea and hypoxia and the condition referred to as methemoglobinemia.¹

Increased levels of methemoglobin relative to normal hemoglobin cause tissue hypoxia by several mechanisms. Methemoglobin cannot efficiently carry oxygen; instead, it binds to water or to a hydroxide ion depending on the pH of the environment.² Therefore, the hemoglobin molecule does not carry its usual load of oxygen, and hypoxia results from the reduced delivery of oxygen to tissues. In addition, an increased concentration of methemoglobin causes a leftward shift in the oxygen-hemoglobin dissociation curve, representing an increased affinity to bound oxygen in the remaining heme groups. The tightly bound oxygen is not adequately released at the tissue level, thus causing cellular hypoxia.

Methemoglobinemia is most often caused by exposure to an oxidizing chemical or drug that increases production of methemoglobin. In rare cases, it is caused by a congenital deficiency of NADH-cytochrome b5 reductase.³

2. Which of the following drugs can cause methemoglobinemia?

• Acetaminophen
• Dapsone
• Benzocaine
• Primaquine

All four of these drugs are common culprits for causing acquired methemoglobinemia; others include chloroquine, nitroglycerin, and sulfonamides.^4–6

The increased production of methemoglobin caused by these drugs overwhelms the protective effect of reducing enzymes and can lead to an accumulation of methemoglobin. However, because of variability in cellular metabolism, not every person who takes these drugs develops dangerous levels of methemoglobin.

Dapsone and benzocaine are the most commonly encountered drugs known to cause methemoglobinemia (Table 1). Dapsone is an anti-inflammatory and antimicrobial agent most commonly used for treating lepromatous leprosy and dermatitis herpetiformis. It is also often prescribed for prophylaxis and treatment of P jirovecii pneumonia in immunosuppressed individuals.⁷ Benzocaine is a local anesthetic and was commonly used before procedures such as oral or dental surgery, transesophageal echocardiography, and endoscopy.^8–10 Even low doses of benzocaine can lead to high levels of methemoglobinemia. However, the availability of other, safer anesthetics now limits the use of benzocaine in major US centers. In addition, the topical anesthetic Emla (lidocaine plus prilocaine) has been recently reported as a cause of methemoglobinemia in infants and children.^11,12

Also, potentially fatal methemoglobinemia has been reported in patients with a deficiency of G-6-phosphate dehydrogenase (G6PD) who received rasburicase, a recombinant version of urate oxidase enzyme used to prevent and treat tumor lysis syndrome.^13,14

Lastly, methemoglobinemia has been reported in patients with inflammatory bowel disease treated with mesalamine.

Although this adverse reaction is rare, clinicians should be aware of it, since these agents are commonly used in everyday medical practice.¹⁵

RECOGNIZING THE DANGER SIGNS

The clinical manifestations of methemoglobinemia are directly proportional to the percentage of methemoglobin in red blood cells. Cyanosis generally becomes apparent at concentrations around 15%, at which point the patient may still have no symptoms. Anxiety, lightheadedness, tachycardia, and dizziness manifest at levels of 20% to 30%. Fatigue, confusion, dizziness, tachypnea, and worsening tachycardia occur at levels of 30% to 50%. Levels of 50% to 70% cause coma, seizures, arrhythmias, and acidosis, and levels over 70% are considered lethal.¹⁶

While these levels provide a general guideline of symptomatology in an otherwise healthy person, it is important to remember that patients with underlying conditions such as anemia, lung disease (both of which our patient had), sepsis, thalassemia, G6PD deficiency, and sickle cell disease can manifest symptoms at lower concentrations of methemoglobin.^1,17

Most patients who develop clinically significant levels of methemoglobin do so within the first few hours of starting one of the culprit drugs.

DIAGNOSIS: METHEMOGLOBINEMIA AND THE SATURATION GAP

In patients with methemoglobinemia, pulse oximetry gives lower values than arterial blood gas oxygen measurements. Regular pulse oximetry works by measuring light absorbance at two distinct wavelengths (660 and 940 nm) to calculate the ratio of oxyhemoglobin to deoxyhemoglobin. Methemoglobin absorbs light at both these wavelengths, thus lowering the pulse oximetry values.¹

In contrast, oxygen saturation of arterial blood gas (oxyhemoglobin) is calculated indirectly from the concentration of dissolved oxygen in the blood and does not include oxygen bound to hemoglobin. Therefore, the measured arterial oxygen saturation is often normal in patients with methemoglobinemia since it relies only on inspired oxygen content and is independent of the methemoglobin concentration.¹⁸

Patients with clinically significant methemoglobinemia usually have a saturation gap > 10%

Oxygen supplementation can raise the level of oxyhemoglobin, which is a measure of dissolved oxygen, but the oxygen saturation as measured by pulse oximetry remains largely unchanged—ie, the saturation gap. A difference of more than 5% between the oxygen saturation by pulse oximetry and blood gas analysis is abnormal. Patients with clinically significant methemoglobinemia usually have a saturation gap greater than 10%.

Several other unique features should raise suspicion of methemoglobinemia. It should be considered in a patient presenting with cyanosis out of proportion to the oxygen saturation and in a patient with low oxygen saturation and a normal chest radiograph. Other clues include blood that is chocolate-colored on gross examination, rather than the dark red of deoxygenated blood.

Co-oximetry measures oxygen saturation using different wavelengths of light to distinguish between fractions of oxyhemoglobin, deoxyhemoglobin, and methemoglobin, but it is not widely available.

THE NEXT STEP

3. What is the next step in the management of our patient?

• Discontinue the dapsone
• Start methylene blue
• Start hyperbaric oxygen
• Give sodium thiosulfate
• Discontinue dapsone and start methylene blue

The next step in her management should be to stop the dapsone and start an infusion of methylene blue. Hyperbaric oxygen is used in treating carbon monoxide poisoning, and sodium thiosulfate is used in treating cyanide toxicity. They would not be appropriate in this patient’s care.

MANAGEMENT OF ACQUIRED METHEMOGLOBINEMIA

The first, most critical step in managing acquired methemoglobinemia is to immediately discontinue the suspected offending agent. In most patients without a concomitant condition such as anemia or lung disease and with a methemoglobin level below 20%, discontinuing the offending agent may suffice. Patients with a level of 20% or greater and patients with cardiac and pulmonary disease, who develop symptoms at lower concentrations of methemoglobin, require infusion of methylene blue.

Methylene blue is converted to its reduced form, leukomethylene blue, by NADPH-methemoglobin reductase. As it is oxidized, leukomethylene blue reduces methemoglobin to hemoglobin. A dose of 1 mg/kg intravenously is given at first. The response is usually dramatic, with a reduction in methemoglobin levels and improvement in symptoms often within 30 to 60 minutes. If levels remain high, the dose can be repeated 1 hour later.¹⁹

A caveat: methylene blue should be avoided in patients with complete G6PD deficiency

A caveat: methylene blue therapy should be avoided in patients with complete G6PD deficiency. Methylene blue works through the enzyme NADPH-methemoglobin reductase, and since patients with G6PD deficiency lack this enzyme, methylene blue is ineffective. In fact, since it cannot be reduced, excessive methylene blue can oxidize hemoglobin to methemoglobin, further exacerbating the condition. In patients with partial G6PD deficiency, methylene blue is still recommended as a first-line treatment, but at a lower initial dose (0.3–0.5 mg/kg). However, in patients with significant hemolysis, an exchange transfusion is the only treatment option.

CASE CONCLUDED

Since dapsone was identified as the likely cause of methemoglobinemia in our patient, it was immediately discontinued. Because she was symptomatic, 70 mg of methylene blue was given intravenously. Over the next 60 minutes, her clinical condition improved significantly. A repeat methemoglobin measurement was 3%.

She was discharged home the next day on oral antibiotics to complete treatment for community-acquired pneumonia.

TAKE-HOME POINTS

• Consider methemoglobinemia in a patient with unexplained cyanosis.
• Pulse oximetry gives lower values than arterial blood gas oxygen measurements in patients with methemoglobinemia, and pulse oximetry readings do not improve with supplemental oxygen.
• A saturation gap greater than 5% strongly suggests methemoglobinemia.
• The diagnosis of methemoglobinemia is confirmed by measuring the methemoglobin concentration.
• Most healthy patients develop symptoms at methemoglobin levels of 20%, but patients with comorbidities can develop symptoms at lower levels.
• A number of drugs can cause methemoglobinemia, even at therapeutic dosages.
• Treatment is generally indicated in patients who have symptoms or in healthy patients who have a methemoglobin level of 20% or greater.
• Identifying and promptly discontinuing the causative agent and initiating methylene blue infusion (1 mg/kg over 5 minutes) is the preferred treatment.

A 48-year-old woman presented to the emergency department after 2 days of nonproductive cough, chest discomfort, worsening shortness of breath, and subjective fever. She had a history of systemic sclerosis. She was currently taking prednisone 20 mg daily and aspirin 81 mg daily.

Physical examination revealed tachypnea (28 breaths per minute), and bronchial breath sounds in the left lower chest posteriorly.

The initial laboratory workup revealed:

• Hemoglobin 106 g/L (reference range 115–155)
• Mean corpuscular volume 84 fL (80–100)
• White blood cell count 29.4 × 10⁹/L (3.70–11.0), with 85% neutrophils
• Platelet count 180 × 10⁹/L (150–350)
• Lactate dehydrogenase 312 U/L (100–220).

Chest radiography showed opacification of the lower lobe of the left lung.

She was admitted to the hospital and started treatment with intravenous azithromycin and ceftriaxone for presumed community-acquired pneumonia, based on the clinical presentation and findings on chest radiography. Because of her immunosuppression (due to chronic prednisone therapy) and her high lactate dehydrogenase level, Pneumocystis jirovecii pneumonia was suspected, and because she had a history of allergy to trimethoprim-sulfamethoxazole and pentamidine, she was started on dapsone.

During the next 24 hours, she developed worsening dyspnea, hypoxia, and cyanosis. She was placed on an air-entrainment mask, with a fraction of inspired oxygen of 0.5. Pulse oximetry showed an oxygen saturation of 85%, but arterial blood gas analysis indicated an oxyhemoglobin concentration of 95%.

THE ‘SATURATION GAP’

1. Which is most likely to have caused the discrepancy between the oxyhemoglobin concentration and the oxygen saturation by pulse oximetry in this patient?

• Methemoglobinemia
• Carbon monoxide poisoning
• Inappropriate placement of the pulse oximeter probe
• Pulmonary embolism

Methemoglobinemia is the most likely cause of the discrepancy between the oxyhemoglobin levels and the oxygen saturation by pulse oximetry, a phenomenon also known as the “saturation gap.” Other common causes are cyanide poisoning and carbon monoxide poisoning.

P jirovecii pneumonia was suspected, and dapsone was started in light of her allergy to trimethoprim-sulfamethoxazole and pentamidine

Carbon monoxide poisoning, however, does not explain our patient’s cyanosis. On the contrary, carbon monoxide poisoning can actually cause the patient’s lips and mucous membranes to appear unnaturally bright pink. Also, carbon monoxide poisoning raises the blood concentration of carboxyhemoglobin (which has a high affinity for oxygen), and this usually causes pulse oximetry to read inappropriately high, whereas in our patient it read low.

Incorrect placement of the pulse oximeter probe can result in an inaccurate measurement of oxygen saturation. Visualization of the waveform on the plethysmograph or the signal quality index can be used to assess adequate placement of the pulse oximeter probe. However, inadequate probe placement does not explain our patient’s dyspnea and cyanosis.

Pulmonary embolism can lead to hypoxia as a result of ventilation-perfusion mismatch. However, pulmonary embolism leading to low oxygen saturation on pulse oximetry will also lead to concomitantly low oxyhemoglobin levels as measured by arterial blood gas analysis, and this was not seen in our patient.

BACK TO OUR PATIENT

Because there was a discrepancy between our patient’s pulse oximetry reading and oxyhemoglobin concentration by arterial blood gas measurement, her methemoglobin level was checked and was found to be 30%, thus confirming the diagnosis of methemoglobinemia.

WHAT IS METHEMOGLOBINEMIA, AND WHAT CAUSES IT?

Oxygen is normally bound to iron in its ferrous (Fe²⁺) form in hemoglobin to form oxyhemoglobin. Oxidative stress in the body can cause iron to change from the ferrous to the ferric (Fe³⁺) state, forming methemoglobin. Methemoglobin is normally present in the blood in low levels (< 1% of the total hemoglobin), and ferric iron is reduced and recycled back to the ferrous form by NADH-cytochrome b5 reductase, an enzyme present in red blood cells. This protective mechanism maintains methemoglobin levels within safe limits. But increased production can lead to accumulation of methemoglobin, resulting in dyspnea and hypoxia and the condition referred to as methemoglobinemia.¹

Increased levels of methemoglobin relative to normal hemoglobin cause tissue hypoxia by several mechanisms. Methemoglobin cannot efficiently carry oxygen; instead, it binds to water or to a hydroxide ion depending on the pH of the environment.² Therefore, the hemoglobin molecule does not carry its usual load of oxygen, and hypoxia results from the reduced delivery of oxygen to tissues. In addition, an increased concentration of methemoglobin causes a leftward shift in the oxygen-hemoglobin dissociation curve, representing an increased affinity to bound oxygen in the remaining heme groups. The tightly bound oxygen is not adequately released at the tissue level, thus causing cellular hypoxia.

Methemoglobinemia is most often caused by exposure to an oxidizing chemical or drug that increases production of methemoglobin. In rare cases, it is caused by a congenital deficiency of NADH-cytochrome b5 reductase.³

2. Which of the following drugs can cause methemoglobinemia?

• Acetaminophen
• Dapsone
• Benzocaine
• Primaquine

All four of these drugs are common culprits for causing acquired methemoglobinemia; others include chloroquine, nitroglycerin, and sulfonamides.^4–6

The increased production of methemoglobin caused by these drugs overwhelms the protective effect of reducing enzymes and can lead to an accumulation of methemoglobin. However, because of variability in cellular metabolism, not every person who takes these drugs develops dangerous levels of methemoglobin.

Dapsone and benzocaine are the most commonly encountered drugs known to cause methemoglobinemia (Table 1). Dapsone is an anti-inflammatory and antimicrobial agent most commonly used for treating lepromatous leprosy and dermatitis herpetiformis. It is also often prescribed for prophylaxis and treatment of P jirovecii pneumonia in immunosuppressed individuals.⁷ Benzocaine is a local anesthetic and was commonly used before procedures such as oral or dental surgery, transesophageal echocardiography, and endoscopy.^8–10 Even low doses of benzocaine can lead to high levels of methemoglobinemia. However, the availability of other, safer anesthetics now limits the use of benzocaine in major US centers. In addition, the topical anesthetic Emla (lidocaine plus prilocaine) has been recently reported as a cause of methemoglobinemia in infants and children.^11,12

Also, potentially fatal methemoglobinemia has been reported in patients with a deficiency of G-6-phosphate dehydrogenase (G6PD) who received rasburicase, a recombinant version of urate oxidase enzyme used to prevent and treat tumor lysis syndrome.^13,14

Lastly, methemoglobinemia has been reported in patients with inflammatory bowel disease treated with mesalamine.

Although this adverse reaction is rare, clinicians should be aware of it, since these agents are commonly used in everyday medical practice.¹⁵

RECOGNIZING THE DANGER SIGNS

The clinical manifestations of methemoglobinemia are directly proportional to the percentage of methemoglobin in red blood cells. Cyanosis generally becomes apparent at concentrations around 15%, at which point the patient may still have no symptoms. Anxiety, lightheadedness, tachycardia, and dizziness manifest at levels of 20% to 30%. Fatigue, confusion, dizziness, tachypnea, and worsening tachycardia occur at levels of 30% to 50%. Levels of 50% to 70% cause coma, seizures, arrhythmias, and acidosis, and levels over 70% are considered lethal.¹⁶

While these levels provide a general guideline of symptomatology in an otherwise healthy person, it is important to remember that patients with underlying conditions such as anemia, lung disease (both of which our patient had), sepsis, thalassemia, G6PD deficiency, and sickle cell disease can manifest symptoms at lower concentrations of methemoglobin.^1,17

Most patients who develop clinically significant levels of methemoglobin do so within the first few hours of starting one of the culprit drugs.

DIAGNOSIS: METHEMOGLOBINEMIA AND THE SATURATION GAP

In patients with methemoglobinemia, pulse oximetry gives lower values than arterial blood gas oxygen measurements. Regular pulse oximetry works by measuring light absorbance at two distinct wavelengths (660 and 940 nm) to calculate the ratio of oxyhemoglobin to deoxyhemoglobin. Methemoglobin absorbs light at both these wavelengths, thus lowering the pulse oximetry values.¹

In contrast, oxygen saturation of arterial blood gas (oxyhemoglobin) is calculated indirectly from the concentration of dissolved oxygen in the blood and does not include oxygen bound to hemoglobin. Therefore, the measured arterial oxygen saturation is often normal in patients with methemoglobinemia since it relies only on inspired oxygen content and is independent of the methemoglobin concentration.¹⁸

Patients with clinically significant methemoglobinemia usually have a saturation gap > 10%

Oxygen supplementation can raise the level of oxyhemoglobin, which is a measure of dissolved oxygen, but the oxygen saturation as measured by pulse oximetry remains largely unchanged—ie, the saturation gap. A difference of more than 5% between the oxygen saturation by pulse oximetry and blood gas analysis is abnormal. Patients with clinically significant methemoglobinemia usually have a saturation gap greater than 10%.

Several other unique features should raise suspicion of methemoglobinemia. It should be considered in a patient presenting with cyanosis out of proportion to the oxygen saturation and in a patient with low oxygen saturation and a normal chest radiograph. Other clues include blood that is chocolate-colored on gross examination, rather than the dark red of deoxygenated blood.

Co-oximetry measures oxygen saturation using different wavelengths of light to distinguish between fractions of oxyhemoglobin, deoxyhemoglobin, and methemoglobin, but it is not widely available.

THE NEXT STEP

3. What is the next step in the management of our patient?

• Discontinue the dapsone
• Start methylene blue
• Start hyperbaric oxygen
• Give sodium thiosulfate
• Discontinue dapsone and start methylene blue

The next step in her management should be to stop the dapsone and start an infusion of methylene blue. Hyperbaric oxygen is used in treating carbon monoxide poisoning, and sodium thiosulfate is used in treating cyanide toxicity. They would not be appropriate in this patient’s care.

MANAGEMENT OF ACQUIRED METHEMOGLOBINEMIA

The first, most critical step in managing acquired methemoglobinemia is to immediately discontinue the suspected offending agent. In most patients without a concomitant condition such as anemia or lung disease and with a methemoglobin level below 20%, discontinuing the offending agent may suffice. Patients with a level of 20% or greater and patients with cardiac and pulmonary disease, who develop symptoms at lower concentrations of methemoglobin, require infusion of methylene blue.

Methylene blue is converted to its reduced form, leukomethylene blue, by NADPH-methemoglobin reductase. As it is oxidized, leukomethylene blue reduces methemoglobin to hemoglobin. A dose of 1 mg/kg intravenously is given at first. The response is usually dramatic, with a reduction in methemoglobin levels and improvement in symptoms often within 30 to 60 minutes. If levels remain high, the dose can be repeated 1 hour later.¹⁹

A caveat: methylene blue should be avoided in patients with complete G6PD deficiency

A caveat: methylene blue therapy should be avoided in patients with complete G6PD deficiency. Methylene blue works through the enzyme NADPH-methemoglobin reductase, and since patients with G6PD deficiency lack this enzyme, methylene blue is ineffective. In fact, since it cannot be reduced, excessive methylene blue can oxidize hemoglobin to methemoglobin, further exacerbating the condition. In patients with partial G6PD deficiency, methylene blue is still recommended as a first-line treatment, but at a lower initial dose (0.3–0.5 mg/kg). However, in patients with significant hemolysis, an exchange transfusion is the only treatment option.

CASE CONCLUDED

Since dapsone was identified as the likely cause of methemoglobinemia in our patient, it was immediately discontinued. Because she was symptomatic, 70 mg of methylene blue was given intravenously. Over the next 60 minutes, her clinical condition improved significantly. A repeat methemoglobin measurement was 3%.

She was discharged home the next day on oral antibiotics to complete treatment for community-acquired pneumonia.

TAKE-HOME POINTS

• Consider methemoglobinemia in a patient with unexplained cyanosis.
• Pulse oximetry gives lower values than arterial blood gas oxygen measurements in patients with methemoglobinemia, and pulse oximetry readings do not improve with supplemental oxygen.
• A saturation gap greater than 5% strongly suggests methemoglobinemia.
• The diagnosis of methemoglobinemia is confirmed by measuring the methemoglobin concentration.
• Most healthy patients develop symptoms at methemoglobin levels of 20%, but patients with comorbidities can develop symptoms at lower levels.
• A number of drugs can cause methemoglobinemia, even at therapeutic dosages.
• Treatment is generally indicated in patients who have symptoms or in healthy patients who have a methemoglobin level of 20% or greater.
• Identifying and promptly discontinuing the causative agent and initiating methylene blue infusion (1 mg/kg over 5 minutes) is the preferred treatment.

