Cold Snare Polypectomy in Patients Taking Dual Antiplatelet Therapy: A Randomized Trial of Discontinuation of Thienopyridines.

INTRODUCTION: Cold snare polypectomy (CSP) is a safe and effective method for removing polyps ≤10 mm. The aim of this study was to compare the risk of clinically significant bleeding and thromboembolic events after CSP between stopping and continuing thienopyridines in patients taking dual antiplatelet therapy (DAPT). METHODS: The study was a single-center, noninferiority, and randomized controlled study involving patients who received colonoscopy from October 2015 to October 2016. Patients receiving DAPT with polyps ≤10 mm were randomly assigned to either the DAPT group (patients continued DAPT) or the aspirin group (patients discontinued thienopyridines for 1 week). Primary outcome was clinically significant bleeding. Secondary outcomes included intraprocedural bleeding, nonsignificant hematochezia, and occurrence of thromboembolic events. RESULTS: Forty-two patients with 104 eligible polyps were allocated to the DAPT group, and 45 patients with 101 eligible polyps were allocated to the aspirin group. Patient demographic characteristics including size, location, shape, and pathology of the removed polyps were similar in the 2 groups. Intraprocedural bleeding and nonsignificant hematochezia rates were also similar between the 2 groups (4.8% vs 2.2%, P = 0.608; 19.0% vs 8.9%, P = 0.170). No thromboembolic event occurred in either group. Only 1 patient (2.4%) in the DAPT group showed clinically significant bleeding. No significant bleeding was found in the aspirin group. DISCUSSION: Clinically significant bleeding rate after CSP for polyps ≤10 mm in patients continuing to take DAPT was 2.4%. Therefore, CSP is a safe method for removing small polyps even in patients taking DAPT (ClincialTrials.gov number, NCT02865824).

Manejo perioperatorio de pacientes usuarios de antiagregantes plaquetarios / Perioperative management of patients using antiplatelet agents

Resumen El uso de fármacos antiagregantes plaquetarios para prevención primaria y secundaria de eventos cardiovasculares es una práctica común en clínica. La terapia antiagregante plaquetaria disminuye significativamente la incidencia de eventos cardiovasculares, incluyendo infarto agudo al miocardio y accidente cerebro-vascular. Cada vez es más frecuente enfrentarse a pacientes en terapia antiagregante plaquetaria que serán sometidos a algún procedimiento quirúrgico, por tanto es fundamental conocer el manejo perioperatorio de estos fármacos, para disminuir los riesgos y complicaciones asociados a la suspensión o mantención de estas drogas en el período perioperatorio. Los antiagregantes plaquetarios de mayor uso en Chile son la aspirina y las tienopiridinas, siendo el clopidogrel el fármaco más utilizado en este grupo. El enfrentamiento perioperatorio de estos fármacos está supeditado al riesgo trombótico individual de cada paciente y al riesgo hemorrágico de cada cirugía. En cirugías no cardiacas, se sugiere mantener la aspirina, excepto en pacientes con bajo-moderado riesgo trombótico que serán sometidos a cirugías con alto riesgo de sangrado, en los cuales se recomienda suspenderla 5-7 días previo a la intervención quirúrgica. El clopidogrel se sugiere suspenderlo 5 días antes de la cirugía, excepto en pacientes con alto riesgo trombótico que se someterán a procedimientos quirúrgicos con riesgo hemorrágico bajo-moderado. En cirugías de revascularización miocárdica, se recomienda mantener aspirina y suspender clopidogrel 5 días antes del procedimiento. En relación al reinicio postquirúrgico de estos fármacos, se sugiere reanudar aspirina 6 h posterior a la cirugía y clopidogrel durante las primeras 24 h postoperatorias, asegurando previamente una adecuada hemostasia quirúrgica.

The use of antiplatelet drugs for primary and secondary prevention of cardiovascular disease events is a common clinical practice. Antiplatelet therapy significantly decreases the incidence of cardiovascular disease events, including acute myocardial infarction and cerebrovascular accident. It is increasingly common to face patients on antiplatelet therapy who will undergo some surgical procedure, so it is essential to know the perioperative management of these drugs, to reduce the risks and complications associated with the suspension or maintenance of these therapies in the perioperative period. The most common antiplatelet agents used in Chile are acetylsalicylic acid and thienopyridines, of which clopidogrel is the most frequent one. The perioperative management of these drugs has to be based on the individual thrombotic risk of each patient and the risk of hemorrhage of each surgery. In noncardiac surgeries, it is suggested to maintain acetylsalicylic acid, except in patients with low to moderate thrombotic risk who will undergo surgeries with a high risk of bleeding, in which case it is recommended to suspend it 5 to 7 days before surgery. Clopidogrel is suggested to be discontinued 5 days before surgery, except in patients with high thrombotic risk who will undergo surgical procedures with low to moderate risk of hemorrhage. In myocardial revascularization surgeries, it is recommended to maintain acetylsalicylic acid and to suspend clopidogrel 5 days before the procedure. Once assuring adequate surgical hemostasis, it is suggested to reinitiate acetylsalicylic acid 6 hours after surgery and to reinitiate clopidogrel during the first 24 postoperative hours.

