12 th Annual Biomarkers in Heart Failure and Acute Coronary Syndromes: Diagnosis, Treatment and Devices. Heart Rate as a Cardiovascular Biomarker

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1 12 th Annual Biomarkers in Heart Failure and Acute Coronary Syndromes: Diagnosis, Treatment and Devices Heart Rate as a Cardiovascular Biomarker Inder Anand, MD, FRCP, D Phil (Oxon.) Professor of Medicine, University of Minnesota, VA Medical Centers, Minneapolis and San Diego, USA

2 Disclosure Information I have no disclosure to report related to this presentation I will not discuss the use of any off-label / Investigational, unapproved drugs or devices during this presentations

3 Resting Heart Rate and Life Expectancy Mouse Hamster Heart rate (bpm) Rat Marmot Monkey Cat Dog Giraffe Tiger Ass Elephant Horse Lion Whale Whale Man Life expectancy (years) Levine HJ, et al. J Am Coll Cardiol. 1997;30:

4 Number of Heart Beats/Lifetime for Each Species is Predetermined and Remarkably Constant Levine, HJ. JACC. 1997;30:

5 Resting Heart Rate and Life Expectancy Among mammals, there is an inverse semilogarithmic relation between heart rate and life expectancy Mammals have a lifetime number of heartbeats that is strikingly constant The faster the heart rate, the shorter the life; the slower the heart rate, the longer animals lives You re probably born with a certain number of heartbeats. Don t use them up too fast God has given each of us just so many heartbeats. The slower we play them out, the longer we live. Can human life be extended by cardiac slowing? Levine, HJ. JACC 1997;30:1104 6

6 Background In humans elevated heart rate is associated with poor long-term outcomes in the normal population and in a number of CV conditions including heart failure Heart rate remains elevated in many HF patients despite treatment with beta-blockers Can reducing heart rate alone improve outcomes in patients with HF?

7 Risk of Sudden Death Increases With Resting Heart Rate in the General Population The Paris Prospective Study (n=5713 men) Relative risk of sudden death from MI (%) P<0.001 < >75 Resting heart rate (bpm) Jouven X, et al., N Engl J Med. 2005;352:

8 The first evidence of the prognostic importance of heart rate: 1945 Mortality Rate per 1000 person-years Transient tachycardia + + Transient hypertension Age (years) Levy RL, et al. JAMA. 1945;129:

9 A high resting heart rate as an independent predictor of mortality in CAD patients The Coronary Artery Surgery Study (CASS) registry; CAD patients; 14.1-year follow-up Adjusted survival curves for overall mortality Adjusted survival curves for cardiovascular mortality Cumulative survival P< P< bpm bpm Years after enrolment Diaz A, et al. Eur Heart J. 2005;26: bpm

10 Hazard of All-cause Mortality for one SD increase in Heart Rate The Coronary Artery Surgery Study (CASS) registry; CAD patients; 14.1-year follow-up Diaz A, et al. Eur Heart J. 2005;26:

11 Resting Heart Rate and All-cause Mortality in HF and Post MI Patients DIAMOND study; 1518 patients with HF and 1510 patients post MI, 10 years follow up Mortality > 91 bpm bpm bpm bpm P< bpm é in HR was associated with 14% é increase in mortality in MI-patients (HR 1.14; 95%-CI: ; P<.0001) 10% é in mortality in HF-patients (HR, 1.10; CI: ; P<.0001) Years (Danish Investigations and Arrhythmia ON Dofetilide) Fosbol et al. Int J Cardiol, 2010;140:

12 Heart rate as a predictor of all-cause mortality in stable CAD patients The TNT study (n=9580) All cause-mortality (%) 0.14 Hazard ratio = 1.66 ( ) 0.12 P< Heart rate > 70 bpm Heart rate < 70 bpm Years Ho JE, et al. Am J Cardiol. 2010;105:

13 Higher Baseline Heart Rate is Associated with Higher Rates of HF Hospitalization Relationship between baseline resting heart rate and outcomes Retrospective analysis of the CHARM 4,576 patients with HFrEF Median baseline HR, bpm, (IQR) n = 1,414 n = 1,617 n = 1,545 P-value for trend 60 (58-64) 72 (70-76) 85 (70-76) <0.001 Hospitalizations for HF %, (n) 69.4% (981) 73.4% (1,186) 76.6% (1,183) <0.001 *CHARM = Candesartan in Heart Failure Assessment of Reduction in Mortality and Morbidity

