Development and assessment of immediate-release tablets containing clopidogrel bisulphate & aspirin-strategy for optimizing the combination formulation.

The main goal of the study was to improve the compliance and convenience of patients by designing and development of an immediate release (IR) fixed-dose combination (Clopidogrel bisulphate and Aspirin) tablets. The proposed combination product utilizes Clopidogrel to protect the moisture-sensitive aspirin component, enhancing its stability against atmospheric conditions. Response-surface approach (Design Expert vs. 13) was used to generate this IR tablet by calculating the right composition of independent variables such as Microcrystalline cellulose 102, pregelatinized starch and Hydroxypropyl cellulose. 32 factorial design was used to estimate the effects of these independent variables on the responses of dependent variables (disintegration & friability) and constructed a total of nine (9) formulations. Pre and Post formulation, quality control parameters were investigated as per pharmacopeia. A systematic approach was used for the optimization process and a prototype checkpoint batch (CPB) based on the better contrast of independent variables was prepared. In vitro analysis of formulations was carried out to estimate the responses. Friability was found in the range of 0.088-1.076%w/w, except F1 = 1.076 all are within limits (NMT 1.0%). Disintegration time was recorded 7.3 ± 1.20 as lower and 24.5 ± 1.63 min was the highest. The release of drugs from their dosage form was fast and rapid, for clopidogrel after 15min was 70.42-96.82% with SD ± 8.71 and aspirin was 69.88-91.49% in 15 min with SD ± 6.41, all the tablets were released more than 80% in 20 min. The stability outcomes of CPB tablets after 15 days of stress study (60 ± 2°C and 75 ± 5%) indicated good compatibility and stability of APIs with excipients. It was concluded that the direct compression method can be preferred to prepare a combination product with cost-effectiveness. It was also concluded that the proposed methodology could increase Aspirin's stability and allow for an aqueous coating system to finish the product with a film coating. By using Design Expert software, the best composition of the formulation can be selected and optimized in a short period of time with minimum trial and errors. The results also demonstrated that the use of a fixed-dose combination tablet instead of the individual is expected to be more convenient to patients and thus improves patient compliance and decreases the occurrence of adverse effects and side effects.

An Evaluation of the Cost-effectiveness of Comprehensive MTM Integrated with Point-of-Care Phenotypic and Genetic Testing for U.S. Elderly Patients After Percutaneous Coronary Intervention.

BACKGROUND: Poor health outcomes after percutaneous coronary intervention (PCI) in elderly patients is an area of concern among policymakers and administrators. In an effort to determine the best strategy to improve outcomes among elderly patients who underwent PCI, several studies have evaluated the cost-effectiveness of genotype-guided antiplatelet therapy compared with universal use of any one of the antiplatelet drugs indicated for patients with acute coronary syndrome (ACS) who underwent PCI. The results have either been in favor of genotype-guided antiplatelet therapy or universal use of ticagrelor. However, no study has yet evaluated the cost-effectiveness of pharmacist-provided face-to-face medication therapy management (MTM) combined with point-of-care genotype-guided antiplatelet therapy (POCP) when compared with universal use of ticagrelor or clopidogrel for the elderly after PCI. OBJECTIVE: To evaluate the cost-effectiveness of a pharmacist integration of MTM with POCP (MTM-POCP) when compared with universal use of ticagrelor or clopidogrel combined with MTM (MTM-ticagrelor or MTM-clopidogrel). METHODS: We conducted a cost-effectiveness analysis from the perspective of the U.S. health care system. A hybrid model, consisting of a 1-year decision tree and a 20-year Markov model, was used to simulate a cohort of elderly patients (aged at least 65 years) with ACS who underwent PCI. Treatment strategies available to patients were POCP, POCP-MTM, MTM-clopidogrel, or MTM-ticagrelor. Data used to populate the model were obtained from the PLATO trial and other published studies. Outcome measures were costs, quality-adjusted life-years (QALYs) and incremental cost per QALY gained. A deterministic and probabilistic sensitivity analysis was conducted to account for the joint uncertainty around the key parameters of the model. Finally, a benchmark willingness to pay of $50,000-200,000 was considered. RESULTS: The use of PCOP (with dual antiplatelet therapy) resulted in 5.29 QALYs, at a cost of $50,207. MTM-clopidogrel resulted in 5.34 QALYs, at a cost of $50,011. The use of POCP-MTM resulted in 5.36 QALYs, at a cost of $50,270. Finally, MTM-ticagrelor resulted in 5.42 QALYs, at a cost of $53,346. MTM-ticagrelor was found to be cost-effective compared with MTM-clopidogrel or MTM-POCP, irrespective of the willingness to pay. The deterministic and probabilistic sensitivity analyses confirmed the robustness of the base-case analysis. CONCLUSIONS: The combination of MTM-ticagrelor was cost-effective when compared with MTM-POCP or MTM-clopidogrel. The transitional probabilities, however, were mostly based on published studies. Analysis based on a prospective randomized clinical study, comparing all the treatment strategies included in this study, is warranted to confirm our findings. DISCLOSURES: No outside funding supported this study. The authors have no conflicts of interest to declare. Study concept and design were contributed by Okere and Diaby. Ezendu took the lead in data collection, along with Okere. Data interpretation was performed by all the authors. The manuscript was written by Okere, Diaby, and Berthe and revised by Okere and Diaby.

