Saudi Arabia February Pr Michel KOMAJDA. Université Pierre et Marie Curie Hospital Pitié Salpétrière

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1 Prevention of Cardiovascular events with Ivabradine: The SHIFT Study Saudi Arabia February 2011 Pr Michel KOMAJDA Université Pierre et Marie Curie Hospital Pitié Salpétrière Paris FRANCE

2 Declaration Of Interest 2010 Speaker : Servier, Menarini, Sanofi, Boehringer Ingelheim, Astra Zeneca, Glaxo Smithkline Consultant / Trial Committee member : Servier, Johnson & Johnson, Nile Therapeutics, Sanofi, Bristol Myers-Squibb

3 Background Elevated heart rate is associated with poor outcome in a number of cardiovascular conditions including heart failure Heart rate remains elevated in many heart failure patients despite treatment by beta-blockers. H t t d ti ith b t bl k i i t d ith Heart rate reduction with beta blockers is associated with better outcome in CHF

4 HF registries: more than 50% of patients have heart rate 70 bpm IMPACT RECO III HF OUTCOME* ESC PILOT HF** 1407 patients 3480 patients 2450 patients Patien nts (%) HR 70 bpm HR >75 bpm HR >80 bpm *Courtesy of Prof Tavazzi **Courtesy of Prof Maggioni

5 Heart rate in European surveys: beta-blocker blocker therapy Beta-blocker (%) HF OUTCOME* Beta-blocker (%) ESC HF PILOT** HR 70 bpm HR >75 bpm HR >80 bpm *Courtesy of Prof Tavazzi **Courtesy of Prof Maggioni

6 Beta blocker dose, heart rate reduction & death in Heart Failure death in Heart Failure Meta-analysis: 23 beta-blocker trials in CHF patients «For every heart rate reduction of 5 beats / mn, an 18% reduction (CI: 6-29%) in the risk of death occured.» Tertile 1: mean HR reduction: 15bpm: HR=0.64 ( ) Tertile 2 HR=0.70 ( ) Tertile 3: mean HR reduction 8bpm : HR=0.91 ( ) No relationship between mortality and dosing Mc Alister,Ann Intern Med 2009,150:784-94

7 Background Ivabradine is a novel heart rate-lowering agent acting by inhibiting the I f current in the sino-atrial node We hypothesized that the addition of ivabradine to recommended therapy would be beneficial in heart failure patients with elevated heart rate

8 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.

9 Systolic Heart failure treatment with the If inhibitor ivabradine Trial Michel Komajda and Karl Swedberg on behalf of the Investigators

10 Primary objective 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 4. Recommended therapy

11 Multinational study Europe Germany Portugal Belgium Greece Spain Denmark Ireland Sweden Finland Italy Turkey France The Netherlands UK Bulgaria Czech Republic Estonia Hungary Latvia Lithuania Norway Poland Romania Russia Slovakia Slovenia Ukraine North America Canada South America Argentina Brazil Chili Asia China Hong Kong India South Korea Malaysia Australia 6505 patients, 37 countries,, 677 centres

12 Inclusion criteria 18 years Class II to IV NYHA heart failure Ischaemic/non-ischaemic aetiology LV systolic dysfunction (EF 35%) Heart rate 70 bpm Sinus rhythm Documented hospital admission for worsening heart failure 12 months Swedberg K, et al. Eur J Heart Fail. 2010;12:75-81.

13 Study design Screening 7 to 30 days Ivabradine 5 mg bid Matching gp 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. Eur J Heart Fail. 2010;12:75-81.

14 Study endpoints Primary composite endpoint Cardiovascular death Hospitalisation for worsening heart failure Other endpoints All-cause / CV / HF death All-cause / CV / HF hospitalisation Composite of CV death, hospitalisation ti for HF or non-fatal MI NYHA class / Patient & Physician Global Assessment In total population and in patients with at least 50% target dose of beta-blockers blockers Swedberg K, et al. Eur J Heart Fail. 2010;12:75-81.

