• ASTRONAUT Trial

    and Heart Failure Readmissions Among Patients Hospitalized for Heart Failure- AliSkiren TRial ON Acute heart failure oUTcomes (ASTRONAUT) Mihai Gheorghiade, MD Center for Cardiovascular Innovation, Northwestern University Feinberg School of Medicine, Chicago, Illinois On behalf of- Michael Böhm, MD; Stephen J. Greene, MD; Gregg C. Fonarow, MD; Eldrin F. Lewis, MD; Faiez Zannad, MD, PhD; Scott D. Solomon, MD; Fabio Baschiera, PhD; Jaco Botha, MSc; TsushungA. Hua, PhD; Claudio R. Gimpelewicz, MD; Xavier Jaumont, MD; Anastasia Lesogor, MD; Aldo P. Maggioni, MD; and the ASTRONAUT Trial Investigators and Coordinators ? Consulting for- Bayer HealthCare Pharmaceuticals, Abbott Labs, Astellas, Astra Zeneca, Corthera, Inc., Cytokinetics, Inc., DebioPharm S.A., Errekappa Terapeutici (Milan, Italy), Glaxo Smith Kline, Johnson & Johnson, Medtronic, Merck, Novartis Pharma AG, Otsuka Pharmaceuticals, Pericor Therapeutics, Protein Design Laboratories, Sanofi Aventis, Sigma Tau, Solvay Pharmaceuticals, Takeda 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 ? Larry Weinrauch, MD ? Ebrahim Barkoudah, MD ? Kayode Odutayo, MD ? Post-discharge mortality and re-hospitalization rates remain high in patients hospitalized for HF, despite the use of evidence-based therapies1–4 ? Inhibition of the RAAS with ACEIs, ARBs and aldosterone antagonists is beneficial in patients with HF and reduced ejection fraction5,6, but induces compensatory increases in renin and downstream RAAS intermediaries7 ? The direct renin inhibitor aliskiren represents a distinct mechanism for RAAS blockade with the theoretical benefit of upstream RAAS inhibition at the point of pathway activation7 ? ASTRONAUT tested the hypothesis that neurohormonal modulation with aliskiren in addition to standard therapy during the early post-discharge period, sometimes referred to as the ‘vulnerable phase’,3 may improve long- term outcomes7 ACEI=angiotensin-converting enzyme inhibitor; ARB=angiotensin receptor blocker; HF=heart failure; RAAS=renin-angiotensin-aldosterone system 1. Gheorghiade M, et al. JAMA 2006;296- 2217–26; 2. Blair JE, et al. J Am Coll Cardiol 2008;52-1640–48; 3. Gheorghiade M, et al. J Am Coll Cardiol 2013;61-391–403; 4. Bueno H, et al. JAMA 2010;303-2141–7; 5. Hunt SA, et al. Circulation 2009;119-e391–e479; 6. McMurray JJ, et al. Eur Heart J 2012;33-1787–1847; 7. Gheorghiade M, et al. Eur J Heart Fail 2011;13-100–6 Primary- ? CV death or HF re-hospitalization within 6 months Key Secondary- ? CV death or HF re-hospitalization within 12 months Secondary- ? First CV event within 12 months (i.e., CV death, HF hospitalization, non-fatal MI, non-fatal stroke, sudden death with resuscitation) ? All-cause mortality within 6 and 12 months ? Change from baseline in NT-proBNP at 1, 6, and 12 months of follow-up CV=cardiovascular; HF=heart failure; MI=myocardial infarction NT-proBNP=N-terminal pro-B-type natriuretic peptide Selected inclusion criteria- ? Patients with chronic HF after a period of acute decompensation ? LVEF =40% and BNP =400 pg/mL or NT-proBNP =1,600 pg/mL ? Hemodynamically/clinically stable, defined as SBP =110 mmHg for at