Contemporary Predictors of Major Adverse Cardiovascular Events Following Percutaneous Coronary Intervention: A Nationally Representative US Sample.

Background: Patient outcomes after percutaneous coronary intervention (PCI) have improved over the last 30 years due to better techniques, therapies, and care processes. This study evaluated contemporary predictors of post-PCI major adverse cardiovascular events (MACE) and summarized risk in a parsimonious risk prediction model. Methods: The Cardiovascular Patient-Level Analytical Platform (CLiPPeR) is an observational dataset of baseline variables and longitudinal outcomes from the American College of Cardiology's CathPCI Registry® and national claims data. Cox regression was used to evaluate 2-6 years of patient follow-up (mean: 2.56 years), ending in December 2017, after index PCI between 2012 and 2015 (N = 1,450,787), to examine clinical and procedural predictors of MACE (first myocardial infarction, stroke, repeat PCI, coronary artery bypass grafting, and mortality). Cox analyses of post-PCI MACE were landmarked 28 days after index PCI. Results: Overall, 12.4% (n = 179,849) experienced MACE. All variables predicted MACE, with cardiogenic shock, cardiac arrest, four diseased coronary vessels, and chronic kidney disease having hazard ratios (HRs) ≥ 1.50. Other major predictors of MACE were in-hospital stroke, three-vessel disease, anemia, heart failure, and STEMI presentation. The index revascularization and discharge prescription of aspirin, P2Y12 inhibitor, and lipid-lowering medication had HR ≤ 0.67. The primary Cox model had c-statistic c = 0.761 for MACE versus c = 0.701 for the parsimonious model and c = 0.752 for the parsimonious model plus treatment variables. Conclusions: In a nationally representative US sample of post-PCI patients, predictors of longitudinal MACE risk were identified, and a parsimonious model efficiently encapsulated them. These findings may aid in assessing care processes to further improve care post-PCI outcomes.

Hospitalization for Myocardial Infarction with Ticagrelor or Clopidogrel in Patients with Acute Coronary Syndrome: An On-Treatment Comparative Effectiveness Analysis.

INTRODUCTION: Prescribing patterns and suboptimal adherence present methodological challenges for real-world head-to-head comparisons of ticagrelor and clopidogrel in intent-to-treat studies. The aim of this study was to compare ticagrelor and clopidogrel in an on-treatment population. METHODS: This retrospective cohort study used the Optum™ Clinformatics™ database to identify patients with acute coronary syndrome (ACS) discharged on ticagrelor or clopidogrel between January 1, 2012 and September 30, 2019. The primary end point was hospitalization for myocardial infarction (MI); the secondary end point was hospitalization for major bleeding. The ticagrelor and clopidogrel cohorts were balanced by propensity score matching (PSM) 1:3 for demographic and clinical characteristics. Outcomes were ascertained from day 31 until day 365 or end of follow-up. RESULTS: Of 339,387 patients with ACS, 14,110 ticagrelor- and 57,482 clopidogrel-treated patients met the study criteria. After PSM, 13,373 ticagrelor- and 29,656 clopidogrel-treated patients provided 4945 and 13,895 patient-years of data, respectively, for the primary end point. Hospitalization for MI was significantly lower in the ticagrelor compared to the clopidogrel cohort (2.22 vs. 3.52 per 100 patient-years; 36.8% relative risk reduction [RRR]; P < 0.0001). Hospitalization for major bleeding was similar in the ticagrelor and clopidogrel cohorts (2.04 vs. 2.06 per 100 patient-years; 1.1% RRR, P = 0.9214). CONCLUSIONS: In this real-world on-treatment analysis, hospitalization for MI was significantly lower with ticagrelor compared to clopidogrel, with similar rates of hospitalization for major bleeding. Study findings underscore the importance of being on the appropriate guideline-recommended therapy and support the use of ticagrelor over clopidogrel.

