Utilization of P2Y12 Inhibitors in Older Adults With ST-Elevation Myocardial Infarction and Frailty.

Choosing optimal P2Y12 inhibitor in frail older adults is challenging because they are at increased risk of both ischemic and bleeding events. We conducted a retrospective cohort study of Medicare Advantage Plan beneficiaries who were prescribed clopidogrel, prasugrel, or ticagrelor after percutaneous coronary intervention-treated ST-elevation myocardial infarction from January 1, 2010 to December 31, 2020. Frailty was defined using claims-based frailty index ≥0.25. We conducted multivariable logistic regression to identify factors associated with using potent P2Y12 inhibitors and multivariable-adjusted competing risk analyses to compare the rate of discontinuation of potent P2Y12 inhibitors in frail versus non-frail patients. There were 11,239 patients (mean age 74 years, 39% women). The prevalence of cardiovascular and geriatric co-morbidities was as follows: 32% chronic kidney disease, 28% heart failure, 10% previous myocardial infarction, 6% dementia, 20% anemia, and 12% frailty. The proportion of patients receiving clopidogrel decreased from 78.3% in 2010 to 2013 to 42.1% in 2018 to 2020, with a concurrent increase in those receiving potent P2Y12 inhibitors (mostly ticagrelor) from 21.7% to 57.9%. Frailty was independently associated with reduced odds of initiation (odds ratio 0.78, 95% confidence interval 0.67 to 0.90) but not with discontinuation of potent P2Y12 inhibitors (subdistribution hazard ratio 1.09, 95% confidence interval 0.98 to 1.22). In conclusion, frail older adults are less likely to receive potent P2Y12 inhibitors after percutaneous coronary intervention-treated ST-elevation myocardial infarction, but they are as likely as non-frail patients to continue with the prescribed P2Y12 inhibitor.

Characteristics and outcomes in patients with a prior myocardial infarction treated with extended dual antiplatelet therapy with ticagrelor 60 mg: findings from ALETHEIA, a multi-country observational study.

BACKGROUND: Guidelines recommend extended dual antiplatelet therapy, including ticagrelor 60 mg twice daily, in high-risk post-myocardial infarction (MI) patients who have tolerated 12 months and are not at high bleeding risk. The real-world utilization and bleeding and ischaemic outcomes associated with long-term ticagrelor 60 mg in routine clinical practice have not been well described. METHODS: Register and claims data from the USA (Optum Clinformatics, IBM MarketScan, and Medicare) and Europe (Sweden, Italy, UK, and Germany) were extracted. Patients initiating ticagrelor 60 mg ≥12 months after MI, meeting eligibility criteria for the PEGASUS-TIMI (Prevention of Cardiovascular Events in Patients with Prior Heart Attack Using Ticagrelor Compared to Placebo on a Background of Aspirin - Thrombolysis in Myocardial Infarction 45) 54 trial, were included. The cumulative incidence of the composite of MI, stroke, or all-cause mortality and that of bleeding requiring hospitalization were calculated. Meta-analyses were performed to combine estimates from each source. RESULTS: A total of 7035 patients treated with ticagrelor 60 mg met eligibility criteria. Median age was 67 years and 29% were females; 12% had a history of multiple MIs. The majority (95%) had been treated with ticagrelor 90 mg prior to initiating ticagrelor 60 mg. At 12 months from initiation of ticagrelor 60 mg, the cumulative incidence [95% confidence interval (CI)] of MI, stroke, or mortality was 3.33% (2.73-4.04) and was approximately three-fold the risk of bleeding (0.96%; 0.69-1.33). CONCLUSIONS: This study provides insights into the use of ticagrelor 60 mg in patients with prior MI in clinical practice. Observed event rates for ischaemic events and bleeding generally align with those in the pivotal trials, support the established safety profile of ticagrelor, and highlight the significant residual ischaemic risk in this population.Clinical Trials.gov Registration NCT04568083.

Utilization Trends In Platelet Adenosine Diphosphate P2Y12 Receptor Inhibitor and Cost Among Medicare Beneficiaries.

