ACE inhibitors and angiotensin receptor blockers (ARB) in patients at high risk of vascular disease

• in patients who have vascular disease or high-risk diabetes without heart failure, angiotensin-converting-enzyme (ACE) inhibitors reduce mortality and morbidity from cardiovascular causes (1,2)
  • ACE inhibitors (ramipril in the HOPE study and perindopril in the EUROPA study) have been shown to be effective in reducing the risk of CV events and death in patients at high risk of these events
• however the role of angiotensin-receptor blockers (ARBs) in such patients is less clear
• the ONTARGET investigators compared the ACE inhibitor ramipril, the ARB telmisartan, and the combination of the two drugs in patients with vascular disease or high-risk diabetes
  • after a median follow-up of 56 months, there was no significant difference in the rates of the primary outcome (a composite of death from CV causes, myocardial infarction, stroke or hospitalisation for heart failure)
    • rate was 16.5% in the ramipril group, 16.7% in the telmisartan group (relative risk [RR] compared to ramipril 1.01, 95%CI 0.94 to 1.09) and 16.3% in the combination group (RR compared to ramipril 0.99, 95%CI 0.92 to 1.07)
  • adverse effects:
    • significantly more patients in the ramipril group than in the telmisartan group stopped treatment due to cough (4.2% vs. 1.1%, P<0.001, number needed to harm [NNH] 32) or angioedema (0.3% vs. 0.1%, P=0.01, NNH 500), but more patients in the telmisartan group stopped treatment due to hypotensive symptoms (2.7% vs. 1.7%, P<0.001, NNH 100)
    • patients taking the combination therapy were more likely than those taking ramipril alone to discontinue treatment due to hypotensive symptoms (4.8% vs. 1.7%, P<0.001, NNH 32), diarrhoea (0.5% vs. 0.1%, P<0.001, NNH 250), syncope (0.3% vs. 0.2%, P=0.03, NNH=1000) and renal impairment (1.1% vs. 0.7%, P<0.001, NNH 250)
  • a MeReC publication (4) concluded that:
    • there seems little to be gained from adding telmisartan to an evidence-based dose of an ACE inhibitor in patients at high risk of CV events who do not also have heart failure. Indeed using the combination increases the risk of adverse effects serious enough to cause patients to stop treatment (for example, hypotensive episodes, diarrhoea and renal impairment). The combination of an ARB and ACE inhibitor may be an option in patients with chronic heart failure

Reference:

• (1) The Heart Outcomes Prevention Evaluation Study Investigators. Effects of an angiotensin-converting–enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. N Engl J Med 2000; 342:145–53
• (2) The EURopean trial On reduction of cardiac events with Perindopril in stable coronary Artery disease Investigators. Efficacy of perindopril in reduction of cardiovascular events among patients with stable coronary artery disease: randomised, double-blind, placebo-controlled, multicentre trial (the EUROPA study). Lancet 2003;362:782–88.
• (3) ONTARGET Investigators. Telmisartan, ramipril, or both in patients at high risk for vascular events.N Engl J Med. 2008 Apr 10;358(15):1547-59.
• (4) MeReC Monthly No.3 June 2008