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[...]determination of a single genotype is only a small extract from the entire genetic basis that determines drug response.11 Other factors including age, bodyweight, diabetes, and renal insufficiency can contribute to drug response and integration of these clinical variables with genetic data might enhance the accuracy by which drug response is determined. [...]CYP2C19 genotype data have taught us that heterozygous loss-of-function (CYP2C19*2) allele carriers show a broad distribution of drug response ranging from enhanced to low responders.12 Second, the timepoint for testing is set in a randomised trial, but the optimal timing for testing in a real-life setting could differ across clinical scenarios (eg, escalation vs de-escalation, acute coronary syndrome vs chronic coronary syndromes) and patient subgroups. While escalation of dual antiplatelet therapy usually requires early testing after the index procedure when the risk of stent thrombosis or reinfarction is highest, a de-escalation strategy may take place early but also in distance to PCI. [...]de-escalation of dual antiplatelet therapy may follow (1) a proactive approach (in line with clinical trial designs) with treatment de-escalation before the occurrence of a bleeding event in patients with a presumed high bleeding risk, or (2) a reactive approach with a change of treatment in reaction to the occurrence of adverse events (eg, side-effects on ticagrelor or prasugrel or bleeding). [...]any desired guided de-escalation of dual antiplatelet therapy entails the risk that test results with confirmation of either high on-treatment platelet reactivity or CYP2C19*2 allele carriage might consequently lead to an escalation back to potent P2Y12 inhibitors.

Pharmacodynamic studies reported an amplified on-clopidogrel platelet inhibition in smokers potentially caused by an increased metabolic drug activation via induction of cytochrome P450 1A2. The aims of this analysis were to evaluate the impact of smoking on the antiplatelet effect of clopidogrel and prasugrel and to test the potential interaction of smoking with the treatment effect of these drugs. A variety of platelet function results was analyzed from 2 large cohorts of patients undergoing coronary intervention after loading with clopidogrel 600 mg (n = 2,533 and n = 1,996), a cohort of patients undergoing dose adaptation from 75 to 150 mg according to response to clopidogrel (n = 117) and a crossover trial comparing clopidogrel 150 mg with prasugrel 10 mg (n = 87). Linear regression analyses were used to test the impact of smoking on platelet function and to identify independent predictors of on-treatment platelet reactivity. The potential interaction of smoking with the clinical effect of clopidogrel versus prasugrel was analyzed in the TRITON-TIMI 38 cohort (n = 13,608). No significant association of smoking with platelet reactivity on clopidogrel was seen in unadjusted and adjusted analyses. The variables most consistently associated with on-clopidogrel platelet function were age, sex, diabetes, and body mass index. There was no significant interaction of smoking status at presentation with the clinical efficacy of prasugrel versus clopidogrel ( P for interaction = .39). Smoking does not impact on platelet reactivity in patients after loading or on different maintenance doses of clopidogrel. The clinical treatment effect of clopidogrel versus prasugrel is not affected by smoking status at presentation.

Platelet function testing has been established and validated to predict ischaemic and bleeding events in patients treated with percutaneous coronary intervention. 3,4 However, previous studies, 5,6 enrolling mostly low-risk patients with little use of potent antiplatelet drugs, have been unable to show clinical superiority of strategies that implemented platelet function testing for treatment guidance. Nevertheless, elderly patients undergoing percutaneous coronary intervention represent a high-risk cohort that might derive clinical benefit from platelet function testing to monitor and adjust the level of platelet inhibition.

Clopidogrel is a prodrug that is metabolized to its active metabolite by the hepatic cytochrome P450 system. Calcium-channel blockers (CCBs) are metabolized by the same pathway and may therefore attenuate the antiplatelet effect of clopidogrel. The aim of this study was to assess the impact of CCB therapy on the pharmacodynamic effect and the clinical efficacy of clopidogrel after drug-eluting stent placement. A total of 1,608 consecutive patients were previously enrolled in a study that aimed to assess the relation between platelet reactivity and outcomes after coronary stenting. Here, this cohort was analyzed according to concomitant CCB therapy at admission. The primary pharmacodynamic end point was adenosine diphosphate–induced platelet aggregation (in AU · min) with multiple electrode platelet aggregometry after loading with 600 mg clopidogrel. The primary clinical end point was combination of death or definite stent thrombosis (ST) at 30 days. Secondary end points included definite ST alone, myocardial infarction, stroke, and death. Two hundred thirty-two patients (14.4%) were on CCBs on admission. Compared with patients with CCB medication, patients without CCB medication showed no significant difference in median [interquartile range] platelet aggregation values (232 [142-365] vs 223 [141-368] AU · min, P = .53). There was also no significant difference regarding the clinical end point of death or ST (2 [0.9%] vs 16 [1.2%], odds ratio 0.74, 95% CI 0.17-3.2, P = .69) between both groups. In our population, concomitant CCB therapy did not alter clopidogrel-mediated platelet aggregation and did not have a measurable impact on ST and mortality after coronary stenting.

