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 1.Gheorghiade et al. JAMA. 2013;309(11):1125-35.  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).

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 5.0 mEq/L  Hyponatremia <130 mEq/L, and  Comorbid conditions with expected survival <3 years

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

8. Patient Flow 821 aliskiren818 placebo 1639 randomized Screening Allocation Pre-specified sub-group with/without DM Primary Analysis 2134 screened Randomization 495 excluded 13 excluded 11 excluded 807 Efficacy analysis 808 Efficacy analysis 319/489 Subgroup analysis 343/464 Subgroup analysis

9. Study Endpoints by Baseline DM Status Aliskiren Non-DM (n=489) DM (n=319) Placebo Non-DM (n=464) DM (n=343) HR (95% CI) Interaction p-value (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 (0.61-1.04) 1.13 (0.86- 1.50)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 (0.64-0.99) 1.16 (0.91-1.47)0.03 All-cause death Non-DM DM 72 (14.7) 72 (22.6) 91 (19.6) 57 (16.6) 0.69 (0.50-0.94) 1.64 (1.15-2.33)<0.01

10. Baseline Characteristics of non-DM Patients Aliskiren (n = 489) Placebo (n = 464) Age, mean (SD), years64.1 (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 Hg123 (12.8)123 (12.2) Heart rate, mean (SD), bpm77 (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 14471 (2840-8540)4472 (2715-8924) NT-proBNP (pg/mL), median (IQR), Visit 22851 (1510-5344)2651 (1555-5257) BNP (pg/mL), mean (IQR), Visit 1936 (592-1650)842 (533-1570) BNP (pg/mL), mean (IQR), Visit 2466 (239-900)437 (220-910)

11. Medical History and Background Therapies in non-DM Patients Aliskiren N = 489, n (%) Placebo N = 464, n (%) Medical history Hypertension353 (72.2)330 (71.1) Coronary artery disease240 (49.1)203 (43.8) Renal insufficiency67 (13.3)79 (17.0) COPD97 (19.8)78 (16.8) Background therapies Diuretic (not including MRA)469 (95.9)445 (95.9) ACEi324 (66.3)318 (68.5) ARB87 (17.8)65 (14.0) β-blocker385 (78.7)391 (84.3) MRA276 (56.4)281 (60.6)

12. HR: 0.80 (95% CI: 0.61-1.04) p = 0.11 10 5 0 25 20 15 Kaplan-Meier estimate of cumulative event rate (%) Aliskiren (102/489 patients with events; 20.9%) Placebo (114/464 patients with events; 24.6%) 0 30 60 90 190 Number of subjects Aliskiren 489 466 444 427 383 Placebo 464 440 410 393 343 Time in study (days) Primary Endpoint in non-DM Patients CV Death or HF Re-hospitalization Within 6 Months Aliskiren n (%) Placebo n (%) HR (95% CI) p-value (two-sided) CV death42 (8.6)49 (10.6)0.73 (0.48-1.12)0.14 HF re-hospitalization74 (15.1)86 (18.5)0.77 (0.56-1.05)0.10 30

13. Aliskiren (148/489 patients with events; 30.3%) Placebo (165/464 patients with events; 35.6%) 30 25 10 0 0 30 60 90 190 365 Time in study (days) Number of subjects Aliskiren489 466 444427 383 134 Placebo464 440 410393 343 113 Kaplan-Meier estimate of cumulative event rate (%) HR: 0.80 (95% CI: 0.64-0.99) p = 0.04 Key Secondary Endpoint in non-DM Patients CV Death or HF Re-hospitalization Within 12 Months Aliskiren n (%) Placebo n (%) HR (95% CI) p-value (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 20 15 5 35

14. Aliskiren (72/489 patients with events; 14.7%) Placebo (91/464 patients with events; 19.6%) 20 10 0 0 30 60 90 190 365 Time in study (days) Kaplan-Meier estimate of cumulative event rate (%) HR: 0.69 (95% CI: 0.50-0.94) p = 0.02 Number of subjects Aliskiren489 480 476 467 441 172 Placebo 464 457 443 434 405 152 25 15 5 All-Cause Death Within 12 Months in non-DM Patients

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

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 Hyperkalemia16 (3.3)10 (2.2)1.52 (0.70-3.32) 0.32 Renal impairment or renal failure 19 (3.9)9 (1.9)2.01 (0.92-4.39) 0.09 Hypotension18 (3.7)9 (1.9)1.90 (0.86-4.19) 0.12 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 (mL/min/1.73 m 2 ) 46 (9.4)42 (9.0)1.04 (0.70-1.55)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 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