Treatment with the renin inhibitor aliskiren did not improve or slow the progression of coronary atherosclerosis in patients with prehypertension and coronary artery disease, according to the prospective, randomized, placebo-controlled Aliskiren Quantitative Atherosclerosis Regression Intravascular Ultrasound Study (AQUARIUS).
The change in the primary efficacy measure – percent atheroma volume (PAV) from baseline to completion – did not differ significantly in 225 subjects who were randomized to receive 300 mg of aliskiren for 104 weeks and 233 subjects who were randomized to receive a placebo (–0.33% vs. 0.11%, respectively), Dr. Stephen J. Nicholls of the South Australian Health and Medical Research Institute, Adelaide, Australia and his colleagues reported.
Dr. Stephen J. Nicholls
A secondary efficacy parameter – the change from baseline in normalized total atheroma volume (TAV) – also did not differ between the aliskiren and placebo groups (–4.1 mm3 vs. –2.1 mm3), and no significant differences were seen between the groups in the proportion of participants who experienced regression of PAV (56.9% vs. 48.9%) and TAV (64.4% vs. 57.5%), the investigators reported at the annual congress of the European Society of Cardiology.
The findings were simultaneously published online Sept. 3 in JAMA.
Patients included in AQUARIUS were adults over age 35 years with coronary artery disease and prehypertension, with systolic blood pressure of 125-139 mm Hg, and diastolic blood pressure less than 90 mm Hg, and with two additional cardiovascular risk factors. They were enrolled during March 2009–February 2011 at 103 participating academic and community hospitals in Europe, Australia, North America, and South America. At baseline, after coronary angiography, they underwent coronary intravascular ultrasound (IVUS) imaging.
A total of 613 participants were enrolled and treated with 150 mg of aliskiren for a 1-week run-in period before randomization. After 104 weeks, three-quarters of the patients, or 458, had a second IVUS on the same vessel (JAMA 2013 Sept. 3[doi:10.1001/jama.2013.277169]).
Patients with diabetes were withdrawn during the study period after a product label change warned that concomitant use of aliskiren in patients with diabetes who were treated with an ACE inhibitor or angiotensin receptor blocker was contraindicated; this alteration in the trial represents "a factor potentially confounding interpretation," the investigators noted.
Nonetheless, the study is among the first to evaluate the effect of renin inhibition on atherosclerotic plaque in patients with coronary atherosclerosis whose blood pressure was considered optimally controlled, they said.
"The benefit of additional blood pressure lowering agents in patients who have reached treatment goals has not been established. However, few trials have examined the benefits and risks of further intensifying blood pressure treatment in patient with established coronary artery disease (CAD) who are in the prehypertension range," they said.
Since renin-angiotensin-aldosterone system (RAAS) activation is known to play an important role in atherosclerosis, and since RAAS inhibition may have a direct beneficial effect on the artery wall, the investigators sought to determine if aliskiren, a direct renin inhibitor, would slow progression of coronary atherosclerosis in these patients.
"Aliskiren moderately reduced blood pressure, substantially reduced plasma renin activity, and produced a compensatory increase in plasma renin concentration," they wrote.
However, the primary and secondary IVUS endpoints failed to demonstrate a significant difference in disease progression between those who received aliskiren and those who received placebo.
"During the prespecified exploratory analysis, we observed fewer adjudicated major adverse cardiovascular events in the aliskiren group (26 vs. 50). Although these exploratory findings support the hypothesis of potential beneficial effects of renin inhibition in patients with preexisting CAD and blood pressure levels treated to goal, the current clinical findings are inconclusive. Definitive demonstration of a clinical outcome benefit will require a larger, adequately powered clinical trial with cardiovascular events prespecified as the primary end point," they said.
This study was sponsored by Novartis Pharmaceuticals. Dr. Nicholls reported receiving research support from AstraZeneca, Novartis, Eli Lilly, Anthera, LipoScience, Roche, and Resverlogix; and receiving honoraria from or serving as a consultant to AstraZeneca, Roche, Esperion, Abbott, Pfizer, Merck, Takeda, LipoScience, Omthera, Novo-Nordisk, sanofi-aventis, Atheronova, Anthera, CSL Behring, and Boehringer Ingelheim. Other authors also reported having disclosures. Details are available with the full text of the article at JAMA.com.