Ticagrelor vs Clopidogrel in Clopidogrel-Naive Patients With Chronic Coronary Syndrome.

BACKGROUND: Whether ticagrelor may reduce periprocedural myocardial necrosis after elective percutaneous coronary intervention (PCI) in patients with and without chronic clopidogrel therapy is unclear. OBJECTIVES: This study sought to compare ticagrelor vs clopidogrel in patients with and without chronic clopidogrel therapy before undergoing elective PCI. METHODS: In this prespecified analysis of the ALPHEUS (Assessment of Loading With the P2Y12 Inhibitor Ticagrelor or Clopidogrel to Halt Ischemic Events in Patients Undergoing Elective Coronary Stenting) trial, patients were defined as clopidogrel(+) and clopidogrel(-) according to the presence and absence of clopidogrel treatment for ≥7 days before PCI, respectively. The primary endpoint was the composite of PCI-related myocardial infarction and major injury as defined by the third and fourth universal definition 48 hours after PCI. RESULTS: A total of 1,882 patients were included, 805 (42.7%) of whom were clopidogrel(+). These patients were older, had more comorbidities, and had more frequent features of complex PCI. The primary endpoint was less frequently present in clopidogrel(-) compared to clopidogrel(+) patients (32.8% vs 40.0%; OR: 0.73; 95% CI: 0.60-0.88), but no significant differences were reported for the risk of death, myocardial infarction, stroke, or transient ischemic attack at 48 hours or 30 days. Ticagrelor did not reduce periprocedural myocardial necrosis or the risk of adverse outcomes, and there was no significant interaction regarding the presence of chronic clopidogrel treatment. CONCLUSIONS: Clopidogrel-naive patients presented less periprocedural complications compared to clopidogrel(+) patients, a difference related to a lower risk profile and less complex PCI. The absence of clopidogrel at baseline did not affect the absence of a difference between ticagrelor and clopidogrel in terms of PCI-related complications supporting the use of clopidogrel as the standard of care in elective PCI in patients with or without chronic clopidogrel treatment.

P2Y12 Inhibitor Loading Time Before Elective PCI and the Prevention of Myocardial Necrosis.

BACKGROUND: There are dated and conflicting data about the optimal timing of initiation of P2Y12 inhibitors in elective percutaneous coronary intervention (PCI). Peri-PCI myocardial necrosis is associated with poor outcomes. We aimed to assess the impact of the P2Y12 inhibitor loading time on periprocedural myocardial necrosis in the population of the randomized Assessment of Loading With the P2Y12 Inhibitor Ticagrelor or Clopidogrel to Halt Ischemic Events in Patients Undergoing Elective Coronary Stenting (ALPHEUS) trial, which compared ticagrelor with clopidogrel in high-risk patients who received elective PCI. METHODS: The ALPHEUS trial divided 1809 patients into quartiles of loading time. The ALPHEUS primary outcome was used (type 4 [a or b] myocardial infarction or major myocardial injury) as well as the main secondary outcome (type 4 [a or b] myocardial infarction or any type of myocardial injury). RESULTS: Patients in the first quartile group (Q1) presented higher rates of the primary outcome (P = 0.01). When compared with Q1, incidences of the primary outcome decreased in patients with longer loading times (adjusted odds ratio [adjOR], 0.70 [0.52.-0.95]; P = 0.02 for Q2; adjOR 0.65 [0.48-0.88]; P < 0.01 for Q3; adjOR 0.66 [0.49-0.89]; P < 0.01 for Q4). Concordant results were found for the main secondary outcome. There was no interaction with the study drug allocated by randomization (clopidogrel or ticagrelor). Bleeding complications (any bleeding ranging between 4.9% and 7.3% and only 1 major bleeding at 48 hours) and clinical ischemic events were rare and did not differ among groups. CONCLUSIONS: In elective PCI, administration of the oral P2Y12 inhibitor at the time of PCI could be associated with more frequent periprocedural myocardial necrosis than an earlier administration. The long-term clinical consequences remain unknown.

Phenotyping coronary plaque by computed tomography in premature coronary artery disease.

