New data on Warfarin Therapy for Atrial Fibrillation
New data on Warfarin Therapy for Atrial Fibrillation
Abstract & Commentary
By Michael H. Crawford, MD
Source: Singer DE, et al. The net clinical benefit of warfarin anti coagulation in atrial fibrillation. Ann Int Med. 2009; 151:297-30 5.
Current recommendations for stroke prophylaxis with warfarin for patients with atrial fibrillation do not take into account the risks of hemorrhage. Thus, Singer et al from Kaiser Permanente studied more than 13,000 patients with non-valvular atrial fibrillation to estimate the net clinical benefit of warfarin therapy for atrial fibrillation (reduction in thromboembolism minus the increase in intracranial hemorrhage). The mean age of the subjects was 73 years, and 20% had no major risk factors for stroke based upon CHADS2. At entry, about half the patients were receiving warfarin, and tended to have a higher prevalence of stroke risk factors, except for those age > 75 years. Over a median follow-up of six years, there were 1,092 embolic events (1,017 strokes) and 299 intracranial hemorrhage events (193 on warfarin). The annual rate of stroke or systemic embolic events was 2.1% in those not on warfarin and 1.3% in those on warfarin. The annual rate of intracranial hemorrhage was 0.32% in those not on warfarin and 0.58% in those on warfarin. The adjusted net clinical benefit of warfarin was 0.68 adverse events prevented per 100 person years. The benefits of warfarin were observed to increase as the risks for thromboembolism increased, but harm increased only modestly. Prior stroke was the strongest risk factor for subsequent stroke and intracranial hemorrhage. The net clinical benefit increased with the presence of any risk factor except hypertension. Also, net clinical benefit increased with age, being near zero at ages < 75 years and as the CHADS2 score increased above one. Singer et al concluded that a risk assessment that includes the risk of thromboembolism and intracranial hemorrhage provides a better basis for decisions regarding warfarin therapy in patients with non-valvular atrial fibrillation.
When faced with starting a patient with atrial fibrillation on warfarin, many physicians demur for a variety of reasons. One is fear of major bleeding. The downsides to warfarin therapy are often applied irrationally to our decision making, as there is no equivalent of the CHADS2 score for the risk of warfarin. Thus, this analysis of the Kaiser Permanente database on warfarin therapy for atrial fibrillation is of interest because it estimates net clinical benefit of warfarin by subtracting the risk of intracerebral hemorrhage, the most serious major bleeding event, from the predicted benefits of treatment based on CHADS2.
There are several clinically useful points made by this analysis. First, the risk of stroke in non-valvular atrial fibrillation is lower now than that observed in the up to 20-year-old prior studies (2% vs. 5%). This makes consideration of adverse effects even more compelling. Second, the risk of stroke increases considerably with increasing CHADS2 score: one point each for congestive heart failure, hypertension, age > 75 years, and diabetes, and 2 points for prior stroke. However, the risk of intracerebral hemorrhage is relatively constant across CHADS2 scores. Thus, the higher the CHADS2 score, the greater the net clinical benefit. In their data, a CHADS2 score of two or more would seem worth considering warfarin therapy. Finally, the net benefits of warfarin increase significantly over age 75 years. Treatment with warfarin should seriously be considered in such individuals, unless there are contraindications to its use.
The strengths of this study include the large population, with ample numbers of events and a relatively long follow-up period. Also, the events were carefully validated. This study represents best practices because in this closed population, INRs were tightly controlled to minimize complications. The major weakness is that it is a non-randomized, observational study. Hence, it is likely that patients at higher risk of stroke and with fewer potential contraindications were treated with warfarin, exaggerating the benefits and minimizing the risks, which will confound the results. Also, concomitant aspirin or other antiplatelet drug use was not recorded for this study, but is estimated to be about half the subjects. Finally, no specific predictors of intracranial bleed were identified, so an estimated net clinical benefit cannot be calculated for each individual. Prior stroke carries a two-point weight in the CHADS2 scoring system because it carries the highest risk of stroke, but this study showed it also carried the greatest risk of an intracranial hemorrhage on warfarin; the proverbial double-edged sword.
My take on this study is that the risk vs. benefit of warfarin is much narrower than previously thought, but warfarin should be seriously considered in those > 75 years old or with a CHADS2 score of two or more, unless they have a prior stroke; then, consultation with a neurologist should be sought before starting warfarin.
An Alternative to Warfarin Therapy for Atrial Fibrillation
Abstract & Commentary
By John P. DiMarco, MD, PhD, Professor of Medicine, Division of Cardiology, University of Virginia, Charlottesville. Dr. DiMarco is a consultant for Novartis, and does research for Medtronic and Guidant.
Source: Holmes DR, et al. Percutaneous closure of the left atrial appendage versus warfarin therapy for prevention of stroke in patients with atrial fibrillation: a randomized non-inferiority trial. Lancet. 2009;374:534-542
Stroke is the most dreaded complication of atrial fibrillation. The left atrial appendage is thought to be the source of many of the emboli in patients with atrial fibrillation. Although anticoagulation with warfarin is effective, warfarin therapy can be difficult to many patients due to unstable INR levels and increased risk for bleeding. This paper describes the use of a new device for occlusion of the left atrial appendage in patients with atrial fibrillation.
