Heart rate lowering treatment in chronic heart failure

Transcription

1 Heart rate lowering treatment in chronic heart failure Jaromir Hradec 3rd Dept. Med., Charles Univ., Prague Czech Republic Things we knew, things we did Things we have learnt, things we should do

2 What I will talk about? 1. Higher resting heart rate (HR) in chronic heart failure is a marker of worse prognosis 2. Pharmacological lowering of increased HR in heart failure decreases both, morbidity and mortality 3. What is the target value for HR in heart failure? 4. What to use to lower HR? 2

3 What I will talk about? 1. Higher resting heart rate (HR) in chronic heart failure is a marker of worse prognosis 2. Pharmacological lowering of increased HR in heart failure decreases both, morbidity and mortality 3. What is the target value of HR in heart failure? 4. What to use to lower HR? 3

4 4 CV mortality (%) MI hospitalizations (%) Heart rate as a predictor of CV events placebo arm (n = 5438) HR = 1.34 ( ) p = HR 70/min SF < 70/min 0 0 0,5 1 1,5 2 Years 8 HR = 1.46 ( ) p = HR 70/min 4 0 HR < 70/min 0 0,5 1 1,5 2 Years HF hospitalizatins (%) Coron. revascular. (%) Fox K., et al. Lancet 2008;372: HR = 1.53 ( ) p < HR 70/min HR < 70/min 0 0 0,5 1 1,5 2 6 Years HR = 1.38 ( ) p = HR 70/min 4 2 HR < 70/min 0 0,5 1 1,5 2 Years

5 Baseline HR is predictor of CV events in the placebo arm P<.,001 Primary combined endpoint (%) 87 /min 80 to <87 /min to <80 /min 72 to <75 /min 70 to <72 /min Months Primary combined endpoint: every increase of HR by 1 beat/min. leads to risk increase by 3%, every increase of HR by 5 beats/min. leads to risk increase by 16% HF hospitalizations (%) 50 Cardiovascular mortality (%) 40 P< /min 40 P< to <87 /min 75 to <80 /min 72 to <75 /min 70 to <72 /min /min 80 to <87 /min 75 to <80 /min 72 to <75 /min 70 to <72 /min Months Months

6 What I will talk about? 1. Higher resting heart rate (HR) in chronic heart failure is a marker of worse prognosis 2. Pharmacological lowering of increased HR in heart failure decreases both, morbidity and mortality 3. What is the target value of HR? 4. What to use to lower HR? 6

7 HR lowerig by betablockers decreases cardiovascular mortality in patients post MI Meta-regression analysis of 2 randomized controlled trials p< HR (beats/min) Every HR drop by 10 beats/min = cardiovascular mortality decrease by 26 % 7 Cucherat M et al. Eur Heart J. 2006, 27(Abstract Suppl):590

8 HR lowerig by betablockers decreases cardiovascular mortality in patients with chronic heart failure Meta-regression analysis of 23 RCTs with BB in chronic heart failure (n= pts): Mortality change was dependent on the HR drop magnitude, not on the dose of BB. Resulting HR for deaths from any cause was 0,76 by every HF drop by 12 beats/min. 1 O Log RR for deaths O O O -3 8 McAlister et al Ann Intern Med 2009;150: Heart rate lowering (beats/min)

9 Ivabradine effect on primary composite EP (total population) Ivabradine effect on primary composite EP (HR 70 /min) Ivabradine effect on MI hospitalizations (HR 70/min) Ivabradine effect on coronary revascularizations (HR 70 /min) 9 Fox K, et al. Lancet 2008;372:

10 Ivabradine effect on CV events rate Cumulative rate (%) HR = 0,82 P<0,0001 Primary composite endpoint Placebo - 18% 20 Ivabradine 10 Cumulative rate (%) HR = 0,74 P<0,0001 HF hospitalization 0 Months Placebo - 26% Ivabradine Cardiovascular death Cumulative rate(%) HR = 0,91 P=0,128 Placebo Ivabradine 10 0 Months Swedberg K, et al. Lancet. 2010;online August Months

11 Ivabradine effect on other endpoints Endpoints Hazard ratio 95% CI p value Primary composite endpoint 0.82 [0.75;0.90] p< CV mortality 0.91 [0.80;1.3] p=0.128 Heart failure hospitalizations 0.74 [0.66;0.83] p< Total mortality 0.90 [0.80;1.02] p=0.92 Heart failure mortality 0.74 [0.58;0.94] p=0.014 All hospitalizations 0.89 [0.82;0.96] p=0.003 CV hospitalizations 0.85 [0.78;0.92] p= Swedberg K, et al. Lancet. 2010;online August 29.