AIMS: Premature coronary artery disease (CAD) is an aggressive disease with multiple recurrences mostly related to new coronary lesions. This study aimed to compare coronary plaque characteristics of individuals with premature CAD with those of incidental plaques found in matched individuals free of overt cardiovascular disease, using coronary computed tomography angiography (CCTA). METHODS AND RESULTS: Of 1552 consecutive individuals who underwent CCTA, 106 individuals with history of acute or stable obstructive CAD ≤45 years were matched by age, sex, smoking status, cardiovascular heredity, and dyslipidaemia with 106 controls. CCTA were analysed for Coronary Artery Disease Reporting and Data System score, plaque composition, and high-risk plaque (HRP) features, including spotty calcification, positive remodelling, low attenuation, and napkin-ring sign. The characteristics of 348 premature CAD plaques were compared with those of 167 incidental coronary plaques of matched controls. The prevalence of non-calcified plaques was higher among individuals with premature CAD (65.1 vs. 30.2%, P < 0.001), as well as spotty calcification (42.5 vs. 17.9%, P < 0.001), positive remodelling (41.5 vs. 9.4%, P < 0.001), low attenuation (24.5 vs. 3.8%, P < 0.001), and napkin-ring sign (1.9 vs. 0.0%). They exhibited an average of 2.2 (2.7) HRP, while the control group displayed 0.4 (0.8) HRP (P < 0.001). Within a median follow-up of 24 (16, 34) months, individuals with premature CAD and ischaemic recurrence (n = 24) had more HRP [4.3 (3.9)] than those without ischaemic recurrence [1.5 (1.9)], mostly non-calcified with low attenuation and positive remodelling. CONCLUSION: Coronary atherosclerosis in individuals with premature CAD is characterized by a high and predominant burden of non-calcified plaque and unusual high prevalence of HRP, contributing to disease progression with multiple recurrences. A comprehensive qualitative CCTA assessment of plaque characteristics may further risk stratify our patients, beyond cardiovascular risk factors.

Impact of transfusion strategy on platelet aggregation and biomarkers in myocardial infarction patients with anemia.

BACKGROUND: Higher rates of thrombotic events have been reported in myocardial infarction (MI) patients requiring blood transfusion. The impact of blood transfusion strategy on thrombosis and inflammation is still unknown. OBJECTIVE: To compare the impact of a liberal vs. a restrictive transfusion strategy on P2Y12 platelet reactivity and biomarkers in the multicentric randomized REALITY trial. METHODS: Patients randomized to a liberal (hemoglobin ≤10 g/dL) or a restrictive (hemoglobin ≤8 g/dL) transfusion strategy had VASP-PRI platelet reactivity measured centrally in a blinded fashion and platelet reactivity unit (PRU) measured locally using encrypted VerifyNow; at baseline and after randomization. Biomarkers of thrombosis (P-selectin, PAI-1, vWF) and inflammation (TNF-α) were also measured. The primary endpoint was the change in the VASP-PRI (difference from baseline and post randomization) between the randomized groups. RESULTS: A total of 100 patients randomized were included in this study (n = 50 in each group). Transfused patients received on average 2.4 ± 1.6 units of blood. We found no differences in change of the VASP PRI (difference 1.2% 95% CI (-10.3-12.7%)) or by the PRU (difference 13.0 95% CI (-21.8-47.8)) before and after randomization in both randomized groups. Similar results were found in transfused patients (n = 71) regardless of the randomized group, VASP PRI (difference 1.7%; 95% CI (-9.5-1.7%)) or PRU (difference 27.0; 95% CI (-45.0-0.0)). We did not find an impact of transfusion strategy or transfusion itself in the levels of P-selectin, PAI-1, vWF, and TNF-α. CONCLUSION: In this study, we found no impact of a liberal vs. a restrictive transfusion strategy on platelet reactivity and biomarkers in MI patients with anemia. A conclusion that should be tempered due to missing patients with exploitable biological data that has affected our power to show a difference.

Systematic analysis of drug-associated myocarditis reported in the World Health Organization pharmacovigilance database.

While multiple pharmacological drugs have been associated with myocarditis, temporal trends and overall mortality have not been reported. Here we report the spectrum and main features of 5108 reports of drug-induced myocarditis, in a worldwide pharmacovigilance analysis, comprising more than 21 million individual-case-safety reports from 1967 to 2020. Significant association between myocarditis and a suspected drug is assessed using disproportionality analyses, which use Bayesian information component estimates. Overall, we identify 62 drugs associated with myocarditis, 41 of which are categorized into 5 main pharmacological classes: antipsychotics (n = 3108 reports), salicylates (n = 340), antineoplastic-cytotoxics (n = 190), antineoplastic-immunotherapies (n = 538), and vaccines (n = 790). Thirty-eight (61.3%) drugs were not previously reported associated with myocarditis. Antipsychotic was the first (1979) and most reported class (n = 3018). In 2019, the two most reported classes were antipsychotics (54.7%) and immunotherapies (29.5%). Time-to-onset between treatment start and myocarditis is 15 [interquartile range: 10; 23] days. Subsequent mortality is 10.3% and differs between drug classes with immunotherapies the highest, 32.5% and salicylates the lowest, 2.6%. These elements highlight the diversity of presentations of myocarditis depending on drug class, and show the emerging role of antineoplastic drugs in the field of drug-induced myocarditis.

