ONTARGET trial of colossal proportions

With over 25,000 participants from 40 countries, the ONTARGET randomised clinical trial is arguably the most ambitious cardiovascular study ever undertaken. The aim of the trial is to investigate whether the AT1 receptor blocker (ARB) telmisartan (Micardis) has similar vascular protective properties to the angiotensin converting enzyme inhibitor (ACE) ramipril (as demonstrated by the HOPE study5 in 1999). The study will determine whether telmisartan is as effective as ramipril in reducing vascular and heart failure end points, and then whether combination therapy is superior to the respective monotherapies for high risk patients with controlled hypertension. The study has important clinical implications. If telmisartan is found to be as effective as ramipril, it will likely become the preferred treatment.

The renin angiotensin aldosterone system (RAAS) is known to play a role in cardiovascular disease because it is a mediator for the development of atherosclerosis and atherothrombotic complications, and subsequent heart disease. This occurs due to angiotensin II mediated stimulation of the AT₁ receptor. These pathological processes can be reduced by suppressing the RAAS, either by blocking the AT₁ receptor with ARBs such as telmisartan, or by using an ACE inhibitor such as ramipril. Rather than blocking the receptor, ACE inhibitors reduce the angiotensin II available to stimulate the AT receptors and elevate bradykinin.¹

Professor Garry Jennings, National Coordinator of the ONTARGET trial in Australia and Chair of the Cardiac MRI sub-study, said, "ARBs and ACE inhibitors work in slightly different ways. The only way to know which is the more effective treatment is to conduct a clinical trial. Since the HOPE study, ramipril has been the gold standard. But there have been few empirical studies and most have used only a specific group of people, such as those with heart failure."

Over the past 12 years, seven different ARBs have been marketed, all with a common mechanism of action but different pharmacological profiles. Telmisartan is marketed in Australia as Micardis. It has a long plasma half life, negligible renal clearance (1%) and greater tissue penetration than other ARBs. In addition, it is the only ARB that improves insulin sensitivity and decreases serum glucose and triglycerides. Clinical trials have evaluated the effectiveness of telmisartan for patients with essential hypertension and coexisting type 2 diabetes or metabolic syndrome, left ventricular hypertrophy or renal failure.² ARBs are thought to be equally as effective as ACE inhibitors in the management of heart failure and left ventricular systolic dysfunction after myocardial infarction (MI).¹

Treatment with ACE inhibitors is known to reduce the risk of mortality and cardiovascular events beyond that which would be expected by simply lowering blood pressure.¹ The question remains whether ARBs offer the same protection in high risk of cardiovascular disease. In 2003, the ONTARGET trial completed its recruitment phase with 25,672 participants, sourced from 40 different countries. Apart from its size, the trial is also unique because of its more representative baseline data. The sample includes greater ethnic diversity, a slightly older population and more people with cerebrovascular disease or hypertension. Compared to the HOPE trial, more than twice as many patients received statins and more than five times as many received ACE inhibitors. Baseline treatments in ONTARGET reflect the changing approach to cardiovascular disease prevention. The use of beta blockers is also higher in the ONTARGET patient population.⁵

To meet the eligibility criteria, participants had to be 55 years or older and at high risk for cardiovascular disease due to coronary artery disease, peripheral arterial occlusive disease, stroke or recent transient ischaemic attack, or diabetes with end organ damage. People with overt heart failure or uncontrolled arterial hypertension were excluded from the trial. Participants will receive follow up examinations over five and a half years.³

Professor Jennings believes that the broad mix of participants makes the trial unique. Further, he said, "The data can also be used for epidemiological studies to identify patterns and see whether there are differences in the prevalence of cardiovascular disease and risk factors among certain ethnic groups and nationalities."

The first aim of the study is to compare telmisartan and ramipril monotherapies for their effectiveness in preventing stroke, myocardial infarction, cardiovascular death and hospitalisation for chronic heart failure.³ Participants have been randomised to receive either telmisartan, ramipril or a placebo.

The second investigation questions whether a combination therapy of both telmisartan and ramipril is more effective than the respective monotherapies. It is expected that combination therapy will enhance the benefits observed in monotherapy. However, the effectiveness of telemisartan compared to ramipril is less certain. Professor Jennings said, "Since patients often report fewer side effects with telmisartan, it may become the favoured treatment if it is equally effective as ramipril."

On the question of the predicted results of the trial, Professor Jennings said, "Only a small number of studies have compared the combination therapy with the single drugs. It seems this is more effective for patients with proteinuria, but there are conflicting data. What is less clear is which drug will be shown to be more effective because there have been no significant studies until now."

The ONTARGET trial also includes seven sub-studies which are designed to enhance understanding of the added benefits of both telmisartan and ramipril beyond the cardiovascular system. Investigations will focus on arterial stiffness, erectile dysfunction, oral glucose tolerance and the cost of hospitalisation due to cardiovascular events on the healthcare system.⁴

The sheer size and representative nature of the ONTARGET clinical trial promises that it will make a significant contribution to scientific literature. The superior tolerability of telmisartan means that it could become the preferred treatment for vascular protection if the results support its effectiveness. Alternatively, the trial may show that combination therapy enhances the benefit derived from monotherapies. Either way, the knowledge gained from the trial will improve protective treatment for patients at high risk of cardiovascular disease.

The results of the study are eagerly awaited and will be presented 31 March at the 57th Annual Scientific Session of the American College of Cardiology (ACC), to be held in Chicago. Results can be accessed online from www.theheart.org

References:

Fitchett D. Clinical trial update: focus on the ONTARGET study. Vascular Health and Risk Management. 2007; 3(6): 1-8.
Costa F. Telemisartan: Standing out in a crowded contest? High Blood Press Cardiovasc Prev. 2006; 13(3): 85-94.
US National Institutes of Health. Effectiveness of Telmisartan and Ramipril Alone and in Combination in CHF Patients [online] 2008 [cited 18 Feb 2008] Available from URL: http://www.clinicaltrials.gov/ct2/show/NCT00153101?term=ontarget&rank=1
ONTARGET/TRANSCEND Investigators. Rationale, design and baseline characteristics of 2 large, simple, randomised trials evaluating telemisartan, ramipril and their combination in high risk patients: The Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial/Telmisartan Randomised Assessment Study in ACE Intolerant Subjects with Cardiovascular Disease (ONTARGET/TRANSCEND trials) American Heart Journal. 2004; 148(1): 52-61.
The Heart Outcomes Prevention Evaluation Study (HOPE) Investigators 2000. Angiotensin-Converting-Enzyme Inhibitor Ramipril on cardiovascular events in high risk patients. New England Journal of Medicine; 342(1): 748.