Massive heart trial makes its mark

With over 25,000 participants from over 40 countries, the ONTARGET clinical trial is arguably the most ambitious cardiovascular study ever undertaken. The aim of the trial is to investigate whether the blood pressure lowering drug telmisartan is equally effective as the drug ramipril in preventing the risk of death from heart attacks or strokes, or  the risk of hospitalisation from heart failure. Researchers will also determine whether it is more beneficial for patients to take both of the drugs, rather than only one or the other. The knowledge gained from the study promises to improve protective treatment for patients at high risk of cardiovascular disease.

Scientists know that a hormone system called the RAAS (renin angiotensin aldosterone system) plays a part in heart disease. It is involved in the development of atherosclerosis, where the arteries narrow and become clogged. Angiotensin-II is an agent which constricts blood vessels and causes blood pressure to increase, which increases the risk of heart disease. The drug telemisartan is an ARB (angiotensin receptor blocker), which means it blocks receptors so that angiotensin-II is ignored and cannot have the same effect on blood pressure. The drug ramipril is an ACE inhibitor, which means it reduces the amount of angiotensin-II available. These drugs work in different ways, but they both lower blood pressure.

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 studies and most have used only a specific group of people, such as those with heart failure."

Over the past 12 years, 7 different ARBs have been marketed. They all work in the same way, but each drug has a unique profile. Telmisartan (Micardis) has low renal excretion (doesn’t put a high strain on the kidneys) and has the added benefit of decreasing the levels of blood sugar and fatty acids in the blood. Clinical trials have shown that telmisartan is effective for patients with hypertension and diabetes or metabolic syndrome, and for those with kidney disease or some heart problems. ARBs are thought to be as effective as ACE inhibitors in the management of heart failure and some heart problems after a heart attack.

Treatment with ACE inhibitors is known to reduce the risk of death and of serious cardiovascular events beyond that which would be expected by simply lowering blood pressure. What is unclear, however, is whether ARBs also prevent cardiovascular events in people who are at high risk. In 2003, the ONTARGET trial completed its recruitment phase with 25,672 participants from 40 different countries. Apart from its size, the trial is also unique because of its more representative sample. The sample includes greater ethnic diversity, a slightly older population and more people with cerebrovascular disease or high blood pressure. To meet the eligibility criteria, participants had to be 55 years or older and at high risk for cardiovascular disease due to problems such as coronary artery disease, stroke or diabetes with end organ damage. People with heart failure or uncontrolled high blood pressure were excluded from the trial. Participants will receive follow up examinations for a period of 5.5 years.

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 aim of the study is to first see whether telmisartan is as effective as ramipril in preventing stroke, heart attack and hospitalisation for heart failure. To investigate this question, participants have been randomly allocated to receive either telmisartan, ramipril or a placebo which contains no active drug. The second investigation is to determine whether it is more beneficial to take both telmisartan and ramipril together, instead of one or the other. It is expected that taking both drugs will enhance the benefits observed when using one. However, the effectiveness of telmisartan compared to ramipril is less certain.

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 [an abnormal amount of protein in the urine], 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 results of this trial could change current practices. 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."

The ONTARGET trial also includes a number of smaller studies which will investigate exactly how telmisartan and ramipril work. These studies may reveal added benefits 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.

Due to the sheer size and representative nature of the ONTARGET clinical trial, it promises to make a significant contribution to scientific literature. Since telmisartan has superior tolerability, 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 using only one drug. 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