Recent guidelines regarding acute coronary syndrome (ACS) have advocated for use of prasugrel and ticagrelor over clopidogrel for acute coronary syndrome. However, analyses from multiple databases have shown that clopidogrel continues to be the most commonly prescribed P2Y12 inhibitor. We aimed to evaluate the trends in utilization and cost of P2Y12 inhibitors for Medicare beneficiaries using data from Medicare Part D Prescription Drug Data Event set from 2011 to 2018 for P2Y12 inhibitors. Medicare part D total beneficiaries for P2Y12 receptor inhibitors increased from 2011 to 2018 by 34.8% from 2.45 million to 3.31 million. The total cost for P2Y12 antiplatelets decreased from $ 3.72 billion in 2011 to $ 0.72 billion in 2018 by 80.4%. The availability of generic clopidogrel drove the considerable total cost reduction. Clopidogrel was the most prescribed P2Y12 inhibitor since its introduction accounting for more than 90% of the Medicare beneficiaries from 2013 to 2018. Overall, the number of beneficiaries on newer P2Y12 inhibitors showed a steady increase with 5.9% beneficiaries on brilinta in 2018 and 2.1 % on prasugrel. The total cost of brilinta beneficiaries grew exponentially accounting for 59.2% of total cost in 2018 and average cost per beneficiary increased by 465% in study period. Despite the availability of generic version clopidogrel and prasugrel, 2,161,175 beneficiaries were on brand plavix and 87,174 on effient which contributed to the increased total expenditure. Earlier introduction and transition to generic versions of medication may help to reduce the drug cost and potentially enhance medication compliance.

Evaluation of Potential Racial Disparities in CYP2C19-Guided P2Y12 Inhibitor Prescribing After Percutaneous Coronary Intervention.

Black patients suffer worse outcomes after percutaneous coronary intervention (PCI) than White patients. Inequities in antiplatelet prescribing may contribute to this health disparity. We compared P2Y12 inhibitor prescribing by race following CYP2C19 genotyping to guide antiplatelet therapy selection after PCI. Patients from 9 sites that performed clinical CYP2C19 genotyping after PCI were included. Alternative therapy (e.g., prasugrel or ticagrelor) was recommended for CYP2C19 no-function allele carriers, in whom clopidogrel is predicted to be less effective. The primary outcome was choice of P2Y12 inhibitor (clopidogrel vs. alternative therapy) based on genotype. Of 3,342 patients included, 2,448 (73%) were White, and 659 (20%) were Black. More Black than White patients had a no-function allele (34.3% vs. 29.7%, P = 0.024). At hospital discharge following PCI, 44.2% of Black and 44.0% of White no-function allele carriers were prescribed alternative therapy. At the time of the last follow-up within 12 months, numerically fewer Black (51.8%) than White (56.7%) no-function allele carriers were prescribed alternative therapy (P = 0.190). However, the difference was not significant after accounting for other factors associated with P2Y12 inhibitor selection (odds ratio 0.79, 95% confidence interval 0.58-1.08). Alternative therapy use did not differ between Black (14.3%) and White (16.7%) patients without a no-function allele (P = 0.232). Among real-world patients who received CYP2C19 testing after PCI, P2Y12 inhibitor prescribing rates did not differ between Black and White patients. Our data suggest an absence of racial disparity in genotype-guided antiplatelet prescribing among patients receiving CYP2C19 testing.

Does the Effectiveness of a Medicine Copay Voucher Vary by Baseline Medication Out-Of-Pocket Expenses? Insights From ARTEMIS.

