Is Heart Rate a Treatment Target?

Is Heart Rate a Treatment Target? M. Böhm Innere Medizin III (Kardiologie / Angiologie / Internistische Intensivmedizin) Universitätsklinikum des Saarlandes Homburg/Saar michael.boehm@uks.eu

Heart Rate New Paradigm per day: 8 x 6 min x 24 h = 115.2 beats per year: 42.48. beats 8 years: 3.363.84. beats ~3 mg ATP per beat ~ 3 kg ATP per day Heart Rate Reduction by 1 beats saves ~ 5 kg ATP per day Ferrari et al., EHJ 28, 1(Suppl) F7-1

Heart Rate (Beats /min) Life Expectancy and Heart Rate 1 5 3 1 5 2 Mouse Hamster Rat Marmot Monkey Cat Dog Giraffe Tiger Ass Horse Lion Elephant Whale Whale Man 5 1 15 2 25 3 Life Expectancy (Years) 35 4 8 1 Levine et al., J Am Coll Cardiol 1997; 3:114-6 CMR5-3

Life Expectancy and Total Number of Heart Beats Life Expectancy (Years) 1 5 3 1 5 2 Man Whale Whale Horse Elephant Lion Dog Cat Ass Monkey Giraffe Tiger Marmot Hamster Rat Mouse 1 2 1 4 1 6 1 8 1 1 1 12 Beats / Lifetime Levine et al., J Am Coll Cardiol 1997; 3:114-6 CMR5-2

SURVIVORS (%) Can We Increase Life Span by Heart Rate Reduction? Digoxin treatment and life span in mice 1 9 8 7 6 Untreated (74) 5% = 7 Days Treated (136) 5% = 85 Days 5 4 3 2 1 1 2 3 4 5 6 7 8 9 1 11 12 Days after experiment began Coburn et al., Hopkins Med J 197;128:169-193

Cardioprotective Effects of Heart Rate Reduction Epidemiology or Observational Chronic heart failure tachycardiomyopathy oxygen demand ventricular efficiency ventricular relaxation Microalbuminuria Comorbidities Heart Rate Remodeling Atherosclerosis cardiac hypertophy Risk Marker Ischemia oxidative stress plaque stability arterial stiffness oxygen consumption diastole length coronary perfusion Reil and Böhm Lancet 372: 779-78, 28

Cardioprotective Effects of Heart Rate Reduction Epidemiology Chronic heart failure tachycardiomyopathy oxygen demand ventricular efficiency ventricular relaxation Microalbuminuria Comorbidities Heart Rate Remodeling Atherosclerosis cardiac hypertophy Risk Marker Ischemia oxidative stress plaque stability arterial stiffness oxygen consumption diastole length coronary perfusion Treatment Events? Heart rate Inhibition I f - Channel Risk Factor Ivabradine Reil and Böhm Lancet 372: 779-78, 28

Change in diastolic tension (mn)/ developed tension (mn) Human Papillary Muscle Strips Contraction Relaxation 2 1.8.6.4 NYHA IV NF -1-2 NF NYHA IV.5 1. 1.5 2. 2.5 3. Frequency (Hz).2. 1 2 3 Frequency (Hz) Böhm et al., Clin Invest, 1992 HPMS.ppt

Pacing-Modulated Heart Rate and O 2 -Uptake with (1) and without (2) Heart Failure 4. VO 2 [l/min] Exercise End 1 End 2 HF [bpm] 2 3 2 7 85 HR 9 1 12 15 11 normal (2) 13 14 15 16 normal (2) 15 1 1. VO 2 5 1 2 3 4 5 6 7 8 9 1 11 12 13 14 15 Kindermann et al., Eur Heart J (22)

Pacing-Modulated Heart Rate and O 2 -Uptake with (1) and without (2) Heart Failure 4. VO 2 [l/min] Exercise End 1 End 2 HF [bpm] 2 3 2 7 85 HR 9 1 HF (#1) 12 15 11 normal (2) 13 14 15 16 HF normal (2) 15 1 1. VO 2 HF(1) 5 1 2 3 4 5 6 7 8 9 1 11 12 13 14 15 Kindermann et al., Eur Heart J (22)

