Transcript PROCORALAN - Landmarktrials

Heart rate in heart failure:
risk marker or risk factor?
A subanalysis of the SHIFT trial
M. Böhm, K. Swedberg, M. Komajda, J. Borer,
I. Ford, L. Tavazzi
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
Heart rate and outcomes in HF:
background
 Elevated resting heart rate is a marker of cardiovascular risk
 Ivabradine slows the heart by selective If current inhibition
and has no known cardiovascular effects other than heart
rate reduction
 SHIFT allows to further explore the prognostic importance
and pathophysiological role of heart rate in heart failure
 We hypothesised that heart rate is a risk factor for
cardiovascular events, and tested the effect of isolated heart
rate reduction with ivabradine on outcomes in a heart failure
population
Study design
Double-blind, placebo-controlled multinational study, 6505 patients
median study duration: 22.9 months

Class II to IV NYHA heart failure

Heart rate 70 bpm

Ischaemic/non-ischaemic aetiolgoy

Sinus rhythm

LV systolic dysfunction (EF 35%)

Hospital admission for worsening HF 12 months
Ivabradine 5 mg bid
Screening
7 to 30 days
Ivabradine 7.5/5/2.5 mg bid according to
HR and tolerability
Matching placebo, bid
D0
D14
D28
End of titration
Mod from Swedberg K, et al. Eur J Heart Fail. 2010;12:75-81.
3.5 years
M4
Every 4 months
Mean heart rate reduction
Heart rate (bpm)
70% of patients on ivabradine 7.5 mg bid
90
80
80
Placebo
75
75
70
67
64
60
Ivabradine
50
0
2 weeks
1
4
8
12
16
Months
Swedberg K, et al. Lancet. 2010;online August 29.
20
24
28
32
Ivabradine effect on outcomes
Primary composite endpoint
Cumulative frequency (%)
40
Placebo
HR = 0.82
P<0.0001
30
- 18%
Ivabradine
20
10
Months
0
0
6
12
18
24
Cardiovascular death
Hospitalization for heart failure
Cumulative frequency (%)
Cumulative frequency (%)
30
HR = 0.74
P<0.0001
30
30
Placebo
HR = 0.91
P=0.128
- 26%
Placebo
20
20
Ivabradine
Ivabradine
10
10
Months
0
0
6
12
18
24
Swedberg K, et al. Lancet. 2010;online August 29.
30
Months
0
0
6
12
18
24
30
Objective of current analysis
To determine whether heart rate at baseline and
on heart rate-lowering treatment with
ivabradine can predict outcomes in SHIFT
patients with HF and systolic dysfunction
Methods
 The relationship between risk and heart rate was tested in the placebo group
divided by quintiles of baseline heart rate
 Heart rate achieved at 28 days by ivabradine (end of titration) was related
to subsequent outcomes
 The effect of ivabradine on outcomes, adjusted for prognostic factors at
baseline, was estimated by heart rate quintiles
 Outcomes analysed:
– primary composite endpoint (cardiovascular death and HF hospitalisation)
– secondary endpoints (all-cause / CV / death from HF; all-cause / CV / HF
hospitalisation; composite of CV death, hospitalisation for HF or non-fatal MI)
Baseline characteristics in population
divided by quintiles of heart rate
Heart rate at baseline (bpm)
P value*
70 - <72
72 - <75
75 - <80
80 - <87
≥87
Heart rate (bpm)
70
73
77
82
96
-
Age (years)
63
61
60
60
58
<0.0001
Caucasian (%)
89
92
89
87
86
0.0009
Smoking (%)
15
14
16
18
23
<0.0001
Ischaemic cause of HF
(%)
74
71
68
67
61
<0.0001
NYHA class III/IV (%)
48
48
47
52
61
<0.0001
Hypertension (%)
69
70
66
66
62
0.0007
Diabetes (%)
26
30
30
32
33
0.008
*p value for interaction (chi-squared test for categorical variables, Kruskal-Wallis test for continuous variables)
Baseline characteristics in population
divided by quintiles of heart rate
Heart rate at baseline (bpm)
P value*
70 - <72 72 - <75 75 - <80
80 - <87
≥ 87
SBP (mm Hg), mean
122
122
122
122
120
0.006
DBP (mm Hg), mean
75
76
76
76
76
0.027
LVEF (%), mean
30
30
29
29
28
<0.0001
Beta-blockers (%)
93
92
92
88
82
<0.0001
ACE inhibitors (%)
81
81
81
76
75
0.0001
Diuretics (%)
82
82
82
85
86
0.004
Aldosterone antagonists
(%)
56
59
59
61
65
0.0001
Cardiac glycosides (%)
18
