Angiotensin receptor blockers may increase risk of myocardial infarction: unraveling the ARB-MI paradox.

Angiotensin-converting enzyme inhibitors (ACEIs) play an important role in the management of patients at increased cardiovascular (CV) risk. ACEIs reduce both myocardial infarction (MI) and mortality in patients with symptomatic congestive heart failure or asymptomatic left ventricular dysfunction,1 as evidenced by a class I recommendation in the American College of Cardiology (ACC)/American Heart Association (AHA) guidelines.2 Early administration of an ACEI after an MI reduces 30-day mortality by 7%.3 In patients with established vascular disease but normal left ventricular function, ACEIs reduce mortality,4 MI,4,5 stroke,4,6 and new-onset congestive heart failure.4,6 ACEIs are recommended as standard therapy in patients with established vascular disease in the ACC7 and European Society of Cardiology8 guidelines, and this recommendation is independent of left ventricular function or concomitant hypertension. The unique cardioprotective benefits of ACEIs are also observed in patients with diabetes mellitus, who may or may not have coexistent atherosclerosis,9 and are considered a first priority in macrovascular risk reduction by the Canadian Diabetes Association and others.10 Additionally, ACEIs exert powerful nephroprotection and offer marked CV risk reduction in diabetic patients with concomitant nephropathy.11,12 Angiotensin II (Ang II) type 1 (AT1) receptor blockers (ARBs), first introduced in 1995, also inhibit the renin angiotensin system (RAS) in a mechanistically distinct fashion from ACEIs. Compared with ACEIs, which reduce the synthesis of Ang II, ARBs competitively and selectively bind to the AT1 receptor, preventing its activation by Ang II. In particular, this is able to reduce vascular resistance and also aldosterone release and hence help to reduce cardiac afterload and prevent salt and water retention. Given this profile, the assumption early on, even before major clinical trials were conducted, was that ARBs would have similar if not greater systemic effects than might result from the use of ACEIs, because ATI blockade would offer a more complete inhibition of the RAS. This assumption, coupled with the better tolerability of ARBs, as well as concerns for the long-term development of tolerance to ACEIs (“escape phenomenon”), has led to the widespread popularity of ARBs for the treatment of patients with hypertension and congestive cardiac failure. Accumulating data thus far confirm that ARBs indeed have many of the same clinical benefits as ACEIs, including effective blood pressure lowering,13–15 improvement of congestive heart failure symptoms,16–18 inhibition of diabetic renal disease,19,20 reduction in stroke rates,14,15,21 and likely the prevention of new onset of diabetes mellitus22 and atrial fibrillation.23 However, despite these obvious similarities, it has become clear that these 2 classes of