Dr. Conti raises an interesting conceptual point regarding our paper (1) concerning the implications of treatment with ranolazine. If ranolazine were to render each ischemic episode less severe than an ischemic episode in the absence of ranolazine, then despite a reduction in symptomatic ischemia (i.e., angina), ranolazine may be associated with more frequent asymptomatic ischemia and, by inference, may expose the patient to an increased risk of cardiac events.

The fundamental premise implicit in this question, however, that asymptomatic episodes of myocardial ischemia represent less severe ischemia than symptomatic episodes, has not been demonstrated in any clinical study. Episodes of asymptomatic ischemia recorded during ambulatory electrocardiogram (ECG) recordings demonstrate the same ECG characteristics of ischemia severity as episodes of symptomatic ischemia (2). There is no evidence to support the notion that asymptomatic ischemia is asymptomatic because it is less severe than symptomatic ischemia and, consequently, does not reach an “angina threshold.”

As Dr. Conti noted, patients in the MERLIN–TIMI 36 (Metabolic Efficiency With Ranolazine for Less Ischemia in Non–ST-Segment Elevation Acute Coronary Syndromes–Thrombolysis In Myocardial Infarction 36) trial had 7 days of continuous ECG recordings following admission with a non–ST-segment elevation acute coronary syndrome. The TIMI (Thrombolysis In Myocardial Infarction) investigators did, in fact, assess ischemic episodes throughout the recording period and found that there was not a significant difference in the rate of positive ECG recordings for ischemia (19.9% on ranolazine vs. 21.0% on placebo; p = 0.21) (3). The investigators did not specifically report the individual number of symptomatic and silent episodes of myocardial ischemia or their duration during ECG monitoring on ranolazine versus placebo. The aggregate risk of cardiovascular death or myocardial infarction in the MERLIN–TIMI 36 trial was similar for patients taking ranolazine and placebo and in the patient subset that was enrolled with prior chronic angina, fewer recurrent ischemic episodes were observed in the ranolazine-treated group after 1-year follow-up, and exercise duration was significantly greater (4). Thus, the hypothesis that converting symptomatic to silent ischemic episodes with ranolazine is harmful is unlikely to be valid.

It would be interesting for the TIMI investigators to address the specific question of the proportion of the number and duration of asymptomatic and symptomatic ischemia episodes in patients taking ranolazine versus placebo from their extensive continuous ECG database and to correlate these findings with 1-year outcome. This type of analysis would expand our knowledge on ranolazine treatment effects and could potentially more completely address the question that Dr. Conti has raised.