Tailored Antiplatelet Therapy in Patients Undergoing PCI: Is Rapid Bedside Genetic Testing the Answer??.
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SUBMITTER: Faxon DP
PROVIDER: S-EPMC7251195 | biostudies-literature | 2020 May
REPOSITORIES: biostudies-literature
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Project description:BackgroundTo mitigate the risk of stent thrombosis, patients treated by percutaneous coronary intervention (PCI) are administered dual anti-platelet therapy comprising aspirin and a platelet P2Y12 receptor inhibitor. Clopidogrel is a prodrug requiring activation by the cytochrome P450 enzyme, CYP2C19. In Saudi Arabia, it has been reported that approximately 26% of the population carries CYP2C19*2 and/or *3 loss-of-function polymorphisms in addition to a high prevalence of CVD.MethodsThis prospective (April 2013-December 2020) parallel assignment clinical trial focuses on ST-Elevation Myocardial Infarction (STEMI) patient outcomes. The clinical trial includes 1500 STEMI patients from two hospitals in the Eastern Province of Saudi Arabia. Patients are assigned to one of two groups; the control arm receives conventional therapy with clopidogrel, while in the active arm the Spartan RX CYP2C19 assay is used to determine the *2 genotype. Carriers of a CYP2C19*2 loss-of-function allele receive prasugrel or ticagrelor, while non-carriers are treated with clopidogrel. Follow-up is one year after primary PCI. The primary end point is the number of patients who develop an adverse major cardiovascular event, including recurrent MI, non-fatal stroke, cardiovascular death, or major bleeding one year after PCI.DiscussionThe risk of stent thrombosis in PCI patients is usually reduced by dual anti-platelet therapy, comprising aspirin and a P2Y12 inhibitor, such as clopidogrel. However, clopidogrel requires activation by the cytochrome P450 enzyme, CYP2C19. Approximately 20% of the population are unable to activate clopidogrel as they possess the CYP2C19*2 loss-of function (LoF) allele. The primary goal of this trial is to study the benefits of treating only those patients that cannot activate clopidogrel with an alternative that has shown to be a more effective platelet inhibitor and does not require bioactivation by the cytochrome P450 enzyme. We expect an improvement in net clinical benefit outcome in the active arm patients, thus supporting pharmacogenetic testing in PCI patients post STEMI.Trial registrationTrial registration name is "Bedside Testing of CYP2C19 Gene for Treatment of Patients with PCI with Antiplatelet Therapy" (number NCT01823185) retrospectively registered with clinicaltrials.gov on April 4, 2013. This trial is currently at the patient recruitment stage.
| S-EPMC7271437 | biostudies-literature
Project description:Background: The clinical benefits of cytochrome P450 (CYP) 2C19 genotype-guided antiplatelet therapy in Asians remain unclear. In this study, we aimed to investigate the clinical outcomes of pharmacogenomic antiplatelet therapy in Chinese patients. Methods: Patients with acute coronary syndrome planning to undergo percutaneous coronary intervention were eligible for this study and were randomly divided into a genotype-guided treatment (GT) group and routine treatment (RT) group, with a ratio of 2:1. Patients in the GT group underwent CYP2C19 genotyping (*2 and *3 alleles), and the results were considered in selecting P2Y12 receptor inhibitors. Patients in the RT group were treated with P2Y12 receptor inhibitors according to their clinical characteristics. The primary endpoint was a composite of major adverse cardiovascular or cerebrovascular events (MACCE). The secondary endpoint was significant bleeding events. Results: Finally, 301 patients were enrolled; 75.1% were men and the mean age was 59.7 ± 9.8 years. In total, 281 patients completed the follow-up procedure. The primary endpoint occurred in 16 patients, 6 patients in the GT group and 10 in the RT group. The GT group showed lower MACCE rates than the RT group (6/189 vs. 10/92, 3.2 vs. 10.9%, hazard ratio: 0.281, 95% confidence interval: 0.102-0.773, P = 0.009). There was no statistically difference in significant bleeding events between the GT and RT groups (4.2 vs. 3.3%, hazard ratio: 1.315, 95% confidence interval: 0.349-4.956, P = 0.685). Conclusion: Personalized antiplatelet therapy that is based on CYP2C19 genotypes could decrease MACCE within a 12-month period in Chinese patients with acute coronary syndrome undergoing percutaneous coronary intervention. Clinical Trial Registration: http://www.chictr.org.cn, identifier: ChiCTR2000034352.