14 Heart Rate as a Risk Factor In Patients with HFrEF The SHIFT placebo arm (n=3264) Patients with hosp. for worsening HF (%) Böhm M, et al. Lancet. 2010;376: P< bpm 80 to <87 bpm 75 to <80 bpm 72 to <75 bpm 70 to <72 bpm Months

15 One-year Mortality by Baseline Heart Rate The CIBIS-2 study (n=2539) One-year mortality (%) Bisoprolol Placebo Baseline HR 72 bpm Baseline HR bpm Baseline HR >84 bpm Lechat P, et al. Circulation. 2001;103:

16 Is Change in Heart rate Related to Change in Mortality and Morbidity

17 Reduction of Heart Rate and Outcomes Changes in mortality (%) in Cardiovascular Trials 60 PROFILE 40 XAMOTEROL 20 0 VHeFT (prazosin) PROMISE -20 CIBIS BHAT SOLVD VHeFT (HDZ/ISDN) NOR TIMOLOL MOCHA GESICA US CARVEDILOL ANZ CONSENSUS Changes in heart rate (bpm) Kjekshus J, et al. Eur Heart J. 1999;1(suppl.H):H64-H69.

18 Beta-blocker dose and heart rate reduction in chronic heart failure patients 23 trials in 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 McAlister FA, et al. Ann Intern Med. 2009;150:

19 Relation Between Magnitude of Heart Rate Reduction and Outcomes in 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 1 O Death Log Risk Ratio O O O -3 McAlister et al Ann Intern Med 2009;150: Heart Rate Reduction (beats/min)

20 Effect of change in heart rate and achieved heart rate on clinical outcomes in HF RRR mortality Annualized mortality r²= r²= Change in heart rate (bpm) Correlation of change in heart rate with RRR in all-cause mortality Heart rate achieved (bpm) Correlation of final achieved heart rate with annualized mortality Flannery G, et al. Am J Cardiol. 2008;101:

21 Change in Heart Rate and LVEF in Heart Failure Meta-regression of beta-blocker trials, n= Change in LVEF r²= Heart rate (bpm) Flannery et al. Am J Cardiol. 2008;101:

22 Effect of change in HR and achieved HR on clinical outcomes in HF Meta-regression of beta-blocker trials n= RRR mortality Annualized mortality r²= r²= Change in heart rate (bpm) Correlation of change in heart rate with RRR in all-cause mortality Heart rate achieved (bpm) Correlation of final achieved heart rate with annualized mortality in 9 betablockers trials Flannery G, et al. Am J Cardiol. 2008;101:

23 What is the optimal HR in patients with HFrEF?

24 All-cause Mortality Hazard in GISSI-HF (n = 6975) Heart rate by FC ECG all'ecg (incrementi increments di 10) of 10 bpm 3 2,5 2 HR 1,5 1 0,5 0 < >=130

25 How to define an optimal HR for CHF patients? CV death & HF hospitalization HF hospitalization 5 HR at D28 <60 bpm 60 - <65 bpm 65 to <70 bpm70 to <75 bpm 75 bpm Primary and secondary endpoints in the ivabradine group according to groups defined by HR achieved at 28 days Böhm M, et al. Lancet 2010; 376:

26 In Practice Heart Rate Remains High in Most Patients with HFrEF Receiving Standard of Care

27 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 Patients (%) HR 70 bpm HR >75 bpm HR >80 bpm *Courtesy of Prof Tavazzi **Courtesy of Prof Maggioni

28 Heart rate in patients with CHF everyday reality in 2010: Poland 2010: 5563 pts with systolic CHF (LVEF 45%) (3394 cardiologists, 2169 GPs/internists) NYHA II-III 84% ACEI 85%, ARB 17%, β-blockers 96% X±SD: 77±15 Median: 75bpm IQR: Rate of use % Dosage mg/day HR achieved (bpm) Carvedilol Bisoprolol Metoprolol Pts treated with 50% recommended β-bl dose median HR: 75 bpm; IQR: Pts treated with < 50% recommended β-bl dose median HR: 75 bpm; IQR: No correlation between resting HR and % recommended β-bl dose Jankowska EA & Ponikowski P Heart rate (bpm)

