Losartan was the first angiotensin receptor blocker approved for use in the United States and entered the market in 1995. At that time, the benefits of ACE inhibitors was well-known, but the correct use of ARBs was still coming into play. The VALIANT Trial (2002) had shown that valsartan was non-inferior to captopril for post-MI patients complicated by heart failure or LV systolic dysfunction, but in patients with vasuclar disease, and without LV systolic dysfunction, it was unknown if there was benefit. The HOPE Trial (2000) was the trial on which the ONTARGET Trial was built. The rationale for the HOPE Trial is descriptive of the academic question of the time as there was suspicion that ACE inhibitors provided vascular benefit in prevention of myocardial infarction. The following is an excerpt from the introduction section of the HOPE Trial publication in NEJM:
“Although dyslipidemia, diabetes, smoking, and hypertension are major risk factors for cardiovascular disease, they do not fully account for the risk. Therefore, other risk factors must be identified in order to reduce mortality and morbidity even further. Epidemiologic and experimental data suggest that activation of the renin– angiotensin–aldosterone system has an important role in increasing the risk of cardiovascular events.”
The HOPE Trial evaluated rampipril vs placebo in a similar patient population to the one described later in the ONTARGET Trial. It was stopped early as it found reduced rates of death, MI, and stroke. The HOPE Trial was important because it showed cardiovascular risk reduction in patients without LV systolic dysfunction. The ONTARGET investigators wanted to see if ARBs had this same vascular protection. Theoretically, it seemed possible that an ARB could provide additional benefit as ACE inhibitors do not block all angiontension II production and and a direct receptor blockade could be beneficial. This trial set out to see if ARBs could be as beneficial in a population similar to that in the HOPE Trial. As such, the investigators of the ONTARGET Trial gathered a patient population similar to that of the HOPE Trial, utilized similar ramipril dosing, confirmed appropriate adherence rates, and aimed to have appropriate statistical power.
In short, this trial evaluated whether telmisartan was noninferior to ramipril in patients with vascular disease or high-risk diabetes for the primary composite outcome of death from CV causes, MI, stroke, or hospitalization from heart failure. It also tested if the combination of these two drugs was superior to ramipril alone. The trial was sponsored by Boehringer Ingelheim, the manufacturer of telmisartan. The trial enrolled 25,620 patients with vascular disease (coronary, peripheral, or cerebrovascular disease) or diabetes with end-organ damage. 8542 patients were assigned to receive telmisartan, 8576 were assigned to receive ramipril, and 8502 were assigned to receive a combination of both drugs. The trial first aimed to test the noninferiority of telmisartan. If this was demonstrated, then it would test the superiority of telmisartan over ramipril. Of course, the trial also assessed if the combination of the two drugs was more effective than ramipril alone. At a median follow-up of 56 months, telmisartan was found to be noninferior, but not superior to ramipril. The combination group provided no additional benefit for reduction in the primary outcome, but did result in an increased risk of hypotensive symptoms, syncope, and renal dysfunction as compared to ramipril. The telmisartan group had lower rates of cough and angioedema than ramipril, but higher rates of hypotensive symptoms. Syncope was similar among telmisartan and ramipril groups. The author’s conclusion was that in this group of patients, physicians could chose between these two medications based on physician or patient preference and a patient’s predisposition to adverse events.
The ONTARGET Trial: Ontarget Investigators. (2008). Telmisartan, ramipril, or both in patients at high risk for vascular events. New England Journal of Medicine, 358(15), 1547-1559.
ONTARGET Trial PMID: 18378520
The HOPE Trial: Yusuf, S., Sleight, P., Pogue, J. F., Bosch, J., Davies, R., & Dagenais, G. (2000). Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. The New England journal of medicine, 342(3), 145-153.
HOPE Trial PMID: 10639539
Useful summaries of the ONTARGET Trial: Wiki Journal Club