Little HOPE for ACE inhibitors in revascularized patients

In an analysis recently published in the American Heart Journal, Kalavrouziotis et al found that the use of post-operative angiotensin-converting enzyme (ACE) inhibitors in coronary artery bypass graft (CABG) surgery was not associated with an improvement in survival or rehospitalizations. In fact, significant improvements were only observed in the subgroup of patients with diabetes, where ACE inhibitors were associated with a small but statistically significant reduction in mortality.

Although the trial was a retrospective review of prescription claims data, it continues a trend of investigations that have found little to no benefit with ACE inhibitors in patients whose coronary artery disease (CAD) has been managed with revascularization (i.e., percutaneous coronary intervention or CABG) and who have their cardiovascular risks aggressively managed with concomitant therapies (e.g., antiplatelet therapy, statins, and beta blockers). It also adds to the results observed in IMAGINE, a trial conducted in 2008 that found that the early post-operative use of ACE inhibitors in CABG did not improve cardiovascular outcomes. If anything, it may have even worsened outcomes, given that a pre-specified sub-analysis of the first 3-months found that ACE inhibitors were actually associated with a 50% increase in risk. However, some critics have argued that ACE inhibitors were started too early in the post-operative course (a median of about 4 days) and this may have contributed to the increased risks.

Perhaps one of the first clinical trials to question the routine use of ACE inhibitors in stable CAD was PEACE (2004), where trandolapril failed to reduce major cardiovascular events compared to placebo. This finding contradicted the results of two earlier trials, HOPE (2000) and EUROPA (2003), where ACE inhibitors were associated with significant improvements in cardiovascular events. In one of the most intriguing comparisons among clinical trials to date, the failure of PEACE to show a significant benefit has largely been attributed to its baseline patient population rather than the actual impact of ACE inhibitors on clinical outcomes. When one compares the baseline characteristics of patients enrolled in HOPE, EUROPA, and PEACE, several interesting trends emerge. First, a higher percentage of patients in PEACE were revascularized (PCI or CABG). Secondly, more patients in PEACE were receiving concomitant medications to manage cardiovascular risk (i.e., antiplatelet agents, beta blockers, and lipid-lowering drugs).

In an era where every health care dollar is carefully scrutinized and clinical decision-making is more often based on what patients can afford rather than what is best supported by the evidence, it may be time to re-examine the use of ACE inhibitors in low-risk patients with CAD. Because there are so many indications where ACE inhibitors have shown benefit, I think we get into the habit of prescribing them for almost everyone with CAD.

Although I have joked that everyone could probably use a little ACE inhibition, I have found myself being far more selective in whom I recommend the addition of an ACE inhibitor. After all, ACE inhibitors did not just fail to show a benefit in PEACE -- they actually increased the number of adverse effects. Given the growing body of evidence that shows little to no benefit with their use in low-risk patients, perhaps we should be asking ourselves the same question in every patient with stable CAD -- "Does this patient look more like HOPE or more like PEACE?"