ACCP Cardiology PRN Journal Club Announcements Thank you
ACCP Cardiology PRN Journal Club
Announcements • Thank you attending the ACCP Cardiology PRN Journal Club – Thank you if you attended last time • Thank you for doing the survey after second journal club – Changes we made include: • Only have 1 resident at time • Improve sound • Changed format with mentors • Offering recordings of the presentations • Our summary article from first journal club will be up soon! I can e-mail if you would like a copy for now.
Spironolactone for Heart Failure with Preserved Ejection Fraction (TOPCAT) Janna Beavers, Pharm. D PGY 2 Cardiology Resident Wake. Med Health & Hospitals Raleigh, NC
Disclosure Statement Janna Beavers has no conflicts of interest to disclose.
Background Heart Failure HF with reduced ejection fraction (HFr. EF, EF≤ 40%) HF with preserved ejection fraction (HFp. EF, EF>40%) Evidence-Based Treatment Options: Beta blockers, ACEis/ARBs, Aldosterone Antagonists, Vasodilators, Diuretics (symptoms) Evidence-Based Treatment Options: Diuretics (symptoms) JACC; 2013: 62(16): e 147 -239 Eur Heart J 2012(33): 1787 -1847
Background RAAS Activation Aldo-DHF Angiotensin II increased release of aldosterone Aldosterone: sodium/water retention, fibrosis, vascular inflammation, hypertrophy JAMA 2013; 300(8): 781 -797 No change in exercise capacity, symptoms, quality of life Improved LV diastolic function at 12 months
TOPCAT Study Objective Determine whether treatment with spironolactone would improve clinical outcomes in patients with symptomatic heart failure with preserved ejection fraction. NEJM 2014; 370: 1383 -1392
Study Population Inclusion Criteria Exclusion Criteria - 50 years of age or older - Severe systemic illness (life-expectancy - At least one sign and at least one <3 years) symptom of heart failure - Severe renal dysfunction (GFR<30 - EF≥ 45% m. L/min/1. 73 m 2 or SCr ≤ 2. 5 mg/d. L) - Controlled BP (SBP<140 mm. Hg or ≤ 160 - Specific coexisting conditions (i. e. , mm. Hg if patients are taking 3 or more COPD requiring oxygen, atrial meds) fibrillation with resting HR >90, - Potassium <5 mmol/L MI/PCI/CABG in the past 90 days) - Hx of hospitalization within 12 months (major component of hospitalization is management of HF) OR elevated BNP within 60 days (BNP≥ 100 pg/m. L or NT-pro. BNP≥ 360 pg/m. L) NEJM 2014; 370: 1383 -1392
Study Design • International, multi-center, double-blind, placebo-controlled, randomized trial • Randomization – Study Groups • Spironolactone 15 mg once daily (max 45 mg/day) • Placebo – Stratification • Previous hospitalization or BNP elevation • Patients received other heart failure medications throughout study Medication Spironolactone Placebo Diuretics 81. 4% 82. 3% Beta blocker 84. 3% 84. 2% ACEi or ARB 78. 2% 77. 3% NEJM 2014; 370: 1383 -1392
Outcomes Primary Outcome • Composite – death from CV causes, aborted cardiac arrest, hospitalization for management of HF Secondary Outcomes • Death from any cause • Hospitalization for any cause • Hyperkalemia (K≥ 5. 5 mmol/L) or hypokalemia (K<3. 5 mmol/L) • Elevated SCr (≥ 2 times above the upper limit of normal OR SCr ≥ 3 mg/d. L) NEJM 2014; 370: 1383 -1392
Statistics & Enrollment Statistics Enrollment • 3, 515 subjects (551 events) required to detect 20% relative reduction in composite primary outcome 80% power • Intention to treat analysis • N=3, 445 • Mean follow-up = 3. 3 years • Regions: – Americas (N=1, 767) – Eastern Europe (N=1, 678) • Mean dose at 8 months: spironolactone 25 mg, placebo 28 mg NEJM 2014; 370: 1383 -1392
Baseline Characteristics Age 68. 7 yrs (median) ~89% white race NYHA II (~64%) & III (~33%) Ejection fraction 56% (median) SCr ~1 (median) Eligibility based on hospitalization (71. 5%) or elevated BNP (28. 5%) NEJM 2014; 370: 1383 -1392
Outcomes NEJM 2014; 370: 1383 -1392
Subgroup Analysis Outcome Hospitalization (n=2464) Elevated BNP (n=981) Spiro (n=1232) Placebo (n=1232) HR (p-value) Spiro (n=490) Placebo (n=491) HR (p-value) Primary Outcome 19. 6% 19. 1% 1. 01 (p=0. 923) 15. 9% 23. 6% 0. 65 (p=0. 003) CV Mortality 9. 7% 9. 5% 1. 01 (p=0. 924) 8. 2% 12% 0. 69 (p=0. 069) Aborted cardiac arrest 0. 1% 0. 4% 0. 2 (p=0. 138) 0. 4% 0 N/A Hospitalization for heart failure 12. 3% 13. 1% 0. 92 (0. 44) 11. 2% 16. 9% 0. 64 (p=0. 011) NEJM 2014; 370: 1383 -1392
Post-hoc Analysis Outcome Primary Outcome Americas Eastern Europe Spiro (n=886) Placebo (n=881) HR (p-value) Spiro (n=836) Placebo (n=842) HR (p-value) 27. 3% 31. 8% 0. 82 (p=0. 026) 9. 3% 8. 4% 1. 1 (p=0. 576) Adjusted Cox Model: HR 3. 96, p<0. 001 NEJM 2014; 370: 1383 -1392
Safety Spironolactone Placebo ↑ Hyperkalemia ↓ Systolic BP D/C due to breast tenderness Doubling of SCr ↑ Hypokalemia NEJM 2014; 370: 1383 -1392
Author’s Conclusions In patients with HFp. EF, spironolactone did NOT significantly reduce the incidence of the primary outcome. Spironolactone -> reduced hospitalizations NEJM 2014; 370: 1383 -1392
Study Critique Strengths • First large study of aldosterone antagonists in HFp. EF to look at morbidity and mortality • Doses achieved similar to other HF studies (i. e. , RALES) • Fewer HF hospitalizations in spironolactone group • Mild adverse event profile for spironolactone Limitations • Inclusion criteria for hospitalization: Major component of hospitalization was heart failure but no standard diagnosis • Different standards of care and definitions of heart failure in different countries • Not powered to detect differences in subgroup or post-hoc analyses
Impact on Clinical Practice • Increased use of aldosterone antagonists in patients with HFp. EF? – Particularly those with elevated BNP • Future Studies – Geographic regions – Include only patients with elevated BNP
Acknowledgements • Carolyn Hempel, Pharm. D, BCPS – State University of New York at Buffalo, School of Pharmacy and Pharmaceutical Sciences • Jenna Huggins, Pharm. D, BCPS-AQ Cardiology – Wake. Med Health & Hospitals • Herb Patterson, Pharm. D, FCCP – UNC Eshelman School of Pharmacy • Craig Beavers, Pharm. D, AACC, BCPS-AQ Cardiology – Tri. Star Centennial Medical Center
Questions? ?
Thank you for attending! • If you would like to have your resident present, would like to be a mentor, or have questions or comments please e-mail the journal club at accpcardsprnjournalclub@gmail. com or craig. beaverspharmd@gmail. com • Our next Journal Club will be November 25 th, same time. – Robert Tunny from Vanderbilt Medical Center will be presenting PARADIGM-HF
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