ASPIRE: Adding Aliskiren to Post-MI Meds Won't Help Ventricular Function

March 24, 2010

March 24, 2010 (Atlanta, Georgia) Adding the direct renin inhibitor aliskiren (Tekturna, Novartis) to standard medical therapy in the weeks following an acute MI doesn't further protect against ventricular remodeling and may cause hypotension or hyperkalemia, suggests a randomized trial reported here at the American College of Cardiology 2010 Scientific Sessions.

As standard therapy in the Aliskiren Study in Post-MI Patients to Reduce Remodeling (ASPIRE) included either an ACE inhibitor or angiotensin-receptor blocker (ARB), but not both, the trial argues against dual-agent suppression of the renin-angiotensin system (RAS) in the post-MI setting, according to the trial's presenter, Dr Scott Solomon (Brigham and Women's Hospital, Boston, MA).

ASPIRE randomized 820 predominantly male patients with large infarcts and an LVEF <45% within two to six weeks of the acute event to receive aliskiren or placebo on top of standard meds; they didn't start randomized therapy until they had been on stable doses of statins, beta blockers, antiplatelets, and either an ACE inhibitor (about 90% of patients) or ARB (about 10% of patients) for two weeks. Less than a third of patients in both groups also were on an aldosterone blocker.

Among those who had evaluable echocardiograms at both baseline and 36 weeks, there was no significant difference between the groups in mean change in left ventricular end-systolic volume (LVESV), the primary end point. Nor were there significant differences in change in LV diastolic volume, LVEF, or infarct size.

As a discussant following Solomon's presentation, Dr Rita F Redberg (University of California, San Francisco) observed that patients in the trial "were already well-treated on statins, beta blockers, and ACE inhibitors. It could be that we're at the point now where more drugs are not better, and in fact more drugs are harmful. We saw that in the ACCORD trial a few days ago, and there's certainly a suggestion of that now."

Responding, Solomon speculated that aliskiren might show a benefit in a different population or with longer follow-up. "We do know that post-MI patients are at significantly higher risk, down the line, of developing heart failure. This was a relatively short-term trial. Maybe the answer is that we need to study sicker patients or study them for a longer period of time."

ASPIRE Primary End Point: Change in LVESV Among Patients With Evaluable Echocardiograms From Baseline to Week 36

LVESV (mL) Placebo, n=329 Aliskiren, n=343
Baseline 84.4 82.4
Week 36 80.9 78.0

LVESV=left ventricular end-systolic volume

p=0.44 for difference between the groups in change in LVESV

In the trial, which wasn't designed to assess clinical end points, all-cause mortality was 2% in the placebo group and 4% among those who received aliskiren. No significant outcomes differences were seen by age, sex, severity of systolic dysfunction, or whether the patient was hypertensive or on aldosterone blockade. There was a "borderline interaction in favor of aliskiren" (p=0.06) for LVESV among diabetics compared with nondiabetics, Solomon reported.

"Although [the trial wasn't] powered to look at clinical events, there was to me a fairly disturbing increase in all-cause deaths, and it looked like 75% of the deaths were cardiovascular deaths," Redberg observed.

"I think we have to be very careful about interpreting mortality results from a trial that was not powered to look at mortality," Solomon said in response. "Yes, we would have rather seen the deaths go the other way, but I think statistically we'd still consider this the play of chance."

ASPIRE: Adverse Events at Week 36 in All Randomized Patients

End point Placebo, n=397 (%) Aliskiren, n=423 (%) p
Renal dysfunction 0.8 2.4 0.09
Hypotension 4.5 8.8 0.02
Hyperkalemia 1.3 5.2 0.001
Total adverse events 67.5 74.9 0.02

To heartwire , Solomon said that to some extent, ASPIRE was designed for comparison with the VALIANT trial, which also tested the addition of a second RAS inhibitor, the ARB valsartan (Diovan, Novartis), against standard therapy that included another, in this case the ACE inhibitor captopril (Capoten, Bristol-Myers Squibb). That trial, similarly to ASPIRE, showed no benefit and more side effects with dual-agent RAS inhibition, he observed.

As Solomon explained, hopes for ASPIRE had been that the addition of aliskiren would attenuate remodeling in patients at increased risk for post-MI heart failure because it directly inhibits renin and therefore works early in the biochemical pathway that produces angiotensin II. Curtailing renin activity at the top of the pathway later affected by ACE inhibitors and ARBs, so the hypothesis went, would prevent the late compensatory rise in plasma renin activity that can follow treatment with those other drugs. But ASPIRE, he noted, certainly doesn't support that hypothesis.

Solomon reports receiving consulting fees and/or honoraria from Sanofi-Aventis and Novartis and conducting research and/or receiving research grants from Abbott, Daiichi-Sankyo, Amgen, Boston Scientific, and Novartis. Redberg had no disclosures.


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