Cleveland Clinic Journal of Medicine

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.