Ticagrelor versus clopidogrel in elective percutaneous coronary intervention (ALPHEUS): a randomised, open-label, phase 3b trial.

BACKGROUND: Percutaneous coronary intervention (PCI)-related myonecrosis is frequent and can affect the long-term prognosis of patients. To our knowledge, ticagrelor has not been evaluated in elective PCI and could reduce periprocedural ischaemic complications compared with clopidogrel, the currently recommended treatment. The aim of the ALPHEUS study was to examine if ticagrelor was superior to clopidogrel in reducing periprocedural myocardial necrosis in stable coronary patients undergoing high-risk elective PCI. METHODS: The ALPHEUS study, a phase 3b, randomised, open-label trial, was done at 49 hospitals in France and Czech Republic. Patients with stable coronary artery disease were eligible for the study if they had an indication for PCI and at least one high-risk characteristic. Eligible patients were randomly assigned (1:1) to either ticagrelor (180 mg loading dose, 90 mg twice daily thereafter for 30 days) or clopidogrel (300-600 mg loading dose, 75 mg daily thereafter for 30 days) by use of an interactive web response system, and stratified by centre. The primary outcome was a composite of PCI-related type 4 (a or b) myocardial infarction or major myocardial injury and the primary safety outcome was major bleeding, both of which were evaluated within 48 h of PCI (or at hospital discharge if earlier). The primary analysis was based on all events that occurred in the intention-to-treat population. The trial was registered with ClinicalTrials.gov, NCT02617290. FINDINGS: Between Jan 9, 2017, and May 28, 2020, 1910 patients were randomly assigned at 49 sites, 956 to the ticagrelor group and 954 to the clopidogrel group. 15 patients were excluded from the ticagrelor group and 12 from the clopidogrel group. At 48 h, the primary outcome was observed in 334 (35%) of 941 patients in the ticagrelor group and 341 (36%) of 942 patients in the clopidogrel group (odds ratio [OR] 0·97, 95% CI 0·80-1·17; p=0·75). The primary safety outcome did not differ between the two groups, but minor bleeding events were more frequently observed with ticagrelor than clopidogrel at 30 days (105 [11%] of 941 patients in the ticagrelor group vs 71 [8%] of 942 patients in the clopidogrel group; OR 1·54, 95% CI 1·12-2·11; p=0·0070). INTERPRETATION: Ticagrelor was not superior to clopidogrel in reducing periprocedural myocardial necrosis after elective PCI and did not cause an increase in major bleeding, but did increase the rate of minor bleeding at 30 days. These results support the use of clopidogrel as the standard of care for elective PCI. FUNDING: ACTION Study Group and AstraZeneca.

Blunting periprocedural myocardial necrosis: Rationale and design of the randomized ALPHEUS study.

BACKGROUND: Clopidogrel associated with aspirin is the recommended treatment for patients undergoing elective percutaneous coronary intervention (PCI). Although severe PCI-related events are rare, evidence suggests that PCI-related myocardial infarction and myocardial injury are frequent complications that can impact the clinical prognosis of the patients. Antiplatelet therapy with a potent P2Y12 receptor inhibitor such as ticagrelor may reduce periprocedural ischemic complications while maintaining a similar safety profile as compared with conventional dual antiplatelet therapy by aspirin and clopidogrel in this setting. METHODS: Assessment of Loading with the P2Y12 inhibitor ticagrelor or clopidogrel to Halt ischemic Events in patients Undergoing elective coronary Stenting (ALPHEUS) (NCT02617290) is an international, multicenter, randomized, parallel-group, open-label study in patients with stable coronary artery disease who are planned for an elective PCI. In total, 1,900 patients will be randomized before a planned PCI to a loading dose of ticagrelor 180 mg or a loading dose of clopidogrel (300 or 600 mg) in addition to aspirin. Patients will then receive a dual antiplatelet therapy with aspirin and ticagrelor 90 mg twice daily or clopidogrel 75 mg once daily for 30 days. The primary ischemic end point is PCI-related myocardial infarction (myocardial infarction type 4a or 4b) or major myocardial injury within 48 hours (or at hospital discharge if earlier) after elective PCI/stent. Safety will be evaluated by major bleeding events (Bleeding Academic Research Consortium type 3 or 5) at 48 hours (or discharge if it occurs earlier). CONCLUSION: ALPHEUS is the first properly sized trial comparing ticagrelor to clopidogrel in the setting of elective PCI and is especially designed to show a reduction in periprocedural events, a surrogate end point for mortality.

