T reatment O f P reserved C ardiac Function Heart Failure with an A - PowerPoint PPT Presentation

T reatment O f P reserved C ardiac Function Heart Failure with an A ldosterone an T agonist (TOPCAT) AHA Nov 18, 2014 Update on Randomized Trials Marc A. Pfeffer, MD, PhD; Brian Claggett, PhD; Susan F. Assmann, PhD; Robin Boineau, MD; Inder S. Anand, MD; Nadine Clausell, MD, PhD; Akshay S. Desai, MD, MPH; Rafael Diaz, MD; Jerome L. Fleg, MD; Ivan Gordeev, MD; John F. Heitner, MD; Eldrin F. Lewis, MD, MPH; Eileen O’Meara, MD; Jean-Lucien Rouleau, MD; Jeffery L. Probstfield, MD; Tamaz Shaburishvili, MD, PhD; Sanjiv J. Shah, MD; Scott D. Solomon, MD; Nancy K. Sweitzer, MD, PhD; Sonja M. McKinlay, PhD; Bertram Pitt, MD On behalf of TOPCAT Investigators ClinTrials.gov NCT00094302 HHS Contract # HHSN268200425207C

TOPCAT International (6), double-blind, placebo-controlled RCT • Pts : Symptomatic Heart Failure, Age ≥ 50, LVEF ≥ 45%, stratified according to: Hospitalization within the past year for management of heart failure,  or Elevated natriuretic peptides ( BNP ≥100 pg/mL or NT - proBNP ≥360 pg/mL )  • Rz: 1:1 to either Spironolactone (15, 30, 45 mg daily) or matching Placebo • Primary Outcome: Composite of CV mortality, HF Hospitalization, or Aborted Cardiac Arrest • Stats: 80% power to detect a 20% relative reduction in primary events: 551 adjudicated primary events (approximately 3,515 subjects), using log-rank test, two-sided p<0.05, ITT Rationale and design: (A. Desai, Am Heart J 2011) Primary Results: (Pitt, NEJM 2014)

1 ° Outcome (CV Death, HF Hosp, or Resuscitated Cardiac Arrest) 351/1723 (20.4%) 320/1722 (18.6%) Placebo Spironolactone HR = 0.89 (0.77 – 1.04) p=0.138 (AHA 2013, NEJM 2014)

Summary Spironolactone Placebo HR (95% CI) (N = 1722) (N = 1723) 320 (18.6%) 351 (20.4%) 0.89 (0.77-1.04) Primary Outcome 5.9/100pt-yr 6.6/100pt-yr P=0.138 0.83 (0.69-0.99) Hospitalization for Heart 206 (12.0%) 245 (14.2%) P=0.042 Failure Multiple HF Hosp 3.8/100pt-yr 4.6/100pt-yr P<0.01 Conclusions: TOPCAT population with HFpEF: • Rx with spironolactone did not alter the 1 ° composite • Reductions in heart failure hospitalizations were observed • Use of spironolactone in these patients requires careful monitoring of K + and creatinine AHA 2013

Placebo Rates: Primary Outcome, by region Placebo: 280/881 (31.8%) Americas N=1767 (51%) US: N=1151 Canada: N=326 Brazil: N=167 12.6 per 100 pt-yr Argentina: N=123 Russia/Georgia N=1678 (49%) Russia: N=1066 Rep Georgia: N=612 Placebo: 71/842 (8.4%) 2.3 per 100 pt-yr AHA 2013

Clinical Outcomes by Region (Irrespective of Treatment) Americas Russia/Georgia Regional Outcome N = 1767 N = 1678 Difference 522 (29.5%) 149 (8.9%) Primary Outcome <0.001 [11.5] [2.4] 223 (12.6%) 113 (6.7%) CV Mortality <0.001 [4.3] [1.8] Hospitalization for 400 (22.6%) 51 (3.0%) <0.001 Heart Failure [8.8] [0.8] Aborted Cardiac 6 (0.3%) 2 (0.1%) --- Arrest 385 (21.8%) 141 (8.4%) All-Cause Mortality <0.001 [7.1] [2.1] Circ 2014. Epub ahead of print [rate per 100 patient-years]

Baseline by Region Americas Russia/Georgia Variable* p N = 1767(51%) N = 1678(49%) NYHA Class II 59.2% 68.6% 0.006 III 34.6% 30.5% LVEF % 58 (53, 64) 55 (50, 60) <0.001 Stratum <0.001 Hosp. for HF 55% 89% Natriuretic Peptide** 45% 11% Age 72 (64, 79) 66 (59, 71) <0.001 Female 50% 53% 0.05 Hypertension 90% 93% 0.002 Any Cardiovascular Disease 46% 72% <0.001 Myocardial Infarction 20% 32% <0.001 Stroke 9% 6% 0.005 Atrial Fibrillation 42% 28% <0.001 Diabetes Mellitus 45% 20% <0.001 Smoking (current) 7% 14% <0.001 AHA 2014 **(BNP ≥100 pg/mL or NT - proBNP ≥360 pg/mL) *Reported as % or median (Q1, Q3)

Baseline by Region Americas Russia/Georgia Variable* p N = 1767 N = 1678 Systolic Blood Pressure 129 (118, 138) 130 (120, 140) <0.001 Diastolic Blood Pressure 70 (62, 80) 80 (80, 85) <0.001 Heart Rate 68 (61, 76) 68 (62, 75) NS BMI (kg/m 2 ) 33 (28, 38) 29 (27, 33) <0.001 eGFR (ml/min/1.73m 2 ) 61 (49, 77) 69 (58, 81) <0.001 < 60 (ml/min/1.73m 2 ) 48% 28% <0.001 Serum Potassium (mEq/L) 4.2 (3.9, 4.5) 4.4 (4.1, 4.7) <0.001 Hemoglobin (g/dl) 12.8 (11.7, 14.0) 13.7 (12.6, 14.8) <0.001 Medications ACE-I or ARB 79% 90% <0.001 Beta-blocker 79% 77% NS Diuretic 89% 74% <0.001 Statin 65% 39% <0.001 Warfarin 34% 12% <0.001 *Reported as % or median (Q1, Q3) AHA 2014

Baseline by Region Americas Russia/Georgia Variable* p N = 1767 N = 1678 Systolic Blood Pressure 129 (118, 138) 130 (120, 140) <0.001 Diastolic Blood Pressure 70 (62, 80) 80 (80, 85) <0.001 Heart Rate 68 (61, 76) 68 (62, 75) NS BMI (kg/m 2 ) 33 (28, 38) 29 (27, 33) <0.001 eGFR (ml/min/1.73m 2 ) 61 (49, 77) 69 (58, 81) <0.001 < 60 (ml/min/1.73m 2 ) 48% 28% <0.001 Serum Potassium (mEq/L) 4.2 (3.9, 4.5) 4.4 (4.1, 4.7) <0.001 In full manuscript (Circ online), 34 of 38 baseline Hemoglobin (g/dl) 12.8 (11.7, 14.0) 13.7 (12.6, 14.8) <0.001 characteristics were significantly different Medications ACE-I or ARB 79% 90% <0.001 Beta-blocker 79% 77% NS Diuretic 89% 74% <0.001 Statin 65% 39% <0.001 Warfarin 34% 12% <0.001 *Reported as % or median (Q1, Q3) Circ 2014. Epub ahead of print

Baseline by Region Americas Russia/Georgia Variable* p N = 1767 N = 1678 Systolic Blood Pressure 129 (118, 138) 130 (120, 140) <0.001 Diastolic Blood Pressure 70 (62, 80) 80 (80, 85) <0.001 Heart Rate 68 (61, 76) 68 (62, 75) NS BMI (kg/m 2 ) 33 (28, 38) 29 (27, 33) <0.001 eGFR (ml/min/1.73m 2 ) 61 (49, 77) 69 (58, 81) <0.001 In full manuscript (Circ online), 34 of 38 baseline < 60 (ml/min/1.73m 2 ) 48% 28% <0.001 characteristics were significantly different Serum Potassium (mEq/L) 4.2 (3.9, 4.5) 4.4 (4.1, 4.7) <0.001 Hemoglobin (g/dl) 12.8 (11.7, 14.0) 13.7 (12.6, 14.8) <0.001 Medications Within each Region, all variables similar by treatment arm ACE-I or ARB 79% 90% <0.001 Beta-blocker 79% 77% NS Diuretic 89% 74% <0.001 Statin 65% 39% <0.001 Warfarin 34% 12% <0.001 *Reported as % or median (Q1, Q3) Circ 2014. Epub ahead of print

