Adjunctive Cilostazol in Patients With High Residual Platelet Reactivity After Drug-Eluting Stent Implantation: A Randomized, Open-Label, Single-Center, Prospective (ADJUST-HPR) Study.

BACKGROUND: Cilostazol as an adjunct to dual antiplatelet therapy (DAPT) postcoronary stenting may further reduce vascular occlusion risks. The aim of this study was to assess the impact of cilostazol on high residual platelet reactivity (HRPR) in patients undergoing drug-eluting coronary stent implantation. METHODS: In a randomized, open-label, single-center, prospective study, the degree of platelet inhibition by cilostazol 100 mg twice daily was assessed on top of conventional DAPT compared with standard clopidogrel and low-dose aspirin combination in poststent patients with HRPR. HRPR was defined as P2Y12 units (PRU) > 240 as measured by the VerifyNow P2Y12 assay. In addition, the platelet activity was assessed by light transmittance aggregometry (LTA) and Multiplate electrode analyzer (MEA). RESULTS: The total of 148 patients were screened, and HRPR was observed in 64 (43.2%). Those were randomized for DAPT versus triple therapy (TAPT). After 30 days, TAPT group exhibited significantly lower rate of HRPR when assessed by all 3 devices (VerifyNow: 40.0 vs. 66.7% P = 0.04, LTA: 6.7 vs. 30.0% P = 0.02, MEA: 10.0 vs. 30.0% P = 0.05 L all vs. DAPT). Also, higher absolute mean difference in TAPT versus DAPT group after 30 days (VerifyNow: 71.3 ± 38.2 vs. 24.6 ± 40.2 P < 0.001, LTA: 23.9 ± 15.1 vs. 9.4 ± 11.8 P < 0.001, MEA: 9.3 ± 12.9 vs. 2.4 ± 17.3 P = 0.08) was observed. CONCLUSIONS: Cilostazol in addition to standard DAPT reduces the incidence of HRPR and diminishes further platelet activity in poststent patients. Whether this favorable laboratory finding will affect clinical outcomes requires an adequately powered randomized trial.

Strokes and Transient Ischemic Attacks Occurrence During Annual Dual Antiplatelet Therapy.

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.

Primary Causes of Death Reported to the FDA Suggest Less Ticagrelor Mortality Benefit than the List Issued to the PLATO Trial Investigators.

Background: The PLATO trial data set reported to the FDA (DRFDA) revealed that some primary deaths causes (PDC) were inaccurately reported favoring ticagrelor. Trial Investigators (DRTI) received different data set with more ticagrelor mortality advantage. We compared these two death lists for the match in PDC. Methods and Results: The DRFDA contains 938 deaths, while the DRTI contains 905. We matched "vascular", "non-vascular", "unknown", "missed", and "other" causes of death between DRFDA and DRTI. The DRFDA used 14 vascular, 9 non-vascular, 1 unknown and 1 other PDC codes, while the DRTI used 14 but different vascular, 14 non-vascular but no unknown or other PDC codes. We observed a significant mismatch for the PDC codes between the DRFDA and DRTI data sets. Most DRFDA deaths were vascular (n = 677), fewer non-vascular (n = 159) and unexpectedly many unknown (n = 95) or other (n = 7) PDC. Surprisingly, the shorter DRTI contains more vascular (n = 795), fewer non-vascular (n = 110), but no unknown, other, or missed causes. There were more sudden deaths in DRTI than in DRFDA (161 vs. 138; p < 0.03), twice as many post-myocardial infarction deaths (373 vs. 178; p < 0.001) but fewer heart failure deaths (73 vs. 109; p = 0.02). The reported non-vascular PDC match better except for 2 extra suicides in the clopidogrel arm of the DRTI. Conclusions: Over 100 "unknown", "missed", or "other" PDC events reported by the trial sponsor to the FDA were omitted from the investigator data set contributing to the inflated differences in vascular mortality benefit of ticagrelor reported in numerous PLATO publications. Synchronization of PDC reporting between regulatory agencies and investigators was lacking in PLATO but remains mandatory to ensure quality for future indication-seeking trials.

FDA PLATO deaths list challenges aspirin dose-ticagrelor interaction.

No abstract present.

Impact of olokizumab on platelets, leukocytes and erythrocytes during mild COVID-19.

No abstract present.