Reasons for the Failure of Platelet Function Testing to Adjust Antiplatelet Therapy: Pharmacodynamic Insights From the ARCTIC Study.

BACKGROUND: In the ARCTIC trial (Assessment by a Double Randomization of a Conventional Antiplatelet Strategy Versus a Monitoring-Guided Strategy for Drug-Eluting Stent Implantation and of Treatment Interruption Versus Continuation One Year After Stenting), treatment adjustment following platelet function testing failed to improve clinical outcomes. However, high-on-treatment platelet reactivity (HPR) is considered as a predictor of poor ischemic outcome. This prespecified substudy evaluated clinical outcomes according to the residual platelet reactivity status after antiplatelet therapy adjustment. METHODS: We analyzed the 1213 patients assigned to the monitoring arm of the ARCTIC trial in whom platelet reactivity was evaluated by the VerifyNow P2Y12 test before percutaneous coronary intervention and during the maintenance phase (at 14 days). HPR was defined as platelet reaction unit≥235U. The primary ischemic end point, a composite of death, myocardial infarction, stent thrombosis, stroke, or urgent revascularization and the safety end point of major bleeding were assessed according to the platelet reactivity status. RESULTS: Before percutaneous coronary intervention, 35.7% of patients displayed HPR (n=419). During the acute phase, between percutaneous coronary intervention and the 14-day platelet function testing, ischemic (adjusted hazard ratio, 0.94 [95% CI, 0.74-1.18]; P=0.58) and safety outcomes (hazard ratio, 1.28 [95% CI, 0.22-7.59]; P=0.78) were similar in HPR and non-HPR patients. During the maintenance phase, the proportion of HPR patients (n=186, 17.4%) decreased by 56%. At 1-year, there was no difference for the ischemic end point (5.9% versus 6.0%; adjusted hazard ratio, 0.79 [95% CI, 0.40-1.58]; P=0.51) and a nonsignificant higher rate of major bleedings (2.7% versus 1.0%, hazard ratio, 2.83 [95% CI, 0.96-8.41]; P=0.06) in HPR versus non-HPR patients. CONCLUSIONS: The proportion of HPR was halved after platelet function testing and treatment adjustment but without significant ischemic benefit at 1 year. HPR seems more as a modifiable risk marker than a risk factor of ischemic outcome. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT00827411.

Long-Term Evolution of Premature Coronary Artery Disease.

BACKGROUND: The long-term evolution of premature coronary artery disease (CAD) is unknown. OBJECTIVES: The objective of this study was to describe the evolution of coronary atherosclerosis in young patients and identify the risk factors of poor outcomes. METHODS: Participants age ≤45 years with acute or stable obstructive CAD were prospectively enrolled and followed. The primary endpoint was all-cause death, myocardial infarction (MI), refractory angina requiring coronary revascularization, and ischemic stroke. RESULTS: Eight hundred-eighty patients with premature CAD were included. They were age 40.1 ± 5.7 years, mainly men, smokers, with a family history of CAD or hypercholesterolemia. At baseline presentation, 91.2% underwent coronary revascularization, predominantly for acute MI (78.8%). Over a follow-up of 20 years, one-third (n = 264) of patients presented with a total of 399 ischemic events, and 36% had at least a second recurrent event. MI was the most frequent first recurrent event (n = 131 of 264), mostly related to new coronary lesions (17.3% vs. 7.8%; p = 0.01; hazard ratio [HR]:1.45; 95% confidence interval [CI]: 1.09 to 1.93 for new vs. initial culprit lesion). All-cause death (n = 55; 6.3%) occurred at 8.4 years (median time). Ethnic origin (sub-Saharan African vs. Caucasian, adjusted hazard ratio [adjHR]: 1.95; 95% CI: 1.13 to 3.35; p = 0.02), inflammatory disease (adjHR: 1.58; 95% CI: 1.05 to 2.36; p = 0.03), and persistent smoking (adjHR: 2.32; 95% CI: 1.63 to 3.28; p < 0.01) were the strongest correlates of a first recurrent event. When considering all recurrent events, the same factors and Asian ethnicity predicted poor outcome, but persistent smoking had the greatest impact on prognosis. CONCLUSIONS: Premature CAD is an aggressive disease despite the currently recommended prevention measures, with high rates of recurrent events and mortality. Ethnicity and concomitant inflammatory disease are associated with poor prognoses, along with insufficient control of risk factors.