| S-EPMC8242578 | biostudies-literature
Project description:Diabetes mellitus (DM) is a metabolic disorder associated with accelerated atherogenesis and an increased risk of atherothrombotic complications. Multiple mechanisms contribute to the pro-thrombotic status which characterizes DM patients underscoring the importance of antiplatelet therapies used for secondary prevention in these patients. For many years, dual antiplatelet therapy (DAPT) with aspirin and the P2Y12 inhibitor clopidogrel has represented the mainstay of treatment following an acute coronary syndrome (ACS) or in patients undergoing percutaneous coronary interventions (PCI). Although DAPT reduces the incidence of atherothrombotic recurrences, these rates remain high in DM patients underscoring the need for more efficacious therapies. Oral platelet P2Y12 receptor inhibitors with enhanced potency, such as prasugrel and ticagrelor, as well as antiplatelet therapies such as vorapaxar inhibiting the thrombin-mediated platelet signaling pathway, constitute treatment opportunities for patients with DM and have shown to be associated with a greater reduction in ischemic recurrences, albeit at the cost of more bleeding. This article reviews currently available antiplatelet agents and delivers an update on the advances and drawbacks of these agents used for secondary prevention in DM patients experiencing an ACS or undergoing PCI.
| S-EPMC6232350 | biostudies-literature
Project description:There are limited data evaluating conformation of antithrombotic therapy usage to the guideline recommendations. We investigated clinical trends and prognoses of patients with atrial fibrillation (AF) according to anticoagulants and antiplatelet agents beyond 1 year after percutaneous coronary intervention (PCI). We analyzed the records of patients with AF who underwent PCI using the Korean National Health Insurance Service database. The primary endpoint was a composite of major adverse cardiac events (MACE). The safety outcome was bleeding complications. Of 4193 participants, 81.6% received antiplatelet therapy, whereas 27.3% had oral anticoagulant (OAC)-based therapy at 18 months after PCI. The dominant therapy was dual antiplatelet therapy (37.2%), and only 3.3% of participants had OAC monotherapy. At the 1-year follow-up, the incidence of MACE was significantly lower among those receiving a combination of OAC and single antiplatelet therapy (SAPT) than among those receiving OAC monotherapy (4.78% vs. 9.42%, p = 0.017). Bleeding complication events (5.01% vs. 5.80%, p = 0.587) did not differ between the groups. In clinical practice, most patients with AF who underwent PCI continued to receive antiplatelet agents beyond 1-year post-PCI. OAC with SAPT seemed to be more effective than OAC monotherapy, without a difference in safety.
| S-EPMC8348599 | biostudies-literature
Project description:Cardiovascular diseases are the leading cause of death in the Western world. Several factors have led to the increase in vascular disorders, including the aging population, unhealthy lifestyles, increasing rates of diabetes and raised lipids, and further risk factors resulting in inflammation and calcification of the vascular endothelium. Activated platelets in damaged blood vessels can trigger arterial thrombus formation, leading to vascular occlusion with subsequent organ hypoperfusion and clinical manifestation of myocardial infarction, stroke, or peripheral artery disease. Platelet inhibitors such as aspirin and clopidogrel (Plavix(®) and generics) are prescribed as primary or secondary prevention to attenuate chronic platelet activation. However, a significant proportion of patients do not respond adequately to uniform antiplatelet treatment. These 'non-responders' have an increased risk for stent thrombosis, stroke, and other ischemic complications. Platelet function (PF) tests can identify these patients thus enabling physicians to offer personalized and alternative treatment strategies. Recent alternatives to clopidogrel include prasugrel (Efient(®)) and ticagrelor (Brilique(®)) - that are both more potent than clopidogrel but also more expensive and associated with a higher risk of bleeding complications. Given these drawbacks, PF testing might help clinicians to prescribe optimal antiplatelet agent to maximize patient safety and efficacy while minimizing costs. While randomized studies using different test systems have left clinicians puzzled about the medical value of tailored antiplatelet therapy, accumulated evidence from recent studies on tailored antiplatelet therapies and the association with improved outcomes have now resulted in a consensus expert opinion for the specific adoption of PF diagnostics into clinical practice.
| S-EPMC4975182 | biostudies-other
Project description:Physician responses to genomic information are vital to the success of precision medicine initiatives. We prospectively studied a pharmacogenomics implementation program for the propensity of clinicians to select antiplatelet therapy based on CYP2C19 loss-of-function variants in stented patients. Among 2,676 patients, 514 (19.2%) were found to have a CYP2C19 variant affecting clopidogrel metabolism. For the majority (93.6%) of the cohort, cardiologists received active and direct notification of CYP2C19 status. Over 12 months, 57.6% of poor metabolizers and 33.2% of intermediate metabolizers received alternatives to clopidogrel. CYP2C19 variant status was the most influential factor impacting the prescribing decision (hazard ratio [HR] in poor metabolizers 8.1, 95% confidence interval [CI] [5.4, 12.2] and HR 5.0, 95% CI [4.0, 6.3] in intermediate metabolizers), followed by patient age and type of stent implanted. We conclude that cardiologists tailored antiplatelet therapy for a minority of patients with a CYP2C19 variant and considered both genomic and nongenomic risks in their clinical decision-making.