Cancer Event Rate and Mortality with Thienopyridines: A Systematic Review and Meta-Analysis.

INTRODUCTION: Thienopyridines are a class of antiplatelet drugs widely used in cardiovascular disease prevention and treatment. A recent concern has come to light regarding the safety of thienopyridines because of the possible risk of malignancy. We therefore performed a systematic review and meta-analysis to evaluate the association between thienopyridine exposure and malignancy. METHODS: We searched the MEDLINE and EMBASE databases in March 2016 for studies that evaluated incident cancer and cancer mortality with and without exposure to thienopyridines. Relevant studies were identified, and data were extracted and analysed using random-effects meta-analysis. RESULTS: A total of nine studies (six randomised controlled trials and three cohort studies) that included 282,084 participants were included. The cancer event rate with clopidogrel and prasugrel was 3.25% and 1.58% respectively. When compared with standard aspirin or placebo, thienopyridines are not significantly associated with cancer mortality and event rate (odds ratio [OR] 1.12, 95% confidence interval [CI] 0.80-1.56, n = 3; and OR 0.92, 95% CI 0.52-1.64, n = 2, respectively. Further analyses examining clopidogrel showed no significant association with cancer event rate or malignancy-related death. When comparing prasugrel with clopidogrel, no significant association was noted for cancer event rate (OR 1.10, 95% CI 0.89-1.37, n = 2]. Subanalyses according to cancer location showed that thienopyridines are not significantly associated with malignancy mortality and/or incidence. CONCLUSIONS: Our results suggest that there is currently insufficient evidence to suggest that thienopyridine exposure is associated with an increased risk of cancer event rate or mortality.

Dual antiplatelet therapy is associated with prolonged survival after lower extremity revascularization.

BACKGROUND: Dual antiplatelet therapy (DAPT) after coronary stenting prolongs survival by preventing both in-stent thrombosis and other cardiovascular atherothrombotic events. Patients with peripheral artery disease (PAD) typically have a heavy burden of unrevascularized coronary artery disease and also stand to benefit from increased atherothrombotic protection with DAPT. The potential benefit of DAPT compared with aspirin alone in patients with PAD is not well described. METHODS: We identified all patients undergoing an initial elective lower extremity revascularization (bypass or endovascular) from 2003 to 2016 in the Vascular Quality Initiative registry discharged on aspirin or aspirin plus a thienopyridine antiplatelet agent (DAPT). We first estimated models predicting the likelihood of receiving DAPT and then used inverse probability weighting to account for baseline differences in the likelihood of receiving DAPT and compared late survival. For sensitivity analysis, we also performed Cox proportion hazard modeling on the unweighted cohorts and generated adjusted survival curves. RESULTS: We identified 57,041 patients undergoing lower extremity revascularization (28% bypass). Of 15,985 bypasses (69% for critical limb ischemia [CLI]), 38% were discharged on DAPT. Of 41,056 endovascular interventions (39% for CLI), 69% were discharged on DAPT. Analyses using inverse probability weighting demonstrated a small survival benefit to DAPT at 1 year for bypass (93% vs 92% [P = .001]) and endovascular interventions (93% vs 92% [P = .005]) that was sustained through 5 years of follow-up (bypass, 80% vs 78% [P = .004]; endovascular, 76% vs 73% [P = .002]). When stratified by severity of PAD, DAPT had a survival benefit for patients with CLI undergoing bypass (5 years, 70% vs 66% [P = .04]) and endovascular intervention (5 years, 71% vs 67% [P = .01]) but not for patients with claudication (bypass, 89% vs 88% [P = .36]; endovascular, 87% vs 85% [P = .46]). The protective effect of DAPT was similar when using Cox proportional hazard models after bypass (hazard ratio, 0.81 [95% confidence interval, 0.72-0.90]) and endovascular intervention (hazard ratio, 0.89 [95% confidence interval, 0.83-0.95]). CONCLUSIONS: DAPT at time of discharge was associated with prolonged survival for patients with CLI undergoing lower extremity revascularization but not for those with claudication. Further research is needed to quantify the risks associated with DAPT and to identify subgroups at increased risk of thrombotic and bleeding complications to guide medical management of patients with PAD.

Genetic determined low response to thienopyridines is associated with higher systemic inflammation in smokers.