least 6 hours and no use of IV vasodilators (except nitrates), and/or any IV inotropic therapy from the time of hospital presentation to randomization Selected exclusion criteria- ? MI, cardiac surgery or stroke within 3 months prior to enrollment ? eGFR <40 mL/min/1.73 m2 or potassium >5.0 mEq/L ? Severe hyponatremia <130 mEq/L BNP=B-type natriuretic peptide; eGFR=estimated glomerular filtration rate; HF=heart failure; IV=intravenous; LVEF=left ventricular ejection fraction; MI=myocardial infarction; NT-proBNP=N-terminal pro-B-type natriuretic peptide; SBP=systolic blood pressure Study Design Randomization* Aliskiren 300 mg† Aliskiren 150 mg Placebo Conventional therapy Hospitalization for acute HF event *Patients were hemodynamically/clinically stable and randomized prior to discharge; †Patients not tolerating the 300 mg study medication dose could be down titrated to the 150 mg dose at the investigators discretion at any time during the study; ‡Study visits scheduled at 2, 3, 6, 9, and 12 months with electrolyte levels (i.e., potassium and sodium) and renal function (i.e., GFR) measured at every visit Screening (median- 5 days [IQR- 3–8]) Event-driven follow-up period‡ (median- 11.3 months [IQR-9.1–12.4]) ? 1,782 patients were required to reach 381 primary events (80% power to reject null hypothesis at 0.05 level) ? A re-assessment of the sample size was conducted following the results of the ALTITUDE trial;1 it was determined that the required number of primary events would be achieved with the 1,639 patients already randomized and therefore enrollment was stopped ALTITUDE=Aliskiren Trial In Type 2 diabetes Using cardio-renal Disease Endpoints 1. Parving H-H, et al. N Engl J Med 2012;367-2204–13 Screening Allocation Follow-up 6 months Follow-up 12 months Analysis Patient Flow 2,134 screened Randomization 495 excluded 821 allocated to aliskiren 13 excluded 802 completed primary efficacy phase (to death or 6 months) 798 competed secondary efficacy phase (to death or 12 months) 808 full analysis set 818 allocated to placebo 11 excluded 796 completed primary efficacy phase (to death or 6 months) 788 completed secondary efficacy phase (to death or 12 months) 807 full analysis set (46 centers; 8% of the study population) Canada (n=13) United States (n=111) Geographic Distribution of Patients in ASTRONAUT EUROPE (182 centers; 55% of the study population) Belgium (n=30) Czech Republic (n=75) Finland (n=5) France (n=32) Germany (n=128) Hungary (n=28) Italy (n=125) Poland (n=92) Romania (n=36) Russia (n=168) Slovakia (n=99) Spain (n=64) Sweden (n=23) ASIA, PACIFIC & OTHER (48 centers; 27% of the study population) India (n=221) Israel (n=36) Philippines (n=70) Singapore (n=16) Taiwan (n=33) Turkey (n=69) 316 sites in 24 countries 2,134 patients were screened between May 2009 and July 2012; 1,639 patients were randomized SOUTH AMERICA (40 centers- 10% of the study population) Argentina (n=92) Brazil (n=32) Colombia (n=41) Baseline characteristic* Age, mean (SD), years Male, n (%) Ischemic heart failure etiology, n (%) LVEF, mean (SD), % SBP, mean (SD), mmHg Heart rate, mean (SD), bpm eGFR, mean (SD), mL/min/1.73 m2 NT-proBNP