Clinical impacts of additive use of olmesartan in hypertensive patients with chronic heart failure:
the supplemental benefit of an angiotensin receptor blocker in hypertensive patients with stable heart failure using olmesartan (SUPPORT) trial

Sakata Y, Shiba N, Takahashi J, et al.
Eur Heart J 2015; 36:915–923.

Background

Clinical guidelines on the treatment of patients with heart failure (HF) with reduced ejection fraction (EF) generally recommend inhibition of renin–angiotensin system (RAS) by angiotensin-converting enzyme (ACE) inhibitors [1,2]. Angiotensin (AT) receptor blockers (ARBs) are considered as reasonable alternatives in the event of ACE intolerance [3]. In patients with HF with preserved EF, however, RAS inhibitors (ACE inhibitors or ARBs) or β-blockers do not have these beneficial effects [3–6]. It is, as yet, unknown whether hypertensive patients with stable chronic heart failure (CHF) treated with ACE inhibitors and/or b-blockers benefit from the additive use of an ARB.
The SUPPORT study examined whether the supplemental use of the AT1 antagonist olmesartan (ARB) reduces mortality and morbidity in hypertensive patients with mildly symptomatic CHF treated with ACE inhibitors or β-blockers [7]. This prospective, randomised, open-label study with a median follow-up period of 4.4 years included a total of 1147 patients. Participants had a mean age of 66 years, 75% was male, 93%  was New York Heart Class (NYHA) 2, and 62% had a preserved EF of 50% or higher. Patients were randomised to additive treatment with olmesartan (n=578) versus no additive treatment (n=569). The primary composite endpoint included all-cause death, non-fatal acute myocardial infarction, non-fatal stroke, and hospitalization for worsening heart failure.

Main results

• The primary endpoint occurred in 33.2% of patients treated with olmesartan and in 29.2% of the control patients (HR: 1.18; 95%CI: 0.96–1.46, P= 0.112).
• Sudden death occurred in 3.1% of olmesartan treated patients versus 1.4% of control patients (HR: 2.24; 95% CI: 0.97- 5.15, P=0.058).
• Subgroup analysis showed that addition of olmesartan to the combination of both ACE inhibitors and β-blockers was related to a higher incidence of the primary endpoint (38.1% vs. 28.2% in the control group; 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).
• Subgroup analyses further showed that olmesartan was associated with decreased mortality when combined with β-blockers alone (9.4%  vs. 22.1%; HR: 0.41; 95% CI: 0.19–0.85, P= 0.017], but not with ACE inhibitors alone
• Renal dysfunction (secondary endpoint) developed in 16.8% of olmesartan treated patients and in 10.7% of the control group (HR: 1.64;CI: 1.19- 2.26,P= 0.003).
  When combined with ACE inhibitors alone, olmesartan use was not associated with renal dysfunction and was associated with decreased incidence of atrial fibrillation (2.4%  vs. 8.8%; HR: 0.26; 95% CI: 0.09–0.80, P= 0.019).
• 16.6%  of the patients treated with olmesartan discontinued olmesartan due to adverse events and other reasons. Hypotension (7.0%), renal dysfunction (1.2%), and worsening HF (0.7%) were the main adverse events.

Conclusions

The supplemental use of olmesartan did not improve clinical outcomes but worsened renal function in hypertensive CHF patients who were treated with ACE inhibitors or β-blockers. Subgroup analysis suggested that triple combination therapy with olmesartan, ACE inhibitors and β-blockers was associated with increased adverse cardiac events and renal dysfunction and should be avoided. Dual combination therapy, particularly olmesartan with β-blockers, could be beneficial in terms of mortality.
The administered olmesartan dose in the present study (9.5-17.9 mg/day) was relatively low compared to previous studies (40mg/day). This leaves the possibility that a full clinical effect may not have been achieved. The present study mainly examined patients with mild symptoms. Future studies should clarify whether the triple combination therapy could be beneficial for patients with more severe CHF symptoms.

Editorial comment [8]

Ewen and Böhm evaluate the SUPPORT trial and present a review of trials examining the effects of ACE inhibitors and ARBs in heart failure. The authors state that “RAAS blockade by ACE inhibition is a main cornerstone in the treatment of HF with reduced EF, with abundant evidence deriving from numerous clinical trials”. [….] “ARBs clearly represent an excellent treatment alternative in patients which are intolerant to ACE inhibitors. As shown by several clinical trials, a combined RAAS blockade
does not provide additional benefit compared with ACE inhibitor/ARB therapy alone but can even cause harm and renal dysfunction. This was again corroborated by the present study, which even
showed increased mortality rates in patients receiving dual RAAS blockade combined with beta-blockers”.
The authors note a limited statistical power to show group differences because of ”[…] low number of patients included and low event rates by selecting patients with a good prognosis by high blood pressure […]”. Furthermore, ”In patients with moderately reduced activation of the RAAS, such as vascular patients, adverse renal effects had to be expected as shown in ONTARGET on double RAAS blockade. Finally, the ejection fraction in this trial was quite high. So, it appeared to be a mixed population of patients with preserved and impaired ejection fraction. Taking into consideration that AT1 antagonists are ineffective in cases of preserved ejection fraction this provides an explanation of the failure of the AT1 antagonist olmesartan to provide beneficial effects. Finally, this study was only performed in an Asian and, in particular, Japanese population. Low body weight, although addressed by dosing, might have contributed to increased adverse effects in renal function”.

Find this article online at European Heart Journal

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