Patterns of antiplatelet therapy in patients with ischaemic stroke or transient ischaemic attack

Background: Antiplatelet drugs are indicated for the secondary prevention in ischaemic stroke or transient ischemic attack (TIA) patients. Objectives: This study aimed to assess the trend in antiplatelet drugs utilisation within 90 days after a first ischaemic stroke/TIA and to identify factors associated with the non-use of antiplatelet therapy. Methods: A cohort study was conducted using data from the UK Clinical Practice Research Datalink. A total of 21,064 patients aged 18 years or older diagnosed with a first ischaemic stroke/TIA between 1999 and 2013 were identified. Antiplatelet drug utilisation was evaluated based on the prescription in 90 days after ischaemic stroke/TIA. Age-adjusted prevalence rates of antiplatelet drug use were calculated. Trends over time were assessed using joinpoint regression. Multivariate logistic regression was used to estimate factors associated with non-use of antiplatelet therapy. Results: The age-adjusted prevalence rate of antiplatelet therapy were 77.5% (ischaemic stroke) and 78.2% (TIA). In the period 1999-2013, the average annual increase in antiplatelet prevalence rates were 2.0% (p <0.01) and 1.8% (p <0.01) in patients with ischaemic stroke and TIA, respectively. Aspirin monotherapy was most commonly used in 1999-2009, but the use declined with an increase in the use of aspirindipyridamole. From 2011, the clopidogrel monotherapy prevalence rates were the highest. Among patients with ischaemic stroke, factors significantly associated with non-use of antiplatelet therapy included female sex (OR 1.1), history of heart failure (OR 1.6), diabetes mellitus (OR 0.8), no prior use of antiplatelet (OR 2.3), previous use of oral anticoagulant (OR 9.2), and year of diagnosis (OR 0.95). As for patients with TIA, significant factors included increasing age (OR 0.91), history of heart failure (OR 1.38), hypertension (OR 0.80), no prior use of antiplatelet (OR 3.2), previous use of oral anticoagulant (OR 16.4), and year of diagnosis (OR 0.93). Conclusions: Antiplatelet drugs utilisation in 90 days after ischaemic stroke/TIA increased over time and the pattern of use were in accordance with the current recommendations. Sex, age, diagnosis year, comorbidity, and prior medications use were independently associated with non-use of antiplatelet therapy following ischaemic stroke/TIA

Clinical reasoning by pharmacists: A scoping review

BACKGROUND: Clinical reasoning is considered a core competency for pharmacists, but there is a lack of conceptual clarity that complicates teaching and assessment. This scoping review was conducted to identify, map, and examine evidence on used cognitive processes and their conceptualization of clinical reasoning by pharmacists. METHODS: In March 2021, seven databases were searched for relevant primary research studies. Included were studies that examined cognitive processes in pharmacists while addressing a clinical scenario in a pharmacy-related setting. Using descriptive analysis, study characteristics, conceptualizations, operationalizations, and key findings were mapped, summarized, and examined. Results were reported using Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews. RESULTS: From 2252 abstracts, 17 studies were included that examined clinical reasoning in the context of forming a diagnosis (n = 9) or determining medication appropriateness (n = 4). Most studies conceptualized clinical reasoning as a context-dependent cognitive process whereby pharmacists apply and integrate knowledge and clinical experience to interpret available clinical data. Different terms labelled pharmacists' reasoning that showed analytical and intuitive approaches to clinical scenarios, either separately or combined. Medication review studies reported a predominance of analytical reasoning. The majority of diagnosis-forming studies in primary care identified no distinct cognitive reasoning pattern when addressing self-care scenarios. IMPLICATIONS: This overview reflects a small but growing body of research on clinical reasoning by pharmacists. It is recommended that this competence be taught by explicating and reflecting on clinical reasoning as separate stage of the clinical decision-making process with transparent cognitive processes

