Heart rate in heart failure: risk marker or risk factor? A subanalysis of the SHIFT trial M. Böhm, B K. Swedberg, M. Komajda, J. Borer, I. Ford, L. Tavazzi on behalf of the Investigators
Heart rate and outcomes in HF: background Elevated resting heart rate is a marker of CV risk including in HF Ivabradine slows the heart by selective If current inhibition and has no known CV effects other than heart rate reduction SHIFT allows to further explore the prognostic importance and pathophysiological role of heart rate in HF We hypothesised that heart rate is a risk factor for CV events, and tested the effect of isolated HR reduction with ivabradine on outcomes in a HF population
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 (CV 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) 70 - <72 72 - <75 75 - <80 80 - <87 87 P value* 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) 70 - <72 72 - <75 75 - <80 80 - <87 87 P value* 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 50 40 30 20 Patients with primary composite endpoint (%) P<0.001 87 bpm 80 to <87 bpm 75 to <80 bpm 72 to <75 bpm 70 to <72 bpm 10 0 0 6 12 18 24 30 Months Primary composite endpoint: risk increases by 2.9% per 1-bpm increase, and by 15.6% per 5-bpm increase 50 40 Patients with first hospital admission for heart failure (%) P<0.001 87 bpm 50 40 Patients with cardiovascular death (%) P<0.001 30 20 10 80 to <87 bpm 75 to <80 bpm 72 to <75 bpm 70 to <72 bpm 30 20 10 87 bpm 80 to <87 bpm 75 to <80 bpm 72 to <75 bpm 70 to <72 bpm 0 0 6 12 18 24 30 Months 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 HR CV death 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 Heart rate at baseline (bpm) HR HF hospitalisation HR Death from HF 70 - <72 1.00 72 - <75 1.55 75 - <80 1.85 80 - <87 2.20 87 2.99 1.00 1.29 2.29 3.40 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
Primary composite endpoint according to heart rate achieved at D28* in the ivabradine group Patients with primary composite endpoint (%) 50 40 30 20 75 bpm 70-<75 bpm 60-<65 bpm 65-<70 bpm <60 bpm 10 0 0Day 28 6 12 18 24 30 Months *Data exclude patients reaching primary composite endpoint in the first 28 days
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) 59.3 60.3 62.4 66.1 72.9 Change 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 86.8 Change in heart rate (bpm) - 2.7-2.7-3.7-4.9-8.8
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 Heart rate at baseline (bpm) 87 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 Heart rate at baseline (bpm) 87
Conclusion Our results indicate that in HF 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