Summary Background Prospective assessment of pharmacogenetic strategies has been limited by an inability to undertake bedside genetic testing. The CYP2C19*2 allele is a common genetic variant ...associated with increased rates of major adverse events in individuals given clopidogrel after percutaneous coronary intervention (PCI). We used a novel point-of-care genetic test to identify carriers of the CYP2C19*2 allele and aimed to assess a pharmacogenetic approach to dual antiplatelet treatment after PCI. Methods Between Aug 26, 2010, and July 7, 2011, 200 patients were enrolled into our prospective, randomised, proof-of-concept study. Patients undergoing PCI for acute coronary syndrome or stable angina were randomly assigned to rapid point-of-care genotyping or to standard treatment. Individuals in the rapid genotyping group were screened for the CYP2C19*2 allele. Carriers were given 10 mg prasugrel daily, and non-carriers and patients in the standard treatment group were given 75 mg clopidogrel daily. The primary endpoint was the proportion of CYP2C19*2 carriers with high on-treatment platelet reactivity (P2Y12 reactivity unit PRU value of more than 234) after 1 week of dual antiplatelet treatment, which is a marker associated with increased adverse cardiovascular events. Interventional cardiologists and data analysts were masked to genetic status and treatment. Patients were not masked to treatment allocation. All analyses were by intention to treat. This study is registered with ClinicalTrials.gov , NCT01184300. Findings After randomisation, 187 patients completed follow-up (91 rapid genotyping group, 96 standard treatment). 23 individuals in each group carried at least one CYP2C19*2 allele. None of the 23 carriers in the rapid genotyping group had a PRU value of more than 234 at day 7, compared with seven (30%) given standard treatment (p=0·0092). The point-of-care genetic test had a sensitivity of 100% (95% CI 92·3–100) and a specificity of 99·3% (96·3–100). Interpretation Point-of-care genetic testing after PCI can be done effectively at the bedside and treatment of identified CYP2C19*2 carriers with prasugrel can reduce high on-treatment platelet reactivity. Funding Spartan Biosciences.
Dual-antiplatelet therapy (DAPT) with aspirin and a P2Y12 receptor inhibitor is the standard treatment for patients undergoing percutaneous coronary intervention. The availability of different P2Y12 ...receptor inhibitors (clopidogrel, prasugrel, ticagrelor) with varying levels of potency has enabled physicians to contemplate individualized treatment regimens, which may include escalation or de-escalation of P2Y12-inhibiting therapy. Indeed, individualized and alternative DAPT strategies may be chosen according to the clinical setting (stable coronary artery disease vs. acute coronary syndrome), the stage of the disease (early- vs. long-term treatment), and patient risk for ischemic and bleeding complications. A tailored DAPT approach may be potentially guided by platelet function testing (PFT) or genetic testing. Although the routine use of PFT or genetic testing in percutaneous coronary intervention–treated patients is not recommended, recent data have led to an update in guideline recommendations that allow considering selective use of PFT for DAPT de-escalation. However, guidelines do not expand on when to implement the selective use of such assays into decision making for personalized treatment approaches. Therefore, an international expert consensus group of key leaders from North America, Asia, and Europe with expertise in the field of antiplatelet treatment was convened. This document updates 2 prior consensus papers on this topic and summarizes the contemporary updated expert consensus recommendations for the selective use of PFT or genotyping in patients undergoing percutaneous coronary intervention.
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•Different P2Y12 inhibitors have enabled physicians to contemplate individualized treatment regimens.•In selective scenarios, PFT and genotyping may be used as optional tools for guiding treatment.•Further studies on DAPT de-escalation and escalation are needed to refine existing treatment options.
