s ystolic h eart failure treatment with the if inhibitor ivabradine t rial
DESCRIPTION
S ystolic H eart failure treatment with the If inhibitor ivabradine T rial. Michel Komajda and Karl Swedberg on behalf of the Investigators. Disclosures. - PowerPoint PPT PresentationTRANSCRIPT
SSystolic ystolic HHeart failure treatment witheart failure treatment with
the the IfIf inhibitor ivabradine inhibitor ivabradine TTrialrial
SSystolic ystolic HHeart failure treatment witheart failure treatment with
the the IfIf inhibitor ivabradine inhibitor ivabradine TTrialrial
Michel Komajda and Karl Swedberg
on behalf of the Investigators
Michel Komajda and Karl Swedberg
on behalf of the Investigators
Disclosures
SHIFT Executive Committee members received fees, research grants, or both from Servier, as well as fees for speaking or consulting from other major cardiovascular pharmaceutical companies
Background
Elevated heart rate is associated with poor outcome in a number of cardiovascular conditions including heart failure
Heart rate remains elevated in many heart failure patients despite treatment by beta-blockers
Ivabradine is a novel heart rate-lowering agent acting by inhibiting the If current in the sino-atrial node
We hypothesized that the addition of ivabradine to recommended therapy would be beneficial in heart failure patients with elevated heart rate
Fosbol et al. Int J Cardiol, 2010;140:279-286.
DIAMOND study; 1518 patients with HF post MI, 10 years follow up
P<0.0001
0 2 4 6 8 10
Years
1.0
0.8
0.4
0.0
0.6
0.2
> 91 bpm81-91 bpm71-80 bpm40-70 bpm
Resting heart rate and mortalityResting heart rate and mortality in HF post MI patients in HF post MI patients
Mortality
Ivabradine: pure heart rate reductionIvabradine: pure heart rate reduction
If inhibition reduces the diastolic depolarization slope, thereby lowering heart rate
RR
Pureheart ratereduction
0 mV
-40 mV
-70 mV
closedopen
closed
Ivabradine
Thollon et al. Br J Pharmacol. 1994;112:37-42.
Primary objectivePrimary objective
To evaluate whether the To evaluate whether the IIff inhibitor ivabradine inhibitor ivabradine
improves cardiovascular outcomes improves cardiovascular outcomes
in patients within patients with
1. Moderate to severe chronic heart failure1. Moderate to severe chronic heart failure
2. Left ventricular ejection fraction 2. Left ventricular ejection fraction 35%35%
3. Heart rate 3. Heart rate 70 bpm and70 bpm and
4. Recommended therapy4. Recommended therapy
To evaluate whether the To evaluate whether the IIff inhibitor ivabradine inhibitor ivabradine
improves cardiovascular outcomes improves cardiovascular outcomes
in patients within patients with
1. Moderate to severe chronic heart failure1. Moderate to severe chronic heart failure
2. Left ventricular ejection fraction 2. Left ventricular ejection fraction 35%35%
3. Heart rate 3. Heart rate 70 bpm and70 bpm and
4. Recommended therapy4. Recommended therapy
EuropeGermany Portugal
Belgium Greece SpainDenmark Ireland SwedenFinland Italy TurkeyFrance The Netherlands UK
BulgariaCzech RepublicEstoniaHungary
South AmericaArgentinaBrazilChili
North AmericaCanada
AsiaChinaHong KongIndiaSouth KoreaMalaysia
AustraliaAustralia
LatviaLithuaniaNorwayPolandRomania
RussiaSlovakiaSloveniaUkraine
Multinational studyMultinational studyMultinational studyMultinational study
6505 patients, 37 6505 patients, 37 countriescountries, 677 , 677 centrescentres
18 years
Class II to IV NYHA heart failure
Ischaemic/non-ischaemic aetiology
LV systolic dysfunction (EF 35%)
Heart rate 70 bpm
Sinus rhythm
Documented hospital admission for worsening heart failure 12 months
Inclusion criteriaInclusion criteria
Swedberg K, et al. Eur J Heart Fail. 2010;12:75-81.Swedberg K, et al. Eur J Heart Fail. 2010;12:75-81.
Study designStudy design
HR and tolerabilityIvabradine 5 mg bid
Matching placebo, bid
Every 4 monthsD0 D14 D28 M4
Ivabradine 7.5/5/2.5 mg bid according to
Swedberg K, et al. Eur J Heart Fail. 2010;12:75-81.Swedberg K, et al. Eur J Heart Fail. 2010;12:75-81.
3.5 years
Screening 7 to 30 days
Study endpointsStudy endpoints
Cardiovascular death
Hospitalisation for worsening heart failure
Primary composite endpointPrimary composite endpoint
Other endpointsOther endpoints
All-cause / CV / HF death
All-cause / CV / HF hospitalisation
Composite of CV death, hospitalisation for HF or non-fatal MI
NYHA class / Patient & Physician Global Assessment
Swedberg K, et al. Eur J Heart Fail. 2010;12:75-81.Swedberg K, et al. Eur J Heart Fail. 2010;12:75-81.