15 Patients and follow-up 7411 screened 6558 randomized 3268 to ivabradine 3290 to placebo Excluded: 27 Excluded: analysed 2 lost to follow-up 3264 analysed 1 lost to follow-up Median study duration: 22.9 months; maximum: 41.7 months Swedberg K, et al. Lancet. 2010;online August 29.

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

17 Baseline characteristics Ivabradine 3241 Placebo 3264 Mean heart rate, bpm Mean LVEF, % Mean SBP, mm Hg Mean DBP, mm Hg egfr, ml/min/1.73 m Swedberg K, et al. Lancet. 2010;online August 29.

18 Patients (%) 100 Chronic HF background treatment Ivabradine Placebo Beta-blockers ACEIs and/or ARBs Diuretics Aldosterone antagonists Digitalis 3 4 ICD/CRT Swedberg K, et al. Lancet. 2010;online August 29.

19 Background beta-blocker treatment Patients (%) Ivabradine Placebo BB at At least 50% Target daily dose randomization target daily dose Swedberg K, et al. Lancet. 2010;online August 29.

20 Background beta-blocker treatment Main reasons for not prescribing beta-blocker, blocker, % IvabradinePlacebo n=344 n=341 Main reasons for not achieving Beta-blocker target dose, % Ivabradine Placebo n=2099 n=2126 COPD Hypotension Hypotension Fatigue Asthma Dyspnea Cardiac decomp. 7 9 Dizziness Fatigue 5 6 Bradycardia 6 6 Swedberg K, et al. Lancet. 2010;online August 29.

21 Background beta-blocker treatment during the study Patients (%) Ivabradine 100 Placebo months 12 months 18 months 24 months N=6176 N=5628 N=4810 N=2675

22 Ivabradine dose by visit in ivabradine group Patients (%) 2.5 mg 5 mg 7.5 mg 100% 0 80% 62 65,5 67,1 69,2 69,8 71,1 71, ,8 60% 99,99 40% 20% 31, ,1 22,1 21,5 19,9 18,5 18,7 19,5 18,1 0% 6,9 8,5 8,8 8,7 8,7 9 9,8 9,3 7,5 6,1 01 0,1 D000 D014 D028 M004 M008 M012 M016 M020 M024 M028 M032 n

23 Baseline heart rate is a predictor of endpoints on placebo SHIFT Patients with primary composite endpoint (%) bpm P< to <87 bpm 75 to <80 bpm 72 to <75 bpm 70 to <72 bpm Months Risk increases by 2.9% per 1-bpm increase, and by 15.6% per 5-bpm increase Boehm Lancet 2010

24 Results

25 Mean heart rate reduction Heart rate (bpm) 90 70% of patients on ivabradine 7.5 mg bid Placebo Ivabradine weeks Swedberg K, et al. Lancet. 2010;online August 29. Months

26 Primary composite endpoint (CV death or hospital admission for worsening HF) Cumulative frequency (%) 40 HR (95% CI), 0.82 ( ), p< Placebo - 18% Ivabradine Swedberg K, et al. Lancet. 2010;online August 29. Months

27 Hospitalization for HF Cumulative frequency (%) HR (95% CI), 0.74 ( ), p< Placebo - 26% Ivabradine Swedberg K, et al. Lancet. 2010;online August 29. Months

28 Cardiovascular death Cumulative frequency (%) 30 HR (95% CI), 0.91 ( ), p= Placebo 10 Ivabradine Swedberg K, et al. Lancet. 2010;online August 29. Months

29 Death from heart failure Cumulative frequency (%) 10 HR (95% CI), 0.74 ( ), p= Placebo - 26% Ivabradine Months Swedberg K, et al. Lancet. 2010;online August 29.

30 Effect of ivabradine on outcomes Endpoints Hazard ratio 95% CI p value Primary composite endpoint 0.82 [0.75;0.90] p< All-cause death 0.90 [0.80;1.02] p=0.092 Death from heart failure 0.74 [0.58;0.94] p=0.014 Hospitalisation for any cause [0.82;0.96] p= Hospitalisation for cardiovascular reason Cardiovascular death / hosp. for HF or non-fatal MI 0.85 [0.78;0.92] p= [0.74;0.89] p< Swedberg K, et al. Lancet. 2010;online August 29.