Antiplatelet therapy with aspirin, clopidogrel, and dipyridamole versus clopidogrel alone or aspirin and dipyridamole in patients with acute cerebral ischaemia (TARDIS): a randomised, open-label, phase 3 superiority trial.

BACKGROUND: Intensive antiplatelet therapy with three agents might be more effective than guideline treatment for preventing recurrent events in patients with acute cerebral ischaemia. We aimed to compare the safety and efficacy of intensive antiplatelet therapy (combined aspirin, clopidogrel, and dipyridamole) with that of guideline-based antiplatelet therapy. METHODS: We did an international, prospective, randomised, open-label, blinded-endpoint trial in adult participants with ischaemic stroke or transient ischaemic attack (TIA) within 48 h of onset. Participants were assigned in a 1:1 ratio using computer randomisation to receive loading doses and then 30 days of intensive antiplatelet therapy (combined aspirin 75 mg, clopidogrel 75 mg, and dipyridamole 200 mg twice daily) or guideline-based therapy (comprising either clopidogrel alone or combined aspirin and dipyridamole). Randomisation was stratified by country and index event, and minimised with prognostic baseline factors, medication use, time to randomisation, stroke-related factors, and thrombolysis. The ordinal primary outcome was the combined incidence and severity of any recurrent stroke (ischaemic or haemorrhagic; assessed using the modified Rankin Scale) or TIA within 90 days, as assessed by central telephone follow-up with masking to treatment assignment, and analysed by intention to treat. This trial is registered with the ISRCTN registry, number ISRCTN47823388. FINDINGS: 3096 participants (1556 in the intensive antiplatelet therapy group, 1540 in the guideline antiplatelet therapy group) were recruited from 106 hospitals in four countries between April 7, 2009, and March 18, 2016. The trial was stopped early on the recommendation of the data monitoring committee. The incidence and severity of recurrent stroke or TIA did not differ between intensive and guideline therapy (93 [6%] participants vs 105 [7%]; adjusted common odds ratio [cOR] 0·90, 95% CI 0·67-1·20, p=0·47). By contrast, intensive antiplatelet therapy was associated with more, and more severe, bleeding (adjusted cOR 2·54, 95% CI 2·05-3·16, p<0·0001). INTERPRETATION: Among patients with recent cerebral ischaemia, intensive antiplatelet therapy did not reduce the incidence and severity of recurrent stroke or TIA, but did significantly increase the risk of major bleeding. Triple antiplatelet therapy should not be used in routine clinical practice. FUNDING: National Institutes of Health Research Health Technology Assessment Programme, British Heart Foundation.

The role of platelet reactivity assessment in dual antiplatelet prophylaxis after transcatheter aortic valve implantation.

BACKGROUND: Dual antiplatelet therapy (DAPT) is recommended prophylaxis after transcatheter aortic valve implantation (TAVI). The usefulness of platelet reactivity (PLTR) tests in predicting the safety of periprocedural DAPT in the TAVI population is unknown. AIM: To analyze the value of aspirin/clopidogrel PLTR testing in predicting the risk of in-hospital TAVI-related bleeding. METHODS: PLTR, expressed as P2Y12/aspirin reaction units (PRU/ARU), was performed using optical aggregometry with the VerifyNow® device, in the 24h before and on the sixth day after TAVI. Follow-up was by telephone. Bleeding was defined according to VARC-2, and comprised in-hospital, major and life-threatening events. RESULTS: Overall, 100 patients undergoing TAVI were included; 30 (30%) had bleeding. Clopidogrel PLTR before TAVI (area under the curve [AUC] 0.686, 95% confidence interval [CI] 0.542-0.808; P=0.02) and after TAVI (AUC 0.970, 95% CI 0.904-0.995; P<0.001) correlated with bleeding, with PRU cut-off values of ≤204 and ≤124 as bleeding predictors, respectively. A significant periprocedural decrease in clopidogrel PLTR was noted, with a PRU drop of >78 as bleeding predictor (AUC 0.851, 95% CI 0.725-0.935; P<0.001). Only postprocedural aspirin PLTR was associated with bleeding (AUC 0.697, 95% CI 0.585-0.794; P=0.008). Follow-up (359±73 days after TAVI) included 85 patients (85%) (after exclusion for in-hospital death [n=4] and lack of contact [n=11]). Major bleeding was noted in four patients (4.7%), all on combined prophylaxis. CONCLUSIONS: TAVI-related bleeding occurs mainly during the procedure or in the early postprocedural period. Testing of periprocedural clopidogrel PLTR, but not aspirin PLTR, seems useful because of its predictive value for TAVI-related bleeding. PLTR testing suggests that premedication with clopidogrel, enhanced response to clopidogrel early after TAVI and significant periprocedural drop in clopidogrel PLTR might increase the risk of TAVI-related bleeding.

