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Background: Clopidogrel, aspirin (ASA), and the fixed-dose combination of extended-release dipyridamole and ASA (ER-DP+ASA) are widely used in post-stroke regimens. Objective: This study compared serial changes in multiple biomarkers of platelet activation with ER-DP+ASA and clopidogrel with or without ASA in patients with type 2 diabetes mellitus and a history of transient ischemic attack (TIA). Methods: This was a randomized, single-blind pilot study conducted at an outpatient center in the United States. Eligible patients were aged 40 years and had a diagnosis of type 2 diabetes and a history of TIA. Patients were allocated to receive ER-DP+ASA 200/25 mg BID, clopidogrel 75 mg/d, or clopidogrel 75 mg/d plus ASA 81 mg/d. Multiple platelet bio-markers were assessed at baseline, day 15, and day 30 using aggregometry, cartridge-based platelet function analyzers, and flow cytometry. The primary end point was the change in platelet receptor expression after 30 days of therapy. Compliance and tolerability were monitored by measuring plasma dipyridamole levels and recording all episodes of headache and vomiting. Results: The study enrolled 60 consecutive patients (20 per treatment arm), all of whom completed the study. There were no significant differences between treatment arms, although the ER-DP+ASA group had a numerically greater mean age, higher proportion of men, and a greater prevalence of vascular disease and smoking compared with the other groups. There were no deaths or serious adverse events during the study, including symptoms attributable to cerebral ischemia, worsening of diabetes, or cerebral or systemic bleeding. Three patients in the ER-DP+ASA group and 1 in the clopidogrel plus ASA group reported headache during the first several days of therapy; 1 patient in the clopidogrel monotherapy group experienced transitory nausea and vomiting. ER-DP+ASA was associated with a significantly delayed (day 30) reduction in expression of glyco-protein (GP) Ilb/IIIa activity (P = 0.02), platelet-endothelial cell adhesion molecule 1 (PECAM-1) (P = 0.03), GP Ib (P = 0.001), vitronectin (P = 0.001), P-selectin (P = 0.001), lysosome-associated membrane protein 1 (P = 0.001), and cluster of differentiation 40 ligand (P = 0.01), as well as significant inhibition of the intact (P = 0.01) and cleaved (P = 0.01) epitopes of protease-activated receptor 1. Clopidogrel monotherapy, on the other hand, was associated with significant inhibition of adenosine diphosphate-induced platelet aggregation (P = 0.001), closure-time prolongation (P = 0.01), and reduction in measurements on the rapid platelet function assay-ASA at day 15 (P = 0.001). Expression of PECAM-1 (P = 0.03) and GP IIb/IIIa activity (P = 0.01) was reduced at day 15 in clopidogrel-treated patients. The addition of ASA to clopidogrel was associated with significant inhibition of collagen-induced platelet aggregation (P = 0.001) and diminished formation of platelet-monocyte microparticles at days 15 (P = 0.02) and 30 (P = 0.03). Conclusions: In these patients with type 2 diabetes and a history of TIA, patterns of platelet inhibition differed significantly according to whether treatment was with ER-DP+ASA or clopidogrel with or with-out ASA. The antiplatelet activity of clopidogrel was more potent and occurred earlier (15 days), whereas ER-DP+ASA was associated with moderate down-regulation of multiple activation-dependent platelet receptors that occurred later (30 days). [ABSTRACT FROM AUTHOR]

Therapy with aspirin and/or adenosine diphosphate (ADP) receptor blockers is associated with better outcomes via inhibition of platelet activity, and subsequent reduction of ischemic vascular events. Non-compliance (NC) is a well-recognised hazard limiting the clinical utility of antiplatelet agents, and, probably worsening outcomes. However, comprehensive platelet characteristics of a confirmed NC patient after acute vascular event have never been reported within a major randomised trial with ADP-receptor antagonists. A 48-year-old male patient, well-educated, was among patients enrolled in the platelet sub-study for the JUMBO trial. He received 325 mg of aspirin daily for 9 months, presented with unstable angina for urgent coronary intervention, and was successfully reperfused with two intracoronary stents. The patient was randomised to a 60 mg prasugrel loading dose, and 10 mg of prasugrel daily for 30 days. Platelets were assessed at baseline, 4 and 24 h, and at 30 days after acute coronary event utilising ADP-, and collagen-induced conventional aggregometry, rapid cartridge-based analyser and flow cytometry. Loading with prasugrel resulted in significant inhibition of platelet activity during and after stenting. However, after assessing platelet biomarkers at 30 days, voluntary withdrawal from the antiplatelet agents was suspected. Based on the platelet activity characteristics, NC was later confirmed, and the patient admitted that he stopped taking both prasugrel and aspirin shortly after discharge due to minor bleeding episodes after shaving. Major platelet activity biomarkers of the index NC patient were compared with those from compliant prasugrel-, clopidogrel-treated patients, and healthy controls. The platelet tests uniformly revealed rebound activation by all platelet measures (at least twofold increase) while being especially high for ADP-, and collagen-induced aggregation, platelet/endothelial cell adhesion molecule-1 (PECAM-1), glycoprotein (GP)Ib, GPIIb/IIIa activity, P-selectin, protease activated receptor (PAR)-1 thrombin receptor (activated and intact epitopes), and thrombospondin expression. The clinical benefits of antiplatelet agents are not only denied in NC outpatients, but may put them at additional risk for worsened vascular outcomes due to the rebound platelet activation. Proclaimed 'resistance' to antiplatelet agents may at least in part be a result of NC, especially in the chronic uncontrolled setting. Enforcing compliance will improve outcomes in the clinical trials, and save lives of patients really receiving antiplatelet therapy. [ABSTRACT FROM AUTHOR]