A 48-year-old woman presented to the emergency department after 2 days of nonproductive cough, chest discomfort, worsening shortness of breath, and subjective fever. She had a history of systemic sclerosis. She was currently taking prednisone 20 mg daily and aspirin 81 mg daily.

Physical examination revealed tachypnea (28 breaths per minute), and bronchial breath sounds in the left lower chest posteriorly.

The initial laboratory workup revealed:

• Hemoglobin 106 g/L (reference range 115–155)
• Mean corpuscular volume 84 fL (80–100)
• White blood cell count 29.4 × 10⁹/L (3.70–11.0), with 85% neutrophils
• Platelet count 180 × 10⁹/L (150–350)
• Lactate dehydrogenase 312 U/L (100–220).

Chest radiography showed opacification of the lower lobe of the left lung.

She was admitted to the hospital and started treatment with intravenous azithromycin and ceftriaxone for presumed community-acquired pneumonia, based on the clinical presentation and findings on chest radiography. Because of her immunosuppression (due to chronic prednisone therapy) and her high lactate dehydrogenase level, Pneumocystis jirovecii pneumonia was suspected, and because she had a history of allergy to trimethoprim-sulfamethoxazole and pentamidine, she was started on dapsone.

During the next 24 hours, she developed worsening dyspnea, hypoxia, and cyanosis. She was placed on an air-entrainment mask, with a fraction of inspired oxygen of 0.5. Pulse oximetry showed an oxygen saturation of 85%, but arterial blood gas analysis indicated an oxyhemoglobin concentration of 95%.

THE ‘SATURATION GAP’

1. Which is most likely to have caused the discrepancy between the oxyhemoglobin concentration and the oxygen saturation by pulse oximetry in this patient?

• Methemoglobinemia
• Carbon monoxide poisoning
• Inappropriate placement of the pulse oximeter probe
• Pulmonary embolism

Methemoglobinemia is the most likely cause of the discrepancy between the oxyhemoglobin levels and the oxygen saturation by pulse oximetry, a phenomenon also known as the “saturation gap.” Other common causes are cyanide poisoning and carbon monoxide poisoning.

P jirovecii pneumonia was suspected, and dapsone was started in light of her allergy to trimethoprim-sulfamethoxazole and pentamidine

Carbon monoxide poisoning, however, does not explain our patient’s cyanosis. On the contrary, carbon monoxide poisoning can actually cause the patient’s lips and mucous membranes to appear unnaturally bright pink. Also, carbon monoxide poisoning raises the blood concentration of carboxyhemoglobin (which has a high affinity for oxygen), and this usually causes pulse oximetry to read inappropriately high, whereas in our patient it read low.

Incorrect placement of the pulse oximeter probe can result in an inaccurate measurement of oxygen saturation. Visualization of the waveform on the plethysmograph or the signal quality index can be used to assess adequate placement of the pulse oximeter probe. However, inadequate probe placement does not explain our patient’s dyspnea and cyanosis.

Pulmonary embolism can lead to hypoxia as a result of ventilation-perfusion mismatch. However, pulmonary embolism leading to low oxygen saturation on pulse oximetry will also lead to concomitantly low oxyhemoglobin levels as measured by arterial blood gas analysis, and this was not seen in our patient.

BACK TO OUR PATIENT

Because there was a discrepancy between our patient’s pulse oximetry reading and oxyhemoglobin concentration by arterial blood gas measurement, her methemoglobin level was checked and was found to be 30%, thus confirming the diagnosis of methemoglobinemia.

WHAT IS METHEMOGLOBINEMIA, AND WHAT CAUSES IT?

Oxygen is normally bound to iron in its ferrous (Fe²⁺) form in hemoglobin to form oxyhemoglobin. Oxidative stress in the body can cause iron to change from the ferrous to the ferric (Fe³⁺) state, forming methemoglobin. Methemoglobin is normally present in the blood in low levels (< 1% of the total hemoglobin), and ferric iron is reduced and recycled back to the ferrous form by NADH-cytochrome b5 reductase, an enzyme present in red blood cells. This protective mechanism maintains methemoglobin levels within safe limits. But increased production can lead to accumulation of methemoglobin, resulting in dyspnea and hypoxia and the condition referred to as methemoglobinemia.¹

Increased levels of methemoglobin relative to normal hemoglobin cause tissue hypoxia by several mechanisms. Methemoglobin cannot efficiently carry oxygen; instead, it binds to water or to a hydroxide ion depending on the pH of the environment.² Therefore, the hemoglobin molecule does not carry its usual load of oxygen, and hypoxia results from the reduced delivery of oxygen to tissues. In addition, an increased concentration of methemoglobin causes a leftward shift in the oxygen-hemoglobin dissociation curve, representing an increased affinity to bound oxygen in the remaining heme groups. The tightly bound oxygen is not adequately released at the tissue level, thus causing cellular hypoxia.

Methemoglobinemia is most often caused by exposure to an oxidizing chemical or drug that increases production of methemoglobin. In rare cases, it is caused by a congenital deficiency of NADH-cytochrome b5 reductase.³

2. Which of the following drugs can cause methemoglobinemia?

• Acetaminophen
• Dapsone
• Benzocaine
• Primaquine

All four of these drugs are common culprits for causing acquired methemoglobinemia; others include chloroquine, nitroglycerin, and sulfonamides.^4–6

The increased production of methemoglobin caused by these drugs overwhelms the protective effect of reducing enzymes and can lead to an accumulation of methemoglobin. However, because of variability in cellular metabolism, not every person who takes these drugs develops dangerous levels of methemoglobin.

Dapsone and benzocaine are the most commonly encountered drugs known to cause methemoglobinemia (Table 1). Dapsone is an anti-inflammatory and antimicrobial agent most commonly used for treating lepromatous leprosy and dermatitis herpetiformis. It is also often prescribed for prophylaxis and treatment of P jirovecii pneumonia in immunosuppressed individuals.⁷ Benzocaine is a local anesthetic and was commonly used before procedures such as oral or dental surgery, transesophageal echocardiography, and endoscopy.^8–10 Even low doses of benzocaine can lead to high levels of methemoglobinemia. However, the availability of other, safer anesthetics now limits the use of benzocaine in major US centers. In addition, the topical anesthetic Emla (lidocaine plus prilocaine) has been recently reported as a cause of methemoglobinemia in infants and children.^11,12

Also, potentially fatal methemoglobinemia has been reported in patients with a deficiency of G-6-phosphate dehydrogenase (G6PD) who received rasburicase, a recombinant version of urate oxidase enzyme used to prevent and treat tumor lysis syndrome.^13,14

Lastly, methemoglobinemia has been reported in patients with inflammatory bowel disease treated with mesalamine.

Although this adverse reaction is rare, clinicians should be aware of it, since these agents are commonly used in everyday medical practice.¹⁵

RECOGNIZING THE DANGER SIGNS

The clinical manifestations of methemoglobinemia are directly proportional to the percentage of methemoglobin in red blood cells. Cyanosis generally becomes apparent at concentrations around 15%, at which point the patient may still have no symptoms. Anxiety, lightheadedness, tachycardia, and dizziness manifest at levels of 20% to 30%. Fatigue, confusion, dizziness, tachypnea, and worsening tachycardia occur at levels of 30% to 50%. Levels of 50% to 70% cause coma, seizures, arrhythmias, and acidosis, and levels over 70% are considered lethal.¹⁶

While these levels provide a general guideline of symptomatology in an otherwise healthy person, it is important to remember that patients with underlying conditions such as anemia, lung disease (both of which our patient had), sepsis, thalassemia, G6PD deficiency, and sickle cell disease can manifest symptoms at lower concentrations of methemoglobin.^1,17

Most patients who develop clinically significant levels of methemoglobin do so within the first few hours of starting one of the culprit drugs.

DIAGNOSIS: METHEMOGLOBINEMIA AND THE SATURATION GAP

In patients with methemoglobinemia, pulse oximetry gives lower values than arterial blood gas oxygen measurements. Regular pulse oximetry works by measuring light absorbance at two distinct wavelengths (660 and 940 nm) to calculate the ratio of oxyhemoglobin to deoxyhemoglobin. Methemoglobin absorbs light at both these wavelengths, thus lowering the pulse oximetry values.¹

In contrast, oxygen saturation of arterial blood gas (oxyhemoglobin) is calculated indirectly from the concentration of dissolved oxygen in the blood and does not include oxygen bound to hemoglobin. Therefore, the measured arterial oxygen saturation is often normal in patients with methemoglobinemia since it relies only on inspired oxygen content and is independent of the methemoglobin concentration.¹⁸

Patients with clinically significant methemoglobinemia usually have a saturation gap > 10%

Oxygen supplementation can raise the level of oxyhemoglobin, which is a measure of dissolved oxygen, but the oxygen saturation as measured by pulse oximetry remains largely unchanged—ie, the saturation gap. A difference of more than 5% between the oxygen saturation by pulse oximetry and blood gas analysis is abnormal. Patients with clinically significant methemoglobinemia usually have a saturation gap greater than 10%.

Several other unique features should raise suspicion of methemoglobinemia. It should be considered in a patient presenting with cyanosis out of proportion to the oxygen saturation and in a patient with low oxygen saturation and a normal chest radiograph. Other clues include blood that is chocolate-colored on gross examination, rather than the dark red of deoxygenated blood.

Co-oximetry measures oxygen saturation using different wavelengths of light to distinguish between fractions of oxyhemoglobin, deoxyhemoglobin, and methemoglobin, but it is not widely available.

THE NEXT STEP

3. What is the next step in the management of our patient?

• Discontinue the dapsone
• Start methylene blue
• Start hyperbaric oxygen
• Give sodium thiosulfate
• Discontinue dapsone and start methylene blue

The next step in her management should be to stop the dapsone and start an infusion of methylene blue. Hyperbaric oxygen is used in treating carbon monoxide poisoning, and sodium thiosulfate is used in treating cyanide toxicity. They would not be appropriate in this patient’s care.

MANAGEMENT OF ACQUIRED METHEMOGLOBINEMIA

The first, most critical step in managing acquired methemoglobinemia is to immediately discontinue the suspected offending agent. In most patients without a concomitant condition such as anemia or lung disease and with a methemoglobin level below 20%, discontinuing the offending agent may suffice. Patients with a level of 20% or greater and patients with cardiac and pulmonary disease, who develop symptoms at lower concentrations of methemoglobin, require infusion of methylene blue.

Methylene blue is converted to its reduced form, leukomethylene blue, by NADPH-methemoglobin reductase. As it is oxidized, leukomethylene blue reduces methemoglobin to hemoglobin. A dose of 1 mg/kg intravenously is given at first. The response is usually dramatic, with a reduction in methemoglobin levels and improvement in symptoms often within 30 to 60 minutes. If levels remain high, the dose can be repeated 1 hour later.¹⁹

A caveat: methylene blue should be avoided in patients with complete G6PD deficiency

A caveat: methylene blue therapy should be avoided in patients with complete G6PD deficiency. Methylene blue works through the enzyme NADPH-methemoglobin reductase, and since patients with G6PD deficiency lack this enzyme, methylene blue is ineffective. In fact, since it cannot be reduced, excessive methylene blue can oxidize hemoglobin to methemoglobin, further exacerbating the condition. In patients with partial G6PD deficiency, methylene blue is still recommended as a first-line treatment, but at a lower initial dose (0.3–0.5 mg/kg). However, in patients with significant hemolysis, an exchange transfusion is the only treatment option.

CASE CONCLUDED

Since dapsone was identified as the likely cause of methemoglobinemia in our patient, it was immediately discontinued. Because she was symptomatic, 70 mg of methylene blue was given intravenously. Over the next 60 minutes, her clinical condition improved significantly. A repeat methemoglobin measurement was 3%.

She was discharged home the next day on oral antibiotics to complete treatment for community-acquired pneumonia.

TAKE-HOME POINTS

• Consider methemoglobinemia in a patient with unexplained cyanosis.
• Pulse oximetry gives lower values than arterial blood gas oxygen measurements in patients with methemoglobinemia, and pulse oximetry readings do not improve with supplemental oxygen.
• A saturation gap greater than 5% strongly suggests methemoglobinemia.
• The diagnosis of methemoglobinemia is confirmed by measuring the methemoglobin concentration.
• Most healthy patients develop symptoms at methemoglobin levels of 20%, but patients with comorbidities can develop symptoms at lower levels.
• A number of drugs can cause methemoglobinemia, even at therapeutic dosages.
• Treatment is generally indicated in patients who have symptoms or in healthy patients who have a methemoglobin level of 20% or greater.
• Identifying and promptly discontinuing the causative agent and initiating methylene blue infusion (1 mg/kg over 5 minutes) is the preferred treatment.

A 38-year-old woman presents to the emergency department after experiencing several days of swelling and mild discomfort in her left calf. She denies chest pain or shortness of breath. She does not recall antecedent trauma, is a nonsmoker, is healthy, and takes no medications apart from a multivitamin. She has not undergone any surgical procedure, has not been hospitalized recently, and has no history of venous thromboembolic disease. She says she started an aerobics program 1 week ago.

On examination, her left lower leg is mildly swollen, but the difference in calf circumference between the right and left legs is less than 1 cm. There is no erythema, no pitting edema, and only mild and rather diffuse tenderness of the calf. A urine pregnancy test is negative and her D-dimer level is 350 ng/mL (reference range < 500 ng/mL). Does she require ultrasonography of the left leg to evaluate for deep vein thrombosis (DVT)?

This patient does not need confirmatory ultrasonography, as her normal D-dimer level of 350 ng/mL is enough to rule out DVT. Her low probability of having DVT is further supported by her Wells score (Table 1), a tool that can help rule out DVT and reduce the need for further testing. DVT is unlikely if a patient’s Wells score is less than 2, and this patient’s score is –1. She receives 1 point for swelling of her left lower leg, but injury from her recent aerobic exercise is at least as likely as DVT to account for her symptoms (–2 points).

GUIDELINES AND CHOOSING WISELY

Compression ultrasonography is the study most commonly used to evaluate for DVT. The diagnosis is made if either the femoral or popliteal vein is noncompressible.¹ In a patient with no history of DVT, the sensitivity of compression ultrasonography is 94%, and its specificity is 98%.

Several guidelines recommend using a clinical decision rule to establish the probability of venous thromboembolic disease before any additional diagnostic testing such as D-dimer measurement or ultrasonography.^2–4 A number of clinical decision rules exist for DVT, but the Wells score is the most studied and validated.¹ It incorporates the patient’s risk factors, symptoms, and signs to categorize the probability of DVT as low, moderate, or high and has been further modified to classify the risk as either likely or unlikely (Table 1).⁵

Guidelines from the American College of Chest Physicians (2012), Scottish Intercollegiate Guidelines Network (2010), and American Academy of Family Physicians and American College of Physicians (2007) recommend against performing imaging if a high-sensitivity D-dimer test is negative in a patient in whom the pretest probability of DVT is unlikely.^2–4 Enzyme-linked immunofluorescence assays, microplate enzyme-linked immunosorbent assays, and latex quantitative assays are considered high-sensitivity D-dimer tests, having 96%, 94%, and 93% sensitivity, respectively, in ruling out DVT.¹ Other D-dimer tests have lower sensitivity and cannot comfortably rule out DVT even if the results are negative.

Since D-dimer measurement is a sensitive but not specific test, it should be used only to rule out DVT—not to rule it in. Moreover, compression ultrasonography may be indicated to rule out other causes of the patient’s symptoms.

The guidelines caution against D-dimer testing if the patient has a comorbid condition that can by itself raise or lower the D-dimer level, leading one to falsely conclude the patient has or does not have DVT (Table 2).^1–4 In these instances, the pretest probability of  DVT may be higher than calculated by a clinical prediction rule, and compression ultrasonography may be an appropriate initial test.⁴ Compression ultrasonography is also recommended as a confirmatory test in low-risk patients who have a positive D-dimer test or as an initial test in patients at higher risk for DVT.^2–4

If a patient has a low pretest probability of DVT as defined by the Wells score and a normal high-sensitivity D-dimer measurement, then ordering imaging studies is a questionable practice according to statements by the American College of Physicians, American College of Emergency Physicians, European Society of Cardiology, American Academy of Family Physicians, and Scottish Intercollegiate Guidelines Network.

HARMS OF ULTRASONOGRAPHY

Although ultrasonography is generally well tolerated, it may be unnecessary. Combining a prediction rule (to assess the probability) with D-dimer testing (to rule out DVT) can significantly reduce the use of ultrasonography and the associated cost.

Wells et al⁵ calculated that clinicians could cut back on ultrasonographic testing by 39% by not doing it in those who had a low pretest probability and a negative D-dimer test result.⁵ In that patient population, fewer than 1% of patients were later found to have DVT.

Ordering compression ultrasonography as additional testing may lead to a false-positive result and to additional unnecessary testing and treatments that would inconvenience the patient, increase the risk of serious complications such as bleeding, and incur increased costs. Cost considerations should include not only the cost of the test and its interpretation, but also the workup and treatment of false-positive results, patient time missed from work while being tested, and potential associated costs for patients who need to be evaluated in the emergency department to obtain same-day testing.

THE CLINICAL BOTTOM LINE

Our patient’s Wells score indicates that DVT is unlikely. A negative D-dimer test is sufficient to rule out DVT, and further testing is unnecessary.

A 38-year-old woman presents to the emergency department after experiencing several days of swelling and mild discomfort in her left calf. She denies chest pain or shortness of breath. She does not recall antecedent trauma, is a nonsmoker, is healthy, and takes no medications apart from a multivitamin. She has not undergone any surgical procedure, has not been hospitalized recently, and has no history of venous thromboembolic disease. She says she started an aerobics program 1 week ago.

On examination, her left lower leg is mildly swollen, but the difference in calf circumference between the right and left legs is less than 1 cm. There is no erythema, no pitting edema, and only mild and rather diffuse tenderness of the calf. A urine pregnancy test is negative and her D-dimer level is 350 ng/mL (reference range < 500 ng/mL). Does she require ultrasonography of the left leg to evaluate for deep vein thrombosis (DVT)?

This patient does not need confirmatory ultrasonography, as her normal D-dimer level of 350 ng/mL is enough to rule out DVT. Her low probability of having DVT is further supported by her Wells score (Table 1), a tool that can help rule out DVT and reduce the need for further testing. DVT is unlikely if a patient’s Wells score is less than 2, and this patient’s score is –1. She receives 1 point for swelling of her left lower leg, but injury from her recent aerobic exercise is at least as likely as DVT to account for her symptoms (–2 points).

GUIDELINES AND CHOOSING WISELY

Compression ultrasonography is the study most commonly used to evaluate for DVT. The diagnosis is made if either the femoral or popliteal vein is noncompressible.¹ In a patient with no history of DVT, the sensitivity of compression ultrasonography is 94%, and its specificity is 98%.

Several guidelines recommend using a clinical decision rule to establish the probability of venous thromboembolic disease before any additional diagnostic testing such as D-dimer measurement or ultrasonography.^2–4 A number of clinical decision rules exist for DVT, but the Wells score is the most studied and validated.¹ It incorporates the patient’s risk factors, symptoms, and signs to categorize the probability of DVT as low, moderate, or high and has been further modified to classify the risk as either likely or unlikely (Table 1).⁵

Guidelines from the American College of Chest Physicians (2012), Scottish Intercollegiate Guidelines Network (2010), and American Academy of Family Physicians and American College of Physicians (2007) recommend against performing imaging if a high-sensitivity D-dimer test is negative in a patient in whom the pretest probability of DVT is unlikely.^2–4 Enzyme-linked immunofluorescence assays, microplate enzyme-linked immunosorbent assays, and latex quantitative assays are considered high-sensitivity D-dimer tests, having 96%, 94%, and 93% sensitivity, respectively, in ruling out DVT.¹ Other D-dimer tests have lower sensitivity and cannot comfortably rule out DVT even if the results are negative.

Since D-dimer measurement is a sensitive but not specific test, it should be used only to rule out DVT—not to rule it in. Moreover, compression ultrasonography may be indicated to rule out other causes of the patient’s symptoms.

The guidelines caution against D-dimer testing if the patient has a comorbid condition that can by itself raise or lower the D-dimer level, leading one to falsely conclude the patient has or does not have DVT (Table 2).^1–4 In these instances, the pretest probability of  DVT may be higher than calculated by a clinical prediction rule, and compression ultrasonography may be an appropriate initial test.⁴ Compression ultrasonography is also recommended as a confirmatory test in low-risk patients who have a positive D-dimer test or as an initial test in patients at higher risk for DVT.^2–4

If a patient has a low pretest probability of DVT as defined by the Wells score and a normal high-sensitivity D-dimer measurement, then ordering imaging studies is a questionable practice according to statements by the American College of Physicians, American College of Emergency Physicians, European Society of Cardiology, American Academy of Family Physicians, and Scottish Intercollegiate Guidelines Network.

HARMS OF ULTRASONOGRAPHY

Although ultrasonography is generally well tolerated, it may be unnecessary. Combining a prediction rule (to assess the probability) with D-dimer testing (to rule out DVT) can significantly reduce the use of ultrasonography and the associated cost.

