Rationale and design of the AXIOMATIC-SSP phase II trial: Antithrombotic treatment with factor XIa inhibition to Optimize Management of Acute Thromboembolic events for Secondary Stroke Prevention
Mukul SharmaCarlos A. MolinaḰazunori ToyodaDániel BereczkiScott E. KasnerHelmi L. LutsepGeorgios TsivgoulisGeorge NtaiosAnna CzłonkowskaAshfaq ShuaibPierre AmarencoMatthias EndresHans‐Christoph DienerDavid GailaniAnja KahlMark DonovanVidya PereraDanshi LiGraeme J. Hankey
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BackgroundIndividuals with ischemic stroke or transient ischemic attack (TIA) have a high early risk of ischemic stroke despite dual antiplatelet therapy. The risk of ischemic stroke, and associated disability, represents a significant unmet clinical need. Genetic variants resulting in reduced factor XI levels are associated with reduced risk for ischemic stroke but are not associated with increased intracranial bleeding. Milvexian is an oral small-molecule inhibitor of FXIa that binds activated factor XI with high affinity and selectivity and may reduce the risk of stroke when added to antiplatelet drugs without significant bleeding. We aimed to evaluate the dose-response relationship of milvexian in participants treated with dual antiplatelets.MethodsWe began a phase II, double-blinded, randomized, placebo-controlled trial at 367 sites in 2019. Participants (N = 2366) with ischemic stroke (National Institutes of Health Stroke Scale score ≤7) or high-risk TIA (ABCD2Xu J Wang A Wangqin R et al.Efficacy of clopidogrel for stroke depends on CYP2C19 genotype and risk profile.Ann Neurol. 2019; 86: 419-426Crossref PubMed Scopus (18) Google Scholar score ≥6) were randomized to 1 of 5 doses of milvexian or placebo for 90 days. Participants also received clopidogrel 75 mg daily for the first 21 days and aspirin 100 mg for 90 days. The efficacy endpoint was the composite of ischemic stroke or incident infarct on magnetic resonance imaging. Major bleeding, defined as type 3 or 5 bleeding according to the Bleeding Academic Research Consortium, was the safety endpoint. Participant follow-up will end in 2022.ConclusionThe AXIOMATIC-SSP trial will evaluate the dose-response of milvexian for ischemic stroke occurrence in participants with ischemic stroke or TIA.Keywords:
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Clopidogrel Prescribing and Concordance with the Pharmaceutical Benefits Scheme in Hospital Patients
ABSTRACT Background Clopidogrel is used for the secondary prevention of cerebrovascular and cardiovascular events. Clopidogrel has a similar safety profile to low‐dose aspirin but is considerably more expensive. Clopidogrel is subsidised for restricted indications via the Pharmaceutical Benefits Scheme (PBS). Aim To examine clopidogrel prescribing in hospital; and to identify patients discharged on clopidogrel according to PBS criteria. Method Cross‐sectional evaluation of patients started on clopidogrel (July 2006 to June 2007) at the Royal Darwin and Royal Hobart Hospitals. Clopidogrel prescribing was examined and the indication for discharge on clopidogrel was documented. The primary outcome was concordance between clopidogrel use and PBS criteria. Results Data were collected for 385 patients. 54% of patients from the Royal Darwin Hospital and 39% of patients from the Royal Hobart Hospital discharged on clopidogrel met PBS criteria. The main reason for noncompliance with the PBS was absence of a history of cardiovascular or cerebrovascular events while on low‐dose aspirin and an absence of contraindications to aspirin at the time of clopidogrel prescribing. Conclusion Although clopidogrel prescribing at the hospitals was often not in accordance with PBS criteria, in most cases prescribing was based on the available evidence.
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Both aspirin and clopidogrel reduce the rate of cardiovascular events in patients with coronary heart disease. We estimated the cost effectiveness of the increased use of aspirin, clopidogrel, or both for secondary prevention in patients with coronary heart disease.