Depression is associated with an increased incidence of vascular events and develops after stroke and myocardial infarction. Beside potential clinical outcome benefits of selective serotonin reuptake inhibitors for vascular diseases, bleeding events were reported. We investigated whether paroxetine and aspirin synergistically inhibit platelet function. Paroxetine (20 mg/d) was administered over 18 days to 20 men in a randomized, placebo-controlled, crossover design. Aspirin (100 mg/d) was coadministered within the last 4 study days. Platelet function was assessed by the platelet function analyzer and by flow cytometry. Paroxetine prolonged epinephrine-dependent predictive index within 14 days (P<.02). Aspirin enhanced the predictive index (P<.004 vs baseline and P>.05 between periods). A trend toward decreased thrombin receptor-activating peptide-induced CD62P expression after paroxetine was further enhanced by aspirin treatment (P>.05 between periods). The combination of paroxetine and aspirin did not further inhibit platelet plug formation under high shear stress in male smokers. [ABSTRACT FROM AUTHOR]

Background: The incidence of stroke/TIA during annual dual antiplatelet therapy (ADAPT) for acute coronary syndrome (ACS) remains high. Some evidence suggests that shorter than ADAPT may diminish such risk, still providing adequate vascular protection. However, the precise timing of strokes/TIA occurrences during ADAPT is unclear but may be important for determining optimal preventive treatment duration., Study Question: The precise timing of secondary cerebrovascular events over ADAPT., Study Design: Access was gained to the FDA-issued Platelet Inhibition and Outcomes (PLATO) trial data set on which post hoc analyses of stroke/TIA timing after ticagrelor and clopidogrel on top of aspirin was explored., Measures and Outcomes: Events were counted and plotted over time from day 1 till day 365 after the index ACS event., Results: Among 18,624 enrollees, 252 strokes and 49 TIAs were reported. After the exclusion of entries with missing dates, unclear randomization codes, and events beyond 1-year follow-up, 238 strokes and 45 TIAs were analyzed. Overall, most frequent strokes/TIAs occurred within the first day after qualifying ACS, with the gradual declines after day 7 and day 40 reaching background counts thereafter. The strokes/TIAs patterns did not differ much between P 2 Y12 inhibitors except for twice more events at day 1 and excess exclusions after day 365 in the ticagrelor arm., Conclusions: Most cerebrovascular events emerged very early after ACS despite ADAPT. This large hypothesis-generating evidence may justify shorter than the ADAPT duration after ACS. Twice more events at day 1 and excess late ticagrelor exclusions in PLATO deserve further scrutiny., Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT00391872., Competing Interests: Diagnostics, Sanofi and Vifor, also research grants to the institution from Medtronic, BMS and Roche diagnostics. The other authors have no conflicts of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Excess mortality remains the cornerstone concern despite dual antiplatelet therapy (DAPT) after acute coronary syndrome. Some data suggest that shorter periods than 12 months of DAPT diminish bleeding risks yet still provide adequate vascular protection and improving survival. However, the precise timing of deaths after acute coronary syndrome has not been mapped in many studies. This knowledge may be critical for defining optimal treatment duration., Methods: Access was gained to the data set for the Platelet Inhibition and Outcomes (PLATO) trial, which was issued by the Food and Drug Administration, in which post hoc analyses of timing of death events during DAPT (with either aspirin/ticagrelor or aspirin/clopidogrel) were performed. All-cause individual deaths were counted and plotted over time from day 1 to day 365 after the index event., Results: Among 18,624 enrollees, 938 total deaths were reported to the Food and Drug Administration in PLATO. After exclusion of deceased patients with missing dates, randomization errors, and deaths beyond 1 year of follow-up, 913 fatalities (509 after clopidogrel and 404 after ticagrelor) were analyzed. The PLATO records did not indicate where exactly deaths occurred making impossible to triage in the hospital versus outpatient fatalities. Most frequent deaths occurred within the Day 1 (n = 41); Day 2 (n = 48); and Day 3 (n = 33) and overall during the first week (n = 202; 22.1%) after the index acute coronary syndrome, with a gradual decline after Day 10 and Day 60, reaching background counts after Day 220., Conclusion: Focusing on mortality reduction, this large data set may support a shorter than 12 months' duration of DAPT., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: Bleeding remains a complication during dual antiplatelet therapy (DAPT) for acute coronary syndrome (ACS). Some data suggest a link between bleeding and worsened vascular outcomes. However, this association is unclear, due to omitting of minor bleedings when applying conservative scales. In contrast, the Platelet