Transcript ESC review 2011 - Vasculaire Geneeskunde

SHIFT:
Systolic Heart failure treatment with
the IF inhibitor ivabradine Trial
Purpose
To examine the effect of ivabradine in addition to
guidelines-based treatment on cardiovascular (CV)
outcomes, symptoms, and quality of life in patients with
chronic heart failure (CHF) and systolic dysfunction
Swedberg K, et al. Lancet 2010;376:875–885.
SHIFT: TRIAL DESIGN
Design
Randomized trial with a 1:1 design.
Patients
6558 patients in sinus rhythm with a resting heart rate of ≥70 beats per minute
(bmp), CHF for ≥4 weeks, previous admission for worsening heart failure (HF)
within the previous 12 months, and left-ventricular ejection fraction (LVEF) of
≤35%.
Follow-up, primary and secondary endpoints
The primary endpoint was a composite of CV death or admission for worsening
HF. The principal secondary endpoint was a composite of CV death or admission
for worsening HF in patients at ≥50% of the target daily dose of a β blocker.
Patients were followed up every 4 months. The median duration of follow-up
was 22.9 months.
Treatment
Patients were randomized to 5 mg twice daily of ivabradine or matching
placebo. After 14 days, the dose was adjusted depending on the patients
resting heart rate.
Swedberg K, et al. Lancet 2010;376:875–885.
SHIFT: Baseline characteristics
Ivabradine
(n=1176)
Placebo
(n=1185)
60.7
60.1
Male sex (%)
76
77
Race/ethnicity (%)
White
89
89
79.7
80.1
Mean LVEF (%)
29
29
NYHA Class (%)
Class II
Class III
Class IV
49
50
2
49
50
2
Duration of HF (years)
3.5
3.5
History of MI (%)
56
56
ß blocker at randomization (%)
89
90
Patients at ≥50% β blocker target dose (%)
56
56
Mean age (years)
Heart rate (bpm)
Abbreviations: MI, myocardial infarction; NYHA, New York Heart Association class..
Swedberg K, et al. Lancet 2010;376:875–885.
SHIFT: RESULTS
Primary endpoint and follow-up
The primary endpoint occurred in 937 (29%) patients in the placebo group versus 793 (24%)
of patients receiving ivabradine (hazard ratio [HR], 0.82; p<0·0001). This result was
primarily due to reductions in admissions for worsening HF, at 672 (21%) in patients
receiving placebo and 514 (16%) of those given ivabradine (HR, 0.74; p<0.0001).
Twenty six patients would need treatment for 1 year in order to prevent one CV death or
admission for HF. Interestingly, there was evidence of a significant treatment effect in
patients with a baseline heart rate over 77 bpm.
Secondary endpoints
In patients receiving ≥50% of the target daily dose of a β blocker, the composite endpoint
and mortality components were not significantly reduced. However, ivabradine reduced
admissions for worsening HF by 19% (HR, 0.81; p=0.021).
Safety endpoints
Although there were more withdrawals in patients given ivabradine than those given placebo,
at 682 (21%) versus 605 (19%), respectively (HR, 1.14; p=0.017), serious adverse
events were less common with ivabradine than with placebo (p=0.025). Symptomatic and
asymptomatic bradycardia was more frequent with ivabradine than with placebo (both
p<0·0001).
Swedberg K, et al. Lancet 2010;376:875–885.
SHIFT:
Effects on primary and major secondary
endpoints
Ivabradine
(n=3241)
Placebo
(n=3264)
Hazard ratio
(95% CI)
p value
Primary endpoint
CV death or hospital admission for worsening HF
793 (24%)
937 (29%)
0.82 (0.75–0.90)
<0.0001
Mortality endpoints
All-cause mortality
CV mortality
Death from HF
503 (16%)
449 (14%)
113 (3%)
552 (17%)
491 (15%)
151 (5%)
0.90 (0.80–1.02)
0.91 (0.80–1.03)
0.74 (0.58–0.94)
0.092
0.128
0.014
1231 (38%)
514 (16%)
997 (30%)
825 (25%)
1356 (42%)
672 (21%)
1122 (34%)
979 (30%)
Other endpoints
All-cause hospital admission
Hospital admission for worsening HF
Any CV hospital admission
CV death, or hospital admission for worsening HF, or
hospital admission for non-fatal MI
0.89
0.74
0.85
0.82
(0.82–0.96)
(0.66–0.83)
(0.78–0.92)
(0.74–0.89)
0.003
<0.0001
0.0002
<0.0001
Abbreviations: CI, confidence interval..
