Servier’s angina drug Procoralan (ivabradine) could significantly lower the risk of death and hospitalisation from chronic heart failure when added to standard CHF therapy, the results of the SHIFT trial indicate.

The SHIFT (Systolic Heart Failure Treatment with the If Inhibitor Ivabradine Trial) study outcomes were presented at the European Society of Cardiology Congress in Stockholm, Sweden and were published simultaneously in The Lancet.

The Servier-funded trial showed that Procoralan reduced the primary endpoint, a composite of cardiovascular death or hospitalisation for worsening heart failure, by 18% in CHF patients versus placebo, with an absolute risk reduction of 4.2%. The main drivers of this benefit were reductions of 26% apiece in the likelihood of death from heart failure and the risk of hospitalisation due to worsening heart failure.

These effects were evident within three months of patients receiving Procoralan and despite them already being on recommended CHF therapy (beta-blockers, ACE inhibitors, diuretics or aldosterone antagonists), Servier noted. Procoralan was also found overall to be safe and well tolerated.

As Servier pointed out, the SHIFT study was the first to confirm specifically that slowing down heart rate (through ivabradine) in isolation cuts the risk or death or hospitalisation due to heart failure.

Major finding

Principal investigator Professor Michel Komajda, head of the cardiovascular and surgical departments at the Pitié Salpetrière hospital in Paris, France, described the results as “a major finding”.

Heart failure and elevated heart rates “are extremely common, so it is very good news for patients and doctors that, even when using the best current drug treatment available, ivabradine further reduces the risk of death or hospitalisation by over 25%”, he said.

Ivabradine “has only one known cardiac action, so this opens a fascinating area of research”, Professor Komajda added.  

SHIFT was a randomised, double-blind, placebo-controlled clinical trial involving a total of 6,505 patients in 37 countries with moderate to severe heart failure and a heart rate above 70 beats per minute.

The trial participants were also on stable background therapy, including a beta-blocker where tolerated. They were randomised to either ivabradine (3,241 patients), titrated to a maximum of 7.5mg twice daily, or to placebo (3,264 patients) and were followed up for an average of 22.9 months.

Beta-blocker effect

While the SHIFT results were heavily hyped in the UK media, some doubts were cast on the study design and how much the outcomes could be extrapolated to the general population.

In an accompanying editorial in The Lancet, for example, Dr John Teerlink, associate professor of medicine at the University of California, San Francisco in the US, noted that only 26% of patients in the trial were on target doses of beta-blockers – even though the lower doses used in the trial were generally in line with clinical practice.

In all, 89% of the SHIFT participants were on beta-blockers at randomisation and 56% were taking at least half of the target daily dose.

Dr Teerlink suggested that the marked reduction in the primary endpoint in SHIFT might not have been achieved had background beta-blocker therapy been optimised. However, Dr Inder Anand, professor of medicine at the University of Minnesota in the US, argued during a discussion of the SHIFT results at the European Society of Cardiology Congress that higher doses of beta-blockers probably would not have changed the outcomes.

A meta-regression analysis of 23 beta-blocker trials in heart failure, involving more than 19,000 patients, had shown that mortality benefit was related to the magnitude of heart rate reduction, not to the dose of beta-blocker used, Dr Anand observed.

In clinical trials, higher doses of BB have not been found to reduce heart rate further, he added. Moreover, in the HIFT trial, the reduction in heart rate was no different for the entire cohort (-15.4 bpm) and for patients on more than 50% of the target dose of beta-blockers (-15.5 bpm). 

Dr Anand estimates that around 40% of all heart failure patients with left-ventricular systolic dysfunction (one of the qualifying criteria for SHIFT) receiving standard-of-care HF therapies could benefit from the addition of ivabradine.