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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
Tardif JC, O'Meara E, Komajda M, et al. Eur Heart J. 2011;32(20):2507-15 www.shift-study.com
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)
Tardif JC, O'Meara E, Komajda M, et al. Eur Heart J. 2011;32(20):2507-15 www.shift-study.com
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
Tardif JC, O'Meara E, Komajda M, et al. Eur Heart J. 2011;32(20):2507-15 www.shift-study.com
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
IvabradineIvabradine
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
Tardif JC, O'Meara E, Komajda M, et al. Eur Heart J. 2011;32(20):2507-15 www.shift-study.com
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, %
Tardif JC, O'Meara E, Komajda M, et al. Eur Heart J. 2011;32(20):2507-15 www.shift-study.com
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
Tardif JC, O'Meara E, Komajda M, et al. Eur Heart J. 2011;32(20):2507-15 www.shift-study.com
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
Ivabradine (n=204) Placebo (n=199)
Baseline 8 months Baseline 8 months
∆ -5.5, P=0.002Left ventricular end-diastolic
volume index
Tardif JC, O'Meara E, Komajda M, et al. Eur Heart J. 2011;32(20):2507-15 www.shift-study.com
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
Ivabradine (n=204) Placebo (n=199)
Baseline 8 months Baseline 8 months
∆ + 2.7, P<0.001Left ventricular ejection fraction
Tardif JC, O'Meara E, Komajda M, et al. Eur Heart J. 2011;32(20):2507-15 www.shift-study.com
Summary of changes in HR, LV end-Summary of changes in HR, LV end-systolic/end-diastolic volume indexessystolic/end-diastolic volume indexes
IvabradineIvabradine
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
Tardif JC, O'Meara E, Komajda M, et al. Eur Heart J. 2011;32(20):2507-15 www.shift-study.com
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
Tardif JC, O'Meara E, Komajda M, et al. Eur Heart J. 2011;32(20):2507-15 www.shift-study.com
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