New Heart Failure After Myocardial Infarction (From the National Cardiovascular Data Registries [NCDR] Linked With All-Payer Claims).

Heart failure (HF) is common in patients presenting with acute myocardial infarction (MI), but incidence and predictors of new onset HF after hospitalization for MI are less well characterized. We evaluated patients hospitalized for acute MI without preceding or concurrent HF in the National Cardiovascular Data Registry (NCDR) CathPCI and Chest Pain-MI registries linked with claims data between April 2010 and March 2017. Cumulative incidence and independent predictors of HF after discharge were determined, and a simplified risk score was developed to predict incident HF following MI. In 337,274 patients with acute MI and no history of HF, 8.0% developed incident HF within 1 year after discharge and 18.8% developed HF within 5 years. Significant predictors of HF after MI included advanced chronic kidney disease (CKD) (HR 2.34, 95% confidence interval [CI] 2.23-2.46 for Stage IV vs Stage I, and HR 2.18, 95% CI 2.07-2.29 for Stage V vs. Stage I), recurrent MI following index MI (HR 2.24, 95% CI 2.19-2.28), African-American race (HR 1.44, 95% CI 1.40-1.48), and diabetes (HR 1.39, 95% CI 1.37-1.42). A risk score of 8 variables predicted HF with modest discrimination (optimism-corrected c-statistic 0.64) and good calibration. In conclusion, nearly 1 in 5 patients in a large nationally representative cohort without preceding or concurrent heart failure at time of MI developed incident HF within 5 years after discharge. Advanced CKD and recurrent MI were the strongest predictors of future HF. Increased recognition of specific risk factors for HF may help inform care strategies following MI.

Difference in Medication Adherence Between Patients Prescribed a 30-Day Versus 90-Day Supply After Acute Myocardial Infarction.

Background Evidence-based medication adherence rates after a myocardial infarction are low. We hypothesized that 90-day prescriptions are underused and may lead to higher evidence-based medication adherence compared with 30-day fills. Methods and Results We examined patients with myocardial infarction treated with percutaneous coronary intervention between 2011 and 2015 in the National Cardiovascular Data Registry. Linking to Symphony Health pharmacy data, we described the prevalence of patients filling 30-day versus 90-day prescriptions of statins, ß-blockers, angiotensin-converting enzyme inhibitors/angiotensin receptor blockers, and P2Y12 inhibitors after discharge. We compared 12-month medication adherence rates by evidence-based medication class and prescription days' supply and rates of medication switches and dosing changes. Among 353 259 patients with myocardial infarction treated with percutaneous coronary intervention, 90-day evidence-based medication fill rates were low: 13.0% (statins), 12.3% (ß-blockers), 14.6% (angiotensin-converting enzyme inhibitors/angiotensin receptor blockers), and 9.7% (P2Y12 inhibitors). Patients filling 90-day prescriptions were more likely older (median 69 versus 62 years) with a history of prior myocardial infarction (25.0% versus 17.9%) or percutaneous coronary intervention (30.3% versus 19.5%; P<0.01 for all) than patients filling 30-day prescriptions. The 12-month adherence rates were higher for patients who filled 90-day versus 30-day supplies: statins, 83.1% versus 75.3%; ß-blockers, 72.7% versus 62.9%; angiotensin-converting enzyme inhibitors/angiotensin receptor blockers, 71.1% versus 60.9%; and P2Y12 inhibitors, 78.5% versus 66.6% (P<0.01 for all). Medication switches and dosing changes within 12 months were infrequent for patients filling 30-day prescriptions-14.7% and 0.3% for 30-day P2Y12 inhibitor fills versus 6.3% and 0.2% for 90-day fills, respectively. Conclusions Patients who filled 90-day prescriptions had higher adherence and infrequent medication changes within 1 year after discharge. Ninety-day prescription strategies should be encouraged to improve post-myocardial infarction medication adherence.

Outcomes of Medicare beneficiaries hospitalised with transient ischaemic attack and stratification using the ABCD2 score.