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Background: Studies regarding the efficacy of Aspirin alone versus combination of Aspirin and Clopidogrel in patients with Unstable Angina are many. But, studies on the comparative role of Aspirin alone versus Aspirin plus Clopidogrel in the background of Acute Coronary Syndrome (ACS) with ST segment elevation myocardial infarction (STEMI) were very few, at the time of starting of this study. Keeping this in mind present study was conducted to compare the efficacy and safety of Aspirin alone with combination of aspirin plus Clopidogrel in prevention of events in Acute Coronary Syndrome with ST segment elevation myocardial infarction.Methods: Patients who are admitted to intensive coronary care unit within 12hrs after the onset of symptoms and whose diagnosis as ACS with ST segment elevation has been established were included in this study. Patients in group 1 received 325 mg of aspirin as loading dose, followed by 150 mg once daily. Patients in group 2 received a combination of aspirin and Clopidogrel 325 and 300 mg, respectively, as loading dose, followed by 150 mg of aspirin and 75 mg of Clopidogrel daily. All the patients received a fibrinolytic agent. Treatment response was weighed against the primary and secondary expected outcomes.Results: Addition of Clopidogrel to Aspirin resulted in significant reduction in severe ischaemia not requiring urgent revascularisation i.e.; 32% in Aspirin alone group versus 10% in Aspirin plus Clopidogrel group and recurrent angina with no ECG changes i.e.; 42% in aspirin alone group versus 20% in Aspirin plus Clopidogrel group. Similarly, there was an improvement in ejection fraction at the end of one month i.e.; 0.3% in Aspirin alone group versus 1.85% in Aspirin plus Clopidogrel group.Conclusions: This study demonstrates the benefit of adding Clopidogrel to Aspirin for myocardial infarction with ST-segment elevation. Treatment with a loading dose of 300mg of Clopidogrel followed by a daily dose of 75mg, in addition to aspirin, resulted in significant improvement in the secondary efficacy related outcomes in patients with acute coronary syndrome with ST-segment elevation.
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Controversy currently surrounds the issue of proton pump inhibitor (PPI)–clopidogrel co-therapy. Some studies have reported that PPIs increase the rate of adverse cardiovascular outcomes in clopidogrel users, although others have not confirmed this. The Food and Drug Administration has advised against the use of certain PPIs by patients who are on clopidogrel. In the first outcomes study from Europe to examine this issue, van Boxel and colleagues found an increased rate of adverse cardiovascular—and gastrointestinal—outcomes among clopidogrel users taking a PPI. The most plausible explanation for this is that it reflects channeling bias.
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Recent studies have suggested an interaction between clopidogrel and proton-pump inhibitors (PPIs) that might attenuate clopidogrel activity. To assess the clinical relevance of this interaction, researchers studied 18,000 people (age, ≥65) in the U.S. and Canada who had been newly treated with clopidogrel after acute coronary …
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Background— It is not known whether further suppression of platelet function can be achieved with clopidogrel beyond that provided by currently recommended loading and maintenance doses. We performed a comparative assessment of the antiplatelet effects of a 600-mg loading dose of clopidogrel given to patients with and without chronic clopidogrel therapy. Methods and Results— Those eligible for this prospective study were aspirin-treated patients with suspected or documented coronary artery disease admitted to hospital for coronary angiography. Two series of 20 consecutive patients each were assessed in this study. The first series included patients who had never received clopidogrel (first-use group); the second series included patients on chronic therapy with a daily dose of 75 mg clopidogrel for ≥1 month (chronic therapy group). Blood samples were drawn before and 6 hours after oral administration of 600 mg clopidogrel for aggregometry and flow cytometry studies. In the first-use group, loading with 600 mg clopidogrel inhibited ADP 5 μmol/L–induced platelet aggregation from 90±9% to 51±19% ( P <0.001). In the chronic therapy group, loading with 600 mg clopidogrel yielded further inhibition of ADP 5 μmol/L–induced platelet aggregation in addition to that achieved by the maintenance dose of 75 mg/d, from 52±14% to 33±12% ( P <0.001). In both groups, 600 mg clopidogrel loading significantly inhibited ADP-induced expression of glycoprotein IIb/IIIa and P-selectin receptors. Conclusions— Further platelet inhibition can be achieved with clopidogrel in addition to that provided by currently recommended loading and maintenance doses. Higher doses may be warranted after assessment of their clinical efficacy and safety.
