ACCP Cardiology PRN Journal Club 1. Announcements Thank you attending the ACCP Cardiology PRN...

1

ACCP Cardiology PRN Journal Club

Announcements

• Thank you attending the ACCP Cardiology PRN Journal Club– Thank you if you attended before or have been attending

• I have created a PB Works Site that will house our recorded calls, handouts, and Summary/Q&A documents. The link is https://accpcardsprnjournalclub.pbworks.com/

• If there are any suggestions, please let us know.

3

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

4

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

5

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

6

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

7

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)

8

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


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


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


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

9

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.

10

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


11

SHIFT: Procedure


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

12

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


13

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.

14

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

15

Results: Beta-Blocker Use


16

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


17

Results: Primary and Secondary Endpoints


Number Needed

to Treat: 26

18

Results: Subgroup Analysis


19

Results: Adverse Events


20

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


21

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.

22

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

23

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

24

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

25

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

26

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

27

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

28

Ivabradine and outcomes in chronic heart failure (SHIFT): a randomized

placebo-controlled study

Ellen B. Yin, Pharm.D. August 27, 2015

29

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 IMPROVE-IT Trial from Kyle Thorner, PharmD PGY-2 Cardiology at WAKEMED with Dave Dixon, PharmD as mentor

mailto:[email protected]



ACCP Cardiology PRN Journal Club 1. Announcements Thank you attending the ACCP Cardiology PRN...

Documents

Transcript of ACCP Cardiology PRN Journal Club 1. Announcements Thank you attending the ACCP Cardiology PRN...