BACKGROUND: Long-term outcomes for Medicare beneficiaries hospitalised with transient ischaemic attack (TIA) and role of ABCD2 score in identifying high-risk individuals are not studied. METHODS: We identified 40 825 Medicare beneficiaries hospitalised from 2011 to 2014 for a TIA to a Get With The Guidelines (GWTG)-Stroke hospital and classified them using ABCD2 score. Proportional hazards models were used to assess 1-year event rates of mortality and rehospitalisation (all-cause, ischaemic stroke, haemorrhagic stroke, myocardial infarction, and gastrointestinal and intracranial haemorrhage) for high-risk versus low-risk groups adjusted for patient and hospital characteristics. RESULTS: Of the 40 825 patients, 35 118 (86%) were high risk (ABCD2 ≥4) and 5707 (14%) were low risk (ABCD2=0-3). Overall rate of mortality during 1-year follow-up after hospital discharge for the index TIA was 11.7%, 44.3% were rehospitalised for any reason and 3.6% were readmitted due to stroke. Patients with ABCD2 score ≥4 had higher mortality at 1 year than not (adjusted HR 1.18, 95% CI 1.07 to 1.30). Adjusted risks for ischaemic stroke, all-cause readmission and mortality/all-cause readmission at 1 year were also significantly higher for patients with ABCD2 score ≥4 vs 0-3. In contrast, haemorrhagic stroke, myocardial infarction, gastrointestinal bleeding and intracranial haemorrhage risk were not significantly different by ABCD2 score. CONCLUSIONS: This study validates the use of ABCD2 score for long-term risk assessment after TIA in patients aged 65 years and older. Attentive efforts for community-based follow-up care after TIA are needed for ongoing prevention in Medicare beneficiaries who were hospitalised for TIA.

Addressing Therapeutic Inertia in 2020 and Beyond: A 3-Year Initiative of the American Diabetes Association.

Research has shown that getting to glycemic targets early on leads to better outcomes in people with type 2 diabetes; yet, there has been no improvement in the attainment of A1C targets in the past decade. One reason is therapeutic inertia: the lack of timely adjustment to the treatment regimen when a person's therapeutic targets are not met. This article describes the scope and priorities of the American Diabetes Association's 3-year Overcoming Therapeutic Inertia Initiative. Its planned activities include publishing a systematic review and meta-analysis of approaches to reducing therapeutic inertia, developing a registry of effective strategies, launching clinician awareness and education campaigns, leveraging electronic health record and clinical decision-support tools, influencing payer policies, and potentially executing pragmatic research to test promising interventions.

Translating clinical evidence into value-based payment models: pooled analyses of innovative real-world outcomes agreements for ticagrelor in the United States.

Innovative value strategies for reimbursement of medications include value-based agreements (VBAs) between payers and pharmaceutical manufacturers, which have the potential to improve affordability and patient access to therapy, as well as lead to a reduction in downstream health events and associated medical costs. VBAs link payment for a medication to its performance in real-world clinical practice measured against prespecified outcomes that are aligned to existing evidence. Given its high prevalence, economic burden, and impact on mortality, cardiovascular disease (namely, coronary heart disease) represents an opportunity for VBAs to contribute to improved health outcomes and patient experiences while reducing or containing total medical costs. AstraZeneca developed a VBA framework directly comparing 2 antiplatelet therapies indicated to treat acute coronary syndrome (ACS)-ticagrelor and clopidogrel-based on the PLATO trial, which demonstrated superiority for ticagrelor in reducing the incidence of recurrent myocardial infarction (MI) in patients with ACS. Between 2015 and 2018, 11 contract-years of VBAs utilizing this framework were implemented in commercial and Part D health insurance plans, totaling nearly 32,000 unique patients in which pooled analyses were conducted. Aggregated VBA results indicate that ticagrelor consistently outperformed expectations in reducing recurrent MI vs clopidogrel, while also illustrating how comparative VBA frameworks of this nature may overcome challenges noted for VBAs and be utilized more broadly in future applications.

