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In a randomized trial involving patients who had a first stroke from an embolus of unknown source, rivaroxaban at a daily dose of 15 mg did not result in a lower incidence of recurrent stroke than aspirin at a dose of 100 mg. Bleeding rates were higher with rivaroxaban.

One month after the implantation of biodegradable-polymer sirolimus-eluting coronary stents, patients at high bleeding risk were randomly assigned to stop dual antiplatelet therapy or to continue it for at least 2 additional months. At 1 year, 1 month of DAPT was noninferior to the longer treatment for ischemic cardiovascular events and was superior for bleeding.

Ticagrelor (AZD6140) is the first reversibly binding oral P2Y(12) receptor antagonist in development for reduction of clinical thrombotic events in patients with acute coronary syndromes. The purpose of our studies was to determine the effect of single-ascending doses of ticagrelor in healthy subjects. In two randomised, double-blind, placebo-controlled single ascending dose studies, healthy subjects received oral doses of 0.1-100 mg or placebo (n = 25) and 30-400 mg or placebo (n = 13). Absorption of ticagrelor was rapid [median time to peak plasma concentration (t(max)) 1.3-2 h], as was the formation of its main (active) metabolite, AR-C124910XX (t(max) 1.5-3 h). For both ticagrelor and AR-C124910XX, the peak plasma concentration (C(max)) and area under the plasma concentration-time curve from time 0 to infinity (AUC(0-infinity)) increased in an apparently dose-proportional manner over the dose range studied, indicating linear pharmacokinetics. The mean terminal-phase half-life (t(1/2)) was approximately 7-8.5 h for ticagrelor and 8.5-10 h for AR-C124910XX; AR-C124910XX exposure was approximately one third that of ticagrelor. Inhibition of platelet aggregation (IPA) was dose related and was nearly complete at 2 h (mean 88-95%; final extent, with 20 microM adenosine diphosphate ADP) at doses of 100-400 mg. Linear and predictable pharmacokinetics of ticagrelor and AR-C124910XX were observed. A consistent and high IPA was maintained over 2-12 h, gradually decreasing with declining plasma concentration starting around 12 h post-dose, indicating that the IPA is reversible. Ticagrelor was well tolerated, with no serious or dose-related adverse events or notable changes in laboratory values observed.

New stroke occurred in 7% of patients who received clopidogrel–aspirin and in 9% who received only aspirin up to 72 hours after atherothrombotic stroke. Bleeding incidence was low but higher with dual antiplatelet treatment.

In a trial, patients who had undergone successful TAVR were assigned to rivaroxaban or antiplatelet therapy. In this substudy in patients who underwent CT, leaflet thickening and reduced leaflet motion at 90 days were less common with rivaroxaban. However, in the main trial, rivaroxaban was associated with a higher risk of death or thromboembolic complications and a higher risk of bleeding.

