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Telmisartan May Be an Effective and Safe Alternative to Ramipril in Patients With Vascular Disease or High-Risk Diabetes: Presented at ACC

By Mike Fillon

CHICAGO -- April 7, 2008 -- In patients with vascular disease or high-risk diabetes but without heart failure, telmisartan is an equally effective alternative to ramipril and is less likely to cause angiooedema.

The results of the Ongoing Telmisartan Alone and in Combination With Ramipril Global Endpoint Trial (ONTARGET) were presented here at the 57th Annual Scientific Session of the American College of Cardiology (ACC).

Researchers evaluated the effectiveness of the angiotensin-receptor blocker (ARB) telmisartan and the angiotensin-converting enzyme (ACE) inhibitor ramipril and whether a combination of the two drugs was superior to ramipril alone for prevention of vascular events in high-risk patients who had cardiovascular disease or diabetes mellitus but who did not have heart failure.

Previous controlled trials involving about 150,000 patients demonstrated that ACE inhibitors reduce rates of death, myocardial infarction (MI), stroke, and hospitalisation for heart failure among patients with heart failure, left ventricular dysfunction, previous vascular disease alone, or high-risk diabetes, said lead researcher Salim Yusuf, MD, Director of Cardiology, McMaster University, Hamilton, Ontario (The SOLVD Investigators. N Engl J Med. 1991;325:293-302).

The primary objectives of the ONTARGET study were to determine the effectiveness of telmisartan 80 mg daily compared with ramipril 10 mg daily, and to investigate whether the combination of the two drugs was more effective than ramipril alone in reducing the composite outcome of death from cardiovascular causes, MI, stroke, or hospitalisation for heart failure.

The main secondary outcome was a composite of death from cardiovascular causes, MI, or stroke.

Dr. Yusuf and colleagues enrolled 25,620 patients at 733 centres in 40 countries. Patients were aged >55 years and had coronary artery disease, peripheral artery disease, cerebrovascular disease, or diabetes, but did not have evidence of heart failure.

During the first 2 weeks after randomisation, 8,542 patients received telmisartan 80 mg once daily, 8,576 patients received ramipril 5 mg once daily, and 8,502 received a combination of the two drugs. After 2 weeks, the dose of ramipril was increased to 10 mg per day.

Follow-up visits occurred at 6 weeks and 6 months, then every 6 months until the last scheduled visit.

The proportion of patients receiving the full dose of ramipril at 2 years was 81.7% in the ramipril group and 75.3% in the combination-therapy group. The proportion of patients receiving the full dose of telmisartan at 2 years was 88.6% in the telmisartan group and 84.3% in the combination-therapy group.

The study drug was discontinued by 23.7% of patients in the ramipril group and 21.0% in the telmisartan group. In the combination-therapy group, 22.7% discontinued both drugs, and an additional 6.7% stopped taking one of the two drugs in their regimen.

Compared with the ramipril group, mean blood pressure was lower in both the telmisartan group (-0.9/0.6 mm Hg) and in the combination therapy group (-2.4/1.4 mm Hg). After 56 months, the median follow-up, telmisartan was shown to be noninferior to ramipril based on the primary outcome, which had occurred in 1,412 patients in the ramipril group versus 1,423 patients in the telmisartan group (16.5% vs 16.7%; relative risk [RR], 1.01; 95% confidence interval [CI], 0.94-1.09).

Dr. Yusuf said that at the targeted dose of 80 mg once daily, telmisartan preserved 94% of the benefit of ramipril 10 mg daily in the earlier HOPE trial (95% CI, 83-105).

Also, compared with the ramipril group, the telmisartan group had lower rates of cough (1.1% vs 4.2%, P < .001) and angiooedema (0.1% vs 0.3%, P = .01), but this benefit was partially offset by a higher rate of hypotensive symptoms (2.6% vs 1.7%, P < .001). This is consistent with the slightly better blood pressure-lowering effects seen in the ARB group. Importantly, the rate of syncope was the same in the two groups (0.2%).

In the combination-therapy group, despite a reduction in systolic blood pressure of 2 to 3 mm Hg beyond that seen in the ramipril group -- a decrease that should have translated into a risk reduction of 4% to 5% -- no significant benefit was seen in the primary composite endpoint, which occurred in 1,386 patients receiving combination therapy (16.3%; RR, 0.99; 95% CI, 0.92-1.07).

However, the two-drug regimen significantly increased the risk of hypotension, syncope, renal dysfunction, and hyperkalaemia, with a trend toward an increased risk of renal dysfunction requiring dialysis. Dr. Yusuf said the safety results are similar to an analysis of the combined effects of an ARB and an ACE inhibitor versus an ACE inhibitor alone in four previous trials (Pfeffer, MA et al. N Engl J Med. 2003;349:1893-1906).

Dr. Yusuf said, "The choice between the two agents will depend on the preferences of patients and physicians and the individual patient's susceptibility to specific adverse events."

He added that there is no additional advantage -- and possibly some harm -- from the combination of telmisartan and ramipril used in full doses in this population as compared with ramipril alone.

Funding for the ONTARGET study was provided by Boehringer Ingelheim. The study was published online ahead of print March 31, 2008 (N Engl J Med. doi: 10.1056/NEJMoa0801317).


[Presentation title: Telmisartan, Ramipril, or Both in Patients at High Risk for Vascular Events. Late Breaker]

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