Evaluation of neutrophil gelatinase-associated lipocalin and cystatin C as biomarkers of acute kidney injury after ST-segment elevation myocardial infarction treated by percutaneous coronary intervention.

BACKGROUND: Two biomarkers of early acute kidney injury-plasmatic neutrophil gelatinase-associated lipocalin (NGAL) and cystatin C-are not used in routine clinical practice in patients with ST-segment elevation myocardial infarction (STEMI) treated by percutaneous coronary intervention (PCI) because of a lack of supporting data. AIMS: To evaluate the predictive value of NGAL and cystatin C regarding the incidence of contrast-induced acute kidney injury (CI-AKI) and clinical outcomes after STEMI in patients treated by primary PCI. METHODS: Plasmatic NGAL and cystatin C were measured on admission, before any contrast exposure, in 701 unselected patients with STEMI. Associations between biomarker concentrations and incidence of CI-AKI (assessed at 48h), haemodialysis requirement at 1 year and all-cause mortality at 1 year were assessed by logistic regression analyses and receiver operating characteristic area under the curve analysis (c-statistic). Discrimination performance comparison was performed using the DeLong test. RESULTS: NGAL and cystatin C had mild discrimination regarding CI-AKI, with c-statistics of 0.60 (P=0.001) and 0.60 (P=0.002), respectively. Combining NGAL and cystatin C did not improve their discrimination (c-statistic 0.61; P=0.001). There was no significant difference in discrimination between NGAL, cystatin C and baseline creatinine (P=0.57). Regression analyses showed no independent association between NGAL and CI-AKI, haemodialysis or 1-year mortality. Similarly, cystatin C was not associated with these clinical outcomes. CONCLUSIONS: In this cohort of patients with STEMI treated by primary PCI, plasmatic NGAL and cystatin C did not provide additional value regarding CI-AKI prediction compared with known risk factors such as baseline creatinine.

Morphine and Ticagrelor Interaction in Primary Percutaneous Coronary Intervention in ST-Segment Elevation Myocardial Infarction: ATLANTIC-Morphine.

BACKGROUND: Morphine adversely impacts the action of oral adenosine diphosphate (ADP)-receptor blockers in ST-segment elevation myocardial infarction (STEMI) patients, and is possibly associated with differing patient characteristics. This retrospective analysis investigated whether interaction between morphine use and pre-percutaneous coronary intervention (pre-PCI) ST-segment elevation resolution in STEMI patients in the ATLANTIC study was associated with differences in patient characteristics and management. METHODS: ATLANTIC was an international, multicenter, randomized study of treatment in the acute ambulance/hospital setting where STEMI patients received ticagrelor 180 mg ± morphine. Patient characteristics, cardiovascular history, risk factors, management, and outcomes were recorded. RESULTS: Opioids (97.6% morphine) were used in 921 out of 1862 patients (49.5%). There were no significant differences in age, sex or cardiovascular history, but more morphine-treated patients had anterior myocardial infarction and left-main disease. Time from chest pain to electrocardiogram and ticagrelor loading was shorter with morphine (both p = 0.01) but not total ischemic time. Morphine-treated patients more frequently received glycoprotein IIb/IIIa inhibitors (p = 0.002), thromboaspiration and stent implantation (both p < 0.001). No significant difference between the two groups was found regarding pre-PCI ≥ 70% ST-segment elevation resolution, death, myocardial infarction, stroke, urgent revascularization and definitive acute stent thrombosis. More morphine-treated patients had an absence of pre-PCI Thrombolysis in Myocardial Infarction (TIMI) 3 flow (85.8% vs. 79.7%; p = 0.001) and more had TIMI major bleeding (1.1% vs. 0.1%; p = 0.02). CONCLUSIONS: Morphine-treatment was associated with increased GP IIb/IIIa inhibitor use, less pre-PCI TIMI 3 flow, and more bleeding. Judicious morphine use is advised with non-opioid analgesics preferred for non-severe acute pain. TRIAL REGISTRATION: clinicaltrials.gov identifier: NCT01347580.

Biomarkers of Thrombosis in ST-Segment Elevation Myocardial Infarction: A Substudy of the ATOLL Trial Comparing Enoxaparin Versus Unfractionated Heparin.

