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No benefit seen with ACE inhibitor/ARB combo: combined therapy was tied to higher rates of renal dysfunction, hypotensive symptoms, and diarrhea.

CHICAGO -- Telmisartan is as effective as ramipril in reducing vascular events in high-risk patients, but combining the two drugs provides no incremental benefit and increases side effects.

That was the key message of ONTARGET (the Ongoing Telmisartan Alone and in Combination With Ramipril Global End Point Trial), a 25,620-patient megatrial presented by Dr. Salim Yusuf at the annual meeting of the American College of Cardiology.

ONTARGET was designed to answer two clinically relevant questions: Is the angiotensin-receptor blocker (ARB) telmisartan an effective alternative to ramipril in the 20%-30% of patients who can't tolerate an angiotensin-converting enzyme (ACE) inhibitor because of cough, angioedema, or other side effects? And does combining two blockers of the renin-angiotensin system provide additional risk reduction?

"We found that combining the two led to some harm. This is important because there are a significant number of people out there who use combination therapy, either to have greater blood pressure lowering or to protect the kidney," said Dr. Yusuf, lead investigator in ONTARGET and director of the Population Health Research Institute at McMaster University, Hamilton, Ont.

ONTARGET participants had vascular disease or high-risk diabetes at entry, but no heart failure. They were randomly assigned in double-blind fashion to receive 10 mg/day of ramipril, 80 mg/day of telmisartan, or both.

The primary composite end point in ONTARGET was cardiovascular death, stroke, MI, or hospitalization for heart failure. At a median follow-up of 56 months, this end point had occurred in 16.5% of the ramipril group, 16.7% in the telmisartan arm, and--to the investigators' surprise--16.3% on combination therapy. They had expected combined therapy. to perform best.

Moreover, the combined therapy group had significantly higher rates of renal dysfunction, hypotensive symptoms, and diarrhea--and a 20% greater relative risk of treatment discontinuation, Dr. Yusuf reported.

Telmisartan was slightly better tolerated than ramipril, but patients known to be intolerant of ACE inhibitors were excluded from the study. They were assigned instead to TRANSCEND (the Telmisartan Randomized Assessment Study in ACE-Intolerant Subjects With Cardiovascular Disease), a placebo-controlled trial that is expected to be presented later this year at the European Society of Cardiology meeting

ONTARGET triggered considerable speculation about whether the observed benefits were unique to ramipril and telmisartan or represented broad drug class effects.

"I think an evidence-based approach is to use the drugs at the doses used in the trial that showed benefit. If you aren't doing that, I won't say you're wrong, but there's a chance you're wrong," Dr. Yusuf said.

But Dr. Stephen Nissen disagreed.

"Most of us think there's nothing special about ramipril, and the ACE inhibitors are all interchangeable. We have generic ACE inhibitors like lisinopril that are dirt cheap," said Dr. Nissen, chairman of cardiovascular medicine at the Cleveland Clinic Foundation.

"My approach is to start with a generic ACE inhibitor and save the much costlier ARBs for patients who cough," Dr. Nissen explained.

Dr. C. Venkata S. Ram, professor of internal medicine at the University of Texas, Dallas, observed that although ONTARGET clearly showed that dual therapy is not beneficial in the type of patients studied, it may be warranted in other circumstances: namely, in patients with persistent heart failure or chronic kidney disease with copious proteinuria.

Dr. Yusuf agreed that two major studies--the Candesartan in Heart Failure: Assessment of Reduction in Mortality and Morbidity and the Valsartan Heart Failure Trial--have shown clinical benefits for combined ACE inhibitor/ARB therapy in patients with heart failure. And in patients with diabetic nephropathy, combined therapy results in reduced proteinuria; however, whether that translates into improved clinical outcomes is unknown and is the subject of an ongoing major clinical trial.

"Right now, except in a heart failure population, I would be very careful about using combination therapy," Dr. Yusuf said.

He reported receiving consulting fees from Boehringer Ingelheim, the ONTARGET sponsor.

The ONTARGET results were simultaneously published online by the New England Journal of Medicine (Epub doi: 10.1056/NEJMoa08013l7). The article will appear in print in the April 10 edition (N. Engl. J. Med. 2008;358: 1547-59).

Denver Bureau
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Title Annotation:News; Angiotensin-converting enzyme
Author:Jancin, Bruce
Publication:Internal Medicine News
Article Type:Report
Geographic Code:1USA
Date:Apr 15, 2008
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