Background-As compared with whites, East Asians more often carry the cytochrome P450 (CYP) 2C19 loss-of-function (LOF) allele with the CYP2C19*3 variant. The influence of the CYP2C19 LOF alleles (*2 and *3) on clopidogrel response and clinical outcomes in East Asians with acute myocardial infarction (AMI) has not been reported. We sought to evaluate the effect of the CYP2C19 variants on clopidogrel pharmacodynamics and long-term prognosis in these patients. Methods and Results-Patients who survived an AMI (nϭ266) were enrolled in a single-center registry. Predischarge platelet reactivity was assessed with light transmittance aggregometry and the VerifyNow P2Y12 assay; the CYP2C19*2, *3, *17 and ABCB1 3435CϾT variants were determined. The primary clinical end point was the composite of cardiovascular death, nonfatal MI, and ischemic stroke. The median exposure to clopidogrel was 21 months (interquartile range, 13-29). The ABCB1 3435CϾT was not related to clopidogrel response or cardiovascular events. Carriage of the CYP2C19 LOF variant allele was relatively high (60.9%, nϭ162; *2/*17ϭ2, *3/*17ϭ1, *1/*2ϭ96, *1/*3ϭ29, *2/*2ϭ20, and *2/*3ϭ14). Platelet reactivity increased proportionally according to the number of the CYP2C19 LOF alleles. In a multivariate regression analysis, the risk of high on-treatment platelet reactivity (HPR) increased depending on the number of CYP2C19 LOF allele [1 LOF allele; odds ratio (OR), 1.

Background-Optimal platelet inhibition is an important therapeutic adjunct in patients acute myocardial infarction (AMI) undergoing coronary stenting. Whether adjunctive cilostazol to dual antiplatelet therapy (triple antiplatelet therapy) can inhibit enhanced platelet reactivity in patients with AMI yet has not been determined. The aim of this study was to assess the degree of platelet inhibition by triple antiplatelet therapy in patients with AMI. Methods and Results-Immediately after emergency room arrival, patients with AMI received clopidogrel (600-mg loading dose, followed by 75 mg daily) and aspirin (300-mg loading dose and 200 mg daily throughout the study period). After patients underwent coronary stenting (nϭ90), they were randomly assigned to 1 of 3 groups before discharge: standard group, clopidogrel of 75 mg daily (nϭ30); high maintenance dose (MD) group, clopidogrel of 150 mg daily (nϭ30); and triple group, adjunctive cilostazol of 100 mg twice daily to clopidogrel of 75 mg daily (nϭ30). Platelet reactivity was assessed at predischarge and 30-day follow-up by conventional aggregometry and the VerifyNow P2Y12 assay. Predischarge platelet reactivities were similar in the 3 groups. At 30-day follow-up, inhibition of maximal aggregation with 20 M ADP stimuli was 6.0% in the standard group, 19.1% in the high-MD group, and 42.4% in the triple group (PϽ0.001), whereas inhibition of late aggregation with 20M ADP stimuli was 10.8%, 38.1%, and 66.4%, respectively (PϽ0.001). Similar results were demonstrated when 5 M ADP was used. Furthermore, percent changes of P2Y12 reaction unit were significantly different among regimens (10.6% in the standard group, 30.7% in the high-MD group, and 43.0% in the triple group; PϽ0.001). With respect to high-postclopidogrel platelet reactivity (prespecified as 20 M ADP-induced maximal aggregation Ͼ50% of light transmission), fewer patients in the triple group (13.3%) met the criteria as compared with those in the standard (76.7%) and high-MD groups (56.7%) at 30-day follow-up (PϽ0.001). In the triple group, there were more potent and consistent platelet inhibitions by all parameters as compared with the high-MD group except for percent changes of P2Y12 reaction unit (Pϭ0.071). Conclusions-Among patients with AMI undergoing coronary stenting, triple antiplatelet therapy results in a greater antiplatelet effect at 30 days as compared with a high-MD clopidogrel or standard dual antiplatelet therapy. (Circ Cardiovasc Interv. 2010;3:17-26.)

In STEMI patients undergoing PPCI, crushed prasugrel leads to faster drug absorption, and consequently, more prompt and potent antiplatelet effects compared with whole tablet ingestion. (Pharmacological Effects of Crushing Prasugrel in STEMI Patients; NCT02212028).

Among PCI-treated patients receiving high-MD clopidogrel, carriage of CYP2C19 variant relates to increased PR and predicts risk of HPPR. (Adjunctive Cilostazol Versus High Maintenance-dose ClopidogrEL in Acute Myocardial Infarction [AMI] Patients According to CYP2C19 Polymorphism [ACCELAMI2C19]; NCT00915733; and Comparison of Platelet Inhibition With Adjunctive Cilostazol Versus High Maintenance-Dose Clopidogrel According to Hepatic Cytochrome 2C19 Allele (CYP2C19) Polymorphism [ACCEL2C19]; NCT00891670).

The CYP2C19*2 genetic variant may be associated with worse outcome in Korean patients treated exclusively with DES and dual-antiplatelet therapy due to a significant increase in cardiac death, myocardial infarction or stent thrombosis.

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Background and ObjectivesThe prognosis and natural history of bradycardia related to drugs such as beta-blockers and non-dihydropyridine calcium channel blockers are not well known.Subjects and MethodsWe retrospectively analyzed 38 consecutive patients (age 69±11, 21 women) with drug-related bradycardia (DRB) between March 2005 and September 2007. A drug-associated etiology for the bradycardia was established based on the medical history and patient response to drug discontinuation. The mean follow-up duration was 18±8 months.ResultsThe initial electrocardiogram (ECG) showed sinus bradycardia (heart rate ≤40/min) in 13 patients, sinus bradycardia with junctional escape beats in 18 patients, and third-degree atrioventricular (AV) block in seven patients. Drug discontinuation was followed by resolution of bradycardia in 60% of patients (n=23). Among them, five (17.8%) patients resumed taking the culprit medication after discharge and none developed bradycardia again. Bradycardia persisted in 10 (26.3%) patients despite drug withdrawal, and a permanent pacemaker was implanted in seven of them. Third-degree AV block, QRS width, and bradycardia requiring temporary transvenous pacing were significantly associated with the bradycardia caused by drugs.ConclusionBeta-blockers were the most common drugs associated with DRB. However, in one quarter of the cases the DRB was not associated with drugs; in these patients permanent pacemaker implantation should be considered.