In total population and in patients with at least 50% target dose of beta-blockers In total population and in patients with at least 50% target dose of beta-blockers In total population and in patients with at least 50% target dose of beta-blockers In total population and in patients with at least 50% target dose of beta-blockers
Patients and follow-up
Median study duration: 22.9 months; maximum: 41.7 monthsMedian study duration: 22.9 months; maximum: 41.7 monthsMedian study duration: 22.9 months; maximum: 41.7 monthsMedian study duration: 22.9 months; maximum: 41.7 months
6558 randomized
3268 to ivabradine 3290 to placebo
3264 analysed1 lost to follow-up
3241 analysed2 lost to follow-up
7411 screened
Excluded: 27Excluded: 27 Excluded: 26Excluded: 26
Swedberg K, et al. Lancet. 2010;online August 29.
Baseline characteristics
IvabradineIvabradine
32413241
PlaceboPlacebo
32643264
Mean age, yMean age, y 60.760.7 60.160.1
Male, %Male, % 7676 7777
Ischaemic aetiology, %Ischaemic aetiology, % 6868 6767
NYHA II, %NYHA II, % 4949 4949
NYHA III/IV, %NYHA III/IV, % 5151 5151
Previous MI, %Previous MI, % 5656 5656
Diabetes, %Diabetes, % 3030 3131
Hypertension, %Hypertension, % 6767 6666
Swedberg K, et al. Lancet. 2010;online August 29.
Baseline characteristics
IvabradineIvabradine
32413241
PlaceboPlacebo
32643264
Mean heart rate, bpmMean heart rate, bpm 8080 8080
Mean LVEF, %Mean LVEF, % 2929 2929
Mean SBP, mm HgMean SBP, mm Hg 122122 121121
Mean DBP, mm HgMean DBP, mm Hg 7676 7676
eGFR, mL/min/1.73 meGFR, mL/min/1.73 m22 7575 7575
Swedberg K, et al. Lancet. 2010;online August 29.
Chronic HF background treatment
89 9184
61
22
3
90 91
83
59
22
40
10
20
30
40
50
60
70
80
90
100
Beta-blockers ACEIs and/orARBs
Diuretics Aldosterone antagonists
Digitalis ICD/CRT
Ivabradine
Placebo
Patients (%)Patients (%)Patients (%)Patients (%)
Swedberg K, et al. Lancet. 2010;online August 29.
Background beta-blocker treatment
0
10
20
30
40
50
60
70
80
90
100
BB at
randomization
At least 50%
target daily dose
Target daily dose
89
56
26
89
56
26
Patients (%)Patients (%)Patients (%)Patients (%)
Ivabradine
Placebo
Swedberg K, et al. Lancet. 2010;online August 29.
Main reasons for not achieving Main reasons for not achieving
Beta-blocker target dose, %Beta-blocker target dose, %
IvabradineIvabradine
n=2099n=2099
PlaceboPlacebo
n=2126n=2126
HypotensionHypotension 4444 4545
FatigueFatigue 3232 3232
DyspneaDyspnea 1414 1414
DizzinessDizziness 1313 1212
BradycardiaBradycardia 66 66
Main reasons for not Main reasons for not
prescribing beta-blocker, %prescribing beta-blocker, %
IvabradineIvabradine
n=344n=344
PlaceboPlacebo
n=341n=341
COPDCOPD 3737 3232
HypotensionHypotension 1717 2020
AsthmaAsthma 1010 1111
Cardiac decomp.Cardiac decomp. 77 99
FatigueFatigue 55 66
Background beta-blocker treatment
Swedberg K, et al. Lancet. 2010;online August 29.
Mean heart rate reduction Mean heart rate reduction
70% of patients on ivabradine 7.5 mg bid70% of patients on ivabradine 7.5 mg bid
0 2 weeks 1 4 8 12 16 20 24 28 32
Months
90
80
70
60
50
67
7575
80
64
Heart rate (bpm)Heart rate (bpm)Heart rate (bpm)Heart rate (bpm)
Placebo
Ivabradine
Swedberg K, et al. Lancet. 2010;online August 29.
0 6 12 18 24 30
Months
40
30
20
10
0
Primary composite endpointPrimary composite endpoint (CV death or hospital admission for worsening HF)(CV death or hospital admission for worsening HF)
- 18%
Cumulative frequency (%)Cumulative frequency (%)Cumulative frequency (%)Cumulative frequency (%)
Placebo
Ivabradine
HR (95% CI), 0.82 (0.75–0.90),
p<0.0001
Swedberg K, et al. Lancet. 2010;online August 29.