Wells et al⁵ calculated that clinicians could cut back on ultrasonographic testing by 39% by not doing it in those who had a low pretest probability and a negative D-dimer test result.⁵ In that patient population, fewer than 1% of patients were later found to have DVT.

Ordering compression ultrasonography as additional testing may lead to a false-positive result and to additional unnecessary testing and treatments that would inconvenience the patient, increase the risk of serious complications such as bleeding, and incur increased costs. Cost considerations should include not only the cost of the test and its interpretation, but also the workup and treatment of false-positive results, patient time missed from work while being tested, and potential associated costs for patients who need to be evaluated in the emergency department to obtain same-day testing.

THE CLINICAL BOTTOM LINE

Our patient’s Wells score indicates that DVT is unlikely. A negative D-dimer test is sufficient to rule out DVT, and further testing is unnecessary.

A 38-year-old woman presents to the emergency department after experiencing several days of swelling and mild discomfort in her left calf. She denies chest pain or shortness of breath. She does not recall antecedent trauma, is a nonsmoker, is healthy, and takes no medications apart from a multivitamin. She has not undergone any surgical procedure, has not been hospitalized recently, and has no history of venous thromboembolic disease. She says she started an aerobics program 1 week ago.

On examination, her left lower leg is mildly swollen, but the difference in calf circumference between the right and left legs is less than 1 cm. There is no erythema, no pitting edema, and only mild and rather diffuse tenderness of the calf. A urine pregnancy test is negative and her D-dimer level is 350 ng/mL (reference range < 500 ng/mL). Does she require ultrasonography of the left leg to evaluate for deep vein thrombosis (DVT)?

This patient does not need confirmatory ultrasonography, as her normal D-dimer level of 350 ng/mL is enough to rule out DVT. Her low probability of having DVT is further supported by her Wells score (Table 1), a tool that can help rule out DVT and reduce the need for further testing. DVT is unlikely if a patient’s Wells score is less than 2, and this patient’s score is –1. She receives 1 point for swelling of her left lower leg, but injury from her recent aerobic exercise is at least as likely as DVT to account for her symptoms (–2 points).

GUIDELINES AND CHOOSING WISELY

Compression ultrasonography is the study most commonly used to evaluate for DVT. The diagnosis is made if either the femoral or popliteal vein is noncompressible.¹ In a patient with no history of DVT, the sensitivity of compression ultrasonography is 94%, and its specificity is 98%.

Several guidelines recommend using a clinical decision rule to establish the probability of venous thromboembolic disease before any additional diagnostic testing such as D-dimer measurement or ultrasonography.^2–4 A number of clinical decision rules exist for DVT, but the Wells score is the most studied and validated.¹ It incorporates the patient’s risk factors, symptoms, and signs to categorize the probability of DVT as low, moderate, or high and has been further modified to classify the risk as either likely or unlikely (Table 1).⁵

Guidelines from the American College of Chest Physicians (2012), Scottish Intercollegiate Guidelines Network (2010), and American Academy of Family Physicians and American College of Physicians (2007) recommend against performing imaging if a high-sensitivity D-dimer test is negative in a patient in whom the pretest probability of DVT is unlikely.^2–4 Enzyme-linked immunofluorescence assays, microplate enzyme-linked immunosorbent assays, and latex quantitative assays are considered high-sensitivity D-dimer tests, having 96%, 94%, and 93% sensitivity, respectively, in ruling out DVT.¹ Other D-dimer tests have lower sensitivity and cannot comfortably rule out DVT even if the results are negative.

Since D-dimer measurement is a sensitive but not specific test, it should be used only to rule out DVT—not to rule it in. Moreover, compression ultrasonography may be indicated to rule out other causes of the patient’s symptoms.

The guidelines caution against D-dimer testing if the patient has a comorbid condition that can by itself raise or lower the D-dimer level, leading one to falsely conclude the patient has or does not have DVT (Table 2).^1–4 In these instances, the pretest probability of  DVT may be higher than calculated by a clinical prediction rule, and compression ultrasonography may be an appropriate initial test.⁴ Compression ultrasonography is also recommended as a confirmatory test in low-risk patients who have a positive D-dimer test or as an initial test in patients at higher risk for DVT.^2–4

If a patient has a low pretest probability of DVT as defined by the Wells score and a normal high-sensitivity D-dimer measurement, then ordering imaging studies is a questionable practice according to statements by the American College of Physicians, American College of Emergency Physicians, European Society of Cardiology, American Academy of Family Physicians, and Scottish Intercollegiate Guidelines Network.

HARMS OF ULTRASONOGRAPHY

Although ultrasonography is generally well tolerated, it may be unnecessary. Combining a prediction rule (to assess the probability) with D-dimer testing (to rule out DVT) can significantly reduce the use of ultrasonography and the associated cost.

Wells et al⁵ calculated that clinicians could cut back on ultrasonographic testing by 39% by not doing it in those who had a low pretest probability and a negative D-dimer test result.⁵ In that patient population, fewer than 1% of patients were later found to have DVT.

Ordering compression ultrasonography as additional testing may lead to a false-positive result and to additional unnecessary testing and treatments that would inconvenience the patient, increase the risk of serious complications such as bleeding, and incur increased costs. Cost considerations should include not only the cost of the test and its interpretation, but also the workup and treatment of false-positive results, patient time missed from work while being tested, and potential associated costs for patients who need to be evaluated in the emergency department to obtain same-day testing.

THE CLINICAL BOTTOM LINE

Our patient’s Wells score indicates that DVT is unlikely. A negative D-dimer test is sufficient to rule out DVT, and further testing is unnecessary.

A 57-year-old man with long-standing systemic sclerosis presented with worsening diffuse abdominal pain associated with several episodes of nonbloody emesis for 5 days. He had been hospitalized numerous times over the past 2 years for similar symptoms. In those instances, abdominal radiography and computed tomography (CT) had revealed nonspecific intestinal pseudo-obstruction that had resolved within a few days with bowel rest, antibiotics for small-intestinal bacterial overgrowth, and supportive care.

At the time of this presentation, physical examination showed stable vital signs, a tympanic, distended abdomen with diffuse tenderness, and diminished bowel sounds with no sign of peritonitis. Complete blood cell counts, renal function testing, and serum lactate levels were unremarkable.

Abdominal radiography showed mildly dilated loops of small bowel with multiple fluid levels, raising concern for intestinal obstruction. Interestingly, abdominal CT revealed extensive pneumatosis cystoides intestinalis of the entire small bowel with sparing of the colon, which raised concern for acute bowel ischemia (Figure 1). However, given the patient’s underlying systemic sclerosis and current stable condition, the general surgeon recommended conservative management with bowel rest, rifaximin to treat the small-intestinal bacterial overgrowth, and intravenous fluids, which resulted in significant clinical improvement. A liquid diet was initiated and advanced as tolerated to a soft diet before he was discharged home after 8 days of hospitalization.

A RARE, USUALLY BENIGN COMPLICATION OF SYSTEMIC SCLEROSIS

Pneumatosis cystoides intestinalis is a rare gastrointestinal complication of systemic sclerosis characterized by intramural accumulation of gas within thin-walled cysts. It is postulated to result either from excess hydrogen gas produced by intraluminal bacterial fermentation and altered partial pressure of nitrogen within the intestinal wall (the bacterial theory),¹ or from the transgression of gas cysts through the layers of bowel wall as a result of high luminal pressure from intestinal obstruction (the mechanical theory).²

The more widespread use of diagnostic CT in recent years has led to increased recognition of this condition, a finding that also often raises concern for intestinal necrosis or perforation.3 Meticulous correlation of the clinical presentation with corroborative laboratory testing should determine whether a conservative medical approach or emergency surgical exploration is appropriate.4

Pneumatosis cystoides intestinalis in patients with systemic sclerosis is a benign condition that generally resolves with bowel rest, antibiotics, inhalational oxygen therapy, and supportive care.⁵ An elevated venous oxygen concentration from high-flow oxygen therapy is believed to attenuate the gaseous cysts by decreasing the partial pressure of the nitrogenous gases and by being toxic to the anaerobic gut bacteria.

About 3% of patients with pneumatosis cystoides intestinalis develop complications such as pneumoperitoneum, intestinal volvulus, obstruction, or hemorrhage. Evidence of pneumoperitoneum or bowel infarction—such as the presence of portomesenteric venous gas, a decreased arterial pH, or an elevated lactic acid or amylase level—warrants immediate surgical intervention. Overall, early recognition and watchful monitoring for bowel necrosis or perforation are preferred over reflexive surgical exploration.

A 57-year-old man with long-standing systemic sclerosis presented with worsening diffuse abdominal pain associated with several episodes of nonbloody emesis for 5 days. He had been hospitalized numerous times over the past 2 years for similar symptoms. In those instances, abdominal radiography and computed tomography (CT) had revealed nonspecific intestinal pseudo-obstruction that had resolved within a few days with bowel rest, antibiotics for small-intestinal bacterial overgrowth, and supportive care.

At the time of this presentation, physical examination showed stable vital signs, a tympanic, distended abdomen with diffuse tenderness, and diminished bowel sounds with no sign of peritonitis. Complete blood cell counts, renal function testing, and serum lactate levels were unremarkable.

Abdominal radiography showed mildly dilated loops of small bowel with multiple fluid levels, raising concern for intestinal obstruction. Interestingly, abdominal CT revealed extensive pneumatosis cystoides intestinalis of the entire small bowel with sparing of the colon, which raised concern for acute bowel ischemia (Figure 1). However, given the patient’s underlying systemic sclerosis and current stable condition, the general surgeon recommended conservative management with bowel rest, rifaximin to treat the small-intestinal bacterial overgrowth, and intravenous fluids, which resulted in significant clinical improvement. A liquid diet was initiated and advanced as tolerated to a soft diet before he was discharged home after 8 days of hospitalization.

A RARE, USUALLY BENIGN COMPLICATION OF SYSTEMIC SCLEROSIS

Pneumatosis cystoides intestinalis is a rare gastrointestinal complication of systemic sclerosis characterized by intramural accumulation of gas within thin-walled cysts. It is postulated to result either from excess hydrogen gas produced by intraluminal bacterial fermentation and altered partial pressure of nitrogen within the intestinal wall (the bacterial theory),¹ or from the transgression of gas cysts through the layers of bowel wall as a result of high luminal pressure from intestinal obstruction (the mechanical theory).²

The more widespread use of diagnostic CT in recent years has led to increased recognition of this condition, a finding that also often raises concern for intestinal necrosis or perforation.3 Meticulous correlation of the clinical presentation with corroborative laboratory testing should determine whether a conservative medical approach or emergency surgical exploration is appropriate.4

Pneumatosis cystoides intestinalis in patients with systemic sclerosis is a benign condition that generally resolves with bowel rest, antibiotics, inhalational oxygen therapy, and supportive care.⁵ An elevated venous oxygen concentration from high-flow oxygen therapy is believed to attenuate the gaseous cysts by decreasing the partial pressure of the nitrogenous gases and by being toxic to the anaerobic gut bacteria.

About 3% of patients with pneumatosis cystoides intestinalis develop complications such as pneumoperitoneum, intestinal volvulus, obstruction, or hemorrhage. Evidence of pneumoperitoneum or bowel infarction—such as the presence of portomesenteric venous gas, a decreased arterial pH, or an elevated lactic acid or amylase level—warrants immediate surgical intervention. Overall, early recognition and watchful monitoring for bowel necrosis or perforation are preferred over reflexive surgical exploration.

A 57-year-old man with long-standing systemic sclerosis presented with worsening diffuse abdominal pain associated with several episodes of nonbloody emesis for 5 days. He had been hospitalized numerous times over the past 2 years for similar symptoms. In those instances, abdominal radiography and computed tomography (CT) had revealed nonspecific intestinal pseudo-obstruction that had resolved within a few days with bowel rest, antibiotics for small-intestinal bacterial overgrowth, and supportive care.

At the time of this presentation, physical examination showed stable vital signs, a tympanic, distended abdomen with diffuse tenderness, and diminished bowel sounds with no sign of peritonitis. Complete blood cell counts, renal function testing, and serum lactate levels were unremarkable.

Abdominal radiography showed mildly dilated loops of small bowel with multiple fluid levels, raising concern for intestinal obstruction. Interestingly, abdominal CT revealed extensive pneumatosis cystoides intestinalis of the entire small bowel with sparing of the colon, which raised concern for acute bowel ischemia (Figure 1). However, given the patient’s underlying systemic sclerosis and current stable condition, the general surgeon recommended conservative management with bowel rest, rifaximin to treat the small-intestinal bacterial overgrowth, and intravenous fluids, which resulted in significant clinical improvement. A liquid diet was initiated and advanced as tolerated to a soft diet before he was discharged home after 8 days of hospitalization.

A RARE, USUALLY BENIGN COMPLICATION OF SYSTEMIC SCLEROSIS

Pneumatosis cystoides intestinalis is a rare gastrointestinal complication of systemic sclerosis characterized by intramural accumulation of gas within thin-walled cysts. It is postulated to result either from excess hydrogen gas produced by intraluminal bacterial fermentation and altered partial pressure of nitrogen within the intestinal wall (the bacterial theory),¹ or from the transgression of gas cysts through the layers of bowel wall as a result of high luminal pressure from intestinal obstruction (the mechanical theory).²

The more widespread use of diagnostic CT in recent years has led to increased recognition of this condition, a finding that also often raises concern for intestinal necrosis or perforation.3 Meticulous correlation of the clinical presentation with corroborative laboratory testing should determine whether a conservative medical approach or emergency surgical exploration is appropriate.4

Pneumatosis cystoides intestinalis in patients with systemic sclerosis is a benign condition that generally resolves with bowel rest, antibiotics, inhalational oxygen therapy, and supportive care.⁵ An elevated venous oxygen concentration from high-flow oxygen therapy is believed to attenuate the gaseous cysts by decreasing the partial pressure of the nitrogenous gases and by being toxic to the anaerobic gut bacteria.

About 3% of patients with pneumatosis cystoides intestinalis develop complications such as pneumoperitoneum, intestinal volvulus, obstruction, or hemorrhage. Evidence of pneumoperitoneum or bowel infarction—such as the presence of portomesenteric venous gas, a decreased arterial pH, or an elevated lactic acid or amylase level—warrants immediate surgical intervention. Overall, early recognition and watchful monitoring for bowel necrosis or perforation are preferred over reflexive surgical exploration.

The question is complicated, as there are different types of thyroid cancer, and a causal relationship is hard to prove.

Glucagon-like peptide 1 (GLP-1) receptor agonists can be safely used in all patients with thyroid cancers that are derived from the thyroid follicular epithelium (papillary and follicular thyroid cancer). However, they are currently contraindicated in patients with medullary thyroid cancer and in patients with multiple endocrine neoplasia 2 (MEN-2), which is not a form of thyroid cancer but is relevant to our discussion. We probably should be cautious about using them in patients with familial thyroid cancer and those with a genetic predisposition for papillary or follicular thyroid cancer.

GLP-1 DRUGS ARE WIDELY USED

The glucagon-like peptide 1 (GLP-1) receptor agonists are widely used to treat type 2 diabetes mellitus. The currently available drugs of this class—exenatide (Byetta), liraglutide (Victoza), albiglutide (Tanzeum), dulaglutide (Trulicity), and extended-release exenatide (Bydureon)—are popular because they lower glucose levels, pose a low risk of hypoglycemia, can induce weight loss,¹ and, in the case of extended-release exenatide and albiglutide, are given once weekly. They are currently recommended as add-on therapy to metformin. These drugs mimic the action of GLP-1, an endogenous hormone released by the intestine in response to food. They bind to receptors on beta cells, stimulating insulin production.¹

FOUR TYPES OF THYROID CANCER

There are four types of thyroid cancer: medullary (a contraindication to GLP-1 agonists), papillary, follicular, and anaplastic.

Medullary thyroid cancer is extremely rare in humans, with 976 cases diagnosed from 1992 to 2006 in the United States, compared with 36,583 cases of papillary and 4,560 cases of follicular cancer. Anaplastic cancer is also rare (556 cases).² The highest incidence rates of medullary thyroid cancer are in people of Hispanic descent (0.21 per 100,000 woman-years and 0.18 per 100,000 man-years).²

EXPERIMENTAL EVIDENCE

Pancreatic beta cells are not the only cells in the body that can express GLP-1 receptors. Notably, the parafollicular cells (also called C cells) of the thyroid, which secrete calcitonin and which are the cells involved in medullary thyroid cancer, also sometimes express these receptors if cancer develops.

GLP-1 receptor agonists are contraindicated in patients with medullary thyroid cancer or multiple endocrine neoplasia 2

In experiments in mice and rats, the incidence of thyroid C-cell tumors was higher in animals given GLP-1 analogues. Liraglutide, exenatide, taspoglutide, and lixisenatide potently activated GLP-1 receptors in thyroid C cells, increasing calcitonin gene expression and stimulating calcitonin release in a dose-dependent manner.³ Moreover, sustained activation of these receptors caused C-cell hyperplasia and resulted in medullary thyroid cancer. However medullary thyroid cancer also occurred in rodents receiving placebo.

C cells in monkeys and humans express fewer GLP-1 receptors than those in rodents; in fact, healthy human C cells do not express them at all.^3,4 In rats with C-cell hyperplasia or medullary thyroid cancer, GLP-1 receptors are present in 100% of cases (and in increased density), compared with 27% of human medullary thyroid cancers.⁴

In addition to medullary thyroid cancer, various other human tumors have been shown to express GLP-1 receptors.⁵ Based on limited data, KÖrner et al⁵ found that these receptors are also present in various other human tumors, eg:

• Pheochromocytoma (60%)
• Paraganglioma (28%)
• Meningioma (35%)
• Astrocytoma (25%)
• Glioblastoma (9%)
• Ependymoma (16%)
• Medulloblastoma (25%)
• Nephroblastoma (22%)
• Neuroblastoma (18%)
• Ovarian adenocarcinoma (16%)
• Prostate carcinoma (5%).

Madsen et al⁶ reported that liraglutide binding to the GLP-1 receptor on murine thyroid C cells led to C-cell hyperplasia. However, prolonged administration of liraglutide at very high doses did not produce C-cell proliferation in monkeys.³

Gier et al⁷ looked at GLP-1 receptor expression in normal human C cells, hyperplastic C cells, and medullary thyroid cancer cells, as well as in papillary thyroid cancer cells, which do not arise from C cells. They demonstrated concurrent calcitonin and GLP-1 receptor immunostaining, not only in those with C-cell hyperplasia (9 of 9 cases) and medullary thyroid cancer (11 of 12 cases), but also in 3 (18%) of 17 patients with papillary thyroid cancer and 5 (33%) of 15 with normal thyroid follicular cells. However, the choice of polyclonal anti­bodies and radioligands used and concerns about methodology have led investigators to interpret these results cautiously.^8–10

STUDIES OF GLP-1 AGONISTS IN HUMANS

Several prospective clinical studies showed no increase in calcitonin levels during therapy with GLP-1 receptor agonists in patients with type 2 diabetes.^3,11 Long-term use of liraglutide in high doses (up to 3 mg per day) did not lead to elevations in serum calcitonin levels.¹¹

In a retrospective Adverse Event Reporting System database review, the incidence rate of thyroid cancer in patients treated with exenatide was higher—with an odds ratio of 4.7 (30 events)—than with a panel of control drugs (3 events).¹² However, this study did not differentiate between types of thyroid cancer, and the inherent limitations of retrospective databases complicate its interpretation. Such a high odds ratio would imply a significant increase in the incidence of medullary thyroid cancer, but this does not seem to be true.

These studies are hypothesis-generating and do not prove that GLP-1 receptor agonists cause medullary thyroid cancer

Alves et al¹³ performed a meta-analysis of randomized controlled trials and long-term observational studies. None of the studies evaluating exenatide reported cases of thyroid cancer, whereas five of the studies evaluating liraglutide did. In total, nine patients treated with liraglutide were diagnosed with thyroid cancer, compared with one patient on glimepiride. The odds ratio for thyroid cancer occurrence associated with liraglutide treatment was 1.54, but that was not statistically significant (95% confidence interval 0.40–6.02, P = .53, I² = 0%).

These studies are hypothesis-generating and do not prove that GLP-1 receptor agonists cause medullary thyroid cancer. Given the extremely low incidence of medullary thyroid cancer, to prove or disprove a causal relationship would require an enormous number of patients, who would need to be followed for several years.

OFFICIAL RECOMMENDATIONS

Considerable differences in the biology of the rodent vs human thyroid GLP-1 receptor systems have led regulatory authorities to conclude that the risk for development of medullary thyroid cancer with GLP-1 therapy in humans is difficult to quantify, but low.¹⁴ Consequently, the US Food and Drug Administration recommends neither monitoring of calcitonin levels nor ultrasound imaging as a screening tool in patients taking GLP-1 agonists.¹⁴

BENEFITS OUTWEIGH RISKS

At present, the benefits of using GLP-1 receptor agonists to treat type 2 diabetes mellitus outweigh the risks, and there seems to be little reason to withhold this effective therapy except in patients who have a personal or family history of medullary thyroid cancer or MEN-2. Until the effects of GLP-1 agonists are systematically studied in follicular-cell-derived thyroid cancer, we also recommend caution when considering their use in patients with familial thyroid cancer and those with a genetic predisposition for papillary and follicular thyroid cancer—eg, patients with familial adenomatous polyposis, phosphate and tensin homolog hamartoma tumor syndrome, Carney complex type 1, Werner syndrome, or familial papillary thyroid cancer.

