AQUARIUS: Aliskiren Fails Primary Endpoint But Surprises with MACE Reduction

AMSTERDAM, The Netherlands—Aliskiren, a renin inhibitor, does nothing to stall progression of atherosclerosis in prehypertensive patients with coronary artery disease, according to results from the AQUARIUS trial presented on September 3, 2013, at the European Society of Cardiology Congress and published simultaneously in the Journal of the American Medical Association.

But surprisingly, even with few major adverse cardiovascular events (MACE) in the trial, there was a significant clinical advantage for the drug, reported Stephen James Nicholls, MBBS, PhD, of the South Australian Health and Medical Research Institute (Adelaide, Australia).

Aliskiren, a direct inhibitor of the renin-algiotensin-aldosterone system, has shown promise for atheroprotection in preclinical models, Dr. Nicholls said. “However, clinical trials of aliskiren have not yet shown a clinical outcomes benefit, and [the ALTITUDE trial] in patients with high-risk type 2 diabetes was terminated for futility and adverse clinical effects,” he continued. “The effects of renin inhibition on atherosclerosis in humans has not been investigated.”

No Defense Against Disease Progression

For AQUARIUS, Dr. Nicholls and colleagues enrolled 613 patients who had at least a 20% stenosis on clinically indicated angiography and a target vessel for imaging with less than 50% obstruction. All were considered prehypertensive (systolic BP 125-139 mmHg and diastolic BP < 90 mmHg at entry plus 2 cardiovascular risk factors).

After undergoing a preliminary 150-mg daily regimen of aliskiren for 1 week to test for tolerability, patients were randomized to receive a 300-mg daily dose of aliskiren (n = 305) or placebo (n = 308) for 104 weeks. IVUS imaging was done at baseline and at follow-up after at least 72 weeks of treatment for 458 patients (74%).

At IVUS follow-up, changes in percent atheroma volume (primary endpoint) were equivalent not only between aliskiren- and placebo-treated patients (P = 0.08) but also for both groups compared with baseline. Total atheroma volume, though also similar between groups (P = 0.18), did decrease between baseline and follow-up within the aliskiren group (table 1).

Table 1. IVUS Follow-up at ≥ 72 Weeks

At 24-month clinical follow-up, both MACE and nonfatal MI rates were lower for aliskiren patients (table 2).

Table 2. Clinical Follow-up at 24 Months

Moreover, on-treatment systolic BP was lower in the aliskiren group compared with the placebo group (128.3 mmHg vs. 130.4 mmHg; P = 0.007), as was diastolic BP (76.8 mmHg vs. 75.3% mmHg; P = 0.001).

After results of the ALTITUDE trial became available, the 115 diabetic patients in AQUARIUS discontinued aliskiren therapy. Subgroup analyses showed that non-diabetic patients had a 0.53% (95% CI -0.93 to -0.13%) decrease in percent atheroma volume vs. baseline with aliskiren but not placebo. Among patients with diabetes, neither placebo nor aliskiren affected the primary endpoint, and overall there was no interaction between treatment and diabetes status (P = 0.55).

A Future for Aliskiren?

The MACE results “are intriguing and compelling,” Dr. Nicholls said. “Yet they warrant further investigation and confirmation in a large, adequately powered clinical outcomes trial.”

He concluded:  “The lack of statistical significance compared with placebo [for the primary endpoint] suggests that AQUARIUS is a neutral study. However, the favorable trend on atheroma progression and the striking effect on clinical events suggests that aliskiren may benefit non-diabetic patients already at their prescribed blood pressure goal.”

Discussant Wolfgang Koenig, MD, of the University of Ulm Medical Center (Ulm, Germany), pointed out that the early discontinuation of aliskiren by diabetes patients “may have potentially contributed to confounding of interpretation” of the overall AQUARIUS results. In addition, both hypotension and discontinuation rates were doubled—though below 10%—among patients taking aliskiren, he said.

“Although formally neutral, this study showed some interesting trends concerning regression of atherosclerosis and an unexpectedly lower MACE rate in an aggressively treated group of patients with CAD and prehypertensive blood pressure values suggesting that this group may benefit from additional blood pressure lowering,” Dr. Koenig commented, adding that APOLLO, another clinical trial of aliskiren, was recently terminated. “This makes further clinical outcomes trials investigating anti-atherosclerotic effects of aliskiren unlikely.”

In an editorial accompanying the JAMA paper, Jean-Claude Tardif, MD, and Jean Grégoire, MD, both of Montreal Heart Institute (Montreal, Canada), also ask what the AQUARIUS results mean for renin inhibition for secondary cardiovascular prevention.

“Angiotensin-converting enzyme inhibitors or, if not tolerated, angiotensin receptor blockers provide clinical benefits and should continue being prescribed to improve outcomes in patients with coronary artery disease. Until additional evidence is available, the role of renin inhibition in this context should be limited,” they comment, advising, “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.”

Study Details

Most laboratory values and BP pressure measurements were equivalent at baseline between the 2 study arms, though the aliskiren group had higher mean HDL cholesterol (48.1 mg/dL vs. 45.3 mg/dL; P = 0.02) and lower triglycerides (115.0 mg/dL vs. 128.0 mg/dL; P = 0.004).

 

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Sources:
1. Nicholls SJ, Bakris GL, Kastelein JJP, et al. Effect of aliskiren on progression of coronary disease in patients with prehypertension: The AQUARIUS randomized clinical trial. JAMA. 2013;Epub ahead of print.

2. Tardif J-C, Grégoire J. Renin-angiotensin system inhibition and secondary cardiovascular prevention [editorial]. JAMA. 2013;Epub ahead of print.

 

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