Renin-Angiotensin System Inhibition and Secondary Cardiovascular Prevention

Abstract

Cardiovascular diseases remain the leading cause of mortality in the world as recently confirmed by the World Health Organization, and atherosclerosis is the main underlying origin. Atherosclerosis-related diseases are also responsible for considerable morbidity in the United States and around the world1 and for health care costs related to hospitalizations for myocardial infarction, heart failure, and stroke. Although nonpharmacological strategies including a hearthealthy diet, physical activity, and smoking cessation should always be recommended, most patients with or at high risk of coronary artery disease should receive several medications including a statin, at least 1 antiplatelet agent, and a renin-angiotensin system inhibitor (angiotensinconverting enzyme [ACE] inhibitor or, if not well tolerated, an angiotensin receptor antagonist).2 However, despite the current therapeutic options available, theburdenof cardiovasculardiseases isneverthelesspredicted to increase over thenext decade, in part because of the epidemicsofobesity,metabolic syndrome,anddiabetesaswell as the aging of the population. Therefore, there is an ongoing search for medications that may provide further protection against theprogressionof atherosclerotic vascular disease; targets include low-density lipoprotein cholesterol (eg, proprotein convertase subtilisin/kexin type 9 inhibition), high-density lipoprotein cholesterol (eg, cholesteryl ester transfer protein inhibition), vascular inflammation (eg, interleukin-1 antagonist), and blood pressure. Theoverall prevalenceofelevatedbloodpressure inadults aged 25 years or older is approximately 40%.3 Blood pressure is positively and continuously related to the risk for coronary heartdisease, startingat systolic/diastolic levelsas lowas115/75 mmHg. Plasma renin activity has been linked to the risk of future cardiovascular events,4 and the renin inhibitor aliskiren has been shown to have favorable effects on atherosclerosis in animalmodels.5 For these reasons, aliskirenhasbeenevaluated in a fairly large program of clinical trials. In this issue of JAMA, Nicholls and colleagues6 report the results of a multicenter, double-blind trial (Aliskiren Quantitative Atherosclerosis Regression Intravascular Ultrasound Study; AQUARIUS) evaluating the effects of aliskiren on changes in coronary atherosclerosismeasured by intravascular ultrasound (IVUS) imaging in patients with a blood pressure in theprehypertension range. A total of 613 patientswith coronary artery disease, systolic blood pressure between 125 and 139 mm Hg, and 2 additional cardiovascular risk factors were randomized to receive 300 mg of aliskiren or placebo taken orally daily. Of these patients, 458 (74.7%) remained in the study formore than 72weeks and had evaluable IVUS images at bothbaseline and follow-up.Overall, therewereno significant differences between the aliskiren group and the placebogroup for theprimaryandsecondary IVUSendpoints.For the study primary end point, the investigators aimed to detect a difference in percent atheroma volume of 0.8% between the aliskiren and placebo groups. Although this targeted difference was small, the difference between study groupswas0.4%andwasnot statistically significant. Thedifference in total atheroma volume between study groups was only 2 mm3 and also was not statistically significant. Differences of 0.4% and 2mm3 in atheroma size are very small and not likely to be clinically significant when considered in isolation. However, therewere fewer positively adjudicated cardiovascular outcomes in the aliskiren group compared with the placebo group (26 vs 50; nominal P = .004), and the majority of these events were coronary revascularizations. A total of 3 and 18 cardiovascular events (death, nonfatal myocardial infarction,ornonfatal stroke)occurred in thealiskirengroupand placebo group, respectively, although the authors do not indicatewhether someof theseeventswereobserved in thesame patients. In addition, AQUARIUSwas limited by the premature discontinuationofall patientswithdiabeteswhoreceiveda reninangiotensin system inhibitor, following the results of the Aliskiren Trial in Type 2 Diabetes Using Cardiorenal Endpoints (ALTITUDE) trial.7 The administrative withdrawal of these patients after randomization in AQUARIUS is problematic for the interpretation of the study results, especially considering that these patients may have had less favorable results from aliskiren in light of the ALTITUDE trial results. In the ALTITUDE trial (which was terminated prematurely), 8561 patientswith type 2 diabetes and chronic kidney disease, cardiovascular disease, or both were randomly assigned to aliskiren or placebo in addition to an ACE inhibitor or an angiotensin receptor blocker.7 The primary cardiorenal outcome occurred in 18.3% and 17.1% of participants in the aliskiren andplacebo groups, respectively (hazard ratio, 1.08; P = .12). The secondary composite cardiovascular outcomeoccurred in 13.8%of patients in the aliskiren group and 12.6% in theplacebogroup (hazard ratio, 1.11;P = .09).Ofnote, all components of the cardiovascular outcome (except for hospitalizations for heart failure)wereobservedmore frequentlywith aliskiren in ALTITUDE. Related article page 1135 Opinion