AHA 2008: I-PRESERVE: Strike Three for RAAS Inhibition in Preserved-LVEF Heart Failure

November 12, 2008

November 12, 2008 (New Orleans, Louisiana) — About four years of treatment with the angiotensin-receptor blocker (ARB) irbesartan (Avapro, Bristol-Myers Squibb/Sanofi-Synthelabo) failed to make a difference in mortality or cardiovascular events in patients with heart failure and preserved LVEF in a randomized trial presented here at the American Heart Association 2008 Scientific Sessions [1].

Irbesartan in Heart Failure with Preserved Ejection Fraction (I-PRESERVE) is the third major prospective trial to test the effects of a drug that inhibits parts of the renin-angiotensin-aldosterone system (RAAS) in patients with the common form of heart failure, note its investigators and other observers at the meeting. Some seemed ready or nearly ready to give up on RAAS-active drugs for filling a frustrating gap in heart-disease therapy, an evidence-based pharmacologic approach to the preserved-LVEF form of the syndrome.

The study's presentation at the meeting coincided with its online publication in the New England Journal of Medicine on November 11, 2008 [2].

Dr Peter E Carson

The results of I-PRESERVE are consistent with both the CHARM-Preserved trial of the ARB candesartan and the PEP-CHF study of the ACE inhibitor perindopril in similar populations, observed Dr Peter E Carson (Washington VA Medical Center, Washington, DC) when presenting the trial.

"For this large group of patients, constituting up to half of all heart failure, there continues to be no specific evidence-based therapy," he observed. "In order for the field to move forward, a better understanding is needed of the mechanisms underlying this syndrome and the additional potential targets for treatment."

 
What you've shown is that this particular drug, in a population absolutely awash with other drugs inhibiting the RAAS system, doesn't add any further benefit.
 

Dr Margaret M Redfield (Mayo Clinic, Rochester, MN), the discussant for Carson's presentation, pointed out that patients in I-PRESERVE were treated with a lot of RAAS-active medications for hypertension. In fact, she said, "in all the trials that have looked at this type of therapy in heart failure with preserved ejection fraction, blood pressure has been well controlled." So the study really tested the effect of irbesartan on top of other drugs targeting the same neurohormonal system.

"I think the three trials taken together don't provide strong support for adding these agents once the blood pressure is well controlled. If you want to use it to control blood pressure, that's a very reasonable approach," Redfield said. "I think [I-PRESERVE] is a very carefully designed and well-performed study and that its results are by and large unambiguous. The findings are important, she said, "because ACE inhibitors and ARBs are very commonly used to treat this condition even though there are no compelling randomized clinical trials to support it."

Panelist Dr Philip Poole-Wilson (Imperial College London, UK), during a question-and-answer period after Carson's presentation, had a different take on the study. "You have here a trial with [about] 40% on ACE inhibitors, [about] 70% on beta blockers, and a quarter on spironolactone. All of those drugs interact with the RAAS system. So what this trial has not shown, in my view, is that inhibiting that system in this group of patients is not beneficial. What you've shown is that this particular drug, in a population absolutely awash with other drugs inhibiting the RAAS system, doesn't add any further benefit."

I-PRESERVE randomized 4128 patients aged >60 years with NYHA class 2-4 heart failure and an LVEF >45% to receive irbesartan or placebo and followed them for a mean of about four years. Excluded were patients with recent ACS or stroke, hypertrophic or restrictive cardiomyopathy, or pericardial or valvular disease.

Irbesartan was initiated at 75 mg/day and titrated to the target dosage of 300 mg/day; the average dosage achieved was 275 mg/day.

