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
Disclosure Cooperation with: Servier, Medtronic, S.Jude Medical, Vifor Pharma, Boston Scientific, Lone Star Heart Inc., Bristol Meyers Squibb, Cardiorentis Quintiles.
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.
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 0.40 0.30 T3: 84 bpm* T2: 72 bpm* T1: 60 bpm* 0.20 0.10 0 6 12 18 24 30 36 42 Time (months) Castagno et al. J Am Coll Cardiol 2012;59:1785 95 *Median HR
Heart Rate Modulators Ca-blockers Beta-blockers Digitalis Amiodarone Vagal stimulation Ivabradine
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.
Change in heart rate and LVEF in heart failure Meta-regression of beta-blocker trials, n=19 537 Change in LVEF r² = 0.61 14 12 10 8 6 4 2-20 -15-10 -5 0 5-2 Heart rate (bpm) Flannery et al. Am J Cardiol. 2008;101:865-869.
Reduction of heart rate and outcomes in beta-blockers trials Reduction in mortality % 50 alprenolol 40 30 20 10 0 0 oxprenolol practolol pindolol oxprenolol metoprolol propranolol timolol propranolol sotalol 2 4 6 8 10 12 14 16 18 20 Reduction in resting heart rate (bpm) Kjekshus J, Gullestad L. Eur Heart J. 1999;1(suppl H):H64-H69.
Beta-Blockade in HF: a Meta-analysis 23 trials in 19 209 HF patients For every HR decrease of 5 bts/min 18% reduction of the risk of death (HR 0.82, CI 0.71-0.94) The survival benefit of Beta-Blockers is not related to the BB dose (HR 1.02, 95% CI 0.93 1.10 per increment) McAlister FA,Ann. Intern. Med 2009;150:784
Heart rate lowering target of therapy in chronic heart failure?
Use of beta-blockers in Europe ESC Registries Proportion of chronic HF patients treated with beta blockers Heart Failure Survey I (2000-01 ys) 37% Heart Failure Survey II (2004-05 ys) 61% EORP Heart Failure Pilot (2010-11) 87%
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.
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. 2011 HR achieved (bpm) Carvedilol 33 21 75 Bisoprolol 49 5 75 Metoprolol 13 64 75 Pts treated with 50% recommended β-bl dose median HR: 75 bpm; IQR: 68-84 Pts treated with < 50% recommended β-bl dose median HR: 75 bpm; IQR: 66-85 No correlation between resting HR and % recommended β-bl dose 1800 1600 1400 1200 1000 800 600 400 200 0 Median: 75bpm IQR: 68-84 40 48 56 64 72 80 88 96 104 112 120 128 136 Heart rate (bpm)
Patients (%) Heart rate in recent HF registries IMPACT RECO III 1407 patients HF OUTCOME* 3480 patients ESC PILOT HF** 2450 patients 54.6 53.4 55.6 31 29.7 33.7 22.5 17.2 20.7 HR 70 bpm HR >75 bpm HR >80 bpm
% of target dose Heart Failure Survey I and II Beta-blocker doses at discharge in % of target doses 50 5 5 50 50 25 12,5 12,5 Target mg Atenolol 100 Bisoprolol 10 Carvedilol 50 Metoprolol 100
EORP Heart Failure Pilot Chronic HF: Prescribed Betablockers and their dosages Rate of use % Dosage mg/die Median [IQR] Target dose % Carvedilol 42.8 25 [12.5-50] 37.3 a Bisoprolol 32.3 5 [2.5-7.5] 20.7 b Metoprolol 18.9 100 [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.
CIBIS - ELD trial Dungen HD, et al. Eur J Heart Fail 2011; 13:670-680
New Bradycardic agent IVABRADINE
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.
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
Background treatment Patients (%) 100 90 89 90 91 91 84 83 Ivabradine 80 Placebo 70 60 61 59 50 40 30 20 22 22 10 0 Beta-blockers ACEIs and/or ARBs Diuretics Aldosterone antagonists Digitalis 3 4 ICD/CRT Swedberg et al, Lancet 376 (2010): 875-885.
Background beta-blocker treatment Patients (%) 100 90 80 89 89 Ivabradine Placebo 70 60 50 40 56 56 30 20 10 0 26 26 BB at randomization At least 50% target daily dose Target daily dose Swedberg K et al. Lancet. 2010;376:875-885
Baseline characteristics Ivabradine Placebo N 3241 N 3264 Mean age, y 60.7 60.1 Male, % 76 77 Ischaemic aetiology, % 68 67 NYHA II, % 49 49 NYHA III/IV, % 51 51 Previous MI, % 56 56 Diabetes, % 30 31 Hypertension, % 67 66 Swedberg K, et al. Lancet. 2010;online August 29.
