Falling HR, Not Beta Blockade, Key to Ivabradine Success in HF: SHIFT

May 21, 2012

May 21, 2012 (Belgrade, Serbia) — Clinical improvements seen with the addition of ivabradine (Procoralan, Servier) to standard heart-failure medications in a recent randomized trial were tied to associated heart-rate reductions, not to the extent of background beta-blocker therapy [1], according to researchers here at the Heart Failure Congress 2012 sessions of the European Society of Cardiology (ESC) Heart Failure Association.

In the primary analysis of the Systolic Heart Failure Treatment with the If Inhibitor Ivabradine Trial (SHIFT), previously reported by heartwire , patients with systolic heart failure given ivabradine showed an 18% fall in the primary end point of CV death or HF hospitalization over about two years (p<0.0001). The trial had randomized more than 6500 patients with NYHA class 2–4 systolic heart failure and a resting heart rate >70 bpm to receive ivabradine or placebo on top of standard meds.

Ivabradine is a selective inhibitor of a sodium-potassium channel highly expressed in the sinoatrial node and has a dampening effect on heart rate; it is currently available in Europe but not in Canada or the US. In SHIFT, the ivabradine dosage was adjusted to achieve a resting heart rate of 50 to 60 bpm.

In a secondary analysis of SHIFT, presented at the meeting by Dr Karl Swedberg (University of Gothenburg, Sweden) and simultaneously published online in the Journal of the American College of Cardiology [2], ivabradine's effect on the primary end point was significant among patients who received beta blockers at 0%, <25%, and 25% to <50% of the ESC-recommended dosage. Also, there was no statistical variation in ivabradine's treatment effect at baseline beta-blocker dosages up to the full recommended amount.

When a heart-failure patient's heart rate is greater than 70 bpm, "reduction in heart rate with ivabradine will provide additional clinical benefit regardless of the beta-blocker dose," Swedberg said when presenting the analysis. "The magnitude of heart-rate reduction with ivabradine beyond that achieved by beta blockers primarily determines subsequent outcomes."

Speaking with heartwire , SHIFT investigator Dr Michel Komajda (Groupe Hospitalier Pitié-Salpêtrière, Paris, France) explained that on the trial's original release, some questioned whether ivabradine would have shown a significant effect on the primary end point had more patients received beta blockers, which also lower heart rate, at recommended target dosages.

The current analysis, he said, "indeed shows that it is the heart rate [reduction] itself and not the beta-blocker dosage that matters."

According to an editorial accompanying the published SHIFT analysis [3], "The data verify that there is something very important about lowering heart rate in patients with heart failure."

Drs Mohammad Sarraf and Gary S Francis (University of Minnesota, Minneapolis) continue, "The authors have essentially demonstrated that it is not the maximal dose of beta blockers that is most important. Rather, it is the magnitude of reduction in heart rate when both drugs are on board that is most closely associated with a favorable clinical outcome."

They point out that "a substantial proportion of patients with heart failure do not tolerate the doses of beta blockers used in the large clinical trials. It follows that patients who are not tolerant to optimal beta-blocker doses may benefit from addition of ivabradine, although there are no data to specifically support this concept."

SHIFT was funded by Servier. Swedberg has received research grants from Servier, Novartis, and Amgen and is a consultant for AstraZeneca and Roche. Komajda discloses receiving grants and/or honorarium from Servier. Disclosures for the coauthors are listed in the paper. Sarraf reports that he has no relevant disclosures. Francis is on the data and safety monitoring board of Novartis.


Comments on Medscape are moderated and should be professional in tone and on topic. You must declare any conflicts of interest related to your comments and responses. Please see our Commenting Guide for further information. We reserve the right to remove posts at our sole discretion.
Post as: