Key Points
- Patients randomized to ranolazine had 37% fewer episodes of ventricular tachycardia compared with patients randomized to placebo.
- Patients who received ranolazine experienced fewer ventricular pauses lasting more than 3 seconds compared with patients who
received placebo.
In a prespecified secondary analysis of the Metabolic Efficiency with Ranolazine for Less Ischemia in Non-ST Elevation Acute
Coronary Syndromes (MERLIN)-TIMI 36 trial, ranolazine was associated with a reduction in the number of episodes of ventricular
tachycardia and supraventricular tachycardia. The results of the analysis were presented at the European Society of Cardiology
Congress 2007 in Vienna, Austria.
The intravenous (IV) formulation of ranolazine, which was used in this trial, is pending FDA approval.
The study's primary end point was the reduction of adverse cardiovascular events; treatment with ranolazine did not meet this
end point in patients with non-ST-elevation acute coronary syndrome (ACS). However, the drug was associated with significant
reductions in the risk of recurrent ischemia and worsening angina. The occurrence of arrhythmias on Holter monitoring was
an established secondary end point of the study.
The MERLIN-TIMI 36 trial included 6,560 patients with non-ST-elevation ACS and with clinical indicators of a moderate-to-high
risk of recurrent ischemic events. The patients were randomized to IV ranolazine (n=3,279) or placebo (n=3,281) in addition
to standard medical therapy. Mean follow-up was 12 months. Ranolazine 200 mg was initiated over 1 hour, followed by an 80-mg/h
infusion for ≤96 hours. The IV treatment was followed with oral extended-release ranolazine 1,000 mg BID. Because of previously observed prolongation of the QT interval in patients treated with approved dosages of ranolazine, patients
enrolled in the MERLIN trial received continuous 7-day Holter monitoring to assess the incidence of clinically significant
arrhythmias.
Prolongation of the QT interval with ranolazine "ranges from 2 to 6 msec, and this does raise the theoretical risk of ventricular
tachycardia," said Benjamin M. Scirica, MD, MPH, a cardiologist at Brigham and Women's Hospital, Boston, Massachusetts.
Patients randomized to ranolazine had 37% fewer episodes of ventricular tachycardia (P<.001) and 19% fewer episodes of supraventricular tachycardia (P<.001) compared with patients randomized to placebo. Patients who received ranolazine experienced fewer ventricular pauses
lasting >3 seconds compared with patients who received placebo (P<.001). Use of ranolazine was associated with a nonsignificant 27% reduction in new-onset atrial fibrillation compared with
placebo (P=.08).
In subgroup analyses, the use of ranolazine was associated with a consistent antiarrythmic effect in patients with depressed
left ventricular function and prior episodes of heart failure.
"This is the first clinical report of the antiarrhythmic effects of ranolazine and [it] supports the antiarrhythmic findings
that have been demonstrated in animal models," Dr Scirica said.
According to A.J. Camm, MD, chair of clinical cardiology, St George's Hospital Medical School, London, UK, "There remains
a regulatory concern about small degrees of QT prolongation since very small incidences of torsades de pointes are seen with
these [anti-arrhythmic] drugs."
Dr Camm said the mechanism of the effect of ranolazine is not clear. "It may be primarily anti-ischemic, or it may be more
related to a specific antiarrhythmic effect because of inhibition of the slow sodium current."
Dr Scirica said that, as a result of the new analysis, studies designed specifically to address the potential role of ranolazine
as an antiarrhythmic agent are warranted.