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

Treatment Of Preserved Cardiac Function Heart Failure with an Aldosterone anTagonist (TOPCAT) AHA Nov 18, 2014 Update on Randomized Trials

ClinTrials.gov NCT00094302 HHS Contract # HHSN268200425207C

On behalf of TOPCAT Investigators

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

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,

• r



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

TOPCAT

Rationale and design: (A. Desai, Am Heart J 2011) Primary Results: (Pitt, NEJM 2014)

Spironolactone Placebo HR = 0.89 (0.77 – 1.04) p=0.138

351/1723 (20.4%) 320/1722 (18.6%)

1°Outcome

(CV Death, HF Hosp, or Resuscitated Cardiac Arrest)

(AHA 2013, NEJM 2014)

Spironolactone (N = 1722) Placebo (N = 1723)

HR (95% CI) Primary Outcome 320 (18.6%) 5.9/100pt-yr 351 (20.4%) 6.6/100pt-yr 0.89 (0.77-1.04) P=0.138 Hospitalization for Heart Failure 206 (12.0%) 3.8/100pt-yr 245 (14.2%) 4.6/100pt-yr 0.83 (0.69-0.99) P=0.042 Multiple HF Hosp P<0.01

• 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

Conclusions: TOPCAT population with HFpEF:

Summary

AHA 2013

Placebo Rates:

Primary Outcome, by region

12.6 per 100 pt-yr 2.3 per 100 pt-yr

Placebo: 280/881 (31.8%) Placebo: 71/842 (8.4%)

Americas N=1767 (51%) US: N=1151 Canada: N=326 Brazil: N=167 Argentina: N=123 Russia/Georgia N=1678 (49%) Russia: N=1066 Rep Georgia: N=612

AHA 2013

Outcome Americas N = 1767 Russia/Georgia N = 1678 Regional Difference

Primary Outcome 522 (29.5%) [11.5] 149 (8.9%) [2.4] <0.001 CV Mortality 223 (12.6%) [4.3] 113 (6.7%) [1.8] <0.001 Hospitalization for Heart Failure 400 (22.6%) [8.8] 51 (3.0%) [0.8] <0.001 Aborted Cardiac Arrest 6 (0.3%) 2 (0.1%)

• All-Cause Mortality

385 (21.8%) [7.1] 141 (8.4%) [2.1] <0.001

Clinical Outcomes by Region

(Irrespective of Treatment)

[rate per 100 patient-years]

Circ 2014. Epub ahead of print

Variable* Americas N = 1767(51%) Russia/Georgia N = 1678(49%) p NYHA Class II III 59.2% 34.6% 68.6% 30.5% 0.006 LVEF % 58 (53, 64) 55 (50, 60) <0.001 Stratum

• Hosp. for HF

Natriuretic Peptide** 55% 45% 89% 11% <0.001 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

**(BNP ≥100 pg/mL or NT-proBNP ≥360 pg/mL) *Reported as % or median (Q1, Q3)

Baseline by Region

AHA 2014

Variable* Americas N = 1767 Russia/Georgia N = 1678 p 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/m2) 33 (28, 38) 29 (27, 33) <0.001 eGFR (ml/min/1.73m2) < 60 (ml/min/1.73m2) 61 (49, 77) 48% 69 (58, 81) 28% <0.001 <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

AHA 2014

Baseline by Region

*Reported as % or median (Q1, Q3)

Circ 2014. Epub ahead of print

Baseline by Region

*Reported as % or median (Q1, Q3)

Variable* Americas N = 1767 Russia/Georgia N = 1678 p 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/m2) 33 (28, 38) 29 (27, 33) <0.001 eGFR (ml/min/1.73m2) < 60 (ml/min/1.73m2) 61 (49, 77) 48% 69 (58, 81) 28% <0.001 <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

In full manuscript (Circ online), 34 of 38 baseline characteristics were significantly different

Variable* Americas N = 1767 Russia/Georgia N = 1678 p 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/m2) 33 (28, 38) 29 (27, 33) <0.001 eGFR (ml/min/1.73m2) < 60 (ml/min/1.73m2) 61 (49, 77) 48% 69 (58, 81) 28% <0.001 <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

Baseline by Region

*Reported as % or median (Q1, Q3)

In full manuscript (Circ online), 34 of 38 baseline characteristics were significantly different Within each Region, all variables similar by treatment arm

Circ 2014. Epub ahead of print

Americas N = 1767 Russia/Georgia N = 1678

Mean follow-up: 2.9 years 3.7 years Unknown Vital Status 37 (2.1%) 95 (5.7%)

Patient Participation by Region

* Treatment delta differs by region (p=0.001)

Americas N = 1767 Russia/Georgia N = 1678 Month 8 Reported Daily Dose Spiro (N=866) Placebo (N=846) Spiro (N=823) Placebo (N=830)