0 6 12 18 24 30
Months
30
20
10
0
Hospitalization for HF
- 26%
Cumulative frequency (%)Cumulative frequency (%)Cumulative frequency (%)Cumulative frequency (%)
Placebo
Ivabradine
HR (95% CI), 0.74 (0.66–0.83),
p<0.0001
Swedberg K, et al. Lancet. 2010;online August 29.
0 6 12 18 24 30
Months
30
20
10
0
Cardiovascular deathCardiovascular death
Cumulative frequency (%)Cumulative frequency (%)Cumulative frequency (%)Cumulative frequency (%)
Placebo
Ivabradine
HR (95% CI), 0.91 (0.80–1.03),
p=0.128
Swedberg K, et al. Lancet. 2010;online August 29.
Death from heart failure
- 26%
0 6 12 18 24 30Months
10
5
0
HR (95% CI), 0.74 (0.58–0.94),
p=0.014
Cumulative frequency (%)Cumulative frequency (%)Cumulative frequency (%)Cumulative frequency (%)
Placebo
Ivabradine
Swedberg K, et al. Lancet. 2010;online August 29.
Effect of ivabradine Effect of ivabradine on outcomes on outcomes
EndpointsEndpoints Hazard ratioHazard ratio 95% CI95% CI pp value value
Primary composite endpoint 0.820.82 [0.75;0.90][0.75;0.90] pp<0.0001<0.0001
All-cause death 0.900.90 [0.80;1.02][0.80;1.02] pp=0.092=0.092
Death from heart failure 0.740.74 [0.58;0.94][0.58;0.94] pp=0.014=0.014
Hospitalisation for any cause 0.890.89 [0.82;0.96][0.82;0.96] pp=0.003=0.003
Hospitalisation for cardiovascular reason
0.850.85 [0.78;0.92][0.78;0.92] pp=0.0002=0.0002
Cardiovascular death / hosp. for HF or non-fatal MI
0.820.82 [0.74;0.89][0.74;0.89] pp<0.0001<0.0001
Swedberg K, et al. Lancet. 2010;online August 29.
Age <65 years ≥65 years
Sex Male Female
Beta-blockers No Yes
Aetiology of heart failure Non-ischaemic Ischaemic
NYHA class NYHA class II NYHA class III or IV
Diabetes No Yes
Hypertension No Yes
Baseline heart rate <77 bpm ≥77 bpm
Test for interaction
p=0.029
1.51.00.5Hazard ratio
Favours ivabradine Favours placebo
Effect of ivabradine in Effect of ivabradine in prespecified subgroupsprespecified subgroups
Swedberg K, et al. Lancet. 2010;online August 29.
NYHA class changesNYHA class changes
28
68
5
24
70
6
0
10
20
30
40
50
60
70
Improvement Stability Worsening
pp=0.0003=0.0003pp=0.0003=0.0003PatientsPatients (%) (%)PatientsPatients (%) (%)
Ivabradine
Placebo
Swedberg K, et al. Lancet. 2010;online August 29.
Patient Global Assessment Patient Global Assessment
8
25
68
7
21
72
0 10 20 30 40 50 60 70 80
Worsening
Stability
Improvement
Patients (%)
pp< 0.05< 0.05pp< 0.05< 0.05
last post randomisation valuelast post randomisation valuelast post randomisation valuelast post randomisation value
Ivabradine
Placebo
Swedberg K, et al. Lancet. 2010;online August 29.
Physician Global Assessment Physician Global Assessment
pp= 0.001= 0.001pp= 0.001= 0.0019
34
57
8
31
61
0 10 20 30 40 50 60 70
Worsening
Stability
Improvement
Patients (%)
Ivabradine
Placebo
Swedberg K, et al. Lancet. 2010;online August 29.
last post randomisation valuelast post randomisation valuelast post randomisation valuelast post randomisation value
Mean heart rate reduction Mean heart rate reduction Patients with >50 % beta-blocker dose Patients with >50 % beta-blocker dose (n= 3181)(n= 3181)
40
50
60
70
80
90
100
Basel
ine
D14 D28M
04M
08M
12M
16M
20M
24M
28M
32M
36
Mean HR in sinus rhythm (bpm)Mean HR in sinus rhythm (bpm)Mean HR in sinus rhythm (bpm)Mean HR in sinus rhythm (bpm)
79
63
67
Patients receiving at least half the target dose of beta-blockersPatients receiving at least half the target dose of beta-blockersPatients receiving at least half the target dose of beta-blockersPatients receiving at least half the target dose of beta-blockers
7475
Placebo
Ivabradine
Swedberg K, et al. Lancet. 2010;online August 29.
