Direct renin inhibition with aliskiren alone, and in combination with enalapril, compared with enalapril, in heart failure: Aliskiren Trial to Minimize OutcomeS in Patients with HEart failuRE (ATMOSPHERE) JJV McMurray 1 , WT Abraham 2 , K Dickstein 3 , LV Køber 4 , MA Ali 5 , Y Chiang 5 , AS Desai 6 , C Gimpelewicz 5 , Q Sho 5 , SD Solomon 6 , G Tarnesby 5 , BM Massie 7 , H Krum 8 on behalf of the ATMOSPHERE committees and investigators. 1 University of Glasgow, UK; 2 Ohio State University, USA; 3 Stavanger University Hospital, Stavanger, Norway; 4 Copenhagen University Hospital, Denmark; 6 Brigham and Women's Hospital, Boston, USA; 5 Novartis Pharma AG, Basel, Switzerland; 7 University of California, San Francisco, USA; 8 Monash University, Australia.
Background: Renin inhibition in heart failure with reduced ejection fraction (HF-REF) • ACE inhibitors reduce mortality and reduce heart failure hospitalization rates in patients with HF-REF, across the spectrum of symptom severity (CONSENSUS, SOLVD). • ARBs are an alternative in patients unable to tolerate an ACE inibitor because of cough (CHARM-Alternative). • ARBs futher reduce cardiovascular mortality (CHARM- Added) and heart failure hospitalization (CHARM- Added, Val-HeFT) when added to an ACE inhibitor. • Might a direct renin inhibitor (aliskiren) add to the benefit of an ACE inhibitor or be a better alternative to an ACE inhibitor?
Aliskiren Trial to Minimize OutcomeS in Patients with HEart failuRE (ATMOSPHERE) In reducing the risk of the primary composite outcome of cardiovascular death or heart failure hospitalization • Aliskiren added to enalapril is superior to enalapril Superiority hypotheses • Aliskiren monotherapy is superior to enalapril • Aliskiren monotherapy is non- Non-inferiority hypothesis inferior to enalapril https://clinicaltrials.gov NCT00853658
ATMOSPHERE: Entry criteria • Age ≥ 18 years. NYHA class II-IV. LVEF ≤ 0.35 • BNP ≥ 150 pg/ml (NTpro-BNP ≥ 600 pg/ml) or if HF hosp. within12 mo. BNP ≥ 100 pg/ml (NTpro-BNP ≥ 400 pg/ml) • Background ACEi therapy equivalent to enalapril ≥ 10 mg/d • Beta-blocker unless contraindicated/not tolerated • SBP ≥ 95 mmHg run-in/ ≥ 90 mmHg at randomization • eGFR ≥ 35 ml/min/1.73m 2 at randomization /no decrease >25% during run in • Potassium <5.0 mmol/l run-in/ <5.2 mmol/l at randomization
ATMOSPHERE: Trial design Primary outcome: CV death or heart failure hospitalization (event driven: target 2318 patients [2369 accrued]) *89% 10mg bid Randomization † Target dose (titrated from 150mg qd) Enalapril 5-10mg bid* (n=2336) Enalapril Enalapril + 5-10mg bid Aliskiren150mg qd Aliskiren 300mg qd † (n=2340) Enalapril 5-10mg bid + Aliskiren300mg qd (n=2340) Open-label run-in Double-blind 4-12 weeks Median follow-up = 36.6 months Prior ACEi use discontinued
ATMOSPHERE: Baseline characteristics Aliskiren+Enalapril Aliskiren Enalapril (n=2340) (n=2340) (n=2336) Age (years) 63.2 ± 11.7 63.3 ± 12.1 63.3 ± 11.7 Women (%) 21.1% 22.7% 21.4% Ischemic etiology (%) 57.1% 55.3% 55.7% LVEF (%) 28.5 ± 5.7 28.4 ± 5.7 28.3 ± 5.7 NYHA class II / III (%) 64.0% / 33.7% 64.0% / 34.3% 61.7% / 36.3% Systolic BP (mm Hg) 124 ± 19 124 ± 18 123 ± 18 Heart rate (beats/min) 72 ± 13 72 ± 12 72 ± 13 NT pro-BNP (pg/ml) 1193 (640-2351) 1167 (627-2173) 1223 (634-2194) History of diabetes 28.4% 26.8% 27.9% Digitalis 32.7% 32.0% 31.2% Beta-blocker 92.0% 91.2% 91.9% MRA 36.6% 36.9% 37.8% CRT-P/CRT-D 6.1% 5.1% 5.6% ICD/CRT-D 15.0% 15.5% 14.4%
ATMOSPHERE: Censoring of patients with diabetes* • Following the results of ALTITUDE (aliskiren added to an ACE-I/ARB in patients with diabetes and CKD/CVD) and ASTRONAUT (aliskiren added to an ACE-I/ARB in patients hospitalized with HF), the Clinical Trials Facilitation Group of the Heads of Medicines Agencies in Europe requested that patients with diabetes have study drug discontinued. • Follow-up for the efficacy analyses in patients with diabetes (and some others) who had treatment discontinued because of a regulatory request was censored at the date of implementation of these requests. Patients off study drug were still followed to end of the trial. • Median follow-up for analysis of efficacy in patients with diabetes was 24.1 months and in patients without diabetes was 46.0 months. *and some others
ATMOSPHERE: Trial conduct Completeness of follow-up for vital status (at end of trial or regulatory censoring date). • Combination therapy: 31/2340 (1.3%) had unknown vital status. • Aliskiren: 19/2340 (0.8%) had unknown vital status. • Enalapril: 19/2336 (0.8%) had unknown vital status. Study drug dose (mean ±SD) • Combination group:19.0 (3.0) mg of enalapril and 272 (58) mg of aliskiren; Aliskiren group: 276 (55) mg; Enalapril group 18.6 (3.5) mg. Study drug discontinuation • Non-diabetics: Combination 44%, aliskiren 40%; enalapril 42%. Proportion of possible treatment time patients took study drug was 77%, 81% and 80%, respectively. • Diabetics: 31%, 28% and 32%; 80%, 84 and 82%, respectively.