Enoxaparin dose impacts blood cell phenotypes during mild SARS-CoV-2 infection: the observational single-center study.

Coronavirus disease 2019 (COVID-19) is associated with various hemostatic abnormalities requiring constant search for better delicate antithrombotic management in these high-risk patients. The choice and the optimal dose of anticoagulant is important, but unclear, especially for mild COVID-19. Enoxaparin has been tested in several COVID trials with mixed results regarding hard clinical outcomes including mortality. We analyzed clinical, laboratory data and changes in platelets, erythrocytes and leukocytes by scanning electron microscopy on admission and at hospital discharge in patients with confirmed COVID-19 treated with enoxaparin (n = 31) and matched healthy controls (n = 32) in a retrospective observational study. The data were triaged by enoxaparin dose comparing 40 mg/daily prophylactic enoxaparin dose (PED) with 80 mg/daily therapeutic (TED) regimens. All patients experienced mild disease, none required pulmonary support, and all survived. The impact of enoxaparin dose was prominent for platelets and erythrocytes, but less evident for leukocytes. PED was associated with significant platelet activation, diminished numbers of silent nonactive discoid cells, and increased number and size of platelet microaggregates with leukocyte involvement. In contrast, TED did not cause extra platelet activation, while circulating platelet microaggregates were smaller and lacking leukocytes in their construction. PED caused significant increase of erythrocyte-platelet aggregates formation, and numerically higher proportion of circulating echinocytes. TED was associated with significant decrease of rouleaux sludge formation compared to only some trend after PED. Changes in leukocytes were less dependent on enoxaparin dose. However, PED has been associated with enhanced aggregate formation in 7 out of 10 patients, while trap net formation has been decreased in 17 out of 21 TED patients. We conclude that over hospital stay TED was superior to PED in patients with mild COVID-19. The inability of PED to adequately protect major circulating blood cells is probably due to enhanced clearance or/and diminished bioavailability of enoxaparin during COVID. These retrospective observational small sample size data may be relevant to better understanding of the mixed results in controlled outcome-driven trials exploring optimal COVID-19 anticoagulant strategies.

Impact of VKORC1, CYP2C9, and CYP4F2 Polymorphisms on Optimal Warfarin Dose: Does Ethnicity Matters?

BACKGROUND: Conventional anticoagulation with warfarin remains the cornerstone strategy for numerous preventive strategies. It is established that Asian patients require lower warfarin doses than Caucasians potentially attributing to the genetic polymorphism (GP) differences. AREAS OF UNCERTAINTY: The impact of GP on optimal warfarin dose (OWD) in Koreans is unclear when compared with other ethnicities. It is also not well established whether GP linked to OWD in Korean patients to the similar extend as in Chinese, Japanese, and Caucasians. DATA SOURCES: Single-center prospective observational study in Koreans, matched with historic cohorts of other ethnicities. THERAPEUTIC ADVANCES: Clinical characteristics, concomitant medications, OWD, international normalized ratio, and VKORC1, CYP2C9, and CYP4F2 GPs were assessed in consecutive Korean patients. The OWD was defined when patient's international normalized ratio was within target range for at least 3 consecutive times separated by 1 week. We included 133 (mean age 62.6 ± 12.1 years, 49% males) warfarin-treated patients of Korean descend. The mean OWD was 3.30 ± 1.34 (range: 1-9) mg/d. Homozygous wild-type patients required lower OWD (3.1 ± 1.1 mg/d vs. 4.7 ± 1.8 mg/d, P < 0.001) for VKORC1 and higher OWD for both CYP2C9 (3.4 ± 1.3 mg/d vs. 2.3 ± 1.1 mg/d, P = 0.002) and CYP4F2 (3.0 ± 1.2 mg/d vs. 3.4 ± 1.3 mg/d vs. 4.0 ± 1.7 mg/d, P = 0.033) than those carrying heterozygote genes. CONCLUSIONS: Korean patients exhibit different VKORC1, CYP2C9, and CYP4F2 profiles impacting lower OWD in Eastern Asians than required in Caucasians. Universal international OWD guidelines may consider patient ethnicity as a confounder; however, this hypothesis needs further clarification.

The FDA and PLATO Investigators death lists: Call for a match.

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.

Verifying Death Reports in the Platelet Inhibition and Patient Outcomes (PLATO) Trial.

