The findings from the Systolic Heart Failure Treatment with the If Inhibitor Ivabradine Trial (SHIFT)(1), presented at ESC 2010, signal a new potential direction for the treatment of heart failure characterized by an elevated heart rate as a therapeutic target.
Ivabradine is a selective inhibitor of a sodium-potassium channel highly expressed in the sinoatrial node, on which it has a mild dampening effect. The drug has few other, if any, known cardiac effects.
In the RCT cardiovascular outcomes in the placebo (n=3264) and ivabradine groups (n=3241) of this trial, divided by quintiles of baseline heart rate in the placebo groups were analyzed.
The primary composite endpoint was cardiovascular death or hospital admission for worsening heart failure. In the ivabradine group, heart rate achieved at 28 days was also analysed in relation to subsequent outcomes. Analysis adjusted to change in heart rate was used to study heart-rate reduction as mechanism for risk reduction by ivabradine directly.
The results show that in the placebo group, patients with the highest heart rates (≥87 beats per min [bpm], n=682, 286 events) were at more than two-fold higher risk for the primary composite endpoint than were patients with the lowest heart rates (70 to <72 bpm, n=461, 92 events; hazard ratio [HR] 2·34, 95% CI 1·84—2·98, p<0·0001). Risk of primary composite endpoint events increased by 3% with every beat increase from baseline heart rate and 16% for every 5-bpm increase. In the ivabradine group, there was a direct association between heart rate achieved at 28 days and subsequent cardiac outcomes.
Patients with heart rates lower than 60 bpm at 28 days on treatment had fewer primary composite endpoint events during the study (n=1192; event rate 17·4%, 95% CI 15·3—19·6) than did patients with higher heart rates. The effect of ivabradine is accounted for by heart-rate reduction, as shown by the neutralisation of the treatment effect after adjustment for change of heart rate at 28 days (HR 0·95, 0·85—1·06, p=0·352).
The authors describe ivabradine as being "well tolerated" despite a 10% rate of bradycardia, which prompted withdrawal from the study by 1% of patients receiving the drug.The authors concluded that high heart rate is a risk factor in heart failure. Selective lowering of heart rates with ivabradine improves cardiovascular outcomes. Heart rate is an important target for treatment of heart failure.
Issues raised:
1.The population of the trial is younger than most patients with heart failure in the US, mostly white, sinus rhythm only, and status post-heart-failure hospitalization within the prior 12 months of enrollment."
Moreover, "the majority of the patients in this study were not only 'outside US' but also 'outside Western Europe.'
2.Dr John R Teerlink (2) focuses on the trial's beta-blocker dosing as a major reason not to consider the trial a conclusive test of ivabradine in chronic heart failure. Conceivably, a significant reduction in the primary end point might not have emerged had beta blockers—which also reduce heart rate—been more consistently given "at or near target doses," he speculates.
Would these benefits have occurred if the dose of beta blocker had been more consistently closer to the recommended doses in the patients studied
(1) http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(10)61259-7/abstract
(2)http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(10)61314-1/fulltext
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