Post on 13-Dec-2015
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ACCP Cardiology PRN Journal Club
Announcements
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Ivabradine and outcomes in chronic heart failure (SHIFT): a randomized
placebo-controlled study
Ellen B. Yin, Pharm.D. PGY2 Cardiology
CHI Baylor St. Luke’s Medical Center, Houston, TXAugust 27, 2015
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Disclosure Presenters have no conflicts to report related to financial or personal relationships with commercial entities (or their competitors) that may be referenced in this presentation
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Background
Swedberg K, et al. Lancet. 2010;376: 875-885; McAlister F, et al. Ann Intern Med. 2009; 150:784-794.
Chronic HF affects roughly 2-3% of the
population
Treatment with beta-blockers
↓ Morbidity and Mortality
Benefits of beta-blockers
in HFrEF
• Likely linked to HR lowering properties• Meta-analysis of 23 trials
• Every HR reduction of 5 beats/min with beta-blocker treatment
• 18% reduction (CI 6%-29%) in risk of death
Concerns of beta-blockers
in HFrEF
• Decrease in myocardial contractility • Effect on peripheral vasculature• Effect on airways
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Background: Ivabradine• Specific inhibitor of the If current in the
sinoatrial node • No other known
action on other channels
• Does not modify myocardial contractility and intracardiac conduction
Swedberg K, et al. Lancet. 2010;376: 875-885
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Background: BEAUTIFUL Trial
Fox K, et al. Lancet. 2008; 372:807-816
Design
• Randomized, double-blind, placebo-controlled, parallel-group, multicenter, international with intention-to-treat analysis
Purpos
e
• To determine whether lowering HR with ivabradine reduces CV death and morbidity in patients with CAD and left ventricular systolic dysfunction
Patients
• N=10917; N=5392 in pre-specified subgroup with HR ≥ 70 bpm• Aged ≥ 55 years, CAD, LVEF ≤ 40%, sinus rhythm, resting HR ≥ 60 bpm
Treatment
• Ivabradine 5 mg BID with target dose of 7.5 mg BID• Standard CV treatment for CAD and HF; 87% on beta-blockers • Median follow-up of 19 months (IQR 16-24)
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Outcome Ivabradine vs. Placebo; Hazard Ratio P-Value
Primary composite endpoint: CV death or admission to hospital for MI or new-onset or worsening HF
Total populationSubgroup HR ≥ 70 bpm
15.4% vs 15.3%; 1.00 (CI 0.91-1.10)17.2% vs 18.5%; 0.91 (CI 0.81-1.04)
0.940.17
Mortality endpoints:All-cause death
Total populationSubgroup HR ≥ 70 bpm
CV deathTotal populationSubgroup HR ≥ 70 bpm
10.4% vs 10.1%; 1.04 (CI 0.92-1.16)12.3% vs 12.0%; 1.02 (CI 0.87-1.19)
8.6% vs 8.0%; 1.07 (CI 0.94-1.22)10% vs 9.8%; 1.02 (CI 0.86-1.21)
0.550.82
0.320.82
Heart failure endpoints:Admission to hospital for HF
Total populationSubgroup HR ≥ 70 bpm
7.8% vs 7.9%; 0.99 (CI 0.86-1.13)9.9% vs 10.1%; 0.97 (CI 0.82-1.15)
0.850.76
Coronary endpoints: Admission to hospital for MI
Total populationSubgroup HR ≥ 70 bpm
Coronary revascularization Total populationSubgroup HR ≥ 70 bpm
3.6% vs 4.2%; 0.87 (CI 0.72-1.06)3.1% vs 4.9%; 0.64 (CI 0.49-0.84)
2.8% vs 3.4%; 0.83 (CI 0.67-1.02)2.8% vs 4.0%; 0.70 (CI 0.52-0.93)
0.160.001
0.0780.016
Fox K, et al. Lancet. 2008; 372:807-816
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SHIFT: Design & Purpose
• Purpose– To assess the effect of heart-rate reduction by the selective
sinus-node inhibitor ivabradine on outcomes in heart failure
• Study Design– International, multicenter, randomized, double-blind,
placebo-controlled, parallel group study – Ivabradine vs placebo given on top of standard heart failure
treatment regimen • Funding– Servier, France
Swedberg K, et al. Lancet. 2010;376: 875-885.