at admission, median (IQR), pg/mL NT-proBNP at randomization, median (IQR), pg/mL Aliskiren (n=808) 64.7 (12.44) 637 (78.8) 520 (64.4) 27.9 (7.3) 123 (13) 78 (16) 67 (20) 4,278 (2,755–7,755) 2,838 (1,516–5,235) Placebo (n=807) 64.5 (11.88) 610 (75.6) 507 (62.8) 27.8 (7.2) 123 (13) 78 (16) 66 (20) 4,184 (2,706–7,921) 2,674 (1,551–5,233) Total (n=1,615) 64.6 (12.16) 1,247 (77.2) 1,027 (63.6) 27.9 (7.3) 123 (13) 78 (16) 67 (20) 4,239 (2,710–7,886) 2,718 (1,531–5,235) *Data collected at time of randomization unless specified otherwise in the protocol eGFR=estimated glomerular filtration rate; IQR=interquartile range; LVEF=left ventricular ejection fraction; NT-proBNP=N-terminal pro-B-type natriuretic peptide; SD=standard deviation Baseline characteristic Hypertension Coronary artery disease Atrial fibrillation Diabetes mellitus Renal insufficiency COPD Aliskiren N=808 n (%) 612 (75.7) 443 (54.8) 337 (41.7) 319 (39.5) 160 (19.8) 168 (20.8) Placebo N=807 n (%) 613 (76.0) 438 (54.3) 339 (42.0) 343 (42.5) 172 (21.3) 154 (19.1) Total N=1,615 n (%) 1,225 (75.9) 881 (54.6) 676 (41.9) 662 (41.0) 332 (20.6) 322 (19.9) COPD=chronic obstructive pulmonary disease Baseline characteristic* Diuretic ACEI/ARB ß-blocker Mineralocorticoid receptor antagonist Digoxin Antiplatelet therapy Implantable cardioverter-defibrillator Permanent pacemaker (including CRT) Aliskiren N=808 n (%) 775 (95.9) 686 (84.9) 660 (81.7) 448 (55.4) 319 (39.5) 528 (65.3) 126 (15.6) 95 (11.8) Placebo N=807 n (%) 773 (95.8) 674 (83.6) 673 (83.4) 473 (58.6) 309 (38.3) 513 (63.6) 127 (15.7) 86 (10.7) Total N=1,615 n (%) 1,548 (95.9) 1,360 (84.2) 1,333 (82.5) 921 (57.0) 628 (38.9) 1,041 (64.5) 253 (15.7) 181 (11.2) *Data collected at time of randomization ACEI=angiotensin-converting enzyme inhibitor; ARB=angiotensin receptor blocker; CRT=cardiac resynchronization therapy cumulative event rate (%) Primary Endpoint- CV Death or HF Re-hospitalization Within 6 Months Aliskiren N=808 Placebo N=807 HR p-value CV death HF re-hospitalization n (%) 77 (9.5) 153 (18.9) n (%) 85 (10.5) 166 (20.6) (95% CI) 0.92 (0.68–1.26) 0.90 (0.72–1.12) (two sided) 0.60 0.35 CI=confidence interval; CV=cardiovascular; HF=heart failure; HR=hazard ratio Patients at risk Aliskiren Placebo 808 807 762 743 716 690 679 655 597 578 Time in study (days) 0 30 60 90 190 40 30 20 10 0 Aliskiren (201/808 patients with events [24.9%]) Placebo (214/807 patients with events [26.5%]) Analysis of events within 6 months Cox-regression model p-value = 0.41 HR (95% CI) = 0.92 (0.76–1.12) cumulative event rate (%) Aliskiren N=808 Placebo N=807 HR p-value CV death HF re-hospitalization n (%) 126 (15.6) 212 (26.2) n (%) 137 (17.0) 224 (27.8) (95% CI) 0.94 (0.73–1.19) 0.93 (0.77–1.12) (two sided) 0.60 0.44 CI=confidence interval; CV=cardiovascular; HF=heart failure; HR=hazard ratio Patients at risk Aliskiren Placebo 808 807 762 743 716 690 679 655 597 578 204 196 Time in study (days) 40 30 20 10 0 0 30 60 90 190 365 Key Secondary Endpoint- CV Death or HF Re-hospitalization Within 12 Months 50 Aliskiren (283/808 patients with events; 35.0%) Placebo (301/807 patients with events; 37.3%) Analysis of events within 12 