Coronary artery disease is a major cause of morbidity and mortality worldwide, and is a consequence of acute thrombotic events involving activation of platelets and coagulation proteins. Factor Xa inhibitors and aspirin each reduce thrombotic events but have not yet been tested in combination or against each other in patients with stable coronary artery disease. In this multicentre, double-blind, randomised, placebo-controlled, outpatient trial, patients with stable coronary artery disease or peripheral artery disease were recruited at 602 hospitals, clinics, or community centres in 33 countries. This paper reports on patients with coronary artery disease. Eligible patients with coronary artery disease had to have had a myocardial infarction in the past 20 years, multi-vessel coronary artery disease, history of stable or unstable angina, previous multi-vessel percutaneous coronary intervention, or previous multi-vessel coronary artery bypass graft surgery. After a 30-day run in period, patients were randomly assigned (1:1:1) to receive rivaroxaban (2·5 mg orally twice a day) plus aspirin (100 mg once a day), rivaroxaban alone (5 mg orally twice a day), or aspirin alone (100 mg orally once a day). Randomisation was computer generated. Each treatment group was double dummy, and the patients, investigators, and central study staff were masked to treatment allocation. The primary outcome of the COMPASS trial was the occurrence of myocardial infarction, stroke, or cardiovascular death. This trial is registered with ClinicalTrials.gov, number NCT01776424, and is closed to new participants. Between March 12, 2013, and May 10, 2016, 27 395 patients were enrolled to the COMPASS trial, of whom 24 824 patients had stable coronary artery disease from 558 centres. The combination of rivaroxaban plus aspirin reduced the primary outcome more than aspirin alone (347 [4%] of 8313 vs 460 [6%] of 8261; hazard ratio [HR] 0·74, 95% CI 0·65–0·86, p<0·0001). By comparison, treatment with rivaroxaban alone did not significantly improve the primary outcome when compared with treatment with aspirin alone (411 [5%] of 8250 vs 460 [6%] of 8261; HR 0·89, 95% CI 0·78–1·02, p=0·094). Combined rivaroxaban plus aspirin treatment resulted in more major bleeds than treatment with aspirin alone (263 [3%] of 8313 vs 158 [2%] of 8261; HR 1·66, 95% CI 1·37–2·03, p<0·0001), and similarly, more bleeds were seen in the rivaroxaban alone group than in the aspirin alone group (236 [3%] of 8250 vs 158 [2%] of 8261; HR 1·51, 95% CI 1·23–1·84, p<0·0001). The most common site of major bleeding was gastrointestinal, occurring in 130 [2%] patients who received combined rivaroxaban plus aspirin, in 84 [1%] patients who received rivaroxaban alone, and in 61 [1%] patients who received aspirin alone. Rivaroxaban plus aspirin reduced mortality when compared with aspirin alone (262 [3%] of 8313 vs 339 [4%] of 8261; HR 0·77, 95% CI 0·65–0·90, p=0·0012). In patients with stable coronary artery disease, addition of rivaroxaban to aspirin lowered major vascular events, but increased major bleeding. There was no significant increase in intracranial bleeding or other critical organ bleeding. There was also a significant net benefit in favour of rivaroxaban plus aspirin and deaths were reduced by 23%. Thus, addition of rivaroxaban to aspirin has the potential to substantially reduce morbidity and mortality from coronary artery disease worldwide. Bayer AG.

Milvexian, an oral activated Factor XI (FXIa) inhibitor, is in clinical studies where it may be combined with antiplatelet agents, including aspirin and/or clopidogrel, to prevent thromboembolic diseases. This phase I trial assessed safety, pharmacokinetics, and pharmacodynamics of milvexian coadministration with aspirin and/or clopidogrel in healthy participants through 3 drug-drug interaction studies using a 3-period, 3-treatment, crossover design. A total of 113 participants were randomized to receive milvexian (200 mg; twice daily for 5 days) or matched placebo coadministered with once-daily aspirin (325 mg for 5 days) and/or clopidogrel (Day 1: 300 mg; Days 2–5: 75 mg). Milvexian was safe and well tolerated, with and without aspirin and/or clopidogrel. Eight mild bleeding adverse events (AEs) were reported in 5 of 113 participants across various treatment arms. Peak and total exposures of milvexian were similar with or without clopidogrel and/or aspirin. Exposure-dependent prolongation of activated partial thromboplastin time and reduction of FXI clotting activity by milvexian were similar with coadministration of aspirin and/or clopidogrel. Milvexian, with or without coadministration of aspirin and/or clopidogrel, did not affect bleeding time or platelet aggregation. Administration of milvexian alone or with aspirin and/or clopidogrel was safe and well tolerated without increased incidence of AEs, including bleeding. Pharmacokinetic and pharmacodynamic effects of milvexian, including bleeding time, were similar with or without aspirin and/or clopidogrel. ClinicalTrials.gov Identifier : NCT03698513.