The WATCHMAN device is an expandable, nickel titanium (nitinol) frame structure with fixation barbs and a permeable polyester fabric cover. The devices are implanted percutaneously via a transseptal approach to seal the ostium of the left atrial appendage. The PROTECT AF study, reported here, was a randomized trial comparing the efficacy and safety of percutaneous closure of the left atrial appendage with this device compared to chronic warfarin therapy.
Adult patients with paroxysmal persistent or permanent nonvalvular atrial fibrillation were eligible for enrollment if they had one or more risk factors for stroke. All patients had to be eligible for warfarin therapy. Patients were randomly assigned to the intervention or control groups in a 2:1 ratio. Patients allocated to left atrial appendage closure had a WATCHMAN device implanted in the catheterization laboratory. Implantation was guided by fluoroscopy and transesophageal echocardiography (TEE) to ensure proper positioning and stability. After implantation, intervention patients were treated with warfarin for 45 days. TEE imaging was performed at 45 days, 6 months and 12 months to assess residual peri-device leakage, device stability, and position. Patients with complete closure of left atrial appendage documented were allowed to stop warfarin. They were then treated with clopidogrel and aspirin until the six-month visit, and aspirin thereafter. Patients in the control group received warfarin for the duration of the study, with a target INR between 2.0 to 3.0. Both groups were seen in follow-up at 45 days and at 6, 9, and 12 months after randomization. Neurologic assessments were performed at baseline, 12 months, and 24 months. The study was a non-inferiority comparison of warfarin to the WATCHMAN device for the composite endpoint of stroke, cardiovascular or unexplained death, or systemic embolism. The primary composite safety endpoint consisted of bleeding events or procedure-related complications.
The trial randomized 707 patients, with 463 assigned to device closure of the left atrial appendage and 244 assigned to chronic warfarin therapy. Device implantation was attempted in 449 patients, but 41 did not have a successful implantation. At the 45-day follow-up, 349 (86%) of the 408 patients who actually had an implanted device met TEE criteria for left atrial appendage closure and were able to stop warfarin. By six months, 92% of these 408 patients had met criteria for closure. In the control group, therapeutic INRs were achieved in 66% of the study visits. Left atrial appendage closure was non-inferior to warfarin in terms of the primary efficacy endpoint. This was 3.0 per 100 patient years in the intervention group vs. 4.9 per 100 patient years in the control group. At two years, the cumulative primary event rate for the intervention group was 5.9%, compared with 8.3% for the control group. Subgroup analysis showed consistent results across all subgroups. Additional observations were reported. The rate of ischemic stroke was higher in the intervention group than in the control group, primarily due to five patients who had periprocedural events related to air embolism. After the immediate periprocedure period, ischemic stroke rates were similar, with 1.3 events per 100 patient years in the intervention group compared with 1.6 events per 100 patient years in the control group. There were five hemorrhagic strokes in the control group, compared to only one hemorrhagic stroke in the intervention group. The latter occurred during the 45-day post-implant period while the patient was on warfarin. There were 21 deaths in the intervention group and 18 deaths in the control group. The cumulative mortality rates for the intervention and control groups were 3.0% vs. 3.1% at one year and 5.9% vs. 9.1% at two years.
Major complications were noted in the intervention group. A serious pericardial effusion occurred in 22 (4.8%) of the patients. Of these, 15 were treated with pericardiocentesis and seven required surgical drainage. Device embolization was noted in three patients. Pericardial effusions that did not require drainage were noted in eight additional patients. One patient in the intervention group suffered an esophageal tear and one had a procedure-related arrhythmia. Major bleeding was noted in 4.1% of the patients in the control group vs. 3.5% in the intervention group. Device-related complications decreased with operator experience.
Holmes et al concluded that percutaneous closure of the left atrial appendage using the WATCHMAN device was non-inferior to warfarin in terms of stroke, cardiovascular death, and systemic embolism. Although there were a significant number of periprocedural adverse complications, long-term outcomes were similar.
It is well established that warfarin markedly reduces the risk of stroke in patients with nonvalvular atrial fibrillation. However, up to one-third of patients are not candidates for warfarin because of risk factors for bleeding at baseline. If warfarin is started, major bleeding occurs in up to 5% to 10% of patients during the first months of therapy and then at a rate of at least 25 per year. The genetic variability in warfarin metabolism, and a high potential for food and drug interactions, make chronic warfarin therapy inconvenient and challenging.
For these reasons, development of a simple and safe method that would reduce stroke risk in patients with atrial fibrillation without the need for warfarin would be highly attractive. This paper describes an initial experience with an innovative device. Although placement is technically difficult and, in this early series, was associated with a significant risk for complications, it is highly likely that increased operator experience and modifications of the device itself will increase the safety profile over time. Long-term follow-up, however, will be necessary to ensure that the promising results seen in this paper are maintained during truly long-term therapy.Current recommendations for stroke prophylaxis with warfarin for patients with atrial fibrillation do not take into account the risks of hemorrhage.
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