The Hearth Rate modulators. How to optimise treatment

Transcription

1 The Hearth Rate modulators How to optimise treatment Munich, ESC Congress 2012 Prof. Luigi Tavazzi GVM Care&Research E.S. Health Science Foundation Cotignola, IT

2 Disclosure Cooperation with: Servier, Medtronic, S.Jude Medical, Vifor Pharma, Boston Scientific, Lone Star Heart Inc., Bristol Meyers Squibb, Cardiorentis Quintiles.

3 Heart Failure Clinical Background Elevated heart rate is associated with poor outcome in heart failure Heart rate reduction with beta blockers is associated with better outcome in CHF Heart rate remains elevated in many heart failure patients despite treatment by beta-blockers.

4 Baseline HR (tertiles) and the composite of CV death or hospitalization for HF CHARM population (n=7597), a median follow-up of 37.7 months Probability of CV death or hospitalization for HF T3: 84 bpm* T2: 72 bpm* T1: 60 bpm* Time (months) Castagno et al. J Am Coll Cardiol 2012;59: *Median HR

5 Heart Rate Modulators Ca-blockers Beta-blockers Digitalis Amiodarone Vagal stimulation Ivabradine

6 Heart Failure Clinical Background Elevated heart rate is associated with poor outcome in heart failure Heart rate reduction with beta blockers is associated with better outcome in CHF Heart rate remains elevated in many heart failure patients despite treatment by beta-blockers.

7 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:

8 Reduction of heart rate and outcomes in beta-blockers trials Reduction in mortality % 50 alprenolol oxprenolol practolol pindolol oxprenolol metoprolol propranolol timolol propranolol sotalol Reduction in resting heart rate (bpm) Kjekshus J, Gullestad L. Eur Heart J. 1999;1(suppl H):H64-H69.

9 Beta-Blockade in HF: a Meta-analysis 23 trials in HF patients For every HR decrease of 5 bts/min 18% reduction of the risk of death (HR 0.82, CI ) The survival benefit of Beta-Blockers is not related to the BB dose (HR 1.02, 95% CI per increment) McAlister FA,Ann. Intern. Med 2009;150:784

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11 Heart rate lowering target of therapy in chronic heart failure?

12 Use of beta-blockers in Europe ESC Registries Proportion of chronic HF patients treated with beta blockers Heart Failure Survey I ( ys) 37% Heart Failure Survey II ( ys) 61% EORP Heart Failure Pilot ( ) 87%

13 Heart Failure Clinical Background Elevated heart rate is associated with poor outcome in heart failure Heart rate reduction with beta blockers is associated with better outcome in CHF Heart rate remains elevated in many heart failure patients despite treatment by beta-blockers.

14 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% Rate of use % Dosage mg/die Courtesy Jankowska EA & Ponikowski P 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 Median: 75bpm IQR: Heart rate (bpm)

15 Patients (%) Heart rate in recent HF registries IMPACT RECO III 1407 patients HF OUTCOME* 3480 patients ESC PILOT HF** 2450 patients HR 70 bpm HR >75 bpm HR >80 bpm

16 % of target dose Heart Failure Survey I and II Beta-blocker doses at discharge in % of target doses ,5 12,5 Target mg Atenolol 100 Bisoprolol 10 Carvedilol 50 Metoprolol 100

17 EORP Heart Failure Pilot Chronic HF: Prescribed Betablockers and their dosages Rate of use % Dosage mg/die Median [IQR] Target dose % Carvedilol [ ] 37.3 a Bisoprolol [ ] 20.7 b Metoprolol [50-150] 21.4 c Other betablockers 6.0 a target dose 50 mg/die, b target dose 10 mg/die, c target dose 200 mg/die Maggioni AP, et al. Eur J Heart Fail 2010;12: 1076.

18 CIBIS - ELD trial Dungen HD, et al. Eur J Heart Fail 2011; 13:

19 New Bradycardic agent IVABRADINE

20 Ivabradine: pure heart rate reduction closed open closed RR 0 mv Pure heart rate reduction -40 mv -70 mv Ivabradine I f inhibition reduces the diastolic depolarization slope, thereby lowering heart rate Thollon et al. Br J Pharmacol. 1994;112:37-42.

21 Primary objective of the trial To evaluate whether the I f inhibitor ivabradine improves cardiovascular outcomes in patients with 1. Moderate to severe chronic heart failure 2. Left ventricular ejection fraction 35% 3. Heart rate 70 bpm and in sinus rhythm 4. Recommended therapy

22 Background treatment Patients (%) Ivabradine 80 Placebo Beta-blockers ACEIs and/or ARBs Diuretics Aldosterone antagonists Digitalis 3 4 ICD/CRT Swedberg et al, Lancet 376 (2010):

23 Background beta-blocker treatment Patients (%) Ivabradine Placebo BB at randomization At least 50% target daily dose Target daily dose Swedberg K et al. Lancet. 2010;376:

24 Baseline characteristics Ivabradine Placebo N 3241 N 3264 Mean age, y Male, % Ischaemic aetiology, % NYHA II, % NYHA III/IV, % Previous MI, % Diabetes, % Hypertension, % Swedberg K, et al. Lancet. 2010;online August 29.