Oral Antiplatelet Therapy Administered Upstream to Patients With NSTEMI.

OBJECTIVE: To describe from a noninterventional registry (Utilization of Ticagrelor in the Upstream Setting for Non-ST-Segment Elevation Acute Coronary Syndrome), the short-term ischemic and hemorrhagic outcomes in patients with non-ST elevation myocardial infarction (MI) are managed with a loading dose (LD) of a P2Y12 inhibitor (P2Y12i) given at least 4 hours before diagnostic angiography and delineation of coronary anatomy. Prior data on the effects of such "upstream loading" have been inconsistent. METHODS: In 53 US hospitals, we evaluated the in-hospital care and outcomes of patients with confirmed non-ST elevation MI managed with an interventional strategy and loaded upstream (at least 4 h before diagnostic angiography) with oral P2Y12i therapy. Patients entered into the database were grouped into 1 of 4 cohorts for analysis: (1) overall cohort, (2) thienopyridine (clopidogrel or prasugrel) load, (3) ticagrelor load, and (4) ticagrelor-consistent. The fourth cohort is a subset of cohort 3 that received ticagrelor throughout the index hospital stay and at discharge. We evaluated in-hospital clinical course and ischemic and bleeding outcomes in all patients and also 30-day outcomes in the ticagrelor-consistent cohort. RESULTS: A total of 3355 patients were enrolled, of whom 1087 had 30-day follow-up. The mean (±SD) age was 63.3 ± 12.5 years, and 62.6% were male. Thrombolysis in MI and Global Registry of Acute Coronary Events scores placed these patients in the intermediate risk range, and CRUSADE scores were in the moderate risk range. The LD in Utilization of Ticagrelor in the Upstream Setting for Non-ST-Segment Elevation Acute Coronary Syndrome was clopidogrel in 45.6%, ticagrelor in 53.6%, and prasugrel in 0.8%. The median upstream interval (LD to angiography) was 17:27 hours and did not change appreciably over the course of the data collection period (2/15-10/19). Access was radial in 48.6% and femoral in 51.4%. Postangiography management was medical only in 32.3%, percutaneous coronary intervention in 59.4%, and coronary artery bypass grafting in 8.3%. Median length of stay was 2.7 days, and median time from angiography to coronary artery bypass grafting was 3.6 days. In-hospital mortality was 0.51%, and major bleeding (thrombolysis in MI) was 0.24%; the in-hospital major adverse cardiovascular events rate was 0.7%, and stent thrombosis occurred in 0.18%. No significant differences were seen between the ticagrelor and clopidogrel cohorts in hospital, but 16% received more than 1 P2Y12i in-hospital. On follow-up (93.2% response), 86.7% of patients reported taking ticagrelor as directed. CONCLUSIONS: Upstream loading of P2Y12i was associated with very low rates of bleeding and short length of stay in a large cohort of non-ST elevation MI (NSTEMI) patients managed invasively.

Agreement and Accuracy of Medication Persistence Identified by Patient Self-report vs Pharmacy Fill: A Secondary Analysis of the Cluster Randomized ARTEMIS Trial.

