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, PharmD PGY2 Cardiology Resident WakeMed Health & Hospitals Raleigh, NC TOPCAT = Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist

Janna Beavers has no conflicts of interest to disclose. Disclosure Statement Janna Beavers has no conflicts of interest to disclose.

Background Heart Failure HF with reduced ejection fraction (HFrEF, EF≤40%) Evidence-Based Treatment Options: Beta blockers, ACEis/ARBs, Aldosterone Antagonists, Vasodilators, Diuretics (symptoms) HF with preserved ejection fraction (HFpEF, EF>40%) Diuretics (symptoms) JACC; 2013:62(16):e147-239 Eur Heart J 2012(33):1787-1847

Background RAAS Activation Angiotensin II  increased release of aldosterone Aldosterone: sodium/water retention, fibrosis, vascular inflammation, hypertrophy Aldo-DHF No change in exercise capacity, symptoms, quality of life Improved LV diastolic function at 12 months JAMA 2013;300(8):781-797

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 At least one sign and at least one symptom of heart failure EF≥45% Controlled BP (SBP<140 mmHg or ≤160 mmHg if patients are taking 3 or more meds) Potassium <5 mmol/L Hx of hospitalization within 12 months (major component of hospitalization is management of HF) OR elevated BNP within 60 days (BNP≥100 pg/mL or NT-proBNP≥360 pg/mL) Severe systemic illness (life-expectancy <3 years) Severe renal dysfunction (GFR<30 mL/min/1.73m2 or SCr ≤2.5 mg/dL) Specific coexisting conditions (i.e., COPD requiring oxygen, atrial fibrillation with resting HR >90, MI/PCI/CABG in the past 90 days) 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 Secondary Outcomes 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/dL) NEJM 2014;370:1383-1392

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) 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) 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

Adjusted Cox Model: HR 3.96, p<0.001 Post-hoc Analysis Outcome Americas Eastern Europe Spiro (n=886) Placebo (n=881) HR (p-value) Spiro (n=836) Placebo (n=842) Primary Outcome 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

D/C due to breast tenderness Safety Spironolactone Placebo Doubling of SCr D/C due to breast tenderness ↓ Systolic BP ↑ Hyperkalemia ↑ Hypokalemia NEJM 2014;370:1383-1392

Author’s Conclusions In patients with HFpEF, spironolactone did NOT significantly reduce the incidence of the primary outcome. Spironolactone -> reduced hospitalizations NEJM 2014;370:1383-1392

Study Critique Strengths Limitations First large study of aldosterone antagonists in HFpEF 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 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 HFpEF? Particularly those with elevated BNP Future Studies Geographic regions Include only patients with elevated BNP

Acknowledgements Carolyn Hempel, PharmD, BCPS State University of New York at Buffalo, School of Pharmacy and Pharmaceutical Sciences Jenna Huggins, PharmD, BCPS-AQ Cardiology WakeMed Health & Hospitals Herb Patterson, PharmD, FCCP UNC Eshelman School of Pharmacy Craig Beavers, PharmD, AACC, BCPS-AQ Cardiology TriStar 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 25th, same time. Robert Tunny from Vanderbilt Medical Center will be presenting PARADIGM-HF