AIM: To investigate whether the interactions of CYP2C19*2 and CYP2C19*17 with smoking are associated with the levels of P2Y12 receptor inhibition and CRP, in on-thienopyridine post-stenting patients. METHODS & RESULTS: At 1-month follow-up, the interactions of smoking and CYP2C19 polymorphisms on the vasodilator-stimulated phosphoprotein - platelet reactivity index (VASP PRI), and CRP were explored in three metabolizing groups (1128 patients) as follow: poor metabolizers (*2 carriers/*17 noncarriers); intermediate metabolizers (*2 carriers/*17 carriers or *2 noncarriers/*17 noncarriers); and ultrarapidmetabolizers (*2 allele noncarriers/*17 carriers). The interactions of metabolizing status and smoking was significant for CRP (p = 0.001) but not for VASP PRI (p = 0.734). CONCLUSION: Interaction between CYP2C19 polymorphisms and smoking modifies on-treatment CRP level of post-stenting, on-thienopyridine patients. This effect seems to be independent to the level of P2Y12 receptor inhibition.

Thienopyridine derivatives as risk factors for bleeding following high risk endoscopic treatments: Safe Treatment on Antiplatelets (STRAP) study.

BACKGROUND AND STUDY AIMS: The optimal method of perioperative management of antiplatelet agents during endoscopic procedures that carry a high risk of bleeding is still controversial. The aim of this study was to evaluate the safety of continuing aspirin treatment during these procedures in an Asian population. PATIENTS AND METHODS: A multicenter, prospective, observational cohort study was conducted at six high volume endoscopy centers in Japan. The study included patients at high risk of thromboembolism who were regularly taking antiplatelet agents (e. g. thienopyridine derivatives and aspirin). Enrolled patients continued their aspirin therapy, and underwent endoscopic procedures that had a high risk of bleeding for treatment of lesions in the upper and lower gastrointestinal tracts. The primary end point was the rate of major bleeding complications after endoscopic procedures. RESULTS: The study was terminated in accordance with predetermined safety criteria because 7 of 28 consecutive patients experienced major bleeding complications (25.0 %; 95 % confidence interval 10.7 % - 44.9 %). All major bleeding complications occurred following endoscopic submucosal dissection (ESD; 6 stomach, 1 colon). Univariate analysis showed that postoperative administration of thienopyridine derivatives was the only significant factor associated with postoperative bleeding (P = 0.01). Subanalysis of gastric ESD (23 lesions in 19 patients) confirmed that the administration of thienopyridine derivatives (P = 0.01) and that of multiple agents (P = 0.02) were the significant factors. All bleeding complications (postoperative day 11.2 ±â€Š3.5) occurred after resuming thienopyridine derivative therapy postoperatively (postoperative day 2.3 ±â€Š2.4). CONCLUSION: In Asian patients taking thienopyridine derivatives with aspirin, cautious postoperative care is necessary for those undergoing endoscopic procedures that are associated with a high risk of bleeding, especially gastric ESD. Continuation of aspirin alone during these endoscopic procedures may be acceptable. STUDY REGISTRATION: UMIN000009176.

Interaction between thienopyridines and proton pump inhibitors.

Adenosin diphospat (ADP) plays a crucial role in thrombus formation. Therefore its inhibition can control excess platelet generation to prevent cardiovascular events in patients with acute coronary syndrome (ACS) or undergoing percutaneous coronary intervention (PCI). One of ADP's target receptors, P2Y12 has a limited tissue distribution and is therefore an attractive pharmacological target. Thienopyridines are class of drugs that specifically and irreversibly inhibit the P2Y12 receptor. Three generations exist and in most patients, they are administered in combination with aspirin. Because of possible gastro-intestinal toxicity, a proton pump inhibitor (PPI) is often concomitantly prescribed. However, several studies suspect an interaction between thienopyridines (in particular with clopidogrel) and PPIs which decreases the inhibition of platelet formation and thus enhances the risk for cardiac events. In this review, a concise overview of pharmacokinetic and pharmacodynamic properties of all thienopyridines is given and a critical discussion of the presumed interaction with PPIs is provided.

[Oral antiplatelet agents can still be used along with proton pump inhibitors in spite of drug interactions]. / Orale trombocythæmmere kan fortsat anvendes med protonpupehæmmere trods farmakologiske interaktioner.

Acetylsalicylic acid and P2Y12-receptor antagonists are antiplatelet agents widely used in the treatment and secondary prevention of cardiovascular disease. Since upper gastrointestinal bleeding is common during antiplatelet treatment, many patients are also treated with a proton pump inhibitor. In recent years it has been heavily discussed if proton pump inhibitors may attenuate the cardiovascular protection achieved with oral antiplatelet agents. Pharmacodynamic studies have suggested important drug interactions, but clinical studies have failed to confirm any clinical impact.