Importance: Pharmacy fill data are increasingly accessible to clinicians and researchers to evaluate longitudinal medication persistence beyond patient self-report. Objective: To assess the agreement and accuracy of patient-reported and pharmacy fill-based medication persistence. Design, Setting, and Participants: This post hoc analysis of the cluster randomized clinical trial ARTEMIS (Affordability and Real-world Antiplatelet Treatment Effectiveness After Myocardial Infarction Study) enrolled patients at 287 US hospitals (131 randomized to intervention and 156 to usual care) from June 5, 2015, to September 30, 2016, with 1-year follow-up and blinded adjudication of major adverse cardiovascular events. In total, 8373 patients with myocardial infarction and measurement of P2Y12 inhibitor persistence by both patient self-report and pharmacy data were included. Serum P2Y12 inhibitor drug levels were measured for 944 randomly selected patients. Data were analyzed from May 2018 to November 2019. Interventions: Patients treated at intervention-arm hospitals received study vouchers to offset copayments at each P2Y12 inhibitor fill for 1 year after myocardial infarction. Main Outcomes and Measures: Nonpersistence was defined as a gap of 30 days or more in P2Y12 inhibitor use (patient report) or supply (pharmacy fill) and as serum P2Y12 inhibitor levels below the lower limit of quantification (drug level). Among patients in the intervention arm, a "criterion standard" definition of nonpersistence was a gap of 30 days or more in P2Y12 inhibitor use by both voucher use and pharmacy fill. Major adverse cardiovascular events were defined as adjudicated death, recurrent myocardial infarction, or stroke. Results: Of 8373 patients included in this analysis, the median age was 62 years (interquartile range, 54-70 years), 5664 were men (67.7%), and 990 (11.8%) self-reported as nonwhite race/ethnicity. One-year estimates of medication nonpersistence rates were higher using pharmacy fills (4042 patients [48.3%]) compared with patient self-report (1277 patients [15.3%]). Overall, 4185 patients (50.0%) were persistent by both pharmacy fill data and patient report, 1131 patients (13.5%) were nonpersistent by both, and 3057 patients (36.5%) were discordant. By application of the criterion standard definition, the 1-year nonpersistence rate was 1184 of 3703 patients (32.0%); 892 of 3318 patients (26.9%) in the intervention arm who self-reported persistence were found to be nonpersistent, and 303 of 1487 patients (20.4%) classified as nonpersistent by pharmacy fill data were actually persistent. Agreement between serum P2Y12 inhibitor drug levels and either patient-reported (κ = 0.11-0.23) or fill-based (κ = 0.00-0.19) persistence was poor. Patients who were nonpersistent by both pharmacy fill data and self-report had the highest 1-year major adverse cardiac event rate (18.3%; 95% CI, 16.0%-20.6%) compared with that for discordant patients (9.7%; 8.7%-10.8%) or concordantly persistent patients (8.2%; 95% CI, 7.4%-9.0%). Conclusions and Relevance: Patient report overestimated medication persistence rates, and pharmacy fill data underestimated medication persistence rates. Patients who are nonpersistent by both methods have the worst clinical outcomes and should be prioritized for interventions that improve medication-taking behavior. Trial Registration: ClinicalTrials.gov Identifier: NCT02406677.

Association of a P2Y12 Inhibitor Copayment Reduction Intervention With Persistence and Adherence With Other Secondary Prevention Medications: A Post Hoc Analysis of the ARTEMIS Cluster-Randomized Clinical Trial.

