AQUARIUS, a randomized trial designed to assess aliskiren’s ability to slow or prevent the progression of coronary atherosclerosis, didn’t provide evidence to support its use in that context. Results presented Sept. 2 at the European Society of Cardiology Congress 2013 in Amsterdam and simultaneously published online in JAMA highlighted opportunities for further research.
AQUARIUS, (Aliskiren Quantitative Atherosclerosis Regression Intravascular Ultrasound Study) was a double-blind, randomized placebo-controlled clinical trial designed to study the effect of renin inhibition on atherosclerotic plaque in prehypertensive patients with coronary artery disease (CAD). The study used intravascular ultrasound (IVUS) to measure atherosclerotic burden.
The primary efficacy endpoint was percent atheroma volume (PAV) and the secondary efficacy measure was normalized total atheroma volume (TAV).
The study enrolled 652 participants from 103 hospitals in Europe, Australia and North and South America between March 2009 and February 2011, randomized to receive either 300 mg aliskiren (Novartis Pharmaceuticals) or placebo. Ninety-one patients with diabetes were withdrawn from the study after a change in the label indicated a contraindication with ACE inhibitor and ARB use.
A total of 458 participants remained in the study for more than 72 weeks and completed IVUS imaging (225 in the aliskiren group and 233 in the placebo group). The groups were similar in demographic characteristics, medication use and laboratory values at baseline.
Lead author Stephen J. Nicholls, MBBS, of South Australia Health and Medical Research institute in Adelaide, and colleagues reported that PAV and TAV did not differ between groups. Regression of PAV was 56.9 percent in the aliskiren group and 48.9 percent in the placebo group; TAV regression was 64.4 percent and 57.5 percent, respectively.
“The primary and secondary IVUS endpoints failed to demonstrate a significant difference in disease progression between patients who received aliskiren and those who received placebo,” they wrote. “During the prespecified exploratory analysis, we observed fewer adjudicated major adverse cardiovascular events in the aliskiren group. 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.”
They proposed that a larger clinical trial might be sufficiently powered to detect prespecified cardiovascular events. The researchers listed several opportunities for further investigation, including studying the mechanisms underlying aliskiren’s potential benefits and the effects of aliskiren on clinical outcomes and on the vasculature of patients with diabetes.
In an accompanying editorial, Jean-Claude Tardif, MD, and Jean Gregoire, MD, of the Montreal Heart Institute in Quebec, wrote that AQUARIUS findings may be hypothesis-generating, but they added that ACE inhibitors and ARBs have a place in patient care and launching a large aliskiren trial might not be justified.
“Because aliskiren does reduce blood pressure, perhaps this agent could be reserved for use in patients with coronary disease and hypertension who cannot tolerate ACE inhibitors and angiotensin receptor blockers,” Tardif and Gregoire suggested.
The trial was funded by Novartis Pharmaceuticals.