1. ACCP Cardiology PRN Journal Club

2. 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 if you would like a copy for now.

3. 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

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

5. 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):e
Eur Heart J 2012(33):

6. 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):

7. 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:

8. 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:

9. 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:

10. 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:

11. 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:

12. 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:

13. Outcomes
NEJM 2014;370:

14. 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:

15. 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:

16. 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:

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

18. 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

19. 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

20. 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

21. Questions??

22. 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 the journal club at or
Our next Journal Club will be November 25th, same time.
Robert Tunny from Vanderbilt Medical Center will be presenting PARADIGM-HF