Effect of Aliskiren on Postdischarge Outcomes Among Non-Diabetic Patients Hospitalized for Heart Failure: Insights from the ASTRONAUT Outcomes Trial Aldo P. Maggioni, MD, FESC Associazione Nazionale Medici Cardiologi Ospedalieri Research Center, Florence, Italy On behalf of: Stephen J. Greene, MD; Gregg C. Fonarow, MD; Michael Böhm, MD; Faiez Zannad, MD; Scott D. Solomon, MD; Eldrin F. Lewis, MD; Fabio Baschiera, PhD; Tsushung A. Hua, PhD; Claudio R. Gimpelewicz, MD; Anastasia Lesogor, MD; Mihai Gheorghiade, MD; for the ASTRONAUT Investigators and Coordinators
Presenter Disclosure Information Dr. Maggioni: · Serving in Committees of studies on Heart Failure sponsored by: Bayer, Abbott Vascular, Cardiorentis, Johnson & Johnson, Novartis Pharma AG
Study Organization Study Executive Committee: Central Endpoint Committee: · Mihai Gheorghiade, MD; Chair · Scott D. Solomon, MD; Chair · Aldo P. Maggioni, MD; Co-Chair · Eldrin F. Lewis, MD; Co-Chair · Michael Böhm, MD · Peter Finn, MD · Gregg C. Fonarow, MD · Howard Hartley, MD · Faiez Zannad, MD, PhD · Larry Weinrauch, MD · Ebrahim Barkoudah, MD Study Data Monitoring Committee: · Kayode Odutayo, MD · Karl Swedberg, MD, PhD; Chair · Jeffrey S. Borer, MD Study was funded by Novartis Pharma AG · Bertram Pitt, MD · Stuart Pocock, PhD · Jean Rouleau, MD
Background and Rationale · ASTRONAUT explored the effect of aliskiren, a direct renin inhibitor, when added to standard therapy on the rate of CV death or HF re-hospitalization among hemodynamically stable hospitalized HF patients. 1 · Pre-specified subgroup analyses suggested potential heterogeneity in post-discharge outcomes with aliskiren in patients with and without baseline diabetes mellitus (DM). · The overall results were presented at the ACC 2013 and ESC HF 2013 and published in JAMA 1 ; the current presentation is focused on the effects of aliskiren in patients without DM (~60% of the study population). 1. Gheorghiade et al. JAMA. 2013;309(11):1125-35.
Objectives Primary: · CV death or HF re-hospitalization within 6 months Key Secondary: · CV death or HF re-hospitalization within 12 months Secondary: · All-cause mortality within 6 and 12 months · Change in biomarkers from baseline (NT-proBNP, PRA, plasma troponin I, and plasma aldosterone) at 1, 6 and 12 months of follow up
Selection Criteria Inclusion criteria: · Patients requiring hospitalization for worsening of chronic HF · LVEF ≤40% · BNP ≥400 pg/mL or NT-proBNP ≥1600 pg/mL · SBP ≥110 mm Hg for at least 6 hours · No use of IV vasodilators (except nitrates)/IV inotropes from the time of hospital presentation to randomization Exclusion criteria: · Recent MI, cardiac surgery or stroke · eGFR <40 mL/min/1.73 m 2 or potassium >5.0 mEq/L · Hyponatremia <130 mEq/L, and · Comorbid conditions with expected survival <3 years
Study Design Hospitalization for worsening chronic HF Randomization Aliskiren Aliskiren 300 mg 150 mg Placebo Conventional therapy 2 weeks Screening Follow-up period median: 5 days median: 11.3 months
Patient Flow 2134 Screening screened 495 excluded 1639 randomized Randomization Allocation 821 aliskiren 818 placebo 11 excluded 13 excluded 808 807 Primary Efficacy analysis Efficacy analysis Analysis Pre-specified 319/489 343/464 sub-group Subgroup analysis Subgroup analysis with/without DM
Study Endpoints by Baseline DM Status Aliskiren Placebo Interaction Non-DM (n=489) Non-DM (n=464) HR p-value DM (n=319) DM (n=343) (95% CI) (two-sided) Primary End Point (6 months) CV death or HF re-hospitalization Non-DM 102 (20.9) 114 (24.6) 0.80 (0.61-1.04) DM 99 (31.0) 100 (29.2) 1.13 (0.86- 1.50) 0.08 Secondary End Points (12 months) CV death or HF re-hospitalization Non-DM 148 (30.3) 165 (35.6) 0.80 (0.64-0.99) DM 135 (42.3) 136 (39.7) 1.16 (0.91-1.47) 0.03 All-cause death Non-DM 72 (14.7) 91 (19.6) 0.69 (0.50-0.94) DM 72 (22.6) 57 (16.6) 1.64 (1.15-2.33) <0.01