Background Persistence to P2Y12 inhibitors after myocardial infarction (MI) remains low. Out-of-pocket cost is cited as a factor affecting medication compliance. We examined whether a copayment intervention affected 1-year persistence to P2Y12 inhibitors and clinical outcomes. Methods and Results In an analysis of ARTEMIS (Affordability and Real-World Antiplatelet Treatment Effectiveness After Myocardial Infarction Study), patients with MI discharged on a P2Y12 inhibitor were stratified by baseline out-of-pocket medication burden: low ($0-$49 per month), intermediate ($50-$149 per month), and high (≥$150 per month). The impact of the voucher intervention on 1-year P2Y12 inhibitor persistence was examined using a logistic regression model with generalized estimating equations. We assessed the rates of major adverse cardiovascular events among the groups using a Kaplan-Meier estimator. Among 7351 MI-treated patients at 282 hospitals, 54.2% patients were in the low copay group, 32.0% in the middle copay group, and 13.8% in the high copay group. Patients in higher copay groups were more likely to have a history of prior MI, heart failure, and diabetes compared with the low copay group (all P<0.0001). Voucher use was associated with a significantly higher likelihood of 1-year P2Y12 inhibitor persistence regardless of copayment tier (low copay with versus without voucher: adjusted odds ratio [OR], 1.44 [95% CI, 1.25-1.66]; middle copay: adjusted OR, 1.63 [95% CI, 1.37-1.95]; high copay group: adjusted OR, 1.41 [95% CI, 1.05-1.87]; P interaction=0.42). Patients in the high copay group without a voucher had similar risk of 1-year major adverse cardiovascular events compared with patients in the high copay group with a voucher (adjusted hazard ratio, 0.89 [95% CI, 0.66-1.21]). Conclusions Medication copayment vouchers were associated with higher medication persistence at 1 year following an MI, regardless of out-of-pocket medication burden. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT02406677.

Prescribing Trends and Health Care Expenditure of P2Y12 Prescriptions in Australia Over the Last Decade.

BACKGROUND: Dual antiplatelet therapy (DAPT) is guideline therapy following acute coronary syndrome (ACS). Novel, potent P2Y12 inhibitors have been developed and studied but it is unclear how this evidence has been incorporated into patient care. We sought to describe the prescribing trends and health care costs of P2Y12therapy in Australia over the last decade. METHOD: The latest statistical data collected by the Pharmaceutical Benefit Scheme (PBS), Australia, was reviewed. PBS codes for coronary indications were selected. Yearly total prescriptions and cost were then compared between all three P2Y12 inhibitors. Linear trend modelling was used to observe general trends over the data collection period. RESULTS: Total yearly P2Y12 scripts have more than doubled between 2010 (403,880 scripts) and 2020 (994,826 scripts). Clopidogrel is the most prescribed P2Y12 inhibitor and has been for the last decade. Ticagrelor represents 26.2% of total prescriptions but accounts for 75% of PBS spending. More than $30 million is spent on ticagrelor every year with a cost per MACE prevented of $72,637. Prasugrel was the least prescribed agent but was 41% cheaper per major adverse cardiac event (MACE) prevented than ticagrelor before being removed from the Australian market. Without prasugrel available, clopidogrel scripts have increased 10% and ticagrelor scripts remain stable. CONCLUSION: Clopidogrel remains the most prescribed P2Y12 agent in Australia, despite emergence of more potent P2Y12 inhibitors. Ticagrelor is increasingly prescribed but represents a disproportionately large burden of spending. Whilst prasugrel is the most efficacious, cheaper than ticagrelor and guideline recommended P2Y12 inhibitor after ACS, it represented the minority of scripts before being withdrawn. Rather than use of a potent P2Y12 agent, clinicians are reverting to prescribing clopidogrel.

Aspirin with Low-Dose Ticagrelor or with Low-Dose Rivaroxaban for Secondary Prevention: A Cost per Outcome Analysis.

INTRODUCTION: Secondary prevention of cardiovascular events among patients with diagnosed cardiovascular disease and high ischemic risk poses a significant challenge in clinical practice. The combinations of aspirin with low-dose (LD) ticagrelor or LD rivaroxaban have shown superiority in preventing major adverse cardiovascular events (MACE) compared with aspirin treatment alone. The comparative value for money of these two regimens remains unexplored. METHODS: We analyzed each regimen's annual cost needed to treat (CNT) by multiplying the annualized number needed to treat (aNNT) by the annual cost of each drug. The aNNTs were based on outcome data from PEGASUS TIMI-54 and COMPASS trials. Scenario analyses were performed to overcome variances in terms of population risk. Costs were calculated as 75% of US National Average Drug Acquisition Cost (NADAC), extracted in January 2022. The primary outcome was defined as CNT to prevent one MACE across the two regimens. Secondary value analysis was performed for myocardial infarction (MI), stroke, and cardiovascular death as separate outcomes. RESULTS: The aNNTs to prevent MACE with LD ticagrelor and with LD rivaroxaban were 229 [95% confidence interval (CI) 141-734] and 147 (95% CI 104-252), respectively. At an annual cost of US$3726 versus US$4533, the corresponding CNTs were US$853,254 (95% CI 525,366-2,734,884) with LD ticagrelor and US$666,351 (95% CI 471,432-1,142,316) with LD rivaroxaban. CONCLUSION: Combining aspirin with LD rivaroxaban provides better value for money than with LD ticagrelor for secondary prevention of MACE.