Methodologically superior studies and careful long-term monitoring of patients treated with GLP-1 agonists are required to clarify the risk vs benefit of these therapies.

The question is complicated, as there are different types of thyroid cancer, and a causal relationship is hard to prove.

Glucagon-like peptide 1 (GLP-1) receptor agonists can be safely used in all patients with thyroid cancers that are derived from the thyroid follicular epithelium (papillary and follicular thyroid cancer). However, they are currently contraindicated in patients with medullary thyroid cancer and in patients with multiple endocrine neoplasia 2 (MEN-2), which is not a form of thyroid cancer but is relevant to our discussion. We probably should be cautious about using them in patients with familial thyroid cancer and those with a genetic predisposition for papillary or follicular thyroid cancer.

GLP-1 DRUGS ARE WIDELY USED

The glucagon-like peptide 1 (GLP-1) receptor agonists are widely used to treat type 2 diabetes mellitus. The currently available drugs of this class—exenatide (Byetta), liraglutide (Victoza), albiglutide (Tanzeum), dulaglutide (Trulicity), and extended-release exenatide (Bydureon)—are popular because they lower glucose levels, pose a low risk of hypoglycemia, can induce weight loss,¹ and, in the case of extended-release exenatide and albiglutide, are given once weekly. They are currently recommended as add-on therapy to metformin. These drugs mimic the action of GLP-1, an endogenous hormone released by the intestine in response to food. They bind to receptors on beta cells, stimulating insulin production.¹

FOUR TYPES OF THYROID CANCER

There are four types of thyroid cancer: medullary (a contraindication to GLP-1 agonists), papillary, follicular, and anaplastic.

Medullary thyroid cancer is extremely rare in humans, with 976 cases diagnosed from 1992 to 2006 in the United States, compared with 36,583 cases of papillary and 4,560 cases of follicular cancer. Anaplastic cancer is also rare (556 cases).² The highest incidence rates of medullary thyroid cancer are in people of Hispanic descent (0.21 per 100,000 woman-years and 0.18 per 100,000 man-years).²

EXPERIMENTAL EVIDENCE

Pancreatic beta cells are not the only cells in the body that can express GLP-1 receptors. Notably, the parafollicular cells (also called C cells) of the thyroid, which secrete calcitonin and which are the cells involved in medullary thyroid cancer, also sometimes express these receptors if cancer develops.

GLP-1 receptor agonists are contraindicated in patients with medullary thyroid cancer or multiple endocrine neoplasia 2

In experiments in mice and rats, the incidence of thyroid C-cell tumors was higher in animals given GLP-1 analogues. Liraglutide, exenatide, taspoglutide, and lixisenatide potently activated GLP-1 receptors in thyroid C cells, increasing calcitonin gene expression and stimulating calcitonin release in a dose-dependent manner.³ Moreover, sustained activation of these receptors caused C-cell hyperplasia and resulted in medullary thyroid cancer. However medullary thyroid cancer also occurred in rodents receiving placebo.

C cells in monkeys and humans express fewer GLP-1 receptors than those in rodents; in fact, healthy human C cells do not express them at all.^3,4 In rats with C-cell hyperplasia or medullary thyroid cancer, GLP-1 receptors are present in 100% of cases (and in increased density), compared with 27% of human medullary thyroid cancers.⁴

In addition to medullary thyroid cancer, various other human tumors have been shown to express GLP-1 receptors.⁵ Based on limited data, KÖrner et al⁵ found that these receptors are also present in various other human tumors, eg:

• Pheochromocytoma (60%)
• Paraganglioma (28%)
• Meningioma (35%)
• Astrocytoma (25%)
• Glioblastoma (9%)
• Ependymoma (16%)
• Medulloblastoma (25%)
• Nephroblastoma (22%)
• Neuroblastoma (18%)
• Ovarian adenocarcinoma (16%)
• Prostate carcinoma (5%).

Madsen et al⁶ reported that liraglutide binding to the GLP-1 receptor on murine thyroid C cells led to C-cell hyperplasia. However, prolonged administration of liraglutide at very high doses did not produce C-cell proliferation in monkeys.³

Gier et al⁷ looked at GLP-1 receptor expression in normal human C cells, hyperplastic C cells, and medullary thyroid cancer cells, as well as in papillary thyroid cancer cells, which do not arise from C cells. They demonstrated concurrent calcitonin and GLP-1 receptor immunostaining, not only in those with C-cell hyperplasia (9 of 9 cases) and medullary thyroid cancer (11 of 12 cases), but also in 3 (18%) of 17 patients with papillary thyroid cancer and 5 (33%) of 15 with normal thyroid follicular cells. However, the choice of polyclonal anti­bodies and radioligands used and concerns about methodology have led investigators to interpret these results cautiously.^8–10

STUDIES OF GLP-1 AGONISTS IN HUMANS

Several prospective clinical studies showed no increase in calcitonin levels during therapy with GLP-1 receptor agonists in patients with type 2 diabetes.^3,11 Long-term use of liraglutide in high doses (up to 3 mg per day) did not lead to elevations in serum calcitonin levels.¹¹

In a retrospective Adverse Event Reporting System database review, the incidence rate of thyroid cancer in patients treated with exenatide was higher—with an odds ratio of 4.7 (30 events)—than with a panel of control drugs (3 events).¹² However, this study did not differentiate between types of thyroid cancer, and the inherent limitations of retrospective databases complicate its interpretation. Such a high odds ratio would imply a significant increase in the incidence of medullary thyroid cancer, but this does not seem to be true.

These studies are hypothesis-generating and do not prove that GLP-1 receptor agonists cause medullary thyroid cancer

Alves et al¹³ performed a meta-analysis of randomized controlled trials and long-term observational studies. None of the studies evaluating exenatide reported cases of thyroid cancer, whereas five of the studies evaluating liraglutide did. In total, nine patients treated with liraglutide were diagnosed with thyroid cancer, compared with one patient on glimepiride. The odds ratio for thyroid cancer occurrence associated with liraglutide treatment was 1.54, but that was not statistically significant (95% confidence interval 0.40–6.02, P = .53, I² = 0%).

These studies are hypothesis-generating and do not prove that GLP-1 receptor agonists cause medullary thyroid cancer. Given the extremely low incidence of medullary thyroid cancer, to prove or disprove a causal relationship would require an enormous number of patients, who would need to be followed for several years.

OFFICIAL RECOMMENDATIONS

Considerable differences in the biology of the rodent vs human thyroid GLP-1 receptor systems have led regulatory authorities to conclude that the risk for development of medullary thyroid cancer with GLP-1 therapy in humans is difficult to quantify, but low.¹⁴ Consequently, the US Food and Drug Administration recommends neither monitoring of calcitonin levels nor ultrasound imaging as a screening tool in patients taking GLP-1 agonists.¹⁴

BENEFITS OUTWEIGH RISKS

At present, the benefits of using GLP-1 receptor agonists to treat type 2 diabetes mellitus outweigh the risks, and there seems to be little reason to withhold this effective therapy except in patients who have a personal or family history of medullary thyroid cancer or MEN-2. Until the effects of GLP-1 agonists are systematically studied in follicular-cell-derived thyroid cancer, we also recommend caution when considering their use in patients with familial thyroid cancer and those with a genetic predisposition for papillary and follicular thyroid cancer—eg, patients with familial adenomatous polyposis, phosphate and tensin homolog hamartoma tumor syndrome, Carney complex type 1, Werner syndrome, or familial papillary thyroid cancer.

Methodologically superior studies and careful long-term monitoring of patients treated with GLP-1 agonists are required to clarify the risk vs benefit of these therapies.

The question is complicated, as there are different types of thyroid cancer, and a causal relationship is hard to prove.

Glucagon-like peptide 1 (GLP-1) receptor agonists can be safely used in all patients with thyroid cancers that are derived from the thyroid follicular epithelium (papillary and follicular thyroid cancer). However, they are currently contraindicated in patients with medullary thyroid cancer and in patients with multiple endocrine neoplasia 2 (MEN-2), which is not a form of thyroid cancer but is relevant to our discussion. We probably should be cautious about using them in patients with familial thyroid cancer and those with a genetic predisposition for papillary or follicular thyroid cancer.

GLP-1 DRUGS ARE WIDELY USED

The glucagon-like peptide 1 (GLP-1) receptor agonists are widely used to treat type 2 diabetes mellitus. The currently available drugs of this class—exenatide (Byetta), liraglutide (Victoza), albiglutide (Tanzeum), dulaglutide (Trulicity), and extended-release exenatide (Bydureon)—are popular because they lower glucose levels, pose a low risk of hypoglycemia, can induce weight loss,¹ and, in the case of extended-release exenatide and albiglutide, are given once weekly. They are currently recommended as add-on therapy to metformin. These drugs mimic the action of GLP-1, an endogenous hormone released by the intestine in response to food. They bind to receptors on beta cells, stimulating insulin production.¹

FOUR TYPES OF THYROID CANCER

There are four types of thyroid cancer: medullary (a contraindication to GLP-1 agonists), papillary, follicular, and anaplastic.

Medullary thyroid cancer is extremely rare in humans, with 976 cases diagnosed from 1992 to 2006 in the United States, compared with 36,583 cases of papillary and 4,560 cases of follicular cancer. Anaplastic cancer is also rare (556 cases).² The highest incidence rates of medullary thyroid cancer are in people of Hispanic descent (0.21 per 100,000 woman-years and 0.18 per 100,000 man-years).²

EXPERIMENTAL EVIDENCE

Pancreatic beta cells are not the only cells in the body that can express GLP-1 receptors. Notably, the parafollicular cells (also called C cells) of the thyroid, which secrete calcitonin and which are the cells involved in medullary thyroid cancer, also sometimes express these receptors if cancer develops.

GLP-1 receptor agonists are contraindicated in patients with medullary thyroid cancer or multiple endocrine neoplasia 2

In experiments in mice and rats, the incidence of thyroid C-cell tumors was higher in animals given GLP-1 analogues. Liraglutide, exenatide, taspoglutide, and lixisenatide potently activated GLP-1 receptors in thyroid C cells, increasing calcitonin gene expression and stimulating calcitonin release in a dose-dependent manner.³ Moreover, sustained activation of these receptors caused C-cell hyperplasia and resulted in medullary thyroid cancer. However medullary thyroid cancer also occurred in rodents receiving placebo.

C cells in monkeys and humans express fewer GLP-1 receptors than those in rodents; in fact, healthy human C cells do not express them at all.^3,4 In rats with C-cell hyperplasia or medullary thyroid cancer, GLP-1 receptors are present in 100% of cases (and in increased density), compared with 27% of human medullary thyroid cancers.⁴

In addition to medullary thyroid cancer, various other human tumors have been shown to express GLP-1 receptors.⁵ Based on limited data, KÖrner et al⁵ found that these receptors are also present in various other human tumors, eg:

• Pheochromocytoma (60%)
• Paraganglioma (28%)
• Meningioma (35%)
• Astrocytoma (25%)
• Glioblastoma (9%)
• Ependymoma (16%)
• Medulloblastoma (25%)
• Nephroblastoma (22%)
• Neuroblastoma (18%)
• Ovarian adenocarcinoma (16%)
• Prostate carcinoma (5%).

Madsen et al⁶ reported that liraglutide binding to the GLP-1 receptor on murine thyroid C cells led to C-cell hyperplasia. However, prolonged administration of liraglutide at very high doses did not produce C-cell proliferation in monkeys.³

Gier et al⁷ looked at GLP-1 receptor expression in normal human C cells, hyperplastic C cells, and medullary thyroid cancer cells, as well as in papillary thyroid cancer cells, which do not arise from C cells. They demonstrated concurrent calcitonin and GLP-1 receptor immunostaining, not only in those with C-cell hyperplasia (9 of 9 cases) and medullary thyroid cancer (11 of 12 cases), but also in 3 (18%) of 17 patients with papillary thyroid cancer and 5 (33%) of 15 with normal thyroid follicular cells. However, the choice of polyclonal anti­bodies and radioligands used and concerns about methodology have led investigators to interpret these results cautiously.^8–10

STUDIES OF GLP-1 AGONISTS IN HUMANS

Several prospective clinical studies showed no increase in calcitonin levels during therapy with GLP-1 receptor agonists in patients with type 2 diabetes.^3,11 Long-term use of liraglutide in high doses (up to 3 mg per day) did not lead to elevations in serum calcitonin levels.¹¹

In a retrospective Adverse Event Reporting System database review, the incidence rate of thyroid cancer in patients treated with exenatide was higher—with an odds ratio of 4.7 (30 events)—than with a panel of control drugs (3 events).¹² However, this study did not differentiate between types of thyroid cancer, and the inherent limitations of retrospective databases complicate its interpretation. Such a high odds ratio would imply a significant increase in the incidence of medullary thyroid cancer, but this does not seem to be true.

These studies are hypothesis-generating and do not prove that GLP-1 receptor agonists cause medullary thyroid cancer

Alves et al¹³ performed a meta-analysis of randomized controlled trials and long-term observational studies. None of the studies evaluating exenatide reported cases of thyroid cancer, whereas five of the studies evaluating liraglutide did. In total, nine patients treated with liraglutide were diagnosed with thyroid cancer, compared with one patient on glimepiride. The odds ratio for thyroid cancer occurrence associated with liraglutide treatment was 1.54, but that was not statistically significant (95% confidence interval 0.40–6.02, P = .53, I² = 0%).

These studies are hypothesis-generating and do not prove that GLP-1 receptor agonists cause medullary thyroid cancer. Given the extremely low incidence of medullary thyroid cancer, to prove or disprove a causal relationship would require an enormous number of patients, who would need to be followed for several years.

OFFICIAL RECOMMENDATIONS

Considerable differences in the biology of the rodent vs human thyroid GLP-1 receptor systems have led regulatory authorities to conclude that the risk for development of medullary thyroid cancer with GLP-1 therapy in humans is difficult to quantify, but low.¹⁴ Consequently, the US Food and Drug Administration recommends neither monitoring of calcitonin levels nor ultrasound imaging as a screening tool in patients taking GLP-1 agonists.¹⁴

BENEFITS OUTWEIGH RISKS

At present, the benefits of using GLP-1 receptor agonists to treat type 2 diabetes mellitus outweigh the risks, and there seems to be little reason to withhold this effective therapy except in patients who have a personal or family history of medullary thyroid cancer or MEN-2. Until the effects of GLP-1 agonists are systematically studied in follicular-cell-derived thyroid cancer, we also recommend caution when considering their use in patients with familial thyroid cancer and those with a genetic predisposition for papillary and follicular thyroid cancer—eg, patients with familial adenomatous polyposis, phosphate and tensin homolog hamartoma tumor syndrome, Carney complex type 1, Werner syndrome, or familial papillary thyroid cancer.

Methodologically superior studies and careful long-term monitoring of patients treated with GLP-1 agonists are required to clarify the risk vs benefit of these therapies.

Dr. Vinay Prasad, in his commentary in this issue of CCJM, argues that, to best inform clinical decision-making, interventional and observational studies should measure multiple outcomes whenever possible, including all-cause mortality. He cites examples, such as calcium supplementation for bone health and aspirin for primary cardiovascular prevention, where favorable effects on focused clinical outcomes were not paralleled by favorable effects on overall morbidity. The study was a success, but the patient died.

Reading his commentary got me thinking about the many ways that the results of interventional studies and population data increasingly affect how we practice and teach medicine. Measuring an outcome in the population of interest (study volunteers, patient panels, trainees) is all the rage and is almost always more useful than only tracking interim metrics. True outcome measures are clearly useful when comparing groups and, hopefully, help assess the core reason the study was done.

Yet at the same time that group outcome measures are emphasized for many useful reasons, personalized medicine has a growing appeal: don’t let the individual get lost in the group, and pay attention to the outliers as well as the mean.

Positive results from a well-designed, prospective, controlled trial provide confidence that a drug or procedure has efficacy compared with placebo or a known effective comparator. But before recommending a therapy to a specific patient, we need to carefully evaluate whether the likely benefit in an individual patient is worth the clinical and financial cost. The information to make that evaluation doesn’t come easily from simply looking at a P value in a clinical study. Not only do we need to look at the size of the effect of an efficacious treatment and ask whether our specific patient is comparable to the study participants, but, as Dr. Prasad emphasizes, we must also look closely at the actual outcome measures of the study to see if they match our patient’s short- and long-term goals.

How significant is a statistically significant finding if the measured outcome is not the one the patient cares the most about? For example, a recent extremely well-done study that led to US Food and Drug Administration (FDA) approval of branded colchicine for acute gout used the efficacy measure of 50% reduction in pain at 24 hours.¹ But what our patients really want is attack resolution (which usually requires medication in addition to what was used in the trial, increasing the risk of side effects). Proof of concept (a rational dose of colchicine has benefit) was very well demonstrated; that this dosing regimen should be standard of care, I think, remains unsupported.

We must also try to assess the long-term relevance (clinical outcome) of results based initially on surrogate markers. For example, not all drugs that increase bone density reduce the long-term fracture rate, and not all drugs that lower the blood glucose level reduce cardiovascular complications of diabetes. This has seemingly become a linchpin concept in the FDA’s approach to drug approval, with attendant increases in the cost and time to get drug approval.

We teach that the tools of evidence-based medicine should be routinely and appropriately employed in clinical practice. The premises of evidence-based medicine are deeply rooted in clinical studies. But our patients’ genetic background, individual preferences, and specific concerns regarding management of their disease and the side effects of medications should also be seriously discussed. We can then jointly define individualized outcome goals in the examination room. These may not exactly match the outcomes chosen by clinical investigators in designing their studies, and the plan may not match the policy of an insurance plan or a “pay-for-performance” metric. I hope that the opportunity for reconciliation of these differences will always be available.

The increasing demand for physicians and health systems to meet specific outcome and performance measures brings up the same concerns that arise when applying the results of a clinical study to a specific patient: will striving to match a group-based outcome be beneficial to the patient in front of us? My major goal­ as a physician is to care for the individual patient. My patient may not exactly match the population studied to prove that an intervention worked (or didn’t), so the data from that study may not fully apply. In the same way, care for all of our patients with the same diagnosis may not fit into the same performance rubric. The same attention that goes into determining appropriately relevant outcome measures for clinical studies needs to go into dictating performance outcome metrics by which physicians and health care systems are measured. They should be patient-centered and, to maintain face validity,  somewhat flexible. On any given night, what keeps me awake is not population-based outcomes, but concern over the outcome of the individual patients I saw in clinic that day.

Dr. Vinay Prasad, in his commentary in this issue of CCJM, argues that, to best inform clinical decision-making, interventional and observational studies should measure multiple outcomes whenever possible, including all-cause mortality. He cites examples, such as calcium supplementation for bone health and aspirin for primary cardiovascular prevention, where favorable effects on focused clinical outcomes were not paralleled by favorable effects on overall morbidity. The study was a success, but the patient died.

Reading his commentary got me thinking about the many ways that the results of interventional studies and population data increasingly affect how we practice and teach medicine. Measuring an outcome in the population of interest (study volunteers, patient panels, trainees) is all the rage and is almost always more useful than only tracking interim metrics. True outcome measures are clearly useful when comparing groups and, hopefully, help assess the core reason the study was done.

Yet at the same time that group outcome measures are emphasized for many useful reasons, personalized medicine has a growing appeal: don’t let the individual get lost in the group, and pay attention to the outliers as well as the mean.

Positive results from a well-designed, prospective, controlled trial provide confidence that a drug or procedure has efficacy compared with placebo or a known effective comparator. But before recommending a therapy to a specific patient, we need to carefully evaluate whether the likely benefit in an individual patient is worth the clinical and financial cost. The information to make that evaluation doesn’t come easily from simply looking at a P value in a clinical study. Not only do we need to look at the size of the effect of an efficacious treatment and ask whether our specific patient is comparable to the study participants, but, as Dr. Prasad emphasizes, we must also look closely at the actual outcome measures of the study to see if they match our patient’s short- and long-term goals.

How significant is a statistically significant finding if the measured outcome is not the one the patient cares the most about? For example, a recent extremely well-done study that led to US Food and Drug Administration (FDA) approval of branded colchicine for acute gout used the efficacy measure of 50% reduction in pain at 24 hours.¹ But what our patients really want is attack resolution (which usually requires medication in addition to what was used in the trial, increasing the risk of side effects). Proof of concept (a rational dose of colchicine has benefit) was very well demonstrated; that this dosing regimen should be standard of care, I think, remains unsupported.

We must also try to assess the long-term relevance (clinical outcome) of results based initially on surrogate markers. For example, not all drugs that increase bone density reduce the long-term fracture rate, and not all drugs that lower the blood glucose level reduce cardiovascular complications of diabetes. This has seemingly become a linchpin concept in the FDA’s approach to drug approval, with attendant increases in the cost and time to get drug approval.

