Heart rate in heart failure:  Heart rate in heart failure:  

risk marker or risk factor?risk marker or risk factor?A subanalysis of the SHIFT trialA subanalysis of the SHIFT trial

Heart rate in heart failure:  Heart rate in heart failure:  

risk marker or risk factor?risk marker or risk factor?A subanalysis of the SHIFT trialA subanalysis of the SHIFT trial

on behalf of the Investigators

on behalf of the Investigators

M. Böhm, K. Swedberg, M. Komajda, J. Borer,M. Böhm, K. Swedberg, M. Komajda, J. Borer, I. Ford, L. TavazziI. Ford, L. Tavazzi

M. Böhm, K. Swedberg, M. Komajda, J. Borer,M. Böhm, K. Swedberg, M. Komajda, J. Borer, I. Ford, L. TavazziI. Ford, L. Tavazzi

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

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

Heart rate and outcomes in HF: background

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

3.5 years

Screening 7 to 30 days

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%)

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

median study duration: 22.9 months

End of titrationEnd of titration

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

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.

HR = 0.82

P<0.0001

0 6 12 18 24 30Months

40

30

20

10

0

- 18%

Cumulative frequency (%)Cumulative frequency (%)Cumulative frequency (%)Cumulative frequency (%)

HR = 0.74

P<0.0001

0 6 12 18 24 30

30

20

10

0 Months

- 26%

Cumulative frequency (%)Cumulative frequency (%)Cumulative frequency (%)Cumulative frequency (%)

Primary composite endpoint

Hospitalization for heart failure

HR = 0.91

P=0.128

0 6 12 18 24 30Months

30

20

10

0

Cumulative frequency (%)Cumulative frequency (%)

Cardiovascular death

Ivabradine effect on outcomes

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

Placebo

Placebo

Placebo

Ivabradine

Ivabradine

Ivabradine

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

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

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

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) *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

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

50

40

30

20

10

00 6 12 18 24 30

Months

≥87 bpm

80 to <87 bpm

75 to <80 bpm

72 to <75 bpm70 to <72 bpm

P<0.001

Patients with primary composite endpoint (%)

50

40

30

20

10

00 6 12 18 24 30

Months

≥87 bpm

80 to <87 bpm

75 to <80 bpm

72 to <75 bpm

70 to <72 bpm

P<0.001

Patients with first hospital admission for HF (%)

≥87 bpm

80 to <87 bpm

75 to <80 bpm72 to <75 bpm70 to <72 bpm

50

40

30

20

10

00 6 12 18 24 30

Months

Patients with cardiovascular death (%)

P<0.001

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

1.0 2.0 3.00.5 1.5 2.5 3.5

70 - <72 1.00

72 - <75 1.15

75 - <80 1.33

80 - <87 1.80

≥ 87 2.34

Heart rate atbaseline (bpm) HR

1.0 2.0 3.00.5 1.5 2.5 3.5

70 - <72 1.00

72 - <75 1.55

75 - <80 1.85

80 - <87 2.20

≥ 87 2.99

Heart rate atbaseline (bpm) HR

4.0 4.5

1.0 2.0 3.00.5 1.5 2.5

1.00

0.87

1.03

1.64

1.85

HR

1.0

1.00

1.29

2.29

3.40

3.56

HR

2.0 3.0 4.0 5.0 6.0 7.0 8.0

Primary composite endpoint

HF hospitalisation

CV death

Death from HF

Distribution of patients by classes of heart rate achieved at D28*

Placebo Ivabradine

Heart rate achieved at day 28 (bpm)

50

40

30

20

10

070 to <7565 to <7060 to <65<60 ≥75

50

40

30

20

10

070 to <7565 to <7060 to <65<60 ≥75

Patients in heart rate group (%) Patients in heart rate group (%)

Heart rate achieved at day 28 (bpm)

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

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

ivabradine group

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

≥75 bpm

70-<75 bpm

60-<65 bpm65-<70 bpm

<60 bpm

Patients with primary composite endpoint (%)

Months0 6 12 18 24 30Day 28

50

40

30

20

10

0

Effect of ivabradine vs placebo according to heart rate at baseline (whole population)

At 28 days (ivabradine group)Heart rate (bpm) 59.3 60.3 62.4 66.1 72.9Change in heart rate (bpm) - 11.1 - 12.6 - 14.2 - 16.2 - 22.5

At 28 days (placebo group)Heart rate (bpm) 67.8 70.2 72.9 77.6 86.8Change in heart rate (bpm) - 2.7 - 2.7 - 3.7 - 4.9 - 8.8

HR and 95% CI for primary composite endpoint

1.8

1.6

1.4

1.2

1.0

0.8

0.6

≥8780 to <8775 to <8072 to <7570 to <72

Heart rate at baseline (bpm)

Effect of ivabradine vs placebo according to heart rate at baseline (whole population)

HR and 95% CI for cardiovascular death

≥8780 to<8775 to <8072 to <7570 to <72

1.81.61.41.21.00.80.6

HR and 95% CI for first hospital admission for heart failure

8780 to <8775 to <8072 to <7570 to <72

1.81.61.41.21.00.80.6

Heart rate at baseline (bpm)

Heart rate at baseline (bpm)

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

Conclusion

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

Clinical implications

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)61259-7