Pulmonary arterial hypertension is a progressive, debilitating disease caused by a dysregulation of the pulmonary vascular tone that inevitably leads to right heart failure and death without treatment. Until relatively recently, the treatment options for those afflicted by pulmonary arterial hypertension were limited; today, a greater understanding of the pathophysiology behind this disease has led to several evidence-based therapies that can improve pulmonary function and quality of life for these patients. One of the primary mediators of pulmonary vascular tone is endothelin-1, which is a potent and long-lasting vasoconstrictor. Macitentan is a second-generation endothelin receptor antagonist that acts selectively as a pulmonary vasodilator without the significant side effects noted with previous endothelin receptor antagonists. This review focuses on the mechanism of action and pharmacokinetics of macitentan, as well as the adverse effects, efficacy, and clinical uses of macitentan in the clinical trials to date. In addition, the authors briefly review clinical trials currently underway to illustrate possible future directions for the use of macitentan.

Abstract The effectiveness of aspirin and clopidogrel in patients with chronic kidney disease (CKD) suffering from acute cardiovascular events is unclear. High on treatment platelet reactivity (HTPR) has been associated with worse outcomes. Here, we assessed the association of dipstick proteinuria (DP) and renal function on HTPR and clinical outcomes. Retrospective cohort analysis of 261 consecutive, non-dialysis patients admitted for Major Adverse Cardiovascular Events (MACE) that had VerifyNow P2Y12 and VerifyNow Aspirin assays performed. HTPR was defined as P2Y12 reactivity unit (PRU) > 208 for clopidogrel and aspirin reaction units (ARU) > 550 for aspirin. Renal function was classified based on the estimated glomerular filtration rate (eGFR), and dipstick proteinuria was defined as ≥30 mg/dl of albumin detected on a spot analysis. All cause mortality, readmissions, and cardiac catheterizations were reviewed over 520 days. In patients on clopidogrel (n = 106), DP was associated with HTPR, independent of eGFR, diabetes mellitus, smoking or use of proton pump inhibitor (AOR = 4.76, p = 0.03). In patients with acute coronary syndromes, HTPR was associated with more cardiac catheterizations (p = 0.009) and readmissions (p = 0.032), but no differences in in-stent thrombosis or re-stenosis were noted in this cohort. In patients on aspirin (n = 155), no associations were seen between DP and HTPR. However, all cause mortality was significantly higher with HTPR in this group (p = 0.038). In this cohort, DP is an independent predictor of HTPR in patients on clopidogrel, but not aspirin, admitted to the hospital for MACE.

Introduction Increased platelet reactivity (PR) while on antiplatelet therapy is associated with worse outcomes. There are conflicting results regarding the influence of renal function on PR in patients taking clopidogrel. Here we assessed the relationship between renal function, PR, and outcomes in a community practice setting. Methods We retrospectively reviewed 98 consecutive, non-dialysis patients admitted for major adverse cardiovascular events (MACE) to our institution between 2011 and 2012 that had PR values measured with the VerifyNow P2Y12 Assay. High PR was defined as a PRU >230 and low PR as a PRU ≤178. Renal function was classified based on estimated glomerular filtration rate at the time of assay. All cause mortality, readmissions, length of stay (LOS), and number of cardiac catheterizations were reviewed over 455 days. Results The prevalence of PRU>230 was 100% in stage 4 and 5 CKD, 42.9% in stage 3, 53.8% in stage 2, and 53.3% in stage 1 (p=0.049, figure 1). In patients presenting with acute coronary syndromes (n=49), a significant positive association existed between PRU and total number of cardiac catheterizations (p=0.014). Overall patients with PRU value >230 had longer LOS when compared to those with PRU≤230 (median of 2 days vs. 1 day, p=0.049). A positive correlation between HbA1c and PRU was also found (p=0.018). All 8 deaths had abnormal PRU (3 patients with PRU≤178, 5 patients with PRU>230). Conclusion Advanced CKD is associated with impairment of platelet inhibition by clopidogrel measured with the VerifyNow P2Y12 Assay. Elevated PRU is associated with worse outcomes. We observed a significant correlation between HbA1c and degree of platelet inhibition.