Average Dose* 21.7 mg 25.9 mg 28.4 mg 29.5 mg

Circ 2014. Epub ahead of print

Americas N = 1767 (18,727 samples) Russia/Georgia N = 1678 (20,344 samples) Outcome Spiro (N = 886) Placebo (N = 881) Spiro (N = 836) Placebo (N = 842) Hyperkalemia1 (K≥5.5) 223 (25%) 78 (9%) 99 (12%) 79 (9%) OR=3.46; 95% CI: (2.62 – 4.56) OR=1.30; 95% CI: (0.95-1.77) Hypokalemia1 (K<3.5) 135 (15%) 231 (26%) 144 (17%) 163 (19%) OR=0.51; 95% CI: (0.40 – 0.64) OR=0.87; 95% CI: (0.68 – 1.11)

Potassium

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)

1Any report during study;

Circ 2014. Epub ahead of print

Americas N = 1767 Russia/Georgia N = 1678 Outcome Spiro (N = 886) Placebo (N = 881) Spiro (N = 836) Placebo (N = 842) Doubling of creatinine2 158 (18%) 102 (12%) 17 (2%) 18 (2%) HR = 1.60; 95% CI: (1.25-2.05) HR = 0.95; 95% CI: (0.49-1.85) Creatinine ≥ 3.0 mg/dL 87 (10%) 80 (9%) 2 (0.2%) 4 (0.4%) HR = 1.10; 95% CI: (0.81-1.49) HR = 0.50; 95% CI: (0.09-2.75)

Creatinine

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)

2Doubling of creatinine to above upper limit of normal

Circ 2014. Epub ahead of print

Americas N = 1767 Russia/Georgia N = 1678 Outcome Spiro (N = 886) Placebo (N = 881) Spiro (N = 836) Placebo (N = 842) Doubling of creatinine2 158 (18%) 102 (12%) 17 (2%) 18 (2%) HR = 1.60; 95% CI: (1.25-2.05) HR = 0.95; 95% CI: (0.49-1.85) Creatinine ≥ 3.0 mg/dL 87 (10%) 80 (9%) 2 (0.2%) 4 (0.4%) HR = 1.10; 95% CI: (0.81-1.49) HR = 0.50; 95% CI: (0.09-2.75)

Creatinine

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)

2Doubling of creatinine to above upper limit of normal

Dialysis: 18 (2%) 32(4%) 1 (0.1%) 0

Systolic Blood Pressure Change by Region

Russia/Georgia N = 1678 Average SBP Change (Spiro-Placebo)

• 0.6 mmHg (NS)

Circ 2014. Epub ahead of print

• 0.6 mm Hg

Systolic Blood Pressure Change by Region

Americas N = 1767 Russia/Georgia 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

• 0.6 mm Hg
• 4.2 mm Hg

HR=0.82 (0.69-0.98) HR=1.10 (0.79-1.51)

Interaction p=0.122

US, Canada, Argentina, Brazil Russia, Rep Georgia

Placebo: 280/881 (31.8%) Placebo: 71/842 (8.4%)

Exploratory-Post Hoc: Placebo vs. Spiro by Region

AHA 2013

Spiro: 242/886 (27.3%) Spiro: 78/836 (9.3%)

Primary Outcome

Outcome Americas N = 1767 Russia/Georgia N = 1678

Spiro (N = 886) Placebo (N = 881) HR (95% CI) p-value Spiro (N = 836) Placebo (N = 842) HR (95% CI) p-value 1° Outcome 242 (27%) 280 (32%) 0.82* (0.69-0.98) 78 (9%) 71 (8%) 1.10 (0.79-1.51) CV Mortality 96 (11%) 127 (14%) 0.74* (0.57-0.97) 64 (8%) 49 (6%) 1.31 (0.91-1.90)

• Hosp. for HF

184 (21%) 216 (25%) 0.82* (0.67-0.99) 22 (3%) 29 (3%) 0.76 (0.44-1.32) Total HF Hosps. (# events) 361 438 IRR = 0.75* (0.58-0.96) 33 37 IRR=0.83 (0.42-1.62)

*95% CI excludes 1.00

Clinical Outcomes by Region

(By Treatment Arm)

Circ 2014. Epub ahead of print

Outcome Americas N = 1767 Russia/Georgia N = 1678

Spiro (N = 886) Placebo (N = 881) HR (95% CI) p-value Spiro (N = 836) Placebo (N = 842) HR (95% CI) p-value All-Cause Mortality 178 (20%) 207 (23%) 0.83 (0.68-1.02) 74 (9%) 67 (8%) 1.12 (0.80-1.55) All-Cause Hospitalization 526 (59%) 535 (61%) 0.94 (0.83-1.05) 240 (29%) 257 (31%) 0.92 (0.77-1.10) Myocardial Infarction 48 (5%) 46 (5%) 1.01 (0.68-1.52) 17 (2%) 18 (2%) 0.95 (0.49-1.84) Stroke 38 (4%) 39 (4%) 0.94 (0.60-1.47) 19 (2%) 21 (2%) 0.91 (0.49-1.69)