25 Mean heart rate reduction Heart rate (bpm) 90 Mean ivabradine dose: 6.4 mg bid at 1 month Ivabradine Placebo 6.5 mg bid at 1 year weeks Months Swedberg et al. Lancet 376 (2010):

26 Main study results: effect of ivabradine on major outcomes Hazard ratio p value Primary composite endpoint 0.82 < All cause mortality Cardiovascular death Death from HF All-cause hospital admission Hospitalization for HF 0.74 < Any CV hospitalization CV death/hospitalization for HF 0.82 < or non-fatal MI Swedberg K, et al. Lancet 2010;376:

27 Primary composite endpoint (CV death or hospitalisation for worsening HF) Cumulative frequency (%) HR = 0.82 p< Placebo - 18% 20 Ivabradine Swedberg K, et al. Lancet 2010;376: Months

28 Main study results: effect of ivabradine on major outcomes Hazard ratio p value Primary composite endpoint 0.82 < All cause mortality Cardiovascular death Death from HF All-cause hospital admission Hospitalization for HF 0.74 < Any CV hospitalization CV death/hospitalization for HF 0.82 < or non-fatal MI Swedberg K, et al. Lancet 2010;376:

29 Hospitalisation for worsening HF Cumulative frequency (%) HR (95% CI), 0.74 ( ) p< Placebo - 26% Ivabradine Months Swedberg K et al. Lancet. 2010;376:

30 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 Swedberg K et al. Lancet. 2010;376: Hazard ratio Favours ivabradine Test for interaction p=0.029 Favours placebo 1.5

31 Effect of ivabradine on major outcomes in patients with HR 75 bpm (n 4150) Hazard ratio 95% CI P Primary composite end point Cardiovascular mortality Hospitalization for worsening HF Death from HF All-cause mortality All-cause hospitalization Any cardiovascular hospitalization < < < < Favors ivabradine Favors placebo Böhm M, et al. Clin Res Cardiol. Online 11 May 2012.

32 EMA indication Ivabradine is indicated in CHF NYHA II-IV class with systolic dysfunction, in patients in sinus rhythm and whose heart rate is 75 bpm, in combination with standard therapy including beta-blocker therapy or when beta-blocker therapy is contraindicated or not tolerated

33 ESC Guidelines on Heart Failure 2012 Recommendations Ivabradine Should be considered to reduce the risk of HF hospitalization in patients in sinus rhythm with an EF 35%, a heart rate remaining 70 bpm, and persisting symptoms (NYHA class II IV) despite treatment with an evidencebased dose of beta-blocker (or maximum tolerated dose below that), ACE inhibitor (or ARB), and an MRA (or ARB). Recommendation IIa, level of evidence B

34 Holter sub-study at 8 months Ivabradine (n=254) Placebo (n=247) 1 episode HR <30 bpm episode HR <40 bpm RR > 2.5 seconds 3 4 RR> 3 seconds 0 1 Atrial fibrillation/flutter 6 5 AV block II or high-degree block 4 9 AV block III 0 0 Non-sustained VT Sustained VT 0 0 Camm J, et al. Eur J Heart Fail Suppl. 2011;10:S134.

35 Systolic Heart failure treatment with the I f inhibitor ivabradine Trial Is ivabradine effective and safe in aged patients?

36 Quartiles of age: <53, 53-59, 60-68, 69 years Kaplan-Meier curves according to age Primary composite endpoint Annual incidence rate Ivabradine Placebo <53 9.8% 15.6% % 15.2% % 17.4% >= % 22.5% Ivabradine Placebo

37 Systolic Heart failure treatment with the I f inhibitor ivabradine Trial Does ivabradine improve quality of life in CHF?

38 HQoL: KCCQ-OSS Change from baseline to 12 months KCCQ OSS 75 = 2.4, p< Baseline M12 Baseline M12 Ivabradine (n=842) Placebo (n=839) Ekman I et al. Eur Heart J 2011; 32:

39 Systolic Heart failure treatment with the I f inhibitor ivabradine Trial Is the beneficial effects of ivabradine supported by pathophysiological findings?

40 Primary endpoint: change ( ) in LV End Systolic Volume Index (LVESVI) LVESVI, ml/m 2 75 = -5.8; p = ml/m ml/m Baseline M 8 Ivabradine (n=208) Baseline M 8 Placebo (n=203) Tardif JC et al. Eur Heart J 2011; 32: ;

41 Ivabradine in patients with severe heart failure (NYHA III-IV) treated with beta-blockers HR (bpm) LVEF (%) LVEDV (ml) LVESV (ml) SBP (mmhg) Main results (n=87) Baseline Change p-value p<0.001 p<0.001 p=0.053 p<0.001 NS DBP (mmhg) NS G. Jondeau, poster P738, Heart failure congress Milan, 16 June 2008

42 Systolic Heart failure treatment with the I f inhibitor ivabradine Trial May Ivabradine be useful in CHF-COPD patients?

43 Ivabradine and beta-blockers in CHF-COPD 730 SHIFT patients had COPD as comorbidity Beta-blockers were prescribed to 92% of NCOPD and 69% of COPD patients. Ivabradine was well tolerated, reduced Heart Rate equally and improved outcomes in both groups. The underuse of beta-blockers in COPD may be in part overcome by the use of ivabradine in association with beta-blockers or in isolation if beta-blockers are not tolerated

44 Systolic Heart failure treatment with the I f inhibitor ivabradine Trial How to define an optimal HR for CHF patients?

45 How to define an optimal HR for CHF patients? CV death & HF hospitalization HF hospitalization 5 HR at day 28 <60/min 60 - <65/min 65 to <70/min 70 to <75/min 75/min Primary and secondary endpoints in the ivabradine group according to groups defined by HR achieved at 28 days Boehm M. et al. Lancet. 2010

46 Clinical implications 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 or a decrease in heart rate 10 bpm when tolerated

47 END