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
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
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
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 54.6 53.4 55.6 Patien nts (%) 31 29.7 33.7 22.5 17.2 20.7 HR 70 bpm HR >75 bpm HR >80 bpm *Courtesy of Prof Tavazzi **Courtesy of Prof Maggioni
Heart rate in European surveys: beta-blocker blocker therapy Beta-blocker (%) 90 80 70 60 50 HF OUTCOME* Beta-blocker (%) 100 80 60 ESC HF PILOT** 40 30 40 20 10 0 20 0 HR 70 bpm HR >75 bpm HR >80 bpm *Courtesy of Prof Tavazzi **Courtesy of Prof Maggioni
Beta blocker dose, heart rate reduction & death in Heart Failure death in Heart Failure Meta-analysis: 23 beta-blocker trials in CHF 19209 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 (0.48-0.86) Tertile 2 HR=0.70 (0.62-0.79) Tertile 3: mean HR reduction 8bpm : HR=0.91 (0.83-0.99) No relationship between mortality and dosing Mc Alister,Ann Intern Med 2009,150:784-94
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
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.
Systolic Heart failure treatment with the If inhibitor ivabradine Trial Michel Komajda and Karl Swedberg on behalf of the Investigators
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
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
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.
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.
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.
Patients and follow-up 7411 screened 6558 randomized 3268 to ivabradine 3290 to placebo Excluded: 27 Excluded: 26 3241 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.
Baseline characteristics Ivabradine Placebo 3241 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.
Baseline characteristics Ivabradine 3241 Placebo 3264 Mean heart rate, bpm 80 80 Mean LVEF, % 29 29 Mean SBP, mm Hg 122 121 Mean DBP, mm Hg 76 76 egfr, ml/min/1.73 m 2 75 75 Swedberg K, et al. Lancet. 2010;online August 29.
Patients (%) 100 Chronic HF background treatment 89 90 91 91 90 84 83 Ivabradine 80 70 60 50 40 61 59 Placebo 30 20 22 22 10 0 Beta-blockers ACEIs and/or ARBs Diuretics Aldosterone antagonists Digitalis 3 4 ICD/CRT Swedberg K, et al. Lancet. 2010;online August 29.
Background beta-blocker treatment Patients (%) 100 90 80 70 89 89 Ivabradine Placebo 60 50 56 56 40 30 20 26 26 10 0 BB at At least 50% Target daily dose randomization target daily dose Swedberg K, et al. Lancet. 2010;online August 29.
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 37 32 Hypotension 17 20 Hypotension 44 45 Fatigue 32 32 Asthma 10 11 Dyspnea 14 14 Cardiac decomp. 7 9 Dizziness 13 12 Fatigue 5 6 Bradycardia 6 6 Swedberg K, et al. Lancet. 2010;online August 29.
Background beta-blocker treatment during the study Patients (%) Ivabradine 100 Placebo 95 90 89 90 89 90 89 90 88 91 85 80 75 70 65 60 55 50 6 months 12 months 18 months 24 months N=6176 N=5628 N=4810 N=2675
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 71,7 72 73 75,8 60% 99,99 40% 20% 31,1 26 24,1 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 3241 3103 3088 2936 2751 2466 2181 1691 976 509 149
Baseline heart rate is a predictor of endpoints on placebo SHIFT Patients with primary composite endpoint (%) 50 87 bpm P<0.001 40 30 20 80 to <87 bpm 75 to <80 bpm 72 to <75 bpm 70 to <72 bpm 10 0 0 6 12 18 24 30 Months Risk increases by 2.9% per 1-bpm increase, and by 15.6% per 5-bpm increase Boehm Lancet 2010
Results
Mean heart rate reduction Heart rate (bpm) 90 70% of patients on ivabradine 7.5 mg bid 80 80 75 Placebo 75 70 67 60 64 Ivabradine 50 0 2 weeks 1 4 8 12 16 20 24 28 32 Swedberg K, et al. Lancet. 2010;online August 29. Months
Primary composite endpoint (CV death or hospital admission for worsening HF) Cumulative frequency (%) 40 HR (95% CI), 0.82 (0.75 0.90), p<0.00010001 Placebo - 18% 30 20 Ivabradine 10 0 0 6 12 18 24 30 Swedberg K, et al. Lancet. 2010;online August 29. Months
Hospitalization for HF Cumulative frequency (%) 30 20 HR (95% CI), 0.74 (0.66 0.83), p<0.00010001 Placebo - 26% Ivabradine 10 0 0 6 12 18 24 30 Swedberg K, et al. Lancet. 2010;online August 29. Months
Cardiovascular death Cumulative frequency (%) 30 HR (95% CI), 0.91 (0.80 1.03), p=0.128 20 Placebo 10 Ivabradine 0 0 6 12 18 24 30 Swedberg K, et al. Lancet. 2010;online August 29. Months
Death from heart failure Cumulative frequency (%) 10 HR (95% CI), 0.74 (0.58 0.94), p=0.014 5 Placebo - 26% Ivabradine 0 0 6 12 18 24 30 Months Swedberg K, et al. Lancet. 2010;online August 29.