Resting heart rate and mortality in heart failure post MI patients Mortality 1..8 DIAMOND study; 1518 patients with HF post MI, 1 years follow up > 91 bpm 81-91 bpm 71-8 bpm 4-7 bpm.6.4.2. P<.1 2 4 6 8 1 Years Fosbol EL, et al. Int J Cardiol. 21;14:279-286. AS-be12-11

Chronic Heart Failure - Therapy NYHA I NYHA II NYHA III NYHA IV key: neurohormonal blockade Exercise HTx, LVAD Digitalis (bei VF) Diuretika Aldosteron-Antag Beta-Blocker ACE-hemmer / ARB CRT / ICD AS-br3-119

Effect of change in heart rate and achieved heart rate on clinical outcomes in HF Meta-regression of beta-blocker trials n=19 537 RRR mortality Annualized mortality.2.6.15 r²=.41.4.1.2.5 r²=.53-12 -1-8 -6-4 -2 6 7 8 9 Change in heart rate (bpm) Correlation of change in HR with relative risk reduction (RRR) in all-cause mortality Heart rate achieved (bpm) Correlation of final achieved HR with annualized mortality in 9 beta-blocker trials in 19 537 patients Flannery G, et al. Am J Cardiol. 28;11:865-869. AS-be15-11

Beta-blocker dose and heart rate reduction in chronic HF patients 23 trials in 19 29 HF patients with beta-blocker (mean EF=17%-36%) Results of 13 univariable meta-regressions evaluating the effect of individual covariates on mortality benefits of beta-blockers in heart failure AS-as44-81 McAlister et al. Ann Intern Med. 29;15:784-794.

Study design Screening 7 to 3 days Ivabradine 5 mg bid Matching placebo, bid Ivabradine 7.5/5/2.5 mg bid according to HR and tolerability D D14 D28 M4 Every 4 months 3.5 years Swedberg K, et al. Eur J Heart Fail. 21;12:75-81. AS-be35-11

Mean heart rate reduction Heart rate (bpm) 9 8 7 6 8 Mean ivabradine dose: 6.4 mg bid at 1 month Ivabradine Placebo 75 64 6.5 mg bid at 1 year 75 67 5 2 weeks 1 4 8 12 16 2 24 28 32 Months Swedberg et al, Lancet 376 (21): 875-885

Primary composite endpoint Cumulative frequency (%) 4 3 Ivabradine n=793 (14.5%PY) Placebo n=937 (17.7%PY) Ivabradine Placebo HR =.82 p<.1-18% 2 1 6 12 18 24 3 Months Lancet. Online 29-8-21 Swedberg et al, Lancet 376 (21): 875-885 AS-ab18-71

Cardiovascular death Cumulative frequency (%) 3 Ivabradine n=449 (7.5%PY) Placebo n=491 (8.3%PY) Ivabradine Placebo HR =.91 p=.128 2 1 6 12 18 24 3 Months Lancet. Online 29-8-21 Swedberg et al, Lancet 376 (21): 875-885

Hospitalization for heart failure Cumulative frequency (%) 3 Ivabradine n=514 (9.4%PY) Placebo n=672 (12.7%PY) Ivabradine Placebo HR =.74 p<.1-26% 2 1 NNT=27 (annualized) 6 12 18 24 3 Months Swedberg et al, Lancet 376 (21): 875-885

Death from heart failure Cumulative frequency (%) 1 Ivabradine Placebo Ivabradine n=113 (1.9% PY) Placebo n=151 (2.6% PY) HR =.74 [95% CI=.58;.94] p=.14 5-26% 6 12 18 24 3 Time from randomisation (months)

Effect of ivabradine on outcomes Endpoints Hazard ratio 95% CI p value Primary composite endpoint.82 [.75;.9] p<.1 CV death.91 [.8;1.3] p=.128 Hospitalization for HF.74 [.66;.83] p<.1 All-cause death.9 [.8;1.2] p=.92 Death from HF.74 [.58;.94] p=.14 Hospitalization for any cause.89 [.82;.96] p=.3 Hospitalization for CV reason.85 [.78;.92] p=.2 Swedberg et al, Lancet 376 (21): 875-885

Effect of ivabradine in prespecified subgroups Age <65 years 65 years Sex Male Female Beta-blockers No Yes Aetiology of heart failure Non-ischaemic Ischaemic NYHA class NYHA class II NYHA class III or IV Diabetes No Yes Hypertension No Yes Baseline heart rate <77 bpm 77 bpm Test for interaction p=.29 Lancet. Online 29-8-21.5 1. Hazard ratio Favours ivabradine Swedberg et al, Lancet 376 (21): 875-885 Favours placebo 1.5