Inhibition and Outcomes (PLATO) trial classification used broad realistic capturing of all bleedings., Methods: Access was gained to the Food and Drug Administration-issued adjudication data set on which post hoc analyses of bleeding, myocardial infarction (MI), stroke, and death were conducted. Bleeding was defined as minimal, minor, major, and life-threatening or fatal (LTOF) as per the original PLATO scale., Results: Among 18,624 enrollees, 10,705 adjudicated events occurred across 7171 patients. There were 618 minimal, 1412 minor, 1216 major, and 536 LTOF bleedings for the total of 3782 events reported in 3387 patients. There were 938 deaths, 2751 MIs and 359 strokes. The overall bleeding was 20.3%, exhibited in 19.2% patients. Total bleeds were associated with less deaths (odds ratio [OR]: 0.55, 95% confidence interval [CI]: 0.47-0.63) and MI (OR: 0.47, 95% CI: 0.41-0.54; P < .001 for both). There were no differences in deaths (OR: 1.11, 95% CI: 0.93-1.34; P = .24), but less MIs (OR: 0.72. 95% CI: 0.59-0.86; P < .001), and more strokes (OR: 2.17, 95% CI: 1.64-2.88; P < .001) after LTOF. Major, minor, and minimal bleeds were associated with less deaths and MI but not strokes., Conclusion: These large uniformly adjudicated data reveal that within 12 months of dual antiplatelet therapy, 1 out of 5 patients experiences bleeding. Overall, bleeding was associated with diminished incidence of death and MI but not strokes., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Purpose: The FDA-issued PLATO trial dataset revealed that some primary death causes (PDCs) were inaccurately reported favouring ticagrelor. However, the PLATO Investigators operated the shorter death list of uncertain quality. We compared if PDC match when trial fatalities were reported to the FDA and by the PLATO Investigators., Method: The FDA list contains precisely detailed 938 PLATO deaths, while shorter investigators dataset consists of 905 deaths. We matched four vascular (sudden, post-MI, heart failure and stroke), and three non-vascular (cancer, sepsis and suicide) PDC between death lists., Results: There were more sudden deaths in the shorter list than in the FDA dataset (161 vs 138; P < .03) and post-AMI (373 vs 178; P < .001) but fewer heart failure deaths (73 vs 109; P = .02). Stroke numbers match well (39 vs 37; P = NS) with only two ticagrelor cases removed. Cancer matched well (32 vs 31; P = NS), and sepsis cases were identical (30 vs 30; P = NS). However, two extra clopidogrel suicides in the shorter list are impossible to comprehend., Conclusions: The PLATO trial PDCs were mismatched between FDA and investigators sets. We are kindly asking the ticagrelor sponsor or/and concerned PLATO Investigators to clarify the PDC dataset match., (© 2021 John Wiley & Sons Ltd.)

Background: Many patients with heart failure (HF) are treated with warfarin or non-vitamin K oral anticoagulants (NOACs). Randomized outcome-driven comparisons of different anticoagulant strategies in HF are lacking. Data from international, government-mandated registries may be useful in understanding the real-life use of various anticoagulants and how they are linked to outcomes., Study Question: To assess 2015 annual all-cause mortality, myocardial infarction, and stroke rates co-reported for warfarin and NOACs in subjects with and without HF in the US Food and Drug Administration Adverse Event Reporting System (FAERS) database., Study Design: We extracted and examined outcome cases in subjects with HF and on warfarin, dabigatran, rivaroxaban, apixaban, or edoxaban and stratified these according to anticoagulants., Measures and Outcomes: Annual all-cause mortality, myocardial infarction, and stroke in FAERS., Analysis Method: Odds ratio (OR) and χ(Equation is included in full-text article.)for oral anticoagulants from FAERS with and without HF among complete primary reports issued in 2015., Results: FAERS reported 137,026 HF cases, with death co-reported in 42,942 (31.3%). In total, 11,278 (8.2%) HF patients were treated with anticoagulants, with more prescribed warfarin (n = 8260) than all NOACs combined (n = 3018). Very few reports for edoxaban were available. Warfarin consistently displayed a signal for excess adverse events compared to NOACs: OR (95% confidence interval) for the composite of mortality, myocardial infarction, and stroke were 1.91 (1.76-2.07) versus apixaban, 1.92 (1.81-2.03) versus dabigatran, 4.09 (3.38-4.37) versus rivaroxaban, and 2.64 (2.53-2.76) versus all NOACs combined (all P < 0.001). Warfarin, compared to all NOACs combined, demonstrated higher rates of all-cause mortality [OR = 2.69 (95% confidence interval, 2.49-2.90)], myocardial infarction [5.30 (4.17-6.74)], stroke [OR = 8.85 (6.61-11.84)], and ischemic stroke [OR = 12.73 (8.87-18.27); all P < 0.001]., Conclusions: Annual 2015 FAERS profiles in HF patients reveal that warfarin was numerically dominant. Warfarin was associated with higher risk of death, myocardial infarction, and stroke compared to NOACs. These observational data provide real-world insight into a potential safety benefit of NOACs over warfarin in the setting of HF.