months Cox-regression model p-value = 0.36 HR (95% CI) = 0.93 (0.79–1.09) Endpoint All-cause death First CV Event CV death HF re-hospitalization Fatal or non-fatal MI Fatal or non-fatal stroke Resuscitated sudden death Patients re-hospitalized for any cause Aliskiren N=808 n (%) 144 (17.8) 293 (36.3) 126 (15.6) 212 (26.2) 18 (2.2) 18 (2.2) 5 (0.6) 389 (48.1) Placebo N=807 n (%) 148 (18.3) 321 (39.8) 137 (17.0) 224 (27.8) 38 (4.7) 27 (3.3) 10 (1.2) 396 (49.1) HR (95% CI) 0.99 (0.78–1.24) 0.88 (0.75–1.03) 0.94 (0.73–1.19) 0.93 (0.77–1.12) 0.47 (0.27–0.83) 0.63 (0.34–1.14) 0.52 (0.18–1.52) –– p-value (two sided) 0.92 0.12 0.60 0.44 ?0.01 0.13 0.23 0.73‡ Data analyzed using Cox-regression model unless otherwise stated; ‡Fisher’s Exact Test CI=confidence interval; CV=cardiovascular; HF=heart failure; HR=hazard ratio; MI=myocardial infarction *p=0.01, **p?0.01 between treatment comparison Data presented as geometric mean +/– 95% confidence interval BL=baseline; NT-proBNP=N-terminal pro-B-type natriuretic peptide 3,200 Aliskiren Placebo 778 776 673 678 573 562 451 430 Change in NT-proBNP With Time Aliskiren (N=808) Placebo (N=807) 3,000 2,800 2,600 2,400 * ** Month 6 Time of visit (months) ** Month 12 2,200 2,000 1,800 1,600 1,400 1,200 0 BL Month 1 Number of subjects Endpoint Patients with =1 AE Patients with =1 SAE Patients who discontinued study drug due to any AEs Patients who discontinued study drug due to any SAEs Patients who discontinued study drug due to non-serious AEs Aliskiren N=808 n (%) 670 (82.9) 421 (52.1) 171 (21.2) 79 (9.8) 95 (11.8) Placebo N=810 n (%) 667 (82.3) 435 (53.7) 163 (20.1) 108 (13.3) 60 (7.4) Total N=1,618 n (%) 1,337 (82.6) 856 52.9) 334 (20.6) 187 (11.6) 155 (9.6) p-value 0.79 0.55 0.62 0.03 <0.01 AE=adverse event; SA=serious adverse event 5.1 14.3 8.1 Safety- Hyperkalemia, Renal Dysfunction and Hypotension 17.5 12.1 12.6 Hyperkalemia† 25 Proportion of patients experiencing stated AE (%) p=0.09 20.9 Renal impairment or renal failure‡ Hypotension¶ 20 15 10 5 0 p=0.01 16.6 p=0.01 17.1 =5.5 and ?6.0 mmol/L Proportion of patients with elevated serum potassium levels (%) Placebo Aliskiren =6.0 mmol/L AE=adverse event †Includes hyperkalemia and increased blood potassium level ‡Includes abnormal renal function test, acute renal failure, decreased urine output , increased blood creatinine, acute pre-renal failure, renal impairment, renal failure, decreased glomerular filtration rate and increased blood urea ¶Includes decreased blood pressure, postural dizziness, hypotension, orthostatic hypotension and procedural hypotension 20 15 10 5 0 HF=heart failure; HR=hazard ratio; NYHA=New York Heart Association Subgroup variable Aliskiren n/N (%) Placebo n/N (%) Favors aliskiren Favors placebo HR (95% CI) Sub-group Analysis for Primary Endpoint of CV Death or HF Re-hospitalization Within 6 months Interaction p-value Age Sex Race Region Baseline eGFR Baseline NYHA 0.38 0.16 0.57 0.86 0.61 0.48 0.40 <65 years ?65 years <75 years ?75 years Male Female Caucasian Black Asian Other North America Latin America Western Europe Eastern Europe Asia Pacific <60 mL/min/1.73 m2 ?60 mL/min/1.73 m2 NYHA I or II NYHA III or