SAN FRANCISCO, CA — A small study in patients with established cardiovascular disease treated with aliskiren (Tekturna, Novartis) suggests the direct renin inhibitor increases aortic atherosclerosis as measured by MRI [1]. Although the totality of the evidence did show a significantly increased risk of plaque progression with aliskiren, the increase was driven by a change in aortic plaque among individuals treated with it in combination with an ACE inhibitor or angiotensin-receptor blocker (ARB).

"When we started the study, there was the expectation that renin inhibition, especially in patients already on an ACE inhibitor or an ARB, would be protective in terms of reducing atherosclerosis," senior investigator Dr Sanjay Rajagopalan (Ohio State University Medical Center, Columbus) told heartwire . "What we found was exactly the opposite, and that was a very strong signal showing that if you are on renin inhibition you actually have an increase in plaque compared with placebo."

Presented May 17, 2013 at the American Society of Hypertension (ASH) 2013 Scientific Sessions and published concurrently in the Journal of the American Heart Association, the study included 37 patients with established cardiovascular disease randomized to placebo and 34 patients randomized to 150-mg aliskiren (dose increased to 300 mg after two weeks of treatment).

However, the MRI study, known as ALPINE , was halted prematurely when the results of the multicenter Aliskiren Trial in Type 2 Diabetes Using Cardio-Renal Endpoints (ALTITUDE) trial were published in November 2012. In that study, aliskiren as an adjunct to renin-angiotensin system (RAS) blockade failed to provide benefit to patients with type 2 diabetes at high risk of cardiovascular and renal events and may have actually been harmful.

Small Patient Numbers

In total, 19 patients treated with placebo and 18 patients treated with aliskiren completed MRI at 36 weeks. Treatment with the direct renin inhibitor resulted in a significant progression of aortic-plaque burden as measured by aortic-wall volume. The increase in aortic-wall volume was statistically significant from baseline in the aliskiren arm but not in the placebo-treated groups, and the between-group differences were statistically significant.

Changes in MRI Aortic-Wall Measurements From Baseline to Follow-up

MRI measurement Placebo Aliskiren p (across groups)
Total wall volume (mm3) 0.15 5.31 0.03
Percentage wall volume (%) 0.97 3.37 0.04
Patients receiving ACE inhibitors/ARBs      
Total wall volume (mm3) -3.01 5.19 0.02
Percentage wall volume (%) -0.06 3.29 0.03
Patients not treated with ACE inhibitors/ARBs      
Total wall volume (mm3) 0.74 6.74 0.45
Percentage wall volume (%) 1.33 3.07 0.99

For patients treated with ARBs and ACE inhibitors, which included approximately 60% of patients in both treatment arms, the rate of aortic-plaque progression as measured by changes in total wall volume and percentage wall volume was significantly higher in the aliskiren arm compared with placebo. This was not the case with patients who were not on background ACE inhibitor/ARB treatment.

"The changes that we observed on the MRI were small, but it's not the magnitude of change or the amount of plaque burden but the fact that is increasing that is of significance," said Rajagopalan. "The fact is that this is a surrogate marker for other pathophysiologic changes that might be going on, including plaque instability, and this can confer an increased risk for cardiovascular events."

Data from clinical trials has shown that the RAS antagonists such as ACE inhibitors and ARBs when used in combination in patients at high risk for vascular disease and/or established cardiovascular disease results in a paradoxical increase in cardiovascular events. As reported by heartwire , the European Medicines Agency (EMA) is currently reviewing the safety of using dual RAS blockade in clinical practice because of concerns of hyperkalemia, low blood pressure, and kidney failure with dual blockade compared with the use of one RAS agent alone. In 2009, the Canadian Hypertension Education Program (CHEP) told physicians and patients to stop using ARBs and ACE inhibitors together and the Canadian Heart and Stroke Foundation advised patients to see their family physicians as soon as possible to get their treatment changed.


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