Cost-Consequence Analysis of Using Cangrelor in High Angiographic Risk Percutaneous Coronary Intervention Patients: A US Hospital Perspective.

OBJECTIVES: The objective of this study was to evaluate a US hospital's cost implications and outcomes of cangrelor use in percutaneous coronary intervention (PCI) patients with two or more angiographic high-risk features (HRFs), including avoidance of oral P2Y12 inhibitor pretreatment in patients requiring cardiac surgery. Intravenous cangrelor provides direct, immediate onset and rapid-offset P2Y12 inhibition, which may reduce the necessity for oral P2Y12 pretreatment. METHODS: A decision analytic model was developed, estimating the annual impact over 3 years of cangrelor availability. Ischemic and bleeding events (48 h) from randomized clinical trial data were extrapolated to 30 days. Event costs were from the CHAMPION PHOENIX Economics substudy. Rates of coronary artery disease (CAD) presentation, PCI, oral P2Y12 pretreatment, and inpatient hospitalization costs were from published literature and clinical experts. Scenario analyses evaluated the impact of cangrelor availability on potential reduced P2Y12 pretreatment rates by 50-100%. Drug costs were 2019 wholesale acquisition costs and, where necessary, all costs were adjusted to 2019 dollars. RESULTS: In a hospital treating 1000 CAD PCI inpatients annually, increasing cangrelor use from 11 to 32% resulted in a reduction in 48-h ischemic events/year by 5.7%, while bleeding events increased by 2.9%. Total costs of $1,135,472 declined 12.8%, with a 50% reduction in P2Y12 pretreatment or 30% with no pretreatment. Savings were driven by a decrease in ischemic events, decrease in glycoprotein IIb/IIIa inhibitor use, and less need for and shorter oral P2Y12 inhibitor washout period for surgery patients. CONCLUSION: Use of cangrelor in patients with two or more angiographic HRFs may improve outcomes and lower hospital budgets, mainly from avoiding surgery delays necessitated by oral P2Y12 inhibitor pretreatment.

Disparities by sex in P2Y12 inhibitor therapy duration, or differences in the balance of ischaemic-benefit and bleeding-risk clinical outcomes in older women versus comparable men following acute myocardial infarction? A P2Y12 inhibitor new user retrospective cohort analysis of US Medicare claims data.

