Effects of selective heart rate reduction with ivabradine on left ventricular remodelling and...

Effects of selective heart rate reduction with Effects of selective heart rate reduction with ivabradine on left ventricular remodelling ivabradine on left ventricular remodelling

and function: results from the SHIFT and function: results from the SHIFT echocardiography substudyechocardiography substudy

Effects of selective heart rate reduction with Effects of selective heart rate reduction with ivabradine on left ventricular remodelling ivabradine on left ventricular remodelling

and function: results from the SHIFT and function: results from the SHIFT echocardiography substudyechocardiography substudy

SSystolic ystolic HHeart failure treatment witheart failure treatment with

the the IIff inhibitor ivabradine inhibitor ivabradine TTrialrial

Tardif JC, O'Meara E, Komajda M, et al. Eur Heart J. 2011;32(20):2507-15 www.shift-study.com

BackgroundBackground

Cardiac remodeling is central to the pathophysiology of heart Cardiac remodeling is central to the pathophysiology of heart

failure (HF) and is a prognostic factor in patients with HF failure (HF) and is a prognostic factor in patients with HF

Left ventricular (LV) enlargement and reduced ejection Left ventricular (LV) enlargement and reduced ejection

fraction are powerful predictors of outcomes in heart failurefraction are powerful predictors of outcomes in heart failure

Therapeutic effects of drugs and devices on LV remodeling Therapeutic effects of drugs and devices on LV remodeling

are associated with their longer-term effects on mortalityare associated with their longer-term effects on mortality


Objective Objective of the pre-specified the pre-specified echocardiography substudyechocardiography substudy

To evaluate the effects of the To evaluate the effects of the IIff inhibitor inhibitor ivabradine on LV ivabradine on LV

remodeling and function: remodeling and function:

Primary endpointPrimary endpoint: the change in the LV end-systolic volume : the change in the LV end-systolic volume

index (LVESVI) from baseline to 8 monthsindex (LVESVI) from baseline to 8 months

Secondary endpointsSecondary endpoints: changes during the same interval in: changes during the same interval in

LV end-diastolic volume index (LVEDVI)LV end-diastolic volume index (LVEDVI)

LV end-systolic, end-diastolic volumes (LVESV, LVEDV)LV end-systolic, end-diastolic volumes (LVESV, LVEDV)

LV ejection fraction (LVEF)LV ejection fraction (LVEF)


Sub-study populationSub-study population

Excluded (N=96)

52: Poor quality of echo recording

19: No baseline and/or 8-month recording

8: Non-matching biplane or 4-chamber views

13: Withdrawn due to death

4: Consent withdrawn

Excluded (N=104)

203 patients

Placebo

208 patients

Ivabradine

Median follow-up after 8-month echocardiogram: 16.1 monthsMedian follow-up after 8-month echocardiogram: 16.1 months

52: Poor quality of echo recording

15: No baseline and/or 8- month recording

1: Non-matching biplane or 4-chamber views

23: Withdrawn due to death

13: Consent withdrawn

611 patients included from

89 centers in 21 countries

304 patients Ivabradine

307 patients Placebo


Baseline characteristicsBaseline characteristics

IvabradineIvabradine

N=304N=304

PlaceboPlacebo

N=307N=307 Mean age, yearsMean age, years 6060 5959 Male, %Male, % 8080 8282 Mean BMI, kg/mMean BMI, kg/m22 2828 2828 Mean HF duration, yearsMean HF duration, years 44 44 HF ischaemic cause, %HF ischaemic cause, % 6767 6565 NYHA class II, %NYHA class II, % 4848 4646 NYHA class III, %NYHA class III, % 5151 5353 Mean LVEF, %Mean LVEF, % 3232 3232 Mean HR, bpmMean HR, bpm 7878 7979

Mean systolic BP, mm HgMean systolic BP, mm Hg 121121 119119

Mean diastolic BP, mm Hg Mean diastolic BP, mm Hg 7575 7575Tardif JC, O'Meara E, Komajda M, et al. Eur Heart J. 2011;32(20):2507-15 www.shift-study.com

Baseline background treatmentBaseline background treatment


N=304N=304

PlaceboPlacebo

N=307N=307 Beta-blocker, %Beta-blocker, % 92 92

ACE inhibitor, %ACE inhibitor, % 80 83

ARB, %ARB, % 17 12

Diuretic (excludes antialdo), Diuretic (excludes antialdo), %%

87 87

Aldosterone antagonist, %Aldosterone antagonist, % 74 71

Digitalis, %Digitalis, % 27 32

Devices, %Devices, % 3 4


LVESVI > 59 mL/m2

LVESVI < 59 mL/m2

HR 1.62, p=0.04

LV end-systolic volume index and LV end-systolic volume index and outcome in the placebo groupoutcome in the placebo group

Patients with primary composite endpoint, %Patients with primary composite endpoint, %


60

40

20

Primary endpoint: change in LVESVIPrimary endpoint: change in LVESVI from baseline to 8 monthsfrom baseline to 8 months

0

50

75

70

65

60

55

mL

/m2

65.2±29.165.2±29.1 58.2±28.358.2±28.3 63.6 ±30.163.6 ±30.1 62.8 ±28.7 62.8 ±28.7

- 7.0 7.0 ± ± 16.316.3 - 0.9 - 0.9 ± ± 17.117.1

∆ -5.8, P<0.001

Left ventricular end-systolic volume index

Ivabradine (n=208) Placebo (n=203)

Baseline 8 months Baseline 8 months


Secondary endpoint: change in LVEDVI Secondary endpoint: change in LVEDVI from baseline to 8 monthsfrom baseline to 8 months

0

75

100

95

90

85

80

mL

/m2

93.9 ±32.893.9 ±32.8 85.9 ±30.985.9 ±30.9 90.8 ±33.190.8 ±33.1 89.0±31.689.0±31.6

-7.9 -7.9 ± ± 18.918.9 -1.8 -1.8 ± ± 19.019.0



∆ -5.5, P=0.002Left ventricular end-diastolic

volume index


Bas

elin

e

Bas

elin

e

M00

8

M00

8

Secondary endpoint: change in LVEF Secondary endpoint: change in LVEF from baseline to 8 monthsfrom baseline to 8 months

65.2

± 29.1

65.2

± 29.1

0

5

10

15

20

25

30

35

40

%

32.3±9.132.3±9.1 34.7±10.2 34.7±10.2 31.6 ±9.331.6 ±9.3 31.5±10.0 31.5±10.0

2.4 2.4 ± ± 7.77.7 - 0.1 - 0.1 ± ± 8.08.0



∆ + 2.7, P<0.001Left ventricular ejection fraction


Summary of changes in HR, LV end-Summary of changes in HR, LV end-systolic/end-diastolic volume indexessystolic/end-diastolic volume indexes


n=304n=304

PlaceboPlacebo

n=307n=307

PP

Change in resting HR at 8 months,

bpm

- 14.7 - 5.8 <0.001

Change in LVESVI at 8 month, mL/m2 - 7.0 - 0.9 <0.001

Change in LVEDVI at 8 month, mL/m2 - 7.9 - 1.8 0.002


Heart rate reduction with ivabradine reverses left ventricular remodeling in patients with heart failure and LV systolic dysfunction:

Marked reductions of LV volumes

Significant improvement of LV ejection fraction

These results suggest that ivabradine modifies disease progression in patients with HF receiving background therapy

ConclusionsConclusions


Effects of selective heart rate reduction with ivabradine on left ventricular remodelling and...

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