18
21
23
28
<0.0001
*p value for interaction (chi-squared test for categorical variables, Kruskal-Wallis test for continuous variables)
Baseline heart rate is a predictor of
endpoints on placebo
Patients with primary composite endpoint (%)
50
≥87 bpm
P<0.001
40
80 to <87 bpm
75 to <80 bpm
30
72 to <75 bpm
70 to <72 bpm
20
10
0
Months
0
6
12
18
24
30
Primary composite endpoint: risk increases by 3% per 1bpm increase, and by 16% per 5bpm increase
50
40
Patients with first hospital admission for HF (%)
50
Patients with cardiovascular death (%)
≥87 bpm
40
P<0.001
P<0.001
30
80 to <87 bpm
75 to <80 bpm
72 to <75 bpm
20
≥87 bpm
30
80 to <87 bpm
20
75 to <80 bpm
72 to <75 bpm
70 to <72 bpm
70 to <72 bpm
10
10
0
Months
0
6
12
18
24
30
0
0
6
12
18
24
30
Months
Relative risk of primary composite endpoint in the
placebo group divided by quintiles of heart rate
Heart rate at
baseline (bpm)
HR
Primary composite endpoint
70 - <72
1.00
1.00
72 - <75
1.15
0.87
75 - <80
1.33
1.03
80 - <87
1.80
1.64
≥ 87
2.34
1.85
0.5
1.0 1.5
2.0
2.5
3.0 3.5
0.5
Heart rate at
baseline (bpm)
HR
70 - <72
1.00
1.00
72 - <75
1.55
1.29
75 - <80
1.85
2.29
80 - <87
2.20
3.40
≥ 87
2.99
3.56
HF hospitalisation
0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0 4.5
CV death
HR
HR
1.0
1.5
2.0
2.5
3.0
Death from HF
1.0 2.0 3.0 4.0 5.0 6.0 7.0 8.0
Distribution of patients by classes of heart
rate achieved at D28*
Ivabradine
Placebo
Patients in heart rate group (%)
Patients in heart rate group (%)
50
50
40
40
30
30
20
20
10
10
0
<60
60 to <65
65 to <70
70 to <75
Heart rate achieved at day 28 (bpm)
≥75
0
<60
60 to <65
65 to <70
70 to <75
Heart rate achieved at day 28 (bpm)
*Data exclude patients reaching primary composite endpoint in the first 28 days
≥75
Primary composite endpoint according to
heart rate achieved at D28* in the
ivabradine group
Patients with primary composite endpoint (%)
50
40
≥75 bpm
70-<75 bpm
30
60-<65 bpm
65-<70 bpm
<60 bpm
20
10
0
0 Day 28
6
12
18
24
30
*Data exclude patients reaching primary composite endpoint in the first 28 days
Months
Effect of ivabradine vs placebo according
to heart rate at baseline (whole population)
HR and 95% CI for primary composite endpoint
1.8
1.6
1.4
1.2
1.0
0.8
0.6
70 to <72
72 to <75
75 to <80
80 to <87
≥87
Heart rate at baseline (bpm)
At 28 days (ivabradine group)
Heart rate (bpm)
Change in heart rate (bpm)
59.3
- 11.1
60.3
- 12.6
62.4
- 14.2
66.1
- 16.2
72.9
- 22.5
At 28 days (placebo group)
Heart rate (bpm)
Change in heart rate (bpm)
67.8
- 2.7
70.2
- 2.7
72.9
- 3.7
77.6
- 4.9
86.8
- 8.8
Effect of ivabradine vs placebo according
to heart rate at baseline (whole population)
HR and 95% CI for first hospital admission for heart failure
1.8
1.6
1.4
1.2
1.0
0.8
0.6
70 to <72
72 to <75
75 to <80
80 to <87
87
Heart rate at baseline (bpm)
HR and 95% CI for cardiovascular death
1.8
1.6
1.4
1.2
1.0
0.8
0.6
70 to <72
72 to <75
75 to <80
Heart rate at baseline (bpm)
80 to<87
≥87
Conclusion
 Our results indicate that in heart failure patients in sinus
rhythm and heart rate ≥70 bpm, there is a positive
continuous relationship between baseline heart rate and
increased risk
 The risk is modified and significantly decreased by
ivabradine, and the effect is related to heart rate at baseline
and heart rate achieved at 28 days
 Patients with lowest heart rates on treatment with ivabradine
have the best outcomes
Clinical implications
 Elevated heart rate is a risk factor in HF
 Heart rate is an important target for therapy in HF
 Shifting patients to lower heart rate profiles with ivabradine
reduces CV events
 Lower heart rates at baseline and lower heart rates achieved
on treatment are associated with better outcomes,
with incremental benefit by achieving heart rate ≤60 bpm
when tolerated
Available now online from Lancet
http://www.lancet.com published online August 29, 2010
DOI:10.1016/S0140-6736(10)61259-7