OBJECTIVES: To determine if comparable older women and men received different durations of P2Y12 inhibitor therapy following acute myocardial infarction (AMI) and if therapy duration differences were justified by differences in ischaemic benefits and/or bleeding risks. DESIGN: Retrospective cohort. SETTING: 20% sample of 2007-2015 US Medicare fee-for-service administrative claims data. PARTICIPANTS: ≥66-year-old P2Y12 inhibitor new users following 2008-2013 AMI hospitalisation (N=30 613). Older women compared to older men with similar predicted risks of study outcomes. PRIMARY AND SECONDARY OUTCOME MEASURES: Primary outcome: P2Y12 inhibitor duration (modelled as risk of therapy discontinuation). SECONDARY OUTCOMES: clinical events while on P2Y12 inhibitor therapy, including (1) death/hospice admission, (2) composite of ischaemic events (AMI/stroke/revascularisation) and (3) hospitalised bleeds. Cause-specific risks and relative risks (RRs) estimated using Aalen-Johansen cumulative incidence curves and bootstrapped 95% CIs. RESULTS: 10 486 women matched to 10 486 men with comparable predicted risks of all 4 study outcomes. No difference in treatment discontinuation was observed at 12 months (women 31.2% risk; men 30.9% risk; RR 1.01; 95% CI 0.97 to 1.05), but women were more likely than men to discontinue therapy at 24 months (54.4% and 52.9% risk, respectively; RR 1.03; 95% CI 1.00 to 1.05). Among patients who did not discontinue P2Y12 inhibitor therapy, women had lower 24-month risks of ischaemic outcomes than men (13.1% and 14.7%, respectively; RR 0.90; 95% CI 0.84 to 0.96), potentially lower 24-month risks of death/hospice admission (5.0% and 5.5%, respectively; RR 0.91; 95% CI 0.82 to 1.02), but women and men both had 2.5% 24-month bleeding risks (RR 0.98; 95% CI 0.82 to 1.14). CONCLUSIONS: Risks for death/hospice and ischaemic events were lower among women still taking a P2Y12 inhibitor than comparable men, with no difference in bleeding risks. Shorter P2Y12 inhibitor durations in older women than comparable men observed between 12 and 24 months post-AMI may reflect a disparity that is not justified by differences in clinical need.

Clopidogrel-herb Interactions: A Pharmacokinetic and Pharmacodynamic Assessment in a Rat Model.

BACKGROUND: Herbs usually contain a mixture of biologically active constituents, which can interact with numerous prescribed drugs and alter their safety profiles. OBJECTIVES: The current investigation was aimed to evaluate the effect of commonly used herbal products including black seed (Nigella sativa), garden cress (Lepidium sativum), and fenugreek (Trigonella foenum-graecum) on the pharmacokinetics and pharmacodynamics of clopidogrel using a Wistar rat model. METHODS: A GC-MS analysis revealed the presence of several phytoconstitutents (polyphenols) in the extracts of black seed, garden cress, and fenugreek. These polyphenols have the potential to interfere with clopidogrel effect. Plasma concentrations of clopidogrel were measured at different time points in the absence and presence of the concurrent use of tested herbal products and the pharmacokinetic parameters were calculated. Bleeding time was measured in various groups as a measure of the antiplatelet effect of clopidogrel. RESULTS: Area under the plasma concentration-time curves (AUC0-∞) of clopidogrel were 35.53 ±0.89 µg/ml*h (p<0.05), 26.01 ±0.90 µg/ml*h (p>0.05) and 32.80 ±2.51 µg/ml*h (p<0.05) in the black seed, garden cress and fenugreek group, respectively, compared with that of the control group (27.02 ±0.42 µg/ml*h). Treatment with black seed also caused an increase in clopidogrel Cmax by 31.52% (p<0.05) and with fenugreek by 21.42% (p<0.05); Cmax, did not changed with garden cress treatment (6.48 ±0.15 µg/ml versus 6.12 ±0.21 µg/ml, p>0.05). The pharmacodynamic evaluation of the antiplatelet effect of clopidogrel in the presence of herbal products treatment showed a significant prolongation in the bleeding time from a control baseline by ~22-26%, and by added ~8-12% in reference to clopidogrel therapeutic effect (p<0.05). CONCLUSION: The concurrent use of black seed, fenugreek, or garden cress can alter the pharmacokinetics and pharmacodynamics of clopidogrel to varying degrees due to the presence of various bioactive polyphenols. This is probably due to changes in drug disposition and its antiplatelet action. Further confirmation can determine the clinical relevance of these observations and identify the exact constituents responsible for such activities.

Assessment of Pretreatment With Oral P2Y12 Inhibitors and Cardiovascular and Bleeding Outcomes in Patients With Non-ST Elevation Acute Coronary Syndromes: A Systematic Review and Meta-analysis.