Clinical Outcomes by Region

(By Treatment Arm)

Circ 2014. Epub ahead of print

Post Hoc Analysis By Region

• Differences in:

Post Hoc Analysis By Region

• Differences in:

 Patient Populations

Post Hoc Analysis By Region

• Differences in:

 Patient Populations  Prognosis

Post Hoc Analysis By Region

• Differences in:

 Patient Populations  Prognosis  Responses to Spiro:

• K+
• Creatinine
• Blood Pressure

Post Hoc Analysis By Region

• Differences in:

 Patient Populations  Prognosis  Responses to Spiro:

• K+
• Creatinine
• Blood Pressure

Post Hoc Analysis By Region

• Differences in:

 Patient Populations  Prognosis  Responses to Spiro:

• K+
• Creatinine
• Blood Pressure
• Rz to spiro associated with reduced CV death

and HF hospitalizations, in pts from the Americas

Post Hoc Analysis By Region

• Differences in:

 Patient Populations  Prognosis  Responses to Spiro:

• K+
• Creatinine
• Blood Pressure
• Rz to spiro associated with reduced CV death

and HF hospitalizations, in pts from the Americas

Thank you!

Circ 2014. Epub ahead of print

• Any SAE:

 Americas: Spiro (63%) vs. Placebo (65%)  R/G: Spiro (33%) vs. Placebo (33%)

No treatment difference within either region, but major differences between regions.

Serious Adverse Events (SAEs)

Stratum Does Not Explain Regional Differences

Outcome

[event rate, per 100py]

BNP Stratum

• Amer. R/G

(n=791) (n=190)

• Hosp. Stratum
• Amer. R/G

(n=976) (n=1488)

Primary

8.1

181 events

2.4

13 events

14.7

341 events

2.4

136 events

HF Hosp

6.2

138 events

0.0

0 events

11.2

262 events

0.9

51 events

Mortality

6.1

155 events

2.6

15 events

8.0

230 events

2.1

126 events

BNP Treatment Effect?

Outcome

Treatment Effect HR (95% CI)

BNP Stratum

• Amer. R/G

(n=791) (n=190)

• Hosp. Stratum
• Amer. R/G

(n=976) (n=1488)

Primary

HR=0.63 (0.47, 0.85) HR=1.35 (0.44, 4.13) HR=0.92 (0.74, 1.14) HR=1.07 (0.77, 1.50)

HF Hosp

HR=0.66 (0.47, 0.93) No events HR=0.89 (0.70, 1.13) HR=0.77 (0.44, 1.34)

Mortality

HR=0.75 (0.55, 1.03) HR=0.96 (0.35, 2.65) HR=0.88 (0.68, 1.14) HR=1.13 (0.80, 1.60)

BNP  Treatment Effect?

• In patients enrolled via the BNP stratum

in the Americas (n=686):

• Treatment Effect for Primary Outcome

 HR=0.46 (0.26, 0.79) for patients with BNP

• r NT-proBNP values below the median

 HR=0.84 (0.55, 1.28) for patients with BNP

• r NT-proBNP values above the median

Potassium Creatinine change by Region

Event Rates by Country (irrespective of therapy)

Country Primary Event Rate Mortality United States 12.2 (11.0, 13.5) 6.7 (5.9, 7.6) Brazil 11.4 (8.2, 15.9) 10.1 (7.2, 14.2) Canada 10.6 (8.7, 12.9) 7.2 (5.8, 9.1) Argentina 7.7 (5.3, 11.2) 8.0 (5.6, 11.5) Russia 3.2 (2.7, 3.9) 2.7 (2.3, 3.3) Georgia 1.2 (0.8, 1.7) 1.2 (0.8, 1.7)

Primary Outcome All-cause Death

Event Rates by Country (irrespective of therapy)

Americas N = 1767 Russia/Georgia N = 1678

Mean follow-up: 2.9 years 3.7 years Unknown Vital Status 37 (2.1%) 95 (5.7%)

Patient Participation by Region

* Treatment delta differs by region (p=0.001)

Americas N = 1767 Russia/Georgia N = 1678 Month 8 Reported Daily Dose Spiro (N=866) Placebo (N=846) Spiro (N=823) Placebo (N=830)

0 mg 212 (24.5%) 160 (18.9%) 59 (7.2%) 61 (7.3%) 15 mg 194 (22.4%) 105 (12.4%) 83 (10.1%) 38 (4.6%) 30 mg 319 (36.8%) 386 (45.6%) 570 (69.3%) 597 (71.9%) 45 mg 141 (16.3%) 195 (23.0%) 111 (13.5%) 134 (16.1%)

Average Dose* 21.7 mg 25.9 mg 28.4 mg 29.5 mg

Circ 2014. Epub ahead of print