Factors influencing pharmacists' clinical decision making in pharmacy practice

BACKGROUND: Pharmacists' clinical decision-making is considered a core process of pharmaceutical care in pharmacy practice, but little is known about the factors influencing this process. OBJECTIVE: To identify factors influencing clinical decision-making among pharmacists working in pharmacy practice. METHODS: Semi-structured interviews were conducted with pharmacists working in primary, secondary, and tertiary care settings in the Netherlands between August and December 2021. A thematic analysis was conducted using an inductive approach. The emerged themes were categorized into the Capability-Opportunity-Motivation-Behaviour (COM-B) model domains. RESULTS: In total, 16 pharmacists working in primary care (n = 7), secondary care (n = 4) or tertiary care (n = 5) were interviewed. Factors influencing pharmacists' capability to make clinical decisions are a broad theoretical knowledge base, clinical experience, and skills, including contextualizing data, clinical reasoning, and clinical judgment. The pharmacy setting, data availability, rules and regulations, intra- and interprofessional collaboration, education, patient perspectives, and time are mentioned as factors influencing their opportunity. Factors influencing pharmacists' motivation are confidence, curiosity, critical thinking, and responsibility. CONCLUSIONS: The reported factors covered all domains of the COM-B model, implying that clinical decision-making is influenced by a combination of pharmacists' capability, opportunity, and motivation. Addressing these different factors in pharmacy practice and education may improve pharmacists' clinical decision-making, thereby improving patient outcomes

Cost-effectiveness of clopidogrel vs. ticagrelor in patients of 70 years or older with non-ST-elevation acute coronary syndrome

OBJECTIVE: The POPular AGE trial showed that clopidogrel significantly reduced bleeding risk compared with ticagrelor without any signs of an increase in thrombotic events. The aim of this analysis was to estimate the long-term cost-effectiveness of clopidogrel compared with ticagrelor in these patients aged 70 years or older with non-ST-elevation acute coronary syndrome (NSTE-ACS). METHODS AND RESULTS: A 1-year decision tree based on the POPular AGE trial in combination with a lifelong Markov model was developed to compare clopidogrel with ticagrelor in terms of clinical outcomes, costs, and quality-adjusted life years (QALYs) in elderly patients (above 70 year) with NSTE-ACS. Cost-effectiveness was assessed from a Dutch healthcare system perspective. Events rates and utility data observed in the POPular AGE trial were combined with lifetime projections to evaluate costs and effects for a fictional cohort of 1000 patients. Treatment with clopidogrel instead of ticagrelor led to a cost saving of €1484 575 (€1485 per patient) and a decrease of 10.96 QALYs (0.011 QALY per patient) in the fictional cohort. In an alternative base case with equal distribution over health states in the first year, treatment with clopidogrel led to an increase in QALYs. In all scenario analyses, treatment with clopidogrel was cost-saving. CONCLUSION: Clopidogrel is a cost-saving alternative to ticagrelor in elderly patients after NSTE-ACS, though regarding overall cost-effectiveness clopidogrel was not superior to ticagrelor, as it resulted in a small negative effect on QALYs. However, based on the results of the alternative base case and clinical outcomes of the POPular AGE trial, clopidogrel could be a reasonable alternative to ticagrelor for elderly NSTE-ACS patients with a higher bleeding risk

Dutch Pharmacogenetics Working Group (DPWG) guideline for the gene-drug interaction of DPYD and fluoropyrimidines

Despite advances in the field of pharmacogenetics (PGx), clinical acceptance has remained limited. The Dutch Pharmacogenetics Working Group (DPWG) aims to facilitate PGx implementation by developing evidence-based pharmacogenetics guidelines to optimize pharmacotherapy. This guideline describes the starting dose optimization of three anti-cancer drugs (fluoropyrimidines: 5-fluorouracil, capecitabine and tegafur) to decrease the risk of severe, potentially fatal, toxicity (such as diarrhoea, hand-foot syndrome, mucositis or myelosuppression). Dihydropyrimidine dehydrogenase (DPD, encoded by the DPYD gene) enzyme deficiency increases risk of fluoropyrimidine-induced toxicity. The DPYD-gene activity score, determined by four DPYD variants, predicts DPD activity and can be used to optimize an individual's starting dose. The gene activity score ranges from 0 (no DPD activity) to 2 (normal DPD activity). In case it is not possible to calculate the gene activity score based on DPYD genotype, we recommend to determine the DPD activity and adjust the initial dose based on available data. For patients initiating 5-fluorouracil or capecitabine: subjects with a gene activity score of 0 are recommended to avoid systemic and cutaneous 5-fluorouracil or capecitabine; subjects with a gene activity score of 1 or 1.5 are recommended to initiate therapy with 50% the standard dose of 5-fluorouracil or capecitabine. For subjects initiating tegafur: subjects with a gene activity score of 0, 1 or 1.5 are recommended to avoid tegafur. Subjects with a gene activity score of 2 (reference) should receive a standard dose. Based on the DPWG clinical implication score, DPYD genotyping is considered "essential", therefore directing DPYD testing prior to initiating fluoropyrimidines