Aims: Clopidogrel is commonly used even after expiring patents. The brand clopidogrel (BC) was dealt by single company, while numerous manufacturers produce generic clopidogrel (GC). There are no convincing data to compare the safety of different formulations. Therefore, the data yielded from international, uniform, government-mandated registries may be useful., Methods and Results: We assessed primary causative adverse events (PCAE) after BC and GC in the US Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS). The outcomes were divided into death, cardiac, thrombotic/embolic, haemorrhagic, and rash/dermal complications. These primary endpoints were then examined by proportional reporting ratios (PRR) and chi-square (χ2). Among total FAERS (n = 9 466 679) reports, overall BC (n = 88 863) cases were more common than after GC (n = 36 559). When triaged by PCAE role, BC (n = 18 328) was also more abundant than GC (n = 3987). The reported death rates were more than doubled after BC [18.4% vs. 7.0%; PRR = 0.38; 95% confidence interval (95% CI) 0.32-0.43; χ2=369.7; P<0.0001] for total FAERS, and consistent for late 2010-2017 (17.6% vs. 7.0% PRR = 0.40; 95% CI 0.37-0.45; χ2=286.2; P<0.004) PCAE cases. In contrast, GC trended to co-report more cardiac (14.6% vs. 13.3%; PRR = 1.12; 95% CI 1.0-1.25; χ2=3.5; P<0.06). The haemorrhagic (40.9% vs. 32.3%; PRR = 1.45; 95% CI 1.33-1.57; χ2=75.8; P<0.0001), and rash/dermal (5.4% vs. 4.6%; PRR = 1.20; 95% CI 1.0-1.44; χ2=3.75; P<0.05) events were also more common for GC. Thrombotic/embolic events were reported equally (at 7.0%) after each formulation., Conclusion: The PCAE profiles differ with BC and GC in FAERS. While deaths reports were higher, the rates of cardiac, haemorrhagic, and skin complications were less common for BC. Despite expected reporting bias, this may indicate that the manufacturers of GC are reluctant to report deaths to the FDA. However, the overall adverse event profile suggests potentially better safety of BC over GC formulations., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2018. For permissions, please email: journals.permissions@oup.com.)

Background: High residual platelet reactivity (HRPR) during dual antiplatelet therapy (DAPT) may impact clinical outcomes following percutaneous coronary interventions (PCI). However, whether any biomarkers assessed before PCI at DAPT loading may predict delayed maintenance HRPR is not clear., Objective: The aim of this study was to determine whether conventional clinical or laboratory indices at loading before stenting may predict HRPR at 6 months of maintenance DAPT., Methods: The study was designed on a single-center prospective cohort, and included 94 pre-PCI patients. All patients underwent elective PCI with drug-eluting stent implantation, and received DAPT with aspirin and clopidogrel. Platelet reactivity was assessed with 5 μmol/L of adenosine diphosphate-induced light transmission aggregometry before PCI, but after 24 h of DAPT loading, and repeated at 6 months. Baseline clinical characteristics, CYP2C19 polymorphism, C-reactive protein, soluble P-selectin, CD40L, interleukin-6, PAI-1 levels, and von Willebrand factor activity were analyzed., Results: The incidence (light transmission aggregometry <50%) of prestent HRPR was 16%. By univariate regression, body mass index (BMI; p = 0.02), total cholesterol (p = 0.01), low-density lipoproteins (p = 0.004), CYP2C19*2 allele carriage (p = 0.006), soluble P-selectin (p = 0.009), and von Willebrand factor (p = 0.04) were linked to future HRPR. However, multivariate regression analysis suggested that only BMI and P-selectin were independent predictors of HRPR., Conclusions: Platelet reactivity before elective stenting is associated with numerous biomarkers; however, only BMI and soluble P-selectin were independent predictors of future HRPR during maintenance-phase DAPT. This may be important for future tailored antiplatelet strategies in patients with metabolic syndrome and diabetics., (© 2018 S. Karger AG, Basel.)

