ONTARGET: ARB noninferior to ACE inhibitor in patients with cardiovascular disease

According to results from the Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial (ONTARGET), the angiotensin receptor blocker (ARB) telmisartan is as effective as the angiotensin-converting enzyme (ACE) inhibitor ramipril in preventing adverse cardiovascular events in high-risk patients with cardiovascular disease but without heart failure. The combination of the agents, however, was no more effective than either agent used as monotherapy and was associated with a higher discontinuation rate. Lead investigator Salim Yusuf, DPhil, director of the Population Health Research Institute, McMaster University and Hamilton Health Sciences, Hamilton, Ontario, Canada, presented these results at the 57th Annual Scientific Session of the American College of Cardiology, March 29 to April 1, 2008, in Chicago, Illinois.

This international, double-blind, randomized study included 25,620 patients with vascular disease or high-risk diabetes without heart failure. A total of 8,576 patients were randomized to ramipril titrated to 10 mg/d; 8,542 were randomized to telmisartan 80 mg/d; and 8,502 were randomized to a combination of the drugs.

The primary end point of ONTARGET was a composite of cardiovascular death, nonfatal myocardial infarction (MI), nonfatal stroke, and hospitalization for congestive heart failure. After a median follow-up of 56 months, this end point had occurred in 1,412 patients assigned to ramipril (16.5%); 1,423 patients assigned to telmisartan (16.7%); and 1,386 patients assigned to combination therapy (16.3%).

For the primary end point, telmisartan demonstrated a value of 1.09 for the upper boundary of the CI for HR, thus meeting the criterion for noninferiority versus ramipril (P=.004). Telmisartan was also noninferior to ramipril for the secondary end point of death from cardiovascular causes, MI, or stroke (P=.001).

Patients treated with telmisartan or with combination therapy demonstrated a greater reduction in blood pressure (BP) than those treated with ramipril (0.9/0.6 mmHg greater reduction and 2.4/1.4 mmHg greater reduction versus ramipril, respectively).

Discontinuation because of cough occurred in 4.2% of patients treated with ramipril and in 1.1% of patients treated with telmisartan (P<.001), and discontinuation because of angioedema occurred in 0.3% of those assigned to ramipril versus 0.1% of those randomized to telmisartan (P=.01). Discontinuation because of hypotension occurred more often with telmisartan monotherapy than with ramipril monotherapy (2.7% vs 1.7%; P<.001).

Syncope, hypotension, diarrhea, and renal impairment were all significantly more likely with combination therapy than with ramipril monotherapy, and the number of discontinuations was significantly greater among patients treated with combination therapy versus those treated with ramipril alone.

The findings with respect to combination therapy apply to the population in ONTARGET but not necessarily to other populations, said Dr. Yusuf. “We know in heart failure, combination therapy-based on the CHARM [Candesartan in Heart Failure: Assessment of Reduction in Mortality and Morbidity] and the Val-HeFT [Valsartan Heart Failure Trial] studies-does have a benefit. But in those trials, it was clear that people needed to be monitored very carefully.”

The results in patients with proteinuria were not analyzed at the time of the presentation, he said.

Affordability may be the driving force behind the choice between an ACE inhibitor and an ARB in the treatment of patients like those enrolled in ONTARGET, added Dr Yusuf.

Now that ACE inhibitors are going off patent, the most cost-effective approach is to use a generic ACE inhibitor first, said Steven Nissen, MD, director of cardiology at the Cleveland Clinic, Cleveland, Ohio. This approach assumes a class effect among ACE inhibitors. “Most of us think that the ACE inhibitors are interchangeable, and we have generic ACE inhibitors,” he said. “I would save the expensive ARB for patients who cough.”

Dr Yusuf stated, “At the very least, people will say if an ACE inhibitor is not tolerated, now [they] can use an ARB like telmisartan with confidence, and patients won’t have the same adverse events.”

The ONTARGET results have been published in the New England Journal of Medicine (2008;358:1547-1559).