| S-EPMC4899238 | biostudies-literature
Project description:OBJECTIVE:To evaluate the clinical utility of individualising dual antiplatelet therapy (DAPT) after percutaneous coronary intervention (PCI) in an all-comers population, including ST-elevation myocardial infarction (STEMI) patients. SETTING:Tertiary care single centre registry. PARTICIPANTS:1008 consecutive PCI patients with stent implantation, without exclusion criteria. INTERVENTION:Peri-interventional individualisation of DAPT, guided by multiple electrode aggregometry (MEA), to overcome high on-treatment platelet reactivity (HPR) to ADP-induced (?50 U) and arachidonic acid (AA)-induced aggregation (>35 U). OUTCOME MEASURES:The primary efficacy end point was definite stent thrombosis (ST) at 30 days. The primary safety end point was thrombolysis in myocardial infarction (TIMI) major and minor bleeding. Secondary end points were probable ST, myocardial infarction, cardiovascular death and the combined end point: major cardiac adverse event (MACE). RESULTS:53% of patients presented with acute coronary syndrome (9% STEMI, 44% non-ST-elevation). HPR to ADP after 600 mg clopidogrel loading occurred in 30% of patients (73±19 U vs 28±11 U; p<0.001) and was treated by prasugrel or ticagrelor (73%), or clopidogrel (27%) reloading (22±12 U; p<0.001). HPR to ADP after prasugrel loading occurred in 2% of patients (82±26 U vs 19±10 U; p<0.001) and was treated with ticagrelor (34±15 U; p=0.02). HPR to AA occurred in 9% of patients with a significant higher proportion in patients with HPR to ADP (22% vs 4%, p<0.001) and was treated with aspirin reloading. Definite ST occurred in 0.09% of patients (n=1); probable ST, myocardial infarction, cardiovascular death and MACE occurred in 0.19% (n=2), 0.09% (n=1) and 1.8% (n=18) of patients. TIMI major and minor bleeding did not differ between patients without HPR and individualised patients (2.6% for both). CONCLUSIONS:Individualisation of DAPT with MEA minimises early thrombotic events in an all-comers PCI population to an unreported degree without increasing bleeding. A randomised multicentre trial utilising MEA seems warranted. TRIAL REGISTRATION NUMBER:http://www.clinicaltrials.gov; NCT01515345.
| S-EPMC4216867 | biostudies-literature
Project description:There is growing research interest in learning the genetic basis of response and adverse effects with psychotropic medications, including antipsychotic drugs. However, the clinical utility of information from genetic studies is compromised by their controversial results, primarily due to relatively small effect and sample sizes. Clinical, demographic, and environmental differences in patient cohorts further explain the lack of consistent results from these genetic studies. Furthermore, the availability of psychopharmacological expertise in interpreting clinically meaningful results from genetic assays has been a challenge, one that often results in suboptimal use of genetic testing in clinical practice. These limitations explain the difficulties in the translation of psychopharmacological research in pharmacogenetics and pharmacogenomics from bench to bedside to manage increasingly treatment-refractory psychiatric disorders, especially schizophrenia. Although these shortcomings question the utility of genetic testing in the general population, the commercially available genetic assays are being increasingly utilized to optimize the effectiveness of psychotropic medications in the treatment-refractory patient population, including schizophrenia. In this context, patients with treatment-refractory schizophrenia are among of the most vulnerable patients to be exposed to the debilitating adverse effects from often irrational and high-dose antipsychotic polypharmacy without clinically meaningful benefits. The primary objective of this comprehensive review is to analyze and interpret replicated findings from the genetic studies to identify specific genetic biomarkers that could be utilized to enhance antipsychotic efficacy and tolerability in the treatment-refractory schizophrenia population.