Background  The U.S. Food and Drug Administration (FDA) Adverse Event (AE) Reporting System (FAERS) is a global passive surveillance repository requiring mandatory updates by pharmaceutical manufacturers. Oral antiplatelet agents (OAAs) including aspirin (acetylsalicylic acid [ASA]) are broadly used to prevent thrombosis, at the expense of extra bleeding risks. However, the OAA filing quality and their comparative patterns in FAERS are unknown. We assessed completeness of original annual FAERS reports for OAA with special attention on ASA. Methods  We extracted AE cases co-reported with OAA including ASA, clopidogrel, prasugrel, ticagrelor, vorapaxar, or their combination. The 2015 FAERS cases were examined based on OAA distribution, suspected causative role, missing gender or age, and most common AEs after ASA. Results  A total of 1,187,729 reports qualified the inclusion criteria. The majority ( n  = 1,121,989) of the reports contain no reference of OAA, while 65,730 reports contain reference of at least one OAA, including 47,900 ASA cases. Therapy with ASA was heavily (>50%) underreported when used with prasugrel or ticagrelor, but still dominant (72.8%) among OAAs, followed by clopidogrel (18.7%), prasugrel (4.1%), ticagrelor (3.6%), and anecdotal vorapaxar (0.05%). Despite current recommendations, some (0.73%) reports contain multi-OAAs. The primary role of ASA in AE reporting was seldom (<1%), followed by clopidogrel (2.9%), prasugrel (3.7%), and highest for ticagrelor (9.3%). Missing gender after OAA was not common (<10%), but age was missing in approximately 25% of reports. Bleeding was the most frequent AE associated with ASA. Conclusion  The quality of reporting for OAA in general and ASA in particular can be improved by stricter FDA rules, better surveillance, and enforcements. Heavy ASA underreporting during dual antiplatelet therapy and missed demographic variables challenge outcome research capacities for establishing drug interactions in FAERS.

The optimal duration and cancer risks of antiplatelet therapy following percutaneous coronary intervention (PCI) are unclear. We compared cancer and all-cause mortality after dual antiplatelet therapy (DAPT) for the combination of clopidogrel and aspirin (ASA) versus ASA alone over 18 months follow-up in event-free patients at 12 months DAPT from the Health Insurance Review and Assessment (HIRA) dataset via the Korean Outcomes Registry Evaluating Antithrombotics (KOREA). We selected PCI patients who were event free for 12 months and maintained a consistent antiplatelet regimen for 18 more months. The primary endpoints were any cancer and all-cause mortality at 30 months follow-up after PCI. From 320,351 screened post-PCI patient HIRA records, we excluded 294,413 and qualified 25,938, constituting DAPT (n=10,992) and ASA (n=14,946) groups. The Propensity Score Matching (PSM), and Inverse Probability of Treatment Weighting (IPTW) revealed no significant differences in background demographics and clinical characteristics for DAPT versus ASA patients. At 30-months post-PCI, after massive (>91 %) exclusions, cancer risk was higher for continuous DAPT [455 (4.15 %) vs 606 (4.04 %); HR=1.221; 95 %CI: 1.061-1.405; p=0.005], which remained significant by PSM (p=0.006) or IPTW (p=0.007), while all-cause mortality was similar [136 (1.24 %) vs 192 (1.28 %) HR=0.999; 95 %CI: 0.736-1.135; p=0.993]. This analysis suggests a potential mild excess cancer risk, but no mortality benefit in Korean post-PCI patients treated with DAPT for an additional 18 months beyond conventional 12 months DAPT. These data are not supporting continuing DAPT for more than one year in East Asians. Analysing cancer types and assessing potential cancer association with bleeding are warranted.

Background: Vorapaxar, a novel antiplatelet thrombin PAR-1 inhibitor, is currently approved for post myocardial infarction and peripheral artery disease indications with concomitant use of clopidogrel and/or aspirin. The vorapaxar safety profile was acceptable. However, aside from heightened bleeding risks, excesses of solid cancers and diplopia, there were more amyotrophic lateral sclerosis (ALS) diagnoses after vorapaxar., Study Question: To assess the Food and Drug Administration (FDA) reviews on the potential association of vorapaxar with ALS., Study Design: The review the public FDA records on reported adverse events after vorapaxar., Measures and Outcomes: Incidence of ALS after vorapaxar and placebo., Results: The ALS risk appears very small, about 1 case per 10,000 treated subjects, but quite probable. Indeed, there were overall 2 placebo and 4 vorapaxar ALS incidences in the Phase III clinical trials., Conclusions: Potential adverse association of vorapaxar with ALS risks may be related to off-target neuronal PAR receptor(s) blockade beyond platelet inhibition.