Cost-effectiveness analysis of 30-month vs 12-month dual antiplatelet therapy with clopidogrel and aspirin after drug-eluting stents in patients with acute coronary syndrome.

Continuation of dual antiplatelet therapy (DAPT) beyond 1 year reduces late stent thrombosis and ischemic events after drug-eluting stents (DES) but increases risk of bleeding. We hypothesized that extending DAPT from 12 months to 30 months in patients with acute coronary syndrome (ACS) after DES is cost-effective. A lifelong decision-analytic model was designed to simulate 2 antiplatelet strategies in event-free ACS patients who had completed 12-month DAPT after DES: aspirin monotherapy (75-162 mg daily) and continuation of DAPT (clopidogrel 75 mg daily plus aspirin 75-162 mg daily) for 18 months. Clinical event rates, direct medical costs, and quality-adjusted life-years (QALYs) gained were the primary outcomes from the US healthcare provider perspective. Base-case results showed DAPT continuation gained higher QALYs (8.1769 vs 8.1582 QALYs) at lower cost (USD42 982 vs USD44 063). One-way sensitivity analysis found that base-case QALYs were sensitive to odds ratio (OR) of cardiovascular death with DAPT continuation and base-case cost was sensitive to OR of nonfatal stroke with DAPT continuation. DAPT continuation remained cost-effective when the ORs of nonfatal stroke and cardiovascular death were below 1.241 and 1.188, respectively. In probabilistic sensitivity analysis, DAPT continuation was the preferred strategy in 74.75% of 10 000 Monte Carlo simulations at willingness-to-pay threshold of 50 000 USD/QALYs. Continuation of DAPT appears to be cost-effective in ACS patients who were event-free for 12-month DAPT after DES. The cost-effectiveness of DAPT for 30 months was highly subject to the OR of nonfatal stroke and OR of death with DAPT continuation.

Quantifying Ischemic Risk After Percutaneous Coronary Intervention Attributable to High Platelet Reactivity on Clopidogrel (From the Assessment of Dual Antiplatelet Therapy with Drug-Eluting Stents Study).

Patients at high risk of thrombotic events after percutaneous coronary intervention (PCI) may potentially benefit from intensified antiplatelet therapy. However, more potent antiplatelet therapy would be expected to only overcome risk that is mediated by high platelet reactivity (PR). We used mediation analysis to determine the contribution of residual PR to the 2-year risk of major adverse cardiac events (MACE; the composite of cardiac death, myocardial infarction, or stent thrombosis) associated with clinical risk factors after PCI with drug-eluting stents (DES) in 8,374 patients from the prospective, multicenter Assessment of Dual AntiPlatelet Therapy with Drug-Eluting Stents (ADAPT-DES) registry. Residual PR on clopidogrel, as measured by the VerifyNow P2Y12 point-of-care assay, was included as a continuous linear mediator variable in Cox proportional hazards regression. Among 7 factors independently associated with 2-year MACE, residual PR partly mediated the effect of diabetes (13.4% attributable risk), anemia (22.9% attributable risk), and acute coronary syndromes (7.3% attributable risk). A PR-mediated effect inversely affected the MACE risk associated with smoking (10.4% attributable risk). The increased ischemic risk of chronic kidney disease, multivessel disease, and previous myocardial infarction were not mediated by residual PR. In conclusion, high residual PR mediates little or none of the increased 2-year MACE risk associated with baseline risk factors in patients treated with clopidogrel after successful PCI with DES. Intensifying antiplatelet therapy is therefore unlikely to substantially mitigate the excess ischemic risk from these variables.

Contemporary Trends and Outcomes Associated With the Preprocedural Use of Oral P2Y12 Inhibitors in Patients Undergoing Percutaneous Coronary Intervention: Insights From the Blue Cross Blue Shield of Michigan Cardiovascular Consortium (BMC2).

