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Heart rate The Lower The Better

Heart rate The Lower The Better. HEART RATE. CONSIDERATIONS IN CARDIOVASCULAR DISEASE. Heart rate – new paradigm. per day: 80 x 60 min x 24 h = 115.200 beats per year: 42.048.000 beats 80 years: 3.363.840.000 beats ~300 mg ATP per beat ~ 30 kg ATP per day

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Heart rate The Lower The Better

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  1. Heart rateThe Lower The Better

  2. HEART RATE CONSIDERATIONS IN CARDIOVASCULAR DISEASE

  3. Heart rate – new paradigm per day: 80 x 60 min x 24 h = 115.200 beats per year: 42.048.000 beats 80 years: 3.363.840.000 beats ~300 mg ATP per beat ~ 30 kg ATP per day Heart Rate Reduction by 10 beats saves ~ 5 kg ATP per day Ferrari et al., Eur Heart J 2008, 10(Suppl) F7-10.

  4. Hypothesis • High heart rate adversely affects prognosis in health and disease • Treatment to reduce heart rate improves prognosis

  5. Detrimental effects of increased HR • Increased MVO21 • Reduced diastole/coronary flow1,6, • Decrease fibrillation threshold1 • Atherogenic effect2,3,4 • Plaque rupture5 • Induces cardiomyopathy1 • Decrease in LV ejection fraction • Decrease arterial compliance1 1) Kjekshus J, EHJ suppl 1999, 2) Yamamoto E, J Hypertens 2006;24 3) Perski, AHJ 1992, 4) Heidland, Circulation 2001, 5) Brown BG, Circulation 1993, 6)Heusch G, Yoshimoto N. Arc. 1983

  6. Life expectancy and heart rate in the animal kingdom • 40 fold difference in life expectancy • Number of heart beats / lifetime is constant (7.3 ± 5.6 x 108) • “life span is predetermined by basic energetics of living cells and heart rate is a main determinant of life [span]” Small animals must produce more heat (↑ Mass : BSA ratio). Thus higher metabolic rate and heart rate 1000 Levine JACC 1997 600 mouse hamster rat 300 Heart rate bpm monkey marmot cat dog 100 giraffe man tiger ass 50 horse lion elephant whale 20 whale 20 40 60 80 Life expectancy, yrs Levine JACC 1997

  7. HR : 6 beats/min HR : 600 beats/min Expected life duration : 177 years Expected life duration : 2 years Heart Rate and Life Duration Comparable number of heart beats across species during a lifetime

  8. Heart rate and myocardial oxygen consumption 20 20 20 DOG 4 DOG 6 DOG 5 Myocardial oxygen consumption (ml/min/100g) 10 10 10 0 0 0 100 200 100 200 100 200 0.1 0.1 0.1 DOG 4 DOG 6 DOG 5 Myocardial oxygen consumption (ml/beat/100g) 0.05 0.05 0.05 0 0 0 100 200 100 200 100 200 Heart rate (min-1) Tanaka et al., Jap J Physiol 40: 503-521, 1990

  9. Heart rate increase. Associated with: • Increase sympathetic tone • Poor fitness • Impaired ventricular function • Cluster of risk factors

  10. Heart rate increase - Detrimental effects • Increase MVO2 • Reduce diastole / (coronary flow) • Decrease fibrillation threshold • Atherogenic effect • Plaque rupture • Induces myocardiopathy • Other

  11. The British Regional Heart Study IHD major events • 7735 males 40-59 yrs • 8 year follow up • No pre-existing IHD • Strong association between resting HR and SCD and IHD (major events & mortality) IHD mortality 10 Sudden Cardiac Death 8 Age adjusted rate per 1000 per year 6 4 2 >60 60-69 70-79 80-89 >90 Heart rate (bpm) Shaper BHJ 1993

  12. 24.913 Men/women Suspected or proved CAD 14.7 y Follow-up CASS Eur Heart J 2005;26:967

  13. Increased heart rate shortens Life Mortality, from hospital discharge to 1 year n = 1807 Myocardial Infarction M & W 45 - 55 y 1 y Follow-up Hjalmarson A Am J Cardiol 1990;65:547

  14. Heart rate and atherosclerosis: angiographically visible collaterals Heart rate <60 beats/min P<0.05 Collaterals Heart rate >60 beats/min Patel et al., Coron Artery Dis11:467-472, 2000

  15. Heart rate and coronary plaque rupture Heidland and Strauer, Circulation 2001;104:1477

  16. Post-MI mortality and heart rate (n=1807) Maximum heart rate Final heart rate 50 50 40 40 30 30 Mortality (%) Mortality (%) 20 20 10 10 0 0 <50 5059 6069 7079 8089 9099 100109 110119 ≥120 <50 5059 6069 7079 8089 9099 ≥100 Heart Rate (bpm) Heart Rate (bpm) Hjalmarson et al, Am J Cardiol 1990;65: 547-553.