1.51.00.5Hazard ratio
Favours ivabradine Favours placebo
Ivabradine Hazard ratio
Primary compositeendpoint 330
(11.9 PY)0.90362
(13.3 PY)
Cardiovascular death 176 (5.9 PY)
1.00175 (5.9 PY)
Hospital admission forworsening HF
213 (7.7 PY)
0.81260 (9.6 PY)
Placebo
Patients with at least 50% BB Patients with at least 50% BB target dose (n=3181) target dose (n=3181)
pp value value
nsns
nsns
pp=0.021=0.021
Swedberg K, et al. Lancet. 2010;online August 29.
Incidence of selected adverse Incidence of selected adverse events events (N = 6492)(N = 6492)
Patients with an eventPatients with an event
Ivabradine Ivabradine
N=3232, % N=3232, % (n)
Placebo Placebo
N=3260, N=3260, %% (n)
pp value value
All serious adverse events 45% 45% (1450) 48% 48% (1553) 0.0250.025
All adverse events 75% 75% (2439) 74% 74% (2423) 0.3030.303
Heart failure 25% 25% (804) 29% 29% (937) 0.00050.0005
Symptomatic bradycardia 5% 5% (150) 1% 1% (32) <0.0001<0.0001
Asymptomatic bradycardia 6% 6% (184) 1% 1% (48) <0.0001<0.0001
Atrial fibrillation 9% 9% (306) 8% 8% (251) 0.0120.012
Phosphenes 3% 3% (89) 1% 1% (17) <0.0001<0.0001
Blurred vision 1% 1% (17) < 1% < 1% (7) 0.0420.042Swedberg K, et al. Lancet. 2010;online August 29.
Incidence of serious adverse Incidence of serious adverse eventsevents
Patients with an eventPatients with an event
Ivabradine Ivabradine
N=3232, % N=3232, % (n)(n)
Placebo Placebo
N=3260, % N=3260, % (n)(n)
pp value value
All serious adverse events All serious adverse events
Cardiac disorders Cardiac disorders
General disorders, administration conditionsGeneral disorders, administration conditions
Infection and infestations Infection and infestations
Respiratory, thoracic, mediastinal disordersRespiratory, thoracic, mediastinal disorders
Surgical and medical proceduresSurgical and medical procedures
Gastrointestinal disordersGastrointestinal disorders
Neoplasm benign, malignant and unspecified Neoplasm benign, malignant and unspecified
Renal and urinary disordersRenal and urinary disorders
Hepatobiliary disordersHepatobiliary disorders
Eyes disordersEyes disorders
45% (1450)
28% (920)
7% (240)
7% (216)
3% (107)
3% (102)
3% (89)
2% (68)
2% (51)
1% (29)
1% (18)
49% (1553)
30% (991)
8% (254)
7% (236)
4% (122)
4% (122)
3% (103)
2% (61)
1% (47)
1% (39)
<1% (13)
0.025
0.091
0.617
0.381
0.347
0.197
0.342
0.534
0.685
0.273
0.374
Swedberg K, et al. Lancet. 2010;online August 29.
Patients with an Patients with an adverse event, adverse event,
leading to withdrawalleading to withdrawal
Ivabradine Ivabradine
N=3232, % N=3232, % (n)
Placebo Placebo
N=3260, N=3260, %% (n)
pp value value
All adverse events 14% 14% (467) 13% 13% (416) 0.0510.051
Heart failure 2% 2% (70) 3% 3% (82) 0.3670.367
Symptomatic bradycardia 1% 1% (20) <1% <1% (5) 0.0020.002
Asymptomatic bradycardia 1% 1% (28) <1% <1% (5) <0.0001<0.0001
Atrial fibrillation 4% 4% (135) 3% 3% (113) 0.1370.137
Phosphenes <1% <1% (7) <1% <1% (3) 0.2240.224
Blurred vision <1% <1% (1) <1% <1% (1) 1.0001.000
Treatment discontinuationTreatment discontinuation
Swedberg K, et al. Lancet. 2010;online August 29.
ConclusionConclusion
Heart failure with systolic dysfunctionwith systolic dysfunction and elevated heart rate
is associated with poor outcomes (primary composite endpoint
in the placebo group is 18%/year)
Ivabradine reduced cardiovascular mortality or heart failure
hospitalisation by 18% (p<0.0001). The absolute risk reduction
was 4.2%
This beneficial effect was mainly driven by a favourable effect
on HF death (26%) and hospitalisation for HF (26%)
Overall, treatment with ivabradine was safe and well tolerated
Clinical implicationsClinical implications
The addition of ivabradine to recommended
therapy significantly reduces death and
hospitalisations related to heart failure in patients
with heart rate 70 bpm
The NNT for 1 year to prevent …
One primary endpoint is 26
One hospitalisation for heart failure is 27
Available now online from Available now online from Lancet Lancet
http://www.lancet.com published online August 29, 2010 DOI:10.1016/S0140-6736(10)61198-1