Effect of ivabradine on outcomes Endpoints Hazard ratio 95% CI p value Primary composite endpoint 0.82 [0.75;0.90] p<0.0001 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 089 0.89 089 0.89 [0.82;0.96] p=0.003 003 Hospitalisation for cardiovascular reason Cardiovascular death / hosp. for HF or non-fatal MI 0.85 [0.78;0.92] p=0.0002 0.82 [0.74;0.89] p<0.0001 Swedberg K, et al. Lancet. 2010;online August 29.
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 0.5 1.0 Hazard ratio Favours ivabradine Swedberg K, et al. Lancet. 2010;online August 29. Test for interaction p=0.029 1.5 Favours placebo
NYHA class changes Patients (%) 70 70 68 p=0.0003 0003 60 Ivabradine 50 Placebo 40 30 20 28 24 10 0 5 6 Improvement Stability Worsening Swedberg K, et al. Lancet. 2010;online August 29.
Patient Global Assessment Improvement 68 72 Stability 21 25 Ivabradine Placebo 7 Worsening p< <005 0.05 8 0 10 20 30 40 50 60 70 80 Swedberg K, et al. Lancet. 2010;online August 29. Patients (%) last post randomisation value
Physician Global Assessment Improvement 57 61 Stability 31 34 Ivabradine Placebo Worsening 8 9 p= = 0.001 001 0 10 20 30 40 50 60 70 Swedberg K, et al. Lancet. 2010;online August 29. Patients (%) last post randomisation value
Mean heart rate reduction Patients with >50 % beta-blocker dose (n= 3181) Mean HR in sinus rhythm (bpm) 100 90 80 79 74 Placebo 75 70 60 63 50 Ivabradine 67 40 Patients receiving at least half the target dose of beta-blockers blockers Swedberg K, et al. Lancet. 2010;online August 29.
Patients with at least 50% BB target dose (n=3181) Ivabradine Placebo Hazard ratio p value Primary composite endpoint 330 362 endpoint (11.9 PY) (13.33 PY) 0.90 ns Cardiovascular death 176 175 (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=0.021 0.5 1.0 1.5 Hazard ratio Favours ivabradine Favours placebo Swedberg K, et al. Lancet. 2010;online August 29.
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) 0.025 All adverse events 75% (2439) 74% (2423) 0.303 Heart failure 25% (804) 29% (937) 0.0005 Symptomatic bradycardia 5% (150) 1% (32) <0.0001 Asymptomatic ti bradycardia di 6% (184) 1% (48) <0.0001 0001 Atrial fibrillation 9% (306) 8% (251) 0.012 Phosphenes 3% (89) 1% (17) <0.0001 0001 Blurred vision 1% (17) < 1% (7) 0.042 Swedberg K, et al. Lancet. 2010;online August 29.
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) 0.051 Heart failure 2% (70) 3% (82) 0.367 Symptomatic bradycardia 1% (20) <1% (5) 0.002 Asymptomatic bradycardia 1% (28) <1% (5) <0.0001 Atrial fibrillation ill 4% (135) 3% (113) 0.137 Phosphenes <1% (7) <1% (3) 0.224 Blurred vision <1% (1) <1% (1) 1.000 Swedberg K, et al. Lancet. 2010;online August 29.
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
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
Risk Ivabradine 60 90 Heart Rate
Distribution of patients by classes of heart rate achieved at D28* Placebo Ivabradine Patients in heart rate group (%) Patients in heart rate group (%) 50 50 40 40 30 30 20 20 10 10 0 <60 60 to <65 65 to <70 70 to <75 75 0 <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
Primary composite endpoint according to heart rate achieved at D28* in the ivabradine group Patients with primary composite endpoint (%) 50 P<0.0001 40 30 20 75 bpm 70-<75 bpm 60-<65 bpm 65-<70 bpm <60 bpm 10 0 0Day 28 6 12 18 24 30 Months
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