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SHIFT: Inclusion and ExclusionInclusion Criteria Exclusion Criteria
• Age ≥ 18 years • Sinus rhythm with resting HR ≥ 70
bpm • NYHA Class II, III, IV for ≥ 4 weeks, in
stable clinical condition• Previous admission for worsening
heart failure within previous 12 months
• LVEF ≤ 35%, documented within previous 3 months
• Recent (<2 months) myocardial infarction or recent or scheduled coronary revascularization
• Pacemaker with atrial or ventricular pacing > 40% of the time, or with stimulation threshold at the atrial or ventricular level ≥ 60 bpm
• Atrial fibrillation or flutter• Symptomatic hypotension • Congenital heart disease • Sick sinus syndrome, sinoatrial block, second
and third atrio-ventricular block • Patients on non-dihydropyridine calcium
channel blockers, class I antiarrhythmics, strong inhibitors of CYP3A4 , selected QT prolonging products
Swedberg K, et al. Lancet. 2010;376: 875-885.
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SHIFT: Procedure
Swedberg K, et al. Lancet. 2010;376: 875-885.
HR ≥ 60 bpm
HR 50 - 60 bpm
HR ≤ 50 bpm or symptomatic bradycardia
Titrate dose up to max of 7.5 mg BID
Keep same dose
Titrate dose down or stop therapy if already taking 2.5 mg BID
Starting dose 5 mg BID, then down-titrated to 2.5 mg, maintained at 5 mg, or uptitrated to 7.5 mg BID
Matching placebo, twice daily
Run-In
Selection Inclusion at D0
D14 visit
D28 visit
M4 visit
M48 visit
Follow-up visits, every 4 months
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SHIFT: Endpoints
Primary Endpoint • Composite of CV death or hospital admission for worsening HF
Secondary Endpoint
• Primary outcome for patients receiving at least 50% of the target daily dose of a beta-blocker
• Readmission: All-cause, any CV, worsening HF• Mortality: All-cause, any CV, HF • Changes in functional capacity based on NYHA
classification
Swedberg K, et al. Lancet. 2010;376: 875-885.
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SHIFT: Statistical Analysis
• Survival analysis done on a time-to-first event basis with an intention-to-treat principle
• Time-to-event curves estimated with Kaplan-Meier method
• Cox’s proportional hazards model adjusted for baseline beta-blocker intake used to estimate treatment effect
• Power: – Assuming an annual incidence rate of the primary
composite endpoint of 14% in the placebo group – Sample size of 6500 patients needed for 90% power to find
15% relative risk reduction with 1600 first events Swedberg K, et al. Lancet. 2010;376: 875-885.
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SHIFT: Baseline Characteristics
Swedberg K, et al. Lancet. 2010;376: 875-885.
• N=3241 in Ivabradine group; N=3264 in placebo group
• Average age 60.4 years (11% > 75 years)• 76% male, 89% white• HR 79 bpm, BP 122/75 mmHg, LVEF 29%• 49% NYHA class II, 50% class III, 2% class IV• 68% ischemic cause of HF• 89% on beta-blockers, 83% on ACE/ARB, 22%
cardiac glycoside, 4% on CRT/ICD
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Results: Beta-Blocker Use
Swedberg K, et al. Lancet. 2010;376: 875-885.
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Results: Heart Rate Reduction
• Median duration of follow-up: 22.9 months
• Mean dose of ivabradine 6.5 mg BID at 1 year
• Heart rate fell by 10.9 bpm at 28 days and 9.1 bpm at 1 year
Swedberg K, et al. Lancet. 2010;376: 875-885.
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Results: Primary and Secondary Endpoints
Swedberg K, et al. Lancet. 2010;376: 875-885.