OBJECTIVES: We sought to describe trends in the use of preprocedural P2Y12 inhibitors and their clinical impact in patients undergoing percutaneous coronary intervention (PCI). BACKGROUND: Oral P2Y12 inhibitors are ubiquitously used medications; however, the specific timing of initial P2Y12 inhibitor administration remains intensely debated. METHODS: Our study population comprised 74,053 consecutive patients undergoing PCI at 47 hospitals in Michigan from January 2013 through June 2015. In-hospital outcomes included stent thrombosis, bleeding, need for transfusion, and death. Hierarchical logistic regression, propensity matching, and targeted maximum likelihood estimation were used to adjust for baseline patient differences and clustering, and to minimize bias. RESULTS: Of 24,733 patients who received a preprocedural P2Y12 inhibitor, 82% received clopidogrel, 8% prasugrel, and 10% ticagrelor. Preprocedural administration of P2Y12 inhibitors declined during the study (49.3% to 24.8%; P<.001), and varied greatly across hospitals (14.5%-95.9%). No significant differences in outcomes were observed between patients receiving preprocedural clopidogrel and a matched cohort of those not receiving any preprocedural P2Y12 inhibitor (stent thrombosis: adjusted odds ratio [OR], 1.55; 95% confidence interval [CI], 0.30-7.84; bleeding: OR, 0.96; 95% CI, 0.63-1.46; transfusion: OR, 1.03; 95% CI, 0.69-1.55; and death: OR, 0.95; 95% CI, 0.38-2.37). Similar findings were demonstrated for preprocedural ticagrelor and prasugrel. Results from a subgroup analysis of patients with non-ST segment elevation acute coronary syndrome (n = 28,072) were consistent with the overall findings. CONCLUSIONS: There was a substantial decline in the rate of preprocedural P2Y12 inhibitor administration during the study. Furthermore, there were no significant differences in outcomes between patients treated with preprocedural P2Y12 inhibitors and those who were not.

Sex Differences in the Clinical Impact of High Platelet Reactivity After Percutaneous Coronary Intervention With Drug-Eluting Stents: Results From the ADAPT-DES Study (Assessment of Dual Antiplatelet Therapy With Drug-Eluting Stents).

BACKGROUND: Sex differences in the outcomes after percutaneous coronary intervention with drug-eluting stents and in the response to clopidogrel therapy have been reported; however, the differential risk of high platelet reactivity (HPR) on clopidogrel in women versus men is unknown. METHODS AND RESULTS: We compared 8448 patients enrolled in the ADAPT-DES study (Assessment of Dual Antiplatelet Therapy With Drug-Eluting Stents) according to sex and the presence/absence of HPR on clopidogrel (defined as P2Y12 reactivity units >208). Study end points were definite and probable stent thrombosis (ST), clinically relevant bleeding, all-cause mortality, myocardial infarction, and major adverse cardiac events (comprising mortality, myocardial infarction, and target lesion revascularization). HPR was more common among women (1118/2163, 51.7%) than men (2491/6285, 39.6%). HPR was associated with a roughly double risk of 1-year ST in both women and men (women with versus without HPR: 1.4% versus 0.7%; hazard ratio [HR], 2.02; 95% confidence interval [CI], 0.82-4.95; P=0.12; and men: 1.2% versus 0.5%; HR, 2.42; 95% CI, 1.36-4.30; P=0.002; Pinteraction=0.73). HPR was associated with almost half the rate of clinically relevant bleeding in women (women: HPR versus no HPR, 5.3% versus 9.8%; HR, 0.54; 95% CI, 0.40-0.74; P<0.001), whereas men had similar rates of bleeding regardless of HPR status (men: HPR versus no HPR, 5.7% versus 5.9%; HR, 0.96; 95% CI, 0.78-1.18; P=0.70; Pinteraction=0.003). In propensity-adjusted models, HPR was an independent predictor of ST and myocardial infarction in men; although both associations were nonsignificant among women, no interaction was observed in the associations between HPR and either ST or myocardial infarction. Conversely, HPR was an independent predictor of reduced bleeding only in women (women: adjusted HR, 0.58; 95% CI, 0.41-0.82; P=0.002; and men: adjusted HR, 0.83; 95% CI, 0.65-1.04; P=0.11; Pinteraction=0.01). CONCLUSIONS: In the current analysis, the associated risk of HPR for ST was similar in both sexes. However, HPR was associated with significantly reduced bleeding only among women. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00638794.

Assessment of platelet function in healthy cats in response to commonly prescribed antiplatelet drugs using three point-of-care platelet function tests.

