Title: ONgoing Telmisartan Alone and in Combination With Ramipril Global Endpoint Trial (ONTARGET — Presented at SCAI-ACC i2 Summit/ACC 2008)
Trial Sponsor: Boehringer Ingelheim, the Heart and Stroke Foundation of Ontario, and Canadian Institutes of Health Research
Year Presented: 2008
Year Published 2008
Topic(s): General Cardiology, Prevention/Vascular
Summary Posted: 3/31/2008
Writer: Dharam J Kumbhani, M.D., S.M.
Author Disclosure: This author has nothing to disclose.
Reviewer: Deepak L. Bhatt, M.D., F.A.C.C.
Author Disclosure: Research Grants: Eisai, Significant (>= $10,000); Research Grants: Sanofi Aventis, Significant (>= $10,000); Research Grants: Bristol Myers Squibb, Significant (>= $10,000); Research Grants: Ethicon, Significant (>= $10,000); Research Grants: The Medicines Company, Significant (>= $10,000); Research Grants: Heartscape, Significant (>= $10,000)
Related Resources
Related Trial: The Heart Outcomes Prevention Evaluation Study (HOPE - Ramipril)
Related Trial: Valsartan in Acute Myocardial Infarction Trial Investigators (VALIANT)

Description
The goal of this trial was to determine whether the angiotensin-receptor blocker (ARB) telmisartan was noninferior to the angiotensin-converting enzyme (ACE) inhibitor ramipril, and whether a combination of the two drugs was superior to ramipril alone as a treatment to prevent vascular events in high-risk patients who had cardiovascular disease or diabetes mellitus, but did not have heart failure.
Hypothesis
In high-risk patients with cardiovascular disease or diabetes, without overt congestive heart failure, telmisartan was noninferior to ramipril, and the combination of telmisartan and ramipril was superior to ramipril alone.
Drugs/Procedures Used
After a single-blind run-in phase to assess for compliance and tolerability, patients were randomized in a 1:1:1 pattern to receive either 80 mg of telmisartan daily, 5 mg of ramipril daily, or combination therapy at the same doses. After 2 weeks, the dose of ramipril was increased to 10 mg daily.
Concomitant Medications
Aspirin (75.7%), beta-blockers (56.9%), statins (61.6%), diuretic (28%), and calcium-channel blockers (33.1%)
Principal Findings
A total of 25,620 patients were randomized in this international multicenter study: 8,576 to ramipril, 8,542 to telmisartan, and 8,502 to the combination of the two. About 85% of these patients had established cardiovascular disease, and 38% had diabetes. The average baseline creatinine was 0.9 mg/dl.

Blood pressure lowering was better in the combination group (2.4 mm Hg) and in the telmisartan group (0.9 mm Hg) compared with ramipril. The primary outcome of death from cardiovascular causes, myocardial infarction, stroke, or hospitalization for heart failure occurred in 1,412 patients (16.5%) in the ramipril group, in 1,423 patients (16.7%) in the telmisartan group (relative risk [RR] 1.01, 95% confidence interval [CI] 0.94-1.09; p = 0.004 for noninferiority), and in 1,386 patients (16.3%) in the combination-therapy group (RR 0.99, 95% CI 0.92-1.07).

There was also no significant difference in the total number of deaths between the ramipril group and the telmisartan group (RR 0.98, 95% CI 0.90-1.07); the number of deaths was higher in the combination-therapy group than in the ramipril group (RR 1.07; 95% CI 0.98-1.16). Similarly, the need for revascularization was similar between the three groups (RR 1.03, 95% CI 0.95-1.11 for telmisartan vs. ramipril; RR 1.04, 95% CI 0.97-1.13 for combination vs. ramipril).

The rates of drug discontinuation were modest (23.7% in the ramipril group, 21% in the telmisartan group, and 22.7% in the combination group). There was a greater incidence of hypotension in the combination (4.8%) and telmisartan (2.7%) groups, compared with the ramipril group (1.7%) (p < 0.001 for both comparisons vs. ramipril). Cough was significantly decreased in the telmisartan group (1.1%) compared with ramipril (4.2%) and the combination groups (4.6%). The incidence of angioedema was lower in the telmisartan group (0.1%) compared with the ramipril group (0.3%) (p = 0.01); it was similar in the combination group (0.2%). Renal dysfunction was significantly higher in the combination group (13.5%) compared with telmisartan (10.6%) or ramipril (10.2%) (RR 1.04, 95% CI 0.96-1.14 for telmisartan vs. ramipril; 1.33, 95% CI 1.22-1.44, p < 0.001 for combination vs. ramipril), although the rates of dialysis were similar between the three groups.

There was a small incidence of crossover (3.3-6.4% at the end of 5 years), and per-protocol analysis did not show significant differences for the primary outcome.
Interpretation
The results of this large, multicenter study show that telmisartan is noninferior to ramipril in reducing the incidence of major adverse cardiovascular events in high-risk patients with cardiovascular disease or diabetes, but combination therapy with both agents is not superior to either agent alone. Moreover, the incidence of side effects—including hypotension, syncope, and renal dysfunction—is higher with the combination therapy compared with ramipril alone. Telmisartan is associated with a lower incidence of cough and angioedema, but a higher incidence of hypotension compared with ramipril.

The findings of this study indicate that either telmisartan or ramipril could be effectively used in the doses studied in patients at high risk for cardiovascular events, based on patient and physician preferences, though cost considerations will also be important.
Conditions
• Coronary heart disease
• Diabetes mellitus
• Prevention

Therapies
• ACE Inhibitor / Ramipril
• Angiotensin-receptor blocker

Study Design
Randomized. Blinded. Parallel. Stratified.

Patients Screened: 29,018
Patients Enrolled: 25,620
Mean Follow-Up: 56 months (median)
Mean Patient Age: 66.4 years
% Female: 27

Primary Endpoints
Death from cardiovascular causes, myocardial infarction, stroke, or hospitalization for heart failure
Secondary Endpoints
• New heart failure
• Diabetes mellitus
• Atrial fibrillation
• Dementia or cognitive decline
• Nephropathy
• Need for revascularization
Patient Population
High-risk patients with cardiovascular disease or diabetes mellitus, but no heart failure
References: The ONTARGET investigators. Telmisartan, ramipril, or both in patients at high risk for vascular events. N Engl J Med 2008;358:1547-59.

Results of the ONTARGET Study Comparing Ramipril With Telmisartan, and Its Combination in High-Risk Individuals Without Heart Failure. Presented by Dr. Salim Yusuf at the SCAI-ACC i2 Summit/American College of Cardiology Annual Scientific Session, Chicago, IL, March/April 2008.

Source
Content provided by the American College of Cardiology Foundation