s ystolic h eart failure treatment with the i f inhibitor ivabradine t rial

Influence of background treatment with mineralocorticoid receptor antagonists on

ivabradine's effects in patients with chronic heart failure

Systolic Heart failure treatment with

the If inhibitor ivabradine Trial

Komajda M, Böhm M, Borer J et al. Eur J Heart Fail. 2013;15(1):79-84 www.shift-study.com

Objective

To explore whether ivabradine is beneficial in patients with

systolic HF, in sinus rhythm, with resting HR ≥70 bpm, and

whose guideline-recommended background therapy includes

mineralocorticoid receptor antagonist

Komajda M, Böhm M, Borer J, et al. Eur J Heart Fail. 2013;15(1):79-84 www.shift-study.com

Statistical method

Effect of ivabradine was assessed

• separately in patients with and without MRA at baseline

• using a time-to-first-event survival analysis (a Cox’s proportional

hazards model including treatment effect and adjusted for

prognostic factors at baseline such as BB intake, HR, NYHA

class, LVEF, ischaemic cause of HF, age, SBP, EGFR)

• p value for interaction between treatment and presence or not of

MRA was provided by adding this interaction to the Cox model


Baseline characteristics

With MRAn=3922

Without MRA n=2583

P

Mean age, years 59 62 <0.0001

Male, % 76 78 0.0782

Mean BMI, kg/m2 28 28 0.0013

Mean HF duration, years 3 4 0.0551

HF ischemic cause, % 63 76 <0.0001

NYHA class II, % 45 54 <0.0001

NYHA class III, % 53 45

Mean LVEF, % 28 30 <0.0001

Mean HR, bpm 80 79 <0.0001

Mean systolic BP, mm Hg 119 126 <0.0001

Mean diastolic BP, mm Hg 75 77 <0.0001


Baseline background treatment

With MRAn=3922

Without MRAn=2583

P

β-Blocker, % 90 89 0.2477

ACE inhibitor/ARB, % 91 91 0.7292

Diuretic (excludes AA), % 88 76 <0.0001

Digitalis, % 28 13 <0.0001


Effect of ivabradine on heart rate

Mean HR, bpm Mean change in HR, bpm

Baseline M1-baseline M12-baseline

Patients with MRAn=1981

80.0 9.5 -15.4 10.7 -14.3 12.4

Patients without MRA

n=1260

79.3 9.4 -15.3 10.8 -14.3 11.7


Effect of ivabradine on major outcomes

1.60.4 0.80.6 1.0 1.41.2

Favors ivabradine Favors placebo

Ivabradine Placebo Hazard ratio*

p interaction

Primary endpoint With MRA, n=3922 28% 33% 0.82

Without MRA, n=2583 19% 23% 0.81

Cardiovascular death

16% 18% 0.88 11% 11% 1.02

Hospitalization for HF

19% 23% 0.77

11% 17% 0.67

Death from any cause

17% 19% 0.88

13% 13% 0.99

Death from heart failure

4% 6% 0.73

3% 3% 0.80

0.916

0.279

0.304

0.366

0.723

With MRA, n=3922 Without MRA, n=2583




* adjusted for prognostic factors at baseline


Safety

Ivabradinen=1977

Placebon=1938

Ivabradinen=1255

Placebon=1322

Serious adverse

events, %

44* 48 40 42

Adverse events leading to withdrawal, %

15 14 13 11

Emergent adverse events, % 75 75 75 72

Selected adverse events, %

• Sym/ bradycardia • Asym/ bradycardia • Atrial fibrillation • Hyperkalemia • Renal failure • Phosphenes

4*5*9123*

<11722

<1

5*6*8

<1*1*3*

11623

<1

* Differences is significant


Ivabradine improves outcomes in the SHIFT population

receiving or not aldosterone antagonists and the magnitude of

the improvement is similar in the two groups

The addition of ivabradine should be considered in patients

with heart failure with reduced LVEF, sinus rhythm and heart

rate of 70 bpm or higher, whatever their background

neurohormonal treatment

Conclusion


s ystolic h eart failure treatment with the i f inhibitor ivabradine t rial

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