Editor's Note: This article is based on Friberg L, Rosenqvist M, Lip GY. Net clinical benefit of warfarin in patients with atrial fibrillation: A report from the swedish atrial fibrillation cohort study. Circulation. 2012;125:2298-2307.

Introduction

Atrial fibrillation (AF) is associated with significant mortality and morbidity from stroke and thromboembolism. Oral anticoagulation (OAC) therapy with warfarin is highly effective in reducing these complications but is unfortunately associated with an increased bleeding risk. Thus, the decision to prescribe OAC often involves weighing this increased bleeding risk against the risk of thromboembolic events.

Some guidelines recommend use of risk models, such as the CHA2DS2-VASc, CHADS2 and HAS-BLED scores, for assessing these risks prior to making a decision about the use of OAC. But assessing the risks of bleeding and thromboembolic events independently can be problematic since risk factors for both complications (e.g., advanced age) frequently overlap.

Accordingly, the study by Friberg and colleagues set out to determine the “net” clinical benefit derived from OAC in patients with AF by simultaneously considering both the risks of ischemic stroke and intracranial bleeding.

Methods

The authors identified 182,678 individuals with a diagnosis of AF through the Swedish National Hospital Discharge Register (HDR). They used HDR to obtain information about current and previous diseases, as well as information about events that occurred during follow-up. Information about medication use was obtained from the National Prescribed Drugs Registry of Sweden, which links prescriptions to individual patients.

The authors compared the risk for ischemic stroke (IS) without OAC with warfarin against the risk of intracranial hemorrhage (ICH) when treated with warfarin for all combinations of CHA2DS2-VASc and HAS-BLED scores as follows: Net benefit = (IS off warfarin - ICH on warfarin). The adjusted net clinical benefit was calculated with the weight of 1.5 given to ICH to account for the more disastrous effects of ICH as follows: Net Benefit= (IS off warfarin - IS on warfarin) -1.5 (ICH on warfarin - ICH off warfarin).

Results

The ischemic stroke rates and composite thromboembolism rates increased with increasing CHA2DS2-VASc scores in patients treated with or without warfarin at baseline. Intracranial bleeding occurred at an annual rate of 0.6% in warfarin-treated and untreated patients alike, whereas bleeding of any type occurred at an annual rate of 2.3% (1.9% in patients on warfarin at baseline and 2.7% in patients who never used warfarin during the study period).

Regardless of whether the CHA2DS2-VASc or the HAS-BLED score was used, the risk of ischemic stroke increased more than the risk of bleeding as the risk score increased. This was true for patients with and without warfarin.

The net result favored warfarin treatment for all patients except for those at very low risk of ischemic stroke, identified using the CHA2DS2-VASc score (score=0). Furthermore, those with the highest net benefit from warfarin were patients also with the highest risk scores for both thromboembolic events, and importantly, bleeding risk. In these high-risk groups, warfarin treatment was associated with up to 12 fewer events per 100 years at risk than if warfarin was not given. In contrast, patients at very low risk of ischemic stroke (CHA2DS2-VASc score=0) and moderately elevated bleeding risk appeared to have net clinical harm from warfarin treatment.

The results were broadly similar with CHADS2, except for patients with very low embolic risk; the greater accuracy of the CHA2DS2-VASc in identifying these patients allowed it to determine who would have no net clinical benefit or even some disadvantage from OAC.

Finally, the outcome of patients treated with warfarin with regard to a composite end point consisting of all cause mortality, ischemic stroke, or intracranial bleed was better for patients treated with warfarin than patients who were not treated with warfarin irrespective of their bleeding and thromboembolic risk.

Conclusion

In the majority of patients with AF, the risk of ischemic stroke without OAC is far higher than the risk of intracranial hemorrhage with OAC. 

Perspective

Atrial fibrillation (AF) is the most prevalent arrhythmia leading to hospital admissions.¹ It has been estimated that the number of patients diagnosed with AF will increase to more than 15 million by 2050.² AF is associated with an increase in the risk of stroke, congestive heart failure and overall mortality.^3-5 Oral anticoagulants (OAC), which typically refers to warfarin, are effective in reducing the risk of stroke. However, they may also increase the risk of bleeding.⁶ Clinicians often struggle with the decision to prescribe OAC and have to weigh the risk of bleeding against the risk of thromboembolic events. As a consequence, many patients with high risk of thromboembolic stroke are not treated with OAC.⁷ Several risk scores offer the clinicians a relatively simple way to assess risk of bleeding and stroke and their use has been recommended by the guidelines.

