Cosa c è di nuovo nelle LLGG e nella gestione del paziente con scompenso cardiaco. Maurizio Volterrani IRCCS San Raffaele Rome Capri, 24 April 2015

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1 Cosa c è di nuovo nelle LLGG e nella gestione del paziente con scompenso cardiaco Maurizio Volterrani IRCCS San Raffaele Rome Capri, 24 April 2015

2 Treatment options for patients with chronic symptomatic systolic heart failure (NYHA class II-IV)

3 Increased heart rate in CHF Increase in risk by 3% per 1 bpm, 16% per 5 bpm One year mortality (%) Bisoprolol Placebo P< bpm 80 to <87 bpm to <80 bpm 72 to <75 bpm 70 to <72 bpm Baseline HR 72 bpm 72 bpm < Baseline HR 84 bpm Baseline HR > 84 bpm CIBIS II: baseline HR and all-cause mortality Lechat P. et al. Circulation 2001; 103: Months SHIFT: baseline HR and CV mortality and HF hospitalization Böhm M. et al. Lancet 2010; 376:

4 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 *Courtesy of Prof Tavazzi **Courtesy of Prof Maggioni

5 IN-HF Outcome Proportion of patients with chronic HF and with HR <70 or 70 bpm Total population (3460 pts) Treated with betablockers (2763 pts, 80%) Treated with Beta Blokers (2763 pts 80%) 52% 48% 47% 53% p<.0001 Not treated with Beta Blokers (697 pts 20%) NOT treated with betablockers (697 pts, 20%) <70 bpm 70 bpm 60% 40% HR: mean±sd: Total population 71±13 Betablocker 70±13 NO betablocker 73±13 p<.0001 Courtesy of Prof Maggioni

6 Heart rate awareness in patients with chronic stable heart failure. Findings of heart rate as measured with electrocardiography. D. Moran, International Journal of Cardiology, 2014

7 Medication classes in those achieving and not achieving target heart rates Total HR< 70 bpm HR 70bpm p All patients % % % < Beta-blocker usage Beta-blocker % % % < At target BB dose % 81 23% 40 29% ns No target BB dose % % 96 71% ns Not on BB 58 11% 18 5% 40 23% < D. Moran, International Journal of Cardiology, 2014 D. Moran, International Journal of Cardiology, 2014

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9 75,7% did not reached primary endpoint 11% 11% 31% 23% 24% Full dose 50% dose bisoprolol carvedilol 25% dose ,5% dose stopped 50 0 Full dose 50% dose 25% dose 12,5% dose stopped Full dose 50% or less Düngen HD et al. Eur J Heart Fail 2011; 13:

10 Magnitude of HR reduction and outcomes in heart failure Meta-regression of 23 beta-blocker HF trials involving patients Heart rate reduction (bpm) Pooled mortality hazard ratio was 0.76 for an average HR reduction of 12 bpm McAlister FA, et al. Ann Intern Med. 2009:150:

11 Primary composite endpoint Hospitalization for heart failure Ivabradine n=793 (14.5%PY) Placebo n=937 (17.7%PY) HR = 0.82 p< Cumulative frequency (%) 40 Cumulative frequency (%) 30 Ivabradine n=514 (9.4%PY) Placebo n=672 (12.7%PY) HR = 0.74 p< Ivabradine 30 Placebo 20 Ivabradine Placebo 20-18% % Months Death from heart failure Months Cumulative frequency (%) 10 Ivabradine Placebo Ivabradine n=113 (1.9% PY) Placebo n=151 (2.6% PY) HR = 0.74 [95% CI=0.58;0.94] p= % Time from randomisation (months) Fox K. Et al, Lancet 2010

12 Ivabradine Treatment in a Chronic Heart Failure Patient Cohort: Symptom Reduction and Improvement in Quality of Life in Clinical Practice Proportion of patients with BNP levels 400 or >400 pg/ml from baseline to study end Christian Zugck, Adv Ther (2014)

13 LV wall stress (g/cm 2 ) Ivabradine increases diastolic time by 6 min/h Saline Ivabradine Atenolol ms 233 ms* 195 ms* * P<0.05 vs saline P<0.05 vs ivabradine Colin P, et al. Am J Physiol Heart Circ Physiol. 2003;284:H676-H682.

