Systolic Heart failure treatment with the If inhibitor ivabradine Trial (SHIFT): a randomised placebo-controlled study

Objective

SHIFT tested the effect of heart rate reduction with Corlanor® in patients with chronic HF.1


Study design
  • SHIFT was an international, multicenter, randomized, double-blind, placebo-controlled outcomes study with a median duration of 22.9 months (N = 6,505)1
  • Inclusion criteria included stable chronic systolic HF for 4 weeks, in sinus rhythm, NYHA class II to IV, with a reduced LVEF ( 35%), a resting heart rate 70 bpm, and hospitalization for worsening HF within 12 months1
  • Exclusion criteria included myocardial infarction within the previous 2 months, ventricular or atrioventricular pacing ( 40% of the day), atrial fibrillation or flutter, and symptomatic hypotension1
  • Corlanor® or placebo was added to SOC, which required optimized and stable treatment for at least 4 weeks of maximally tolerated doses of beta-blockers and, in most cases, ACE inhibitors or ARBs, spironolactone, and diuretics1,2
  • The starting dose of Corlanor® was 5 mg orally twice daily which, after 2 weeks of treatment, was increased to 7.5 mg twice daily or decreased to 2.5 mg twice daily to maintain the resting heart rate between 50 and 60 bpm, as tolerated1,2

Primary endpoint

For patients with stable, symptomatic chronic HF with LVEF 35% and in sinus rhythm with resting heart rate 70 bpm:

Corlanor® significantly reduced the relative risk of hospitalization for worsening HF or CV death1,2
  • Composite endpoint result reflected only a reduction in the risk of hospitalization for worsening HF with no favorable effect on CV death

TIME TO FIRST EVENT OF PRIMARY COMPOSITE ENDPOINT (RANDOMIZED SET)

18% reduction 18% reduction

SOC was a clinical regimen that included maximally tolerated doses of beta-blockers and, in most cases, ACE inhibitors or ARBs, spironolactone, and diuretics.


Secondary endpoint
  • Corlanor® reduced the relative risk of hospitalization for worsening HF by 26% (4.7% ARR)1,2

Safety

Corlanor® has an established safety profile2

MOST COMMON ADVERSE DRUG REACTIONS

At least 1% more frequent with Corlanor® than placebo and occurred in greater than 1% of patients treated with Corlanor®

  Corlanor®
(n = 3,260)
Placebo
(n = 3,278)
Bradycardia 10% 2.2%
Hypertension, blood pressure increased 8.9% 7.8%
Atrial fibrillation 8.3% 6.6%
Phosphenes, visual brightness 2.8% 0.5%
  • Phosphenes are a transiently enhanced brightness in a limited area of the visual field (ie, halos, image decomposition, colored bright lights, or multiple images) usually triggered by sudden variations in light intensity
  • Onset is generally within the first 2 months of treatment, reported to be of mild to moderate intensity, and led to discontinuation in < 1% of patients; most resolved during or after treatment

Read more about the effect of heart rate reduction with Corlanor®

ACCESS ARTICLE

ACE = angiotensin-converting enzyme; ARB = angiotensin II receptor blocker; ARR = absolute risk reduction; BPM = beats per minute; CI = confidence interval; CV = cardiovascular; HF = heart failure; HR = hazard ratio; LVEF = left ventricular ejection fraction; NYHA = New York Heart Association; SOC = standard of care.

References
  1. Swedberg K, Komajda M, Böhm M, et al. Lancet. 2010;376:875-885.
  2. Corlanor® (ivabradine) Prescribing Information, Amgen.
IMPORTANT SAFETY INFORMATION
SEE MORELESS

IMPORTANT SAFETY INFORMATION Contraindications: Corlanor® is contraindicated in patients with acute decompensated heart failure, blood pressure < 90/50 mmHg, sick sinus syndrome, sinoatrial block, 3rd degree atrioventricular block (unless a functioning demand pacemaker is present), a resting heart rate < 60 bpm prior to treatment, severe hepatic impairment, pacemaker dependence (heart rate maintained exclusively by the pacemaker), and concomitant use of strong cytochrome P450 3A4 (CYP3A4) inhibitors.

Fetal Toxicity: Corlanor® may cause fetal toxicity when administered to a pregnant woman based on embryo-fetal toxicity and cardiac teratogenic effects observed in animal studies. Advise females to use effective contraception when taking Corlanor®.

Atrial Fibrillation: Corlanor® increases the risk of atrial fibrillation. The rate of atrial fibrillation in patients treated with Corlanor® compared to placebo was 5% vs. 3.9% per patient-year, respectively. Regularly monitor cardiac rhythm. Discontinue Corlanor® if atrial fibrillation develops.

