The results of the landmark ONTARGET^® trial show that telmisartan is as protective as the ACE inhibitor ramipril, the current gold standard, in reducing the risk of cardiovascular death, myocardial infarction, stroke, and hospitalization for congestive heart failure in a broad cross-section of high-risk cardiovascular patients, and offers greater tolerability.

Efficacy

Both telmisartan monotherapy and telmisartan/ramipril combination therapy were non-inferior to ramipril monotherapy with respect to cardiovascular protection. The primary outcome (death from cardiovascular causes, myocardial infarction, or stroke) occurred in 16.7% of patients receiving telmisartan, 16.5% of patients receiving ramipril, and 16.3% of patients receiving combination therapy (Figure 1). The main secondary outcome (composite of death from cardiovascular causes, myocardial infarction, or stroke) occurred in 1,210 patients (14.1%) in the ramipril group 1,190 patients (13.9%) in the telmisartan group and 1,200 patients (14.1%) in the combination group.

Figure 1. Incidence of the primary outcome of death from cardiovascular causes, myocardial infarction,
or stroke in the three treatment groups.

Tolerability and safety

Telmisartan was shown to be better tolerated than ramipril and was associated with significantly greater adherence (Figure 2). Even though patients who could not tolerate ACE inhibitors were specifically excluded from the ONTARGET^® trial, 360 patients in the ramipril treatment arm stopped their treatment due to cough, versus 93 patients in the telmisartan arm (p=0.02). Significantly more patients discontinued ramipril due to angioedema (p=0.01) and cough (p<0.001) (Figure 3).

Combination therapy was associated with a higher incidence of adverse events and reduced adherence compared to ramipril.

Figure 2. Permanent discontinuation of study medication in the three treatment groups.

Figure 3. Reasons for permanent discontinuation of study medication.

There was no significant difference in the total number of deaths between the ramipril group and the telmisartan group (1,014 deaths and 989 deaths, respectively); the number of deaths was higher in the combination-therapy group than in the ramipril group (1,065 deaths vs. 1,014 deaths), but the difference was not significant. Analyses of the cause of death did not indicate significant differences with respect to any particular cause.

Implications of ONTARGET^®

The ONTARGET^® results showed that telmisartan is as effective as ramipril in preventing heart attacks, stroke, hospitalisations for heart failure, and deaths in high-risk cardiovascular patients, and is better tolerated. Until now, only ramipril had shown these protective effects. Telmisartan is therefore the only ARB with proven cardiovascular protective benefits beyond blood pressure reduction in a high-risk population.

The HOPE trial showed that ramipril reduces cardiovascular risk by roughly 20% compared to placebo in high-risk patients. Telmisartan can now claim the same effect.

The 25,620 high-risk patients who participated in the ONTARGET^® trial were already receiving best-practice therapy, including statins, antiplatelet therapy, beta blockers, and/or other antihypertensives. The addition of telmisartan to this therapy resulted in equal or better protection compared to adding ramipril.

ONTARGET^® also studied the value of combining telmisartan with ramipril to determine whether the dual blockade of the RAS by an ACE inhibitor and an ARB results in better protection than monotherapy. Results indicated that the combination of ramipril and telmisartan provides no additional protective benefit and was associated with more adverse events.

Telmisartan has unique pharmacokinetic and pharmacodynamic properties including the longest half-life of any ARB, a high volume of distribution, a slow rate of dissociation from the receptor, high lipophilicity with high tissue penetration, and cardiometabolic effects mediated by its action as a selective PPAR-γ modulator. Telmisartan is supported by some of the strongest, most ambitious clinical programmes (PROTECTION^® and ONTARGET^®), and is the only ARB proven to offer the CV protection of the current gold standard treatment, ramipril. These differences may have an important impact on clinical endpoints, meaning that in the absence of scientific evidence, the ONTARGET^® results cannot be applied to ARBs as a class.

99.8% of participating patients were monitored during the course of the study, with a median follow-up of 56 months. This makes ONTARGET^® one of the best-managed landmark trials ever and provides an extremely robust data base that will enable the medical community to answer questions where previously no scientific evidence was available.

References
1 The ONTARGET^® Investigators. Telmisartan, ramipril, or both in patients at high risk for vascular events. N Eng J Med. published online 31 Mar 2008.
2 Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. The Heart Outcomes Prevention Evaluation Study Investigators. N Engl J Med. 2000;342:145-53.