Objectives The objective was to determine if decreased platelet function could be detected after treatment with aspirin and/or clopidogrel in healthy cats using three point-of-care platelet function tests that evaluate platelet function by different methods: Multiplate (by impedance), Platelet Function Analyzer 100 (by mechanical aperture closure) and Plateletworks (by platelet counting). Methods Thirty-six healthy cats were randomly assigned to receive one of three oral treatments over an 8 day period: (1) aspirin 5 mg q72h; (2) aspirin 20.25 mg q72h; or (3) clopidogrel 18.75 mg q24h. Cats treated with 5 and 20.25 mg aspirin also received clopidogrel on days 4-8. Platelet aggregation in response to adenosine diphosphate and collagen ± arachidonic acid was assessed on days 1 (baseline), 4 and 8. Aspirin and clopidogrel metabolites were measured by high-performance liquid chromatography. Platelet function in response to treatment was analyzed by ANCOVA, linear regression and Spearman correlation. Results The only solitary aspirin effect was detected using Plateletworks with collagen in cats treated with 20.25 mg. The only effect detected by Multiplate was using arachidonic acid in cats treated with both aspirin 20.25 mg and clopidogrel. All clopidogrel treatment effects were detected by Platelet Function Analyzer 100, Plateletworks (adenosine diphosphate) and Plateletworks (collagen). Drug metabolites were present in all cats, but concentrations were minimally correlated to platelet function test results. Conclusions and relevance Platelet Function Analyzer 100 and Plateletworks using adenosine diphosphate ± collagen agonists may be used to detect decreased platelet function in response to clopidogrel treatment. Either aspirin is not as effective an antiplatelet drug as clopidogrel, or the tests used were not optimal to measure aspirin effect. Cats with heart disease are commonly prescribed antiplatelet drugs to decrease the risk of aortic thromboembolism. Platelet Function Analyzer 100 and Plateletworks may be useful for confirming clopidogrel treatment in these cats.

Comparative pharmacodynamic effects of two clopidogrel formulations under steady-state conditions in healthy Thai volunteers
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OBJECTIVE: Clopidogrel is a commonly used antiplatelet aggregation agent. Compared with the reference clopidogrel product, most commercially available generic clopidogrel products contain different crystalline forms of clopidogrel. This study was aimed to compare the pharmacodynamics of a commonly used generic clopidogrel product in Thailand with the reference clopidogrel product under steady state conditions. METHODS: A multiple-dose, randomized 2-way crossover study was conducted in 32 healthy male Thai volunteers. The subjects were assigned to receive 75 mg once daily of the test or the reference product for 7 days with a 2-week wash out period. Blood samples were collected on days 1, 5, 6, and 7 prior to drug administration and at 1, 2, 3, 4, 8, 12, and 24 hours after the last dose administered. The antiplatelet aggregation effects of clopidogrel were determined by using two different ex-vivo platelet aggregation tests including the whole blood impedance assay (WBA) and the VerifyNow® P2Y12 assay. Both pharmacodynamic parameters, the maximal antiplatelet effect (Emax) and the areas under the antiplatelet effect-time curve (AUEC0-24h), were calculated. RESULTS: Neither the mean values of Emax (90.70 ± 15.15 vs. 89.50 ± 10.71% inhibition) nor of AUEC0-24h (1,892.84 ± 657.22 vs. 1,853.58 ± 673.95% inhibition × h) under steady-state conditions obtained using the WBA method of these two clopidogrel products were significantly different. The results obtained using the VerifyNow® P2Y12 assay were consistent with those of the WBA assay. CONCLUSION: This study clearly demonstrated that ex-vivo antiplatelet aggregation effect under steady-state conditions of the test product was not significantly different from the reference product.
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[Budget impact analysis of antiplatelet therapy with ticagrelor and clopidogrel in patients with acute coronary syndrome after coronary artery bypass surgery]. / Analiz «vliyaniya na byudzhet¼ primeneniya antitrombotsitarnoi terapii tikagrelorom i klopidogrelom u patsientov s ostrym koronarnym sindromom, perenesshikh operatsiyu koronarnogo shuntirovaniya.

AIM: Clinical and economic examinations were made to study whether it is appropriate to use antiplatelet therapy (APT) with ticagrelor in combination with acetylsalicylic acid (ASA) versus a combination of clopidogrel and ASA in patients with acute coronary syndrome (ACS) following coronary artery bypass surgery (CABS). MATERIAL AND METHODS: A budget impact analysis was used. Data on the efficiency and safety of APT were taken from a relevant analysis in the subgroups of the randomized controlled trial PLATO. Direct medical cost due to APT and expenses on therapy for acute myocardial infarction, stroke, and massive bleeding, and those on medical care for patients dying from cardiovascular events and other causes, as well as indirect cost - gross domestic product (GDP) losses due to untimely death, were taken into account. The findings were assessed from the perspectives of society. RESULTS: The analysis indicated that direct medical costs per patient following CABS, both in case of calculation based on the recorded price for ticagrelor and on the median registered prices for clopidogrel generics, and based on the auction prices for comparison agents proved to be lower when clopidogrel was administered because of the higher cost of ticagrelor-based APT. At the same time GDP losses due to untimely death, as calculated per patient with ACS during post-CABS therapy with clopidogrel + ASA, were more than twice above average losses per patient taking ticagrelor in combination with ACA (107,122 and 221,645 rubles, respectively). From the registered price for ticagrelor and the median registered prices for clopidogrel generics, the total costs per patient with ACS following CABS were lower if Brilinta was used in combination with ASA versus therapy with clopidogrel in combination with ASA (210,092 and 273,257 rubles per year, respectively; the cost savings were 63,165 rubles per patient per year when ticagrelor was administered). On the basis of the auction prices for comparison drugs, the total costs per patient with ACS after CABS proved to be lower if Brilinta was used in combination with ASA versus therapy with brand name clopidogrel in combination with ASA (201,018 and 293,982 rubles per patients year, respectively; the cost savings were 92,963 rubles per patient per year when ticagrelor was used). CONCLUSION: The use of ticagrelor in combination with ASA ensures resource savings to treat ACS patients undergoing CABS as compared with a regiment including a combination of clopidogrel and ASA.