  17. Increased heart rate shortens Life GRACE 6 month Risk Score for ACS JAMA. 2004;291:2727

  18. Increased heart rate shortens Life HR at discharge an 6 months mortality Myocardial Infarction 6 months Follow-up % GISSI-3 Eur Heart J 1999;H52

  19. Relationship between Heart Rate and Heart Failure COMET Heart Rate after 4 months of treatment with Beta-blockers  68 bpm > 68 bpm All cause mortality Reduced risk Increased risk 0.50 0.75 1.00 1.25 1.50 Relative risk (95% CI) The benefits of Beta-Blocker therapy in Heart Failure patients are related to their ability to decrease Heart Rate Metra M, et al. Eur Heart J. 2005;26:2259-2268.

  20. CIBIS II One-year mortality (%) n=2539 18 16 14 12 10 8 6 4 Bisoprolol 2 Placebo 0 > 84 bpm 72 bpm 72 to 84 bpm Baseline Heart Rate Relationship between Heart Rate and Heart Failure Heart Failure patients with a higher baseline Heart Rate have a greater risk of dying CIBIS II. Lechat P, et al. Circulation. 2001;13:1428-1433.

  21. 1 O 0 Death Log Risk Ratio O -1 O -2 O -3 -20 -15 -10 -5 Heart Rate Reduction (beats/min) Meta analysis: BB dose, Heart Rate Reduction and Death in patients with Heart Failure Meta-regression of 23 beta-blocker HF trials involving 19,209 patients Mortality benefit was related to magnitude of HR reduction and not to the dose of BB. Pooled Mortality Hazard Ratio was 0.76 for an average HR Reduction 12 bpm McAlister et al Ann Intern Med 2009;150:784-794

  22. SystolicHeart Failure treatment with the IfInhibitor Procoralan Trial

  23. 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 Bohm M et al. The Lancet, published online August 29, 2010.

  24. 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 Bohm M et al. The Lancet, published online August 29, 2010.

  25. To evaluate whether theIf inhibitor ivabradine improves cardiovascular outcomes in patients with moderate to severe chronic heart failure, reduced left ventricular ejection fraction and heart rate  70 bpm receiving recommended therapy Swedberg K, et al. Lancet. 2010;online August 29.

  26. Primary composite endpoint according to heart rate achieved at D28* in the ivabradine group 50 40 30 20 10 0 0 Day 28 6 12 18 24 30 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 Bohm M et al. The Lancet, published online August 29, 2010.

  27. Ivabradine Placebo Ivabradine n=793 (14.5%PY) Placebo n=937 (17.7%PY) HR = 0.82 p<0.0001 Primary composite endpoint Cumulative frequency (%) 40 - 18% 30 20 10 NNT = 26 0 0 6 12 18 24 30 Months Swedberg K, et al. Lancet. 2010;online August 29.

  28. Ivabradine Placebo Hospitalization for heart failure Ivabradine n=514 (9.4%PY) Placebo n=672 (12.7%PY) HR = 0.74 p<0.0001 Cumulative frequency (%) 30 - 26% 20 10 NNT = 27 0 0 6 12 18 24 30 Months Swedberg K, et al. Lancet. 2010;online August 29.

  29. Death from heart failure Cumulative frequency (%) 10 HR = 0.74 (0.58–0.94) P = 0.014 Placebo 26% 5 Ivabradine 0 0 6 12 18 24 30 Months Swedberg K, et al. Lancet. 2010;online August 29.

  30. HF registries: more than 50% of patients have heart rate 70 bpm IMPACT RECO III 1407 patients HF OUTCOME 3480 patients ESC PILOT HF 2450 patients 54.6 55.6 53.4 Patients (%) 31 33.7 29.7 22.5 20.7 17.2 HR 70 bpm HR >75 bpm HR >80 bpm

  31. CV events are directly related to resting HRin patients with CAD and hypertension 60 4.5 Outcome (all-cause death, non fatal MI, or non fatal stroke) 60 4.5 4.0 Outcome (all-cause death, non-fatal MI, or nonfatal stroke) 50 4.0 Hazard ratio 3.5 50 Hazard ratio 3.5 40 3.0 40 3.0 Estimated hazard ratio 2.5 2.5 30 Adverse outcome incidence (%) Estimated hazard ratio 30 Adverse outcome incidence (%) 2.0 2.0 20 20 1.5 1.5 1.0 10 1.0 10 0.5 0.5 0 0 0 0 < 50 > 100 > 80 to < 85 > 50 to < 55 ≤ 50 > 90 to < 95 > 60 to < 65 > 65 to < 70 > 55 to < 60 > 75 to < 80 > 85 to < 90 > 100 > 70 to < 75 > 95 to < 100 > 85 to ≤ 90 > 50 to ≤ 55 > 65 to ≤ 70 > 80 to ≤ 85 > 70 to ≤ 75 > 75 to ≤ 80 > 60 to ≤ 65 > 55 to < 60 > 90 to ≤ 95 > 95 to ≤ 100 Mean follow-up heart rate (bpm) Mean follow-up heart rate (bpm) INVEST study, 22 192 CAD patients; 2.7-year follow-up Kolloch et al., Eur Heart J. 2008;29:1327-34.

