Evidence-Based Co-Medication in Heart Failure: Necessary or Bystander?

This article refers to ‘Impact of aspirin and statins on long-term survival in patients with acute myocardial infarction complicated by heart failure: an analysis in 1746 patients’ by C. Lewinter et al., published in this issue on page xxx–xxx. The prognosis in heart failure is relatively poor because several unfavourable mechanisms may lead to premature death, e.g. malignant arrhythmia and progressive remodelling of the heart. Since heart failure may have several causes, fighting the basis of the syndrome may also be helpful in improving prognosis. Besides hypertension, valvular heart disease, and AF, CAD is a major cause of congestive heart failure. CAD has two faces: chronic atherosclerosis and acute coronary thrombosis. Both antithrombotic1 and antiatherosclerotic strategies2 may play a role in better outcomes for these patients. In this issue of the European Journal of Heart Failure, an interesting registry on these issues with a very long follow-up is published.3 This registry shows a long-term benefit of both strategies, either alone or in combination, when compared with neither. Although well performed, this registry raises several questions, since the results are at odds with those of randomized controlled trials as well as large registries. Patients with congestive heart failure have a significant risk for thrombo-embolic complications. Due to the diminished blood flow in the dilated atria and ventricles, these chambers are thought to be responsible for the development of thrombi, which can subsequently be embolized. The risk of thrombo-embolism is further enhanced by the presence of AF, which is common in patients with heart failure. Furthermore, (recurrent) coronary events may further damage the left ventricle. In some cases, a ventricular aneurysm may be formed, in which thrombosis is a common complication. Some physicians prescribe warfarin after anterior myocardial infarction complicated by LV aneurysm, which is not evidence based. Oral anticoagulation after myocardial infarction is nowadays largely replaced by aspirin and clopidogrel. One disadvantage of aspirin is its theoretical interaction with ACE inhibitors, a standard therapy in heart failure. Aspirin is thought to block kidney prostaglandin production leading to slightly elevated blood pressure. Previous observational studies have addressed this issue. A decreased long-term mortality benefit of ACE inhibitors was found in six placebo-controlled trials in patients on aspirin4 (Table 1). However, until the WATCH, WASH, and WARCEF trials,567 there had not been a randomized study investigating aspirin in heart failure patients on ACE inhibitors. The American WATCH trial evaluated the optimal antithrombotic strategy in 1587 patients with heart failure in sinus rhythm and the clinical interactions between aspirin and ACE inhibitors.5 The trial was planned to include 4500 patients, but randomization was prematurely discontinued due to slow recruitment. The patients were randomized to 162 mg aspirin daily, to 75 mg clopidogrel daily, or to warfarin. Hospitalization for heart failure was seen in 16% on warfarin, 22% on aspirin (P < 0.01 vs. warfarin), and 18% on clopidogrel (P = 0.38 vs. warfarin). The WASH trial randomized 279 ACE inhibitor-treated patients with heart failure in sinus rhythm to warfarin, aspirin, or no prophylaxis in the prevention of stroke, myocardial infarction, and death.6 Although the sample size was too small to be conclusive, there was no difference in the primary endpoints between groups. However, hospitalization for heart failure was seen in 58% of aspirin patients vs. 42% on warfarin and 48% without prophylaxis (P = 0.05). Both studies show that for patients receiving ACE inhibitors for heart failure the inhibition of prostaglandin production by aspirin may lead to more hospital admissions than for patients not taking aspirin. In contrast, clopidogrel does not seem to have this disadvantage in WATCH. Better answers came from the WARCEF (Warfarin versus Aspirin in Reduced Ejection Fraction) study, in which 2305 patients with heart failure in sinus rhythm and an EF of <35% were randomized to warfarin [with an international normalized ratio (INR) of 2.0–3.5] or aspirin (325 mg daily) for the prevention of stroke or death, and were followed for a mean of 3.5 years.7 Hospitalization for heart failure was seen in 21% on warfarin and 18% on aspirin (P = 0.06). These are important findings from the randomized studies, although in many European countries the daily aspirin dose is under 160 mg. Therefore, the unfavourable results of aspirin in the first two trials (162 mg in WATCH and 300 mg in WASH) and the possible favourable outcome in WARCEF with 325 mg may be of limited value. However, in a large American registry of 24 012 elderly patients with heart failure with CAD, the benefit of aspirin on 1-year mortality (Table 2) and readmission for heart failure was not influenced by the concomitant use of ACE inhibitors.8 In another registry in 7352 Canadian heart failure patients, again no interaction between ACE inhibitors and aspirin was found.9 Of course, the above post-hoc meta-analysis and registries lack the power of randomized trials, but in the WARCEF, WATCH, and WASH trials hospitalizations for heart failure were only secondary endpoints. They still were insufficiently powered to support warfarin or clopidogrel and discourage aspirin use and, thus, to change current practice in heart failure and sinus rhythm. Thus it is unlikely that the use of aspirin has negative consequences in heart failure patients on ACE inhibitors, but it cannot be fully excluded. It is most unlikely that a placebo-controlled trial with aspirin alone or clopidogrel alone in heart failure will ever be done. On the other hand, aspirin may have positive effects in heart failure given its effect in secondary prevention of coronary disease. The study by Lewinter et al. still has the bias of large baseline differences between the three study groups, e.g. the large age differences.3 Age is by and large the strongest risk factor for adverse outcomes, also in heart failure. Although the authors have corrected for this by their own methods, a strong bias cannot be excluded. More or less the same can be said about lipid-lowering strategies in heart failure. Two well-performed large randomized trials with a large number of coronary patients were neutral in outcome, 10, 11 whereas observational studies showed benefit, 2, 12 as seen in the study of Lewinter et al.3 Our guidelines are based on randomized clinical trials or, in the absence of randomized evidence, on large registries. The randomized trials give enough support not to administer statins as a routine to patients with heart failure, even when CAD is present. For aspirin there is much less evidence, given the lack of a large amount of randomized data. Here too benefits of aspirin are lacking, but there seems no harm either. Thus, physicians seeing patients with heart failure should decide who needs lipid-lowering and/or antithrombotic prophylaxis on a case-by-case basis, especially since many heart failure patients do have significant co-morbidity precluding the use of antithrombotic and lipid-lowering strategies. Conflict of interest: none declared.