Reports

This report is based on medical evidence presented at sanctioned medical congress, from peer reviewed literature or opinion provided by a qualified healthcare practitioner. The consumption of the information contained within this report is intended for qualified Canadian healthcare practitioners only.

57th Annual Scientific Sessions of the American College of Cardiology

Chicago, Illinois / March 29-April 1, 2008

ONTARGET (Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial) addressed two major hypotheses. The hypothesis proven by this study is that 80 mg of the angiotensin receptor blocker (ARB) telmisartan once daily is as effective as ramipril 10 mg q.d. for the composite outcome of death from cardiovascular (CV) causes, myocardial infarction (MI), stroke or hospitalization for heart failure. After a median follow-up of 56 months, the proportion of patients with one of these outcomes, 16.5% and 16.7%, were almost identical both numerically and statistically (95% CI, 0.94-1.09; P=0.8). The second hypothesis was that the ARB/ACE inhibitor combination would be superior to ramipril alone for the same composite end point. Although this hypothesis was not confirmed, the proportion of patients on dual therapy experiencing a primary event—16.3%—was also essentially indistinguishable from telmisartan alone or ramipril alone (95% CI, 0.92-1.07; P=0.8), while the rate of side effects was increased. However, the equivalence of telmisartan and ramipril is a landmark result.

“Many general practitioners who participated in the study thought that this was a great result because in their practice, it tells them they can use telmisartan with confidence,” reported ONTARGET principal investigator Dr. Salim Yusuf, Population Health Research Institute, McMaster University, Hamilton, Ontario. In hypertensive patients in particular, Dr. Yusuf remarked that physicians “would prefer to start with telmisartan [than an ACE inhibitor] because it lowers blood pressure (BP) to a greater extent and it is better tolerated.”

In this study, 25,620 patients age 55 or older with coronary, peripheral, or cerebral vascular disease or diabetes with end-organ damage were randomized to one of three treatment arms: telmisartan 80 mg q.d. (n=8542), ramipril 10 mg q.d. (n=8576), or the combination of telmisartan 80 mg and ramipril 10 mg q.d. (n=8502). At entry, 85% had CV disease, 69% had hypertension and 38% had diabetes. The therapies were evaluated in a population already aggressively treated. More than 60% were on a statin, more than 80% were on an antiplatelet therapy: more than 50% were on a beta blocker, and almost 30% were on a diuretic. The average age of this treatment population, of which 27% were women, was 66.5 years. Of the 25,000 patients randomized in 40 countries worldwide, approximately 5000 participants were enrolled in ONTARGET by more than 70 participating Canadian investigators.

While the rates of primary events were almost identical in the three study groups, telmisartan was associated with lower rates of cough (1.1% vs. 4.2%; P<0.001) and angioedema (0.1% vs. 0.3%; P=0.01) than ramipril. Although hypotensive symptoms did occur more commonly in those on telmisartan relative to ramipril (2.6% vs. 1.7%; P<0.001), the rates of syncope, perhaps the most bothersome hypotensive manifestation, was the same in both groups (2.0%).

The ONTARGET study finally answers the question of whether an ARB can produce the same benefits achieved with the ACE inhibitor ramipril in the landmark HOPE (Heart Outcomes Protection Evaluation). In HOPE, ramipril was credited with reducing CV death independent of BP control through its ability to inhibit the renin angiotensin system (RAS). In ONTARGET, a similar population was enrolled. In ONTARGET, telmisartan was specifically selected to test the hypothesis that an alternative mechanism of RAS inhibition could be employed to achieve the same benefits as an ACE inhibitor. This agent was considered an ideal comparator because of its half-life that is more than double that of many other commonly used ARBs, and its strong affinity for the angiotensin II receptor.

While the evidence that telmisartan is as effective as ramipril was anticipated, the failure of the ARB/ACE inhibitor combination to provide additional benefit was not. Rather, the event rate on the combination group was similar to that observed in either the ARB or ACE inhibitor group. Moreover, the greatest rate of adverse events occurred in those on dual therapy. When compared to ramipril, the combination was associated with increased rates of hypotensive symptoms (4.8% vs. 1.7%; P<0.001), syncope (0.3% vs. 0.2%; P=0.03) and renal dysfunction (13.5% vs. 10.2%; P<0.001). The failure to show any reduction in the risk of events was observed despite a 2 to 3 mm Hg greater reduction in BP.

“This degree of added reduction in BP would only predict a 4% to 5% reduction in events, which this study was not powered to detect. What the study was designed to show was an added clinical benefit from increased RAS inhibition independent of BP changes, and this was not detected,” Dr. Yusuf told delegates. However, he observed that this result does not preclude benefit from dual RAS blockade in subpopulations, such as those with heart failure or renal disease.

Considerations for Patient Subpopulations

Indeed, an evaluation of subpopulations will produce a river of data from the ONTARGET investigation over the next several years. Important substudies include those looking at relative effects of the three tested strategies on the kidney and the cerebrovascular system. These may yet show different relative benefits in the tested strategies among specific populations of patients. Again, the properties of telmisartan, such as its long half-life and effects on nuclear receptors, may be particularly relevant to protection against specific organs. In a previous comparative study called PRISMA II (Prospective Randomized Investigation of the Safety and Efficacy of Micardis Versus Ramipril Using ABPM), telmisartan was found more effective than ramipril in achieving 24-hour BP control, including morning BP surge, which may be relevant to diurnal-related events. Overall, the specific and unique properties of telmisartan have been a barrier to concluding that the comparable efficacy of telmisartan to ramipril in ONTARGET can be extrapolated to other ARBs.

“I think an evidence-based approach is to use the same drug at the same doses that were used in the trial that showed benefit [i.e. ramipril 10 mg q.d. and telmisartan 80 mg q.d.]. If you are not doing that, I will not say you are wrong, but there is a chance that you are wrong,” noted Dr. Yusuf, who emphasized that he follows this approach in his own prescription practices. He identified telmisartan as “now providing an alternative” to ACE inhibitors on an evidence basis. He described the choice between telmisartan and ramipril as “a personal preference for the doctor and the patient.” Conversely, he suggested that the practice of prescribing dual RAS inhibition has been discredited as a general principle, although it may still emerge as a viable approach in selected groups.

Summary

The results of ONTARGET, the largest clinical trial ever undertaken with an ARB, provide a simple message, according to Dr. Yusuf. The ARB telmisartan has now been proven to be an acceptable alternative to an ACE inhibitor for treating patients who have vascular disease or high-risk diabetes without heart failure. In the high-risk CV patients randomized in ONTARGET, it provided an equal degree of protection against the combined risk of CV death, MI, stroke, and hospitalization for congestive heart failure as the previous standard but was better tolerated.