Emphasis trial

1. Journal club
Dr Biplave Karki

2. Eplerenone in Patients with
Systolic Heart Failure and Mild
Symptoms
Faiez Zannad, M.D., Ph.D., John J.V. McMurray, M.D.,
Henry Krum, M.B., Ph.D., Dirk J. van Veldhuisen, M.D.,
Ph.D., Karl Swedberg, M.D., Ph.D., Harry Shi, M.S., John
Vincent, M.B., Ph.D., Stuart J. Pocock, Ph.D., Bertram
Pitt, M.D., for the EMPHASIS-HF Study Group
Original Article
N Engl J Med
Volume 364(1):11-21
January 6, 2011

3. EMPHASIS-HF
 Eplerenone in Mild Patients Hospitalization
and Survival Study in Heart Failure

4. Definition of Heart Failure
 The current American College of Cardiology Foundation
(ACCF)/American Heart Association (AHA) guidelines
define HF as
 “a complex clinical syndrome that results from structural or
functional impairment of ventricular filling or ejection of blood,
which in turn leads to the cardinal clinical symptoms of dyspnea
and fatigue and signs of HF, namely edema and rales.
 Because many patients present without signs or
symptoms of volume overload, the term “heart failure” is
preferred over the older term “congestive heart failure.”

5. Classification EF (%) Description
HF with reduced EF
(HFrEF)
≤40 “systolic HF”; RCTs have mainly enrolled
these HF patients; only in these pts have
efficacious therapies been demonstrated
HF with preserved EF
(HFpEF)
≥50 “diastolic HF”; dx is challenging due to
excluding other noncardiac causes of
symptoms suggestive of HF; efficacious
therapies have not been identified
HFpEF, borderline 41-49 Characteristics, treatment patterns, and
outcomes appear similar to those of pts
with HFpEF
HFpEF, improved >40 Subset of pts who previously had HFrEF

6. Rationale for Medications used in
Heart Failure

7. Mortality benefit of drugs used in
Heart failure

8. Aldosterone Antagonists
Drugs Spironolactone Eplerenone
MOA Non selective Selective
Effect on androgen and
progesterone
+++ +/-
S/E Increase K, Mg
Decrease CO2,
Metabolic acidosis
Gynecomastia, hirsutism,
Increase K, Mg
Decrease CO2,
Metabolic acidosis
Dose 25 mg OD 25-50mg OD
Use HF (IV) Post MI HF (II/III)
Cost Cheaper Expensive

9. Disclosure Information
 EMPHASIS-HF was funded by Pfizer.inc
 Eplerenone is approved for treating heart
failure after myocardial infarction.

10. Mineralocorticoid Receptor
Antagonists in Heart Failure
 Randomized Aldactone Evaluation Study
(RALES) 1999
 Eplerenone Post–Acute Myocardial
Infarction Heart Failure Efficacy and
Survival Study (EPHESUS) 2003

11. RALES:
Randomized Aldactone Evaluation Study
 In patients with severe heart failure and
left ventricular ejection fraction <35%,
 Spironolactone reduced:
• All-cause mortality
• Sudden death and death due to
progression of heart failure
 Benefit was independent of age, ejection
fraction, cause of heart failure and
concurrent therapy

12. EPHESUS:
Eplerenone Post–Acute Myocardial Infarction Heart
Failure Efficacy and Survival Study
 The addition of eplerenone to optimal
medical therapy contributes to the
continued improvement in survival and
hospitalization rates among patients with
acute myocardial infarction complicated by
left ventricular dysfunction and heart
failure

13. Aim of EMPHASIS-HF
 to investigate the effects of eplerenone,
added to evidence-based therapy, on
clinical outcomes in patients with systolic
heart failure and mild symptoms (i.e.,
NYHA functional class II symptoms.

14. Methods

15. Inclusion Criteria
 >55 years of age
 NYHA functional class II
 Ejection fraction <30% (or, if betwn 30 to 35%, a QRS
>130 msec)
 Treated with the recommended or maximal tolerated
dose of ACE inhibitor (or an ARB or both) and a beta-
blocker (unless contraindicated)
 Within 6 months of hospitalization for a cardiovascular
reason (if no such hospitalization, BNP>250 pg/ml or N-
pro-BNP>500 pg/ml in men and 750 pg/ml in women

16. Exclusion Criteria
 Acute myocardial infarction
 NYHA class III or IV heart failure
 Serum potassium level >5.0 mmol/L
 eGFR<30 ml/min/1.73 m2
 Need for a potassium sparing diuretic, and
 Any other clinically significant coexisting
condition

17. Study Design
 Primary outcome: CV death or
hospitalization for HF

18. Sample Size
 The initial assumptions
 2584 patients
 Annual event rate 18% in the placebo group
 813 primary events in 48 months
 80% power to detect an 18% risk reduction
 June 2009
 Overall blinded event rate lower than expected
 Sample size increased to 3100 patients

19. Early Stopping
 May 6th 2010
 DSMC’s second interim analysis showed
overwhelming benefit beyond the prespecified
stopping boundary for benefit (2 sided P-value
=0.000001in favour of eplerenone)
 May 9th 2010
 Agreed to stop patient enrollment
 May 25th 2010
 Trial cut off date

20. Results
Median follow up time 21 months
March 30, 2006, through May 25, 2010

21. Baseline Characteristics

22. Baseline Characteristics

23. Baseline Therapy

24. Patient Follow up and Dosing

25. Primary Endpoint CV Death or
Hospitalization for HF- 37%

26. Mortality From Any Cause-24%

27. Hospitalization From Any Cause-
23%

28. Heart Failure Hoapitalization-42%

29. Primary And Adjudicated
Secondary Outcome

30. Other Adjudicated Secondary
Outcome

31. Other Outcomes

32. Subgroup Analysis

33. Subgroup Analysis

34. Subgroup Analysis

35. Subgroup Analysis

36. Safety

37. Summary
 The addition of eplerenone to
recommended treatment resulted in:

38. Conclusion
 In patients with systolic heart failure and
mild symptoms, addition of eplerenone to
recommended medical therapy

39. TOPCAT 2014:
Treatment of Preserved Cardiac Function Heart Failure
With an Aldosterone Antagonist Trial
 Addition of spironolactone for heart failure
with preserved ejection fraction didn’t
reduce the primary outcome.

40. Thank you