Patient Participation by Region Americas Russia/Georgia N = 1767 N = 1678 Mean follow-up: 2.9 years 3.7 years Unknown Vital Status 37 (2.1%) 95 (5.7%) Americas Russia/Georgia N = 1767 N = 1678 Month 8 Reported Spiro Placebo Spiro Placebo Daily Dose (N=866) (N=846) (N=823) (N=830) Average Dose* 21.7 mg 25.9 mg 28.4 mg 29.5 mg * Treatment delta differs by region (p=0.001) Circ 2014. Epub ahead of print

Potassium Americas Russia/Georgia N = 1767 N = 1678 (18,727 samples) (20,344 samples) Outcome Spiro Placebo Spiro Placebo (N = 886) (N = 881) (N = 836) (N = 842) Hyperkalemia 1 223 (25%) 78 (9%) 99 (12%) 79 (9%) (K≥5.5) OR=3.46; 95% CI: (2.62 – 4.56) OR=1.30; 95% CI: (0.95-1.77) Hypokalemia 1 135 (15%) 231 (26%) 144 (17%) 163 (19%) (K<3.5) OR=0.51; 95% CI: (0.40 – 0.64) OR=0.87; 95% CI: (0.68 – 1.11) In addition , regional differences in changes in potassium by treatment persisted, with adjustment for baseline K, age, eGFR, DM, ACE/ARB use, enrollment stratum (p<0.001) Circ 2014. Epub ahead of print 1 Any report during study;

Creatinine Americas Russia/Georgia N = 1767 N = 1678 Outcome Spiro Placebo Spiro Placebo (N = 886) (N = 881) (N = 836) (N = 842) Doubling of 158 (18%) 102 (12%) 17 (2%) 18 (2%) creatinine 2 HR = 1.60; 95% CI: (1.25-2.05) HR = 0.95; 95% CI: (0.49-1.85) Creatinine 87 (10%) 80 (9%) 2 (0.2%) 4 (0.4%) ≥ 3.0 mg/dL HR = 1.10; 95% CI: (0.81-1.49) HR = 0.50; 95% CI: (0.09-2.75) In addition , regional differences in changes in creatinine by treatment persisted, with adjustment for baseline K, age, eGFR, DM, ACE/ARB use, enrollment stratum (p<0.001) Circ 2014. Epub ahead of print 2 Doubling of creatinine to above upper limit of normal

Creatinine Americas Russia/Georgia N = 1767 N = 1678 Outcome Spiro Placebo Spiro Placebo (N = 886) (N = 881) (N = 836) (N = 842) Doubling of 158 (18%) 102 (12%) 17 (2%) 18 (2%) creatinine 2 HR = 1.60; 95% CI: (1.25-2.05) HR = 0.95; 95% CI: (0.49-1.85) Creatinine 87 (10%) 80 (9%) 2 (0.2%) 4 (0.4%) ≥ 3.0 mg/dL Dialysis: 18 (2%) 32(4%) 1 (0.1%) 0 HR = 1.10; 95% CI: (0.81-1.49) HR = 0.50; 95% CI: (0.09-2.75) In addition , regional differences in changes in creatinine by treatment persisted, with adjustment for baseline K, age, eGFR, DM, ACE/ARB use, enrollment stratum (p<0.001) 2 Doubling of creatinine to above upper limit of normal

Systolic Blood Pressure Change by Region -0.6 mm Hg Russia/Georgia N = 1678 Average SBP Change (Spiro-Placebo) -0.6 mmHg (NS) Circ 2014. Epub ahead of print

Systolic Blood Pressure Change by Region -0.6 mm Hg -4.2 mm Hg Americas Russia/Georgia N = 1767 N = 1678 Average SBP Change (Spiro-Placebo) -4.2 mmHg (p<0.001) -0.6 mmHg (NS) SBP delta differed by region (p<0.001), adjusted Circ 2014. Epub ahead of print

Exploratory-Post Hoc: Placebo vs. Spiro by Region Primary Outcome Placebo: 280/881 (31.8%) US, Canada, Spiro: Argentina, Brazil 242/886 (27.3%) HR=0.82 (0.69-0.98) Interaction p=0.122 Spiro: 78/836 (9.3%) Placebo: 71/842 (8.4%) Russia, Rep Georgia HR=1.10 (0.79-1.51) AHA 2013