P2Y12 Inhibition in Patients Requiring Oral Anticoagulation after Percutaneous Coronary Intervention: The SWAP-AC-2 Study.

BACKGROUND: Among patients treated with a novel oral anticoagulant (NOAC) undergoing percutaneous coronary intervention (PCI), combination therapy with clopidogrel (i.e., known as dual antithrombotic therapy [DAT]) is the treatment of choice. However, there are concerns for individuals with impaired response to clopidogrel. OBJECTIVES: To assess the pharmacodynamic (PD) effects of clopidogrel vs. low-dose ticagrelor in patients with impaired clopidogrel response assessed by the ABCD-GENE score. METHODS: This was a prospective, randomized PD study of NOAC-treated patients undergoing PCI. Patients with an ABCD-GENE score ≥10 (n=39), defined as having impaired clopidogrel response, were randomized to low-dose ticagrelor (n=20; 60 mg/bid) or clopidogrel (n=19; 75 mg/qd). Patients with an ABCD-GENE<10 (n=42) were treated with clopidogrel (75 mg/qd; control cohort). PD assessments at baseline and 30 days post-randomization (trough and peak) were performed to assess P2Y12 signaling [VerifyNow P2Y12 reaction units (PRU), light transmittance aggregometry (LTA), and vasodilator-stimulated phosphoprotein (VASP)]; makers of thrombosis not specific to P2Y12 signaling were also assessed. The primary endpoint was PRU (trough levels) at 30 days. RESULTS: At 30 days, PRU levels were reduced with ticagrelor-based DAT compared with clopidogrel-based DAT at trough (23.0 [3.0-46.0] vs. 154.5 [77.5-183.0]; p<0.001) and peak (6.0 [4.0-14.0] vs. 129.0 [66.0-171.0]; p<0.001). Trough PRU levels in the control arm (104.0 [35.0-167.0]) were higher than ticagrelor-based DAT (p=0.005) and numerically lower than clopidogrel-based DAT (p=0.234). Results were consistent by LTA and VASP. Markers measuring other pathways leading to thrombus formation were largely unaffected. CONCLUSIONS: In NOAC-treated patients undergoing PCI with an ABCD-gene score ≥10, ticagrelor-based DAT using a 60 mg bid regimen reduced platelet P2Y12 reactivity compared to clopidogrel-based DAT.

Switching from Dual Antiplatelet Therapy with Aspirin Plus a P2Y12 Inhibitor to Dual Pathway Inhibition with Aspirin Plus Vascular-Dose Rivaroxaban: The Switching Anti-Platelet and Anti-Coagulant Therapy (SWAP-AC) Study.

BACKGROUND: To date, there are no data on switching to dual pathway inhibition (DPI) patients who have completed a guideline-recommended dual antiplatelet therapy (DAPT) regimen. OBJECTIVES: To assess the feasibility of switching from DAPT to DPI and to compare the pharmacodynamic (PD) profiles of these treatments. METHODS: This was a prospective, randomized, PD study conducted in 90 patients with chronic coronary syndrome (CCS) on DAPT with aspirin (81 mg/qd) plus a P2Y12 inhibitor (clopidogrel [75 mg/qd; n = 30], ticagrelor [90 mg/bid; n = 30], or prasugrel [10 mg/qd; n = 30]). Patients in each cohort were randomized to maintain DAPT or switch to DPI (aspirin 81 mg/qd plus rivaroxaban 2.5 mg/bid). PD assessments included: VerifyNow P2Y12 reaction units; light transmittance aggregometry following stimuli with adenosine diphosphate (ADP), tissue factor (TF), and a combination of collagen, ADP, and TF (maximum platelet aggregation %); thrombin generation (TG). Assays were performed at baseline and 30 days postrandomization. RESULTS: Switching from DAPT to DPI occurred without major side effects. DAPT was associated with enhanced P2Y12 inhibition, while DPI with reduced TG. Platelet-mediated global thrombogenicity (primary endpoint) showed no differences between DAPT and DPI in the ticagrelor (14.5% [0.0-63.0] vs. 20.0% [0.0-70.0]; p = 0.477) and prasugrel (20.0% [0.0-66.0] vs. 4.0% [0.0-70.0]; p = 0.482), but not clopidogrel (27.0% [0.0-68.0] vs. 53.0% [0.0-81.0]; p = 0.011), cohorts. CONCLUSION: In patients with CCS, switching from different DAPT regimens to DPI was feasible, showing enhanced P2Y12 inhibition with DAPT and reduced TG with DPI, with no differences in platelet-mediated global thrombogenicity between DPI and ticagrelor- and prasugrel-, but not clopidogrel-, based DAPT. CLINICAL TRIAL REGISTRATION: http://www. CLINICALTRIALS: gov Unique Identifier: NCT04006288.