31 Effect of ivabradine in prespecified p 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 Hazard ratio Favours ivabradine Swedberg K, et al. Lancet. 2010;online August 29. Test for interaction p= Favours placebo

32 NYHA class changes Patients (%) p= Ivabradine 50 Placebo Improvement Stability Worsening Swedberg K, et al. Lancet. 2010;online August 29.

33 Patient Global Assessment Improvement Stability Ivabradine Placebo 7 Worsening p< < Swedberg K, et al. Lancet. 2010;online August 29. Patients (%) last post randomisation value

34 Physician Global Assessment Improvement Stability Ivabradine Placebo Worsening 8 9 p= = Swedberg K, et al. Lancet. 2010;online August 29. Patients (%) last post randomisation value

35 Mean heart rate reduction Patients with >50 % beta-blocker dose (n= 3181) Mean HR in sinus rhythm (bpm) Placebo Ivabradine Patients receiving at least half the target dose of beta-blockers blockers Swedberg K, et al. Lancet. 2010;online August 29.

36 Patients with at least 50% BB target dose (n=3181) Ivabradine Placebo Hazard ratio p value Primary composite endpoint endpoint (11.9 PY) (13.33 PY) 0.90 ns Cardiovascular death (5.9 PY) (5.9 PY) 1.00 ns Hospital admission for worsening HF 213 (7.7 PY) 260 (9.6 PY) 0.81 p= Hazard ratio Favours ivabradine Favours placebo Swedberg K, et al. Lancet. 2010;online August 29.

37 Incidence of selected adverse events (N = 6492) Patients with an event Ivabradine N=3232, % (n) Placebo N=3260, % (n) p value All serious adverse events 45% (1450) 48% (1553) All adverse events 75% (2439) 74% (2423) Heart failure 25% (804) 29% (937) Symptomatic bradycardia 5% (150) 1% (32) < Asymptomatic ti bradycardia di 6% (184) 1% (48) < Atrial fibrillation 9% (306) 8% (251) Phosphenes 3% (89) 1% (17) < Blurred vision 1% (17) < 1% (7) Swedberg K, et al. Lancet. 2010;online August 29.

38 Treatment Discontinuation Patients with an adverse event, Ivabradine N=3232, % (n) leading to withdrawal Placebo N=3260, % (n) p value All adverse events 14% (467) 13% (416) Heart failure 2% (70) 3% (82) Symptomatic bradycardia 1% (20) <1% (5) Asymptomatic bradycardia 1% (28) <1% (5) < Atrial fibrillation ill 4% (135) 3% (113) Phosphenes <1% (7) <1% (3) Blurred vision <1% (1) <1% (1) Swedberg K, et al. Lancet. 2010;online August 29.

39 Conclusion Heart failure with systolic dysfunction and elevated heart rate is associated with poor outcomes (primary composite endpoint in the placebo group is 18%/year) Ivabradine reduced cardiovascular mortality or heart failure hospitalisation by 18% (p<0.0001). The absolute risk reduction was 4.2% This beneficial effect was mainly driven by a favourable effect on HF death (26%) and hospitalisation for HF (26%) Overall, treatment t t with ivabradine was safe and well tolerated t

40 Clinical implications The addition of ivabradine to recommended therapy significantly reduces death and hospitalisations related to heart failure in patients with heart rate 70 bpm The NNT for 1 year to prevent One primary endpoint is 26 One hospitalisation for heart failure is 27

41 Risk Ivabradine Heart Rate

42 Distribution of patients by classes of heart rate achieved at D28* Placebo Ivabradine Patients in heart rate group (%) Patients in heart rate group (%) <60 60 to <65 65 to <70 70 to < <60 60 to <65 65 to <70 70 to <75 75 Heart rate achieved at day 28 (bpm) Heart rate achieved at day 28 (bpm) *Data exclude patients reaching primary composite endpoint in the first 28 days

43 Primary composite endpoint according to heart rate achieved at D28* in the ivabradine group Patients with primary composite endpoint (%) 50 P< bpm 70-<75 bpm 60-<65 bpm 65-<70 bpm <60 bpm Day Months

44 Conclusion شكرا جزيال لكم