Platelet Inhibition And Patient Outcomes Research Articles

Frailty and Clinical Outcomes of Ticagrelor Versus Clopidogrel in Older Adults With Acute Myocardial Infarction.

Ticagrelor is recommended over clopidogrel in acute coronary syndrome based on the results of the PLATO (Study of Platelet Inhibition and Patient Outcomes) trial. We aimed to emulate PLATO in older adults with and without frailty and with acute coronary syndrome treated with percutaneous coronary intervention. We created a new-user cohort of Medicare fee-for-service beneficiaries aged ≥65 years hospitalized for acute coronary syndrome from 2014 to 2018 and initiated ticagrelor or clopidogrel following percutaneous coronary intervention. Frailty was defined using a validated claims-based frailty index ≥0.25. Coprimary outcomes were major adverse cardiovascular events and major bleeding. Follow-up began on the date of first outpatient prescription for ticagrelor or clopidogrel and ended on the earliest date for an outcome event, death, discontinuation of the index drug, or disenrollment from Medicare. The study included 42 843 older adults; 23% were frail. After propensity score matching, the rates of major adverse cardiovascular events per 100 person-years comparing ticagrelor versus clopidogrel groups were 7.8 and 7.3 in the frail cohort (hazard ratio [HR], 1.07 [95% CI, 0.84-1.36]) and 3.7 and 4.2 in the nonfrail cohort (HR, 0.87 [95% CI, 0.75-1.02]). The corresponding rates of major bleeding were 4.3 and 3.8 in the frail cohort (HR, 1.12 95% CI, [0.80-1.56]) and 2.2 and 1.8 in the nonfrail cohort (HR, 1.22 [95% CI, 0.98-1.51]). There was a trend toward a modest reduction in risk of major adverse cardiovascular events and a trend toward a modest increase in risk of major bleeding with ticagrelor compared with clopidogrel in the nonfrail cohort. There was insufficient evidence for the benefit of ticagrelor in frail older adults.

Temporal biomarker concentration patterns during the early course of acute coronary syndrome.

Biomarker concentrations and their changes during acute coronary syndrome (ACS) provide clinically useful information on pathophysiological processes, e.g. myocardial necrosis, hemodynamic stress and inflammation. However, current evidence on temporal biomarker patterns early during ACS is limited, and studies investigating multiple biomarkers are lacking. We measured concentrations of high-sensitivity cardiac troponin T (hs-cTnT) and I (hs-cTnI), NT-terminal pro-B-type natriuretic peptide, C-reactive protein, and growth-differentiation factor-15 (GDF-15) in plasma samples obtained at randomization in ACS patients from the PLATelet inhibition and patient Outcomes (PLATO) trial. Linear regressions with interaction analyses were used to investigate the associations of biomarker concentrations with the time from symptom onset and to model temporal biomarker concentration patterns. The study population consisted of 16,944 patients (median age 62 years; 71.3 % males) with 6,853 (40.3 %) having ST-elevation myocardial infarction (STEMI) and 10,141 (59.7 %) having non-ST-elevation ACS (NSTE-ACS). Concentrations of all biomarkers were associated with time from symptom onset (pinteraction<0.001), apart for GDF-15 (pinteraction=0.092). Concentration increases were more pronounced in STEMI compared to NSTE-ACS. Temporal biomarker patterns for hs-cTnT and hs-cTnI were different depending on sex whereas biomarker patterns for the other biomarkers were similar in cohorts defined by age and sex. Temporal concentration patterns differ for various biomarkers early during ACS, reflecting the variability in the activation and duration of different pathophysiological processes, and the amount of injured myocardium. Our data emphasize that the time elapsed from symptom onset should be considered for the interpretation of biomarker results in ACS.

Clopidogrel Loading Dose 300 vs. 600 mg in Patients Undergoing One-Stop Hybrid Coronary Revascularization: A Prospective Single-Center Randomized Pilot Study.

Background: The optimal loading dose of clopidogrel in one-stop hybrid coronary revascularization (HCR) remains an “evidence-free” zone. This study aimed to compare the major bleeding and ischemic thrombotic events between different clopidogrel loading doses (300 vs. 600 mg) in one-stop HCR.Methods: In this prospective, single-center, randomized, and parallel pilot study, 100 patients receiving one-stop HCR were randomly assigned to the clopidogrel loading dose 300-mg group or 600-mg group in a 1:1 ratio. Major bleeding events and composite in-hospital ischemic thrombotic and adverse complications were evaluated after the procedure.Results: The results showed that postoperative mean chest drainage of the first 4 days and total drainage were comparable between the two groups. No differences were found in Bleeding Academic Research Consortium (BARC) coronary artery bypass grafting (CABG) related bleeding (4 vs. 2%, P = 1), PLATelet inhibition and patient Outcomes (PLATO) life-threatening bleeding (20 vs. 26%, P = 0.48), and PLATO major bleeding (70 vs. 76%, P = 0.5) in the two groups. The composite ischemic thrombotic and adverse events were also similar.Conclusions: In patients receiving one-stop HCR, clopidogrel 600 mg loading dose did not increase major bleeding events compared with 300 mg. More sufficient data is necessary to evaluate the potential benefits of 600 mg loading dose in one-stop HCR.

Temporal changes of biomarkers in myocardial infarction patients with non-obstructive compared to obstructive coronary arteries

Abstract Background About 5–10% of all myocardial infarction (MI) patients have non-obstructive coronary arteries (MINOCA). The pathobiology of MINOCA is largely unknown compared to myocardial infarction with obstructive coronaries (MI-CAD). Purpose To investigate whether baseline concentrations and temporal changes of circulating biomarkers may offer insights into the activation of pathophysiological pathways in MINOCA compared to MI-CAD. Methods From the PLATelet inhibition and patient Outcomes (PLATO) trial, we retrospectively identified 114 patients with MINOCA (adjudicated MI, coronary stenoses &amp;lt;50% and excluding patients with previous coronary revascularization) and 2750 patients with MI-CAD (adjucated MI and stenoses ≥50%) with available biomarker data. Concentrations of high sensitivity cardiac troponin T (hs-cTnT), C-reactive protein (CRP) and N-terminal pro-B-type natriuretic peptide (NT-proBNP) were centrally measured by immunoassays in plasma samples obtained at randomization/baseline (median 15 hours from index event) and after one month. Differences in biomarker concentrations and their changes were evaluated by Wilcoxon-Mann-Whitney tests and data at one month were also analysed with adjusted linear regression models. Results In MINOCA patients, median concentrations decreased during one month from 238 to 9 ng/L for hs-cTnT, from 3.5 to 1.6 mg/L for CRP and from 507 to 228 pmol/L for NT-proBNP (Figure 1 and 2). In MI-CAD patients, median concentrations decreased from 198 to 13 ng/L for hs-cTnT, from 3.2 to 2.3 mg/L for CRP and increased from 372 to 566 pmol/L for NT-proBNP. Compared to MI-CAD, the baseline concentrations were higher in MINOCA for NT-proBNP (p=0.011), but similar for hs-cTnT (p=0.555) and CRP (p=0.834). However, patients with MINOCA had statistically larger reductions of concentrations from baseline to one month for hs-cTnT (p=0.002), CRP (p=0.005) and NT-proBNP (p&amp;lt;0.001) as compared to patients with MI-CAD. At one month, concentrations were lower in MINOCA than MI-CAD patients for all three biomarkers, which remained significant after adjustment for the baseline biomarker concentration, clinical characteristics and medications (p&amp;lt;0.001). Conclusions In MINOCA compared to MI-CAD patients, higher concentrations of NT-proBNP and similar concentrations of hs-cTnT and CRP at baseline indicate a higher degree of acute myocardial dysfunction but similar degree of acute myocardial injury and inflammation. Furthermore, concentrations of these biomarkers were lower at one month in MINOCA, suggesting other or less remaining underlying disease processes after MI in MINOCA than MI-CAD. Funding Acknowledgement Type of funding sources: Other. Main funding source(s): The present study was supported by Swedish Foundation for Strategic Research/Swedish Association of Local Authorities and Regions. The PLATO study and the biomarker analyses were sponsored by AstraZeneca.

Efficacy and safety of glycoprotein IIb/IIIa inhibitors in addition to P2Y12 inhibitors in ST-segment elevation myocardial infarction: A subanalysis of the POPular Genetics trial.

Glycoprotein IIb/IIIa inhibitors (GPI) are still used in patients with ST-segment elevation myocardial infarction (STEMI) who undergo primary percutaneous coronary intervention (PCI), although discussion about its clinical benefit is ongoing. GPI use was analyzed in this subanalysis of the POPular Genetics trial, which randomized STEMI patients to CYP2C19 genotype-guided treatment (clopidogrel or ticagrelor) or standard treatment with ticagrelor/prasugrel. The composite thrombotic endpoint consisted of cardiovascular death, myocardial infarction (MI), definite stent thrombosis, and stroke at 30 days. The combined bleeding endpoint consisted of Platelet Inhibition and Patient Outcomes (PLATO) major and minor bleeding at 30 days. Univariable and multivariable analyses in addition to a propensity score-matched (PSM) analysis were conducted. In total, 2378 patients, of whom 1033 received GPI and 1345 did not, were included. In multivariable analysis, GPI administration was associated with fewer thrombotic events (hazard ratio [HR] 0.22, 95% confidence interval [CI] 0.09-0.55) and MIs (HR 0.24, 95% CI 0.08-0.73). Furthermore, GPI administration was associated with an increase in bleedings (HR 2.02, 95% CI 1.27-3.19), driven by minor bleedings (HR 2.32, 95% CI 1.43-3.76), without a significant difference in major bleedings (HR 0.69, 95% CI 0.19-2.57). In the PSM analysis, no significant association was found. In STEMI patients undergoing primary PCI, GPI administration was associated with a reduction in thrombotic events at a cost of an increase in (mostly minor) bleedings in multivariable analysis, while propensity score analysis did not show significant associations.

Cost-Effectiveness of Ticagrelor Compared with Clopidogrel in Patients with Acute Coronary Syndrome from Vietnamese Healthcare Payers' Perspective.

The PLATelet inhibition and patient Outcomes (PLATO) trial (NCT00391872) demonstrated that ticagrelor compared to clopidogrel significantly reduced the rate of death from cardiovascular causes, myocardial infarction or stroke in patients with acute coronary syndrome (ACS). The aim of this study is to analyze the long-term cost-effectiveness of ticagrelor compared to clopidogrel in ACS patients from a Vietnamese healthcare payers' perspective. A two-part cost-effectiveness model was developed to estimate long-term costs and quality-adjusted life-years (QALY). Cardiovascular event rates, hospital bed days, interventions, investigations, study drug utilization and EuroQol 5 Dimension (EQ-5D) data were derived from the PLATO trial. Unit costs of medical services were derived from the Vietnamese governmental price list, and drug costs were based on the weighted average price from the Vietnamese social security report (in VND; 10.000 VND = 0.405 USD). An annual discount rate of 3% was used. Probabilistic and deterministic sensitivity analyses were conducted to evaluate uncertainty of the results. Ticagrelor was associated with an incremental cost of VND 5.34 million (USD 216.49) and a QALY gain of 0.11. This resulted in a cost per QALY gained of VND 49.58 million (USD 2009.96) from the Vietnamese healthcare payers' perspective. Probabilistic sensitivity analysis indicates that ticagrelor has 59% probability of being cost-effective compared with clopidogrel when using a willingness-to-pay threshold of one gross domestic products (GDP) per capita. Deterministic sensitivity analysis using clinical outcomes from the Asian sub-population of PLATO resulted in a cost per QALY of VND 42.25 million (USD 1712.80). Ticagrelor can be considered a cost-effective treatment for ACS compared with clopidogrel from a Vietnamese healthcare payers' perspective.

Differential effect of clopidogrel and ticagrelor on leukocyte count in relation to patient characteristics, biomarkers and genotype: a PLATO substudy

Inflammation plays a key role in cardiovascular disease by contributing to atherothrombosis. The PLATelet inhibition and patient Outcomes (PLATO) study (NCT00391872) compared ticagrelor to clopidogrel in patients with acute coronary syndromes and demonstrated fewer cardiovascular events with ticagrelor but lower white blood cell counts (WBC) with clopidogrel. In this further analysis of the PLATO biomarker substudy, we assessed associations between WBC and clinical characteristics, biomarker levels, and CYP2C19 polymorphisms. On-treatment mean (SD) WBC in the clopidogrel group was mildly reduced at each stage of follow-up compared with either the ticagrelor group (1 month: 7.27 (2.1) and 7.67 (2.23) x109/L for clopidogrel and ticagrelor, respectively; p < .001) or following cessation of clopidogrel (7.23 (1.97) x109/L, at 6 months vs 7.56 (2.28) x109/L after treatment cessation; P < .001). This occurred independently of baseline biomarkers and CYP2C19 genotype (where known). Adjusting for clinical characteristics and other biomarkers, no significant interaction was detected between clinical risk factors and the observed effect of clopidogrel on WBC. Clopidogrel weakly suppresses WBC, independent of clinical characteristics, baseline inflammatory biomarker levels, and CYP2C19 genotype. Further work is required to determine the mechanism for this effect and whether it contributes to clopidogrel’s efficacy as well as therapeutic interaction with anti-inflammatory drugs.

Differential modulation of polyunsaturated fatty acids in patients with myocardial infarction treated with ticagrelor or clopidogrel

SummaryUntargeted metabolomics is used to refine the development of biomarkers for the diagnosis of cardiovascular disease. Myocardial infarction (MI) has major individual and societal consequences for patients, who remain at high risk of secondary events, despite advances in pharmacological therapy. To monitor their differential response to treatment, we performed untargeted plasma metabolomics on 175 patients from the platelet inhibition and patient outcomes (PLATO) trial treated with ticagrelor and clopidogrel, two common P2Y12 inhibitors. We identified a signature that discriminates patients, which involves polyunsaturated fatty acids (PUFAs) and particularly the omega-3 fatty acids docosahexaenoate and eicosapentaenoate. The known cardiovascular benefits of PUFAs could contribute to the efficacy of ticagrelor. Our work, beyond pointing out the high relevance of untargeted metabolomics in evaluating response to treatment, establishes PUFA metabolism as a pathway of clinical interest in the recovery path from MI.

Clopidogrel in noncarriers of CYP2C19 loss-of-function alleles versus ticagrelor in elderly patients with acute coronary syndrome: A pre-specified sub analysis from the POPular Genetics and POPular Age trials CYP2C19 alleles in elderly patients

BackgroundPatients with acute coronary syndrome (ACS) who are carrying CYP2C19 loss-of-function alleles derive less benefit from clopidogrel treatment. Despite this, in elderly patients, clopidogrel might be preferred over more potent P2Y12 inhibitors due to a lower bleeding risk. Whether CYP2C19 genotype-guided antiplatelet treatment in the elderly could be of benefit has not been studied specifically. MethodsPatients aged 70 years and older with known CYP2C19*2 and *3 genotype were identified from the POPular Genetics and POPular Age trials. Noncarriers of loss-of-function alleles treated with clopidogrel were compared to patients, irrespective of CYP2C19 genotype, treated with ticagrelor and to clopidogrel treated carriers of loss-of-function alleles. We assessed net clinical benefit (all-cause death, myocardial infarction, stroke and Platelet Inhibition and Patient Outcomes (PLATO) major bleeding), atherothrombotic outcomes (cardiovascular death, myocardial infarction, stroke) and bleeding outcomes (PLATO major and minor bleeding). ResultsA total of 991 patients were assessed. There was no significant difference in net clinical benefit (17.2% vs. 15.1%, adjusted hazard ratio (adjHR) 1.05, 95% confidence interval (CI) 0.77–1.44), atherothrombotic outcomes (9.7% vs. 9.2%, adjHR 1.00, 95%CI 0.66–1.50), and bleeding outcomes (17.7% vs. 19.8%, adjHR 0.80, 95%CI 0.62–1.12) between clopidogrel in noncarriers of loss-of-function alleles and ticagrelor respectively. ConclusionIn ACS patients aged 70 years and older, there was no significant difference in net clinical benefit and atherothrombotic outcomes between noncarriers of a loss-of-function allele treated with clopidogrel and patients treated with ticagrelor. The bleeding rate was numerically; though not statistically significant, lower in patients using clopidogrel.

Risk of Major Bleeding With Potent Antiplatelet Agents After an Acute Coronary Event: A Comparison of Ticagrelor and Clopidogrel in 5116 Consecutive Patients in Clinical Practice

BackgroundMajor bleeding after acute coronary syndrome predicts a poor outcome but is challenging to define. The choice of antiplatelet influences bleeding risk.Methods and ResultsMajor bleeding, subsequent myocardial infarction (MI), and all‐cause mortality to 1 year were compared in consecutive patients with acute coronary syndrome treated with clopidogrel (n=2491 between 2011 and 2013) and ticagrelor (n=2625 between 2012 and 2015) in 5 English hospitals. Clinical outcomes were identified from national hospital episode statistics. Bleeding and MI events were independently adjudicated by 2 experienced clinicians, blinded to drug, sequence, and year. Bleeding events were categorized using Bleeding Academic Research Consortium 3 to 5 and PLATO (Platelet Inhibition and Patient Outcomes) criteria and MI by the Third Universal Definition. Multivariable regression analysis was used to adjust outcomes for case mix. The median age was 68 years and 34% were women. 39% underwent percutaneous coronary intervention and 13% coronary artery bypass graft surgery. Clinical outcome data were 100% complete for bleeding and 99.7% for MI. No statistically significant difference was seen in crude or adjusted major bleeding for ticagrelor compared with clopidogrel (Bleeding Academic Research Consortium 3–5, hazard ratio [HR], 1.23; 95% CI, 0.90–1.68; P=0.2, PLATO major adjusted HR, 1.30; 95% CI, 0.98–1.74; P=0.07) except in the non‐coronary artery bypass graft cohort (n=4464), where bleeding was more frequent with ticagrelor (Bleeding Academic Research Consortium 3–5, adjusted HR, 1.58; 95% CI, 1.09–2.31; P=0.017; and PLATO major HR, 1.67; 95% CI, 1.18–2.37; P=0.004). There was no difference in crude or adjusted subsequent MI (adjusted HR, 1.20; 95% CI, 0.87–1.64; P=0.27). Crude mortality was higher in the clopidogrel group but not after adjustment, using either Cox proportional hazards or propensity matched population (HR, 0.90; 95% CI, 0.76–1.10; P=0.21) as was the case for stroke (HR, 0.82; 95% CI, 0.52–1.32; P=0.42).ConclusionsThis observational study indicates that the apparent benefit of ticagrelor demonstrated in a clinical trial population may not be observed in the broader population encountered in clinical practice.RegistrationURL: https://www.clinicaltrials.gov; Unique identifier: NCT02484924.

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.

Ticagrelor Versus Clopidogrel in Older Patients with NSTE-ACS Using Oral Anticoagulation: A Sub-Analysis of the POPular Age Trial.

There are no randomised data on which antiplatelet agent to use in elderly patients with non-ST-elevation acute coronary syndrome (NSTE-ACS) and an indication for oral anticoagulation (OAC). The randomised POPular Age trial, in patients of 70 years or older with NSTE-ACS, showed a reduction in bleeding without increasing thrombotic events in patients using clopidogrel as compared to ticagrelor. In this sub-analysis of the POPular AGE trial, we compare clopidogrel with ticagrelor in patients with a need for oral anticoagulation. The follow-up duration was one year. The primary bleeding outcome was Platelet Inhibition and Patient Outcomes (PLATO) major and minor bleeding. The primary thrombotic outcome consisted of cardiovascular death, myocardial infarction and stroke. The primary net clinical benefit outcome was a composite of all-cause death, myocardial infarction, stroke, and PLATO major and minor bleeding. A total of 184/1011 (18.2%) patients on OAC were included in this subanalysis; 83 were randomized to clopidogrel and 101 to ticagrelor. The primary bleeding outcome was lower in the clopidogrel group (17/83, 20.9%) compared to the ticagrelor group (33/101, 33.5%; p = 0.051), as was the thrombotic outcome (7/83, 8.4% vs. 19/101, 19.2%; p = 0.035) and the primary net clinical benefit outcome (23/83, 27.7% vs. 49/101, 48.5%; p = 0.003). In this subgroup of patients using OAC, clopidogrel reduced PLATO major and minor bleeding compared to ticagrelor without increasing thrombotic risk. This analysis therefore suggests that, in line with the POPular Age trial, clopidogrel is a better option than ticagrelor in NSTE-ACS patients ≥70 years using OAC.

Legumain in Acute Coronary Syndromes: A Substudy of the PLATO (Platelet Inhibition and Patient Outcomes) Trial.

BackgroundThe cysteine protease legumain is increased in patients with atherosclerosis, but its causal role in atherogenesis and cardiovascular disease is still unclear. The aim of the study was to investigate the association of legumain with clinical outcome in a large cohort of patients with acute coronary syndrome.Methods and ResultsSerum levels of legumain were analyzed in 4883 patients with acute coronary syndrome from a substudy of the PLATO (Platelet Inhibition and Patient Outcomes) trial. Levels were analyzed at admission and after 1 month follow‐up. Associations between legumain and a composite of cardiovascular death, spontaneous myocardial infarction or stroke, and its individual components were assessed by multivariable Cox regression analyses. At baseline, a 50% increase in legumain level was associated with a hazard ratio (HR) of 1.13 (95% CI, 1.04–1.21), P=0.0018, for the primary composite end point, adjusted for randomized treatment. The association remained significant after adjustment for important clinical and demographic variables (HR, 1.10; 95% CI, 1.02–1.19; P=0.013) but not in the fully adjusted model. Legumain levels at 1 month were not associated with the composite end point but were negatively associated with stroke (HR, 0.62; 95% CI, 0.44–0.88; P=0.0069), including in the fully adjusted model (HR, 0.57; 95% CI, 0.37–0.88; P=0.0114).ConclusionsBaseline legumain was associated with the primary outcome in patients with acute coronary syndrome, but not in the fully adjusted model. The association between high levels of legumain at 1 month and decreased occurrence of stroke could be of interest from a mechanistic point of view, illustrating the potential dual role of legumain during atherogenesis and acute coronary syndrome.RegistrationURL: https://www.clini​caltr​ials.gov; Unique identifier: NCT00391872.

Efficacy and Safety of Ticagrelor Compared to Clopidogrel in Patients Undergoing Percutaneous Coronary Intervention: A Meta-Analysis.

The Platelet Inhibition and Patient Outcomes (PLATO) study found that ticagrelor plus aspirin (TA) was more effective than clopidogrel plus aspirin (CA), without an increase in the risk of massive bleeding in patients undergoing percutaneous coronary intervention (PCI). Data from other studies indicate that the conclusion is controversial with the results obtained by PLATO. To investigate the efficacy and safety of TA, compared with CA, in patients with acute coronary syndrome (ACS) after PCI. A systematic literature search was performed in the MEDLINE, EMBASE, and Cochrane databases to compare the efficacy and safety of CA and TA treatment in patients with ACS after PCI. The endpoints were major adverse cardiac events (MACEs), death, stroke, myocardial infarction (MI), stent thrombosis, and bleeding events. The data analysis was performed using RevMan 5.3 software, and the odds ratios (ORs) and their 95% confidence intervals (CI) were calculated. The standards of reporting were in accordance with the PRISMA guidelines. 13 studies with a total of 58,062 patients were included in this study with a subgroup analysis of the European/American and Asian populations. In terms of effectiveness for MACEs, the European, American and Asian populations benefitted more from the TA treatment than the CA treatment (European and American populations, OR = 0.82, P = 0.0002; Asian, OR = 0.66, P < 0.0001; total, OR = 0.78, P < 0.0001). In terms of specific effectiveness indicators, such as stroke, MI, and stent thrombosis, the results of TA and CA groups in the European, American, and Asian populations were not consistent. In terms of safety, there was no statistical difference in total bleeding events between TA and CA treatments (OR = 1.19, P = 0.21). However, in the Asian population, the incidence of total bleeding events (OR = 1.52, P = 0.0004) in the TA group was higher than that in the CA group. The TA treatment in the European and American populations is more beneficial and safer than CA treatment. However, although the Asian population has this benefit, the risk of bleeding is significantly increased as well, and antiplatelet drugs should be chosen carefully.

Comparison between ticagrelor versus clopidogrel in long term outcomes of Taiwanese diabetic subjects with acute coronary syndrome undergoing successful revascularization: From TSOC ACS-DM registry.

Although previous clinical trials demonstrated that ticagrelor could reduce cardiovascular events and mortality versus clopidogrel in patients with acute coronary syndrome (ACS), the real-world evidence of its clinical impacts on East Asian Diabetic population has rarely been investigated.Between November 2013 and June 2015, 1534 patients were recruited into the Acute Coronary Syndrome-Diabetes Mellitus Registry of the Taiwan Society of Cardiology (TSOC ACS-DM registry). After propensity score matching, a total of 730 patients undergoing successful revascularization and discharged on ticagrelor (N = 365) or clopidogrel (N = 365) were analyzed. The primary and secondary endpoints were all-cause mortality and re-hospitalization, respectively. The all-cause death associated with ticagrelor vs clopidogrel was 3.6% vs 7.4% (adjusted hazard ratio (HR) 0.34 [0.15–0.80]; P = .0138) at 24 months. The re-hospitalization rate at 24 months was 38.9% vs 39.2% (P = .3258).For diabetic patients with ACS, ticagrelor provided better survival benefit than clopidogrel without an increase of re-hospitalization in 24 months after successful percutaneous coronary intervention. This study in real-world circumstance provided valuable complementary data to externally validate platelet inhibition and patient outcomes (PLATO) finding especially in Asian diabetic population.

Factors for recurrent stroke among Asian patients with non-valvular atrial fibrillation under non-vitamin K antagonist oral anticoagulant therapy

Atrial fibrillation (AF) patients with a history of ischemic stroke or transient ischemic attack (TIA) carry excessive risk of recurrent stroke. Real-world data for the Asian population is scarce. This study aimed to investigate the thromboembolism and major bleeding risk of non-vitamin K antagonist oral anticoagulant (NOAC) therapy among Asian patients, and to identify the risk factors of recurrent stroke. This retrospective study recruited AF patients aged over 20 years, who had a previous stoke or TIA, and received NOAC therapy. Thromboembolic events were recurrent ischemic stroke or TIA, and the major bleeding events were classified according to the PLATO (Platelet Inhibition and Patient Outcomes) criteria. A total of 361 patients (61.2% male) were enrolled for data analysis. The incidence rate for recurrent ischemic stroke or TIA was 3.6 (95% CI=2.5 to 5.5) per 100 person-years, and 0.9 (95% CI=0.4 to 1.7) per 100 person-years for major bleeding. Patients with recurrent ischemic stroke or TIA were more likely to have malignancy (hazard ratio [HR] for malignancy=4.4, 95% CI=1.9 to 10.3, p=0.001) and concomitantly take enzyme inducing antiepileptic drugs (EIAED, HR=8.1, 95% CI=2.7 to 24.1, p<0.001). Atrial fibrillation patients with underlying malignancy or concurrently use of EIAED may have increased risk of treatment failure in secondary stroke prevention.

The Prognostic Significance of Different Bleeding Classifications in off-pump coronary artery bypass grafting

BackgroundPerioperative bleeding during cardiac surgery are known to make patients susceptible to adverse outcomes and several bleeding classifications have been developed to stratify the severity of bleeding events. Further validation of different classifications was needed. The aim of present study was to validate and explore the prognostic value of different bleeding classifications in patients undergoing off-pump coronary artery bypass grafting (OPCAB).MethodsData on baseline and operative characteristics of 3988 patients who underwent OPCAB in Beijing Anzhen Hospital from February 2008 to December 2014 were available. The primary endpoint was a composite of in-hospital death and nonfatal postoperative myocardial infarction (MI). The secondary endpoint was postoperative acute kidney injury (AKI). We explored the association of major bleeding defined by the European registry of Coronary Artery Bypass Grafting (E-CABG), Universal Definition of Perioperative Bleeding (UDPB), Bleeding Academic Research Consortium (BARC) classification and Study of Platelet Inhibition and Patient Outcomes (PLATO) with primary endpoints by multivariable logistic regression analysis and investigated their significance of adverse event prediction using goodness-of-fit tests of − 2 log likelihood.ResultsIn-hospital mortality was 1.23% (n = 49) and postoperative MI was observed in 4.76% (n = 190) of patients, AKI in 24.69% (n = 985). The incidence of the primary outcome was 5.99% (n = 239). Multivariable logistic regression analysis showed that BARC type 4 (OR = 2.64, 95% CI: 1.66–4.19, P < 0.001), UDPB class 4 (OR = 3.52, 95% CI: 2.05–6.02, P < 0.001) and E-CABG class 2–3 (class 2: OR = 2.24, 95% CI: 1.36–3.70, P = 0.001; class 3: OR = 12.65, 95% CI: 2.74–18.43, P = 0.002) bleeding but not PLATO bleeding were associated with an increased risk of in-hospital death and postoperative MI. Major bleeding defined by all the four classifications mentioned above was an independent risk factor of AKI after surgery. Inclusion of major bleeding defined by these four classifications improved the predictive performance of the multivariable model with baseline characteristics.ConclusionsBleeding assessed by BARC, E-CABG and UDPB classifications were significantly associated with poorer immediate outcomes. These classifications seemed to be valuable tool in the assessment of prognostic effect of perioperative bleeding.

ALCAM predicts future cardiovascular death in acute coronary syndromes: Insights from the PLATO trial

Background and aimsActivated leukocyte cell adhesion molecule (ALCAM) is upregulated during inflammation and involved in transmigration of leukocytes and T-cell activation. We hypothesized that ALCAM might be associated with recurrent events in patients with acute coronary syndromes (ACS). MethodsALCAM was measured in serum obtained on admission, at discharge, 1 month and 6 months in a subgroup of 5165 patients admitted with ACS and included in the PLATelet inhibition and patient Outcomes (PLATO) trial (NCT00391872). The association between ALCAM and the composite endpoint and its components, including cardiovascular (CV) death, non-procedural spontaneous myocardial infarction (MI) or stroke during 1-year follow-up, was assessed by Cox proportional hazards models with incremental addition of clinical risk factors and biomarkers (including high-sensitivity troponin T, N-terminal pro−B-type natriuretic peptide and growth differentiation factor-15). ResultsThe median (Q1-Q3) concentration of ALCAM at admission was 97 (80–116) ng/mL. A 50% higher level of ALCAM on admission was associated with a hazard ratio (HR) of 1.16 (95% confidence interval [1.00–1.34] p = 0.043) for the composite endpoint in fully adjusted analysis, mainly driven by the association with CV death (HR 1.45 [1.16–1.82] p = 0.0012). ConclusionsIn patients with ACS, admission level of ALCAM was independently associated with adverse outcome including CV death even after adjustment for established inflammatory and cardiac biomarkers.