Objectives: The PLATO trial revealed superiority of ticagrelor over clopidogrel for the prevention of atherothrombotic events in patients with acute coronary syndrome. However, adverse events such as bleeding, dyspnea, and bradycardia were frequently reported, potentially leading to excess early ticagrelor discontinuation (ETD), later confirmed in the PEGASUS trial. We here evaluated the incidence and causes for ETD in a real-world patient cohort in a high-volume nonacademic percutaneous coronary intervention center in the Netherlands., Methods: In a retrospective single-center registry, all patients discharged from the hospital with a new ticagrelor prescription were screened for ETD. Follow-up data were obtained using the hospital electronic patient file records and confirmed by telephone contact with the patient and/or general practitioner, if necessary, to complement the data., Results: Ticagrelor was prescribed in 354 patients between December 2011 and December 2012. The follow-up data were available in 301 patients with a mean follow-up duration of 330 days. ETD or switching to another antiplatelet agent occurred in 73 patients (24.3%), mostly due to dyspnea (11.6%), bleeding (3.7%), or planned major surgery (2.7%)., Conclusions: Almost one quarter of ticagrelor patients were discontinued prematurely or switched to another antiplatelet agent within 1 year, mostly due to dyspnea or bleeding., (© 2017 S. Karger AG, Basel.)

Background: The US Food and Drug Administration Adverse Event Reporting System (FAERS) is a global passive surveillance database that relies on voluntary reporting by health care professionals and consumers as well as required mandatory reporting by pharmaceutical manufacturers. However, the initial filers and comparative patterns for oral P2Y12 platelet inhibitor reporting are unknown. We assessed who generated original FAERS reports for clopidogrel, prasugrel, and ticagrelor in 2015., Methods: From the FAERS database we extracted and examined adverse event cases coreported with oral P2Y12 platelet inhibitors. All adverse event filing originating sources were dichotomized into consumers, lawyers, pharmacists, physicians, other health care professionals, and unknown., Results: Overall, 2015 annual adverse events were more commonly coreported with clopidogrel (n = 13,234) with known source filers (n = 12,818, or 96.9%) than with prasugrel (2,896; 98.9% out of 2,927 cases) or ticagrelor (2,163, or 82.3%, out of 2,627 cases, respectively). Overall, most adverse events were filed by consumers (8,336, or 44.4%), followed by physicians (5,290, or 28.2%), other health care professionals (2,997, or 16.0%), pharmacists (1,125, or 6.0%), and finally by lawyers (129, or 0.7%). The origin of 811 (4.7%) initial reports remains unknown. The adverse event filing sources differ among drugs. While adverse events coreported with clopidogrel and prasugrel were commonly originated by patients (40.4 and 84.3%, respectively), most frequently ticagrelor reports (42.5%) were filed by physicians., Conclusion: The reporting quality and initial sources differ among oral P2Y12 platelet inhibitors in FAERS. The ticagrelor surveillance in 2015 was inadequate when compared to clopidogrel and prasugrel. Patients filed most adverse events for clopidogrel and prasugrel, while physicians originated most ticagrelor complaints. These differences justify stricter compliance control for ticagrelor manufacturers and may be attributed to the confusion of treating physicians with unexpected fatal, cardiac, and thrombotic adverse events linked to ticagrelor., (© 2017 S. Karger AG, Basel.)

Background: Acute pulmonary thromboembolism (APTE) is a life-threatening condition, often manifesting with chest pain, dyspnea, and increased cardiac biomarkers including cardiac troponin I (CTI) and D-dimer. Therefore, APTE is often misdiagnosed with classical non-ST elevation myocardial infarction (NSTEMI), resulting in unnecessary coronary interventions and a delay of therapy., Objectives: Our aim was to distinguish APTE from NSTEMI based on CTI and D-dimer levels., Methods: Complete clinical and laboratory data sets from APTE patients (n = 123) were compared with matched NSTEMI patients (n = 123) who presented with chest pain. The APTE diagnosis was confirmed by chest tomography, angiography, or radionuclide ventilation-perfusion scan, while NSTEMI was established by clinical symptoms, cardiac biomarkers, and coronary angiography. Clinical characteristics, CTI (initial and peak), and D-dimer levels at presentation were retrospectively analyzed., Results: The clinical characteristics were not different between APTE and NSTEMI patients. However, significantly lower initial CTI (0.2 ± 0.5 vs. 4.4 ± 9.5 ng/ml) and peak CTI (0.7 ± 2.7 vs. 17.1 ± 20.4 ng/ml), but higher initial D-dimer (9.8 ± 9.4 vs. 1.6 ± 3.6 ng/ml), distinguished APTE from NSTEMI. By receiver operating characteristic curve analysis, the cutoff values for initial CTI, peak CTI, and D-dimer were 0.25, 0.98, and 3.18 ng/ml, respectively., Conclusion: Patients with APTE exhibited lower initial and peak CTI but higher D-dimer levels than NSTEMI patients. Assessing cardiac biomarkers is useful for differentiating APTE from NSTEMI. Further large randomized biomarker studies are urgently needed to facilitate a better APTE diagnosis since clinical characteristics are not particularly helpful., (© 2016 S. Karger AG, Basel.)