IV 92/378 (24.3) 109/430 (25.3) 149/625 (23.8) 52/183 (28.4) 162/637 (25.4) 39/171 (22.8) 132/574 (23.0) 13/36 (36.1) 48/167 (28.7) 8/31 (25.8) 17/62 (27.4) 17/81 (21.0) 48/198 (24.2) 50/249 (20.1) 69/218 (31.7) 92/315 (29.2) 99/454 (21.8) 74/284 (26.1) 123/509 (24.2) 94/395 (23.8) 120/412 (29.1) 171/619 (27.6) 43/188 (22.9) 169/610 (27.7) 45/197 (22.8) 147/566 (26.0) 14/42 (33.3) 45/169 (26.6) 8/30 (26.7) 19/61 (31.1) 17/82 (20.7) 56/197 (28.4) 60/246 (24.4) 62/221 (28.1) 91/314 (29.0) 107/449 (23.8) 65/263 (24.7) 145/533 (27.2) 1.01 (0.76–1.35) 0.85 (0.66–1.11) 0.85 (0.69–1.06) 1.19 (0.79–1.78) 0.89 (0.72–1.10) 1.02 (0.66–1.57) 0.88 (0.70–1.12) 1.16 (0.54–2.48) 1.03 (0.69–1.55) 0.88 (0.33–2.36 ) 0.89 (0.46–1.72) 0.99 (0.50–1.94) 0.83 (0.56–1.22) 0.78 (0.53–1.13) 1.15 (0.81–1.62) 1.02 (0.76–1.36) 0.88 (0.69–1.16) 1.04 (0.75–1.46) 0.87 (0.69–1.11) 0.08 Diabetes mellitus? Yes No 99/319 (31.0) 102/489 (20.9) 100/343 (29.2) 114/464 (24.6) 1.13 (0.86–1.50) 0.80 (0.61–1.04 0.2 0.4 0.6 0.8 1 2 3 4 5 Aliskiren n/N (%) Placebo n/N (%) Favors aliskiren Favors placebo HR (95% CI) p-value Baseline digoxin use? Use beta-blockers? Use aldosterone blockers? Use aldo blockers + ACEI or ARB? Use ACEI or ARB? Ejection fraction Baseline NT-proBNP Baseline PRA Baseline troponin I Atrial fibrillation at baseline Baseline SBP HF etiology ICD Baseline QRS ?120 msec 0.63 0.46 0.05 0.08 0.61 0.45 0.31 0.72 0.47 0.61 0.62 0.45 0.22 0.49 Yes No Yes No Yes No Yes No Yes No ?median >median ?median >median ?median >median ?median >median Yes No <median ?median Ischemic Non-ischemic ICD CRT Both Yes No 76/356 (21.3) 68/452 (15.0) 113/698 (16.2) 31/110 (28.2) 94/507 (18.5) 50/301 (16.6) 79/463 (17.1) 65/345 (18.8) 123/733 (16.8) 21/75 (28.0) 75/393 (19.1) 69/415 (16.6) 35/379 (9.2) 98/399 (24.6) 57/329 (17.3) 62/327 (19.0) 65/440 (14.8) 63/300 (21.0) 39/242 (16.1) 103/546 (18.9) 66/303 (21.8) 78/505 (15.4) 111/520 (21.3) 33/288 (11.5) 11/84 (13.1) 11/53 (20.8) 7/42 (16.7) 73/354 (20.6) 69/431 (16.0) 1.04 (0.75–1.45) 0.93 (0.67–1.29) 1.03 (0.79–1.33) 0.83 (0.50–1.37) 0.85 (0.65–1.13) 1.42 (0.92–2.20) 0.83 (0.62–1.13) 1.29 (0.89–1.89) 0.97 (0.76–1.24) 1.15 (0.62–2.14) 1.07 (0.78–1.47) 0.90 (0.64–1.26) 0.78 (0.51–1.21) 1.03 (0.77–1.37) 1.14 (0.77–1.68) 1.04 (0.73–1.48) 1.03 (0.73–1.46) 0.86 (0.61–1.21) 0.92 (0.59–1.43) 1.05 (0.80–1.39) 1.06 (0.75–1.49) 0.94 (0.69–1.28) 1.05 (0.80–1.37) 0.86 (0.54, 1.36) 0.67 (0.32–1.41) 1.49 (0.60–3.76) 2.43 (0.50–11.81) 1.11 (0.79–1.55) 0.94 (0.67–1.30) Sub-group Analysis for Primary Endpoint of CV Death or HF Re-hospitalization Within 6 months Interaction ACEI=angiotensin-converting enzyme inhibitor; Aldo=aldosterone; ARB=angiotensin receptor blocker; CI=confidence interval; CV=cardiovascular; eGFR=estimated glomerular filtration rate; HF=heart failure; HR=hazard ratio; ICD=implantable cardioverter-defibrillator; NT-proBNP=N-terminal pro-B-type natriuretic peptide; PRA=plasma renin activity; SBP=systolic blood pressure 69/342 (20.2) 79/465 (17.0) 117/689 (17.0) 31/118 (26.3) 113/512 (22.1) 35/295 (11.9) 97/454 (21.4) 51/353 (14.4) 128/718 (17.8) 20/89 (22.5) 82/419 (19.6) 66/387 (17.1) 48/399 (12.0) 94/377 (24.9) 