The optimal strategy for long-term antiplatelet maintenance for patients who underwent percutaneous coronary intervention (PCI) remains uncertain. This study aimed to compare the efficacy and safety of clopidogrel versus aspirin monotherapy in patients who completed a standard duration of dual antiplatelet therapy (DAPT) following PCI with drug-eluting stents. In this multicentre, randomised, open-label trial, patients aged 19 years or older at high risk of recurrent ischaemic events (previous myocardial infarction at any time before enrolment, medication-treated diabetes, or complex coronary lesions) who completed a standard duration of DAPT after PCI were randomly assigned (1:1) to receive clopidogrel (75 mg once a day) or aspirin (100 mg once a day) oral monotherapy at 26 sites in South Korea. The primary endpoint was the cumulative incidence of a composite of death from any cause, myocardial infarction, or stroke, assessed in the intention-to-treat population. Adverse events were captured as part of the secondary endpoints. This trial is registered with ClinicalTrials.gov (NCT04418479). It is closed to accrual and extended follow-up is ongoing. Between Aug 10, 2020, and July 31, 2023, 5542 patients were assessed for eligibility and 5506 were randomly assigned (2752 to clopidogrel monotherapy and 2754 to aspirin monotherapy). The median time between PCI and randomisation was 17·5 months (IQR 12·6–36·1 months). During a median follow-up period of 2·3 years (IQR 1·6–3·0), the primary endpoint occurred in 92 patients in the clopidogrel group and 128 patients in the aspirin group (Kaplan–Meier estimated 3-year incidence 4·4% [95% CI 3·4–5·4] vs 6·6% [5·4–7·8]; hazard ratio 0·71 [95% CI 0·54–0·93]; p=0·013). Death from any cause occurred in 50 patients in the clopidogrel group and 70 in the aspirin group (2·4% [1·6–3·1] vs 4·0% [2·9–5·0] at 3 years; 0·71 [0·49–1·02]); myocardial infarction in 23 patients in the clopidogrel group and 42 in the aspirin group (1·0% [0·6–1·4] vs 2·2% [1·4–2·9] at 3 years; 0·54 [0·33–0·90]); and stroke in 23 in the clopidogrel group and 29 in the aspirin group (1·3% [0·7–2·0] vs 1·3% [0·8–1·7] at 3 years; 0·79 [0·46–1·36]). There was no difference in the risk of bleeding between the clopidogrel and aspirin groups (3·0% [2·0–3·9] vs 3·0% [2·2–3·9] at 3 years; 0·97 [0·67–1·42]). Clopidogrel was not associated with a higher incidence of any adverse event compared with aspirin. Among patients who were at high risk of recurrent ischaemic events and who completed the standard duration of DAPT following PCI, clopidogrel monotherapy, compared with aspirin monotherapy, significantly reduced the cumulative incidence of a composite of death from any cause, myocardial infarction, and stroke, without an apparent increase in the risk of bleeding. Dong-A ST.

Background Morphine decreases the concentrations and effects of clopidogrel, which could lead to treatment failure in myocardial infarction. Objectives To clarify whether more potent P2Y 12 -inhibitors may provide an effective alternative, we examined drug–drug interactions between morphine and prasugrel. Methods Twelve healthy volunteers received 60 mg prasugrel with placebo or 5 mg morphine intravenously in a randomized, double-blind, placebo-controlled, cross-over trial. Pharmacokinetics were determined by liquid chromatography tandem mass spectrometry, and prasugrel effects were measured by platelet function tests. Results Morphine neither diminished total drug exposure (AUC), which was the primary endpoint, nor significantly delayed drug absorption of prasugrel. However, morphine reduced maximal plasma concentrations ( C max ) of prasugrel active metabolite by 31 % ( p  = 0.019). Morphine slightly, but not significantly, delayed the onset of maximal inhibition of platelet plug formation under high shear rates (30 vs. 20 min). Whole blood aggregation was not influenced. Conclusions Although morphine significantly decreases the maximal plasma concentrations of prasugrel active metabolite, it does not diminish its effects on platelets to a clinically relevant degree in healthy volunteers. However, it should be considered that the observed decrease in C max of prasugrel active metabolite caused by morphine co-administration may gain relevance in STEMI patients. Clinical Trial Registration : NCT01369186, EUDRA-CT#: 2010-023761-22.

Patients who had undergone successful TAVR were randomly assigned to receive either a rivaroxaban-based antithrombotic regimen or an antiplatelet-based antithrombotic regimen. At 17 months, the primary outcome of death or thromboembolic complications occurred more frequently with rivaroxaban.