Hazard Ratios (95% CI) for Outcomes in I-PRESERVE, Irbesartan vs Placebo, Over a Mean of 50 Months

End point HR (95% CI) p
Primary end point* 0.95 (0.86–1.05) 0.35
CV mortality 1.02 (0.87–1.19) 0.85
HF death or hospitalization 1.01 (0.88–1.16) 0.89
*Composite of death from any cause or hospitalization for heart failure, MI, unstable angina, arrhythmia, or stroke

Carson said the high prevalence of RAAS-active medications was the result of a special effort to control hypertension in the trial. Although only 25% and 15% of I-PRESERVE patients, respectively, were on ACE inhibitors or the aldosterone inhibitor spironolactone at baseline, the rates increased as the trial progressed. The use of beta blockers, which suppress renin, also climbed.

Use of Other RAAS-Active Drug Therapies in Patients Treated With Irbesartan or Placebo in I-PRESERVE

Other RAAS-active drug therapy Placebo group at baseline (%) Placebo group during follow-up (%) Irbesartan group at baseline (%) Irbesartan group during follow-up (%)
ACE inhibitors 25 39 26 38
Spironolactone 15 28 15 27
Beta blockers 58 72 59 72
RAAS=renin-angiotensin-aldosterone system

With the three negative trials for RAAS-active drugs in this population, Redfield observed, "It's becoming increasingly apparent that the pathophysiology [of preserved-LVEF heart failure] is not as simple as we at first thought. . . . I think we have much more work to do to really understand the pathophysiology of this syndrome and to develop and test novel therapies that may produce a different result."

Dr Milton Packer (University of Texas Southwestern Medical Center, Dallas), who has championed the idea that most preserved-LVEF heart failure is primarily a disorder of peripheral arterial stiffness and abnormal venous return, commented at a briefing on I-PRESERVE for the media, "There are many of us who believe that there is very little wrong with the heart in these patients, that the abnormalities are primarily in the periphery, and the heart is an innocent bystander. . . . Maybe we ought to find out what we're studying; we don't understand this disease at all."

I-PRESERVE also renews questions about the neurohormonal system that plays such a large role in systolic heart failure as a culprit in the preserved-LVEF form of the syndrome.

According to Dr Barry M Massie (University of California and Veterans Affairs Medical Center, San Francisco), co–principal investigator of I-PRESERVE along with Carson, there is indeed neurohormonal activation in preserved-LVEF heart failure, but not nearly as much as in systolic HF. "You don't see very high catecholamine levels. There's significantly higher plasma renin activity, higher levels of aldosterone, but only about a third as activated as in low-ejection-fraction heart failure," he told heartwire . "So it's probably less important to the pathophysiology."

That idea is supported by I-PRESERVE, he observed; the patients probably didn't have so much neurohormonal activation that they needed so many RAAS-active drugs on board.

On the other hand, it's okay to use ARBs in heart failure with preserved-LVEF, "because they usually have other indications." But, Massie said, it has become clear that they won't improve clinical outcomes when added on top of other RAAS-active therapy.

The ongoing Treatment of Preserved–Cardiac-Function Heart Failure (TOPCAT) trial, he said, is exploring whether spironolactone will improve outcomes in the same setting. The trial is funded by the National Heart, Lung, and Blood Institute. "We're very excited that we have at least one last shot at it [targeting the RAAS in preserved-LVEF heart failure], but if that fails, we're going to have to wait for something completely new."

I-PRESERVE was supported by Bristol-Myers Squibb and Sanofi-Aventis. Massie reports receiving grant support from Bristol-Myers Squibb, Sanofi-Aventis, and Merck; consulting fees from Bristol-Myers Squibb, Sanofi-Aventis, Merck, Momentum Research, Novartis, GlaxoSmithKline, Scios/Johnson & Johnson, Corthera, and Niles Therapeutics; and lecture fees from Merck. Carson discloses receiving consulting fees from Bristol-Myers Squibb, Sanofi-Aventis, and Merck and lecture fees from Novartis and AstraZeneca. Redfield reports receiving research funding from Scios/Johnson & Johnson, Biosite, Alteon, Medtronic, Guidant, St Jude Medical, CDI, Atcor, and Pfizer; consulting fees from Novartis; and honoraria from Annexion.

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