Effect of Aliskiren on Postdischarge Outcomes Among Non-Diabetic Patients Hospitalized for Heart Failure: Insights from the ASTRONAUT Outcomes Trial

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1 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

2 Presenter Disclosure Information Dr. Maggioni: Serving in Committees of studies on Heart Failure sponsored by: Bayer, Abbott Vascular, Cardiorentis, Johnson & Johnson, Novartis Pharma AG

3 Study Organization Study Executive Committee: Mihai Gheorghiade, MD; Chair Aldo P. Maggioni, MD; Co-Chair Michael Böhm, MD Gregg C. Fonarow, MD Faiez Zannad, MD, PhD Study Data Monitoring Committee: Karl Swedberg, MD, PhD; Chair Jeffrey S. Borer, MD Bertram Pitt, MD Stuart Pocock, PhD Jean Rouleau, MD Central Endpoint Committee: Scott D. Solomon, MD; Chair Eldrin F. Lewis, MD; Co-Chair Peter Finn, MD Howard Hartley, MD Larry Weinrauch, MD Ebrahim Barkoudah, MD Kayode Odutayo, MD Study was funded by Novartis Pharma AG

4 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):

5 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

6 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

7 Study Design Hospitalization for worsening chronic HF Randomization Aliskiren 150 mg Aliskiren 300 mg Placebo Conventional therapy Screening median: 5 days 2 weeks Follow-up period median: 11.3 months

8 Patient Flow Screening 2134 screened 495 excluded Randomization 1639 randomized Allocation 821 aliskiren 818 placebo 13 excluded 11 excluded Primary Analysis 808 Efficacy analysis 807 Efficacy analysis Pre-specified sub-group with/without DM 319/489 Subgroup analysis 343/464 Subgroup analysis

9 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 DM 102 (20.9) 99 (31.0) 114 (24.6) 100 (29.2) 0.80 ( ) 1.13 ( ) 0.08 Secondary End Points (12 months) CV death or HF re-hospitalization Non-DM DM 148 (30.3) 135 (42.3) 165 (35.6) 136 (39.7) 0.80 ( ) 1.16 ( ) 0.03 All-cause death Non-DM DM 72 (14.7) 72 (22.6) 91 (19.6) 57 (16.6) 0.69 ( ) 1.64 ( ) <0.01

10 Baseline Characteristics of non-dm Patients Aliskiren (n = 489) Placebo (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 (20.4) 67.0 (19.9) NT-proBNP (pg/ml), median (IQR), Visit ( ) 4472 ( ) NT-proBNP (pg/ml), median (IQR), Visit ( ) 2651 ( ) BNP (pg/ml), mean (IQR), Visit ( ) 842 ( ) BNP (pg/ml), mean (IQR), Visit ( ) 437 ( )

11 Medical History and Background Therapies in non-dm Patients Aliskiren N = 489, n (%) Placebo 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)

12 Primary Endpoint in non-dm Patients CV Death or HF Re-hospitalization Within 6 Months Aliskiren (102/489 patients with events; 20.9%) Placebo (114/464 patients with events; 24.6%) Kaplan-Meier estimate of cumulative event rate (%) HR: 0.80 (95% CI: ) p = Time in study (days) Number of subjects Aliskiren Placebo Aliskiren n (%) Placebo n (%) HR (95% CI) p-value (two-sided) CV death 42 (8.6) 49 (10.6) 0.73 ( ) 0.14 HF re-hospitalization 74 (15.1) 86 (18.5) 0.77 ( ) 0.10

13 Key Secondary Endpoint in non-dm Patients CV Death or HF Re-hospitalization Within 12 Months Aliskiren (148/489 patients with events; 30.3%) Placebo (165/464 patients with events; 35.6%) Kaplan-Meier estimate of cumulative event rate (%) HR: 0.80 (95% CI: ) p = Time in study (days) Number of subjects Aliskiren Placebo Aliskiren n (%) Placebo n (%) HR (95% CI) p-value (two-sided) CV death 64 (13.1) 85 (18.3) 0.63 ( ) <0.01 HF re-hospitalization 104 (21.3) 116 (25.0) 0.79 ( ) 0.09

14 All-Cause Death Within 12 Months in non-dm Patients Aliskiren (72/489 patients with events; 14.7%) Placebo (91/464 patients with events; 19.6%) Kaplan-Meier estimate of cumulative event rate (%) HR: 0.69 (95% CI: ) p = Time in study (days) Number of subjects Aliskiren Placebo

15 Changes in Biomarkers With Time in non-dm Patients NT-proBNP (pg/ml) 3,200 3,000 2,800 2,600 2,400 2,200 2,000 1,800 1,600 1,400 ** * NT-proBNP PRA (ng/ml/l) ** ** PRA ** 1,200 BL Month 1 Month 6 Month 12 0 BL Month 1 Month 6 Month 12 Troponin I (ng/l) ** ** Troponin I * Aldosterone (pmol/l) ** ** Aldosterone ** 0 BL Month 1 Month 6 Month 12 BL Month 1 Month 6 Month 12 BL, baseline; * p 0.05; ** p 0.01 Aliskiren (N = 489) Placebo (N = 464)

16 Safety profile in Non-DM Patients Aliskiren N = 489 n (%) Placebo N = 465 n (%) Aliskiren vs. Placebo relative risk (95% CI) P-value (2-sided) Rate of treatment discontinuation due to AEs Hyperkalemia 16 (3.3) 10 (2.2) 1.52 ( ) 0.32 Renal impairment or renal failure 19 (3.9) 9 (1.9) 2.01 ( ) 0.09 Hypotension 18 (3.7) 9 (1.9) 1.90 ( ) 0.12 Maximum or minimum post -baseline values Potassium 6 (mmol/l) 32 (6.5) 26 (5.6) 1.17 ( ) 0.59 egfr <30 (ml/min/1.73 m 2 ) 46 (9.4) 42 (9.0) 1.04 ( ) 0.91

17 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.

18 Conclusions In the pre-specified subgroup of ASTRONAUT patients without DM representing 60% of study population, the addition of aliskiren to standard therapy appeared to improve postdischarge outcomes, serum biomarker profile and was generally well tolerated. In contrast, diabetic patients appeared to have worse postdischarge outcomes with aliskiren. Results suggest the potential of aliskiren in hospitalized HF patients without DM, where, despite of available therapies, post-discharge event rate remains high. Future prospective investigations are encouraged to confirm potential benefits of renin inhibition in the large cohort of hospitalized HF patients without DM.

19 Publication Snapshot of published manuscript Aldo P. Maggioni and coauthors Effect of Aliskiren on Postdischarge Outcomes Among Diabetic and Nondiabetic Patients Hospitalized for Heart Failure: Insights from the ASTRONAUT Trial Published online September 2nd, 2013 Available at www. eurheartj.oxfordjournals.org