Cangrelor in Patients With Coronary Artery Disease Pretreated With Ticagrelor: The Switching Antiplatelet (SWAP)-5 Study.

BACKGROUND: There are no studies specifically designed to rule out a drug-drug interaction (DDI) when cangrelor is used among patients who have been pretreated with ticagrelor. OBJECTIVES: This study sought to rule out a DDI among cangrelor-treated patients who have been pretreated with ticagrelor. METHODS: In this prospective, randomized, double-blind, placebo-controlled, crossover, pharmacokinetic (PK) and pharmacodynamic (PD) study, patients with coronary artery disease (N = 20) were pretreated with a 180-mg ticagrelor loading dose and after 1 hour randomized to placebo or cangrelor (bolus and infusion for 2 hours). Patients crossed over after 1 to 4 weeks of washout. PK analysis included ticagrelor plasma levels and its active metabolite. PD assessments included VerifyNow P2Y12 reaction units (PRU), light transmittance aggregometry, vasodilator-stimulated phosphoprotein, and Total Thrombus-Formation Analysis System. PK/PD assessments were performed at 7 time points. RESULTS: Compared with placebo, adding cangrelor to patients pretreated with ticagrelor resulted in a significant reduction in PRU at 30 minutes and 1 hour after starting infusion. At 2 hours after stopping cangrelor/placebo infusion, PRU were low and similar in both groups (16.9 vs 12.6; mean difference: 4.3; 95% CI: -28.6 to 37.3), meeting the noninferiority primary endpoint (predefined noninferiority margin 45 PRU). Consistent findings were shown with all PD assays. PK tracked PD findings with no differences between groups in plasma levels of ticagrelor and its metabolite. CONCLUSIONS: Compared with placebo, the use of cangrelor in patients pretreated with ticagrelor results in enhanced platelet inhibition with no differences in PK/PD profiles after discontinuation of drug infusion indicating the absence of a DDI. (PD and PK Profiles of Switching Between Cangrelor and Ticagrelor Following Ticagrelor Pre-treatment [SWAP-5]; NCT04634162).

Cutaneous leishmaniasis: an evolving disease with ancient roots.

BACKGROUND: Cutaneous leishmaniasis (CL) remains a prioritized neglected tropical disease. CL novel presentations call for updating its features. METHODS: A multiregional cohort of 396 patients with confirmed CL was reviewed. Lesion's clinical stage and eruption type were assigned. Disease was considered as extensive if numerous (≥5), large (>3 cm), disfiguring, threatening vital sensory organs, and/or older than 12 months. Microscopically, Ackerman's inflammatory pattern, Ridley's pattern (RP), and parasitic index (PI) were recorded. Microscopic variables pertaining to the organisms, epidermis, and host's inflammatory response were also assessed. All cases were confirmed and speciated molecularly. RESULTS: In our region, 71.8% of cases showed extensive disease with 15.7% exceeding 12 months duration. Leishmania tropica accounted for 91.3% of cases while Leishmania major constituted 8.7% and presented solely as dry lesions. The dominant inflammatory composite consisted of plasma cells, lymphocytes, and histiocytes. Granulomatous inflammation was present in 55.5%. Most cases showed interface changes (72.7%), spongiosis (75.3%), and marked epidermal hyperplasia (63.9%). Transepidermal elimination of organisms was present in 29.2% of cases. None of traditional classification patterns (clinical stage, microscopic pattern, and RP) showed the predicted linear correlation with lesion age. High and low PI levels correlated with early and healing microscopic patterns, respectively, but did not correlate with the corresponding RPs. PI was bimodal with peaks at 3-6 and 9-12 months. CONCLUSION: Cutaneous leishmaniasis is an evolving disease defying the traditional prediction classifications. Our study sets the ground for adopting updated clinical courses, microscopic presentation, and species mapping.