Pharmacodynamic Assessment of Platelet Reactivity After a Loading Dose of Prasugrel or Clopidogrel in Patients With ST-Segment Elevation Myocardial Infarction.

BACKGROUND: Few studies have compared the platelet reactivity of prasugrel and clopidogrel in the acute phase of ST-segment elevation myocardial infarction (STEMI).Methods and Results:Primary percutaneous coronary intervention (PCI) was performed in 78 patients with STEMI within 12 h of onset. Patients were randomly assigned to receive a Japanese standard loading dose of prasugrel 20 mg or clopidogrel 300 mg. Platelet reactivity was serially assessed using the VerifyNow-P2Y12 assay, the results of which were expressed as P2Y12-reaction-units (PRU). PRU values were significantly lower in the prasugrel group (n=38) than in the clopidogrel group (n=40) at 3 h, 24 h, and 14 days after loading (191±101 vs. 271±50, 147±80 vs. 261±57, and 171±67 vs. 221±70, respectively, P<0.05), although the PRU levels at baseline (231±57 vs. 237±58, P=0.65) and 1 h after loading (282±65 vs. 291±62, P=0.54) were similar. As compared with the baseline values, the PRU levels at 1, 3 and 24 h after clopidogrel loading were significantly higher (respectively, P<0.05), whereas only the PRU at 1 h after prasugrel was elevated (P<0.001). CONCLUSIONS: In Japanese patients with STEMI who undergo primary PCI, prasugrel provides stronger platelet inhibition than clopidogrel from 3 h after loading, whereas platelet reactivity remained elevated within 24 h after clopidogrel loading. (Circ J 2016; 80: 2520-2527).

Early Cessation of Adenosine Diphosphate Receptor Inhibitors Among Acute Myocardial Infarction Patients Treated With Percutaneous Coronary Intervention: Insights From the TRANSLATE-ACS Study (Treatment With Adenosine Diphosphate Receptor Inhibitors: Longitudinal Assessment of Treatment Patterns and Events After Acute Coronary Syndrome).

BACKGROUND: Guidelines recommend the use of adenosine diphosphate receptor inhibitor (ADPri) therapy for 1 year postacute myocardial infarction; yet, early cessation of therapy occurs frequently in clinical practice. METHODS AND RESULTS: We examined 11 858 acute myocardial infarction patients treated with percutaneous coronary intervention discharged alive on ADPri therapy from 233 United States TRANSLATE-ACS study (Treatment With Adenosine Diphosphate Receptor Inhibitors: Longitudinal Assessment of Treatment Patterns and Events After Acute Coronary Syndrome) participating hospitals to determine the prevalence of early ADPri cessation (within 1 year), patient-reported reasons for cessation, and associated risk of major adverse cardiovascular events at 1 year. Overall, 2514 (21.2%) of percutaneous coronary intervention-treated patients stopped ADPri by 1 year postmyocardial infarction; the median time from discharge to cessation was 200.5 days (25th, 75th percentiles: 71, 340). Among those with early ADPri cessation, 53.9% received drug-eluting stents and had a median duration of 301 treatment days (25th, 75th percentiles: 137, 353); 33.3% of drug-eluting stent patients stopped treatment within 6 months compared with 64.2% of bare metal stent patients. Those discharged on prasugrel (versus clopidogrel) had a slightly higher likelihood of early ADPri cessation (23.2% versus 21.0%; P=0.03; adjusted hazard ratio, 1.28; 95% confidence interval, 1.17-1.40). Patient-reported reasons for early ADPri cessation included physician-recommended discontinuation (54%), as well as patient self-discontinuation, because of cost (19%), medication side effects (9%), and procedural interruption (10%). Using a time-dependent covariate model, early cessation of ADPri therapy was associated with increased major adverse cardiovascular event (adjusted hazard ratio, 1.40; 95% confidence interval, 1.19-1.65; P<0.0001). CONCLUSIONS: One in 5 percutaneous coronary intervention-treated myocardial infarction patients stopped ADPri treatment within 1 year. Early cessation was associated with increased major adverse cardiovascular event risk. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01088503.

Aspirin, Plavix, and Other Antiplatelet Medications: What the Oral and Maxillofacial Surgeon Needs to Know.