After an acute coronary syndrome (ACS) it is imperative to balance the bleeding vs. the ischemic risk given the similar prognostic impact of the two events. Since the post-discharge bleeding risk is substantially stable over time whereas the ischemic risk accumulates in the first weeks to months, a strategy of de-escalation of antithrombotic treatment, consisting in the reduction of either the duration (i.e., early interruption of one antiplatelet agent) or the intensity (i.e., switching from the more potent P2Y12-inhibitors prasugrel or ticagrelor to clopidogrel) of dual antiplatelet therapy (DAPT), has been proposed. Reducing the intensity of DAPT can be carried out as a default strategy (unguided approach) or based on the results of either platelet function tests or genetic tests (guided approach). Overall, all de-escalation strategies have shown to consistently decrease bleeding events with no apparent increase in ischemic events as compared to 12-month standard-of-care DAPT. Owing however to several limitations and weaknesses of the available evidence, de-escalation strategies are currently not recommended as a routine, but should rather be considered for selected ACS patients, such as those at increased risk of bleeding.

Extension of DAPT might mitigate risk of stent thrombosis or subsequent thrombotic events elsewhere in the circulation. However, it will also increase bleeding risk and costs. Therefore, a key question that remained to be addressed by adequately powered clinical trials is whether or not extension of DAPT beyond 1 year after PCI provides any net clinical benefit.

[...] why do we not fi nd a higher incidence of ischaemic events in patients treated with PPIs in today's study? Because of exclusion criteria, patients in TRITON-TIMI 38 were much younger and less likely to have diabetes mellitus or renal failure than were those included in previous observational studies.5-7 At least some of these patients' characteristics have a reducing eff ect on the platelet response to clopidogrel.11 In their presence, the additional eff ect of a PPI might aff ect clinical outcomes.

Preclinical studies suggest a relationship between early thrombotic response after vascular injury and later development of restenosis. The aim of this study was to assess the impact of platelet response to clopidogrel on the risk of restenosis after drug-eluting stenting (DES). A total of 1,608 consecutive patients were previously enrolled in a study on the relation between platelet reactivity and outcomes after DES. All patients received a loading dose of 600 mg clopidogrel. Blood samples for the assessment of adenosine diphosphate–induced platelet aggregation with multiple electrode platelet aggregometry were drawn directly before percutaneous coronary intervention. Clopidogrel low response was defined as upper quintile of multiple electrode platelet aggregometry measurements. Accordingly, 323 patients (20%) were considered as low and 1,285 (80%) as normal responders. Primary end point of the present study was target lesion revascularization at 1 year. Secondary end points included binary angiographic restenosis and late lumen loss at 6- to 8-month angiography. Target lesion revascularization rates were comparable in both groups (10.9% vs 9.5%, hazard rate [HR] 1.2, 95% CI 0.8-1.7, P = .441). Follow-up angiography revealed no difference in binary angiographic restenosis (13.9% vs 15.9%, P = .445) and late lumen loss (0.32 ± 0.64 vs 0.35 ± 0.63 mm, P = .477). Low responders had significantly more stent thromboses (2.5% vs 0.5%, HR 5.4, 95% CI 1.9-15.6, P = .002), Q wave myocardial infarctions (2.5% vs 0.6%, HR 4.0, 95% CI 1.5-10.7, P = .005), and ischemic strokes (1.3% vs 0.2%, HR 5.4, 95% CI 1.2-24.0, P = .028) at 1 year. Low platelet responsiveness to clopidogrel, a known predictor of thrombotic complications, does not have a significant impact on restenosis after DES.

A randomized trial involving patients with acute coronary syndromes showed that prasugrel was superior to ticagrelor with regard to the incidence of death, myocardial infarction, or stroke within 1 year, with no increased risk of bleeding.