14 content of interstitial content collagen of interstitial (A) and the collagen density of mast cells (B) in the left ventricular free wall and septum of sham, MI and MI + IVA rats. Eduard I. Dedkov et al. J CARDIOVASC PHARMACOL THER 2014

15 LV end-systolic volume index and outcome in the placebo group Patients with primary composite endpoint, % HR 1.62, p=0.04 LVESVI > 59 ml/m 2 LVESVI < 59 ml/m 2

16 Primary endpoint: change in LVESVI from baseline to 8 months Left ventricular end-systolic volume index , P= D ± 16.3 D ± 17.1 ml/m ± ± ± ± Baseline 8 months Ivabradine (n=208) Baseline 8 months Placebo (n=203)

17 % Secondary endpoint: change in LVEF from baseline to 8 months + 2.7, P= LVEF D 2.4 ± 7.7 D ± ± ± ± ± ± Baseline 8 months Baseline 8 months Ivabradine (n=204) Placebo (n=199)

18 Holter sub-study 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 highdegree block 4 9 AV block III 0 0 Non-sustained VT Sustained VT 0 0 Camm J. et al. Poster session 797; HF congress 2011.

19 Heart failure in real life: multiple profiles % The ESC Heart Failure Long-term Registry: 21 European countries, 7401 patients with CHF ( ) HR 70 bpm Age 75 years NYHA III/IV COPD egfr<60 ml/min/1.73m 2* SBP<110 mm Hg Diabetes Maggioni AP et al. Eur J Heart Fail. 2013;15(7): * Maggioni AP et al. Eur J Heart Fail. 2013;15(7):

20 Primary composite endpoint and different levels of blood pressure Ivabradina Pts trattati con ivabradina

21 Heart failure in real life: multiple profiles % The ESC Heart Failure Long-term Registry: 21 European countries, 7401 patients with CHF ( ) HR 70 bpm Age 75 years NYHA III/IV COPD egfr<60 ml/min/1.73m 2* SBP<110 mm Hg Diabetes Maggioni AP et al. Eur J Heart Fail. 2013;15(7): * Maggioni AP et al. Eur J Heart Fail. 2013;15(7):

22 Ivabradine improves outcomes independently of HF severity Incidence of primary composite endpoint of cardiovascular death or hospitalization for heart failure in 712 severe HF patients (LVEF 20% and/or NYHA class IV) and 5973 less severe HF patients 16% RRR 18% RRR P for interaction = In severe HF and HR 75 bpm (n=272) Procoralan reduced CV death by 32% (p=0.034) Borer JS et al. Am J Cardiol. 2013

23 Ivabradine improves symptoms in daily practice 1956 patients with chronic heart failure, treated with BBs (79%), ACEI/ARB (83%), MRA (18%) NYHA classification Signs of decompensation Zugck C et al. ESC HF congress, 2013 Lisbon.

24 Kansas City Cardiomyopathy Questionnaire (KCCQ) Self reported instrument with 23 items, ranging from 0 to 100 (higher score better HQoL)

25 Ivabradine Treatment in a Chronic Heart Failure Patient Cohort: Symptom Reduction and Improvement in Quality of Life in Clinical Practice Quality of life of pts evaluated by EQ-5D score index and visual analog scale C. Zugck, Adv Ther (2014)

