Heart Rate-Lowering Drug Shows Promise for STEMI Patients After PCI

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In patients with ST-segment elevation myocardial infarction (STEMI) who have rapid heart rates following percutaneous coronary intervention (PCI), the IV drug ivabradine appears to effectively restore heart rates to a controlled state without affecting blood pressure or hemodynamics, according to a small pilot study published online May 13, 2013, ahead of print in the European Heart Journal: Acute Cardiovascular Care.

The results were first presented at the American Heart Association Scientific Sessions in Chicago, IL, in November 2010.

Ivabradine is an If channel blocker, which produces pure heart rate reduction in patients in sinus rhythm. It also has antianginal properties similar to those of atenolol and amlodipine and has been associated with a reduction in the composite of death or heart failure admission in heart failure patients when given with standard therapy.

For the VIVIFY (eValuation of the IntraVenous If inhibitor ivabradine after ST-segment elevation mYocardial infarction) trial, investigators led by Philippe G. Steg, MD, of Hôpital Bichat (Paris, France), randomized STEMI patients from 24 centers in 5 countries (France, Germany, Spain, Belgium, and Australia) who had undergone successful PCI to IV ivabradine (n = 81) or placebo (n = 40). All patients were in sinus rhythm, had a heart rate above 80 beats per minute, and had a systolic blood pressure of greater than 90 mm Hg. Ivabradine was given as a 5-mg bolus over 30 seconds, followed by a 5-mg infusion over 8 hours.

Electrocardiography (ECG) was used to measure heart rate (2 measurements, 10 minutes apart before treatment), on day 1, day 3, and at hospital discharge. Continuous ECG monitoring was performed over the first 24 hours.

Rapid, Reversible Slowing of Heart Rate

Overall, heart rate at 8 hours was reduced to a greater extent with ivabradine than with placebo (-22.2 ± 1.3 bpm vs. -8.9 ± 1.8 bpm; P < 0.001) with most of the reduction achieved by 4 hours after starting therapy.

Similarly, patients on ivabradine demonstrated greater changes in heart rate than placebo on continuous heart rate monitoring (-19.3 ± 10.9 bpm from baseline to last value over 12 hours vs. -8.4 ± 11.6 bpm; P < 0.001). After the infusion, heart rate returned to placebo levels by 48 hours, and remained similar in both groups at hospital discharge.

ECG at baseline and last post-treatment (mean 1.16 ± 0.98 days) showed no differences between ivabradine and placebo in baseline left ventricular volumes. However, final volumes were lower in the ivabradine group for left ventricular end-diastolic volume compared with placebo (87.1 ± 28.2 ml vs. 117.8 ± 21.4 ml; P = 0.01) and left ventricular end-systolic volume (42.5 ± 19.0 ml vs. 59.1 ± 11.3 ml; P = 0.03). There were no significant differences in the changes in volumes between groups nor were there differences in baseline or final LVEF. Throughout the study period, there was no difference between groups in biomarker levels (creatine kinase and troponin I and T).

Mean systolic and diastolic blood pressures decreased slightly from baseline to hospital discharge to a similar extent in both treatment groups.

Adverse events occurred in 63 patients over the first 48 hours—56% in the ivabradine group vs. 42% in the placebo group. The most frequent events were tachyarrhythmias (16% vs. 12%) including ventricular tachycardia (11% vs. 9%), headache (5% in both groups), and hypotension (6% vs. 0). The most frequent drug-related event was bradycardia (4% vs. 0). Two patients in the study arm died of unrelated causes.

An MRI substudy at hospital discharge and at 4 months in 26 patients in the ivabradine group and 14 patients in the control group showed no difference in infarct size at follow up between the ivabradine and placebo groups (8.7 g vs. 6.3 g; P = 0.726).

Pomising, But Underpowered for Clinical Outcomes

“This first study of IV ivabradine in the context of STEMI suggests that it produces a rapid and reversible slowing of heart rate, which is not associated with changes in blood pressure or major side effects,” Dr. Steg and colleagues write.

However, they point out that the study is underpowered to demonstrate a reduction in biomarker release, infarct size, or clinical outcomes. They note that “[f]urther larger trials are required to determine whether early heart rate reduction with IV ivabradine added to standard care translates into benefit on clinical outcomes.”

Study Details

The mean age of the popula­tion was 59.4 ± 11.0 years, and 78% were male. The majority of patients received BMS, with 28% of the ivabradine patients and 37% of the placebo patients receiving at least 1 DES.

Source:

Steg PG, Lopez-de-Sà E, Schiele F, et al. Safety of intravenous ivabradine in acute ST-segment elevation myocardial infarction patients treated with primary percutaneous coronary intervention: A randomized, placebo-controlled, double-blind, pilot study. Eur Heart J: Acute Cardiovasc Care. 2013;Epub ahead of print.