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Heart rate in heart failure:   risk marker or risk factor? A subanalysis of the SHIFT trial

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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Heart rate in heart failure:   risk marker or risk factor? A subanalysis of the SHIFT trial

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  1. 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

  2. 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

  3. 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

  4. 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.

  5. 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.

  6. 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.

  7. 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

  8. 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)

  9. 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)

  10. 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)

  11. 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

  12. 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

  13. 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

  14. 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

  15. 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)

  16. 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)

  17. 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

  18. 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

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

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