26 Addition of Ivabradine to bisoprolol improves exercise capacity more than uptitration of bisoprolol 29 patients with stable angina and moderate LV systolic dysfunction, 2-month treatment Changes in physical activity (6-min walk test, meters) 450 р= Bisoprolol 5 mg Bisoprolol 5 mg + ivabradine Bisoprolol 5 mg Bisoprolol 5 mg + Bisoprolol 5 mg Amosova E et al Cardiovasc Drugs Ther 2011;25:

27 Addition of ivabradine shortens carvedilol uptitration and improves exercise capacity in patients with CHF Addition of ivabradine to carvedilol in patients with CHF resulted in a shorter β-blocker uptitration, higher final β-blocker dose, greater HR reduction, and better exercise capacity Bagriy AE et al. J Am Coll Cardiol. 2013;61(10_S)

28 work performed last repetition/work performed first repetition 100 Score in VAS (cm) Pts % change versus baseline Change in exercise capacity Patients improving at least 1 NYHA Class * * * * 78% 50% 10% Fatigue index Quality of Life - VAS Volterrani M et al. Int J Cardiol 2011

29 Ivabradine Versus Beta-Blockers in Pts with Conduction Abnormalities or Left Ventricular Dysfunction Undergoing Cardiac Surgery RR of ivabradine and combined therapy with ivabradine and metoprolol versus metoprolol for early postoperative AF, complete AV block/need for pacing and postoperative HF worsening L. Iliuta, Cardiol Ther (2014)

30 Ivabradine Versus Beta-Blockers in Pts with Conduction Abnormalities or Left Ventricular Dysfunction Undergoing Cardiac Surgery composite endpoint of 30-day mortality, in-hospital AF/arrhythmias, in-hospital AVblock/need for pacing, or in hospital HF worsening L. Iliuta, Cardiol Ther (2014)

31 Vicious circle induced by dobutamine-induced tachycardia Ivabradine in cardiogenic shock to prevent tachycardia induced by dobutamine F. Roubille Medical Hypotheses, Volume 81, Issue 2, 2013,

32 Ivabradine control undesirable tachycardia induced by dobutamine in cardiogenic shock patient treated successfully with ivabradine while presenting dobutamine-induced tachycardia. F. Roubille Medical Hypotheses 2013

33 Effectiveness of the combination therapy with lisinopril, ivabradine and multivitamin suppl. in anthracycline-induced severe cardiotoxicity C. De Gregorio, International Journal of Cardiology, 2014

34 EF 35% Intoll. βblocker ACE-i+Diuretics SBP < 100mmHg SBP >100mmHg IVABRADINE + HR >70 bpm βblockers - HAEMODINAMIC INSTABILITY

35 Pharmacological treatment of patients with chronic symptomatic systolic heart failure 1 1-McMurray JJ et al. Eur J Heart Fail. 2012;14(8): Shlipak MG. Ann Intern Med. 2003;138(11):

36 Secondary prevention of CVD Number needed to treat to prevent one event per 1 year (NNT-1) Study Event NNT-1 Scandinavian Major coronary 63 patients Statins Simvastatin Survival Study (4S) 1 event (coronary death and nonfatal MI) ACE inhibitors Study on effect of captopril in patients with LVD after MI (SAVE) 2 Fatal and nonfatal MI 105 patients Beta-blockers Meta-analysis of 82 randomized trials of betablockers after MI 3 Nonfatal MI 107 patients Ivabradine SHIFT study 4 Death and 26 patients Hosp. for HF 1- Kjekshus J. Am J Cardiol.1995;76:64C-68C. 2- Pfeffer MA. N Engl J Med. 1992;327: Fox K et al. Lancet. 2010

37 Conclusion 1 In patients with HF Ivabradine reduces CV mortality, mortality for HF and HF hospitalization This beneficial effect is present in ischemic and in nonischemic HF

38 Conclusion 2 Beta-blockers improve prognosis but are often underused in clinical practise Ivabradine alone or in combination with βblockers is more effective than βblockers alone at improving exercise tolerance and quality of life in HF