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European Society of Cardiology Congress

Munich, Germany / August 30-September 3, 2008

The long-awaited results of the TRANSCEND (Telmisartan Randomized AssessmeNt in Study in aCE iNtolerant subjects with cardiovascular Disease) study has confirmed that the angiotensin receptor blocker (ARB) telmisartan offers cardioprotection in high-risk patients who are candidates but cannot tolerate an ACE inhibitor. A companion to the previously reported results of ONTARGET (ONgoing Telmisartan Alone and in Combination With Ramipril Global Endpoint Trial), which demonstrated that telmisartan is as effective but better tolerated than the ACE inhibitor ramipril in patients who can tolerate an ACE inhibitor, TRANSCEND has filled an important gap in clinical knowledge. Before TRANSCEND, it was unclear how ACE-intolerant patients should be managed.

“The TRANSCEND study demonstrates that telmisartan significantly reduces the risk of cardiovascular (CV) events in an ACE inhibitor-intolerant population when administered on top of optimal therapy,” confirmed Dr. Koon Teo, McMaster University, Hamilton, Ontario. Its benefit on top of optimal therapy is an important point, because this double-blind, placebo-controlled trial, like ONTARGET and HOPE (Heart Outcomes Protection Evaluation), was not a hypertension study. Blood pressures (BP) in both groups were comparable.

ONTARGET/TRANSCEND

The ONTARGET/TRANSCEND program was designed to determine whether the ARB telmisartan provided the type of BP independent benefits associated with ramipril in the HOPE study, which was published in 2000. In a series of previous trials, ACE inhibitors had demonstrated efficacy in preventing recurrent myocardial infarctions (MI) and other CV events in a post-MI population as well as events associated with left ventricular (LV) dysfunction, but HOPE expanded the population who achieve BP independent benefits from inhibition of the renin angiotensin system (RAS). The study showed that these benefits extend to the much larger group of high-risk patients who did not necessarily have a previous MI or are in heart failure. In industrialized countries, this high-risk population is more than double that of post-MI and heart failure patients combined.

“Patients at high risk for CV disease are the types of patients we see every day and who are already being treated for their modifiable risk factors, but HOPE demonstrated we could do something more,” reported Dr. Michael Böhm, Department of Internal Medicine and Cardiology, University of the Saarland, Hamburg, Germany. While the previous results of the ONTARGET study demonstrated that telmisartan is equally effective but better tolerated than ramipril in this population, “now we have the evidence that we can also offer additional protection for patients intolerant to ACE inhibitors.”

The TRANSCEND population of 5926 patients was comparable to that of ONTARGET with the main exception that they were intolerant to ACE inhibitors. Like the ONTARGET population, they were defined as high risk by having established coronary artery, peripheral vascular, or cerebrovascular disease or diabetes with end-organ damage. Although half of the patients had a previous MI, many of those with coronary artery disease had not had a previous event and were therefore receiving primary risk prevention therapy. The patients were randomized to telmisartan or placebo on top of standard therapies, which included, at the time of randomization, statins in 55%, beta blockers in almost 60%, and antiplatelet therapies in almost 80%. About one-third of the patients were on diuretics and approximately 40% were on calcium channel blockers at the start of the study.

Study Findings

On the basis of the same composite outcome of CV death, MI, or stroke employed in HOPE, patients randomized to telmisartan had a 13% (HR 0.87, 0.76–1.00; P=0.048) relative risk reduction. This reduction was achieved despite the far more challenging conditions with which telmisartan had to demonstrate benefit relative to ramipril in HOPE eight years earlier. Most notable was that almost 65% of patients were taking a statin by the end of the study, a proportion that was more than double that among patients participating in HOPE. Other baseline therapies were also used more aggressively. The difficulty of demonstrating benefit was emphasized by the insignificant 8% reduction (P=0.216) in the primary composite outcome which also included hospitalization for heart failure. However, the benefit in the secondary composite HOPE outcome remains clinically important.

“The HOPE and the ONTARGET/TRANSCEND patients are exactly the same except in the eight years that separate them, the ONTARGET/TRANSCEND population is extremely better treated, particularly in regard to statins and beta blockers,” reported Dr. Roberto Ferrari, the incoming president of the European Society of Cardiology and a Professor of Cardiology, Cardiovascular Institute, University of Ferrara, Italy. “For me, the tolerability in TRANSCEND is very important, because it tells us that for those patients who are intolerant to a drug [ramipril] that we know to be effective, telmisartan is an alternative to reduce CV death, MI and stroke.”

While TRANSCEND found that telmisartan was an effective alternative for patients intolerant to an ACE inhibitor, ONTARGET demonstrated that it was equally effective but better tolerated than the gold standard of ramipril in the same high-risk population. The senior author of that study, Dr. Salim Yusuf, McMaster University, and others, such as Dr. Peter Sleight, Oxford University, UK, concluded that telmisartan could be considered a first-line therapy equivalently effective relative to ramipril but easier to administer for CV protection in high-risk populations. According to Dr. Sleight, in countries where cost is not an issue, telmisartan would be the preferred therapy because of its more favourable tolerability.

Issue of Compliance

“You have to remember that in real life, the therapies go on for much longer than the few years that we evaluate a drug in a clinical trial. In addition, patients are being [asked] to stay on their assigned therapy. But in real life, the difference in tolerability is a very big issue and side effects matter terribly, and, of course, you cannot get the benefits of a therapy if you do not stay on the therapy,” Dr. Sleight told delegates.

In ONTARGET, discontinuations for side effects were significantly more common (P=0.02) in the ramipril group when compared to the group randomized to telmisartan even though patients were screened for tolerance to ACE inhibitors prior to randomization. In TRANSCEND, the difference in the rate of discontinuations favouring telmisartan over placebo approached statistical significance (P=0.055). The advantage appears to be explained by the need for the placebo group of patients to receive more antihypertensive therapies, such as beta blockers and diuretics, to achieve a similar BP control as the telmisartan arm over the course of the study. These are blamed for the tolerability difference.

“From the perspective of a general practitioner, it is hard enough to keep patients on effective therapies, particularly when they have no symptoms. In TRANSCEND, the data suggest that we might do even better than placebo in keeping patients on therapy, because we avoid less well tolerated drugs and still reduce clinical risk,” noted Dr. Sarah Jarvis, Richford Gate Medical Practice, London, UK, who emphasized that the placebo population, like the telmisartan population, was on best medical therapy.

Several investigators, including Dr. Yusuf, have suggested that the benefit of telmisartan in the ONTARGET/TRANSCEND program is not necessarily relevant to other ARBs on an evidence-based approach to therapy. Several unique features of telmisartan make it important for other ARBs to demonstrate the same degree of effect. “What is know is that, compared with other ARBs, telmisartan is more lipophilic, displays the highest binding affinity to the angiotensin II type 1 receptor, and possess the longest plasma half-life,”stated Dr. Gilles Dagenais, Université Laval, Heart and Lung Institute, Quebec City, who noted that telmisartan has shown greater 24-hour BP reductions than valsartan and losartan in comparative trials.

Summary

Results of the TRANSCEND part of the ONTARGET/TRANSCEND program have made it possible to conclude that telmisartan can be considered a first-line therapy for preventing CV events in high-risk patients, including those that are ACE inhibitor-intolerant. Better tolerated but equally effective when compared to ramipril, the proven ACE inhibitor, in this population, telmisartan provides BP independent benefits with a low risk of adverse events, facilitating its use on top of other therapies these patients often require for risk prevention.