Most patients with coronary artery disease and peripheral vascular disease are on long-term antiplatelet therapy and dual therapy. Achieving a balance between ischemic and bleeding risk remains an important factor in managing patients on antiplatelet therapy. For most outpatient surgical procedures, maintenance and continuation of this therapy are recommended. Consultation with the patient's cardiologist, physician, and/or vascular surgeon is always recommended before interrupting or withholding this treatment modality.

Assessment of P2Y12 inhibitor usage and switching in acute coronary syndrome patients undergoing percutaneous coronary revascularization.

BACKGROUND: Dual antiplatelet therapy is recommended for patients with acute coronary syndrome (ACS) that undergo percutaneous coronary intervention (PCI). However, the effect of switching P2Y12 inhibitors between the loading dose and therapy after discharge is not well described. METHODS: This post-hoc analysis of a prospectively collected registry included 3219 consecutive ACS patients who underwent PCI. Patients were categorized into four groups: clopidogrel at load and discharge (C-C), loading dose of clopidogrel and discharged on prasugrel/ticagrelor (C-PT), loading dose of prasugrel/ticagrelor and discharged on clopidogrel (PT-C), and prasugrel/ticagrelor at load and discharge (PT-PT). RESULTS: While 77.6% of patients received the C-C treatment regimen and 13.6% received the PT-PT strategy, the strategy of P2Y12 switching was fairly common with 6.2% in the PT-C group and 2.6% in the C-PT group. While C-C was the most common treatment regimen, PT-C and PT-PT were more commonly used in STEMI patients than in NSTEMI or unstable angina patients. A significantly lower unadjusted incidence of the composite outcome (death, MI, and repeat revascularization) was appreciated in both the PT-C (1.0%) and PT-PT (2.3%) groups than the C-C group (4.0%). Propensity-score matched analysis still showed significantly reduced risk (HR=0.22, 95% CI 0.05-0.93, p=0.04) in the PT-C group vs. a matched group of C-C controls. CONCLUSIONS: The strategy of utilizing a newer P2Y12 inhibitor and then switching to clopidogrel in ACS patients following PCI is used with some frequency in routine clinical practice and further studies should evaluate the safety and efficacy of such a strategy.

EBUS-TBNA and EUS-FNA: Risk Assessment for Patients Receiving Clopidogrel.

BACKGROUND: Clopidogrel is widely used for the prevention of thrombotic vascular complications. Its primary potential toxicity is bleeding. Management of clopidogrel therapy for patients undergoing invasive procedures is an area of ongoing study. We sought to evaluate the bleeding risk for patients undergoing needle aspiration biopsy by endobronchial ultrasound (EBUS) or esophageal ultrasound (EUS) while taking clopidogrel. METHODS: Retrospective review of sequential cases of endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) and esophageal ultrasound fine needle aspiration (EUS-FNA). RESULTS: Three hundred ninety-five consecutive procedures were reviewed. Thirty-seven patients were taking clopidogrel at time of biopsy. The patients taking clopidogrel were significantly older than those in the control group. Two patients (1%) in the control group were admitted for observation, but neither was found to have a significant bleed. There were no clinically significant bleeding complications in either of the study groups. CONCLUSIONS: It is reasonable to proceed with EBUS-TBNA or EUS-FNA when both, (1) clopidogrel cannot be stopped and, (2) an important diagnostic question is at stake.

Triple vs Dual Antithrombotic Therapy in Patients with Atrial Fibrillation and Coronary Artery Disease.

BACKGROUND: The role of triple antithrombotic therapy vs dual antithrombotic therapy in patients with both atrial fibrillation and coronary artery disease remains unclear. This study explores the differences in treatment practices and outcomes between triple antithrombotic therapy and dual antithrombotic therapy in patients with atrial fibrillation and coronary artery disease. METHODS: Using the Outcomes Registry for Better Informed Treatment of Atrial Fibrillation (n = 10,135), we analyzed outcomes in patients with coronary artery disease (n = 1827) according to treatment with triple antithrombotic therapy (defined as concurrent therapy with an oral anticoagulant, a thienopyridine, and aspirin) or dual antithrombotic therapy (comprising either an oral anticoagulant and one antiplatelet agent [OAC plus AA] or 2 antiplatelet drugs and no anticoagulant [DAP]). RESULTS: The use of triple antithrombotic therapy, OAC plus AA, and DAP at baseline was 8.5% (n = 155), 80.4% (n = 1468), and 11.2% (n = 204), respectively. Among patients treated with OAC plus AA, aspirin was the most common antiplatelet agent used (90%), followed by clopidogrel (10%) and prasugrel (0.1%). The use of triple antithrombotic therapy was not affected by patient risk of either stroke or bleeding. Patients treated with triple antithrombotic therapy at baseline were hospitalized for all causes (including cardiovascular) more often than patients on OAC plus AA (adjusted hazard ratio 1.75; 95% confidence interval, 1.35-2.26; P <.0001) or DAP (hazard ratio 1.82; 95% confidence interval, 1.25-2.65; P = .0018). Rates of major bleeding or a combined cardiovascular outcome were not significantly different by treatment group. CONCLUSIONS: Choice of antithrombotic therapy in patients with atrial fibrillation and coronary artery disease was not affected by patient stroke or bleeding risks. Triple antithrombotic therapy-treated patients were more likely to be hospitalized for all causes than those on OAC plus AA or on DAP.