The optimal length of dual antiplatelet therapy (DAPT) after percutaneous coronary intervention (PCI) remains debated. Current guidelines recommend individualized treatment with consideration of risk ...scores. We sought to evaluate the degree of agreement in treatment recommendations and the ability to predict ischemic and bleeding complications of the PRECISE-DAPT (predicting bleeding complications in patients undergoing stent implantation and subsequent dual antiplatelet therapy) and DAPT scores. Consecutive patients receiving 12 months of DAPT were grouped based on score treatment recommendation at the time of PCI: PRECISE-DAPT prolonged or shortened (PRECISE DAPT <25 vs ≥25) and DAPT prolonged or shortened (DAPT ≥2 vs <2). One-year ischemic and bleeding outcomes were compared for each group. In 451 patients, the PRECISE-DAPT and DAPT score recommendations were concordant in 56.7% of patients (Cohen's kappa for agreement of k = 0.139, 95% confidence interval 0.065 to 0.212). There was no difference in composite major adverse cardiovascular and cerebrovascular events between patients with high versus low PRECISE-DAPT or DAPT scores. In patients with a high PRECISE-DAPT score versus a low score, there was an increased incidence of 1-year all-cause mortality (2.13% vs 0%, p = 0.04) and an increase in bleeding (Bleeding Academic Research Consortium ≥3a: 17.0% vs 2.8%; p <0.001; Bleeding Academic Research Consortium 3b/c and 5: 8.5% vs 1.4%; p = 0.001). There were no differences in rates of mortality or bleeding for patients with high versus low DAPT scores. In conclusion, when applied at the baseline, the PRECISE-DAPT and DAPT scores frequently make discordant DAPT duration recommendations. The PRECISE-DAPT, but not the DAPT score, demonstrated associations with all-cause mortality and bleeding in patients prescribed 12 months of DAPT after PCI.
Loss-of-function CYP2C19 variants are associated with increased cumulative ischemic outcomes warranting CYP2C19 genotyping prior to clopidogrel administration. TAILOR-PCI was an international, ...multicenter (40 sites), prospective, randomized trial comparing rapid point of care (POC) genotype-guided vs. conventional anti-platelet therapy. The performance of buccal-based rapid CYP2C19 genotyping performed by non-laboratory-trained staff in TAILOR-PCI was assessed. Pre-trial training and evaluation involved rapid genotyping of 373 oral samples, with 99.5% (371/373) concordance with Sanger sequencing. During TAILOR-PCI, 5302 patients undergoing PCI were randomized to POC rapid CYP2C19 *2, *3, and *17 genotyping versus no genotyping. At 12 months post-PCI, TaqMan genotyping determined 99.1% (2,364/2,385) concordance with the POC results, with 90.7-98.8% sensitivity and 99.2-99.6% specificity. In conclusion, non-laboratory personnel can be successfully trained for on-site instrument operation and POC rapid genotyping with analytical accuracy and precision across multiple international centers, thereby supporting POC genotyping in patient-care settings, such as the cardiac catheterization laboratory.Clinical Trial Registration: https://www.clinicalTrials.gov (Identifier: NCT01742117).
In patients undergoing primary percutaneous coronary intervention (PPCI) ticagrelor is superior to clopidogrel in reducing cardiovascular events. This study sought to evaluate the effect of ...clopidogrel pretreatment on the pharmacodynamics of ticagrelor in patients undergoing PPCI.
We measured platelet reactivity using the VerifyNow P2Y12 assay at baseline, 1, 2, 4, 6, 12, 24, and 48 hours following ticagrelor bolus in patients previously loaded with clopidogrel (C+T) and in thienopyridine-naive patients (T) referred to our centre for PPCI.
In total, 52 consecutive eligible patients with ST-elevation myocardial infarction (STEMI) were enrolled (27 C+T and 25 T). Baseline characteristics and mean baseline platelet reactivity units (PRUs) were similar between the groups. The primary endpoint, the proportion of patients achieving a PRU<208 at 2 hours, was more frequently achieved in the C+T group compared to T treatment (76.0% vs 44.4%, p= 0.026). Notably, C+T therapy resulted in fewer patients with high platelet reactivity at 1 hour (56.0% vs. 14.8%), 4 hours (100.0% vs. 61.5%) and 6 hours (100.0% vs. 64%, p<0.01 for all comparisons). Furthermore, C+T therapy was associated with lower PRU values from 2 to 48 hours.
In patients referred for PPCI, ticagrelor bolus following clopidogrel resulted in more rapid and profound platelet inhibition, demonstrating a positive pharmacodynamic interaction. Further study is needed to determine if this pharmacodynamic effect translates into reduced clinical events.
