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Ivabradine Shows Promise in Phase III Heart Failure Trial

FDA approval decision expected in February 2015

Positive data have been reported from the phase III Systolic Heart Failure Treatment With the If Inhibitor Ivabradine Trial (SHIFT) evaluating ivabradine (Amgen) in patients with chronic heart failure (HF).

A post hoc analysis from the SHIFT study confirmed that low systolic blood pressure (SBP) is associated with poor outcomes in chronic HF, and that ivabradine reduced the primary composite endpoint of cardiovascular death or hospitalization for worsening HF in this subgroup with low baseline SBP.

The results were published in the July 2014 issue of the European Journal of Heart Failure and were presented at the 18th Annual Scientific Meeting of the Heart Failure Society of America (HFSA), held September 14–17 in Las Vegas, Nevada.

Ivabradine is an oral drug that inhibits the If current (“funny” current) in the sinoatrial node, the body’s cardiac pacemaker. The drug slows the heart rate without negatively affecting myocardial contractility or ventricular repolarization.

In August 2014, the FDA granted ivabradine a “priority review” designation, which is assigned to applications for drugs that treat serious conditions and that would, if approved, provide significant improvements in the safety or effectiveness of the treatment, diagnosis, or prevention of serious conditions compared with available therapies. The FDA set a Prescription Drug User Fee Act (PDUFA) action date of February 27, 2015.

The SHIFT study, completed in May 2010, was a randomized, double-blind, placebo-controlled outcomes trial involving more than 6,500 patients in 37 countries. The study compared ivabradine with placebo on top of standard-of-care therapies (including beta blockers, angiotensin converting enzyme (ACE) inhibitors, angiotensin II receptor blockers (ARBs), diuretics, and/or aldosterone antagonists) in patients with symptomatic chronic HF in sinus rhythm with reduced left ventricular function and a heart rate of 70 bpm or more.

After a run-in period of 14 days without study treatment, eligible patients were randomly assigned to receive ivabradine or placebo at a starting dosage of 5 mg daily. After a 14-day titration period, the dosage was increased to 7.5 mg twice daily unless the resting heart rate was 60 bpm or less. If the resting heart rate fell below 50 bpm or patients experienced signs or symptoms of bradycardia, the dosage was reduced to 2.5 mg twice daily. The double-blind treatment period was approximately 12 to 48 months.

The study’s primary endpoint was the composite of cardiovascular death or hospitalization for worsening HF. The first secondary endpoint was the composite of cardiovascular death or hospitalization for worsening HF in patients receiving at least 50% of the target daily dose of beta blockers at randomization. Other secondary endpoints included all-cause death, any cardiovascular death, hospitalization for worsening HF, all-cause hospitalization, any cardiovascular hospitalization and death from HF, and the composite of cardiovascular death, hospitalization for worsening HF, or hospitalization for non-fatal myocardial infarction.

At the HFSA meeting, data were presented from a post hoc analysis of the SHIFT study that evaluated the efficacy and safety of ivabradine across three blood pressure groups: low SBP (less than 115 mm Hg; n = 2,010); intermediate SBP (115 to 130 mm Hg; n = 1,968), and high SBP (130 mm Hg or greater; n = 2,427).

The analysis confirmed that chronic HF with low SBP is associated with poor outcomes, and that ivabradine reduced the primary composite endpoint of cardiovascular death and hospitalization for worsening HF independent of baseline SBP. Safety was similar across the three SBP groups. The most common adverse events were phosphenes and bradycardia, which occurred more frequently with ivabradine.

Additional findings presented at the HFSA meeting included data from a Holter electrocardiography substudy, which evaluated 501 patients in the SHIFT trial to better understand the relationship between the heart rate and the safety/incidence of adverse events while being treated with ivabradine on top of optimized HF therapy, including beta blockers.

The results showed that at 8 months, the 24-hour heart rate was significantly reduced by 9.5 bpm in the ivabradine group (n = 254) compared with a reduction of 1.2 bpm in the placebo group (n = 247) (P P

Ivabradine was approved in Europe as Procoralan in 2005 for the symptomatic treatment of stable angina and in 2012 for the treatment of chronic HF in patients with elevated heart rates.

Source: Amgen; September 14, 2014.

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