Number Needed
to Treat: 26
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Results: Subgroup Analysis
Swedberg K, et al. Lancet. 2010;376: 875-885.
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Results: Adverse Events
Swedberg K, et al. Lancet. 2010;376: 875-885.
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Study Conclusions
• Ivabradine significantly reduced major risks associated with heart failure
• In patients treated with ivabradine, relative risk of cardiovascular death or hospital admission for heart failure fell by 18%
• Shows importance of heart-rate reduction for improvement of clinical outcomes in heart failure
Swedberg K, et al. Lancet. 2010;376: 875-885.
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Discussion: Patients and Outcomes • Significant difference mainly due to the favorable
effect on heart failure events • CV and all-cause deaths were not significantly
reduced• May not benefit patients with a HR < 77 bpm• 56% of patients achieved at least 50% of target
beta-blocker • Primary event rate per year was fairly higher in
placebo group (18% per year) compared with what was assumed for power analysis (14% per year)Swedberg K, et al. Lancet. 2010;376: 875-885.
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Discussion: Patients and Outcomes
Teerlinik JR. Lancet. 2010; 376:875-886
• Leading reason for failure to reach target dose was hypotension
• HR of patients included similar to patients naïve to beta-blockers
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Discussion: Adverse Events • Patients on ivabradine experienced more
events of bradycardia, phosphene-type visual disturbances , atrial fibrillation
• In SIGNIFY, atrial fibrillation and QT prolongation significant
• Higher number of withdrawals in the ivabradine group when compared with placebo arm (HR 1.14; 95% CI, 1.02-1.7; P = 0.017)
Swedberg K, et al. Lancet. 2010;376: 875-885; Fox K, et al. N Engl J Med. 2014; 371 (12) :1091-1099c
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Discussion: Current Guidelines
• Ivabradine approved April 2015 to reduce the risk of hospitalization for worsening HF in CHF with LVEF ≤ 35% with resting HR ≥ 70 bpm
• ESC 2012 HF guidelines recommend ivabradine in patients with HR ≥ 70 bpm despite evidence based treatment (Class IIa, Level B)
Corlanor (ivabradine) [package insert]. Thousand Oaks, CA: Amgen Inc.; 2015; McMurray J, et al. Eur Heart J. 2012; 33:1787-1847
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Critique Strengths Limitations
• Study design• Based off previous study
targeting patients that may benefit from therapy
• Subgroup analysis
• Generalizability • Limited NYHA Class IV• Few patients with ICD or CRT• Limited number of elderly
patients• Did not include any patients from
US• Medication therapy not optimized
• Beta-blockers may not have been titrated
• Used non-recommended beta-blockers
• Medication compliance not described
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Practical Implications • Moving towards HR as possible target of therapy• Confirmed importance of titration of beta-
blocker therapy• Avoid pre-mature initiation of ivabradine • Ivabradine may be beneficial in patients who
truly cannot tolerate higher doses of beta-blockers and still have elevated HR
• Patient consideration: compliance, cost• Monitor for bradycardia, visual disturbances,
atrial fibrillation
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Acknowledgements
• Journal Club Mentor: – Toni L. Ripley, Pharm.D., BCPS-AQ Cardiology
• Program Directors:– ACCP Cardiology PRN Journal Club Coordinator:• Craig Beavers, Pharm.D., FAHA, AACC, BCPS-AQ
Cardiology, CACP
– Maryam Bayat, Pharm.D., BCPS-AQ Cardiology
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Ivabradine and outcomes in chronic heart failure (SHIFT): a randomized
placebo-controlled study
Ellen B. Yin, Pharm.D. August 27, 2015
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Thank you for attending!
• If you would like to have your resident present, would like to be a mentor, or have questions or comments please e-mail the journal club at accpcardsprnjournalclub@gmail.com or craig.beaverspharmd@gmail.com
• Join us next month when we hear the IMPROVE-IT Trial from Kyle Thorner, PharmD PGY-2 Cardiology at WAKEMED with Dave Dixon, PharmD as mentor