Direct renin inhibition with aliskiren alone, and in combination - - PowerPoint PPT Presentation

JJV McMurray1, WT Abraham2, K Dickstein3, LV Køber4, MA Ali5, Y Chiang5, AS Desai6, C Gimpelewicz5, Q Sho5, SD Solomon6, G Tarnesby5, BM Massie7, H Krum8 on behalf of the ATMOSPHERE committees and investigators.

1University of Glasgow, UK; 2Ohio State University, USA; 3Stavanger University

Hospital, Stavanger, Norway; 4Copenhagen University Hospital, Denmark; 6Brigham and Women's Hospital, Boston, USA; 5Novartis Pharma AG, Basel, Switzerland;

7University of California, San Francisco, USA; 8Monash University, Australia.

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)

• 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?

Background: Renin inhibition in heart failure with reduced ejection fraction (HF-REF)

• Aliskiren added to enalapril is

superior to enalapril

• Aliskiren monotherapy is

superior to enalapril

• Aliskiren monotherapy is non-

inferior to enalapril Non-inferiority hypothesis Superiority hypotheses

https://clinicaltrials.gov NCT00853658

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

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/1.73m2 at randomization /no decrease

>25% during run in

• Potassium <5.0 mmol/l run-in/ <5.2 mmol/l at randomization

Median follow-up = 36.6 months 4-12 weeks Randomization Double-blind

Primary outcome: CV death or heart failure hospitalization (event driven: target 2318 patients [2369 accrued])

Open-label run-in

ATMOSPHERE: Trial design

Prior ACEi use discontinued

Enalapril 5-10mg bid Enalapril + Aliskiren150mg qd Enalapril 5-10mg bid* (n=2336) Aliskiren 300mg qd† (n=2340) Enalapril 5-10mg bid + Aliskiren300mg qd (n=2340)

*89% 10mg bid

†Target dose (titrated from 150mg qd)

Aliskiren+Enalapril (n=2340) Aliskiren (n=2340) Enalapril (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: Baseline characteristics

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

• f 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
• f 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 added to enalapril is

superior to enalapril

• Aliskiren monotherapy is

superior to enalapril

• Aliskiren monotherapy is non-

inferior to enalapril Non-inferiority hypothesis Superiority hypotheses

https://clinicaltrials.gov NCT00853658

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

ATMOSPHERE: Primary outcome

ATMOSPHERE: Components of the primary composite outcome

HF hospitalization CV death

ATMOSPHERE: Effect of combination therapy in patients with and without diabetes

Aliskiren+ Enalapril Enalapril HR (95% CI) P value Patients without diabetes n (%)* 574/1675 (34.3%) 592/1684 (35.2%) 0.96 (0.85-1.07) 0.46 Patients with diabetes n (%) 196/665 (29.5%) 216/652 (33.1%) 0.86 (0.71-1.04) 0.13

Interaction P-value = 0.35 Effect of combination therapy on the primary outcome in patients without diabetes (*additional superiority hypothesis in revised statistical analysis plan)

• Aliskiren added to enalapril is

superior to enalapril

• Aliskiren monotherapy is

superior to enalapril

• Aliskiren monotherapy is non-

inferior to enalapril Non-inferiority hypothesis Superiority hypotheses

https://clinicaltrials.gov NCT00853658

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

ATMOSPHERE: Comparison of enalapril and aliskiren monotherapy (non-inferiority)

Aliskiren (n=2340) Enalapril (n=2336) HR (95% CI) P value All patients n (%) 791 (33.8%) 808 (34.6%) 0.99 (0.90-1.10) 0.0184*

*Did not meet the pre-specified P-value for significance Pre-specified criterion for declaring non-inferiority was a P-value ≤0.0123 (one-sided)

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

Aliskiren+ Enalapril Aliskiren Enalapril Difference (95% CI) (1) Difference (95% CI) (2) P value (1) P value (2) KCCQ: change in CSS from baseline to 12 months, points (95% CI)

• 5.04

(±0.56)

• 6.03

(±0.57)

• 5.01

(±0.55)

• 0.03

(-1.56-1.50)

• 1.02

(-2.56-0.52) 0.97 0.20 (1) = Comparison of enalapril plus aliskiren versus enalapril; (2)= Comparison of aliskiren versus enalapril

ATMOSPHERE: Pre-specified exploratory outcomes†

Aliskiren+ Enalapril (n=2340) Aliskiren (n=2340) Enalapril (n=2336) HR (95% CI) (1) HR (95% CI) (2) P value (1) P value (2) CV death, HF hospitalization, MI, stroke or resuscitated cardiac arrest n (%) 841 (35.9) 874 (37.4) 877 (37.5) 0.94 (0.86-1.04) 1.01 (0.92-1.11) 0.23 0.81 Composite renal

• utcome* n (%)

39 (1.7) 26 (1.1) 18 (0.8) 2.17 (1.24-3.79) 1.50 (0.82-2.74) 0.007 0.18 † 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

Combination n/N (%) Interaction P-value Aliskiren n/N (%) Interaction P-value

ATMOSPHERE: Pre-specified subgroups

Favors combination Favors enalapril Favors enalapril Favors aliskiren

Enalapril n/N (%) Enalapril n/N (%)

Aliskiren+ Enalapril (n=2340) Aliskiren (n=2340) Enalapril (n=2336) P value (1) P value (2) Hypotension n (%) Symptoms Symptoms and SBP <90mmHg 322 (13.8%) 87 (3.7%) 249 (10.6%) 31 (1.3%) 258 (11.0%) 55 (2.4%) 0.005 0.008 0.67 0.009 Renal impairment n (%) Cr ≥2.5mg/dl Cr ≥3.0mg/dl 95 (4.1%) 46 (2.0%) 63 (2.7%) 35 (1.5%) 62 (2.7%) 29 (1.2%) 0.009 0.06 1.00 0.53 Hyperkalemia n (%) K+ >5.5mmol/l K+ >6.0mmol/l 401 (17.1%) 116 (5.0%) 255 (10.9%) 70 (3.0%) 291 (12.5%) 83 (3.6%) <0.0001 0.02 0.10 0.29 Cough n (%) 290 (12.4%) 241 (10.3%) 284 (12.2%) 0.83 <0.05

ATMOSPHERE: Safety outcomes

(1) = Comparison of enalapril plus aliskiren versus enalapril; (2)= Comparison of aliskiren versus enalapril

Combination therapy

• The addition of aliskiren to an evidence-based dose of

enalapril led to more adverse events without an increase in benefit.

• This finding differs from the prior ARB “add-on” trials and

may reflect a difference in study design (the previous trials did not require an evidence-based dose of background ACE inhibitor).

• There is probably a ceiling to RAS blockade in heart

failure, above which there is no further benefit

Aliskiren monotherapy

• Non-inferiority was not demonstrated for aliskiren

compared with enalapril.

Summary and conclusions

Henry Krum, 1958-2015

Henry Krum, 1958-2015

In memory of our colleague and friend

Thank You

ATMOSPHERE

43 countries, 844 Sites, 7064 Patients