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Update on heart failure management – recent data in context – Prof. Martin Cowie

Quality of life in heart failure has been shown to be very poor: in fact, evidence suggests that this is worse than for those on haemodialysis. Many patients remain symptomatic after discharge from hospital, with 40% classified as NYHF stage 3 or 4 following an inpatient stay. There is already good evidence for the use of ACE inhibitors and beta blockers in heart failure. However, evidence for the use of aldosterone antagonists is also mounting.
The RALES Study (1999) demonstrated the efficacy of spironolactone 25mg vs. placebo in those with NYHA 3 or 4 and an ejection fraction < 35%. Meanwhile, the EPHESUS trial showed the benefit of eplerenone versus placebo in addition to “standard medical therapy” in those with heart failure following a myocardial infarction. Compared with spironolactone, eplerenone was also found to be less likely to cause gynaecomastia or breast tenderness though monitoring of potassium was still required.
However, the EMPHASIS-HF trial showed overwhelming evidence for the use of eplerenone in those with symptoms of mild heart failure (NHYA 2) but a low ejection fraction (<35%). This trial was actually stopped prematurely as the evidence for eplerenone was so significant that it was not deemed ethical to continue. Here eplerenone was shown to result in a 37% relative risk reduction in either death from cardiovascular causes or hospitalisation for heart failure, a 23% relative risk reduction in hospitalisation for any reason and a 42% relative risk reduction in hospitalisation for heart failure.

However, 8% of patients on eplerenone experienced hyperkalaemia compared with 4% of those randomised to placebo. In terms of discontinuation, there was no difference between eplerenone and placebo. This resulted in a number needed to treat of 19 to prevent one primary end point per year of follow-up and 51 to prevent one death per year of follow-up. As a result, eplerenone is soon to be licensed for use in chronic heart failure. This is good news as even those with “mild symptoms of heart failure” (i.e. NYHA 2) have an 18% chance of dying within 2 years.
The SHIFT study considered the use of ivabradine (an If channel blocker which acts purely on the sino-atrial node to slow heart rate) in heart failure. In particular, it compared ivabradine with placebo in those with moderate to severe chronic heart failure who are already on best recommended therapy but have a heart rate greater than 70 bpm in sinus rhythm. The primary composite end point of the study was either cardiovascular death or hospitalisation for worsening heart failure, whilst the median study duration was 22.9 months. Those treated with placebo had a mean heart rate of 75 bpm, whilst those randomised to ivabradine had a mean heart rate of 67 bpm. This resulted in an 18% relative risk reduction in the primary composite end point, a 26% relative risk reduction in hospitalisation from worsening heart failure and a 26% relative risk reduction in death from heart failure.

However, there was a higher incidence of both bradycardias and phosphenes (brief spots of light brought on by eye movements) in those taking ivabradine. Overall, the number needed to treat to prevent one patient from experiencing the primary end point was 26, and to postpone one hospitalisation for heart failure per year of follow-up was 27. This implies that in those with moderate to severe heart failure, ivabradine should be prescribed if the heart rate remains above 70 bpm on maximal beta-blockade.

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Update on heart failure management	Survival is improving Scotland
Trend to reduced admission ratesScotland: 1986-2003	Quality of Life in Heart Failure
Many patients remain symptomatic evenat time of discharge from hospital	The new data....
Neurohormonal activation	Heart Failure spectrum
Aldosterone antagonist therapy for HF with LVSDRALES	Aldosterone antagonist therapy for HF after MI EPHESUS trial
NEJM 2011; 364: 11-21	NEJM 2011; 364: 11-21
Slide 13	Concomitant medication: ACEI and BB
37% RRR	24% RRR for mortality
All hospitalisations	EMPHASIS-HF StudySAFETY ADVERSE EVENTS
EMPHASIS-HF StudySAFETY: DRUG DISCONTINUATIONS DUE TO AE	EMPHASIS-HF StudySAFETY: PRESPECIFIED ADJUDICATED EVENTS
Important addition to therapy....For HF with low EF	NB ‘Mild’ heart failure is not benign!
NYHA II is not benign!	And the other big trial....
Systolic Heart failure treatment withthe If inhibitor ivabradine Trial	Primary objective
Study end points	Chronic heart failure background treatment
Background beta-blocker treatment	Mean heart rate reduction
Primary composite end point (CV death or hospital admission for worsening HF)	Hospitalization for worsening heart failure
Cardiovascular death	Death from heart failure
Effect of ivabradine in prespecified subgroups	Incidence of selected adverse events
Treatment discontinuation	Important addition to therapy....For those in sinus rhythm with HR > 70bpm and low EF
ESC guidance 2008..needs update	Canadian guideline update 2011
Australian guideline 2011 update	So – how should this affect practice for those with low EF HF?