Baseline heart rate is a predictor of endpoints on placebo 5 4 The Slower the Better? Patients with primary composite endpoint (%) P<.1 87 bpm 8 to <87 bpm 3 2 75 to <8 bpm 72 to <75 bpm 7 to <72 bpm 1 6 12 18 24 3 Months Primary composite endpoint: risk increases by 2.9% per 1-bpm increase, and by 15.6% per 5-bpm increase 5 4 Patients with first hospital admission for heart failure (%) P<.1 87 bpm 5 4 Patients with cardiovascular death (%) P<.1 3 2 1 8 to <87 bpm 75 to <8 bpm 72 to <75 bpm 7 to <72 bpm 3 2 1 87 bpm 8 to <87 bpm 75 to <8 bpm 72 to <75 bpm 7 to <72 bpm 6 12 18 24 3 Months 6 12 18 24 3 Months Böhm et al, Lancet 376 (21): 886-894

Böhm et al, Lancet 376 (21): 886-894 AS-aq13-81 The Slower the Better? Distribution of patients by classes of heart rate achieved at D28* Placebo Ivabradine Patients in heart rate group (%) Patients in heart rate group (%) 5 5 4 4 3 3 2 2 1 1 <6 6 to <65 65 to <7 7 to <75 75 <6 6 to <65 65 to <7 7 to <75 75 Heart rate achieved at day 28 (bpm) Heart rate achieved at day 28 (bpm)

Primary composite endpoint according to heart rate achieved at D28* in the ivabradine group Patients with primary composite endpoint (%) 5 The Slower the Better? 4 3 2 75 bpm 7-<75 bpm 6-<65 bpm 65-<7 bpm <6 bpm 1 Day 28 6 12 18 24 3 Months Böhm et al, Lancet 376 (21): 886-894

Primary composite endpoint according to heart rate achieved at D28* in the ivabradine group Patients with primary composite endpoint (%) 5 4 3 2 75 bpm 7-<75 bpm 6-<65 bpm 65-<7 bpm <6 bpm 1 Day 28 6 12 18 24 3 Months Before Adjustment for Change in Heart Rate at 28 Days: HR.82,.75.87, p =.1 Böhm et al, Lancet 376 (21): 886-894

AS-ar38-81 Do HF patients frequently have heart rate 7 bpm?

Patients (%) HF registries: more than 5% of patients have heart rate 7 bpm IMPACT RECO III 147 patients HF OUTCOME* 348 patients ESC PILOT HF** 245 patients 54.6 53.4 55.6 31 29.7 33.7 22.5 17.2 2.7 HR 7 bpm HR >75 bpm HR >8 bpm AS-ar39-81 *Courtesy of Prof Tavazzi **Courtesy of Prof Maggioni

Heart rate in European surveys: beta-blocker therapy Beta-blocker (%) 9 8 7 6 5 4 HF OUTCOME* ESC HF PILOT** Beta-blocker (%) 1 8 6 4 3 2 2 1 HR 7 bpm HR >75 bpm HR >8 bpm AS-ar4-81 *Courtesy of Prof Tavazzi **Courtesy of Prof Maggioni

Chronic HF background treatment Patients (%) 1 9 89 9 91 91 84 83 8 7 6 61 6 Ivabradine Placebo 5 4 3 2 22 22 1 Beta-blockers ACEIs and/or ARBs Diuretics Aldosterone antagonists Digitalis 3 4 ICD/CRT Lancet. Online 29-8-21 Swedberg et al, Lancet 376 (21): 875-885

Is Heart Rate a Treatment Target? Yes! Chronic heart failure tachycardiomyopathy oxygen demand ventricular efficiency ventricular relaxation Trial Programme: Microalbuminuria Comorbidities Heart Rate Remodeling Atherosclerosis cardiac hypertophy Ischemia But: Renal Disease, Stroke, HFPEF, Vascular Comorbidities oxidative stress plaque stability arterial stiffness oxygen consumption diastole length coronary perfusion

Thank You! M. Böhm Innere Medizin III (Kardiologie / Angiologie / Internistische Intensivmedizin) Universitätsklinikum des Saarlandes Homburg/Saar