Bradycardia and Conduction Disturbances: Bradycardia, sinus arrest and heart block have occurred with Corlanor®. The rate of bradycardia in patients treated with Corlanor® compared to placebo was 6% (2.7% symptomatic; 3.4% asymptomatic) vs. 1.3% per patient‐year, respectively. Risk factors for bradycardia include sinus node dysfunction, conduction defects, ventricular dyssynchrony, and use of other negative chronotropes. Bradycardia may increase the risk of QT prolongation which may lead to severe ventricular arrhythmias, including torsades de pointes, especially in patients with risk factors such as use of QTc prolonging drugs.

Concurrent use of verapamil or diltiazem also increases Corlanor® exposure, contributes to heart rate lowering, and should be avoided. Avoid use of Corlanor® in patients with 2nd degree atrioventricular block unless a functioning demand pacemaker is present

Adverse Reactions: The most common adverse drug reactions reported at least 1% more frequently with Corlanor® than placebo and that occurred in more than 1% of patients treated with Corlanor® were bradycardia (10% vs. 2.2%), hypertension or increased blood pressure (8.9% vs. 7.8%), atrial fibrillation (8.3% vs. 6.6%), and luminous phenomena (phosphenes) or visual brightness (2.8% vs. 0.5%).

In postmarketing experience, torsades de pointes has been observed.


INDICATION

Corlanor® (ivabradine) is indicated to reduce the risk of hospitalization for worsening heart failure in patients with stable, symptomatic chronic heart failure with left ventricular ejection fraction 35%, who are in sinus rhythm with resting heart rate 70 beats per minute and either are on maximally tolerated doses of beta-blockers or have a contraindication to beta-blocker use.

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PLEASE READ THE FOLLOWING AND CLICK "I ACKNOWLEDGE" AT THE BOTTOM OF THE PAGE.

Some information included in this article may not be consistent with the approved product labeling. For specific information regarding the approved use of Corlanor® (ivabradine), please see the attached full Prescribing Information.

INDICATION

Corlanor® (ivabradine) is indicated to reduce the risk of hospitalization for worsening heart failure in patients with stable, symptomatic chronic heart failure with left ventricular ejection fraction 35%, who are in sinus rhythm with resting heart rate 70 beats per minute and either are on maximally tolerated doses of beta-blockers or have a contraindication to beta-blocker use.

IMPORTANT SAFETY INFORMATION

Contraindications: Corlanor® is contraindicated in patients with acute decompensated heart failure, blood pressure < 90/50 mmHg, sick sinus syndrome, sinoatrial block, 3rd degree atrioventricular block (unless a functioning demand pacemaker is present), a resting heart rate < 60 bpm prior to treatment, severe hepatic impairment, pacemaker dependence (heart rate maintained exclusively by the pacemaker), and concomitant use of strong cytochrome P450 3A4 (CYP3A4) inhibitors.

Fetal Toxicity: Corlanor® may cause fetal toxicity when administered to a pregnant woman based on embryo-fetal toxicity and cardiac teratogenic effects observed in animal studies. Advise females to use effective contraception when taking Corlanor®.

Atrial Fibrillation: Corlanor® increases the risk of atrial fibrillation. The rate of atrial fibrillation in patients treated with Corlanor® compared to placebo was 5% vs. 3.9% per patient-year, respectively. Regularly monitor cardiac rhythm. Discontinue Corlanor® if atrial fibrillation develops.

Bradycardia and Conduction Disturbances: Bradycardia, sinus arrest and heart block have occurred with Corlanor®. The rate of bradycardia in patients treated with Corlanor® compared to placebo was 6% (2.7% symptomatic; 3.4% asymptomatic) vs. 1.3% per patient-year, respectively. Risk factors for bradycardia include sinus node dysfunction, conduction defects, ventricular dyssynchrony, and use of other negative chronotropes. Concurrent use of verapamil or diltiazem also increases Corlanor® exposure, contributes to heart rate lowering, and should be avoided. Avoid use of Corlanor® in patients with 2nd degree atrioventricular block unless a functioning demand pacemaker is present.

Adverse Reactions: The most common adverse reactions reported at least 1% more frequently with Corlanor® than placebo and that occurred in more than 1% of patients treated with Corlanor® were bradycardia (10% vs. 2.2%), hypertension or increased blood pressure (8.9% vs. 7.8%), atrial fibrillation (8.3% vs. 6.6%), and luminous phenomena (phosphenes) or visual brightness (2.8% vs. 0.5%).

Click "I Acknowledge" to be redirected to an abstract of the Systolic Heart Failure Treatment with the If Inhibitor Trial (SHIFT)

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