PPAR-α genetic variants influence on-treatment platelet reactivity in patients treated with clopidogrel and lipid-lowering drugs and undergoing non-urgent percutaneous coronary intervention with stent implantation

Background: Response to clopidogrel varies between patients, due to many factors, like polymorphisms in genes encoding for metabolizing enzymes. The CYP3A4∗22 polymorphism has been proven to decrease the expression of CYP3A4, while the PPAR-α genetic variants G209A and A208G have been identified as determinants that affect CYP3A4. Statins and fibrates, which are the ligands of PPAR-α as well as being metabolized by CYP3A4, might also affect the response of clopidogrel through these two proteins. Objectives: To investigate the association between on-treatment platelet reactivity and the CYP3A4∗22 allele and genetic variations of the PPAR-α genes in clopidogrel-treated patients undergoing non-urgent percutaneous coronary intervention (PCI) with stenting and to evaluate the influence of statin/fibrate co-medication on these associations. Methods: A total of 1126 patients with non-urgent PCI and stenting pre-treated with clopidogrel and aspirin were genotyped for CYP3A4∗22 and PPAR-α (G209A and A208G). Platelet reactivity was measured using the VerifyNow® P2Y12-assay, expressed in PRU. Multivariate linear regression analysis was used to assess the association between the genetic variants and platelet reactivity, adjusted for confounders, including the CYP2C19 metabolizer status. A stratified analysis was conducted for patients with statin/fibrate co-medication. A recessive model was used for all associations. Results: The CYP3A4∗22/∗22 genotype was present in 0.4% of patients, 6.8% had the PPAR-α G209A AA genotype, and 7.0% had the PPAR-α A208G GG genotype. CYP3A4∗22 was not associated with platelet reactivity. PPAR-α genetic variants were significantly associated with platelet reactivity (PPAR-α G209A AA: -23.87 PRU [-43.54, -4.19]; PPAR-α A208G GG: -23.70 PRU [-43.13, -4.27]). In patients who were on statin/fibrate co-medication, these PPAR-α genetic variants were associated with an even lower platelet reactivity (-29.74 PRU [-50.94, -8.54], and -29.38 PRU [-50.26, -8.49], respectively), while those without statin/fibrate co-medication did not show a significant change in platelet reactivity (13.00 PRU [-39.79, 65.80]). Conclusions: Two genetic variants in PPAR-α (G209A and A208G) were associated with lower platelet reactivity in patients with non-urgent PCI and stenting co-treated with clopidogrel and lipid-lowering drugs

CYP2C19 genotype-guided antithrombotic treatment versus conventional clopidogrel therapy in peripheral arterial disease: study design of a randomized controlled trial (GENPAD)

BACKGROUND: Clopidogrel is recommended in international guidelines to prevent arterial thrombotic events in patients with peripheral arterial disease (PAD). Clopidogrel itself is inactive and metabolism is dependent on the CYP2C19 enzyme. About 30% of Caucasian PAD patients receiving clopidogrel carry 1 or 2 CYP2C19 loss-of-function allele(s) and do not or to a limited extent convert the prodrug into its active metabolite. As a result, platelet inhibition may be inadequate which could lead to an increased risk of adverse clinical events related to arterial thrombosis. A CYP2C19 genotype-guided antithrombotic treatment might be beneficial for PAD patients. METHODS: GENPAD is a multicenter randomized controlled trial involving 2,276 PAD patients with an indication for clopidogrel monotherapy. Patients with a separate indication for dual antiplatelet therapy or stronger antithrombotic therapy are not eligible for study participation. Patients randomized to the control group will receive clopidogrel 75 mg once daily without pharmacogenetic guidance. Patients randomized to the intervention group will be tested for carriage of CYP2C19 *2 and *3 loss-of-function alleles, followed by a genotype-guided antithrombotic treatment with either clopidogrel 75 mg once daily for normal metabolizers, clopidogrel 150 mg once daily for intermediate metabolizers, or acetylsalicylic acid 80 mg once daily plus rivaroxaban 2.5 mg twice daily for poor metabolizers. The primary outcome is a composite of myocardial infarction, ischemic stroke, cardiovascular death, acute or chronic limb ischemia, peripheral vascular interventions, or death. The secondary outcomes are the individual elements of the primary composite outcome and clinically relevant bleeding complications. CONCLUSION: The aim of the GENPAD study is to evaluate the efficacy, safety, and cost-effectiveness of a genotype-guided antithrombotic treatment strategy compared to conventional clopidogrel treatment in PAD patients

