Stroke in Heart Failure: Atrial Fibrillation Revisited?

Like the dysfunctional left atrial appendage, the dilated left ventricle appears to be a site of thrombus formation. Cardioembolism is likely the main pathogenesis of stroke in heart failure (HF), as it is in atrial fibrillation (AF). Warfarin used widely to prevent stroke in both conditions, but clear scientific underpinning for this use is available only for AF. The role of warfarin in the prevention of stroke in AF is clearly defined. Multiple prospective randomized clinical studies have shown that warfarin reduces the risk of stroke in AF1 and have provided a clear understanding of the risk factors for stroke in AF. We also know the risk reduction that can be obtained when balancing warfarin's effect on stroke reduction and central nervous system hemorrhage, which allows selection of a population at high risk for stroke, in whom warfarin's benefits outweigh its risks.2 The use of CHADS2, the best validated risk stratification scheme for identifying patients at high risk for stroke, results in about 31% of AF patients being classified as high risk (stroke rate > 4% per year), for whom warfarin is recommended.3

HF, the second most frequent cardiac condition associated with cardioembolic stroke after AF (Table 1), is associated with about 9% of all strokes, compared with 15% for AF. HF and AF are present together in about 2% of strokes. There are some major differences between stroke in HF and stroke in AF. The overall rate of stroke in HF (1.6% per year) is about one-third of that in AF; however, the prevalence of HF is almost double that of AF, with over 5 million persons in the United States affected. Up to now, the use of warfarin to prevent stroke in patients with HF has been based on either old, inadequate studies or small, nonrandomized studies.4 The recently published WATCH (Warfarin versus Antiplatelet Therapy in Chronic Heart Failure) Study is the first large prospective randomized study of warfarin in HF patients in sinus rhythm.5 The composite primary endpoint (death, myocardial infarction, or nonfatal stroke) did not differ between warfarin and either asprin or clopidogrel; however, nonfatal stroke, a secondary endpoint, was significantly reduced in patients receiving warfarin compared with those receiving either aspirin or clopidogrel (P < .01). The relative risk reduction comparing a combination of stroke and central nervous system hemorrhage between warfarin and aspirin was 35%, almost exactly the same as the previously known risk reduction of 36% (95% confidence interval = 14%–52%) between warfarin and aspirin in AF.2 This important finding suggests that warfarin has a similar biological effect on stroke in HF and in AF. The WATCH results are based on only a small number of strokes, however, and both the presence and the magnitude of a stroke risk reduction effect by warfarin in HF remain to be confirmed. The WARCEF (Warfarin versus Aspirin in Reduced Cardiac Ejection Fraction) Study, which is nearing the end of its recruitment phase, should provide more data on this. The WATCH and WARCEF investigators have also agreed to perform a combined analysis.

Table 1. AF and HF statistics.

		AF	HF
	US prevalence	2.3 million	5.6 million
	Annual US strokes	105,000	60,000
	Annual stroke rate	5%	1.6%
	Annual mortality	3%	19%
	Number needed to treat with warfarin	45	200

If we assume that the biological effect of warfarin is similar in HF and AF, then the next important question is: Which HF patients should receive anticoagulation therapy? Selecting a small high-risk subgroup from a very large low-risk population is difficult clinically and is currently done in a very arbitrary fashion by both neurologists and cardiologists. Baseline data on the use of warfarin from clinical HF studies suggest that up to 28% of HF patients are currently treated with warfarin.6, 7 Because CHADS2 identifies only 31% of AF patients as being at high risk for stroke,8 it is unlikely that more than about 10% of HF patients are at high risk for stroke, given the lower overall stroke rate in HF compared with AF. Many HF patients receiving warfarin probably are not benefiting from it, or worse, are suffering needless hemorrhagic complications. Developing a scheme for stroke risk stratification in HF is important, but our knowledge of risk factors for stroke in HF is still very incomplete, and there appear to be significant differences from the risk factors for AF.4 Many clinicians use low ejection fraction (EF) as an indication to administer anticoagulation therapy to patients with HF or cardiomyopathy; however, there are inconsistencies in the data supporting low EF as a risk factor for stroke in HF, which come largely from case-control studies or secondary analyses of clinical trials.4 A previous population study did not identify low EF as a risk factor for stroke,9 and the status of low EF as a risk factor for stroke in HF awaits confirmation. The same population study also did not find hypertension to be a risk factor for stroke in HF.9 Low blood pressure is associated with poor survival in HF, probably reflecting a failing cardiac pump.10 The odds of prevalent self-reported stroke/transient ischemic attack were found to be increased most markedly with low systolic blood pressure in HF,11 suggesting that a failing ventricle may be thrombogenic and that systolic hypotension merits further investigation as a risk factor for stroke in HF. As in AF, previous stroke does appear to be a major risk for stroke in HF, with a recurrent stroke risk of only 9%–10% per year.12, 13 This is similar to the recurrent stroke rate in AF of 10.8 per 100 patient years.3 Previous stroke is the main driver for high stroke risk in AF, and previous stroke by itself identified 71% of AF patients at high risk for stroke.3 It is likely that previous stroke is a major risk factor for stroke in HF as well, as supported by results from the Olmsted County Study.9 More data from population studies and the WARCEF Study are needed to allow the development of a comprehensive risk stratification scheme for stroke in HF.