Assessment of platelet-derived thrombogenicity with the total thrombus-formation analysis system in coronary artery disease patients receiving antiplatelet therapy.

BACKGROUND: Accurate evaluation of thrombogenicity helps to prevent thrombosis and excessive bleeding. The total thrombus-formation analysis system (T-TAS) was developed for quantitative analysis of platelet thrombus formation by the use of microchips with thrombogenic surfaces (collagen, platelet chip [PL-chip]; collagen plus tissue factor, atherome chip [AR-chip]). We examined the utility of the T-TAS in the assessment of the efficacy of antiplatelet therapy in patients with coronary artery disease (CAD). METHODS AND RESULTS: In this cross-sectional study, 372 consecutive patients admitted to the cardiovascular department were divided into three groups: patients not receiving any antiplatelet therapy (control, n = 56), patients receiving aspirin only (n = 69), and patients receiving aspirin and clopidogrel (n = 149). Blood samples were used for the T-TAS to measure the platelet thrombus-formation area under the curve (AUC) at various shear rates (1500 s(-1) [PL18 -AUC10 ] and 2000 s(-1) [PL24 -AUC10 ] for the PL-chip; 300 s(-1) [AR10 -AUC30 ] for the AR-chip). The on-clopidogrel platelet aggregation was measured by the use of P2Y12 reaction units (PRUs) with the VerifyNow system. The mean PL24 -AUC10 levels were 358 ± 111 (± standard deviation) (95% confidence interval [CI] 328.9-387.1) in the control group, 256 ± 108 (95% CI 230.5-281.5) in the aspirin group, and 113 ± 91 (95% CI 98.4-127.6) in the aspirin/clopidogrel group. In the aspirin/clopidogrel group, the PL24 -AUC10 was higher in poor metabolizers (PMs) with cytochrome P450 2C19(CYP2C19) polymorphisms (152 ± 112, 95% CI 103.4-200.6) than in the non-PM group (87 ± 74, 95% CI 73.8-100.2). CONCLUSIONS: Our findings suggest that the PL24 -AUC10 level measured by the T-TAS is a potentially suitable index for the assessment of antiplatelet therapy in CAD patients.

Long-Term Outcomes in Patients With Diabetes Mellitus Related to Prolonging Clopidogrel More Than 12 Months After Coronary Stenting.

BACKGROUND: Recent large clinical trials show lower rates of late cardiovascular events by extending clopidogrel >12 months after percutaneous coronary revascularization (PCI). However, concerns of increased bleeding have elicited support for limiting prolonged treatment to high-risk patients. OBJECTIVES: The aim of this analysis was to determine the effect of prolonging clopidogrel therapy >12 months versus ≤12 months after PCI on very late outcomes in patients with diabetes mellitus (DM). METHODS: Using the Veterans Health Administration, 28,849 patients undergoing PCI between 2002 and 2006 were categorized into 3 groups: 1) 16,332 without DM; 2) 9,905 with DM treated with oral medications or diet; and 3) 2,612 with DM treated with insulin. Clinical outcomes, stratified by stent type, ≤4 years after PCI were determined from the Veterans Health Administration and Medicare databases and risk was assessed by multivariable and propensity score analyses using a landmark analysis starting 1 year after the index PCI. The primary endpoint of the study was the risk of all-cause death or myocardial infarction (MI). RESULTS: In patients with DM treated with insulin who received drug-eluting stents (DES), prolonged clopidogrel treatment was associated with a decreased risk of death (hazard ratio [HR]: 0.59; 95% confidence interval [CI]: 0.42 to 0.82) and death or MI (HR: 0.67; 95% CI: 0.49 to 0.92). Similarly, in patients with noninsulin-treated DM receiving DES, prolonged clopidogrel treatment was associated with less death (HR: 0.61; 95% CI: 0.48 to 0.77) and death or MI (HR: 0.61; 95% CI: 0.5 to 0.75). Prolonged clopidogrel treatment was not associated with a lower risk in patients without DM or in any group receiving bare-metal stents. CONCLUSIONS: Extending the duration of clopidogrel treatment >12 months may decrease very late death or MI only in patients with DM receiving first-generation DES. Future studies should address this question in patients receiving second-generation DES.