Mechanism of action of the new anti-ischemia drug ranolazine

Myocardial ischemia is associated with reduced ATP fluxes and decreased energy supply resulting in disturbances of intracellular ion homeostasis in cardiac myocytes. In the recent years, increased persistent (late) sodium current was suggested to contribute to disturbed ion homeostasis by elevating intracellular sodium concentration with subsequent elevation of intracellular calcium. The new anti-ischemia drug ranolazine, a specific inhibitor of late sodium current, reduces sodium overload and hence ameliorates disturbed ion homeostasis. This is associated with symptomatic improvement of angina in patients. Moreover, ranolazine was shown to exhibit anti-arrhythmic effects. In the present article, we review the relevant pathophysiological concepts for the role of late sodium inhibition and summarize the most recent data from basic as well as clinical studies

Expert consensus document: A 'diamond' approach to personalized treatment of angina.

In clinical guidelines, drugs for symptomatic angina are classified as being first choice (β-blockers, calcium-channel blockers, short-acting nitrates) or second choice (ivabradine, nicorandil, ranolazine, trimetazidine), with the recommendation to reserve second-choice medications for patients who have contraindications to first-choice agents, do not tolerate them, or remain symptomatic. No direct comparisons between first-choice and second-choice treatments have demonstrated the superiority of one group of drugs over the other. Meta-analyses show that all antianginal drugs have similar efficacy in reducing symptoms, but provide no evidence for improvement in survival. The newer, second-choice drugs have more evidence-based clinical data that are more contemporary than is available for traditional first-choice drugs. Considering some drugs, but not others, to be first choice is, therefore, difficult. Moreover, double or triple therapy is often needed to control angina. Patients with angina can have several comorbidities, and symptoms can result from various underlying pathophysiologies. Some agents, in addition to having antianginal effects, have properties that could be useful depending on the comorbidities present and the mechanisms of angina, but the guidelines do not provide recommendations on the optimal combinations of drugs. In this Consensus Statement, we propose an individualized approach to angina treatment, which takes into consideration the patient, their comorbidities, and the underlying mechanism of disease

Racial differences in human platelet PAR4 reactivity reflect expression of PCTP and miR-376c.

Racial differences in the pathophysiology of atherothrombosis are poorly understood. We explored the function and transcriptome of platelets in healthy black (n = 70) and white (n = 84) subjects. Platelet aggregation and calcium mobilization induced by the PAR4 thrombin receptor were significantly greater in black subjects. Numerous differentially expressed RNAs were associated with both race and PAR4 reactivity, including PCTP (encoding phosphatidylcholine transfer protein), and platelets from black subjects expressed higher levels of PC-TP protein. PC-TP inhibition or depletion blocked PAR4- but not PAR1-mediated activation of platelets and megakaryocytic cell lines. miR-376c levels were differentially expressed by race and PAR4 reactivity and were inversely correlated with PCTP mRNA levels, PC-TP protein levels and PAR4 reactivity. miR-376c regulated the expression of PC-TP in human megakaryocytes. A disproportionately high number of microRNAs that were differentially expressed by race and PAR4 reactivity, including miR-376c, are encoded in the DLK1-DIO3 locus and were expressed at lower levels in platelets from black subjects. These results suggest that PC-TP contributes to the racial difference in PAR4-mediated platelet activation, indicate a genomic contribution to platelet function that differs by race and emphasize a need to consider the effects of race when developing anti-thrombotic drugs

Vorapaxar for secondary prevention of thrombotic events for patients with previous myocardial infarction: a prespecified subgroup analysis of the TRA 2°P-TIMI 50 trial

Background Vorapaxar inhibits platelet activation by antagonising thrombin-mediated activation of the protease-activated receptor 1 on human platelets. The effect of adding other antiplatelet drugs to aspirin for long-term secondary prevention of thrombotic events in stable patients with previous myocardial infarction is uncertain. We tested this effect in a subgroup of patients from the Thrombin Receptor Antagonist in Secondary Prevention of Atherothrombotic Ischemic Events (TRA 2 degrees P)-TIMI 50 trial. Methods In TRA 2 degrees P-TIMI 50-a randomised, placebo-controlled, parallel trial-we randomly assigned patients with a history of atherothrombosis to receive vorapaxar (2.5 mg daily) or matching placebo in a 1:1 ratio. Patients, and those giving treatment, assessing outcomes, and analysing results were masked to treatment allocation. Patients with a qualifying myocardial infarction within the previous 2 weeks to 12 months were analysed as a pre-defined subgroup. The primary efficacy endpoint was cardiovascular death, myocardial infarction, or stroke, analysed by intention to treat. We analysed events by Kaplan-Meier analysis and compared groups with a Cox proportional hazard model. TRA 2 degrees P-TIMI 50 is registered at ClinicalTrials.gov (NCT00526474). Findings 17 779 of 26 449 patients had a qualifying myocardial infarction and were assigned treatment (8898 to vorapaxar and 8881 to placebo). Median follow-up was 2.5 years (IQR 2.0-2.9). Cardiovascular death, myocardial infarction, or stroke occurred in 610 of 8898 patients in the vorapaxar group and 750 of 8881 in the placebo group (3-year Kaplan-Meier estimates 8.1% vs 9.7%, HR 0.80, 95% CI 0.72-0.89; p<0.0001). Moderate or severe bleeding was more common in the vorapaxar group versus the placebo group (241/8880 [3.4%, 3-year Kaplan-Meier estimate] vs 151/8849 [2.1%, 3-year Kaplan-Meier estimate], HR 1.61, 95% CI 1.31-1.97; p<0.0001). Intracranial haemorrhage occurred in 43 of 8880 patients (0.6%, 3-year Kaplan-Meier estimate) with vorapaxar versus 28 of 8849 (0.4%, 3-year Kaplan-Meier estimate) with placebo (p=0.076). Other serious adverse events were equally distributed between groups. Interpretation For patients with a history of myocardial infarction, inhibition of protease-activated receptor 1 with vorapaxar reduces the risk of cardiovascular death or ischaemic events when added to standard antiplatelet treatment, including aspirin, and increases the risk of moderate or severe bleeding