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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, FESCAssociazione 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; EldrinF. Lewis, MD; Fabio Baschiera, PhD; Tsushung A. Hua, PhD; Claudio R. Gimpelewicz, MD; Anastasia Lesogor, MD; MihaiGheorghiade, 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 • FaiezZannad, 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 • EbrahimBarkoudah, MD • KayodeOdutayo, 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 JAMA1; the current presentation is focused on the effects of aliskiren in patients without DM (~60% of the study population). Gheorghiade et al. JAMA. 2013;309(11):1125-35.

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 m2 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 2 weeks Screening Follow-up period median: 5 days median: 11.3 months

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

9. Study Endpoints by Baseline DM Status

10. Baseline Characteristics of non-DM Patients

11. Medical History and Background Therapies in non-DM Patients

12. Primary Endpoint in non-DM PatientsCV 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 20 15 • Kaplan-Meier estimate of cumulative event rate (%) 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

13. Key Secondary Endpoint in non-DM PatientsCV 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 20 • Kaplan-Meier estimate of cumulative event rate (%) 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

14. All-Cause Death Within 12 Months in non-DM Patients 25 Aliskiren (72/489 patients with events; 14.7%) Placebo (91/464 patients with events; 19.6%) 20 15 • Kaplan-Meier estimate of cumulative event rate (%) 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

15. Changes in Biomarkers With Time in non-DM Patients 6 ** ** ** PRA 5 3,200 500 ** NT-proBNP 3,000 450 4 2,800 400 * PRA (ng/ml/L) 3 NT-proBNP (pg/mL) 350 2,600 300 2,400 2 250 2,200 200 1 2,000 150 100 0 1,800 50 BL Month 1 Month 6 Month 12 1,600 0.05 ** 1,400 BL Month 1 Month 6 Month 12 ** Aldosterone ** 0.045 1,200 Troponin I 0.04 ** ** * Aldosterone (pmol/L) Troponin I (ng/L) 0.035 0.03 0.025 0.02 0 Month 12 BL Month 1 Month 6 Month 12 Month 6 BL Month 1 Aliskiren (N = 489) Placebo (N = 464) BL, baseline; * p≤0.05; ** p≤0.01

16. Safety profile in Non-DM Patients

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 post-discharge outcomes, serum biomarker profile and was generally well tolerated. • In contrast, diabetic patients appeared to have worse post-discharge 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 Aldo P. Maggioni and coauthors Effect of Aliskiren on Postdischarge Outcomes Among Diabetic and Non-diabetic Patients Hospitalized for Heart Failure: Insights from the ASTRONAUT Trial Published online September 2nd, 2013 Available at www. eurheartj.oxfordjournals.org Snapshot of published manuscript