Cost Effectiveness of a CYP2C19 Genotype-Guided Strategy in Patients with Acute Myocardial Infarction:Results from the POPular Genetics Trial

INTRODUCTION: The POPular Genetics trial demonstrated that a CYP2C19 genotype-guided P2Y12 inhibitor strategy reduced bleeding rates compared with standard treatment with ticagrelor or prasugrel without increasing thrombotic event rates after primary percutaneous coronary intervention (PCI). OBJECTIVE: In this analysis, we aimed to evaluate the cost effectiveness of a genotype-guided strategy compared with standard treatment with ticagrelor or prasugrel. METHODS: A 1-year decision tree based on the POPular Genetics trial in combination with a lifelong Markov model was developed to compare costs and quality-adjusted life-years (QALYs) between a genotype-guided and a standard P2Y12 inhibitor strategy in patients with myocardial infarction undergoing primary PCI. The cost-effectiveness analysis was conducted from a Dutch healthcare system perspective. Within-trial survival and utility data were combined with lifetime projections to evaluate lifetime cost effectiveness for a cohort of 1000 patients. Costs and utilities were discounted at 4 and 1.5%, respectively, according to Dutch guidelines for health economic studies. Besides deterministic and probabilistic sensitivity analyses, several scenario analyses were also conducted (different time horizons, different discount rates, equal prices for P2Y12 inhibitors, and equal distribution of thrombotic events between the two strategies). RESULTS: Base-case analysis with a hypothetical cohort of 1000 subjects demonstrated 8.98 QALYs gained and €725,550.69 in cost savings for the genotype-guided strategy (dominant). The deterministic and probabilistic sensitivity analysis confirmed the robustness of the model and the cost-effectiveness results. In scenario analyses, the genotype-guided strategy remained dominant. CONCLUSION: In patients undergoing primary PCI, a CYP2C19 genotype-guided strategy compared with standard treatment with ticagrelor or prasugrel resulted in QALYs gained and cost savings. TRIAL REGISTRATION: Clinicaltrials.gov number: NCT01761786, Netherlands trial register number: NL2872

Effect of Adding Ticagrelor to Standard Aspirin on Saphenous Vein Graft Patency in Patients Undergoing Coronary Artery Bypass Grafting (POPular CABG) A Randomized, Double-Blind, Placebo-Controlled Trial

BACKGROUND: Approximately 15% of saphenous vein grafts (SVGs) occlude during the first year after coronary artery bypass graft surgery (CABG) despite aspirin use. The POPular CABG trial (The Effect of Ticagrelor on Saphenous Vein Graft Patency in Patients Undergoing Coronary Artery Bypass Grafting Surgery) investigated whether ticagrelor added to standard aspirin improves SVG patency at 1 year after CABG. METHODS: In this investigator-initiated, randomized, double-blind, placebo-controlled, multicenter trial, patients with ≥1 SVGs were randomly assigned (1:1) after CABG to ticagrelor or placebo added to standard aspirin (80 mg or 100 mg). The primary outcome was SVG occlusion at 1 year, assessed with coronary computed tomography angiography, in all patients that had primary outcome imaging available. A generalized estimating equation model was used to perform the primary analysis per SVG. The secondary outcome was 1-year SVG failure, which was a composite of SVG occlusion, SVG revascularization, myocardial infarction in myocardial territory supplied by a SVG, or sudden death. RESULTS: Among 499 randomly assigned patients, the mean age was 67.9±8.3 years, 87.1% were male, the indication for CABG was acute coronary syndrome in 31.3%, and 95.2% of procedures used cardiopulmonary bypass. Primary outcome imaging was available in 220 patients in the ticagrelor group and 223 patients in the placebo group. The SVG occlusion rate in the ticagrelor group was 10.5% (51 of 484 SVGs) versus 9.1% in the placebo group (43 of 470 SVGs), odds ratio, 1.29 [95% CI, 0.73-2.30]; P=0.38. SVG failure occurred in 35 (14.2%) patients in the ticagrelor group versus 29 (11.6%) patients in the placebo group (odds ratio, 1.22 [95% CI, 0.72-2.05]). CONCLUSIONS: In this randomized, placebo-controlled trial, the addition of ticagrelor to standard aspirin did not reduce SVG occlusion at 1 year after CABG. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02352402