Importance: The Affordability and Real-World Antiplatelet Treatment Effectiveness After Myocardial Infarction Study (ARTEMIS) cluster-randomized trial found that copayment reduction for P2Y12 inhibitors improved 1-year patient persistence in taking that medication. Objective: To assess whether providing copayment reduction for P2Y12 inhibitors increases patient persistence in taking other secondary prevention cardiovascular medications. Design, Setting, and Participants: This post hoc analysis of the ARTEMIS trial includes data from 287 hospitals that enrolled patients between June 2015 and September 2016. Patients hospitalized with acute myocardial infarction were included. Data analysis occurred from May 2018 through August 2019. Interventions: Hospitals randomized to the intervention provided patients vouchers that waived copayments for P2Y12 inhibitors fills for 1 year. Hospitals randomized to usual care did not provide study vouchers. Main Outcomes and Measures: Persistence in taking ß-blocker, statin, and angiotensin-converting enzyme inhibitor or angiotensin II receptor blocker medications at 1 year, defined as the absence of a gap in medication supply of 30 or more days by pharmacy fill data in the intervention-arm (intent-to-treat) population. Results: A total of 131 hospitals (with 5109 patients) were randomized to the intervention, and 156 hospitals (with 3264 patients) randomized to the control group. Patients discharged from intervention hospitals had higher persistence in taking statins (2247 [46.1%] vs 1300 [41.9%]; adjusted odds ratio, 1.11 [95% CI, 1.00-1.24]), and ß-blockers (2235 [47.6%] vs 1277 [42.5%]; odds ratio, 1.23 [95% CI, 1.10-1.38]), although the association was smaller than that seen for P2Y12 inhibitors (odds ratio, 1.47 [95% CI, 1.29-1.66]). Persistence in taking angiotensin-converting enzyme inhibitors or angiotensin II-receptor blockers were also numerically higher among patients in the intervention arm than in the usual-care arm, but this was not significant after risk adjustment (1520 [43.9%] vs 847 [40.5%]; adjusted odds ratio, 1.10 [95% CI, 0.97-1.24]). Patients in the intervention arm reported greater financial burden associated with medication cost than the patients in the usual-care arm at baseline, but these differences were no longer significant at 1 year. Conclusions and Relevance: Reducing patient copayments for 1 medication class increased persistence not only to that therapy class but may also have modestly increased persistence to other post-myocardial infarction secondary prevention medications. These findings have important implications for the clinical utility and cost-effectiveness of medication cost-assistance programs. Trial Registration: ClinicalTrials.gov identifier: NCT02406677.

Effect of Medication Co-payment Vouchers on P2Y12 Inhibitor Use and Major Adverse Cardiovascular Events Among Patients With Myocardial Infarction: The ARTEMIS Randomized Clinical Trial.

Importance: Despite guideline recommendations, many patients discontinue P2Y12 inhibitor therapy earlier than the recommended 1 year after myocardial infarction (MI), and higher-potency P2Y12 inhibitors are underutilized. Cost is frequently cited as an explanation for both of these observations. Objective: To determine whether removing co-payment barriers increases P2Y12 inhibitor persistence and lowers risk of major adverse cardiovascular events (MACE). Design, Setting, and Participants: Cluster randomized clinical trial among 301 hospitals enrolling adult patients with acute MI (June 5, 2015, through September 30, 2016); patients were followed up for 1 year after discharge (final date of follow-up was October 23, 2017), with blinded adjudication of MACE; choice of P2Y12 inhibitor was per clinician discretion. Interventions: Hospitals randomized to the intervention (n = 131 [6436 patients]) provided patients with co-payment vouchers for clopidogrel or ticagrelor for 1 year (median voucher value for a 30-day supply, $137 [25th-75th percentile, $20-$339]). Hospitals randomized to usual care (n = 156 [4565 patients]) did not provide study vouchers. Main Outcomes and Measures: Independent coprimary outcomes were patient-reported persistence with P2Y12 inhibitor (defined as continued treatment without gap in use ≥30 days) and MACE (death, recurrent MI, or stroke) at 1 year among patients discharged with a prescription for clopidogrel or ticagrelor. Results: Among 11 001 enrolled patients (median age, 62 years; 3459 [31%] women), 10 102 patients were discharged with prescriptions for clopidogrel or ticagrelor (clopidogrel prescribed to 2317 [36.0%] in the intervention group and 2497 [54.7%] in the usual care group), 4393 of 6135 patients (72%) in the intervention group used the voucher, and follow-up data at 1 year were available for 10 802 patients (98.2%). Patient-reported persistence with P2Y12 inhibitors at 1 year was higher in the intervention group than in the control group (unadjusted rates, 5340/6135 [87.0%] vs 3324/3967 [83.8%], respectively; P < .001; adjusted difference, 2.3% [95% CI, 0.4% to 4.1%]; adjusted odds ratio, 1.19 [95% CI, 1.02 to 1.40]). There was no significant difference in MACE at 1 year between intervention and usual care groups (unadjusted cumulative incidence, 10.2% vs 10.6%; P = .65; adjusted difference, 0.66% [95% CI, -0.73% to 2.06%]; adjusted hazard ratio, 1.07 [95% CI, 0.93 to 1.25]). Conclusions and Relevance: Among patients with MI, provision of vouchers to offset medication co-payments for P2Y12 inhibitors, compared with no vouchers, resulted in a 3.3% absolute increase in patient-reported persistence with P2Y12 inhibitors and no significant reduction in 1-year MACE outcomes. Trial Registration: ClinicalTrials.gov Identifier: NCT02406677.