BACKGROUND: The aim was to compare the peri-procedural biomarkers of coagulation and platelet activation in patients randomly allocated to intravenous enoxaparin or unfractionated heparin (UFH) in the ATOLL randomized trial (NCT00718471). METHODS AND RESULTS: A total of 129 patients (n = 58 enoxaparin and n = 71 UFH) admitted for ST-segment elevation myocardial infarction (STEMI) treated by percutaneous coronary intervention (PCI) were included in this substudy of the ATOLL trial. Activated partial thromboplastin time ratio, anti-Xa activity, von Willebrand factor antigen, prothrombin fragment 1 + 2 (F1 + 2), thrombin-antithrombin complex (TAT), tissue factor pathway inhibitor and soluble CD40 ligand were measured at sheath insertion (T1) and at the end of the PCI (T2) and correlated with 1-month clinical outcomes. Target anticoagulation levels at T2 were more readily achieved in patients receiving enoxaparin compared to those receiving UFH (80.3 vs 18.2%, p < 0.0001). Increased levels of F1 + 2 and TAT measured at T2 were associated with the incidence of the composite ischemic endpoint (p = 0.04 and p = 0.03) and all-cause mortality (p < 0.0001 and p = 0.002). Release of F1 + 2 between T1 and T2 also predicted the composite ischemic endpoint (312 ± 513 vs 37 ± 292, p = 0.04) and net clinical outcome (185 ± 405 vs 3.2 ± 278, p = 0.03). CONCLUSIONS: During primary PCI, enoxaparin achieved therapeutic levels more frequently than UFH. Higher level of thrombin generation measured at the end of the PCI procedure was associated with more frequent ischemic events.

Impact of age on the effect of pre-hospital P2Y12 receptor inhibition in primary percutaneous coronary intervention for ST-segment elevation myocardial infarction: the ATLANTIC-Elderly analysis

AIMS: The aim of the study was to examine the main results of the ATLANTIC trial in patients with ST-elevation myocardial infarction (STEMI), randomised to pre- versus in-hospital ticagrelor, according to age. METHODS AND RESULTS: Patients were evaluated by age class (<75 vs. ≥75 years) for demographics, prior cardiovascular history, risk factors, management, and outcomes. Elderly patients (≥75 years; 304/1,862) were more likely to be women, diabetic, lean, with a prior history of myocardial infarction and CABG, and with comorbidities (p<0.01 for all). Elderly patients presented more frequently with acute heart failure and less frequently had thromboaspiration, a stent implanted (p<0.01) and an aggressive antithrombotic regimen. Elderly patients had lower rates of pre- and post-PCI ≥70% ST-segment elevation resolution (43.9% vs. 51.6%; p=0.035), of pre- and post-PCI TIMI 3 flow (17.1% vs. 27.5%, p=0.0002), and a higher rate of the composite of death/MI/stroke/urgent revascularisation (9.9% vs. 2.9%; OR 3.67, 95% CI [2.27; 5.93], p<0.0001) and mortality (8.5% vs. 1.5%; OR 6.45, 95% CI [2.75; 15.11], p<0.0001). There was a non-significant trend towards more frequent major bleedings among elderly patients (TIMI major 2.3% vs. 1.1%; OR 2.13, 95% CI [0.88; 5.18], p=0.095). There was no significant interaction between time of ticagrelor administration (pre-hospital versus in-lab) and class of age for all outcomes. CONCLUSIONS: Elderly patients, who represented one sixth of the patients randomised in the ATLANTIC trial, had less successful mechanical reperfusion and a sixfold increase in mortality at 30 days, probably due to comorbidities and possible undertreatment. The effect of early ticagrelor was consistent irrespective of age.

The efficacy of early versus delayed P2Y12 inhibition in percutaneous coronary intervention for ST-elevation myocardial infarction: a systematic review and meta-analysis.

AIMS: The aim of this meta-analysis was to compare the benefit of "early" vs. "delayed" P2Y12 inhibition in patients undergoing percutaneous coronary intervention (PCI) for ST-elevation myocardial infarction (STEMI). METHODS AND RESULTS: We conducted a meta-analysis including seven randomised controlled trials (RCTs) which compared early vs. delayed P2Y12inhibition in STEMI patients scheduled for PCI, providing data on major adverse cardiac events (MACE), all-cause death, and major bleeding. The primary endpoint was MACE. Secondary endpoints included stent thrombosis and the use of GP IIb/IIIa inhibitors (GPI). All endpoints were analysed at the shortest follow-up available. A total of 9,648 patients were included ("early"=4,792, "delayed"=4,856). "Early" P2Y12 inhibition was associated with a significant reduction in MACE rate (OR 0.73, 95% CI: 0.61-0.88, p=0.0008), myocardial infarction (OR 0.71, 95% CI: 0.57-0.90, p=0.004), bail-out GPI use (OR 0.87, 95% CI: 0.75-1.00, p=0.04) and improved coronary reperfusion before PCI (OR for Thrombolysis In Myocardial Infarction [TIMI] flow grade 2-3=1.12, 95% CI: 1.00-1.26, p=0.04). Major bleeding was not increased (OR 0.87, 95% CI: 0.62-1.21, p=0.41). CONCLUSIONS: A strategy of early effective P2Y12 inhibition in PCI of STEMI appears to improve coronary reperfusion before PCI, and reduce MACE, MI and bail-out GPI use without increase of major bleeding.

Contrast-induced acute kidney injury and mortality in ST elevation myocardial infarction treated with primary percutaneous coronary intervention.

OBJECTIVES: Contrast-induced acute kidney injury (CI-AKI) is a common and potentially severe complication in patients with ST elevation myocardial infarction (STEMI) treated with primary percutaneous coronary intervention (pPCI). There is no consensus on the best definition of CI-AKI to identify patients at risk of haemodialysis or death. The objective of this study was to assess the association of CI-AKI, using four definitions, on inhospital mortality, mortality or haemodialysis requirement over 1-year follow-up, in patients with STEMI treated with pPCI. METHODS: In this prospective, observational study, all patients with STEMI referred for pPCI were included. We identified independent variables associated with CI-AKI and mortality. RESULTS: We included 1114 consecutive patients with STEMI treated by pPCI. CI-AKI occurred in 18.3%, 12.2%, 15.6% and 10.5% of patients according to the CIN, Acute Kidney Injury Network (AKIN), Risk, Injury, Failure, Loss of kidney function, and End-stage kidney disease (RIFLE) Modification of Diet in Renal Disease (MDRD) and RIFLE Chronic Kidney Disease - Epidemiology Collaboration (CKD-EPI) definitions, respectively. The RIFLE (CKD-EPI) definition was the most discriminant definition to identify patients at higher risk of inhospital mortality (27.1% vs 4.0%; adjusted OR 2.7 (95% CI 1.4 to 5.1), p=0.003), 1-year mortality (27.4% vs 6.6%; adjusted OR 2.8 (95% CI 1.5 to 5.3), p=0.002) and haemodialysis requirement at 1-year follow-up (15.6% vs 2.7%; adjusted OR 6.7 (95% CI 3.3 to 13.6), p=0.001). Haemodynamic instability, cardiac arrest, preexisting renal failure, elderly age and a high contrast media volume were independently associated with 1-year mortality. Of interest, contrast-media volume was not correlated to increase of creatininaemia (r=0.06) or decrease in estimated glomerular filtration rate (r=0.05) after percutaneous coronary intervention in our population. CONCLUSIONS: CI-AKI is a frequent and serious complication of STEMI treated by pPCI. The RIFLE definition is the most accurate definition to identify patients with CI-AKI at high risk of mortality or haemodialysis.

Platelet reactivity in human immunodeficiency virus infected patients on dual antiplatelet therapy for an acute coronary syndrome: the EVERE2ST-HIV study.

AIM: To explore platelet reactivity on dual antiplatelet therapy (DAPT) of acute coronary syndrome (ACS) patients infected with HIV. METHODS AND RESULTS: Acute coronary syndrome patients infected with HIV (n = 80) were matched to ACS patients without HIV (n = 160) on age, sex, diabetes, and DAPT (aspirin 100%, clopidogrel 68%, prasugrel 31%, ticagrelor 1%). Platelet reactivity was evaluated after ACS (>30 days) by measuring residual platelet aggregation (RPA) to aspirin and to P2Y12 inhibitors with light transmission aggregometry (LTA), VerifyNow aspirin assay (ARU), and P2Y12 assay (PRU) and with the VASP platelet reactivity index (VASP-PRI). Proportion of patients with high residual platelet reactivity (HPR) was evaluated. HIV-infected ACS patients had higher levels of platelet reactivity in response to P2Y12 inhibitors (RPA: 23.8 ± 2.7% vs. 15.3 ± 1.3%; P = 0.001; PRU: 132 ± 10 vs. 107.4 ± 6.6; P = 0.04; and VASP-PRI: 45.2 ± 2.6% vs. 32.0 ± 2.0%; P < 0.001) and to aspirin (RPA: 3.6 ± 1.5% vs. 0.4 ± 0.1%; P = 0.004 and ARU: 442 ± 11 vs. 407 ± 5; P = 0.002) compared with non-HIV. HIV-infection was independently associated with increased platelet reactivity regardless of the test used (RPA: P = 0.005; PRU: P < 0.001 and VASP-PRI: P < 0.001) and a higher proportion of HPR (OR = 7.6; P < 0.001; OR = 2.06; P = 0.06; OR = 2.91; P = 0.004, respectively) in response to P2Y12 inhibitors. Similar results were found with aspirin. Protease inhibitors use was associated with increased platelet reactivity and higher rate of HPR. CONCLUSIONS: Acute coronary syndrome patients infected with HIV have increased levels of platelet reactivity and higher prevalence of HPR to P2Y12 inhibitors and aspirin than non-HIV patients. These results could provide potential explanations for the observed increase risk of recurrent ischemic events in the HIV-infected population.

P2Y12 receptor inhibition and effect of morphine in patients undergoing primary PCI for ST-segment elevation myocardial infarction. The PRIVATE-ATLANTIC study.

PRIVATE-ATLANTIC (P2Y12 Receptor Inhibition with VASP Testing using Elisa kit during the ATLANTIC study) is a pre-specified substudy of the randomised, double-blind ATLANTIC trial in patients with ST-segment elevation myocardial infarction, designed to help interpret the main trial results. The primary objective of ATLANTIC was to assess coronary reperfusion prior to percutaneous coronary intervention (PCI) with pre- vs in-hospital ticagrelor 180 mg loading dose (LD). PRIVATE-ATLANTIC assessed platelet inhibition in 37 patients by measurement of vasodilator-associated stimulated phosphoprotein (VASP) platelet reactivity index (PRI) and VerifyNow platelet reactivity units (PRU) before angiogram (T1), immediately after PCI (T2), 1 (T3), and 6 (T4) hours (h) after PCI, and before next study drug administration (T5). The median time difference between the two ticagrelor LD was 41 minutes. Platelet reactivity was unaffected at T1 when measured by VASP-PRI (89.8 vs 93.9 % for pre- and in-hospital ticagrelor, respectively; p = 0.18) or PRU (239 vs 241; p = 0.82). Numerical differences were apparent at T2 and maximal at T3. Morphine administration significantly delayed onset of platelet inhibition at T3 (VASP-PRI 78.2 vs 23.4 % without morphine; p = 0.0116) and T4 (33.1 vs 11.0 %; p = 0.0057). In conclusion, platelet inhibition in ATLANTIC was unaffected by pre-hospital ticagrelor administration at the time of initial angiogram due to the short transfer delay. The maximum difference in platelet inhibition was detected 1 h after PCI (T3). Morphine administration was associated with delayed onset of action of ticagrelor and appeared more important than timing of ticagrelor administration.

Effect of Pre-Hospital Ticagrelor During the First 24 h After Primary Percutaneous Coronary Intervention in Patients With ST-Segment Elevation Myocardial Infarction: The ATLANTIC-H²4 Analysis.

OBJECTIVES: The aim of this landmark exploratory analysis, ATLANTIC-H(24), was to evaluate the effects of pre-hospital ticagrelor during the first 24 h after primary percutaneous coronary intervention (PCI) in the ATLANTIC (Administration of Ticagrelor in the cath Lab or in the Ambulance for New ST elevation myocardial infarction to open the Coronary artery) study. BACKGROUND: The ATLANTIC trial in patients with ongoing ST-segment elevation myocardial infarction showed that pre-hospital ticagrelor was safe but did not improve pre-PCI coronary reperfusion compared with in-hospital ticagrelor. We hypothesized that the effect of pre-hospital ticagrelor may not have manifested until after PCI due to the rapid transfer time (31 min). METHODS: The ATLANTIC-H(24) analysis included 1,629 patients who underwent PCI, evaluating platelet reactivity, Thrombolysis In Myocardial Infarction flow grade 3, ≥ 70% ST-segment elevation resolution, and clinical endpoints over the first 24 h. RESULTS: Following PCI, largest between-group differences in platelet reactivity occurred at 1 to 6 h; coronary reperfusion rates numerically favored pre-hospital ticagrelor, and the degree of ST-segment elevation resolution was significantly greater in the pre-hospital group (median, 75.0% vs. 71.4%; p = 0.049). At 24 h, the composite ischemic endpoint was lower with pre-hospital ticagrelor (10.4% vs. 13.7%; p = 0.039), as were individual endpoints of definite stent thrombosis (p = 0.0078) and myocardial infarction (p = 0.031). All endpoints except death (1.1% vs. 0.2%; p = 0.048) favored pre-hospital ticagrelor, with no differences in bleeding events. CONCLUSIONS: The effects of pre-hospital ticagrelor became apparent after PCI, with numerical differences in platelet reactivity and immediate post-PCI reperfusion, associated with reductions in ischemic endpoints, over the first 24 h, whereas there was a small excess of mortality. (Administration of Ticagrelor in the cath Lab or in the Ambulance for New ST elevation myocardial infarction to open the Coronary artery [ATLANTIC, NCT01347580]).