49/326 (15.0) 62/324 (19.1) 63/420 (15.0) 71/309 (23.0) 42/243 (17.3) 101/546 (18.5) 66/311 (21.2) 82 /495 (16.6) 107/507 (21.1) 40/299 (13.4) 20/94 (21.3) 8/53 (15.1) 2/33 (6.1) 65/355 (18.3) 78/433 (18.0) 0.2 0.4 0.6 0.8 1 2 3 4 5 cumulative event rate (%) Kaplan-Meier estimate of cumulative event rate (%) Kaplan-Meier estimate of cumulative event rate (%) Kaplan-Meier estimate of cumulative event rate (%) Secondary Endpoints of CV Death or HF Re-hospitalization Within 12 Months or All-cause Death Within 12 Months by Diabetes Status CV death or HF re-hospitalization within 12 months 50 40 30 20 10 0 0 30 60 90 190 365 Diabetes Aliskiren (135/319 patients with events; 42.3%) Placebo (136/343 patients with events; 39.7%) HR- 1.16 (95% CI- 0.91–1.47) 50 40 30 20 10 0 0 30 60 90 190 365 Time in study (days) No diabetes Aliskiren (148/489) patients with events; 30.3%) Placebo (165/464 patients with events; 35.6%) HR- 0.80 (95% CI- 0.64–0.99) Time in study (days) p-value for treatment by diabetes interaction = 0.03 All-cause death within 12 months 30 20 10 0 0 30 60 90 190 365 Time in study (days) p-value for treatment by diabetes interaction ?0.01 Overall 41.0% of patients randomized had a history of diabetes mellitus CI=confidence interval; CV=cardiovascular; HF=heart failure; HR=hazard ratio Diabetes Aliskiren (72/319 patients with events; 22.6%) Placebo (57/343 patients with events; 16.6%) HR- 1.64 (95% CI- 1.15–2.33) 30 20 10 0 0 30 60 90 190 365 Time in study (days) No diabetes Aliskiren (72/489) patients with events; 14.7%) Placebo (91/464 patients with events; 19.6%) HR- 0.69 (95% CI- 0.50–0.94) ? In patients recently hospitalized with worsening chronic HF and reduced ejection fraction, aliskiren did not improve post-discharge mortality and/or hospitalizations when added to evidence-based therapy for HF ? Aliskiren was associated with a significant and sustained decrease in NT-proBNP through 1 year follow-up ? Hyperkalemia, renal dysfunction and hypotension were reported more frequently in the aliskiren group than the placebo group ? For all pre-specified subgroups there was no difference in treatment effect for the primary endpoint ? Subgroup analysis for secondary endpoints was consistent with previous reports of poor outcomes with the use of aliskiren in patients with diabetes already receiving RAAS inhibitors. Contrasting effects of aliskiren in patients with vs without diabetes warrant further analysis ? ASTRONAUT did not support the routine administration of aliskiren in patients recently hospitalized for worsening chronic HF CV=cardiovascular; HF=heart failure; NT-proBNP=N-terminal pro-B-type natriuretic peptide ? ASTRONAUT demonstrated again that post-discharge mortality and re-hospitalization rate is unacceptably high in spite of evidence-based therapies, even in patients who are stabilized at discharge and have a relatively preserved renal function ? Further investigations are needed to evaluate the effects of direct renin inhibition in addition to standard therapy in patients without diabetes who have recently been hospitalized for worsening HF

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