Background To manage overcrowding and bed shortages in Canadian hospitals, same-day discharge (SDD) after percutaneous coronary intervention (PCI) has emerged as a solution to improve resource ...utilization. However, limited information exists regarding current trends, hospital variation, and safety of SDD PCI in Canada. Methods and Results We evaluated outpatients undergoing elective PCI in Ontario, Canada, from October 2008 to March 2016. SDD was defined when patients were discharged on the day of PCI, and non-SDD was defined as those patients who had 1 overnight stay. The primary outcome was 30-day all-cause death or hospitalization for acute coronary syndrome. Inverse probability of treatment weighting with propensity score was used to account for differences in baseline and clinical characteristics between SDD and non-SDD groups. Among 35 972 patients who underwent elective PCI at 17 PCI centers in Ontario, 10 801 patients (30%) had SDD PCI and 25 121 patients (70%) had non-SDD PCI. Substantial hospital variation for SDD PCI was observed, ranging from 0% to 87% during the study period. In the propensity-weighted cohort, SDD patients had no significant difference in 30-day rates of death or hospitalization for acute coronary syndrome (1.3% versus 1.6%; hazard ratio: 0.84 95% CI, 0.65-1.08; P=0.17) compared with non-SDD patients. SDD and non-SDD patients also had no significant difference in 30-day rates of mortality or coronary revascularization. Conclusions In this large population-based cohort of elective PCI patients, we demonstrated the safety of SDD PCI. Increased adoption of this strategy could lead to improved bed-flow efficiency and substantial savings for the Canadian healthcare system without comprising outcomes.
Dual antiplatelet therapy (DAPT) with aspirin and a P2Y12 inhibitor is prescribed for 1-year after myocardial infarction. Two clinical strategies are considered at 1-year: continuation of DAPT or ..."Dual Pathway" (DP), using aspirin and rivaroxaban. No head-to-head comparative studies exist. In our in-vitro study, 24 samples of donor blood were treated with clinically proven concentrations of 5 antithrombotic regimens: aspirin, ticagrelor, rivaroxaban, DAPT, and DP. Thrombosis was analyzed using the Total Thrombus Analysis System (T-TAS) to measure both antiplatelet and anticoagulant effects. Flow cytometry was performed to quantify platelet activation. DAPT was the most potent antiplatelet regimen, delaying thrombus onset (p < .0001) and reducing thrombogenicity (p < .0001), relative to control. DP did not delay thrombus formation relative to aspirin alone (p = .69). DP was the most potent anticoagulant regimen, delaying thrombus onset (p < .0001) and reducing thrombogenicity (p < .0001), relative to control. DP showed synergistic antithrombotic effects by delaying thrombus onset (p < .0001) and reducing thrombogenicity (p = .0003), relative to rivaroxaban alone. Flow cytometry showed only DAPT (p = .0023) reduced platelet activation. DP treatment demonstrated synergistic antithrombotic effects over rivaroxaban alone, but no additional antiplatelet synergism over aspirin alone.
Abstract Background Therapeutic hypothermia improves neurologic outcome and survival in patients following out-of-hospital cardiac arrest (OHCA). Endovascular cooling devices are commonly used to ...rapidly achieve and maintain hypothermia. The use of these devices may be associated with catheter related thrombosis. The objective of this study was to determine the risk of catheter related thrombosis associated with the use of an endovascular cooling catheter in patients referred for therapeutic hypothermia following OHCA. Methods and results We conducted a retrospective cohort study on consecutive patients, referred for therapeutic hypothermia following OHCA, between February 2012 and May 2013. Of 80 patients initially treated with therapeutic hypothermia, 61 completed the cooling protocol using an endovascular cooling device. The primary outcome was catheter related thrombosis defined as evidence of thrombus in the inferior vena cava, deep vein thrombosis or pulmonary embolism during the index hospitalization. We further evaluated the incidence of the primary outcome between patients on dose adjusted intravenous unfractionated heparin compared to those on a subcutaneous prophylactic regimen alone. Catheter related thrombosis was observed in 9/61 (14.7%), with nine events in the prophylaxis group compared to none in the full dose unfractionated heparin group (22.0% vs. 0.0%, p = 0.02). Conclusions The use of endovascular catheters for induction of therapeutic hypothermia is associated with a high rate of catheter related thrombosis. This risk appears to be abrogated with dose adjusted unfractionated heparin infusion.
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