Ivabradine in Stable Angina - Ivabradine in Stable Angina

Description:

The goal of the trial was to compare placebo vs ivabradine, a selective heart rate–lowering agent that acts specifically on the sinoatrial node (SAN), in stable angina patients.

Hypothesis:

To assess the safety and efficacy of ivabradine in stable angina patients.

Study Design

Study Design:

Patients Screened: 529
Patients Enrolled: 360
Mean Follow Up: 3 months
Mean Patient Age: 35-86
Female: 10%

Patient Populations:

Age >=18 years, >=3-month history of chronic, stable, effort-induced angina (without prior mechanical therapy or >3 months after CABG or >6 months after PTCA) relieved by rest or nitroglycerin, plus catheterization-documented coronary artery disease or previous MI >=3 months before randomization; positive ETT (with both limiting angina and ST-segment depression >=1 mm compared with rest) at selection (day 7) and at inclusion (day 0). ETT performance between day 7 and day 0 could not differ by >20% or >1 minute in time to 1-mm ST-segment depression.

Exclusions:

Unstable angina, Prinzmetal angina or microvascular angina, significant valvular disease, atrial fibrillation/flutter or indwelling pacemaker, 2° and 3° AV block, or inability to perform ETT.

Primary Endpoints:

Changes in time to 1-mm horizontal or downsloping ST-segment depression >=0.08 seconds after the J point; Time to limiting angina during ETT performed at the trough of drug activity (12 hours after last drug administration)

Secondary Endpoints:

Changes in ETT at peak drug activity (4 hours after drug administration), angina attack frequency, adverse events, vital signs, blood pressure during ETT, ECG at rest, 24-hour Holter monitoring

Drug/Procedures Used:

Patients were randomized to ivabradine (2.5, 5, or 10 mg BID) or placebo for 2 weeks, followed by an open-label 2 or 3 month extension on ivabradine (10 mg BID) and a 1 week randomized withdrawal to ivabradine (10 mg BID) or placebo.

Principal Findings:

Time to 1 mm ST-segment depression increased by 32.0 sec in the 2.5 mg ivabradine group (n=64), by 44.1 sec in the 5 mg group (n=59), and by 46.2 sec in the 10 mg group (n=66) compared with 9.0 sec in the placebo arm (n=68; p<0.005 vs placebo for the 5 mg and 10 mg arms). Time to symptom limiting angina increased significant vs placebo in the 10 mg (40.8 sec vs 12.7 sec, p<0.05), as did time to angina onset (69.4 sec vs 24.7 sec, p<0.05). Angina attacks decreased from 4.14 attacks/wk at baseline to 0.95 attacks/wk at the end of the open-label extension (p<0.001), while use of short-acting nitrates decreased from 2.28 U/wk to 0.50 U/wk (p<0.001). The frequency of adverse events in the ivabradine arm were similar to placebo with the exception of visual symptoms (abrupt changes in light intensity) which occurred in 1 patient in each of the 2.5 and 5 mg ivabradine arms and 13 patients (14.8%) in the 10 mg arm vs 0 in the placebo arm. Three patients withdrew from the trial due to visual symptoms. All visual symptoms resolved spontaneously during or after drug discontinuation. There were no serious cardiac events after treatment withdrawl.

Interpretation:

Among patients with stable angina, treatment with ivabradine, a selective heart rate–lowering agent that acts specifically on the sinoatrial node, was associated with an improvement in ETT time to 1 mm ST-segment depression and time to symptom limiting angina. This was the first large clinical trial of ivabradine in patients with chronic stable angina, and the drug was shown to be efficacious and safe during the short study term, with the exception of an increase in visual symptoms with ivabradine. Given the positive findings of the trial, a trial with longer follow-up and longer duration of therapy to assess safety appears warranted. Ivabradine may be promising in patients with contraindications to standard stable angina therapy of beta blockers, nitrates, and calcium channel blockers.

References:

Circulation. 2003;107:817-823.

Clinical Topics: Arrhythmias and Clinical EP, Stable Ischemic Heart Disease, Implantable Devices, EP Basic Science, Chronic Angina

Keywords: Coronary Artery Disease, Follow-Up Studies, Angina, Stable, Nitrates, Catheterization, Sinoatrial Node, Heart Rate, Calcium Channel Blockers, Benzazepines, Nitroglycerin


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