B-type natriuretic peptide and the effect of ranolazine in patients with non-ST-segment elevation acute coronary syndromes: observations from the MERLIN-TIMI 36 (Metabolic Efficiency With Ranolazine for Less Ischemia in Non-ST Elevation Acute Coronary-Thrombolysis In Myocardial Infarction 36) trial

Abstract

Objectives: We designed a prospective evaluation of the interaction between B-type natriuretic peptide (BNP) and the effect of ranolazine in patients with acute coronary syndromes (ACS) as part of a randomized, blinded, placebo-controlled trial.

Background: Ranolazine is believed to exert anti-ischemic effects by reducing myocardial sodium and calcium overload and consequently ventricular wall stress. BNP increases in response to increased wall stress and is a strong risk indicator in ACS.

Methods: We measured plasma BNP in all available baseline samples (n = 4,543) among patients with non-ST-segment elevation ACS randomized to ranolazine or placebo in the MERLIN-TIMI 36 (Metabolic Efficiency With Ranolazine for Less Ischemia in Non-ST Elevation Acute Coronary-Thrombolysis In Myocardial Infarction 36) trial and followed them for a mean of 343 days. The primary end point was a composite of cardiovascular death, myocardial infarction, and recurrent ischemia. BNP elevation was defined as >80 pg/ml.

Results: Patients with elevated BNP (n = 1,935) were at significantly higher risk of the primary trial end point (26.4% vs. 20.4%, p < 0.0001), cardiovascular death (8.0% vs. 2.1%, p < 0.001), and myocardial infarction (10.6% vs. 5.8%, p < 0.001) at 1 year. In patients with BNP >80 pg/ml, ranolazine reduced the primary end point (hazard ratio [HR]: 0.79; 95% confidence interval [CI]: 0.66 to 0.94, p = 0.009). The effect of ranolazine in patients with BNP >80 pg/ml was directionally similar for recurrent ischemia (HR: 0.78; 95% CI: 0.62 to 0.98; p = 0.04) and cardiovascular death or myocardial infarction (HR: 0.83; 95% CI: 0.66 to 1.05, p = 0.12). There was no detectable effect in those with low BNP (p interaction value = 0.05).

Conclusions: Our findings indicate that ranolazine may have enhanced efficacy in high-risk patients with ACS identified by increased BNP. The interaction of biomarkers of hemodynamic stress and the effects of ranolazine warrants additional investigation. (Metabolic Efficiency With Ranolazine for Less Ischemia in Non-ST Elevation Acute Coronary Syndromes; NCT00099788).