We teach that the tools of evidence-based medicine should be routinely and appropriately employed in clinical practice. The premises of evidence-based medicine are deeply rooted in clinical studies. But our patients’ genetic background, individual preferences, and specific concerns regarding management of their disease and the side effects of medications should also be seriously discussed. We can then jointly define individualized outcome goals in the examination room. These may not exactly match the outcomes chosen by clinical investigators in designing their studies, and the plan may not match the policy of an insurance plan or a “pay-for-performance” metric. I hope that the opportunity for reconciliation of these differences will always be available.

The increasing demand for physicians and health systems to meet specific outcome and performance measures brings up the same concerns that arise when applying the results of a clinical study to a specific patient: will striving to match a group-based outcome be beneficial to the patient in front of us? My major goal­ as a physician is to care for the individual patient. My patient may not exactly match the population studied to prove that an intervention worked (or didn’t), so the data from that study may not fully apply. In the same way, care for all of our patients with the same diagnosis may not fit into the same performance rubric. The same attention that goes into determining appropriately relevant outcome measures for clinical studies needs to go into dictating performance outcome metrics by which physicians and health care systems are measured. They should be patient-centered and, to maintain face validity,  somewhat flexible. On any given night, what keeps me awake is not population-based outcomes, but concern over the outcome of the individual patients I saw in clinic that day.

Dr. Vinay Prasad, in his commentary in this issue of CCJM, argues that, to best inform clinical decision-making, interventional and observational studies should measure multiple outcomes whenever possible, including all-cause mortality. He cites examples, such as calcium supplementation for bone health and aspirin for primary cardiovascular prevention, where favorable effects on focused clinical outcomes were not paralleled by favorable effects on overall morbidity. The study was a success, but the patient died.

Reading his commentary got me thinking about the many ways that the results of interventional studies and population data increasingly affect how we practice and teach medicine. Measuring an outcome in the population of interest (study volunteers, patient panels, trainees) is all the rage and is almost always more useful than only tracking interim metrics. True outcome measures are clearly useful when comparing groups and, hopefully, help assess the core reason the study was done.

Yet at the same time that group outcome measures are emphasized for many useful reasons, personalized medicine has a growing appeal: don’t let the individual get lost in the group, and pay attention to the outliers as well as the mean.

Positive results from a well-designed, prospective, controlled trial provide confidence that a drug or procedure has efficacy compared with placebo or a known effective comparator. But before recommending a therapy to a specific patient, we need to carefully evaluate whether the likely benefit in an individual patient is worth the clinical and financial cost. The information to make that evaluation doesn’t come easily from simply looking at a P value in a clinical study. Not only do we need to look at the size of the effect of an efficacious treatment and ask whether our specific patient is comparable to the study participants, but, as Dr. Prasad emphasizes, we must also look closely at the actual outcome measures of the study to see if they match our patient’s short- and long-term goals.

How significant is a statistically significant finding if the measured outcome is not the one the patient cares the most about? For example, a recent extremely well-done study that led to US Food and Drug Administration (FDA) approval of branded colchicine for acute gout used the efficacy measure of 50% reduction in pain at 24 hours.¹ But what our patients really want is attack resolution (which usually requires medication in addition to what was used in the trial, increasing the risk of side effects). Proof of concept (a rational dose of colchicine has benefit) was very well demonstrated; that this dosing regimen should be standard of care, I think, remains unsupported.

We must also try to assess the long-term relevance (clinical outcome) of results based initially on surrogate markers. For example, not all drugs that increase bone density reduce the long-term fracture rate, and not all drugs that lower the blood glucose level reduce cardiovascular complications of diabetes. This has seemingly become a linchpin concept in the FDA’s approach to drug approval, with attendant increases in the cost and time to get drug approval.

We teach that the tools of evidence-based medicine should be routinely and appropriately employed in clinical practice. The premises of evidence-based medicine are deeply rooted in clinical studies. But our patients’ genetic background, individual preferences, and specific concerns regarding management of their disease and the side effects of medications should also be seriously discussed. We can then jointly define individualized outcome goals in the examination room. These may not exactly match the outcomes chosen by clinical investigators in designing their studies, and the plan may not match the policy of an insurance plan or a “pay-for-performance” metric. I hope that the opportunity for reconciliation of these differences will always be available.

The increasing demand for physicians and health systems to meet specific outcome and performance measures brings up the same concerns that arise when applying the results of a clinical study to a specific patient: will striving to match a group-based outcome be beneficial to the patient in front of us? My major goal­ as a physician is to care for the individual patient. My patient may not exactly match the population studied to prove that an intervention worked (or didn’t), so the data from that study may not fully apply. In the same way, care for all of our patients with the same diagnosis may not fit into the same performance rubric. The same attention that goes into determining appropriately relevant outcome measures for clinical studies needs to go into dictating performance outcome metrics by which physicians and health care systems are measured. They should be patient-centered and, to maintain face validity,  somewhat flexible. On any given night, what keeps me awake is not population-based outcomes, but concern over the outcome of the individual patients I saw in clinic that day.

Before we dispense advice about staying healthy, we should know the effect of whatever we are recommending—be it diet, supplements, chemoprevention, or screening—on all meaningful outcomes, including overall mortality, quality of life, harms, inconveniences, and cost. Even though looking at all these outcomes may seem self-evidently wise, many research studies do not do it, and health care providers do not do it enough.

How would looking at all the outcomes change our opinion of health practices?

COMPARING GRAPEFRUIT AND PEACHES

A 2013 study linked eating berries with lower rates of myocardial infarction in women,¹ another found that people who ate some fruits (blackberries and grapefruit) but not others (peaches and oranges) had a lower rate of incident diabetes,² and a third linked a healthy diet to a lower incidence of pancreatic cancer.³ However, none of these studies examined all-cause mortality rates. A fourth study found that drinking green tea was associated with a lower risk of death from pneumonia in Japanese women, but not men.⁴

For the sake of argument, let us put aside concern about whether observational studies can reliably inform recommendations for clinical practice⁵ and concede that they can. The point is that studies such as those above look at some but not all meaningful outcomes, undermining the utility of their findings. If healthy people conclude that they should eat grapefruit instead of peaches, they may miss out on benefits of peaches that the study did not examine. Eating a healthy diet remains prudent, but the study linking it to a lower rate of pancreatic cancer is no tipping point, as pancreatic cancer is just one way to die. And advocating green tea to Japanese women but not men, to avoid pneumonia, would be a questionable public health strategy. Pneumonia is the sixth leading cause of death and accounts for 3.9% of disability-adjusted life-years lost,⁶ but what about the first five causes, which account for 96.1%?

We should know the effect of what we recommend on all meaningful outcomes

These and many other studies of dietary habits of people who are well fail to consider end points that healthy people care about. Suppose that drinking more coffee would prevent all deaths from pancreatic cancer but would modestly increase cardiovascular deaths—say, by 5%. On a population level, recommending more coffee would be wrong, because it would result in far more deaths. Suppose that drinking tea decreased deaths from pneumonia—we should still not advise patients to drink tea, as we do not know whether tea’s net effect is beneficial.

Some may argue that these epidemiologic studies are merely hypothesis-generating, but my colleagues and I analyzed all the nonrandomized studies published in several leading medical journals in 1 year and found that 59% made specific practice recommendations.⁵ Other studies may be misused in this fashion, even though the authors refrained from doing so.

CALCIUM PROTECTS BONES, BUT WHAT ABOUT THE HEART?

Narrow end points are not limited to dietary studies. Calcium supplementation with or without vitamin D has been vigorously promoted for decades⁷ to treat and prevent osteoporosis in pre- and postmenopausal women, and data confirm that these agents decrease the risk of fracture.⁸

But bone health is only one end point important to women, and long-term supplementation of a mineral or vitamin with the goal of strengthening bones may have unforeseen adverse effects.

In 2010, calcium supplementation without vitamin D was linked to higher rates of myocardial infarction (with some suggestion of increased rates of all-cause death) in pooled analyses of 15 trials.⁹ In 2011, a higher risk of cardiovascular events (stroke and myocardial infarction) was found in recipients of calcium with vitamin D in a reanalysis of the Women’s Health Initiative Calcium/Vitamin D Supplementation Study,¹⁰ adjusting for the widespread use of these supplements at baseline, and this was corroborated by a meta-analysis of eight other studies.¹⁰ A more recent study confirmed that supplemental calcium increases cardiovascular risk in men.¹¹

Although the increase in cardiovascular risk seems to be modest, millions of people take calcium supplements; thus, many people may be harmed. Our exuberance for bone health suggests that, at times, a single outcome can distract.

DOES SCREENING IMPROVE SURVIVAL?

On the whole, the evidence for screening continues to focus only on certain outcomes. With the exception of the National Lung Cancer Screening Trial,¹² to date, no cancer screening trial has shown an improvement in the overall survival rate.

In fact, a 2013 Cochrane review¹³ found that mammographic screening failed to lower the rate of death from all cancers, including breast cancer, after 10 years (relative risk [RR] 1.02, 95% confidence interval [CI] 0.95–1.10) and the rate of death from all causes after 13 years (RR 0.99, 95% CI 0.95–1.03). Although screening lowered the breast cancer mortality rate, the authors argued that we should not look at only some outcomes and concluded that “breast cancer mortality was an unreliable outcome” that was biased in favor of screening, mainly because of “differential misclassification of cause of death.”¹³

Significance-chasing and selective reporting are common in observational studies

Black et al¹⁴ found that of 12 major cancer screening trials examining both disease-specific mortality and all-cause mortality, 5 had differences in mortality rates that went in opposite directions (eg, the rate of disease-specific mortality improved while overall survival was harmed, or vice-versa), suggesting paradoxical effects. In another 2 studies, differences in all-cause mortality exceeded gains in disease-specific mortality. Thus, in 7 (58%) of the 12 trials, inconsistencies existed between rates of disease-specific mortality and all-cause mortality, prompting doubt about the conclusions of the studies.¹⁴

For some cancers, data suggest that screening increases deaths from other causes, and these extra deaths are not included in the data on disease-specific mortality. For instance, men who are screened for prostate cancer have higher rates of death from cardiovascular disease and suicide,¹⁵ which might negate the tenuous benefits of screening in terms of deaths from prostate cancer.

Studies of screening for diseases other than cancer have also focused on only some outcomes. For example, the United States Preventive Services Task Force supports screening for abdominal aortic aneurysm once with ultrasonography in men ages 65 to 75 who have ever smoked,¹⁶ but the recommendation is based on improvements in the death rate from abdominal aortic aneurysm, not in all-cause mortality.¹⁷ This, along with a declining incidence of this disease and changes in how it is treated (with endovascular repair on the rise and open surgical repair declining), has led some to question if we should continue to screen for it.¹⁸

CHEMOPREVENTION: NO FREE LUNCH

Finasteride

In 2013, an analysis¹⁹ that looked at all of the outcomes laid to rest 10 years of debate over the Prostate Cancer Prevention Trial, which had randomized more than 18,000 healthy men over age 55 with no signs or symptoms of prostate cancer to receive finasteride or placebo, with the end point of prostate cancer incidence. The initial results, published in 2003,²⁰ had found that the drug decreased the rate of incident prostate cancer but paradoxically increased the rate of high-grade (Gleason score ≥ 7) tumors. Whether these results were real or an artifact of ascertainment was debated, as was whether the adverse effects—decreases in sexual potency, libido, and ejaculation—were worth the 25% reduction in prostate cancer incidence.

Much of the debate ended with the 2013 publication, which showed that regardless of finasteride’s effect on prostate cancer, overall mortality curves at 18-year follow-up were absolutely indistinguishable.¹⁹ Healthy patients hoping that finasteride will help them live longer or better can be safely told that it does neither.

Statins as primary prevention

As for statin therapy as primary prevention, the best meta-analysis to date (which meticulously excluded secondary-prevention patients after analyzing individual patient-level data) found no improvement in overall mortality despite more than 240,000 patient-years of follow-up.²¹ Because of this, and because the harms of statin therapy are being increasingly (but still poorly) documented, widespread use of statins has been questioned.²²

Proponents point to the ability of statins to reduce end points such as revascularization, stroke, and nonfatal myocardial infarction.²³ But the main question facing healthy users is whether improvement in these end points translates to longer life or better quality of life. These questions remain unresolved.

Aspirin as primary prevention

Another example of the importance of considering all the outcomes is the issue of aspirin as primary prevention.

Enthusiasm for aspirin as primary prevention has been recently reinvigorated, with data showing it can prevent colorectal cancers that overexpress cyclooxygenase-2.²⁴ But a meta-analysis of nine randomized trials of aspirin²⁵ with more than 1,000 participants found that, although aspirin decreases the rate of nonfatal myocardial infarction (odds ratio [OR] 0.80, 95% CI 0.67–0.96), it does not significantly reduce cancer mortality (OR 0.93, 95% CI 0.84–1.03), and it increases the risk of nontrivial bleeding (OR 1.31; 95% CI 1.14–1.50). Its effects on overall mortality were not statistically significant but were possibly favorable (OR 0.94, 95% CI 0.88–1.00), so this requires further study.

After broad consideration of the risks and benefits of aspirin, the US Food and Drug Administration has issued a statement that aspirin is not recommended as primary prevention.²⁶

WHY STUDIES LOOK ONLY AT SOME OUTCOMES

There are many reasons why researchers favor examining some outcomes over others, but there is no clear justification for ignoring overall mortality. Overall mortality should routinely be examined in large population studies of diet and supplements and in trials of medications²⁷ and cancer screening.

Healthy people do not care about some outcomes; they care about all outcomes

With regard to large observational studies, it is hard to understand why some would not include survival analyses, unless the results would fail to support the study’s hypothesis. In fact, some studies do report overall survival results,²⁸ but others do not. The omission of overall survival in large data-set research should raise concerns of multiple hypothesis testing and selective reporting. Eating peaches as opposed to grapefruit may not be associated with differences in rates of all-cause mortality, myocardial infarction, pneumonia, or lung cancer, but if you look at 20 different variables, chances are that one will have a P value less than .05, and an investigator might be tempted to report it as statistically significant and even meaningful.

Empirical studies support this claim. One group found that for 80% of ingredients randomly selected from a cookbook, there existed Medline-indexed articles assessing cancer risk, with 65% of studies finding nominally significant differences in the risk of some type of cancer.²⁹

An excess of significant findings such as this argues that significance-chasing and selective reporting are common in this field and has led to calls for methodologic improvements, including routine falsification testing³⁰ and up-front registration of observational studies.³¹

WHY ALL OUTCOMES MATTER

Healthy people do not care about some outcomes; they care about all outcomes. Some patients may truly have unique priorities (quality of life vs quantity of life), but others may overestimate their risk of death from some causes and underestimate their risk from others, and practitioners have the obligation to counsel them appropriately.

For instance, a patient who watches a brother pass away from pancreatic adenocarcinoma may wish to do everything possible to avoid that illness. But often, as in this case, fear may surpass risk. The patient’s risk of pancreatic cancer is no different than that in the general population: the best data show³² an odds ratio of 1.8, with a confidence interval spanning 1. As such, pancreatic cancer is still not among his five most likely causes of death.

Some patients may care about their bone mineral density or cholesterol level. But again, physicians have an obligation to direct patients’ attention to all of the outcomes that should be of interest to them.

OBJECTIONS TO INCLUDING ALL OUTCOMES

There are important objections to the argument I am presenting here.

First, including all outcomes is expensive. For studies involving retrospective analysis of existing data, looking at overall mortality would not incur additional costs, only an additional analysis. But for prospective trials to have statistical power to detect a difference in overall mortality, larger sample sizes or longer follow-up might be needed—either of which would add to the cost.

In chemoprevention trials, the rate of incident cancer has been called the gold standard end point.³³ To design a thrifty chemoprevention study, investigators can either target a broad population and aim for incident malignancy, or target a restricted, high-risk population and aim for overall mortality. The latter is preferable because although it can inform the decisions of only some people, the former cannot inform any people, as was seen with difficulties in interpreting the Prostate Cancer Prevention Trial and trials showing reduced breast cancer incidence from tamoxifen, raloxifene, and exemestane.

In large cancer screening trials, the cost of powering the trial for overall mortality would be greater, and though a carefully selected, high-risk population can be enrolled, historically this has not been popular. In cancer screening, it is a mistake to contrast the costs of trials powered for overall mortality with those of lesser studies examining disease-specific death. Instead, we must consider the larger societal costs incurred by cancer screening that does not truly improve quantity or quality of life.³⁴

The recent reversal of recommendations for prostate-specific antigen testing by the United States Preventive Services Task Force³⁵ suggests that erroneous recommendations, practiced for decades, can cost society hundreds of billions of dollars but fail to improve meaningful outcomes.

The history of medicine is replete with examples of widely recommended practices and interventions that not only failed to improve the outcomes they claimed to improve, but at times increased the rate of all-cause mortality or carried harms that far outweighed benefits.^36,37 The costs of conducting research to fully understand all outcomes are only a fraction of the costs of a practice that is widely disseminated.³⁸

The history of medicine is replete with practices that harmed more than helped

A second objection to my analysis is that there is more to life than survival, and outcomes besides overall mortality are important. This is a self-evident truth. That an intervention improves the rate of overall mortality is neither necessary nor sufficient for its recommendation. Practices may improve survival but worsen quality of life to such a degree that they should not be recommended. Conversely, practices that improve quality of life should be endorsed even if they fail to prolong life.

Thus, overall mortality and quality of life must be considered together, but the end points that are favored currently (disease-specific death, incident cancer, diabetes mellitus, myocardial infarction) do not do a good job of capturing either. Disease-specific death is not meaningful to any patient if deaths from other causes are increased so that overall mortality is unchanged. Furthermore, preventing a diagnosis of cancer or diabetes may offer some psychological comfort, but well-crafted quality-of-life instruments are best suited to capture just how great that benefit is and whether it justifies the cost of such interventions, particularly if the rate of survival is unchanged.

Preventing stroke or myocardial infarction is important, but we should be cautious of interpreting data when decreasing the rate of these morbid events does not lead to commensurate improvements in survival. Alternatively, if morbid events are truly avoided but survival analyses are underpowered, quality-of-life measurements should demonstrate the benefit. But the end points currently used capture neither survival nor quality of life in a meaningful way.

WHEN ADVISING HEALTHY PEOPLE

Looking at all outcomes is important when caring for patients who are sick, but even more so for patients who are well. We need to know an intervention has a net benefit before we recommend it to a healthy person. Overall mortality should be reported routinely in this population, particularly in settings where the cost to do so is trivial (ie, in observational studies). Designers of thrifty trials should try to include people at high risk and power the trial for definite end points, rather than being broadly inclusive and reaching disputed conclusions. Research and decision-making should look at all outcomes. Healthy people deserve no less.

Before we dispense advice about staying healthy, we should know the effect of whatever we are recommending—be it diet, supplements, chemoprevention, or screening—on all meaningful outcomes, including overall mortality, quality of life, harms, inconveniences, and cost. Even though looking at all these outcomes may seem self-evidently wise, many research studies do not do it, and health care providers do not do it enough.

How would looking at all the outcomes change our opinion of health practices?

COMPARING GRAPEFRUIT AND PEACHES

A 2013 study linked eating berries with lower rates of myocardial infarction in women,¹ another found that people who ate some fruits (blackberries and grapefruit) but not others (peaches and oranges) had a lower rate of incident diabetes,² and a third linked a healthy diet to a lower incidence of pancreatic cancer.³ However, none of these studies examined all-cause mortality rates. A fourth study found that drinking green tea was associated with a lower risk of death from pneumonia in Japanese women, but not men.⁴

For the sake of argument, let us put aside concern about whether observational studies can reliably inform recommendations for clinical practice⁵ and concede that they can. The point is that studies such as those above look at some but not all meaningful outcomes, undermining the utility of their findings. If healthy people conclude that they should eat grapefruit instead of peaches, they may miss out on benefits of peaches that the study did not examine. Eating a healthy diet remains prudent, but the study linking it to a lower rate of pancreatic cancer is no tipping point, as pancreatic cancer is just one way to die. And advocating green tea to Japanese women but not men, to avoid pneumonia, would be a questionable public health strategy. Pneumonia is the sixth leading cause of death and accounts for 3.9% of disability-adjusted life-years lost,⁶ but what about the first five causes, which account for 96.1%?

We should know the effect of what we recommend on all meaningful outcomes

These and many other studies of dietary habits of people who are well fail to consider end points that healthy people care about. Suppose that drinking more coffee would prevent all deaths from pancreatic cancer but would modestly increase cardiovascular deaths—say, by 5%. On a population level, recommending more coffee would be wrong, because it would result in far more deaths. Suppose that drinking tea decreased deaths from pneumonia—we should still not advise patients to drink tea, as we do not know whether tea’s net effect is beneficial.

Some may argue that these epidemiologic studies are merely hypothesis-generating, but my colleagues and I analyzed all the nonrandomized studies published in several leading medical journals in 1 year and found that 59% made specific practice recommendations.⁵ Other studies may be misused in this fashion, even though the authors refrained from doing so.

CALCIUM PROTECTS BONES, BUT WHAT ABOUT THE HEART?

Narrow end points are not limited to dietary studies. Calcium supplementation with or without vitamin D has been vigorously promoted for decades⁷ to treat and prevent osteoporosis in pre- and postmenopausal women, and data confirm that these agents decrease the risk of fracture.⁸

But bone health is only one end point important to women, and long-term supplementation of a mineral or vitamin with the goal of strengthening bones may have unforeseen adverse effects.