Importance: The practice of pretreatment with oral P2Y12 inhibitors in non-ST elevation acute coronary syndromes (NSTEACS) remains common; however, its association with improved cardiovascular outcomes is unclear. Objective: To assess the association between oral P2Y12 inhibitor pretreatment and cardiovascular and bleeding outcomes in patients with NSTEACS. Data Sources: On March 20, 2021, PubMed, MEDLINE, Embase, Scopus, Web of Science, Science Direct, clinicaltrials.gov, and the Cochrane Central Register for Controlled Trials were searched from database inception. Study Selection: Randomized clinical trials of patients with NSTEACS randomized to either oral P2Y12 inhibitor pretreatment (defined as prior to angiography) or no pretreatment (defined as following angiography, once coronary anatomy was known) among patients undergoing an invasive strategy. Data Extraction and Synthesis: This study followed Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines. Data on publication year, sample size, clinical characteristics, revascularization strategy, P2Y12 inhibitor type and dosage, time from pretreatment to angiography, and end point data were independently extracted by 2 authors. A random-effects model was used, including stratification by (1) P2Y12 inhibitor type, (2) revascularization strategy, and (3) access site. Main Outcomes and Measures: The primary end point was 30-day major adverse cardiac events (MACEs). Secondary end points were 30-day myocardial infarction (MI) and cardiovascular death. The primary safety end point was 30-day major bleeding (defined according to individual studies). Results: A total of 7 trials randomizing 13 226 patients to either pretreatment (6603 patients) or no pretreatment (6623 patients) were included. The mean age of patients was 64 years and 3598 (27.2%) were female individuals. Indication for P2Y12 inhibitors was non-ST elevation myocardial infarction in 7430 patients (61.7%), radial access was used in 4295 (32.6%), and 10 945 (82.8%) underwent percutaneous coronary intervention. Pretreatment was not associated with a reduction in 30-day MACE (odds ratio [OR], 0.95; 95% CI, 0.78-1.15; I2 = 28%), 30-day MI (OR, 0.90; 95% CI, 0.72-1.12; I2 = 19%), or 30-day cardiovascular death (OR, 0.79; 95% CI, 0.49-1.27; I2 = 0%). The risk of 30-day major bleeding was increased among patients who underwent pretreatment (OR, 1.51; 95% CI, 1.16-1.97; I2 = 41%). The number needed to harm to bring about 1 major bleeding event with oral P2Y12 inhibitor pretreatment was 63 patients. Conclusions and Relevance: In this study, pretreatment with oral P2Y12 inhibitors among patients with NSTEACS prior to angiography, compared with treatment once coronary anatomy is known, was associated with increased bleeding risk and no difference in cardiovascular outcomes. Routine pretreatment with oral P2Y12 inhibitors in patients with NSTEACS receiving an early invasive strategy is not supported by this study.

Platelet Reactivity in Patients With Acute Coronary Syndromes Awaiting Surgical Revascularization.

BACKGROUND: Dual antiplatelet therapy is recommended for patients with acute coronary syndromes (ACS). Approximately 10% to 15% of these patients will undergo coronary artery bypass graft (CABG) surgery for index events, and current guidelines recommend stopping clopidogrel at least 5 days before CABG. This waiting time has clinical and economic implications. OBJECTIVES: This study aimed to evaluate if a platelet reactivity-based strategy is noninferior to standard of care for 24-h post-CABG bleeding. METHODS: In this randomized, open label noninferiority trial, 190 patients admitted with ACS with indications for CABG and on aspirin and P2Y12 receptor inhibitors, were assigned to either control group, P2Y12 receptor inhibitor withdrawn 5 to 7 days before CABG, or intervention group, daily measurements of platelet reactivity by Multiplate analyzer (Roche Diagnostics GmbH, Vienna, Austria) with CABG planned the next working day after platelet reactivity normalization (pre-defined as ≥46 aggregation units). RESULTS: Within the first 24 h of CABG, the median chest tube drainage was 350 ml (interquartile range [IQR]: 250 to 475 ml) and 350 ml (IQR: 255 to 500 ml) in the intervention and control groups, respectively (p for noninferiority <0.001). The median waiting period between the decision to undergo CABG and the procedure was 112 h (IQR: 66 to 142 h) and 136 h (IQR: 112 to 161 h) (p < 0.001), respectively. In the intention-to-treat analysis, a 6.4% decrease in the median in-hospital expenses was observed in the intervention group (p = 0.014), with 11.2% decrease in the analysis per protocol (p = 0.003). CONCLUSIONS: A strategy based on platelet reactivity-guided is noninferior to the standard of care in patients with ACS awaiting CABG regarding peri-operative bleeding, significantly shortens the waiting time to CABG, and decreases hospital expenses. (Evaluation of Platelet Aggregability in the Release of CABG in Patients With ACS With DAPT; NCT02516267).