Pharmacokinetics and pharmacodynamics of ticagrelor in subjects on hemodialysis and subjects with normal renal function.

PURPOSE: This single-dose, randomized, open-label, parallel-group, and crossover study assessed pharmacokinetics (PK), pharmacodynamics (PD), and safety of ticagrelor in subjects on hemodialysis versus healthy subjects. METHODS: Hemodialysis subjects were randomized, receiving a single ticagrelor 90-mg dose 1 day post-hemodialysis or just before hemodialysis, with an intervening washout of ≥ 7 days. Healthy subjects (creatinine clearance ≥ 90 mL/min) received a single ticagrelor 90-mg dose. PK, PD (P2Y12 reaction units [PRU], inhibition of platelet aggregation [IPA]), and safety were evaluated. RESULTS: Twenty-seven subjects (14 hemodialysis, 13 healthy) received ticagrelor. The mean maximum plasma concentration (Cmax) and area under the plasma concentration curve from time zero to infinity (AUC0-∞) of ticagrelor were 598.4 ng/mL and 3256.1 ng·h/mL, respectively, in pre-hemodialysis subjects; 560.3 ng/mL and 3015.1 ng·h/mL, respectively, in post-hemodialysis subjects; and 370.8 ng/mL and 2188.8 ng·h/mL, respectively, in healthy subjects. Cmax and AUC0-∞ of AR-C124910XX, the active metabolite, were 152.3 ng/mL and 1144.2 ng·h/mL, respectively, in pre-hemodialysis subjects; 130.8 ng/mL and 1127.8 ng·h/mL, respectively, in post-hemodialysis subjects; and 111.7 ng/mL and 1000.4 ng·h/mL, respectively, in healthy subjects. Mean IPA time curves over 24 h post-dose were almost indistinguishable for all three treatments. The greatest reduction in mean PRU occurred approximately 2 h post-dose for all three treatments. No safety or tolerability issues were identified. CONCLUSION: Hemodialysis resulted in modestly higher exposure to ticagrelor and AR-C124910XX, with no clinically significant effect on PD or tolerability. Accordingly, no dose adjustment is required for hemodialysis patients. Timing of hemodialysis has little impact on ticagrelor PK, or the effect of ticagrelor on IPA.

Ticagrelor in Peripheral Artery Disease Endovascular Revascularization (TI-PAD): Challenges in clinical trial execution.

There is limited evidence to guide clinical decision-making for antiplatelet therapy in peripheral artery disease (PAD) in the setting of lower extremity endovascular treatment. The Ticagrelor in Peripheral Artery Disease Endovascular Revascularization Study (TI-PAD) evaluated the role of ticagrelor versus aspirin as monotherapy in the management of patients following lower extremity endovascular revascularization. The trial failed to recruit the targeted number of patients, likely due to aspects of the design including the lack of option for dual antiplatelet therapy, and inability to identify suitable patients at study sites. In response, the protocol underwent amendments, but these changes did not adequately stimulate recruitment, and thus TI-PAD was prematurely terminated. This article describes the rationale for TI-PAD and challenges in trial design, subject recruitment and trial operations to better inform the conduct of future trials in PAD revascularization. ClinicalTrials.gov Identifier: NCT02227368.

Clinically feasible stratification of 1-year to 3-year post-myocardial infarction risk.

