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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.

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slide1

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
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

slide3

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
slide4

3.5 years

Study design

Double-blind, placebo-controlled multinational study, 6505 patients

median study duration: 22.9 months

  • Heart rate 70 bpm
  • Sinus rhythm
  • Hospital admission for worsening HF 12 months
  • Class II to IV NYHA heart failure
  • Ischaemic/non-ischaemic aetiolgoy
  • LV systolic dysfunction (EF 35%)

Ivabradine 7.5/5/2.5 mg bid according to

Ivabradine 5 mg bid

HR and tolerability

Screening

7 to 30 days

Matching placebo, bid

Every 4 months

D0 D14 D28 M4

End of titration

Mod from Swedberg K, et al. Eur J Heart Fail. 2010;12:75-81.

mean heart rate reduction
Mean heart rate reduction

70% of patients on ivabradine 7.5 mg bid

Heart rate (bpm)

90

80

80

Placebo

75

75

70

67

Ivabradine

64

60

50

0

2 weeks

1

4

8

12

16

20

24

28

32

Months

Swedberg K, et al. Lancet. 2010;online August 29.

primary composite endpoint
Primary composite endpoint

Cumulative frequency (%)

40

HR = 0.82

P<0.0001

- 18%

30

20

10

Months

0

0

6

12

18

24

30

HR = 0.74

P<0.0001

30

20

10

0

0

6

12

18

24

30

Ivabradine effect on outcomes

Placebo

Ivabradine

Cardiovascular death

Hospitalization for heart failure

Cumulative frequency (%)

Cumulative frequency (%)

30

Placebo

HR = 0.91

P=0.128

- 26%

Placebo

20

Ivabradine

Ivabradine

10

Months

Months

0

0

6

12

18

24

30

Swedberg K, et al. Lancet. 2010;online August 29.

objective of current analysis
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
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
Baseline characteristics in population divided by quintiles of heart rate

*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 rate10
Baseline characteristics in population divided by quintiles of heart rate

*p value for interaction (chi-squared test for categorical variables, Kruskal-Wallis test for continuous variables)

slide11

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

Months

0

0

6

12

18

24

30

Primary composite endpoint: risk increases by 3% per 1bpm increase, and by 16% per 5bpm increase

Patients with first hospital admission for HF (%)

Patients with cardiovascular death (%)

50

50

P<0.001

40

40

≥87 bpm

P<0.001

30

≥87 bpm

30

80 to <87 bpm

75 to <80 bpm

80 to <87 bpm

20

20

72 to <75 bpm

75 to <80 bpm

70 to <72 bpm

72 to <75 bpm

70 to <72 bpm

10

10

Months

0

0

Months

0

6

12

18

24

30

0

6

12

18

24

30

relative risk of primary composite endpoint in the placebo group divided by quintiles of heart rate
Relative risk of primary composite endpoint in the placebo group divided by quintiles of heart rate

CV death

Primary composite endpoint

Heart rate atbaseline (bpm)

HR

HR

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

1.0

1.5

2.0

2.5

3.0

Death from HF

HF hospitalisation

Heart rate atbaseline (bpm)

HR

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

0.5

1.0

1.5

2.0

2.5

3.0

3.5

4.0

4.5

1.0

2.0

3.0

4.0

5.0

6.0

7.0

8.0

slide13

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

0

<60

60 to <65

65 to <70

70 to <75

<60

60 to <65

65 to <70

70 to <75

≥75

≥75

Heart rate achieved at day 28 (bpm)

Heart rate achieved at day 28 (bpm)

*Data exclude patients reaching primary composite endpoint in the first 28 days

slide14

50

40

30

20

10

0

0

Day 28

6

12

18

24

30

Primary composite endpoint according to heart rate achieved at D28* in the ivabradine group

Patients with primary composite endpoint (%)

≥75 bpm

70-<75 bpm

60-<65 bpm

65-<70 bpm

<60 bpm

Months

*Data exclude patients reaching primary composite endpoint in the first 28 days

slide15

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)

slide16

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

80 to<87

≥87

Heart rate at baseline (bpm)

slide17

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
slide18

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
slide19

Available now online from Lancet

http://www.lancet.com published online August 29, 2010 DOI:10.1016/S0140-6736(10)61259-7