In 2010, calcium supplementation without vitamin D was linked to higher rates of myocardial infarction (with some suggestion of increased rates of all-cause death) in pooled analyses of 15 trials.⁹ In 2011, a higher risk of cardiovascular events (stroke and myocardial infarction) was found in recipients of calcium with vitamin D in a reanalysis of the Women’s Health Initiative Calcium/Vitamin D Supplementation Study,¹⁰ adjusting for the widespread use of these supplements at baseline, and this was corroborated by a meta-analysis of eight other studies.¹⁰ A more recent study confirmed that supplemental calcium increases cardiovascular risk in men.¹¹

Although the increase in cardiovascular risk seems to be modest, millions of people take calcium supplements; thus, many people may be harmed. Our exuberance for bone health suggests that, at times, a single outcome can distract.

DOES SCREENING IMPROVE SURVIVAL?

On the whole, the evidence for screening continues to focus only on certain outcomes. With the exception of the National Lung Cancer Screening Trial,¹² to date, no cancer screening trial has shown an improvement in the overall survival rate.

In fact, a 2013 Cochrane review¹³ found that mammographic screening failed to lower the rate of death from all cancers, including breast cancer, after 10 years (relative risk [RR] 1.02, 95% confidence interval [CI] 0.95–1.10) and the rate of death from all causes after 13 years (RR 0.99, 95% CI 0.95–1.03). Although screening lowered the breast cancer mortality rate, the authors argued that we should not look at only some outcomes and concluded that “breast cancer mortality was an unreliable outcome” that was biased in favor of screening, mainly because of “differential misclassification of cause of death.”¹³

Significance-chasing and selective reporting are common in observational studies

Black et al¹⁴ found that of 12 major cancer screening trials examining both disease-specific mortality and all-cause mortality, 5 had differences in mortality rates that went in opposite directions (eg, the rate of disease-specific mortality improved while overall survival was harmed, or vice-versa), suggesting paradoxical effects. In another 2 studies, differences in all-cause mortality exceeded gains in disease-specific mortality. Thus, in 7 (58%) of the 12 trials, inconsistencies existed between rates of disease-specific mortality and all-cause mortality, prompting doubt about the conclusions of the studies.¹⁴

For some cancers, data suggest that screening increases deaths from other causes, and these extra deaths are not included in the data on disease-specific mortality. For instance, men who are screened for prostate cancer have higher rates of death from cardiovascular disease and suicide,¹⁵ which might negate the tenuous benefits of screening in terms of deaths from prostate cancer.

Studies of screening for diseases other than cancer have also focused on only some outcomes. For example, the United States Preventive Services Task Force supports screening for abdominal aortic aneurysm once with ultrasonography in men ages 65 to 75 who have ever smoked,¹⁶ but the recommendation is based on improvements in the death rate from abdominal aortic aneurysm, not in all-cause mortality.¹⁷ This, along with a declining incidence of this disease and changes in how it is treated (with endovascular repair on the rise and open surgical repair declining), has led some to question if we should continue to screen for it.¹⁸

CHEMOPREVENTION: NO FREE LUNCH

Finasteride

In 2013, an analysis¹⁹ that looked at all of the outcomes laid to rest 10 years of debate over the Prostate Cancer Prevention Trial, which had randomized more than 18,000 healthy men over age 55 with no signs or symptoms of prostate cancer to receive finasteride or placebo, with the end point of prostate cancer incidence. The initial results, published in 2003,²⁰ had found that the drug decreased the rate of incident prostate cancer but paradoxically increased the rate of high-grade (Gleason score ≥ 7) tumors. Whether these results were real or an artifact of ascertainment was debated, as was whether the adverse effects—decreases in sexual potency, libido, and ejaculation—were worth the 25% reduction in prostate cancer incidence.

Much of the debate ended with the 2013 publication, which showed that regardless of finasteride’s effect on prostate cancer, overall mortality curves at 18-year follow-up were absolutely indistinguishable.¹⁹ Healthy patients hoping that finasteride will help them live longer or better can be safely told that it does neither.

Statins as primary prevention

As for statin therapy as primary prevention, the best meta-analysis to date (which meticulously excluded secondary-prevention patients after analyzing individual patient-level data) found no improvement in overall mortality despite more than 240,000 patient-years of follow-up.²¹ Because of this, and because the harms of statin therapy are being increasingly (but still poorly) documented, widespread use of statins has been questioned.²²

Proponents point to the ability of statins to reduce end points such as revascularization, stroke, and nonfatal myocardial infarction.²³ But the main question facing healthy users is whether improvement in these end points translates to longer life or better quality of life. These questions remain unresolved.

Aspirin as primary prevention

Another example of the importance of considering all the outcomes is the issue of aspirin as primary prevention.

Enthusiasm for aspirin as primary prevention has been recently reinvigorated, with data showing it can prevent colorectal cancers that overexpress cyclooxygenase-2.²⁴ But a meta-analysis of nine randomized trials of aspirin²⁵ with more than 1,000 participants found that, although aspirin decreases the rate of nonfatal myocardial infarction (odds ratio [OR] 0.80, 95% CI 0.67–0.96), it does not significantly reduce cancer mortality (OR 0.93, 95% CI 0.84–1.03), and it increases the risk of nontrivial bleeding (OR 1.31; 95% CI 1.14–1.50). Its effects on overall mortality were not statistically significant but were possibly favorable (OR 0.94, 95% CI 0.88–1.00), so this requires further study.

After broad consideration of the risks and benefits of aspirin, the US Food and Drug Administration has issued a statement that aspirin is not recommended as primary prevention.²⁶

WHY STUDIES LOOK ONLY AT SOME OUTCOMES

There are many reasons why researchers favor examining some outcomes over others, but there is no clear justification for ignoring overall mortality. Overall mortality should routinely be examined in large population studies of diet and supplements and in trials of medications²⁷ and cancer screening.

Healthy people do not care about some outcomes; they care about all outcomes

With regard to large observational studies, it is hard to understand why some would not include survival analyses, unless the results would fail to support the study’s hypothesis. In fact, some studies do report overall survival results,²⁸ but others do not. The omission of overall survival in large data-set research should raise concerns of multiple hypothesis testing and selective reporting. Eating peaches as opposed to grapefruit may not be associated with differences in rates of all-cause mortality, myocardial infarction, pneumonia, or lung cancer, but if you look at 20 different variables, chances are that one will have a P value less than .05, and an investigator might be tempted to report it as statistically significant and even meaningful.

Empirical studies support this claim. One group found that for 80% of ingredients randomly selected from a cookbook, there existed Medline-indexed articles assessing cancer risk, with 65% of studies finding nominally significant differences in the risk of some type of cancer.²⁹

An excess of significant findings such as this argues that significance-chasing and selective reporting are common in this field and has led to calls for methodologic improvements, including routine falsification testing³⁰ and up-front registration of observational studies.³¹

WHY ALL OUTCOMES MATTER

Healthy people do not care about some outcomes; they care about all outcomes. Some patients may truly have unique priorities (quality of life vs quantity of life), but others may overestimate their risk of death from some causes and underestimate their risk from others, and practitioners have the obligation to counsel them appropriately.

For instance, a patient who watches a brother pass away from pancreatic adenocarcinoma may wish to do everything possible to avoid that illness. But often, as in this case, fear may surpass risk. The patient’s risk of pancreatic cancer is no different than that in the general population: the best data show³² an odds ratio of 1.8, with a confidence interval spanning 1. As such, pancreatic cancer is still not among his five most likely causes of death.

Some patients may care about their bone mineral density or cholesterol level. But again, physicians have an obligation to direct patients’ attention to all of the outcomes that should be of interest to them.

OBJECTIONS TO INCLUDING ALL OUTCOMES

There are important objections to the argument I am presenting here.

First, including all outcomes is expensive. For studies involving retrospective analysis of existing data, looking at overall mortality would not incur additional costs, only an additional analysis. But for prospective trials to have statistical power to detect a difference in overall mortality, larger sample sizes or longer follow-up might be needed—either of which would add to the cost.

In chemoprevention trials, the rate of incident cancer has been called the gold standard end point.³³ To design a thrifty chemoprevention study, investigators can either target a broad population and aim for incident malignancy, or target a restricted, high-risk population and aim for overall mortality. The latter is preferable because although it can inform the decisions of only some people, the former cannot inform any people, as was seen with difficulties in interpreting the Prostate Cancer Prevention Trial and trials showing reduced breast cancer incidence from tamoxifen, raloxifene, and exemestane.

In large cancer screening trials, the cost of powering the trial for overall mortality would be greater, and though a carefully selected, high-risk population can be enrolled, historically this has not been popular. In cancer screening, it is a mistake to contrast the costs of trials powered for overall mortality with those of lesser studies examining disease-specific death. Instead, we must consider the larger societal costs incurred by cancer screening that does not truly improve quantity or quality of life.³⁴

The recent reversal of recommendations for prostate-specific antigen testing by the United States Preventive Services Task Force³⁵ suggests that erroneous recommendations, practiced for decades, can cost society hundreds of billions of dollars but fail to improve meaningful outcomes.

The history of medicine is replete with examples of widely recommended practices and interventions that not only failed to improve the outcomes they claimed to improve, but at times increased the rate of all-cause mortality or carried harms that far outweighed benefits.^36,37 The costs of conducting research to fully understand all outcomes are only a fraction of the costs of a practice that is widely disseminated.³⁸

The history of medicine is replete with practices that harmed more than helped

A second objection to my analysis is that there is more to life than survival, and outcomes besides overall mortality are important. This is a self-evident truth. That an intervention improves the rate of overall mortality is neither necessary nor sufficient for its recommendation. Practices may improve survival but worsen quality of life to such a degree that they should not be recommended. Conversely, practices that improve quality of life should be endorsed even if they fail to prolong life.

Thus, overall mortality and quality of life must be considered together, but the end points that are favored currently (disease-specific death, incident cancer, diabetes mellitus, myocardial infarction) do not do a good job of capturing either. Disease-specific death is not meaningful to any patient if deaths from other causes are increased so that overall mortality is unchanged. Furthermore, preventing a diagnosis of cancer or diabetes may offer some psychological comfort, but well-crafted quality-of-life instruments are best suited to capture just how great that benefit is and whether it justifies the cost of such interventions, particularly if the rate of survival is unchanged.

Preventing stroke or myocardial infarction is important, but we should be cautious of interpreting data when decreasing the rate of these morbid events does not lead to commensurate improvements in survival. Alternatively, if morbid events are truly avoided but survival analyses are underpowered, quality-of-life measurements should demonstrate the benefit. But the end points currently used capture neither survival nor quality of life in a meaningful way.

WHEN ADVISING HEALTHY PEOPLE

Looking at all outcomes is important when caring for patients who are sick, but even more so for patients who are well. We need to know an intervention has a net benefit before we recommend it to a healthy person. Overall mortality should be reported routinely in this population, particularly in settings where the cost to do so is trivial (ie, in observational studies). Designers of thrifty trials should try to include people at high risk and power the trial for definite end points, rather than being broadly inclusive and reaching disputed conclusions. Research and decision-making should look at all outcomes. Healthy people deserve no less.

Before we dispense advice about staying healthy, we should know the effect of whatever we are recommending—be it diet, supplements, chemoprevention, or screening—on all meaningful outcomes, including overall mortality, quality of life, harms, inconveniences, and cost. Even though looking at all these outcomes may seem self-evidently wise, many research studies do not do it, and health care providers do not do it enough.

How would looking at all the outcomes change our opinion of health practices?

COMPARING GRAPEFRUIT AND PEACHES

A 2013 study linked eating berries with lower rates of myocardial infarction in women,¹ another found that people who ate some fruits (blackberries and grapefruit) but not others (peaches and oranges) had a lower rate of incident diabetes,² and a third linked a healthy diet to a lower incidence of pancreatic cancer.³ However, none of these studies examined all-cause mortality rates. A fourth study found that drinking green tea was associated with a lower risk of death from pneumonia in Japanese women, but not men.⁴

For the sake of argument, let us put aside concern about whether observational studies can reliably inform recommendations for clinical practice⁵ and concede that they can. The point is that studies such as those above look at some but not all meaningful outcomes, undermining the utility of their findings. If healthy people conclude that they should eat grapefruit instead of peaches, they may miss out on benefits of peaches that the study did not examine. Eating a healthy diet remains prudent, but the study linking it to a lower rate of pancreatic cancer is no tipping point, as pancreatic cancer is just one way to die. And advocating green tea to Japanese women but not men, to avoid pneumonia, would be a questionable public health strategy. Pneumonia is the sixth leading cause of death and accounts for 3.9% of disability-adjusted life-years lost,⁶ but what about the first five causes, which account for 96.1%?

We should know the effect of what we recommend on all meaningful outcomes

These and many other studies of dietary habits of people who are well fail to consider end points that healthy people care about. Suppose that drinking more coffee would prevent all deaths from pancreatic cancer but would modestly increase cardiovascular deaths—say, by 5%. On a population level, recommending more coffee would be wrong, because it would result in far more deaths. Suppose that drinking tea decreased deaths from pneumonia—we should still not advise patients to drink tea, as we do not know whether tea’s net effect is beneficial.

Some may argue that these epidemiologic studies are merely hypothesis-generating, but my colleagues and I analyzed all the nonrandomized studies published in several leading medical journals in 1 year and found that 59% made specific practice recommendations.⁵ Other studies may be misused in this fashion, even though the authors refrained from doing so.

CALCIUM PROTECTS BONES, BUT WHAT ABOUT THE HEART?

Narrow end points are not limited to dietary studies. Calcium supplementation with or without vitamin D has been vigorously promoted for decades⁷ to treat and prevent osteoporosis in pre- and postmenopausal women, and data confirm that these agents decrease the risk of fracture.⁸

But bone health is only one end point important to women, and long-term supplementation of a mineral or vitamin with the goal of strengthening bones may have unforeseen adverse effects.

In 2010, calcium supplementation without vitamin D was linked to higher rates of myocardial infarction (with some suggestion of increased rates of all-cause death) in pooled analyses of 15 trials.⁹ In 2011, a higher risk of cardiovascular events (stroke and myocardial infarction) was found in recipients of calcium with vitamin D in a reanalysis of the Women’s Health Initiative Calcium/Vitamin D Supplementation Study,¹⁰ adjusting for the widespread use of these supplements at baseline, and this was corroborated by a meta-analysis of eight other studies.¹⁰ A more recent study confirmed that supplemental calcium increases cardiovascular risk in men.¹¹

Although the increase in cardiovascular risk seems to be modest, millions of people take calcium supplements; thus, many people may be harmed. Our exuberance for bone health suggests that, at times, a single outcome can distract.

DOES SCREENING IMPROVE SURVIVAL?

On the whole, the evidence for screening continues to focus only on certain outcomes. With the exception of the National Lung Cancer Screening Trial,¹² to date, no cancer screening trial has shown an improvement in the overall survival rate.

In fact, a 2013 Cochrane review¹³ found that mammographic screening failed to lower the rate of death from all cancers, including breast cancer, after 10 years (relative risk [RR] 1.02, 95% confidence interval [CI] 0.95–1.10) and the rate of death from all causes after 13 years (RR 0.99, 95% CI 0.95–1.03). Although screening lowered the breast cancer mortality rate, the authors argued that we should not look at only some outcomes and concluded that “breast cancer mortality was an unreliable outcome” that was biased in favor of screening, mainly because of “differential misclassification of cause of death.”¹³

Significance-chasing and selective reporting are common in observational studies

Black et al¹⁴ found that of 12 major cancer screening trials examining both disease-specific mortality and all-cause mortality, 5 had differences in mortality rates that went in opposite directions (eg, the rate of disease-specific mortality improved while overall survival was harmed, or vice-versa), suggesting paradoxical effects. In another 2 studies, differences in all-cause mortality exceeded gains in disease-specific mortality. Thus, in 7 (58%) of the 12 trials, inconsistencies existed between rates of disease-specific mortality and all-cause mortality, prompting doubt about the conclusions of the studies.¹⁴

For some cancers, data suggest that screening increases deaths from other causes, and these extra deaths are not included in the data on disease-specific mortality. For instance, men who are screened for prostate cancer have higher rates of death from cardiovascular disease and suicide,¹⁵ which might negate the tenuous benefits of screening in terms of deaths from prostate cancer.

Studies of screening for diseases other than cancer have also focused on only some outcomes. For example, the United States Preventive Services Task Force supports screening for abdominal aortic aneurysm once with ultrasonography in men ages 65 to 75 who have ever smoked,¹⁶ but the recommendation is based on improvements in the death rate from abdominal aortic aneurysm, not in all-cause mortality.¹⁷ This, along with a declining incidence of this disease and changes in how it is treated (with endovascular repair on the rise and open surgical repair declining), has led some to question if we should continue to screen for it.¹⁸

CHEMOPREVENTION: NO FREE LUNCH

Finasteride

In 2013, an analysis¹⁹ that looked at all of the outcomes laid to rest 10 years of debate over the Prostate Cancer Prevention Trial, which had randomized more than 18,000 healthy men over age 55 with no signs or symptoms of prostate cancer to receive finasteride or placebo, with the end point of prostate cancer incidence. The initial results, published in 2003,²⁰ had found that the drug decreased the rate of incident prostate cancer but paradoxically increased the rate of high-grade (Gleason score ≥ 7) tumors. Whether these results were real or an artifact of ascertainment was debated, as was whether the adverse effects—decreases in sexual potency, libido, and ejaculation—were worth the 25% reduction in prostate cancer incidence.

Much of the debate ended with the 2013 publication, which showed that regardless of finasteride’s effect on prostate cancer, overall mortality curves at 18-year follow-up were absolutely indistinguishable.¹⁹ Healthy patients hoping that finasteride will help them live longer or better can be safely told that it does neither.

Statins as primary prevention

As for statin therapy as primary prevention, the best meta-analysis to date (which meticulously excluded secondary-prevention patients after analyzing individual patient-level data) found no improvement in overall mortality despite more than 240,000 patient-years of follow-up.²¹ Because of this, and because the harms of statin therapy are being increasingly (but still poorly) documented, widespread use of statins has been questioned.²²

Proponents point to the ability of statins to reduce end points such as revascularization, stroke, and nonfatal myocardial infarction.²³ But the main question facing healthy users is whether improvement in these end points translates to longer life or better quality of life. These questions remain unresolved.

Aspirin as primary prevention

Another example of the importance of considering all the outcomes is the issue of aspirin as primary prevention.

Enthusiasm for aspirin as primary prevention has been recently reinvigorated, with data showing it can prevent colorectal cancers that overexpress cyclooxygenase-2.²⁴ But a meta-analysis of nine randomized trials of aspirin²⁵ with more than 1,000 participants found that, although aspirin decreases the rate of nonfatal myocardial infarction (odds ratio [OR] 0.80, 95% CI 0.67–0.96), it does not significantly reduce cancer mortality (OR 0.93, 95% CI 0.84–1.03), and it increases the risk of nontrivial bleeding (OR 1.31; 95% CI 1.14–1.50). Its effects on overall mortality were not statistically significant but were possibly favorable (OR 0.94, 95% CI 0.88–1.00), so this requires further study.

After broad consideration of the risks and benefits of aspirin, the US Food and Drug Administration has issued a statement that aspirin is not recommended as primary prevention.²⁶

WHY STUDIES LOOK ONLY AT SOME OUTCOMES

There are many reasons why researchers favor examining some outcomes over others, but there is no clear justification for ignoring overall mortality. Overall mortality should routinely be examined in large population studies of diet and supplements and in trials of medications²⁷ and cancer screening.

Healthy people do not care about some outcomes; they care about all outcomes

With regard to large observational studies, it is hard to understand why some would not include survival analyses, unless the results would fail to support the study’s hypothesis. In fact, some studies do report overall survival results,²⁸ but others do not. The omission of overall survival in large data-set research should raise concerns of multiple hypothesis testing and selective reporting. Eating peaches as opposed to grapefruit may not be associated with differences in rates of all-cause mortality, myocardial infarction, pneumonia, or lung cancer, but if you look at 20 different variables, chances are that one will have a P value less than .05, and an investigator might be tempted to report it as statistically significant and even meaningful.

Empirical studies support this claim. One group found that for 80% of ingredients randomly selected from a cookbook, there existed Medline-indexed articles assessing cancer risk, with 65% of studies finding nominally significant differences in the risk of some type of cancer.²⁹

An excess of significant findings such as this argues that significance-chasing and selective reporting are common in this field and has led to calls for methodologic improvements, including routine falsification testing³⁰ and up-front registration of observational studies.³¹

WHY ALL OUTCOMES MATTER

Healthy people do not care about some outcomes; they care about all outcomes. Some patients may truly have unique priorities (quality of life vs quantity of life), but others may overestimate their risk of death from some causes and underestimate their risk from others, and practitioners have the obligation to counsel them appropriately.

For instance, a patient who watches a brother pass away from pancreatic adenocarcinoma may wish to do everything possible to avoid that illness. But often, as in this case, fear may surpass risk. The patient’s risk of pancreatic cancer is no different than that in the general population: the best data show³² an odds ratio of 1.8, with a confidence interval spanning 1. As such, pancreatic cancer is still not among his five most likely causes of death.

