Despite the extensive use of pharmacotherapy and revascularization, the number of patients with chronic angina in developed countries is increasing. Based on a number of clinical studies * In 2006, the U.S. FDA approved a new antianginal drug ranolazine for the treatment of angina pectoris. Scientists who conducted a major test of MERLIN-TIMI 36, completed a planned analysis of efficacy and safety of ranolazine in a subgroup of study participants with acute coronary syndrome (ACS) without ST segment elevation ST, before whose hospitalization had stable angina.
Methods and progress in the study.
MERLIN-TIMI 36 (Metabolic Efficiency With Ranolazine for Less Ischemia in Non-ST Elevation Acute Coronary Syndromes) was an international randomized double-blind, placebo-controlled trial conducted in patients of ACS without ST segment elevation ST **. It excluded were patients with severe hepatic pathology, chronic hemodialysis therapy, drugs, extending the interval QT, cardiogenic shock, persistent segment elevation, ST, life expectancy <12 months.
Patients were randomized in a 1:1 ratio to intravenous ranolazine followed by taking ranolazine prolonged-release (1000 mg twice a day, with creatinine clearance <30 ml / minimum-minimum 500mg twice daily) or placebo within.
The primary endpoint of the study was a combination of death from cardiovascular causes, myocardial infarction (MI) and recurrent ischemia. Recurrent ischemia was defined as recurrent ischemia with changes in the electrocardiogram (ECG), recurrence of ischemia, requiring hospitalization or revascularization, worse functional class (FC), angina pectoris, require additional therapy.
Median follow-up was 350 days.
Of the 6,560 participants tested 3,565 (54%) had a history of angina pectoris. The characteristics of these patients in the ranolazine (n = 1789) or placebo (n = 1776) were well balanced. Average duration of history of angina was 5.2 years. Most of the patients one month before hospitalization were II (41%) and III-IV (32%), angina and received the most modern drug therapy: aspirin (95%), beta-blockers (89%), statins (78%). More than a third of patients (n = 866) suffered myocardial revascularization in history.
During hospitalization, coronary angiography was performed 49% of participants. At discharge, has been appointed to an average 1.9 antianginal drug (between-group differences are not significant, p = 0, 20), including nitrates and calcium antagonists in 58% of patients. For all the time observing the number of antianginal drugs was 2.9 per patient, while 67.5% of patients received 2 or more drugs of different classes.
The frequency of the primary endpoint in patients with previous angina pectoris was lower in the ranolazine group: 25, 2% against 29, 4% in the controls (risk ratio [RR] - 0.86, 95% confidence interval [CI], 0,75-0, 97; p = 0.017) the effect of ranolazine was obtained by reducing the frequency of recurrent ischemia (OR - 0.78, p = 0, 002), including reducing the risk of worsening angina (RR - 0.77, p = 0.048) and the need for intensification of antianginal therapy (RR - 0.77 p = 0, 005), the frequency of severe angina with ECG changes, the need for hospitalization and revascularization (11.9% versus 14.4% in control; Alternatively, - 0.81, p = 0.026). However, the incidence of cardiovascular mortality and MI between the groups did not differ (RR - 0.97, 95% CI 0,80-1,16, p = 0.71).
The effectiveness of ranolazine on the primary endpoint, and recurrence of ischemia was noted in a subgroup of 1,184 patients undergoing an early invasive strategy (RR - 0.75, p = 0.013 and OR - 0.71, p = 0.015 respectively). Interestingly, in the subgroup of patients without previous angina, ACS, efficacies of ranolazine on recurrent ischemia were observed (RR - 1.03, p = 0.83).
After 8 months of ranolazine therapy resulted in increased duration of exercise treadmill test (514 s versus 482 s in controls, p = 0.007), time to occurrence of angina (508 s versus 477 in controls, p = 0.002) and time to the onset of depression was ST 1 mm (509 s versus 479 s, respectively, p = 0, 003).
Ranolazine therapy generally was well tolerated. In the group of ranolazine were observed more frequently dizziness (12.4% versus 7.4% in controls), nausea (9.7% vs 6.1%) and constipation (8.5% vs 3.3%, respectively). Due to adverse events ranolazine abolished more frequently than placebo (8.1% vs 4.1%, p <0,001). However, overall mortality, the incidence of sudden-death and the frequency of symptomatic documented arrhythmia's did not differ between groups (RR- 1.01, p = 0.96, OR - 0.81, p = 0.035, OR - 0.98, p = 0.92 respectively).
Analysis of more than 3500 patients with ACS prior stable angina showed that in this population, ranolazine exerts the significant antianginal effect, significantly reducing the incidence of recurrent myocardial ischemia.
Drug therapy has demonstrated its safety without increasing the risk of total mortality, incidence of sudden death and symptomatic documented arrhythmia.
Based on the evidence obtained ranolazine is an effective antianginal and anti-ischemic medium, which, however, has no effect on mortality from cardiovascular causes and risk of MI and therefore, cannot be used for secondary cardiovascular prevention, as well as for the prevention of recurrence of angina in asymptomatic patients after ACS.
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