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The Heart Outcomes Prevention Evaluation study established the angiotensin-converting enzyme inhibitor ramipril, versus placebo, for prevention of cardiovascular events in high-risk patients. The ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial (ONTARGET) was later conducted in similar high-risk patients using multifactorial treatment to control hypertension, platelet aggregation, and dyslipidemia, while comparing ramipril, telmisartan, or their combination, without placebo. In ONTARGET, the first angiotensin II receptor blocker-based study to be performed in a broader population of patients without congestive heart failure and/or left ventricular hypertrophy/dysfunction, telmisartan provided cardiovascular protection that was noninferior to ramipril. However, greater blockade of the renin–angiotensin system, using their combination, was not superior to ramipril alone. Telmisartan was better tolerated than ramipril in this high-risk population: notably, the incidence of cough and angioedema was significantly lower with telmisartan alone. Thus, telmisartan provides comparable efficacy to ramipril with less adverse events, which may encourage patient compliance.