| S-EPMC8301006 | biostudies-literature
Project description:Dual antiplatelet therapy using acetylsalicylic acid (ASA, aspirin) and clopidogrel is of great importance following coronary stenting. However, the variable platelet inhibitory effectiveness compromises the antithrombotic advantages provided by dual antiplatelet therapy. The aim of this single-center prospective study was to reduce the low response incidence of dual antiplatelet therapy with ASA and clopidogrel according to a prespecified therapy algorithm.Platelet function testing using whole blood aggregometry (Chronolog 590) was performed 48 hours following coronary stenting (for either acute coronary syndromes or stable coronary artery disease) on 504 patients. The antiplatelet therapy included a loading dose of 600 mg clopidogrel and 500 mg ASA, followed by 75 mg clopidogrel and 100 mg ASA once daily. Clopidogrel low responders (CLR: >5 ohm; adenosine diphosphate (ADP) 5 ?M) and/or ASA low responders (ALR: >0 ohm; arachidonic acid 10 ?M) were treated according to a structured therapy plan: in the case of CLR, the maintenance + dose was doubled (repeated loading dose followed by 150 mg daily), and when still ineffective ticlopidine or prasugrel, if available and not contraindicated, were used. ALR was treated by increasing the dose to 300 mg in a first step or to 500 mg ASA when the first modification did not take effect sufficiently. In addition, ADP receptor antagonist 2-methylthioadenosine 5'-monophosphate triethylammonium salt (MeSAMP) testing and ASA incubation were performed to rule out either a platelet ADP-receptor defect or an ASA pharmacokinetic resistance.Of the total cohort of 504 patients, we detected 30.8% clopidogrel low-responders and 19.4% aspirin low-responders. For ALR, with a dose adjustment of 300 mg ASA daily, 94.6% of ALR were effectively treated and the residual 5.4% by administration of daily dosages of 500 mg ASA. This means that after modification of the ASA maintenance dose, all initial ALRs had an adequate antiplatelet response. The results for clopidogrel revealed that 69% of the CLR were treated effectively by increasing the clopidogrel dose to 150 mg daily. When prasugrel was not available or contraindicated, 12.7% of the remaining low responders showed an adequate result after being switched to ticlopidine. Consequently, by applying the therapy algorithm, we were able to reduce the CLR prevalence by 86.6%. On including prasugrel in the therapy plan, we were finally able to eliminate thienopyridine low response. In addition, no ADP receptor defect was found in this study as a potential reason for CLR. We identified the following factors associated with both CLR and ALR status: acute coronary syndromes, positive troponin values as well as diabetes mellitus and elevated HbA1C values and a higher platelet count. Furthermore, our data revealed for CLR elevated C-reactive protein values and a high PREDICT-score (including an age >65 years, acute coronary syndrome, diabetes mellitus, renal failure, and reduced left ventricular function) as risk factors. The following factors correlated with the risk of ASA low response: patients with elevated hemoglobin, serum creatinine and C-reactive protein values. In addition, medication with nitrates reduced the risk of being CLR. As also holds true for CLR, we found the PREDICT-score to be correlated to the risk of being ALR. However, by far the strongest risk factor for CLR or ALR was the fact of dual resistance.Following a structured therapy plan based on a "test and treat" strategy, the prevalence of clopidogrel or aspirin low response can be significantly reduced and the risk of inadequate dual antiplatelet therapy minimized.
| S-EPMC3033359 | biostudies-literature
Project description:Background Clopidogrel nonresponsiveness is a prognostic marker after percutaneous coronary intervention. Prasugrel and ticagrelor provide a better platelet inhibition and represent the first-line antiplatelet treatment in acute coronary syndrome. We sought to assess the prognostic impact of high platelet reactivity (HPR) and the potential clinical benefit of a "tailored" escalated or changed antiplatelet therapy in patients with chronic total occlusion. Methods and Results From Florence CTO-PCI (chronic total occlusion-percutaneous coronary intervention) registry, platelet function assessed by light transmission aggregometry, was available for 1101 patients. HPR was defined by adenosine diphosphate test ≥70% and optimal platelet reactivity by adenosine diphosphate test <70%. The endpoint of the study was long-term cardiac survival. Patients were stratified according to light transmission aggregometry results: optimal platelet reactivity (82%) and HPR (18%). Means for the adenosine diphosphate test were 44±16% versus 77±6%, respectively. Three-year survival was significantly higher in the optimal platelet reactivity group compared with HPR patients (95.3±0.8% versus 86.2±2.8%; P<0.001). With the availability of new P2Y12 inhibitors, a deeper platelet inhibition (46±17%) and similar survival to the optimal platelet reactivity group were achieved in patients with HPR on clopidogrel therapy after escalation. Conversely, HPR on clopidogrel therapy "not switched" was associated with cardiac mortality (hazard ratio 2.37; P=0.003) after multivariable adjustment. Conclusions HPR on treatment could be a modifiable prognostic marker by new antiaggregants providing a deeper platelet inhibition associated with clinical outcome improvement in complex chronic total occlusion patients. A "tailored" antiplatelet therapy, also driven by the entity of platelet inhibition, could be useful in these high risk setting patients.
| S-EPMC7070214 | biostudies-literature