  32. 1.0 0.9 0.8 0.7 0.6 0.5 ≤62 63-70 5 10 15 20 0 71-76 77-82 ≥83 bpm Epidemiologic Evidence Coronary Artery Disease Adjusted survival curves for overall mortality P<0.0001 • CASS registry • 24 913 CAD patients • 14.1-year follow-up Cumulative survival Years after enrolment Diaz A, et al. Eur Heart J 2005;26:967-974

  33. MorBidity-mortalityEvAlUation of The If inhibitor ivabradine in paients with CAD and left ventricULar dysfunction.

  34. 0 0.5 1 1.5 2 Heart rate as a predictor ofcardiovascular death 15 Hazard ratio = 1.34 (1.10 – 1.63) Heart rate ≥ 70 bpm P = 0.0041 10 % with cardiovascular death 5 Heart rate < 70 bpm 0 Years Analysis from the BEAUTIFUL placebo arm Fox K et al. Lancet 2008;372:779-780

  35. 0 0.5 1 1.5 2 Heart rate as a predictor ofhospitalization for MI 8 Hazard ratio = 1.46 (1.11 – 1.91) Heart rate ≥ 70 bpm P = 0.0066 6 % with hospitalization for fatal & non-fatal MI 4 Heart rate < 70 bpm 2 0 Years Analysis from the BEAUTIFUL placebo arm Fox K et al. Lancet 2008;372:779-780

  36. 0 0.5 1 1.5 2 Heart rate as a predictor ofhospitalization for HF 15 Hazard ratio = 1.53 (1.25 – 1.88) Heart rate ≥ 70 bpm P < 0.0001 10 % with hospitalization for fheart failure 5 Heart rate < 70 bpm 0 Years Analysis from the BEAUTIFUL placebo arm Fox K et al. Lancet 2008;372:779-780

  37. 0 0.5 1 1.5 2 Heart rate as a predictor ofcoronary revascularization 6 Hazard ratio = 1.38 (1.02 – 1.86) P = 0.037 Heart rate ≥ 70 bpm 4 % with coronary revascularization 2 Heart rate < 70 bpm 0 Years Analysis from the BEAUTIFUL placebo arm Fox K et al. Lancet 2008;372:779-780

  38. Epidemiologic Evidence Hypertension 60 CHD 50 CVD All cause 40 Age-adjusted 2-year rate per 1000 30 20 10 0 < 65 65-74 75-84 > 84 Heart Rate (bpm) Framingham Study Gillman MW, et al. Am Heart J 1993;125:1148

  39. Conclusions Heart rate is linked (epidemiologically) to long term outcomes in a variety of cardiovascular conditions. Heart rate is predictive of outcomes in ischaemic heart disease and in heart failure. Heart rate is a modifiable risk factor in ischaemic heart disease and in heart failure. It is important to be cognisant of heart rate in cardiac patients, and endeavor to lower the rate to below 70 bpm where possible. Ivabradine, on top of beta blocker therapy, gives additional benefit in cardiac patients with heart failure.

  40. Is heart rate a risk marker or a risk factor? • Positive association with total and/or cardiovascular mortality in 37 out of 39 studies. • Association independent of other risk factors for atherosclerosis or cardiovascular events. • Consistency similar to that for smoking. • Association present in different clinical settings and in subjects with or without co-morbidities. • Association present at all ages. • Association still present after exclusion of first years after baseline evaluation. • Association less consistent for women. Palatini P, et al. J Hypertension 2006;24:603-610

  41. The prognostic validity of resting heart rate • Are prognostic data consistent? Is heart rate an independent riskmarker/risk factor? • Is association valid in both genders, in elderly, in differentethnicities? • Can resting heart rate be used to assess risk in patients andpopulations with coronary artery disease? • Is heart rate related to known pathophysiologic mechanisms ofcoronary artery disease? • Is there evidence of clinical outcome benefit associated withheart rate reduction?

  42. Questions How applicable is this data to my everyday practice? Is treating to target beta-blocker dose the answer? Is it important how we lower the heart rate?

  43. Heart Rate Reduction - A Therapeutic Target • Heart rate and life expectancy - population studies • All cause mortality • Cardiovascular disease • Cancer • Age and gender effects • Heart rate and prognosis in established heart disease • Stable CAD • AMI • CCF • Diabetes • Heart rate reduction and prognosis: a new therapeutic target?

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