Pathophysiology of thromboembolism in heart failure
Patients with congestive heart failure run a significant risk of malignant arrhythmia and of thromboembolic complications. The dilated atria and ventricles are thought to be responsible for the development of thrombi, which can subsequently be embolised. The risk of thromboembolism is further enhanced by the presence of atrial fibrillation, which is very common in patients with heart failure, whereas patients with left-ventricular dysfunction and sinus rhythm are also at significant risk of thromboembolic complications and might benefit from oral anticoagulation, as observed in a large patient cohort Citation[1]. Many heart failure patients have underlying ischemic heart disease and are, therefore, treated with aspirin. One disadvantage of aspirin is its theoretical interaction with angiotensin-converting-enzyme (ACE) inhibitors, a standard therapy in heart failure. Aspirin is thought to block kidney prostaglandin production, which leads to elevated blood pressure. Previous observations have addressed this and found a decreased long-term mortality benefit of ACE inhibitors for complicated myocardial infarction in patients on aspirin compared with those without aspirin Citation[2]. However, until the Warfarin and Antiplatelet Therapy in Heart Failure (WATCH) Citation[3,4] and Warfarin/Aspirin Study in Heart failure (WASH) Citation[5] trials, there had not been a randomized trial investigating aspirin in heart failure patients on ACE inhibitors.
Randomized trials of antithrombotic therapy in heart failure
The WATCH trial evaluated the optimal antithrombotic strategy for thromboembolism prevention in patients with heart failure in sinus rhythm and the clinical interactions between aspirin and ACE inhibitors. In total, 1587 heart failure patients with sinus rhythm were randomized to 162 mg aspirin daily, 75 mg clopidogrel daily or warfarin with a target international normalized ratio between 2.5 and 3.0 (median achieved 2.6). After 23 months of follow-up, there were no differences in the occurrences of the primary end point, myocardial infarction, stroke or death. Stroke occurred in 0.7% of the warfarin patients, compared with 2.1% of aspirin and 2.5% of clopidogrel patients (p < 0.05 vs aspirin/clopidogrel combined). Hospitalization for heart failure was seen in 16.1% of the warfarin group, 22.2% of the aspirin group (p < 0.01 vs warfarin) and 18.3% of the clopidogrel group (p = 0.38 vs warfarin). Cerebral bleeding was most common on warfarin therapy (1.3%), but this was not significantly different from aspirin or clopidogrel (0.6 and 0.5%, respectively). Severe extracranial bleeding was most frequent in the warfarin patients (5.6%) and was seen less with clopidogrel and aspirin (2.5 and 3.1%, respectively). The WATCH trial does not address whether antithrombotic therapy is necessary in heart failure in the first place, since it had no placebo group.
The WASH trial studied the role of warfarin, aspirin or no prophylaxis in 279 ACE inhibitor-treated patients with heart failure in sinus rhythm against stroke, myocardial infarction and death Citation[5]. Although the sample size was too small to be conclusive, there was no difference in the primary end points among groups. However, hospitalization for heart failure was observed in 58% of aspirin patients versus 42% on warfarin and 48% without prophylaxis (p = 0.05). Stroke occurred in no warfarin patients, compared with 2% of patients on aspirin and 2% of patients without prophylaxis. Severe bleeding was seen in 4% of patients on warfarin, 1% of patients on aspirin and none without prophylaxis. Despite the numbers in WASH being small, warfarin was the best therapy for preventing stroke and hospitalization for heart failure, but at the cost of increased bleeding complications.
Neither WATCH nor WASH answers the question of what the optimal antithrombotic prophylaxis should be, if needed. All patients were in sinus rhythm, but most had coronary artery disease. A placebo-controlled comparison was not, therefore, deemed ethically acceptable in the large WATCH study, although it was used in the much smaller WASH trial.
Both studies demonstrate that, for patients receiving ACE inhibitors for heart failure, the inhibition of prostaglandin production by aspirin leads to more hospital admissions than for patients not taking aspirin. By contrast, clopidogrel does not seem to have this disadvantage in WATCH. This is a new and important finding, although, in many European countries, the daily aspirin dose is less than 160 mg and, therefore, the unfavorable results of aspirin in both trials (162 mg in WATCH and 300 mg in WASH) are of limited value. Furthermore, in a large registry of 24,012 elderly patients with heart failure and coronary artery disease, the use of aspirin was associated with a significant lower one-year rate of mortality and re-admission for heart failure Citation[6].
Of course, the aforementioned registries lack the power of randomized trials, but unfortunately the WATCH and WASH trials are insufficiently powered to support warfarin and discourage aspirin use and, thus, change current practice in heart failure and sinus rhythm. The observational data suggest that aspirin-associated (re-)admissions for heart failure, if any, do not translate into increased risk of death Citation[2,6].
Better answers may come from the recently initiated WARCEF (Warfarin versus Aspirin in Reduced Ejection Fraction) study. This trial will include 2860 patients with a left ventricular ejection fraction of less than 35% and sinus rhythm. Stroke and death will be the primary end point and myocardial infarction and hospitalization for heart failure are prespecified secondary end points.
Physicians seeing such patients should decide who needs antithrombotic prophylaxis on a case-by-case basis, especially since many heart failure patients do have significant comorbidity precluding the use of oral anticoagulants.
Table 1. Long-term risk of death on aspirin and no aspirin in randomized post-myocardial infarction trials with ACE inhibitors.
Table 2. 1-year risk of death on aspirin (n = 13,049) and no aspirin (n = 10,963) in elderly patients taking ACE inhibitors for heart failure.
References
- Loh E, St John Sutton M, Wun CC et al. Ventricular dysfunction and the risk of stroke after myocardial infarction. N. Engl. J. Med.336, 251–257 (1997).
- Teo KK, Yusuf S, Pfeffer M et al. Effects of long-term treatment with angiotensin-converting enzyme inhibitors in the presence or absence of aspirin: a systematic review. Lancet360, 1037–1043 (2002).
- Massie BM, Krol WF, Ammon SE et al. The Warfarin and Antiplatelet Therapy in Heart Failure trial (WATCH): rationale, design, and baseline patient characteristics. J. Card. Fail.10, 101–112 (2004).
- Massie BM. The Warfarin and Antiplatelet Therapy in Heart Failure trial (WATCH). Presented at the American College of Cardiology Annual Scientific Session, New Orleans, USA. March 2004.
- Cleland JGF, Findlay I, Jafri S et al. The Warfarin/Aspirin Study in Heart failure (WASH): a randomized trial comparing antithrombotic strategies in patients with heart failure. Am. Heart J.148, 157–164 (2004).
- Masoudi FA, Wolfe P, Havranek et al. Aspirin use in older patients with heart failure and coronary artery disease: national prescription patterns and relationship with outcomes. J. Am. Coll. Cardiol.46, 955–962 (2005).