Clinical effects and outcomes with new P2Y12 inhibitors in ACS.

Thienopyridines have become the cornerstone of treatment for percutaneous coronary intervention although no survival benefit has ever been shown with clopidogrel despite increasing loading doses. Newly developed P2Y12 inhibitors are more potent, more predictable, and have a faster onset of action than clopidogrel, characteristics that make them particularly attractive for high-risk percutaneous coronary intervention (PCI). Four new P2Y12 inhibitors have been tested each of them having particular individual properties. Prasugrel is an oral pro-drug leading to irreversible blockade of the P2Y12 receptor and is approved worldwide for ACS PCI. Ticagrelor is a direct-acting and reversible inhibitor of the P2Y12 receptor with potentially more pleiotropic effects. Cangrelor is an intravenous direct and reversible inhibitor of the P2Y12 receptor providing the highest level of inhibition, and elinogrel is an intravenous and oral P2Y12 antagonist with a direct and reversible action. Both prasugrel and ticagrelor, opposed to clopidogrel, have shown that stronger P2Y12 inhibition led respectively to significant 19 and 16% relative risk reduction of a similar primary end point combining cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke. Both drugs showed a significant 0.6% absolute excess of TIMI major bleeding not related to CABG surgery. Because in clinical trials, patients perceived to be at higher risk of bleeding usually are excluded, the risk of major and even fatal bleeding might even be higher in a 'real-world' setting, i.e. in the elderly patient with comorbidities. On the other hand, these newly developed P2Y12 inhibitors decrease mortality after PCI compared with clopidogrel. The risk/benefit ratio is particularly favorable in PCI for patients with STEMI.

Dual antiplatelet therapy duration and clinical outcomes following treatment with zotarolimus-eluting stents.

OBJECTIVES: We sought to evaluate differences in late safety outcomes relative to dual antiplatelet therapy (DAPT) duration in patients treated with zotarolimus-eluting stents (ZES). BACKGROUND: Despite treatment recommendations for at least 12 months of DAPT following drug-eluting stent revascularization, device-specific outcomes relative to DAPT duration are absent. METHODS: Among 2,032 patients undergoing percutaneous coronary revascularization with ZES in 5 trials, late safety events were compared relative to DAPT duration for patients with ≥ 6 months DAPT adherence and survival free of major ischemic and bleeding events. RESULTS: A total of 1,414 event-free patients on DAPT at 6 months were identified. Patient group comparisons relative to DAPT included: 6 months versus ≥ 12 months, and 6 months versus ≥ 24 months. Through 3 years, risk-adjusted ischemic event rates did not significantly differ between groups: 6 versus ≥ 12 months: death (2.7% vs. 2.2%), myocardial infarction (MI, 0.3% vs. 1.1%), and definite/probable stent thrombosis (ST, 0.3% vs. 0%); 6 versus ≥ 24 months: death (1.6% vs. 1.6%), MI (0.4% vs. 1.2%), and definite/probable ST (0.1% vs. 0.2%). Composite events also did not statistically vary between DAPT durations. In multivariable analysis, 6-month versus longer DAPT duration was not associated with increased likelihood of thrombotic events at 3-year follow-up. Major bleeding was negligible across groups. CONCLUSIONS: Among patients treated with ZES, late-term events of death, MI, stroke, and ST do not significantly differ between patients taking 6 months DAPT compared with continuation beyond 1 year. These findings merit further study to identify the appropriate duration of DAPT according to specific drug-eluting stents.

Oral antiplatelet agents in ACS: from pharmacology to clinical differences.

Antiplatelet agents play an essential role in the treatment of acute coronary syndrome (ACS). Numerous clinical trials have established the value of antiplatelet therapies for ACS. Aspirin (ASA), thienopyridines and GP IIb/IIIa antagonists comprise the major classes of antiplatelet therapies demonstrated to be of benefit in the treatment of ACS. Thienopyridines are a class of drugs that function via inhibition of the adenosine diphosphate (ADP) P2Y12 platelet receptors. Currently, clopidogrel, a second generation thienopyridine, is the main drug of choice and the combination of aspirin and clopidogrel is administered orally for the treatment of ACS. Recently, a third generation of thienopyridines has been introduced represented by prasugrel that has demonstrated promising results in ACS patients treated with percutaneous coronary intervention (PCI). A number of nonthienopyridine oral antiplatelet drugs are under development, and one of them, ticagrelor has already been tested in a major phase III clinical trial, PLATO, with the inclusion of a broad spectrum of patients with ACS. The present review aims to discuss the present knowledge about the safety and efficacy of oral antiplatelet treatment of patients with ACS.