Aliskiren alone or in combination with enalapril vs. enalapril among patients with chronic heart failure with and without diabetes: a subgroup analysis from the ATMOSPHERE trial

Abstract

Aims Because of concerns about the safety of aliskiren in patients with diabetes, study treatment was stopped prematurely in the Aliskiren Trial of Minimizing OutcomeS for Patients with HEart failuRE (ATMOSPHERE). We examined outcomes and treatment effect in these patients compared with those without diabetes. Methods and results ATMOSPHERE included 7016 patients with heart failure and a reduced ejection fraction (HFrEF) randomly assigned to enalapril plus aliskiren, aliskiren alone, or enalapril. At baseline, 1944 (27.7%) patients had diabetes. Median follow‐up was shorter in patients with diabetes compared with those without (24 months vs. 46 months). Among patients with diabetes, the primary endpoint of cardiovascular death or hospitalization for heart failure occurred in 216 patients (33.1%) in the enalapril group (reference), 172 (27.4%) in the aliskiren group [hazard ratio (HR) 0.82, 95% confidence interval (CI) 0.67–1.00; P = 0.053], and 196 (29.5%) in the combination group (HR 0.86, 95% CI 0.71–1.04; P = 0.13). The effects of the treatments studied did not differ significantly compared with patients without diabetes. In patients with diabetes, aliskiren monotherapy was associated with a lower risk of symptomatic hypotension compared to enalapril [42 (6.7%) vs. 65 (10.0%); P = 0.04], whereas other adverse events were generally balanced between the three groups. Conclusion In patients with HFrEF and diabetes, there was no signal of harm and a trend towards benefit when direct renin inhibition monotherapy was compared with an angiotensin‐converting enzyme inhibitor, whereas combined aliskiren and enalapril treatment led to more adverse events with no improvement in outcomes. Treatment effects did not differ in patients with diabetes compared with those without. Clinical Trial Registration URL: http://www.clinicaltrials.gov. Unique identifier: NCT00853658.

The Dapagliflozin And Prevention of Adverse‐outcomes in Heart Failure (DAPA‐HF) trial: baseline characteristics

“…The patients randomized in DAPA‐HF were also broadly similar, in other respects, to those in the recent registries, although, as has been recognized previously, atrial fibrillation was less frequent in Asian patients . Patients in DAPA‐HF were also generally similar to those in the comparator trials with globally diverse enrolment (particularly PARADIGM‐HF and ATMOSPHERE), taking account of specific inclusion and exclusion criteria and other issues such as the cessation of randomization of patients with diabetes part‐way through recruitment in ATMOSPHERE . One of the few exceptions included the fraction obese, which was larger in DAPA‐HF, in keeping with higher prevalence of diabetes and hypertension in DAPA‐HF.…”

“…[11][12][13][14][15][16][17] Patients in DAPA-HF were also generally similar to those in the comparator trials with globally diverse enrolment (particularly PARADIGM-HF and ATMOSPHERE), taking account of specific inclusion and exclusion criteria and other issues such as the cessation of randomization of patients with diabetes part-way through recruitment in ATMOSPHERE. 23 One of the few exceptions included the fraction obese, which was larger in DAPA-HF, in keeping with higher prevalence of diabetes and hypertension in DAPA-HF. The worse kidney function in DAPA-HF probably also reflects the slightly older age and high prevalence of diabetes and hypertension in the current trial, as well as the very high rate of use of renin-angiotensin-aldosterone system blockers, including an MRA in 71% of patients (see below).…”

Dapagliflozin in heart failure: new frontiers

“…The overall prevalence of a history of diabetes was comparatively higher in patients enrolled in DAPA‐HF (42%) compared to PARADIGM‐HF (35%) and ATMOSPHERE (28%), although in the latter study inclusion of patients with diabetes was halted by European regulators due to safety concerns . The prevalence of a history of diabetes in DAPA‐HF more closely resembled patient characteristics seen in the recent COMMANDER‐HF trial (41%).…”

“…However, if SGLT2 inhibitors improve outcomes in patients with HF both with and without diabetes, these variable definitions may be less important. Importantly, it is encouraging to see that the clinical characteristics of patients without a history of diabetes are largely similar to those of patients without a history of diabetes enrolled in ATMOSPHERE and PARADIGM‐HF …”

“…Importantly, it is encouraging to see that the clinical characteristics of patients without a history of diabetes are largely similar to those of patients without a history of diabetes enrolled in ATMOSPHERE and PARADIGM-HF. 10,11 The possible mechanisms underlying the potential cardioprotective effects of SLGT2 inhibitors have been much debated. The potential beneficial effects of SGLT2 inhibitors might be mediated through their natriuretic effects and subsequent decrease in afterload 13,14 ; a recent secondary analysis in the EMPA-REG OUTCOME study suggests changes in markers of plasma volume were the most important mediators of the reduction in risk of cardiovascular death with empagliflozin vs. placebo without negative renal effects.…”