Some patients may care about their bone mineral density or cholesterol level. But again, physicians have an obligation to direct patients’ attention to all of the outcomes that should be of interest to them.

OBJECTIONS TO INCLUDING ALL OUTCOMES

There are important objections to the argument I am presenting here.

First, including all outcomes is expensive. For studies involving retrospective analysis of existing data, looking at overall mortality would not incur additional costs, only an additional analysis. But for prospective trials to have statistical power to detect a difference in overall mortality, larger sample sizes or longer follow-up might be needed—either of which would add to the cost.

In chemoprevention trials, the rate of incident cancer has been called the gold standard end point.³³ To design a thrifty chemoprevention study, investigators can either target a broad population and aim for incident malignancy, or target a restricted, high-risk population and aim for overall mortality. The latter is preferable because although it can inform the decisions of only some people, the former cannot inform any people, as was seen with difficulties in interpreting the Prostate Cancer Prevention Trial and trials showing reduced breast cancer incidence from tamoxifen, raloxifene, and exemestane.

In large cancer screening trials, the cost of powering the trial for overall mortality would be greater, and though a carefully selected, high-risk population can be enrolled, historically this has not been popular. In cancer screening, it is a mistake to contrast the costs of trials powered for overall mortality with those of lesser studies examining disease-specific death. Instead, we must consider the larger societal costs incurred by cancer screening that does not truly improve quantity or quality of life.³⁴

The recent reversal of recommendations for prostate-specific antigen testing by the United States Preventive Services Task Force³⁵ suggests that erroneous recommendations, practiced for decades, can cost society hundreds of billions of dollars but fail to improve meaningful outcomes.

The history of medicine is replete with examples of widely recommended practices and interventions that not only failed to improve the outcomes they claimed to improve, but at times increased the rate of all-cause mortality or carried harms that far outweighed benefits.^36,37 The costs of conducting research to fully understand all outcomes are only a fraction of the costs of a practice that is widely disseminated.³⁸

The history of medicine is replete with practices that harmed more than helped

A second objection to my analysis is that there is more to life than survival, and outcomes besides overall mortality are important. This is a self-evident truth. That an intervention improves the rate of overall mortality is neither necessary nor sufficient for its recommendation. Practices may improve survival but worsen quality of life to such a degree that they should not be recommended. Conversely, practices that improve quality of life should be endorsed even if they fail to prolong life.

Thus, overall mortality and quality of life must be considered together, but the end points that are favored currently (disease-specific death, incident cancer, diabetes mellitus, myocardial infarction) do not do a good job of capturing either. Disease-specific death is not meaningful to any patient if deaths from other causes are increased so that overall mortality is unchanged. Furthermore, preventing a diagnosis of cancer or diabetes may offer some psychological comfort, but well-crafted quality-of-life instruments are best suited to capture just how great that benefit is and whether it justifies the cost of such interventions, particularly if the rate of survival is unchanged.

Preventing stroke or myocardial infarction is important, but we should be cautious of interpreting data when decreasing the rate of these morbid events does not lead to commensurate improvements in survival. Alternatively, if morbid events are truly avoided but survival analyses are underpowered, quality-of-life measurements should demonstrate the benefit. But the end points currently used capture neither survival nor quality of life in a meaningful way.

WHEN ADVISING HEALTHY PEOPLE

Looking at all outcomes is important when caring for patients who are sick, but even more so for patients who are well. We need to know an intervention has a net benefit before we recommend it to a healthy person. Overall mortality should be reported routinely in this population, particularly in settings where the cost to do so is trivial (ie, in observational studies). Designers of thrifty trials should try to include people at high risk and power the trial for definite end points, rather than being broadly inclusive and reaching disputed conclusions. Research and decision-making should look at all outcomes. Healthy people deserve no less.

HUNTINGTON BEACH, CALIF. – Researchers are making significant headway in developing objective, reliable, and valid biomarkers to discriminate individuals with warzone post traumatic stress disorder from healthy controls, according to Dr. Charles R. Marmar.

“It’s clear that over the next four or five years we will identify very clear biological, psychological, and other behavioral risk and resilience profiles,” Dr. Marmar told attendees at the annual meeting of the American College of Psychiatrists.

Currently, clinicians largely rely on patient self-reports and clinical observations to diagnose PTSD in military personnel, said Dr. Marmar, professor and chair of the department of psychiatry at NYU Langone Medical Center and director of NYU’s Steven and Alexandra Cohen Veterans Center.

“The problem from the military and law enforcement perspective is that the majority of war fighters experience tremendous stigma in acknowledging their symptoms, particularly active duty military personnel,” he said. “A minority will exaggerate to avoid service or for compensation. Given that we’ve had nearly three million men and women serve in Iraq and Afghanistan, and the fact that we have no objective way yet of determining which ones continue to be fit for redeployment, which ones are in urgent need of help, and which ones deserve compensation, we need to develop better ways to determine if treatments are effective, to inform new treatment selection, and to define new targets for treatment.”

The scope of the problem is underscored in an analysis of data from 289,328 veterans entering VA Healthcare for the first time beginning on April 1, 2002 through March 31, 2006 (Am J. Pub. Health 2009;99[9]:1651-8). Prior to the invasion of Iraq, the distribution of mental health problems was very similar among veterans as in the general population: depression being most common, and low rates of PTSD and alcohol and drug abuse. However, “with each quarter since the invasion of Iraq, there’s been an incubative growth in the prevalence of PTSD, which has now eclipsed depression,” Dr. Marmar said. “We have a toll, a generational effect which looks similar in magnitude with the Vietnam War, both in the number of men and women who serve and in the prevalence of PTSD, depression and alcohol- and drug-related disorders.”

In the general population, risk factors include female sex, child abuse, genetics, which in twin studies account for 30-40% of the risk, lower IQ and lower educational attainment, stressful life events in the prior and following year, and panic reaction at the time of event, such as racing heart, shaking, and sweating.

According to findings from the National Vietnam Veterans Readjustment Study, risk factors for chronic warzone PTSD include high school dropout rate, history of child abuse, high warzone exposure, serious warzone injury, killing combatants, prisoners, and civilians, peritraumatic dissociation, hostile homecoming, post-discharge trauma, and genetics. “These are the risk profiles, and they should give us some clues about where to look for biological factors,” Dr. Marmar said.

The risks of service are not limited to stress, anxiety, depression, alcohol and drug abuse, or traumatic brain injury (TBI). “If you compare men and women returning from Iraq and Afghanistan with no mental health issues to those who have a diagnosis of either PTSD, depression, or the combination, the [diagnosed] cases have 2.5 times the risk of tobacco use, hypertension, dyslipidemia, obesity, and type 2 diabetes,” he said. “These are people in their late 20s and early 30s. So the costs of warzone-related stress and depression are enormous on general health.”

Dr. Marmar presented preliminary findings from the ongoing PTSD Systems Biology Consortium, an effort by researchers at seven universities to establish biomarkers for PTSD. Funded by the Department of Defense, the National Institutes of Health, and other sources, the consortium is comprised of integrated cores including neurocognition, genetics, structural and functional brain imaging, endocrinology, metabolism, genomics, proteomics, metabolomics, and bioinformatics.

To date, the researchers have screened 2,215 veterans from service in Iraq and Afghanistan, all of whom have been deployed to war at least once. Cases were PTSD positive and had a CAPS (Clinician-Administered PTSD scale) score of 20 or greater. Controls were PTSD negative and had a CAPS score of less than 20. They excluded subjects with lifetime psychosis, bipolar disorder, or OCD, as well as alcohol dependence in the past eight months, and drug abuse in the past year. They also excluded veterans with TBI “because we’re trying to be very careful to see if we can get a biological signal comparing combat PTSD cases with controls,” Dr. Marmar noted.

Dr. Marmar presented preliminary findings from 52 PTSD cases and 52 controls that were matched for sex, ethnicity, and age. The sample was entirely men, their mean age was 34 years, and they had a mean of 14.8 years of education. The researchers covaried for depression and other known confounders. “It’s very difficult to disentangle the effects of PTSD and depression because 50% of the cases of warzone PTSD also meet criteria for current major depression, and over 80% meet criteria for lifetime depression,” he said.

In results from the clinical diagnostic evaluation, PTSD cases, compared with controls, were significantly more likely to have current anxiety (7% vs. 0%, respectively; P = .041); lifetime anxiety (9.6% vs. 0%; P = .022); current major depressive disorder (51.5% vs. 1.9%; P<.001); lifetime MDD (84.6% vs. 23.1%; P<.001); and lifetime alcohol abuse dependence (63.5% vs. 25%; P = .001). There was also a non-signficant trend toward lifetime substance abuse/dependence (13.5% vs. 3.9%; P = .081).

Results from the neurocognitive assessments revealed that PTSD positive men had a significantly lower estimated IQ, compared with their PTSD negative counterparts (a mean of 99.3 vs. 107.9, respectively; P = .031). Other significant differences between the two groups were observed in tests of auditory and working memory, specifically digit span (8.67 vs. 10.04; P = .02), and the visual memory sum (9.1 vs. 10.67; P = .01).

One of the consortium collaborators developed a test to compare reward and punishment learning. For the test, “the subject is required to understand what the meaning of a symbol is in a task, and they have no prior knowledge [of the meaning],” Dr. Marmar explained. “They’re either rewarded for guessing correctly or punished for guessing incorrectly.” So far, the healthy controls “are performing much better in identifying the symbols when they’re rewarded, compared with the PTSD cases, and there’s no difference in punishment,” he said. “So there’s impaired reward learning and intact punishment learning in PTSD cases compared to controls, which likely reflects underlying disturbances in dopamine reward circuitry.”

Investigators in the neurogenetics core hypothesized that DNA variants in stress-response genes identified from previous medical studies will be associated with PTSD. These included FKBP5, COMT, APOE, BDNF, PACAP/PAC1R, and OPRL1. Initial analysis revealed that there were a greater number of BDNF allele frequencies among cases, compared with controls (P = .008). “It would appear that BDNF variants confer resilience for combat-related PTSD,” Dr. Marmar said.

The researchers also found a single nucleotide polymorphism never previously described on Chromosome 4. “It’s in a region between genes, probably a micro-RNA regulatory gene on the 4th chromosome,” he said. “That gene in our sample was associated with higher levels of PTSD. In addition, fMRI studies found that carrying this allele was associated with weaker activation of prefrontal cortical areas in the brain to empirical faces tasks.”

The endocrine core found that PTSD cases had lower ambient cortisol levels, compared with controls (P = .051). They also had significantly greater cortisol suppression following dexamethasone administration, compared with controls (P = .013). “This is evidence that there is increased glucocorticoid receptor sensitivity in PTSD expressing as elevated cortisol suppression,” Dr. Marmar said.

Investigators from the structural imaging core found no significant differences in overall hippocampal volume or in the five major hippocampal subfields between PTSD cases and controls, nor in difference in the volume of other brain structures previously implicated in PTSD, such as the amygdala and the thalamus. However, the researchers are finding some differences between cases and controls on functional imaging, including increased spontaneous activity in the amygdala and the insula, and decreased spontaneous activity in the precuneus. “The overall findings on fMRI are that there’s increased activity in the regions [of the brain] associated with fear and decreased connectivity between the frontal cortex and the amygdala,” he said. “This is consistent with the model of dysregulated fear activity in PTSD.”

Researchers have also observed that many markers of metabolic syndrome are significantly elevated between PTSD cases and controls, including fasting glucose (P = .001), weight (P = .03), and resting pulse (P = .003). “When you covary for depression, these findings remain,” Dr. Marmar said. “It’s important to note that these are men mostly in their early 30s recently returned from war and recently in military training, physically fit to be deployed to war.”

He closed his presentation by noting that mounting evidence from animal and human studies suggests evidence of mitochondrial dysfunction in PTSD. In the current analysis, researchers observed a reduced abundance of citrate and other mitochondrial metabolites in PTSD cases compared with controls, as well as an increased abundance of “premitochondrial” metabolites such as pyruvate and lactate. “These findings stand when you covary for depression and for metabolic syndrome,” Dr. Marmar said.

“We believe that these may be very important potential future candidate biomarkers to differentiate PTSD cases from controls.”

The next step in this effort, he added, is to replicate the consortium’s overall findings in a cross-validation sample of 50 male cases and 50 male controls. “We also have a sample of 40 female cases and 40 controls to see if the markers are the same or different,” he said. The researchers are also conducting a prospective study of 1,200 active duty military personnel, who will be evaluated before and after deployment.

For now, some clinicians wonder what should be done for men and women who carry the PTSD risk alleles, or carry the endocrine or metabolism vulnerability to develop complications from combat exposure. “That’s a very sensitive national question,” Dr. Marmar said. “People want to serve their country. The answer may be to allow service but to have a more nuanced approach to what people’s roles should be within the military, to match individuals’ stress resilience with the responsibilities they have.”

Dr. Marmar reported that he had no relevant financial conflicts.

[email protected]

On Twitter @dougbrunk

HUNTINGTON BEACH, CALIF. – Researchers are making significant headway in developing objective, reliable, and valid biomarkers to discriminate individuals with warzone post traumatic stress disorder from healthy controls, according to Dr. Charles R. Marmar.

“It’s clear that over the next four or five years we will identify very clear biological, psychological, and other behavioral risk and resilience profiles,” Dr. Marmar told attendees at the annual meeting of the American College of Psychiatrists.

Currently, clinicians largely rely on patient self-reports and clinical observations to diagnose PTSD in military personnel, said Dr. Marmar, professor and chair of the department of psychiatry at NYU Langone Medical Center and director of NYU’s Steven and Alexandra Cohen Veterans Center.

“The problem from the military and law enforcement perspective is that the majority of war fighters experience tremendous stigma in acknowledging their symptoms, particularly active duty military personnel,” he said. “A minority will exaggerate to avoid service or for compensation. Given that we’ve had nearly three million men and women serve in Iraq and Afghanistan, and the fact that we have no objective way yet of determining which ones continue to be fit for redeployment, which ones are in urgent need of help, and which ones deserve compensation, we need to develop better ways to determine if treatments are effective, to inform new treatment selection, and to define new targets for treatment.”

The scope of the problem is underscored in an analysis of data from 289,328 veterans entering VA Healthcare for the first time beginning on April 1, 2002 through March 31, 2006 (Am J. Pub. Health 2009;99[9]:1651-8). Prior to the invasion of Iraq, the distribution of mental health problems was very similar among veterans as in the general population: depression being most common, and low rates of PTSD and alcohol and drug abuse. However, “with each quarter since the invasion of Iraq, there’s been an incubative growth in the prevalence of PTSD, which has now eclipsed depression,” Dr. Marmar said. “We have a toll, a generational effect which looks similar in magnitude with the Vietnam War, both in the number of men and women who serve and in the prevalence of PTSD, depression and alcohol- and drug-related disorders.”

In the general population, risk factors include female sex, child abuse, genetics, which in twin studies account for 30-40% of the risk, lower IQ and lower educational attainment, stressful life events in the prior and following year, and panic reaction at the time of event, such as racing heart, shaking, and sweating.

According to findings from the National Vietnam Veterans Readjustment Study, risk factors for chronic warzone PTSD include high school dropout rate, history of child abuse, high warzone exposure, serious warzone injury, killing combatants, prisoners, and civilians, peritraumatic dissociation, hostile homecoming, post-discharge trauma, and genetics. “These are the risk profiles, and they should give us some clues about where to look for biological factors,” Dr. Marmar said.

The risks of service are not limited to stress, anxiety, depression, alcohol and drug abuse, or traumatic brain injury (TBI). “If you compare men and women returning from Iraq and Afghanistan with no mental health issues to those who have a diagnosis of either PTSD, depression, or the combination, the [diagnosed] cases have 2.5 times the risk of tobacco use, hypertension, dyslipidemia, obesity, and type 2 diabetes,” he said. “These are people in their late 20s and early 30s. So the costs of warzone-related stress and depression are enormous on general health.”

Dr. Marmar presented preliminary findings from the ongoing PTSD Systems Biology Consortium, an effort by researchers at seven universities to establish biomarkers for PTSD. Funded by the Department of Defense, the National Institutes of Health, and other sources, the consortium is comprised of integrated cores including neurocognition, genetics, structural and functional brain imaging, endocrinology, metabolism, genomics, proteomics, metabolomics, and bioinformatics.

To date, the researchers have screened 2,215 veterans from service in Iraq and Afghanistan, all of whom have been deployed to war at least once. Cases were PTSD positive and had a CAPS (Clinician-Administered PTSD scale) score of 20 or greater. Controls were PTSD negative and had a CAPS score of less than 20. They excluded subjects with lifetime psychosis, bipolar disorder, or OCD, as well as alcohol dependence in the past eight months, and drug abuse in the past year. They also excluded veterans with TBI “because we’re trying to be very careful to see if we can get a biological signal comparing combat PTSD cases with controls,” Dr. Marmar noted.

Dr. Marmar presented preliminary findings from 52 PTSD cases and 52 controls that were matched for sex, ethnicity, and age. The sample was entirely men, their mean age was 34 years, and they had a mean of 14.8 years of education. The researchers covaried for depression and other known confounders. “It’s very difficult to disentangle the effects of PTSD and depression because 50% of the cases of warzone PTSD also meet criteria for current major depression, and over 80% meet criteria for lifetime depression,” he said.

In results from the clinical diagnostic evaluation, PTSD cases, compared with controls, were significantly more likely to have current anxiety (7% vs. 0%, respectively; P = .041); lifetime anxiety (9.6% vs. 0%; P = .022); current major depressive disorder (51.5% vs. 1.9%; P<.001); lifetime MDD (84.6% vs. 23.1%; P<.001); and lifetime alcohol abuse dependence (63.5% vs. 25%; P = .001). There was also a non-signficant trend toward lifetime substance abuse/dependence (13.5% vs. 3.9%; P = .081).

Results from the neurocognitive assessments revealed that PTSD positive men had a significantly lower estimated IQ, compared with their PTSD negative counterparts (a mean of 99.3 vs. 107.9, respectively; P = .031). Other significant differences between the two groups were observed in tests of auditory and working memory, specifically digit span (8.67 vs. 10.04; P = .02), and the visual memory sum (9.1 vs. 10.67; P = .01).

One of the consortium collaborators developed a test to compare reward and punishment learning. For the test, “the subject is required to understand what the meaning of a symbol is in a task, and they have no prior knowledge [of the meaning],” Dr. Marmar explained. “They’re either rewarded for guessing correctly or punished for guessing incorrectly.” So far, the healthy controls “are performing much better in identifying the symbols when they’re rewarded, compared with the PTSD cases, and there’s no difference in punishment,” he said. “So there’s impaired reward learning and intact punishment learning in PTSD cases compared to controls, which likely reflects underlying disturbances in dopamine reward circuitry.”

Investigators in the neurogenetics core hypothesized that DNA variants in stress-response genes identified from previous medical studies will be associated with PTSD. These included FKBP5, COMT, APOE, BDNF, PACAP/PAC1R, and OPRL1. Initial analysis revealed that there were a greater number of BDNF allele frequencies among cases, compared with controls (P = .008). “It would appear that BDNF variants confer resilience for combat-related PTSD,” Dr. Marmar said.

The researchers also found a single nucleotide polymorphism never previously described on Chromosome 4. “It’s in a region between genes, probably a micro-RNA regulatory gene on the 4th chromosome,” he said. “That gene in our sample was associated with higher levels of PTSD. In addition, fMRI studies found that carrying this allele was associated with weaker activation of prefrontal cortical areas in the brain to empirical faces tasks.”

The endocrine core found that PTSD cases had lower ambient cortisol levels, compared with controls (P = .051). They also had significantly greater cortisol suppression following dexamethasone administration, compared with controls (P = .013). “This is evidence that there is increased glucocorticoid receptor sensitivity in PTSD expressing as elevated cortisol suppression,” Dr. Marmar said.

Investigators from the structural imaging core found no significant differences in overall hippocampal volume or in the five major hippocampal subfields between PTSD cases and controls, nor in difference in the volume of other brain structures previously implicated in PTSD, such as the amygdala and the thalamus. However, the researchers are finding some differences between cases and controls on functional imaging, including increased spontaneous activity in the amygdala and the insula, and decreased spontaneous activity in the precuneus. “The overall findings on fMRI are that there’s increased activity in the regions [of the brain] associated with fear and decreased connectivity between the frontal cortex and the amygdala,” he said. “This is consistent with the model of dysregulated fear activity in PTSD.”

Researchers have also observed that many markers of metabolic syndrome are significantly elevated between PTSD cases and controls, including fasting glucose (P = .001), weight (P = .03), and resting pulse (P = .003). “When you covary for depression, these findings remain,” Dr. Marmar said. “It’s important to note that these are men mostly in their early 30s recently returned from war and recently in military training, physically fit to be deployed to war.”

He closed his presentation by noting that mounting evidence from animal and human studies suggests evidence of mitochondrial dysfunction in PTSD. In the current analysis, researchers observed a reduced abundance of citrate and other mitochondrial metabolites in PTSD cases compared with controls, as well as an increased abundance of “premitochondrial” metabolites such as pyruvate and lactate. “These findings stand when you covary for depression and for metabolic syndrome,” Dr. Marmar said.