A Genotype-Guided Strategy for Oral P2Y12 Inhibitors in Primary PCI

BackgroundIt is unknown whether patients undergoing primary percutaneous coronary intervention (PCI) benefit from genotype-guided selection of oral P2Y12 inhibitors.MethodsWe conducted a randomized, open-label, assessor-blinded trial in which patients undergoing primary PCI with stent implantation were assigned in a 1:1 ratio to receive either a P2Y12 inhibitor on the basis of early CYP2C19 genetic testing (genotype-guided group) or standard treatment with either ticagrelor or prasugrel (standard-treatment group) for 12 months. In the genotype-guided group, carriers of CYP2C19*2 or CYP2C19*3 loss-of-function alleles received ticagrelor or prasugrel, and noncarriers received clopidogrel. The two primary outcomes were net adverse clinical events — defined as death from any cause, myocardial infarction, definite stent thrombosis, stroke, or major bleeding defined according to Platelet Inhibition and Patient Outcomes (PLATO) criteria — at 12 months (primary combined outcome; tested for noninferiority, with a noninferiority margin of 2 percentage points for the absolute difference) and PLATO major or minor bleeding at 12 months (primary bleeding outcome).ResultsFor the primary analysis, 2488 patients were included: 1242 in the genotype-guided group and 1246 in the standard-treatment group. The primary combined outcome occurred in 63 patients (5.1%) in the genotype-guided group and in 73 patients (5.9%) in the standard-treatment group (absolute difference, −0.7 percentage points; 95% confidence interval [CI], −2.0 to 0.7; P<0.001 for noninferiority). The primary bleeding outcome occurred in 122 patients (9.8%) in the genotype-guided group and in 156 patients (12.5%) in the standard-treatment group (hazard ratio, 0.78; 95% CI, 0.61 to 0.98; P=0.04).ConclusionsIn patients undergoing primary PCI, a CYP2C19 genotype–guided strategy for selection of oral P2Y12 inhibitor therapy was noninferior to standard treatment with ticagrelor or prasugrel at 12 months with respect to thrombotic events and resulted in a lower incidence of bleeding. (Funded by the Netherlands Organization for Health Research and Development; POPular Genetics ClinicalTrials.gov number, NCT01761786; Netherlands Trial Register number, NL2872.)

Interleukin-18 in patients with acute coronary syndromes.

BackgroundWe aimed to assess associations between circulating IL‐18 concentrations and cardiovascular outcomes in patients with acute coronary syndromes (ACS).Hypothesis and MethodsPlasma IL‐18 concentrations were measured at admission, discharge, 1 month, and 6 months in patients with ACS in the PLATelet inhibition and patient Outcomes (PLATO) trial. Associations with outcomes were evaluated with Cox regression models on the composite of CV death, spontaneous myocardial infarction (sMI), or stroke; and on CV death or sMI separately, including adjustment for clinical risk factors and biomarkers (cTnT‐hs, NT‐proBNP, cystatin C, CRP‐hs, and GDF‐15).ResultsMedian IL‐18 concentrations at baseline, discharge, 1 month, and 6 months were 237, 283, 305, and 320 ng/L (n = 16 636). Male sex, obesity, diabetes, and plasma levels of cystatin C, GDF‐15, and CRP‐hs were independently associated with higher IL‐18 levels. Higher baseline IL‐18 levels were associated with the composite endpoint and with CV death (hazard ratio [HR] 1.05, 95% confidence interval [95% CI] 1.02‐1.07 and HR 1.10, 95% CI 1.06‐1.14, respectively, per 25% increase of IL‐18 levels). Associations remained significant after adjustment for clinical variables but became non‐significant after adjustment for all biomarkers (HR 1.01, 95% CI 0.98‐1.04 and HR 1.04, 95% CI 1.00‐1.08, respectively). There were no associations with sMI.ConclusionsIn ACS patients, IL‐18 concentrations increased after the acute event and remained increased for 6 months. Baseline IL‐18 levels were significantly associated with CV mortality, independent of clinical characteristics and indicators of renal/cardiac dysfunction but this association was attenuated after adjustment for multiple biomarkers.