Baseline Characteristics of non-DM Patients Aliskiren Placebo (n = 489) (n = 464) Age, mean (SD), years 64.1 (13.3) 63.4 (13.0) Male, n (%) 394 (80.6) 345 (74.4) Ischemic heart failure etiology, n (%) 287 (58.7) 248 (53.4) LVEF, mean (SD), % 28 (7.3) 27 (7.5) SBP, mean (SD), mm Hg 123 (12.8) 123 (12.2) Heart rate, mean (SD), bpm 77 (16.0) 78 (16.5) eGFR, mean (SD), mL/min/1.73 m 2 68.5 (20.4) 67.0 (19.9) NT-proBNP (pg/mL), median (IQR), Visit 1 4471 (2840-8540) 4472 (2715-8924) NT-proBNP (pg/mL), median (IQR), Visit 2 2851 (1510-5344) 2651 (1555-5257) BNP (pg/mL), mean (IQR), Visit 1 936 (592-1650) 842 (533-1570) BNP (pg/mL), mean (IQR), Visit 2 466 (239-900) 437 (220-910)
Medical History and Background Therapies in non-DM Patients Aliskiren Placebo N = 489, n (%) N = 464, n (%) Medical history Hypertension 353 (72.2) 330 (71.1) Coronary artery disease 240 (49.1) 203 (43.8) Renal insufficiency 67 (13.3) 79 (17.0) COPD 97 (19.8) 78 (16.8) Background therapies Diuretic (not including MRA) 469 (95.9) 445 (95.9) ACEi 324 (66.3) 318 (68.5) ARB 87 (17.8) 65 (14.0) β-blocker 385 (78.7) 391 (84.3) MRA 276 (56.4) 281 (60.6)
Primary Endpoint in non-DM Patients CV Death or HF Re-hospitalization Within 6 Months 30 Aliskiren (102/489 patients with events; 20.9%) Placebo (114/464 patients with events; 24.6%) 25 Kaplan-Meier estimate of cumulative event rate (%) 20 15 10 5 HR: 0.80 (95% CI: 0.61-1.04) p = 0.11 0 0 30 60 90 190 Time in study (days) Number of subjects Aliskiren 489 466 444 427 383 Placebo 464 440 410 393 343 Aliskiren Placebo HR p-value n (%) n (%) (95% CI) (two-sided) CV death 42 (8.6) 49 (10.6) 0.73 (0.48-1.12) 0.14 HF re-hospitalization 74 (15.1) 86 (18.5) 0.77 (0.56-1.05) 0.10
Key Secondary Endpoint in non-DM Patients CV Death or HF Re-hospitalization Within 12 Months 35 Aliskiren (148/489 patients with events; 30.3%) Placebo (165/464 patients with events; 35.6%) 30 25 Kaplan-Meier estimate of cumulative event rate (%) 20 15 10 5 HR: 0.80 (95% CI: 0.64-0.99) p = 0.04 0 0 30 60 90 190 365 Time in study (days) Number of subjects Aliskiren 489 466 444 427 383 134 Placebo 464 440 410 393 343 113 Aliskiren Placebo HR p-value n (%) n (%) (95% CI) (two-sided) CV death 64 (13.1) 85 (18.3) 0.63 (0.45-0.87) <0.01 HF re-hospitalization 104 (21.3) 116 (25.0) 0.79 (0.61-1.04) 0.09
All-Cause Death Within 12 Months in non-DM Patients 25 Aliskiren (72/489 patients with events; 14.7%) 20 Placebo (91/464 patients with events; 19.6%) Kaplan-Meier estimate of cumulative event rate (%) 15 10 5 HR: 0.69 (95% CI: 0.50-0.94) p = 0.02 0 0 30 60 90 190 365 Time in study (days) Number of subjects Aliskiren 489 480 476 467 441 172 Placebo 464 457 443 434 405 152
Changes in Biomarkers With Time in non-DM Patients 6 3,200 ** 3,000 ** ** PRA 5 2,800 NT-proBNP ** 2,600 NT-proBNP (pg/mL) 4 PRA (ng/ml/L) 2,400 * 2,200 3 2,000 1,800 2 1,600 1 1,400 1,200 0 BL Month 1 Month 6 Month 12 BL Month 1 Month 6 Month 12 0.05 ** 500 450 ** Aldosterone 0.045 ** Aldosterone (pmol/L) 400 Troponin I (ng/L) Troponin I 0.04 350 ** 300 ** * 0.035 250 0.03 200 150 0.025 100 0.02 50 0 Month 12 BL Month 1 Month 12 BL Month 1 Month 6 Month 6 Aliskiren (N = 489) Placebo (N = 464) BL, baseline; * p≤0.05; ** p≤0.01
Safety profile in Non-DM Patients Aliskiren vs. Aliskiren Placebo Placebo N = 489 N = 465 relative risk P-value n (%) n (%) (95% CI) (2-sided) Rate of treatment discontinuation due to AEs 0.32 Hyperkalemia 16 (3.3) 10 (2.2) 1.52 (0.70-3.32) 0.09 Renal impairment or renal 19 (3.9) 9 (1.9) 2.01 (0.92-4.39) failure 0.12 Hypotension 18 (3.7) 9 (1.9) 1.90 (0.86-4.19) Maximum or minimum post -baseline values Potassium ≥6 (mmol/L) 32 (6.5) 26 (5.6) 1.17 (0.71-1.93) 0.59 eGFR <30 46 (9.4) 42 (9.0) 1.04 (0.70-1.55) 0.91 (mL/min/1.73 m 2 )
Limitations · The major limitation of this work is that these results are based on a subgroup analysis. Therefore these results can be considered hypothesis generating only. · An additional limitation is the definition of DM used. The presence or absence of underlying diabetes was determined solely by the investigator and it was not mandatory to use objective criteria.
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