“We believe that these may be very important potential future candidate biomarkers to differentiate PTSD cases from controls.”

The next step in this effort, he added, is to replicate the consortium’s overall findings in a cross-validation sample of 50 male cases and 50 male controls. “We also have a sample of 40 female cases and 40 controls to see if the markers are the same or different,” he said. The researchers are also conducting a prospective study of 1,200 active duty military personnel, who will be evaluated before and after deployment.

For now, some clinicians wonder what should be done for men and women who carry the PTSD risk alleles, or carry the endocrine or metabolism vulnerability to develop complications from combat exposure. “That’s a very sensitive national question,” Dr. Marmar said. “People want to serve their country. The answer may be to allow service but to have a more nuanced approach to what people’s roles should be within the military, to match individuals’ stress resilience with the responsibilities they have.”

Dr. Marmar reported that he had no relevant financial conflicts.

[email protected]

On Twitter @dougbrunk

HUNTINGTON BEACH, CALIF. – Researchers are making significant headway in developing objective, reliable, and valid biomarkers to discriminate individuals with warzone post traumatic stress disorder from healthy controls, according to Dr. Charles R. Marmar.

“It’s clear that over the next four or five years we will identify very clear biological, psychological, and other behavioral risk and resilience profiles,” Dr. Marmar told attendees at the annual meeting of the American College of Psychiatrists.

Currently, clinicians largely rely on patient self-reports and clinical observations to diagnose PTSD in military personnel, said Dr. Marmar, professor and chair of the department of psychiatry at NYU Langone Medical Center and director of NYU’s Steven and Alexandra Cohen Veterans Center.

“The problem from the military and law enforcement perspective is that the majority of war fighters experience tremendous stigma in acknowledging their symptoms, particularly active duty military personnel,” he said. “A minority will exaggerate to avoid service or for compensation. Given that we’ve had nearly three million men and women serve in Iraq and Afghanistan, and the fact that we have no objective way yet of determining which ones continue to be fit for redeployment, which ones are in urgent need of help, and which ones deserve compensation, we need to develop better ways to determine if treatments are effective, to inform new treatment selection, and to define new targets for treatment.”

The scope of the problem is underscored in an analysis of data from 289,328 veterans entering VA Healthcare for the first time beginning on April 1, 2002 through March 31, 2006 (Am J. Pub. Health 2009;99[9]:1651-8). Prior to the invasion of Iraq, the distribution of mental health problems was very similar among veterans as in the general population: depression being most common, and low rates of PTSD and alcohol and drug abuse. However, “with each quarter since the invasion of Iraq, there’s been an incubative growth in the prevalence of PTSD, which has now eclipsed depression,” Dr. Marmar said. “We have a toll, a generational effect which looks similar in magnitude with the Vietnam War, both in the number of men and women who serve and in the prevalence of PTSD, depression and alcohol- and drug-related disorders.”

In the general population, risk factors include female sex, child abuse, genetics, which in twin studies account for 30-40% of the risk, lower IQ and lower educational attainment, stressful life events in the prior and following year, and panic reaction at the time of event, such as racing heart, shaking, and sweating.

According to findings from the National Vietnam Veterans Readjustment Study, risk factors for chronic warzone PTSD include high school dropout rate, history of child abuse, high warzone exposure, serious warzone injury, killing combatants, prisoners, and civilians, peritraumatic dissociation, hostile homecoming, post-discharge trauma, and genetics. “These are the risk profiles, and they should give us some clues about where to look for biological factors,” Dr. Marmar said.

The risks of service are not limited to stress, anxiety, depression, alcohol and drug abuse, or traumatic brain injury (TBI). “If you compare men and women returning from Iraq and Afghanistan with no mental health issues to those who have a diagnosis of either PTSD, depression, or the combination, the [diagnosed] cases have 2.5 times the risk of tobacco use, hypertension, dyslipidemia, obesity, and type 2 diabetes,” he said. “These are people in their late 20s and early 30s. So the costs of warzone-related stress and depression are enormous on general health.”

Dr. Marmar presented preliminary findings from the ongoing PTSD Systems Biology Consortium, an effort by researchers at seven universities to establish biomarkers for PTSD. Funded by the Department of Defense, the National Institutes of Health, and other sources, the consortium is comprised of integrated cores including neurocognition, genetics, structural and functional brain imaging, endocrinology, metabolism, genomics, proteomics, metabolomics, and bioinformatics.

To date, the researchers have screened 2,215 veterans from service in Iraq and Afghanistan, all of whom have been deployed to war at least once. Cases were PTSD positive and had a CAPS (Clinician-Administered PTSD scale) score of 20 or greater. Controls were PTSD negative and had a CAPS score of less than 20. They excluded subjects with lifetime psychosis, bipolar disorder, or OCD, as well as alcohol dependence in the past eight months, and drug abuse in the past year. They also excluded veterans with TBI “because we’re trying to be very careful to see if we can get a biological signal comparing combat PTSD cases with controls,” Dr. Marmar noted.

Dr. Marmar presented preliminary findings from 52 PTSD cases and 52 controls that were matched for sex, ethnicity, and age. The sample was entirely men, their mean age was 34 years, and they had a mean of 14.8 years of education. The researchers covaried for depression and other known confounders. “It’s very difficult to disentangle the effects of PTSD and depression because 50% of the cases of warzone PTSD also meet criteria for current major depression, and over 80% meet criteria for lifetime depression,” he said.

In results from the clinical diagnostic evaluation, PTSD cases, compared with controls, were significantly more likely to have current anxiety (7% vs. 0%, respectively; P = .041); lifetime anxiety (9.6% vs. 0%; P = .022); current major depressive disorder (51.5% vs. 1.9%; P<.001); lifetime MDD (84.6% vs. 23.1%; P<.001); and lifetime alcohol abuse dependence (63.5% vs. 25%; P = .001). There was also a non-signficant trend toward lifetime substance abuse/dependence (13.5% vs. 3.9%; P = .081).

Results from the neurocognitive assessments revealed that PTSD positive men had a significantly lower estimated IQ, compared with their PTSD negative counterparts (a mean of 99.3 vs. 107.9, respectively; P = .031). Other significant differences between the two groups were observed in tests of auditory and working memory, specifically digit span (8.67 vs. 10.04; P = .02), and the visual memory sum (9.1 vs. 10.67; P = .01).

One of the consortium collaborators developed a test to compare reward and punishment learning. For the test, “the subject is required to understand what the meaning of a symbol is in a task, and they have no prior knowledge [of the meaning],” Dr. Marmar explained. “They’re either rewarded for guessing correctly or punished for guessing incorrectly.” So far, the healthy controls “are performing much better in identifying the symbols when they’re rewarded, compared with the PTSD cases, and there’s no difference in punishment,” he said. “So there’s impaired reward learning and intact punishment learning in PTSD cases compared to controls, which likely reflects underlying disturbances in dopamine reward circuitry.”

Investigators in the neurogenetics core hypothesized that DNA variants in stress-response genes identified from previous medical studies will be associated with PTSD. These included FKBP5, COMT, APOE, BDNF, PACAP/PAC1R, and OPRL1. Initial analysis revealed that there were a greater number of BDNF allele frequencies among cases, compared with controls (P = .008). “It would appear that BDNF variants confer resilience for combat-related PTSD,” Dr. Marmar said.

The researchers also found a single nucleotide polymorphism never previously described on Chromosome 4. “It’s in a region between genes, probably a micro-RNA regulatory gene on the 4th chromosome,” he said. “That gene in our sample was associated with higher levels of PTSD. In addition, fMRI studies found that carrying this allele was associated with weaker activation of prefrontal cortical areas in the brain to empirical faces tasks.”

The endocrine core found that PTSD cases had lower ambient cortisol levels, compared with controls (P = .051). They also had significantly greater cortisol suppression following dexamethasone administration, compared with controls (P = .013). “This is evidence that there is increased glucocorticoid receptor sensitivity in PTSD expressing as elevated cortisol suppression,” Dr. Marmar said.

Investigators from the structural imaging core found no significant differences in overall hippocampal volume or in the five major hippocampal subfields between PTSD cases and controls, nor in difference in the volume of other brain structures previously implicated in PTSD, such as the amygdala and the thalamus. However, the researchers are finding some differences between cases and controls on functional imaging, including increased spontaneous activity in the amygdala and the insula, and decreased spontaneous activity in the precuneus. “The overall findings on fMRI are that there’s increased activity in the regions [of the brain] associated with fear and decreased connectivity between the frontal cortex and the amygdala,” he said. “This is consistent with the model of dysregulated fear activity in PTSD.”

Researchers have also observed that many markers of metabolic syndrome are significantly elevated between PTSD cases and controls, including fasting glucose (P = .001), weight (P = .03), and resting pulse (P = .003). “When you covary for depression, these findings remain,” Dr. Marmar said. “It’s important to note that these are men mostly in their early 30s recently returned from war and recently in military training, physically fit to be deployed to war.”

He closed his presentation by noting that mounting evidence from animal and human studies suggests evidence of mitochondrial dysfunction in PTSD. In the current analysis, researchers observed a reduced abundance of citrate and other mitochondrial metabolites in PTSD cases compared with controls, as well as an increased abundance of “premitochondrial” metabolites such as pyruvate and lactate. “These findings stand when you covary for depression and for metabolic syndrome,” Dr. Marmar said.

“We believe that these may be very important potential future candidate biomarkers to differentiate PTSD cases from controls.”

The next step in this effort, he added, is to replicate the consortium’s overall findings in a cross-validation sample of 50 male cases and 50 male controls. “We also have a sample of 40 female cases and 40 controls to see if the markers are the same or different,” he said. The researchers are also conducting a prospective study of 1,200 active duty military personnel, who will be evaluated before and after deployment.

For now, some clinicians wonder what should be done for men and women who carry the PTSD risk alleles, or carry the endocrine or metabolism vulnerability to develop complications from combat exposure. “That’s a very sensitive national question,” Dr. Marmar said. “People want to serve their country. The answer may be to allow service but to have a more nuanced approach to what people’s roles should be within the military, to match individuals’ stress resilience with the responsibilities they have.”

Dr. Marmar reported that he had no relevant financial conflicts.

[email protected]

On Twitter @dougbrunk

Pelvic ultrasonography remains the preferred imaging method to evaluate most adnexal cysts, given its ability to accurately characterize their various aspects:

In the first of this 4-part series on the sonographic features of cystic adnexal pathology, we focus on simple and hemorrhagic cysts. In the following parts we will highlight:

An earlier installment of this series entitled “Hemorrhagic ovarian cysts: one entity with many appearances” (May 2014) also focused on cystic pathology.

Figure 1: Simple cyst

A simple cyst in a 32-year-old patient. Figure 2: Hemorrhagic cyst Note the lacy/reticular internal echoes and lack of internal blood flow on color Doppler. Figure 3: Cystic teratoma This cyst exhibits the “dermoid mesh” and hyperechoic lines that correspond with hair. Figure 4: Endometrioma Note diffuse low-level internal echoes (“ground glass”) and no “ring of fire” on color Doppler.

Characteristics of simple cysts
A simple cyst typically is round or oval, anechoic, and has smooth, thin walls. It contains no solid component or septation (with rare exceptions), and no internal flow is visible on color Doppler imaging.

Levine and colleagues observed that simple adnexal cysts as large as 10 cm carry a risk of malignancy of less than 1%, regardless of the age of the patient. In its 2010 Consensus Conference Statement,¹ the Society of Radiologists in Ultrasound recommended the following management strategies for women with simple cysts:

Reproductive-aged women

Postmenopausal women

Characteristics of hemorrhagic cysts
These cysts can be quite variable in appearance. Among their sonographic features:

In its 2010 Consensus Conference Statement, the Society of Radiologists in ­Ultrasound recommended the following management strategies¹:

Premenopausal women

Recently menopausal women

Later postmenopausal women

Share your thoughts on this article! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

Pelvic ultrasonography remains the preferred imaging method to evaluate most adnexal cysts, given its ability to accurately characterize their various aspects:

In the first of this 4-part series on the sonographic features of cystic adnexal pathology, we focus on simple and hemorrhagic cysts. In the following parts we will highlight:

An earlier installment of this series entitled “Hemorrhagic ovarian cysts: one entity with many appearances” (May 2014) also focused on cystic pathology.

Figure 1: Simple cyst

A simple cyst in a 32-year-old patient. Figure 2: Hemorrhagic cyst Note the lacy/reticular internal echoes and lack of internal blood flow on color Doppler. Figure 3: Cystic teratoma This cyst exhibits the “dermoid mesh” and hyperechoic lines that correspond with hair. Figure 4: Endometrioma Note diffuse low-level internal echoes (“ground glass”) and no “ring of fire” on color Doppler.

Characteristics of simple cysts
A simple cyst typically is round or oval, anechoic, and has smooth, thin walls. It contains no solid component or septation (with rare exceptions), and no internal flow is visible on color Doppler imaging.

Levine and colleagues observed that simple adnexal cysts as large as 10 cm carry a risk of malignancy of less than 1%, regardless of the age of the patient. In its 2010 Consensus Conference Statement,¹ the Society of Radiologists in Ultrasound recommended the following management strategies for women with simple cysts:

Reproductive-aged women

Postmenopausal women

Characteristics of hemorrhagic cysts
These cysts can be quite variable in appearance. Among their sonographic features:

In its 2010 Consensus Conference Statement, the Society of Radiologists in ­Ultrasound recommended the following management strategies¹:

Premenopausal women

Recently menopausal women

Later postmenopausal women

Share your thoughts on this article! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

Pelvic ultrasonography remains the preferred imaging method to evaluate most adnexal cysts, given its ability to accurately characterize their various aspects:

In the first of this 4-part series on the sonographic features of cystic adnexal pathology, we focus on simple and hemorrhagic cysts. In the following parts we will highlight:

An earlier installment of this series entitled “Hemorrhagic ovarian cysts: one entity with many appearances” (May 2014) also focused on cystic pathology.

Figure 1: Simple cyst

A simple cyst in a 32-year-old patient. Figure 2: Hemorrhagic cyst Note the lacy/reticular internal echoes and lack of internal blood flow on color Doppler. Figure 3: Cystic teratoma This cyst exhibits the “dermoid mesh” and hyperechoic lines that correspond with hair. Figure 4: Endometrioma Note diffuse low-level internal echoes (“ground glass”) and no “ring of fire” on color Doppler.

Characteristics of simple cysts
A simple cyst typically is round or oval, anechoic, and has smooth, thin walls. It contains no solid component or septation (with rare exceptions), and no internal flow is visible on color Doppler imaging.

Levine and colleagues observed that simple adnexal cysts as large as 10 cm carry a risk of malignancy of less than 1%, regardless of the age of the patient. In its 2010 Consensus Conference Statement,¹ the Society of Radiologists in Ultrasound recommended the following management strategies for women with simple cysts:

Reproductive-aged women

Postmenopausal women

Characteristics of hemorrhagic cysts
These cysts can be quite variable in appearance. Among their sonographic features:

In its 2010 Consensus Conference Statement, the Society of Radiologists in ­Ultrasound recommended the following management strategies¹:

Premenopausal women

Recently menopausal women

Later postmenopausal women

Share your thoughts on this article! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

FEMALE URINARY INCONTINENCE DEVICE

The InTone system for moderate to severe incontinence combines muscle stimulation with pelvic-floor exercises. A hand-held control unit allows the patient to listen to prerecorded exercises at home. The control unit also offers visual biofeedback to ensure that the exercises are being completed properly. The patient can present the data from her workouts, stored by the handheld control unit, to her physician, who can then individualize the exercise plan. InTone is indicated for use in 12-minute sessions, six times a week, for 90 days to treat stress urinary incontinence, and for 180 days for urgency or mixed incontinence.
FOR MORE INFORMATION, VISIT www.incontrolmedical.com

TISSUE RETRIEVAL SACS

PANNICULUS RETRACTOR

traxi can be applied and used as a sterile or nonsterile product in conjunction with both external and internal retractors. The manufacturer explains that traxi works by anchoring at the xiphoid and distributing the patient’s weight rather than applying it fully on the sternum, which can make it difficult for the patient to breathe. traxi should not be left on the patient for longer than 24 hours. traxi is labeled with HOLD and PULL HERE tabs, as well as A, B, and C tabs to guide the clinician through the retractor application process.
FOR MORE INFORMATION, VISIT www.clinicalinnovations.com

SALIVA FERTILITY MONITOR

First thing each morning, before eating, drinking, smoking, or brushing teeth, a woman applies a thick drop of saliva to the glass surface and waits for it to dry (5–15 minutes). Then she compares the image she sees through the lens to the chart supplied with the kit and inputs her results on the KNOWHEN app. If she is not ovulating, dots and circles may appear. When she sees a few fernlike crystals, it means she is starting to ovulate, or has just finished ovulating. Consistent fern-like crystals in the viewer indicate that she is ovulating. During ovulation, high estrogen levels raise the percentage of salt in a woman’s body. In saliva, these salts take the shape of ferns under the 60X magnification of the KNOWHEN microscope. The kit includes the app and educational material, including an instructional video.
FOR MORE INFORMATION, VISIT www.knowhen.com  

FEMALE URINARY INCONTINENCE DEVICE

The InTone system for moderate to severe incontinence combines muscle stimulation with pelvic-floor exercises. A hand-held control unit allows the patient to listen to prerecorded exercises at home. The control unit also offers visual biofeedback to ensure that the exercises are being completed properly. The patient can present the data from her workouts, stored by the handheld control unit, to her physician, who can then individualize the exercise plan. InTone is indicated for use in 12-minute sessions, six times a week, for 90 days to treat stress urinary incontinence, and for 180 days for urgency or mixed incontinence.
FOR MORE INFORMATION, VISIT www.incontrolmedical.com

TISSUE RETRIEVAL SACS

PANNICULUS RETRACTOR

traxi can be applied and used as a sterile or nonsterile product in conjunction with both external and internal retractors. The manufacturer explains that traxi works by anchoring at the xiphoid and distributing the patient’s weight rather than applying it fully on the sternum, which can make it difficult for the patient to breathe. traxi should not be left on the patient for longer than 24 hours. traxi is labeled with HOLD and PULL HERE tabs, as well as A, B, and C tabs to guide the clinician through the retractor application process.
FOR MORE INFORMATION, VISIT www.clinicalinnovations.com

SALIVA FERTILITY MONITOR

First thing each morning, before eating, drinking, smoking, or brushing teeth, a woman applies a thick drop of saliva to the glass surface and waits for it to dry (5–15 minutes). Then she compares the image she sees through the lens to the chart supplied with the kit and inputs her results on the KNOWHEN app. If she is not ovulating, dots and circles may appear. When she sees a few fernlike crystals, it means she is starting to ovulate, or has just finished ovulating. Consistent fern-like crystals in the viewer indicate that she is ovulating. During ovulation, high estrogen levels raise the percentage of salt in a woman’s body. In saliva, these salts take the shape of ferns under the 60X magnification of the KNOWHEN microscope. The kit includes the app and educational material, including an instructional video.
FOR MORE INFORMATION, VISIT www.knowhen.com  

FEMALE URINARY INCONTINENCE DEVICE

The InTone system for moderate to severe incontinence combines muscle stimulation with pelvic-floor exercises. A hand-held control unit allows the patient to listen to prerecorded exercises at home. The control unit also offers visual biofeedback to ensure that the exercises are being completed properly. The patient can present the data from her workouts, stored by the handheld control unit, to her physician, who can then individualize the exercise plan. InTone is indicated for use in 12-minute sessions, six times a week, for 90 days to treat stress urinary incontinence, and for 180 days for urgency or mixed incontinence.
FOR MORE INFORMATION, VISIT www.incontrolmedical.com

TISSUE RETRIEVAL SACS

PANNICULUS RETRACTOR

traxi can be applied and used as a sterile or nonsterile product in conjunction with both external and internal retractors. The manufacturer explains that traxi works by anchoring at the xiphoid and distributing the patient’s weight rather than applying it fully on the sternum, which can make it difficult for the patient to breathe. traxi should not be left on the patient for longer than 24 hours. traxi is labeled with HOLD and PULL HERE tabs, as well as A, B, and C tabs to guide the clinician through the retractor application process.
FOR MORE INFORMATION, VISIT www.clinicalinnovations.com

SALIVA FERTILITY MONITOR

First thing each morning, before eating, drinking, smoking, or brushing teeth, a woman applies a thick drop of saliva to the glass surface and waits for it to dry (5–15 minutes). Then she compares the image she sees through the lens to the chart supplied with the kit and inputs her results on the KNOWHEN app. If she is not ovulating, dots and circles may appear. When she sees a few fernlike crystals, it means she is starting to ovulate, or has just finished ovulating. Consistent fern-like crystals in the viewer indicate that she is ovulating. During ovulation, high estrogen levels raise the percentage of salt in a woman’s body. In saliva, these salts take the shape of ferns under the 60X magnification of the KNOWHEN microscope. The kit includes the app and educational material, including an instructional video.
FOR MORE INFORMATION, VISIT www.knowhen.com