Pharmacodynamic Profile and Prevalence of Bleeding Episode in East Asian Patients with Acute Coronary Syndromes Treated with Prasugrel Standard-Dose versus De-escalation Strategy: A Randomized A-MATCH Trial.

Compared with Caucasian patients, East Asian patients have the unique risk-benefit trade-off and different responsiveness to antithrombotic regimens. The aim of this study was to compare pharmacodynamic profile in East Asian patients with acute coronary syndromes (ACSs) treated with prasugrel standard-dose versus a de-escalation strategy. Before discharge, ACS patients with age <75 years or weight ≥60 kg (n = 255) were randomly assigned to the standard-dose (10-mg group) or de-escalation strategy (5-mg group or platelet function test [PFT]-guided group). After 1 month, VerifyNow P2Y12 assay-based platelet reactivity (P2Y12 reaction unit [PRU]) and bleeding episodes were evaluated. Primary endpoint was the percentage of patients with the therapeutic window (85 ≤ PRU ≤ 208). The 250 patients completed 1-month treatment. The percentage of patients within the therapeutic window was significantly lower in the 10-mg group (n = 85) compared with the 5-mg (n = 83) and PFT-guided groups (n = 82) (35.3 vs. 67.5 vs. 65.9%) (odds ratio [OR]: 3.80 and 3.54; 95% confidence interval [CI]: 2.01-7.21 and 1.87-6.69, respectively). Compared with the 10-mg group, the bleeding rate was tended to be lower with de-escalation strategies (35.3 vs. 24.1% vs. 23.2%) (hazard ratio [HR]: 0.58 and 0.55; 95% CI: 0.30-1.14 and 0.28-1.09, respectively). "PRU < 127" was the optimal cut-off for predicting 1-month bleeding events (area under the curve: 0.616; 95% CI: 0.543-0.689; p = 0.005), which criteria was significantly associated with early discontinuation of prasugrel treatment (HR: 2.00; 95% CI: 1.28-3.03; p = 0.001). In conclusion, compared with the standard-dose prasugrel, the prasugrel de-escalation strategy in East Asian patients presented with ACS showed a higher chance within the therapeutic window and a lower tendency toward bleeding episodes. REGISTRATION: URL: https://clinicaltrials.gov. Unique identifier:NCT01951001.

Exploring Medication Adherence with P2Y12 Inhibitors Using Conditional and Unconditional Quantile Regression Approaches.

BACKGROUND: Previous research assessing medication adherence with P2Y12 inhibitors has shown good adherence rates, ranging from 78% to 92%. Studies that used administrative claims data defined adherence using an arbitrary cut point of ≥ 80% medication possession ratio (MPR) or proportion of days covered (PDC). While this method is used frequently, it does not allow the researcher to observe how each factor impacts adherence along the entire distribution. The objective of the study was to use conditional quantile regression (CQR) and unconditional quantile regression (UQR) to assess heterogenous effects of adherence to P2Y12 inhibitors and covariates of interest and compare these results to those from a traditional logistic regression framework. METHODS AND RESULTS: This study used the commercial claims and encounters databases from IBM® MarketScan® from 2010 to 2017. We included patients who had an incident percutaneous coronary intervention, used a drug-eluting stent, and filled an incident prescription for a P2Y12 inhibitor. Adherence was measured for 185 days using PDC. Adherence to branded clopidogrel, generic clopidogrel, branded prasugrel, and branded ticagrelor was assessed, along with factors that could impact adherence, using logistic regression, CQR, and UQR. We found that while adherence to the antiplatelets was generally high, prasugrel and ticagrelor had significantly lower PDC compared to branded clopidogrel, especially around the 30th percentile. Across all quantiles in both the CRQ and UQR frameworks, comorbidities such as diabetes and depression and living in the southern region had significant negative effects on adherence, although the relative impact differed across quantiles. CONCLUSIONS: Using CQR and UQR allowed for heterogenous assessment of covariates along the adherence distribution, which is not possible with the traditional logistic regression method. The UQR framework revealed patients who initiate prasugrel or ticagrelor generally have lower adherence compared to those treated with branded clopidogrel, especially around the 30th quantile. Using these methods in other types of data sets, such as electronic health records, could help strengthen our results to develop policies to improve antiplatelet adherence in a targeted population.