Objective: Post-myocardial infarction (MI) care is crucial to preventing recurrent major adverse cardiovascular events (MACE), but can be complicated to personalise. A tool is needed that effectively stratifies risk of cardiovascular (CV) events 1-3 years after MI but is also clinically usable. Methods: Patients surviving ≥1 year after an index MI with ≥1 risk factor for recurrent MI (ie, age ≥65 years, prior MI, multivessel coronary disease, diabetes, glomerular filtration rate <60 mL/min/1.73 m2) were studied. Cox regression derived sex-specific Intermountain Major Adverse Cardiovascular Events (IMACE) risk scores for the composite of 1-year to 3-year MACE (CV death, MI or stroke). Derivation was performed in 70% of subjects (n=1342 women; 3047 men), with validation in the other 30% (n=576 women; 1290 men). Secondary validations were also performed. Results: In women, predictors of CV events were glucose, creatinine, haemoglobin, platelet count, red cell distribution width (RDW), age and B-type natriuretic peptide (BNP); among men, they were potassium, glucose, blood urea nitrogen, haematocrit, white blood cell count, RDW, mean platelet volume, age and BNP. In the primary validation, in women, IMACE ranged from 0 to 11 (maximum possible: 12) and had HR=1.44 per +1 score (95% CI 1.29 to 1.61; P<0.001); men had IMACE range 0-14 (maximum: 16) and HR=1.29 per +1 score (95% CI 1.20 to 1.38; P<0.001). IMACE ≥5 in women (≥6 in men) showed strikingly higher MACE risk. Conclusions: Sex-specific risk scores strongly stratified 1-year to 3-year post-MI MACE risk. IMACE is an inexpensive, dynamic, electronically delivered tool for evaluating and better managing post-MI patient care.

Impact of Diabetes Mellitus on the Pharmacodynamic Effects of Ticagrelor Versus Clopidogrel in Troponin-Negative Acute Coronary Syndrome Patients Undergoing Ad Hoc Percutaneous Coronary Intervention.

BACKGROUND: Diabetes mellitus (DM) is associated with enhanced platelet reactivity and impaired response to oral antiplatelet therapy, including clopidogrel. This post hoc analysis investigated the pharmacodynamic effects of ticagrelor versus clopidogrel loading dose (LD) in troponin-negative acute coronary syndrome patients with or without DM undergoing percutaneous coronary intervention in the Ad Hoc PCI study. METHODS AND RESULTS: Patients randomized (1:1) to receive ticagrelor 180 mg LD or clopidogrel 600 mg LD were assessed by diabetic status. Platelet reactivity (P2Y12 reaction units [PRU] on VerifyNow® assay) was measured pre-LD, at 0.5, 2, and 8 hours post-LD, and at the end of the percutaneous coronary intervention. The primary endpoint was PRU levels 2 hours post-LD; secondary endpoints included rates of high on-treatment platelet reactivity (PRU≥208). Of 100 randomized patients, 51 received ticagrelor (DM, n=20; non-DM, n=31) and 49 clopidogrel (DM, n=16; non-DM, n=33). At 2 hours post-LD, mean (SD) PRU levels in DM patients were 130.1 (111.7) with ticagrelor versus 287.6 (71.9) with clopidogrel (mean [95%CI] difference -157.5 [-225.3, -89.8]; P<0.001); in non-DM patients, they were 75.3 (75.7) versus 243.0 (72.4) (mean difference -167.7 [-207.1, -128.3]; P<0.001). High on-treatment platelet reactivity rates at 2 hours post-LD were also significantly (P<0.001) reduced with ticagrelor versus clopidogrel in DM and non-DM patients. Between-treatment differences for PRU and high on-treatment platelet reactivity were not significant at earlier time points but were at 8 hours post-LD (P<0.001). CONCLUSIONS: Compared with clopidogrel, ticagrelor achieved faster, enhanced platelet inhibition and reduced high on-treatment platelet reactivity rates, in DM and non-DM patients. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01603082.