Background: The optimal strategy to manage chronic total occlusion (CTO) remains unclear. The Japanese CTO multicenter registry (J-CTO) score is an established tool for predicting successful recanalization. However, it does not take into account nonangiographic predictors for final technique success. In the present study, we designed and tested a scoring model called the Busan single-center CTO registry (B-CTO) score combining clinical and angiographic characteristics to predict successful CTO recanalization in Korean patients., Methods: Prospectively enrolled CTO patients (n = 438) undergoing coronary intervention (1999-2015) were assessed. The B-CTO score comprises 6 independent predictors: age 60-74 years and lesion length ≥20 mm were assigned 1 point each, while age ≥75 years, female gender, lesion location in the right coronary artery, blunt stump, and bending >45° were assigned 2 points each. For each predictor, the points assigned were based on the associated odds ratio by multivariate analysis. The lesions were classified into 4 groups according to the summation of points scored to assess the probability of successful CTO recanalization: easy (score 0-1), intermediate (score 2-3), difficult (score 4-5), and very difficult (score ≥6). CTO opening was designated as the primary endpoint regardless of the interventional era or the skill of the operator., Results: The final success rate for B-CTO was 81.1%. The probability of successful recanalization for patient groups classified as easy (n = 64), intermediate (n = 148), difficult (n = 134), and very difficult (n = 92) was 95.3, 86.5, 79.1 and 65.2%, respectively (p for trend <0.001). When compared to the J-CTO, the B-CTO score demonstrated a significant improvement in discrimination as indicated by the area under the receiver-operator characteristic curve (AUC 0.083; 95% CI 0.025-0.141), with a positive integrated discrimination improvement of 0.042 and a net reclassification improvement of 56.0%., Conclusions: The B-CTO score has been designed and validated in Korean patients with native coronary CTO and is an improved tool for predicting successful recanalization. Wider application of the B-CTO score remains to be explored., (© 2017 S. Karger AG, Basel.)

Objective: The impact of thienopyridine reloading on clinical outcomes, and residual high platelet reactivity (HPR) is unclear. We sought to compare the HRP-related effect of prasugrel and clopidogrel reloading in the already clopidogrel-loaded patients undergoing percutaneous coronary intervention (PCI)., Materials and Methods: In this prospective, two-center, randomized, open-label study, patients with HPR who had undergone PCI after a clopidogrel (300-600mg) loading dose (LD) were enrolled. Among screened (n=153), HPR was determined in seventy-six patients, who were randomized to either repeated clopidogrel (300mg LD, followed by 75mg MD daily) or prasugrel (20mg LD, followed by 5mg MD daily). The primary endpoint was HPR at 24h after PCI, as determined by the VerifyNow assay. The rates of sustained high and low platelet reactivity, periprocedural myocardial injury (PMI) and 30-day clinical outcomes were also assessed., Results: Higher inhibition of platelet reactive units (PRU) was observed in the prasugrel group than after clopidogrel reloading (Pre-PCI: 284.4±32.0 vs 279.5±32.5, p=0.504; Post-PCI: 100.0±67.0 vs 202.9±65.8, p<0.001; 30days: 170.8±69.8 vs 215.1±62.4, p=0.007). There were less HRP post-PCI after prasugrel compared with the clopidogrel group (2.7 vs 36.1%, p<0.001). However, reloading with prasugrel did not reduce PMI compared to clopidogrel (36.8% vs 39.5%, p=0.813)., Conclusion: Prasugrel reloading led to a greater reduction in HPR, but similar with clopidogrel PMI in post-PCI patients. Larger randomized evidence is needed for optimization of loading strategies with thienopyridines., Clinical Trial Registration Information: NCT01609647., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Background and Purpose: Vorapaxar, a novel platelet thrombin protease-activated receptor 1 blocker, is currently approved for post-myocardial infarction and peripheral artery disease indications on top of clopidogrel or/and aspirin. We sought to summarize the conflicting stroke data after vorapaxar for justifying a secondary stroke prevention trial., Methods: Analyses of the stroke data after vorapaxar yielded from thrombin-receptor antagonist vorapaxar in acute coronary syndromes (TRACER) and TRA2P clinical trials, and affiliated Food and Drug Administration (FDA) reviews., Results: The stroke data are mixed, with catastrophic 2.5 excess of intracranial bleeding risks (HR = 2.52; 95% CI = 1.46-4.36, p < 0.0001); trend to worsened second stroke rates (13.0% vs. 11.7%; HR = 1.03; 95% CI = 0.85-1.25, p = NS), but a hint towards less primary ischemic strokes in vorapaxar indicated population (HR = 0.57; 95% CI = 0.43 to 0.75; p < 0.001). These conflicting data are not solely attributed to vorapaxar, but rather reflect unreasonably aggressive triple antiplatelet strategies utilized frequently in TRA2P and dominant in TRACER. Overall, the FDA-confirmed evidence advocates future vorapaxar secondary stroke prevention trial due to being first-in-class agent, unique pharmakynetics, and exhibiting very mild "comfort zone" antiplatelet profile. The three arm trial testing head-to-head monotherapy with vorapaxar (Zontivity®), versus clopidogrel (Plavix®), and versus extended-released dipyridamole with very low dose aspirin (Aggrenox®) is warranted., Conclusions: Vorapaxar may be superior to currently recommended antiplatelet strategies and should be tested as a monotherapy in a randomized outcome-driven secondary stroke prevention trial., (© 2016 World Stroke Organization.)