29 Heart Rate In Most Recent HF Trials

30 Heart Rate as a Predictor of Cardiovascular Outcomes Prospective data from the BEAUTIFUL Trial on 5438 patients with stable CAD and LVSD In placebo arm of Beautiful Trial, patients with HR >70 bpm compared with HR <70 bpm: 34% 53 % Fox et al Lancet 2008;372:

31 Can a Pure Heart Reducing Agent Added to Standard of Care Therapy Including Betablockers Improve Outcomes by Decreasing Heart Rate in Patients with HFrEF?

32 Systolic Heart failure treatment with the If inhibitor ivabradine Trial SHIFT tested the effects of heart rate reduction with ivabradine on outcomes in patients with HFrEF Swedberg K, et al. Lancet. 2010;376:

33 Ivabradine is a First-in-Class, HCN Channel Blocker that Lowers Heart Rate Pure heart rate reducing agent by blocking the HCN closed open closed channel reduces the pacemaker if current reduces RR the diastolic depolarization slope and slows the heart rate. No effect on myocardial contractility. At recommended doses, 0 mv -40 mv -70 mv Ivabrad ine Pure heart rate reducti on ivabradine heart rate by approximately 10 bpm.

34 Primary Objective To evaluate whether the I f inhibitor ivabradine improves cardiovascular outcomes in patients with: Moderate to severe chronic heart failure Left ventricular ejection fraction 35% Heart rate 70 bpm in sinus rhythm Best recommended therapy

35 Inclusion and Exclusion Criteria Swedberg K, et al. Eur J Heart Fail. 2010;12:75-81.

36 Study design Mortality-Morbidity Event-Driven trial of 6,505 patients with Chronic HF. Patients received Civabradine or Placebo in addition to SOC meds that included maximally tolerated doses of beta-blockers and in most cases, ACE inhibitors and/or ARBs, spironolactone, and diuretics Screening 7 to 30 days Ivabradine 5 mg bid Matching placebo, bid Ivabradine 7.5/5/2.5 mg bid according to HR and tolerability D0 D14 D28 M4 Every 4 months 3.5 years Swedberg K, et al. Lancet. 2010;376:

37 Swedberg K, et al. Eur J Heart Fail. 2010;12: Study Endpoints Primary composite end point Cardiovascular death Hospitalization for worsening heart failure Other end points All-cause / CV / HF death All-cause / CV / hospitalization for heart failure Composite of CV death, hospitalization for HF or nonfatal MI NYHA class / Patient & Physician Global Assessment

38 Swedberg K, et al. Lancet. 2010;376: Baseline Characteristics

39 Mean Heart Rate Reduction Heart rate (bpm) Placebo Ivabradine weeks Months Swedberg K, et al. Lancet. 2010;376:

40 Ivabradine Improved Outcomes Primary outcome CV death or hospitalization for HF HR = 0.82 p< Placebo - 18% HR = 0.74 p< Hospitalization for HF Placebo - 26% 20 Ivabradine Ivabradine ARR 4.2 NNT for 1 year = 24 ARR 4.7 NNT for 1 year = Months Months Swedberg K, et al. Lancet 2010;376:

41 Heart Rate Achieved on Treatment Predicted of Outcomes with Ivabradine Patients with CV death and hosp. for worsening HF (%) P< bpm 70-<75 bpm 60-<65 bpm 65-<70 bpm <60 bpm D Months Primary composite end point according to heart rate achieved at day 28 Böhm M, et al. Lancet. 2010;376:

42 Conclusions There is an inverse semi-logarithmic relation between heart rate and life expectancy in mammals. The faster the heart rate, the shorter the life; the slower the heart rate, the longer animals lives. In humans elevated heart rate is associated with poor long-term outcomes in the normal population and in a number of CV conditions including heart failure, suggesting a significant role of heart rate as a cardiovascular Biomarker. Heart rate remains elevated in many HF patients despite treatment with beta-blockers. SHIFT confirms the importance of HR in the pathophysiology of HF and supports the concept that reduction in HR contributes significantly to beneficial outcomes in patients with HF. HR is not only a risk factor but may well be a mediator of progression of HF