Aliskiren Trial to Minimize OutcomeS in Patients with HEart failuRE (ATMOSPHERE) In reducing the risk of the primary composite outcome of cardiovascular death or heart failure hospitalization • Aliskiren added to enalapril is superior to enalapril Superiority hypotheses • Aliskiren monotherapy is superior to enalapril • Aliskiren monotherapy is non- Non-inferiority hypothesis inferior to enalapril https://clinicaltrials.gov NCT00853658
ATMOSPHERE: Primary outcome
ATMOSPHERE: Components of the primary composite outcome CV death HF hospitalization
ATMOSPHERE: Effect of combination therapy in patients with and without diabetes Effect of combination therapy on the primary outcome in patients without diabetes (*additional superiority hypothesis in revised statistical analysis plan) Aliskiren+ HR Enalapril P value Enalapril (95% CI) 574/1675 592/1684 0.96 Patients without diabetes 0.46 (34.3%) (35.2%) (0.85-1.07) n (%)* 196/665 216/652 0.86 Patients with diabetes 0.13 (29.5%) (33.1%) (0.71-1.04) n (%) Interaction P-value = 0.35
Aliskiren Trial to Minimize OutcomeS in Patients with HEart failuRE (ATMOSPHERE) In reducing the risk of the primary composite outcome of cardiovascular death or heart failure hospitalization • Aliskiren added to enalapril is superior to enalapril Superiority hypotheses • Aliskiren monotherapy is superior to enalapril • Aliskiren monotherapy is non- Non-inferiority hypothesis inferior to enalapril https://clinicaltrials.gov NCT00853658
ATMOSPHERE: Comparison of enalapril and aliskiren monotherapy (non-inferiority) Pre-specified criterion for declaring non-inferiority was a P-value ≤ 0.0123 (one-sided) Aliskiren Enalapril HR P value (n=2340) (n=2336) (95% CI) 791 808 0.99 All patients 0.0184* (33.8%) (34.6%) (0.90-1.10) n (%) *Did not meet the pre-specified P-value for significance
ATMOSPHERE: Secondary and exploratory outcomes Secondary outcome: • Kansas City Cardiomyopathy Questionnaire (KCCQ) - Change in the clinical summary score (CSS) from baseline to 12 months Exploratory outcomes (selected): • Composite CV outcome: CV death, HF hospitalization, MI, stroke or resuscitated cardiac arrest • Composite renal outcome: renal death, ESRD (initiation of dialysis, renal transplantation, or a serum Cr above 6.0 mg/ dl [530 µmol/l]), or doubling of serum Cr from baseline (to >upper limit of normal) sustained for at least 1 month
ATMOSPHERE: Pre-specified secondary outcome Difference Difference P P Aliskiren+ Aliskiren Enalapril (95% CI) (95% CI) value value Enalapril (1) (2) (1) (2) KCCQ: change in CSS -5.04 -6.03 -5.01 -0.03 -1.02 from baseline to 12 0.97 0.20 (±0.56) (±0.57) (±0.55) (-1.56-1.50) (-2.56-0.52) months, points (95% CI) (1) = Comparison of enalapril plus aliskiren versus enalapril; (2)= Comparison of aliskiren versus enalapril
ATMOSPHERE: Pre-specified exploratory outcomes † Aliskiren+ HR HR P P Aliskiren Enalapril Enalapril (95% CI) (95% CI) value value (n=2340) (n=2336) (n=2340) (1) (2) (1) (2) CV death, HF 841 874 877 0.94 1.01 hospitalization, MI, 0.23 0.81 (35.9) (37.4) (37.5) (0.86-1.04) (0.92-1.11) stroke or resuscitated cardiac arrest n (%) 39 26 18 2.17 1.50 Composite renal 0.007 0.18 (1.7) (1.1) (0.8) (1.24-3.79) (0.82-2.74) outcome* n (%) † Selected pre-specified outcomes (1) = Comparison of enalapril plus aliskiren versus enalapril; (2)= Comparison of aliskiren versus enalapril * renal death, ESRD (initiation of dialysis, renal transplantation, or a serum Cr above 6.0 mg/dl [530 µmol/l]), or doubling of serum Cr from baseline (to >upper limit of normal) sustained for at least 1 month
ATMOSPHERE: All-cause mortality
ATMOSPHERE: Pre-specified subgroups Aliskiren Combination Enalapril Enalapril Interaction Interaction n/N (%) n/N (%) n/N (%) n/N (%) P-value P-value Favors aliskiren Favors enalapril Favors combination Favors enalapril
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