BACKGROUND: Excess vascular deaths in the PLATO trial comparing ticagrelor to clopidogrel have been repeatedly challenged by the Food and Drug Administration (FDA) reviewers and academia. Based on the Freedom of Information Act, BuzzFeed won a court order and shared with us the complete list of reported deaths for the ticagrelor FDA New Drug Application (NDA) 22-433. This dataset was matched against local patient-level records from PLATO sites monitored by the sponsor. STUDY QUESTION: Whether FDA death data in the PLATO trial matched the local site records. STUDY DESIGN: The NDA spreadsheet contains 938 precisely detailed PLATO deaths. We obtained and validated local evidence for 52 deaths among 861 PLATO patients from 14 enrolling sites in 8 countries and matched those with the official NDA dataset submitted to the FDA. MEASURES AND OUTCOMES: Existence, precise time, and primary cause of deaths in PLATO. RESULTS: Discrepant to the NDA document, sites confirmed 2 extra unreported deaths (Poland and Korea) and failed to confirm 4 deaths (Malaysia). Of the remaining 46 deaths, dates were reported correctly for 42 patients, earlier (2 clopidogrel), or later (2 ticagrelor) than the actual occurrence of death. In 12 clopidogrel patients, cause of death was changed to "vascular," whereas 6 NDA ticagrelor "nonvascular" or "unknown" deaths were site-reported as of "vascular" origin. Sudden death was incorrectly reported in 4 clopidogrel patients, but omitted in 4 ticagrelor patients directly affecting the primary efficacy PLATO endpoint. CONCLUSIONS: Many deaths were inaccurately reported in PLATO favoring ticagrelor. The full extent of mortality misreporting is currently unclear, while especially worrisome is a mismatch in identifying primary death cause. Because all PLATO events are kept in the cloud electronic Medidata Rave capture system, securing the database content, examining the dataset changes or/and repeated entries, identifying potential interference origin, and assessing full magnitude of the problem are warranted.

Should We Use Tegaserod for Irritable Bowel Syndrome?

BACKGROUND: Tegaserod, a serotonin (5-HT4) agonist initially approved for constipation but withdrawn from use in 2007 because of concerns about cardiovascular adverse effects, was resubmitted to the Food and Drug Administration (FDA) in 2018 for use in a restricted population. AREAS OF UNCERTAINTY: Despite an 18-year regulatory history, there remain pharmacology and clinical trial concerns that have not been addressed but are critical for proper assessment of the drug safety and efficacy profile. SOURCES: Original FDA reviews, FDA and developer advisory committee briefing documents, and published literature. RESULTS: The major pharmacology concern is that the fate and effects of half of the molecule, the pentylaminoguanidine moiety, are unknown. There is evidence that pentylaminoguanidine may contribute to both efficacy and safety. There are other metabolites that are poorly characterized, and potential receptor interactions that suggest cardiovascular effects are possible. The major clinical trial concern is that, while the trial data support a low but definite cardiovascular risk, both subject follow-up and cardiovascular event descriptions were incomplete such that an accurate estimate of cardiovascular risk is not possible. CONCLUSIONS: The uncertainties and lack of reliable evidence regarding tegaserod metabolism and cardiovascular risk estimates may discourage clinical use. Signals for cardiovascular toxicity in typical drug development programs are subtle and must be pursued aggressively, with complete case follow-up and cardiovascular event capture in the clinical trials.

All-Cause Mortality and Cardiovascular Outcomes With Non-Vitamin K Oral Anticoagulants Versus Warfarin in Patients With Heart Failure in the Food and Drug Administration Adverse Event Reporting System.

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.

Impact of CYP2C19 Polymorphisms on Clinical Outcomes and Antiplatelet Potency of Clopidogrel in Caucasian Poststroke Survivors.