Swedberg K, et al. Lancet 2010;376:875–885.
SHIFT: cumulative event curves
Patients with primary composite endpoint (%)
Patients with primary composite
endpoint (%)
40
30
20
10
Placebo
(937 events)
HR, 0.82; 95% Cl, 0.75–0.90; p<0.0001.
0
0
6
12
Ivabradine
(793 events)
18
24
30
Months
Swedberg K, et al. Lancet 2010;376:875–885.
Swedberg K, et al. Lancet 2010;376:875–885.
SHIFT: Cumulative event curves
Patients with first hospital admission for worsening HF
Patients with first hospital
admission for worsening HF (%)
30
20
10
Placebo
(672 events)
0
Ivabradine
(514 events)
0
6
HR, 0.74; 95% Cl, 0.66–0.83; p<0.0001.
12
18
24
30
Months
Swedberg K, et al. Lancet 2010;376:875–885.
Swedberg K, et al. Lancet 2010;376:875–885.
SHIFT: cumulative event curves
Patients with CV death (%)
Patients withCV death (%)
40
20
10
Placebo
(491 events)
0
0
6
HR, 0.91; 95% Cl, 0.80–1.03; p=0.128.
12
18
24
30
Ivabradine
(449 events)
Months
Swedberg K, et al. Lancet 2010;376:875–885.
Swedberg K, et al. Lancet 2010;376:875–885.
SHIFT: Effect of treatment on primary
composite endpoint in prespecified subgroups
Ivabradine
group
Placebo
group
Hazard ratio (95% CI)*
Test for
interaction
Age
<65 years (n=4031)
≥65 years (n=2427)
407 (20.6%)
386 (30.5%)
527 (25.6%)
410 (33.9%)
0.76 (0.67–0.87)
0.89 (0.77–1.02)
p=0.099
Sex
Male (n=4970)
Female (n=1535)
624 (25.4%)
169 (21.7%)
725 (28.9%)
212 (28.0%)
0.84 (0.76–0.94)
0.74 (0.60–0.91)
p=0.260
101 (29.4%)
692 (23.9%)
134 (39.3%)
803 (27.5%)
0.68 (0.52–0.88)
0.85 (0.76–0.94)
p=0.103
218 (21.3%)
575 (26.0%)
296 (27.9%)
641 (29.1%)
0.72 (0.60–0.85)
0.87 (0.78–0.97)
p=0.059
NYHA class
NYHA class II (n=3169)
NYHA class III or IV (n=3334)
300 (18.9%)
493 (29.8%)
356 (22.5%)
580 (34.5%)
0.81 (0.69–0.94)
0.83 (0.74–0.94)
p=0.793
Diabetes
No history of diabetes (n=4526)
History of diabetes (n=1979)
525 (23.2%)
268 (27.5%)
611 (27.1%)
326 (32.4%)
0.83 (0.74–0.93)
0.81 (0.69–0.95)
p=0.861
Hypertension
No history of hypertension (n=2191)
History of hypertension (n=4314)
274 (25.4%)
519 (24.0%)
330 (29.7%)
607 (28.2%)
0.81 (0.69–0.95)
0.83 (0.74–0.93)
p=0.779
Baseline heart rate
<77 bpm (n=3144)
≥77 bpm (n=3357)
339 (21.4%)
454 (27.4%)
356 (22.8%)
581 (34.2%)
0.93 (0.80–1.08)
0.75 (0.67–0.85)
p=0.029
β blockers
No β-intake at randomization (n=685)
β-blocker intake at randomization
(n=5820)
Cause of HF
Non-ischemic (n=2087)
Ischemic (n=4418)
* 0.5–1.0, favors ivabradine; 1.0–1.5, favors placebo.
Swedberg K, et al. Lancet 2010;376:875–885.
SHIFT: Systolic Heart failure treatment
with the IF inhibitor ivabradine Trial SUMMARY Ivabradine, when added to guideline-based and evidence-based
treatment, substantially and significantly reduced the major risks
associated with HF.
The risk of the primary endpoint reduced by 18% with ivabradine,
which was primarily because of a beneficial effect on HF events that
became apparent within 3 months of initiating treatment.
Patients with heart rates higher than the median were at increased
risk of an event and experienced a greater reduction in events with
ivabradine than those with lower heart rates. This variation indicates
that the magnitude of benefit associated with ivabradine varies
directly with pretreatment heart rate.
Swedberg K, et al. Lancet 2010;376:875–885.