Design and rationale of the XIENCE short DAPT clinical program: An assessment of the safety of 3-month and 1-month DAPT in patients at high bleeding risk undergoing PCI with an everolimus-eluting stent.

Dual antiplatelet therapy (DAPT) is key for the prevention of recurrent ischemic events after percutaneous coronary intervention (PCI); however, it increases the risk of bleeding complications. While new generation drug-eluting stents have been shown superior to bare-metal stents after a short DAPT course, the optimal DAPT duration in patients at high bleeding risk (HBR) remains to be determined. TRIAL DESIGN: The XIENCE Short DAPT program consists of three prospective, single-arm studies (XIENCE 90, XIENCE 28 Global and XIENCE 28 USA) investigating 3- or 1-month DAPT durations in HBR patients undergoing PCI with the XIENCE stent. The XIENCE 90 study is being conducted in the US and enrolled 2047 subjects who discontinued DAPT at 3 months if they were free from myocardial infarction (MI), repeat coronary revascularization, stroke, or stent thrombosis. The XIENCE 28 program includes the USA study, enrolling 642 patients in US and Canada, and the Global study, enrolling 963 patients in Europe and Asia. In XIENCE 28, patients were to discontinue DAPT at 1 month post-PCI if event-free. The primary hypothesis for both XIENCE 90 and XIENCE 28 is that a short DAPT regimen will be non-inferior to a conventional DAPT duration with respect to the composite of all-cause death or MI. Patients enrolled in the prospective multicenter post-market XIENCE V USA study will be used as historical control group in a stratified propensity-adjusted analysis. CONCLUSIONS: The XIENCE Short DAPT Program will provide insights into the safety and efficacy of 2 abbreviated DAPT regimens of 3- and 1-month duration in a large cohort of HBR patients undergoing PCI with the XIENCE stent.

Utility of P2Y12 Reactive Unit Assessment on Ticagrelor in Cerebral Aneurysms Treated with Intracranial Stenting and Flow Diversion: Cohort Study and Case Report From Two Neurovascular Centers.

BACKGROUND: Dual antiplatelet therapy consisting of aspirin and clopidogrel is the standard of care for neurointerventional stenting and flow diversion. Platelet function testing has been increasingly performed to identify patients with a hypo- or hyper-response to clopidogrel. Ticagrelor has been a popular alternative antiplatelet agent for such patients. We assessed the role of platelet function testing in patients receiving ticagrelor and undergoing stenting or flow diversion. METHODS: The data from patients who had undergone stent-assisted coiling or Pipeline flow diversion of a cerebral aneurysm with ticagrelor therapy at any point during their treatment course from May 2017 to August 2019 at a single academic institution in the United States were retrospectively reviewed. Platelet function testing was used to determine the P2Y12 reactive units (PRUs), and the results were correlated with the procedural complications. RESULTS: A total of 28 patients with 29 aneurysms were treated while receiving ticagrelor. Of the 29 aneurysms, 16 (55.2%) were treated with flow diversion and 13 (44.8%) with stent-assisted coiling. Four thromboembolic complications (13.8%) and no hemorrhagic complications developed. Of the 8 patients with ≥1 PRU value >100, 4 (50%) had experienced a thromboembolic complication. The patients without a PRU value >100 did not experience any complications. CONCLUSION: A risk of thromboembolic complications exists for patients receiving ticagrelor, which correlated with the PRUs in the present preliminary study. The findings from the present study suggest that the safe PRU range for patients receiving ticagrelor should be shifted to 0-100, which is lower than that of clopidogrel, thought to be 60-210. Further validation of the optimal PRU range for patients receiving ticagrelor is necessary.