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 80 80 75 75 70 67 60 64 50 0 2 weeks 1 4 8 12 16 20 24 28 32 Months Swedberg et al. Lancet 376 (2010): 875-885.
Main study results: effect of ivabradine on major outcomes Hazard ratio p value Primary composite endpoint 0.82 <0.0001 All cause mortality 0.90 0.092 Cardiovascular death 0.91 0.128 Death from HF 0.74 0.014 All-cause hospital admission 0.89 0.003 Hospitalization for HF 0.74 <0.0001 Any CV hospitalization 0.85 0.0002 CV death/hospitalization for HF 0.82 <0.0001 or non-fatal MI Swedberg K, et al. Lancet 2010;376: 875-885. 0.5 0.6 0.7 0.8 0.9 1.0 1.1
Primary composite endpoint (CV death or hospitalisation for worsening HF) Cumulative frequency (%) 40 30 HR = 0.82 p<0.0001 Placebo - 18% 20 Ivabradine 10 0 0 6 12 18 24 30 Swedberg K, et al. Lancet 2010;376: 875-885. Months
Main study results: effect of ivabradine on major outcomes Hazard ratio p value Primary composite endpoint 0.82 <0.0001 All cause mortality 0.90 0.092 Cardiovascular death 0.91 0.128 Death from HF 0.74 0.014 All-cause hospital admission 0.89 0.003 Hospitalization for HF 0.74 <0.0001 Any CV hospitalization 0.85 0.0002 CV death/hospitalization for HF 0.82 <0.0001 or non-fatal MI Swedberg K, et al. Lancet 2010;376: 875-885. 0.5 0.6 0.7 0.8 0.9 1.0 1.1
Hospitalisation for worsening HF Cumulative frequency (%) 30 20 HR (95% CI), 0.74 (0.66 0.83) p<0.0001 Placebo - 26% Ivabradine 10 0 0 6 12 18 24 30 Months Swedberg K et al. Lancet. 2010;376:875-885
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 Swedberg K et al. Lancet. 2010;376:875-885 0.5 1.0 Hazard ratio Favours ivabradine Test for interaction p=0.029 Favours placebo 1.5
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 0.76 0.68-0.85 0.83 0.71-0.97 0.70 0.61-0.80 0.61 0.46-0.81 0.83 0.72-0.96 0.82 0.75-0.90 0.79 0.71-0.88 <0.0001 0.0166 <0.0001 0.0006 0.0109 <0.0001 <0.0001 0.20 0.40 0.60 0.80 Favors ivabradine 1.00 1.20 Favors placebo Böhm M, et al. Clin Res Cardiol. Online 11 May 2012.
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
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
Holter sub-study at 8 months Ivabradine (n=254) Placebo (n=247) 1 episode HR <30 bpm 0 0 1 episode HR <40 bpm 54 21 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 71 81 Sustained VT 0 0 Camm J, et al. Eur J Heart Fail Suppl. 2011;10:S134.
Systolic Heart failure treatment with the I f inhibitor ivabradine Trial Is ivabradine effective and safe in aged patients?
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% 54-59 13.0% 15.2% 60-68 15.9% 17.4% >=69 18.5% 22.5% Ivabradine Placebo
Systolic Heart failure treatment with the I f inhibitor ivabradine Trial Does ivabradine improve quality of life in CHF?
HQoL: KCCQ-OSS Change from baseline to 12 months KCCQ OSS 75 = 2.4, p<0.001 6.7 4.3 70 65 60 55 Baseline M12 Baseline M12 Ivabradine (n=842) Placebo (n=839) Ekman I et al. Eur Heart J 2011; 32:2395-2404.
Systolic Heart failure treatment with the I f inhibitor ivabradine Trial Is the beneficial effects of ivabradine supported by pathophysiological findings?
Primary endpoint: change ( ) in LV End Systolic Volume Index (LVESVI) LVESVI, ml/m 2 75 = -5.8; p =0.02 70-7.0 ml/m 2-0.9 ml/m 2 65 60 55 50 0 Baseline M 8 Ivabradine (n=208) Baseline M 8 Placebo (n=203) Tardif JC et al. Eur Heart J 2011; 32:2507-2515;
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 74 10 29 5 224 81 162 61 121 15 Change -10 11 +5 6-8 37-18 30-0 16 p-value p<0.001 p<0.001 p=0.053 p<0.001 NS DBP (mmhg) 75 9-1 11 NS G. Jondeau, poster P738, Heart failure congress Milan, 16 June 2008
Systolic Heart failure treatment with the I f inhibitor ivabradine Trial May Ivabradine be useful in CHF-COPD patients?
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
Systolic Heart failure treatment with the I f inhibitor ivabradine Trial How to define an optimal HR for CHF patients?
How to define an optimal HR for CHF patients? 35 30 25 20 CV death & HF hospitalization 15 10 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
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
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