The study by Friberg et al.⁸ provides important insight into this clinical conundrum. Using the Swedish National Hospital Discharge Register, patients were classified according to stroke risk (CHADS2 and CHA2DS2-VASc) and bleeding risk (HAS-BLED). As the risk of ischemic stroke increased, the risk of intracranial hemorrhage and other bleeding also increased. Patients with high bleeding risk scores suffered more ischemic strokes than bleeding events, so the net clinical benefit almost always favored anticoagulation, except those patients with very low embolic risk. The CHA2DS2-VASc was able to identify those very-low risk patients who had no net clinical benefit or even potential harm from anticoagulant treatment with warfarin.

This study’s strengths include its large size, “real-world” setting, and comprehensive data collection methods. However, it was limited by its observational design, and therefore, is vulnerable to selection bias in the patients who were treated with OAC. As the authors correctly indicate, residual confounding may over-estimate their calculation of net clinical benefit. Also the study evaluated a Swedish cohort with diagnosis of AF in the hospital, and therefore, the results may not be generalizable to all contemporary populations of AF, including outpatients with AF. Authors also had to modify the HAS-BLED score because some of the information was not readily available from the registry (e.g. non-steroidal, anti-inflammatory use and labile international normalized ratio). Therefore, estimates based on the HAS-BLED score must be interpreted with caution. Another issue is that the time in therapeutic, sub and supra-therapeutic range of INR for individual patients may affect the rates of stroke and bleeding, and this information was not readily available for the patients in this study. Finally, the authors were not able to directly assess the risk of actual consequences of thromboembolic or bleeding events and therefore assigned a 1.5 times increased in the weight of ICH to account for the more severe consequences of cerebral bleeding.

We believe a key observation of the article is the application of CHA2DS2-VASc, which has been promoted as a more sensitive risk score for stroke in AF. As others have shown it is more effective than CHADS2 score in identifying patients with a very low risk of thromboembolism. This is critical as it can potentially identify a unique population of patients who may derive no net clinical benefit from OAC.⁹

In conclusion, the findings by Friberg and colleagues are important and should give pause to physicians when considering withholding anticoagulation in AF patients due to presumed bleeding risk. This is a point further emphasized by Fuster and Chinitz in their excellent accompanying editorial.¹⁰ We agree with both the authors and the editorialists that, in general, only patients with CHA2DS2-VASc of 0 should routinely be considered for more conservative strategies that avoid OAC. Although bleeding risk is an important concern for clinicians and should be discussed with patients, using this information in isolation from assessments of thromboembolic risk could lead to erroneous decision-making given the complex inter-relationship between the risk of bleeding and thromboembolic events. Of course, it remains to be seen how novel anticoagulants with typically lower bleeding risk, like dabigatran, may alter these challenging decisions between patients and their physicians.

References

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2. Miyasaka Y, Barnes ME, Gersh BJ, Cha SS, Bailey KR, Abhayaratna WP, Seward JB, Tsang TS. Secular trends in incidence of atrial fibrillation in olmsted county, minnesota, 1980 to 2000, and implications on the projections for future prevalence. Circulation. 2006;114:119-125.
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6. Hart RG, Pearce LA, Aguilar MI. Meta-analysis: Antithrombotic therapy to prevent stroke in patients who have nonvalvular atrial fibrillation. Ann Intern Med. 2007;146:857-867.
7. Glazer NL, Dublin S, Smith NL, French B, Jackson LA, Hrachovec JB, Siscovick DS, Psaty BM, Heckbert SR. Newly detected atrial fibrillation and compliance with antithrombotic guidelines. Arch Intern Med. 2007;167:246-252.
8. Friberg L, Rosenqvist M, Lip GY. Net clinical benefit of warfarin in patients with atrial fibrillation: A report from the swedish atrial fibrillation cohort study. Circulation. 2012;125:2298-2307.
9. Olesen JB, Torp-Pedersen C, Hansen ML, Lip GY. The value of the cha2ds2-vasc score for refining stroke risk stratification in patients with atrial fibrillation with a chads2 score 0-1: A nationwide cohort study. Thrombosis and haemostasis. 2012;107:1172-1179.
10. Fuster V, Chinitz JS. Net clinical benefit of warfarin: Extending the reach of antithrombotic therapy for atrial fibrillation. Circulation. 2012;125:2285-2287.

Keywords: Anticoagulants, Atrial Fibrillation, Heart Failure, International Normalized Ratio, Stroke, Sweden, Thromboembolism, Warfarin

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