BACKGROUND: Variable response after clopidogrel is well documented and may affect major adverse clinical events after stroke. Impact of CYP2C19 genetic polymorphisms is an established marker linked to variable response after clopidogrel. However, the association of certain genetic polymorphisms with prediction of major adverse clinical events following stroke still remains controversial, especially in Caucasians. STUDY QUESTION: The primary aim was to evaluate the impact of CYP2C19 allele *2 in heterozygote form on major adverse clinical events in Caucasian poststroke survivors treated with clopidogrel. The secondary aim was to analyze the potential link between CYP2C19 genetic polymorphism and variable response after clopidogrel. STUDY DESIGN: One hundred thirty patients of Caucasian origin following documented ischemic stroke were included. Platelet reactivity was assessed by light transmittance aggregometry (LTA) and matched with various CYP2C19 loss-of-function genetic polymorphisms and major adverse clinical events (composite of vascular deaths, stroke/transient ischemic attack, and myocardial infarction). RESULTS: Over the mean follow-up of 14.9 months, 19 patients experienced major adverse clinical events. The risk of major adverse clinical events was nearly 3-fold in loss-of-function allele carriers (hazard ratio = 2.904; 95% confidence interval, 1.083-7.786; P = 0.013), whereas the risk of ischemic stroke or transient ischemic attack alone was also higher (hazard ratio = 3.170; 95% confidence interval, 1.281-7.849; P = 0.034). Platelet activity was strongly associated with allele *2 status (rs = 0.21, P = 0.016) but not with other genetic polymorphisms. Carriers of allele*2 exhibited lower platelet response to adenosine diphosphate-mean LTA (30.1% vs. 42.0%; P = 0.017). There were no significant differences in LTA results with other agonists. Strong association of increase in adenosine diphosphate-induced aggregation with diabetes mellitus (rs = 0.20, P = 0.023), increasing age (rs = 0.23, P = 0.008), and conversely diminishing over increased weight (rs = 0.23, P = 0.009) was also detected. The carriers of other gene allele variants lack uniformed impact on variable response after clopidogrel. CONCLUSIONS: Even heterozygous CYP2C19*2 allele carriers among Caucasian patients after ischemic stroke had a higher risk of major adverse clinical events. The LTA, however, did not predict major adverse clinical events. The exact clinical utility of these findings is still uncertain and requires large outcome-driven randomized trial in Caucasians for proof of concept.

Body Mass Index and Plasma P-Selectin before Coronary Stenting Predict High Residual Platelet Reactivity at 6 Months on Dual Antiplatelet Therapy.

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.

Assessing Vessel Tone during Coronary Artery Spasm by Dual-Acquisition Multidetector Computed Tomography Angiography.

BACKGROUND: Diminished vascular tone is an established biomarker of heart damage. Little is known about the extent of coronary vessel tone (CVT) with spasm as assessed by dual-acquisition multidetector computed tomography angiography (MCTA) in patients with vasospastic angina (VSA). OBJECTIVE: We evaluated the CVT modulated by intravenous nitrate injection (INI) using MCTA imaging in VSA patients. METHODS: Twenty-one VSA patients (60 ± 9 years; 76% males) who underwent initial MCTA (without morning vasodilation), followed by an intracoronary ergonovine provocation test were included. Within 3 days after the initial MCTA patients received INI followed by 28-vessel segment spasm analyzed by MCTA 3D software, applying the following formula as the definition of CVT index (CVTI): (CSAIV nitrate - CSAinitial/CSAIV nitrate) ×100 %, where CSA is the cross-sectional area. RESULTS: Compared to the initial MCTA measures, the INI provocation resulted in the significant increase of average diameter and CSA at the spasm site (2.60 mm [2.11-3.16] vs. 1.42 mm [1.13-2.13]; 5.37 mm2 [3.67-7.54] vs. 1.62 mm2 [1.02-3.02]; p < 0.001). The CVTI at the spastic segments was higher than at the proximal reference segments (41.0% [21.8-52.3] vs. 18.8% [5.9-26.6] for CVTI diameter; 65.1% [38.6-77.0] vs. 33.9% [5.2-48.1] for CVTI CSA, respectively). To predict VSA, the cut-off value for CVTI diameter was 38.6% (AUC 0.777; 95% CI 0.653-0.901) and 62.5% (AUC 0.779; 95% CI 0.657-0.902) for CVTI CSA in a receiver-operating characteristic curve analysis, with 57.1% sensitivity and 92.9% specificity. CONCLUSIONS: This novel imaging technique for assessing CVT by dual-acquisition MCTA after applying INI provocation is suitable for the detection of coronary artery spasm in patients with VSA.

Impact of CYP2C19 Polymorphism on Antiplatelet Potency of Prasugrel 5 and 10 mg Daily Maintenance.

