Abstract and Introduction
Abstract
We examined whether an additive treatment with an angiotensin receptor blocker, olmesartan, reduces the mortality and morbidity in hypertensive patients with chronic heart failure (CHF) treated with angiotensin-converting enzyme (ACE) inhibitors, β-blockers, or both. In this prospective, randomized, open-label, blinded endpoint study, a total of 1147 hypertensive patients with symptomatic CHF (mean age 66 years, 75% male) were randomized to the addition of olmesartan (n = 578) to baseline therapy vs. control (n = 569). The primary endpoint was a composite of all-cause death, non-fatal acute myocardial infarction, non-fatal stroke, and hospitalization for worsening heart failure. During a median follow-up of 4.4 years, the primary endpoint occurred in 192 patients (33.2%) in the olmesartan group and in 166 patients (29.2%) in the control group [hazard ratio (HR) 1.18; 95% confidence interval (CI), 0.96–1.46, P = 0.112], while renal dysfunction developed more frequently in the olmesartan group (16.8 vs. 10.7%, HR 1.64; 95% CI 1.19–2.26, P = 0.003). Subgroup analysis revealed that addition of olmesartan to combination of ACE inhibitors and β-blockers was associated with increased incidence of the primary endpoint (38.1 vs. 28.2%, HR 1.47; 95% CI 1.11–1.95, P = 0.006), all-cause death (19.4 vs. 13.5%, HR 1.50; 95% CI 1.01–2.23, P = 0.046), and renal dysfunction (21.1 vs. 12.5%, HR 1.85; 95% CI 1.24–2.76, P = 0.003). Additive use of olmesartan did not improve clinical outcomes but worsened renal function in hypertensive CHF patients treated with evidence-based medications. Particularly, the triple combination therapy with olmesartan, ACE inhibitors and β-blockers was associated with increased adverse cardiac events. This study is registered at clinicaltrials.gov-NCT00417222.
Introduction
In patients with heart failure (HF) with reduced ejection fraction (EF) (HFrEF), inhibition of renin–angiotensin system (RAS) by angiotensin-converting enzyme (ACE) inhibitors is generally recommended to improve mortality and morbidity in the clinical guidelines. Angiotensin receptor blockers (ARBs) are considered as reasonable alternatives of ACE inhibitors since they improve outcomes in patients with HFrEF and intolerance of ACE inhibitors. However, it is still controversial whether the additive use of ARBs to evidence-based medications is beneficial in patients with HFrEF, particularly in the subset of those who have a history of hypertension. Furthermore, unlike in HFrEF patients, beneficial impacts of RAS inhibitors (ACE inhibitors or ARBs) or β-blockers have not been shown in the randomized clinical trials in patients with HF with preserved EF (HFpEF), and thus neither RAS inhibitors nor β-blockers are recommended for the treatment of HFpEF in the clinical guidelines. In case of hypertensive patients with HFpEF, however, RAS inhibitors and/or β-blockers could be used as anti-hypertensive medication, but the supplemental benefit of ARBs in combination with anti-hypertensive medications has not been examined.
These lines of evidence suggest a need to elucidate whether additive use of ARB is beneficial or not in the general practice of hypertensive chronic heart failure (CHF) patients treated with ACE inhibitors and/or β-blockers. In the supplemental benefit of ARB in hypertensive patients with stable heart failure using olmesartan (SUPPORT) trial, we thus aimed to examine whether a supplemental use of olmesartan provides beneficial impacts in patients with a broad spectrum of HF, who are treated with conventional therapies, namely with ACE inhibitors and/or β-blockers.