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Current consensus recommendations that patients prescribed clopidogrel plus aspirin should receive a proton pump inhibitor(PPI) to reduce gastrointestinal bleeding.However,recent studies have shown higher rates of adverse cardiovascular events in patients on PPI and clopidogrel,in comparison to patients on clopidogrel only.This article reviews the controversies and advances in clinical research on the interaction between clopidogrel and PPI.
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Objective To study the relationship between plasma concentration of clopidogrel and difference of individual response or major adverse cardiovascular events(MACE) in patients with acute coronary syndrome(ACS) after PCI. Methods The patients(n=200) diagnosed as CHD and having selected PCI were chosen and divided into high-reaction clopidogrel group(ADP inhibitory rate80%, n=105) and low-reaction clopidogrel group(ADP inhibitory rate80%, n=95) according to the outcomes of thrombelastogram(TEG). The plasma concentration of clopidogrel, 2-oxo-clopidogrel and carboxylic acid metabolites were detected by using high-throughput liquid chromatography-mass spectrometric(HTLC-MS/MS). The incidence of MACE was followed up after PCI for one year. Results The plasma concentration of clopidogrel was significantly lower, and that of carboxylic acid metabolites was slightly higher in low-reaction clopidogrel group than those in high-reaction clopidogrel group(all P0.05). The difference in plasma concentration of 2-oxo-clopidogrel had no statistical significance between two groups(P0.05). The incidences of relapsed angina and bleeding events were higher in low-reaction clopidogrel group than those in high-reaction clopidogrel group(P0.05). Conclusion The plasma concentration of clopidogrel effects on individual response, and low reaction to clopidogrel will increase the risk of MACE in clinic.
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Summary Clopidogrel is an effective and specific inhibitor of ADP-induced platelet aggregation. After metabolic activation, the active clopidogrel metabolite irreversibly impairs the human platelet P2Y12 ADP receptor. Gialpha-protein activation and inhibition of vasodilator-stimulated phosphoprotein (VASP) phosphorylation are two key elements of the P2Y12 receptor pathway suitable for quantitation of clopidogrel effects. So far, only limited data exist about a diminished responsiveness to clopidogrel and underlying possible mechanisms. We investigated clopidogrel effects in 57 patients after percutaneous coronary intervention and stent implantation by flow cytometry for the analysis of intracellular VASP phosphorylation. Patients were treated with a 300 mg clopidogrel loading dose, followed by 75 mg/day clopidogrel in combination with 100 mg/day aspirin. Samples were drawn after a median of 5 days of clopidogrel treatment. Considerable differences in the responsiveness to clopidogrel could be observed and it was shown that 17.5% (10/57) of the patients revealed an inadequate responsiveness to clopidogrel despite continuation of clopidogrel intake. Comparable amounts of Gialpha and VASP were found in two clopidogrel low-responding patients as well as in two responding patients. To exclude a molecular defect of P2Y12 ADP receptor, the P2Y12 receptor gene of eight clopidogrel treated patients (seven patients with inadequate responsiveness, one responder) was sequenced. We only found a single silent mutation in exon 2 at position 1828 (GA). We suggest that individual differences in clopidogrel metabolization could cause relevant variations in clopidogrel responsiveness despite the use of a 300 mg clopidogrel loading dose.
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