Transcript resting HR ≥ 70 bpm - accpcardsprnjournalclub

ACCP Cardiology PRN Journal Club
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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, TX
August 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
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 betablocker 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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Swedberg K, et al. Lancet. 2010;376: 875-885; McAlister F, et al. Ann Intern Med. 2009; 150:784-794.
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
Design
Purpose
Patients
• Randomized, double-blind, placebo-controlled, parallel-group,
multicenter, international with intention-to-treat analysis
• To determine whether lowering HR with ivabradine reduces CV death and
morbidity in patients with CAD and left ventricular systolic dysfunction
• N=10917; N=5392 in pre-specified subgroup with HR ≥ 70 bpm
• Aged ≥ 55 years, CAD, LVEF ≤ 40%, sinus rhythm, resting HR ≥ 60 bpm
• Ivabradine 5 mg BID with target dose of 7.5 mg BID
• Standard CV treatment for CAD and HF; 87% on beta-blockers
Treatment • Median follow-up of 19 months (IQR 16-24)
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Fox K, et al. Lancet. 2008; 372:807-816
Outcome
Primary composite endpoint:
CV death or admission to hospital for MI or
new-onset or worsening HF
Total population
Subgroup HR ≥ 70 bpm
Mortality endpoints:
All-cause death
Total population
Subgroup HR ≥ 70 bpm
CV death
Total population
Subgroup HR ≥ 70 bpm
Heart failure endpoints:
Admission to hospital for HF
Total population
Subgroup HR ≥ 70 bpm
Coronary endpoints:
Admission to hospital for MI
Total population
Subgroup HR ≥ 70 bpm
Coronary revascularization
Total population
Subgroup HR ≥ 70 bpm
Ivabradine vs. Placebo; Hazard Ratio
P-Value
15.4% vs 15.3%; 1.00 (CI 0.91-1.10)
17.2% vs 18.5%; 0.91 (CI 0.81-1.04)
0.94
0.17
10.4% vs 10.1%; 1.04 (CI 0.92-1.16)
12.3% vs 12.0%; 1.02 (CI 0.87-1.19)
0.55
0.82
8.6% vs 8.0%; 1.07 (CI 0.94-1.22)
10% vs 9.8%; 1.02 (CI 0.86-1.21)
0.32
0.82
7.8% vs 7.9%; 0.99 (CI 0.86-1.13)
9.9% vs 10.1%; 0.97 (CI 0.82-1.15)
0.85
0.76
3.6% vs 4.2%; 0.87 (CI 0.72-1.06)
3.1% vs 4.9%; 0.64 (CI 0.49-0.84)
0.16
0.001
2.8% vs 3.4%; 0.83 (CI 0.67-1.02)
2.8% vs 4.0%; 0.70 (CI 0.52-0.93)
0.078
0.016
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Fox K, et al. Lancet. 2008; 372:807-816
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
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Swedberg K, et al. Lancet. 2010;376: 875-885.
SHIFT: Inclusion and Exclusion
Inclusion 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
Starting dose 5 mg BID, then down-titrated to 2.5 mg,
maintained at 5 mg, or uptitrated to 7.5 mg BID
Run-In
Matching placebo, twice daily
Selection
Inclusion
at D0
D14
visit
D28
visit
M4
visit
Follow-up visits,
every 4 months
M48
visit
HR ≥ 60 bpm
Titrate dose up to max of 7.5 mg BID
HR 50 - 60 bpm
Keep same dose
HR ≤ 50 bpm or
symptomatic
bradycardia
Titrate dose down or stop therapy if
already taking 2.5 mg BID
Swedberg K, et al. Lancet. 2010;376: 875-885.
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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
• 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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Swedberg K, et al. Lancet. 2010;376: 875-885.
Results: Beta-Blocker Use
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Swedberg K, et al. Lancet. 2010;376: 875-885.
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
Number Needed
to Treat: 26
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Swedberg K, et al. Lancet. 2010;376: 875-885.
Results: Subgroup Analysis
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Swedberg K, et al. Lancet. 2010;376: 875-885.
Results: Adverse Events
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Swedberg K, et al. Lancet. 2010;376: 875-885.
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
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Swedberg K, et al. Lancet. 2010;376: 875-885.
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)
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Swedberg K, et al. Lancet. 2010;376: 875-885.
Discussion: Patients and Outcomes
• Leading reason for failure to reach target dose was
hypotension
• HR of patients included similar to patients naïve to
beta-blockers
Teerlinik JR. Lancet. 2010; 376:875-886
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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)
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Swedberg K, et al. Lancet. 2010;376: 875-885; Fox K, et al. N Engl J Med. 2014; 371 (12) :1091-1099c
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)
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Corlanor (ivabradine) [package insert]. Thousand Oaks, CA: Amgen Inc.; 2015; McMurray J, et al. Eur Heart J. 2012; 33:1787-1847
Critique
Strengths
Limitations
• Generalizability
• Study design
• Limited NYHA Class IV
• Based off previous study
• Few patients with ICD or CRT
targeting patients that
• Limited number of elderly
may benefit from therapy
patients
• Subgroup analysis
• Did not include any patients from
US
• Medication therapy not optimized
• Beta-blockers may not have been
titrated
• Used non-recommended betablockers
• 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
[email protected] or
[email protected]
• Join us next month when we hear the IMPROVEIT Trial from Kyle Thorner, PharmD PGY-2
Cardiology at WAKEMED with Dave Dixon,
PharmD as mentor
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