Aims: Clinical utilization of dual antiplatelet therapy (DAPT) in patients with renal impairment (RI) following percutaneous coronary interventions (PCI) represents an urgent, unmet need choosing optimal agents, duration of treatment, and potential dose/regimen adjustment. The lack of any large randomized trials specifically in RI patients, and the absence of the uniformed clinical data reporting policy, clouds the reality. Moreover, triaging RI patients is problematic due to ongoing kidney deterioration, and the fact that RI patients are prone to both vascular occlusions and bleeding., Methods and Results: Seven hundred and one Korean patients receiving DAPT with aspirin 100 mg/daily and clopidogrel 75 mg/daily after PCI were prospectively enrolled in the study. Patients were dichotomized into five groups according to RI: estimated glomerular filtration rate (eGFR) >90 mL/min/1.73 m(2) (RI1), 60-89 mL/min/1.73 m(2) (RI2), 30-59 mL/min/1.73 m(2) (RI3), <30 mL/min/1.73 m(2) (RI4), and undergoing dialysis (RI5). Major adverse clinical events (MACEs; cardiovascular death, myocardial infarction, stent thrombosis, and stroke) were collected for 1 year. Platelet reactivity by VerifyNow™ assay and eGFR were simultaneously assessed at 1 month after maintenance DAPT. Patients with RI exhibited a gradual significant increase of residual platelet reactivity during DAPT, dependent on eGFR deterioration [191 ± 72 PRU (RI1) vs. 216 ± 78 PRU (RI2) vs. 248 ± 80 PRU (RI3) vs. 264 ± 70 PRU (RI4) vs. 317 ± 96 PRU (RI5), P < 0.001] being the highest in the dialyses group. Declined eGFR has been gradually associated with advancing age (OR = 1.03, 95% CI = 1.00-1.05; P = 0.032), female gender (OR = 1.7, 95% CI = 1.1-2.5; P = 0.01), diminished smoking rates (OR = 0.6, 95% CI = 0.37-1.00; P = 0.05), hypertension (OR = 1.8, 95% CI = 1.3-2.5; P < 0.001); diabetes (OR = 1.5, 95% CI = 1.1-2.1; P = 0.007), and MACE (HR = 13.9; 95% CI = 1.6-124.3; P = 0.02 for RI4; and HR = 31.9; 95% CI = 2.9-351.9; P = 0.005 for dialysis), but not for bleeding (P = 0.143). Major adverse clinical event risks still remained significant for RI4 (P = 0.027) and RI5 (P = 0.002) by multivariate Cox hazard regression estimates., Conclusion: Renal impairment is associated with gradual elevation of residual platelet reactivity while on DAPT, enhancing MACE risks, but not bleeding events. These data should be confirmed in a large randomized outcome-driven trial, and may justify future maintenance-phase DAPT regimen/dose adjustment in RI patients., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2015. For permissions please email: journals.permissions@oup.com.)

Vorapaxar, a novel antiplatelet thrombin PAR-1 inhibitor, has been evaluated in the successful TRA2P trial and the failed TRACER trial. The drug is currently approved for post myocardial infarction and peripheral artery disease indications with concomitant use of clopidogrel and/or aspirin. The FDA ruled that the vorapaxar safety profile is acceptable. However, both trials revealed excess diplopia (double vision) usually reversible after vorapaxar. The diplopia risk appears to be small (about 1 extra case per 1,000 treated subjects), but real. Overall, there were 10 placebo and 34 vorapaxar diplopia cases (p=0.018) consistent for TRACER (2 vs 13 cases; p=0.010) and for TRA2P (8 vs 21 cases; p=0.018). Hence, we review the FDA-confirmed evidence and discuss potential causes and implications of such a surprising adverse association, which may be related to off-target PAR receptor mismodulation in the eye.