12 Ivabradine effect in subgroup of patients with HR > 75 beats/min Rate of the primary composite endpoint was decreased by 24 % (HR = 0.76; 95% CI = ; p<0.0001) Total mortality was decreased by 17 % (HR = 0.83; 95% CI = ; p = ) CV mortality was decreased by 17 %; p = ) Safety profile of ivabradine in this subgroup was comparable to that in total Shift population 12

13 What I will talk about? 1. Higher resting heart rate (HR) in chronic heart failure is a marker of worse prognosis 2. Pharmacological lowering of increased HR in heart failure decreases both, morbidity and mortality 3. What is the target value of HR in heart failure? 4. What to use to lower HR? 13

14 Rate of primary composite endpoint according to HR reached on the 28. day of ivabradine treatment Patients with primary composite endpoint (%) Day P < /min 70-<75 /min 60-<65 /min 65-<70 /min <60 /min Months 14 Böhm et al, Lancet, 2010;376:

15 What I will talk about? 1. Higher resting heart rate (HR) in chronic heart failure is a marker of worse prognosis 2. Pharmacological lowering of increased HR in heart failure decreases both, morbidity and mortality 3. What is the target value of HR in heart failure? 4. What to use to lower HR? 15

16 Differences in effects of betablockers and ivabradine CV effect Chronotropy betablockers Negative ivabradine Negative Inotropy Negative No effect Lusitropy Dromotropy Bathmotropy Negative Negative Negative No effect No effect No effect Neurohum. activation Decrease No effect 16

17 Ivabradine preserves coronary vasodilatation on exercise Coronary artery diameter Change vs. baseline (%) phys. sol. 2 0 ivabradine betablocker -8 Baseline On exercise ST 5 ST 10 ST 12 * p<0.01 vs. propranolol ** p<0.01 vs. phys. sol. 17 Simon L, et al. J Pharmacol Exp Ther. 1995;275: Km/h

18 NORADRENALINE β α Coronary dilatation Coronary constriction 18

19 In comparison to betablockers ivabradine does not prevent coronary flow to increase on exercise Mean coronary flow (ml/min) At the same heart rate Resting ivabradine atenolol p<0.05 vs. ivabradine On exercise 19 Colin P et al. Am J Physiol 2003;284:H676-82

20 Effect of ivabradine in prespecified patient subgroups Primary endpoint (CV mortality/hf hospitalizations) Interakce mezi skupinami -32% 20 Swedberg K, et al. Lancet 2010; 376: Ivabradine benefit Placebo benefit

21 EURO HEART Survey Mean baseline resting HR Total CAD population (n = 3674), patients treated with betablockers (n= 2005) 60 Total CAD population Pts. treated with betablockers > 70 HR (beats/min) 21

22 CARVIVA HF Study Effect of Carvedilol, Ivabradine or their combination on exercise capacity in patients with Heart Failure Ivabradine, up to 7.5 mg bid (n = 41) Carvedilol, up to 25 mg bid (n = 38) - Discontinuation of beta-blocker - Uptitration of ACE inhibitors End optimisation of background Rx Carvediolol/ivabradine, up to 12.5/5 mg bid (n = 42) Time (weeks) 12 Screening Baseline Randomisation End of study - Incl./excl. criteria -Clinical evaluation -6-MWT - 6-MWT -6-MWT - MVO2 -MVO2 - Quality of life - Echocardiography - ECG - Laboratory parameters End of uptitration Study type: prospective, randomised, open, blinded endpoint (PROBE) - 6-MWT - Exercise test - Quality of life - Echocardiography - ECG - Laboratory parameters 22 Volterrani M et al. Int J Card 2011

23 CARVIVA HF Effect of treatment on exercise tolerance % change vs. baseline value * Exercise tolerance (MVO2) * * * 6min walk test 23 Carvedilol Ivabradine Ivabradine + Carvedilol *p<0.01 vs. baseline; p<0.01; p<0.02 vs. carvedilol Volterrani M et al. Int J Card 2011

24 To take home messages 1. Increased resting HR (> 70/min) is an independent risk factor in chronic heart failure. 2. Pharmacological slowing of HR in heart failure by or betablockers or ivabradine decreases significantly CV mortality and morbidity. 3. HR target value during the heart rate lowering treatment of heart failure is 60beats/min. 4. Most experience is with HR lowering treatment of heart failure by betablockers. In the case of their contraindications or intolerance ivabradin is an alternative. 5. Combination of ivabradine and betablockers is safe. 24.

25 Procorolan (ivabradine) Therapeutic indication Treatment of chronic heart failure Ivabradine is indicated in chronic heart failure with systolic LV dysfunction, NYHA class II IV, in patients on sinus rhythm with resting heart rate 75 beats/min, on top of the standard therapy including betablockers or as an alternative to betablockers if they are contraindicated or not tolerated 25

26 THANK YOU FOR YOUR ATTENTION 26

27 Questions? ~ Answers! Otázky? ~ Odpovědi! Things we knew, things we did Things we have learnt, things we should do