BACKGROUND: Whether genetic polymorphisms (GP) impact residual platelet aggregation (RPA) following prasugrel is unclear, especially during maintenance phase. We assessed the influence of CYP2C19 GP carriers on RPA in the prospective observational cohort study. METHODS AND RESULTS: All post-stent patients (n = 206) received prasugrel 60 mg loading and either 5 or 10 mg daily maintenance with aspirin100 mg. RPA levels by light transmission aggregometry (LTA), multiplate electrode aggregometry (MEA), and VerifyNow (P2Y12 reaction units, PRU) with CYP2C19 GP were measured simultaneously. Demographics and clinical characteristics were not useful for predicting response after prasugrel. GP carriers exhibited higher RPA (PRU: p = 0.001, LTA: p = 0.001, MEA: p = 0.023) than noncarriers. CYP2C19 carriers had higher RPA for 5 mg (n = 35; LTA: p = 0.043, MEA: p = 0.023) and reached significance for 10 mg (n = 27; LTA: p = 0.001, PRU: p = 0.001) prasugrel. When divided into extensive, intermediate, and poor metabolizers, all exhibited statistical differences among the 3 groups (LTA: 14.9 ± 12.3%, 22.6 ± 14.9%, 22.9 ± 15.6%, p = 0.002; PRU: 104.1 ± 70.8%, 141.8 ± 78.0%, 151.0 ± 84.8%, p = 0.003; MEA: 19.7 ± 8.9%, 24.4 ± 12.2%, 28.1 ± 14.7%, p = 0.002). CONCLUSION: CYP2C19 GP impacts RPA during maintenance phase prasugrel in Korean outpatients. This effect is consistent for both of the approved prasugrel doses potentially affecting long-term outcomes including bleeding risks. However, the clinical utility of these findings is still uncertain, and requires more evidence from larger randomized trials beyond East Asians.

Vorapaxar and Amyotrophic Lateral Sclerosis: Coincidence or Adverse Association?

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.

A Prospective, Randomized, Open-Label, Blinded, Endpoint Study Exploring Platelet Response to Half-Dose Prasugrel and Ticagrelor in Patients with the Acute Coronary Syndrome: HOPE-TAILOR Study.

BACKGROUND: The optimal dosing of novel oral P2Y12 receptor platelet inhibitors such as prasugrel or ticagrelor is unclear and especially challenging in East Asians. We hypothesize that half-dose prasugrel and ticagrelor may be sufficient for long-term maintenance management in Korean patients with the acute coronary syndrome (ACS) compared with conventional dosages. DESIGN: HOPE-TAILOR (Half Dose of Prasugrel and Ticagrelor in Platelet Response after Acute Coronary Syndromes) is a prospective, randomized, open-label, blinded, endpoint (PROBE) single-center, clinical trial. A total of 100 patients with ACS undergoing drug-eluting stent implantation will be randomly assigned to prasugrel, ticagrelor, or clopidogrel, and the patients in each treatment group will receive 1-month therapy with 100 mg q.d. aspirin plus prasugrel 10 mg q.d., ticagrelor 90 mg b.i.d., or clopidogrel 75 mg q.d., followed by half-dose prasugrel 5 mg q.d. or ticagrelor 45 mg b.i.d. for maintenance treatment but without clopidogrel dose reduction. The primary endpoint will be optimal platelet reactivity 3 months after coronary intervention, defined by VerifyNow Analyzer (PRU: 85-208) and vasodilator-stimulated phosphoprotein P2Y12 flow cytometry assay (platelet reactivity indices: 16-50%). Clinical outcomes will also be assessed, including major efficacy (composite of cardiac death, nonfatal myocardial infarction, repeat revascularization, or stroke) and safety (bleeding ≥2 according to the Bleeding Academic Research Consortium). CONCLUSION: HOPE-TAILOR is a prospective, randomized, open-label, blinded, endpoint study to explore the efficacy and safety of novel P2Y12 receptor inhibitors administered orally at half the dose in Korean patients with ACS. The results will be available late in 2017.

Filing Sources after Oral P2Y12 Platelet Inhibitors to the Food and Drug Administration Adverse Event Reporting System (FAERS).

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.

Troponin I and D-Dimer for Discriminating Acute Pulmonary Thromboembolism from Myocardial Infarction.

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.

Predicting Successful Recanalization in Patients with Native Coronary Chronic Total Occlusion: The Busan CTO Score.

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.