Search

Hypercoagulability and thrombosis caused by coronavirus disease 2019 (COVID‐19) are related to the higher mortality rate. Because of limited data on the antiplatelet effect, we aimed to evaluate the impact of aspirin add‐on therapy on the outcome of the patients hospitalized due to severe COVID‐19. In this cohort study, patients with a confirmed diagnosis of severe COVID‐19 admitted to Imam Hossein Medical Center, Tehran, Iran from March 2019 to July 2020 were included. Demographics and related clinical data during their hospitalization were recorded. The mortality rate of the patients was considered as the primary outcome and its association with aspirin use was assessed. Nine hundred and ninety‐one patients were included, of that 336 patients (34%) received aspirin during their hospitalization and 655 ones (66%) did not. Comorbidities were more prevalent in the patients who were receiving aspirin. Results from the multivariate COX proportional model demonstrated a significant independent association between aspirin use and reduction in the risk of in‐hospital mortality (0.746 [0.560–0.994], p = 0.046). Aspirin use in hospitalized patients with COVID‐19 is associated with a significant decrease in mortality rate. Further prospective randomized controlled trials are needed to assess the efficacy and adverse effects of aspirin administration in this population., Highlights Aspirin administration decrease the rate of mortality in hospitalized patients with severe COVID‐19, independently.Although the crude analysis showed higher mortality rate in patients recieved aspirin, these patients have higher rate of underlying conditions.By performing stepwise COX regression analysis and adjusting the effect of comorbidities, aspirin administration was protective in hospitalized patients with severe COVID‐19.

BACKGROUND: Reduced levels of hemoglobin (Hb) represent an established marker of impaired outcomes and increased cardiovascular risk in patients with coronary artery disease, challenging the management of dual antiplatelet therapy (DAPT). However, while anemia has emerged as an independent predictor of suboptimal platelet inhibition in patients receiving clopidogrel, no study has so far evaluated the impact of Hb levels on high-on treatment platelet reactivity (HRPR) with ticagrelor and their prognostic consequences, that were the aim of the present study. METHODS: Patients on DAPT with ASA + Ticagrelor (90 mg/twice a day) after percutaneous coronary revascularization for ACS were scheduled for platelet function assessment 30-90 days post-discharge. Aggregation tests were performed by multiple electrode aggregometry. Suboptimal platelet inhibition (HRPR-high residual platelet reactivity was defined if above the lower limit of normality (417 AU*min). The primary study endpoint was defined as the occurrence of major cardiovascular events (a composite of cardiovascular death, recurrent acute coronary syndrome [MI], target vessel revascularization) at longest available follow-up. RESULTS: We included 397 patients that were divided according to tertiles values of Hb (< 12.7, 12-7-14.09, ≥14.1 g/dl). Patients with lower Hb were older and displayed a more severe cardiovascular risk profile. Mean levels of platelet reactivity were enhanced in patients with lower Hb after stimulation with TRAP peptide (TRAP test, p = .03) and ADP (p = .02). Elevated platelet reactivity (HRPR) on Ticagrelor was more frequent among patients with reduced Hb (16.4% vs. 12% vs. 5.4%, p = .005, adjusted OR [95%CI] = 1.71[0.996;3.01], p = .056). At a mean follow-up of 820.9 ± 553.4 days, 21.4% of the patients experienced the primary composite endpoint, with a higher rate of events in patients with lower Hb (27.6% vs. 22.6% vs. 13.5%, p = .006, adjusted HR [95%CI] = 1.51[1.12; 2.03], p = .006), mainly driven by a higher rate of recurrent ACS. After correction for baseline differences lower Hb tertiles but not HRPR emerged as independent predictor of MACE (adjusted HR [95%CI] = 0.98[0.50; 1.92], p = .95). CONCLUSIONS: In the present study, we demonstrated that among patients on DAPT with ASA and ticagrelor after PCI for ACS, lower Hb levels are independently associated with a higher rate of HRPR and an increased rate of major ischemic events, and especially for recurrent ACS, although with no impact on survival. Neutral prognostic effect of HRPR was observed across Hb tertiles.

Background Studies have shown that the concomitant use of a vitamin K antagonist (VKA) and an antiplatelet (APL) drug increased the bleeding risk and was less effective at preventing ischemic events. This study aimed to investigate the control status of international normalized ratio (INR) and the discontinuation rate of a VKA in patients taking VKA plus an APL drug compared with those taking a VKA alone. Methods Data were extracted from the KORean Atrial Fibrillation Investigation II registry, a multicenter noninterventional prospective observational study. Nonvalvular atrial fibrillation (NVAF) patients with CHADS 2 scores ≥ 1 who newly started (within 3 months) a VKA were enrolled and followed up for 1 year. Results A total of 866 NVAF patients (mean age, 67.7 years; 60.3% men) without a bleeding history were divided into the VKA+APL (n = 229) and VKA alone (n = 637) groups. During follow‐up, mean INR level was lower in the VKA+APL group than in the VKA alone group (1.7 ± 0.8 vs 1.9 ± 0.9, P = 0.0005). INR levels were poorly controlled in both groups (66.1% and 64.7%, respectively). Patients in the VKA+APL group more frequently discontinued VKA than patients in the VKA alone group (28.8% vs 24.2%, P = 0.045). Major causes of VKA discontinuation were uncontrolled INR level and patient dissatisfaction or concerns. Conclusions The conditions of NVAF patients were inadequately controlled with VKA with or without an APL. These findings suggest that other antithrombotic treatment options are warranted in NVAF patients to achieve INR control.

OBJECTIVES We investigated whether the dual antiplatelet therapy (DAPT) score (DS) predicts clinical outcome in an East-Asian population that received exclusively second generation drug-eluting stent (DES). BACKGROUNDS It is uncertain whether the DS could adequately risk stratify patients exclusively receiving second generation DES. METHODS From the Grand-DES registry, we evaluated patients who were treated with DAPT for at least 12 months and were event-free at 12 months after DES implantation. Patients were classified into two categories: high DS (≧2) (n = 3,157); and low DS (

Background Ticagrelor reduces ischemic risk but increases bleeding in patients with prior myocardial infarction. Identification of patients at lower bleeding risk is important in selecting patients who are likely to derive more favorable outcomes versus risk from this strategy. Methods and Results PEGASUS‐TIMI 54 (Prevention of Cardiovascular Events in Patients With Prior Heart Attack Using Ticagrelor Compared to Placebo on a Background of Aspirin—Thrombolysis in Myocardial Infarction 54) randomized 21 162 patients with prior myocardial infarction in a 1:1:1 fashion to ticagrelor 60 mg or 90 mg twice daily or placebo, with ticagrelor 60 mg approved for long‐term use. TIMI major or minor bleeding was the primary end point for this analysis. Causes of bleeding were categorized by site and etiology, and independent predictors were identified. At 3 years, ticagrelor 60 mg increased the rate of TIMI major or minor bleeding by 2.0% versus placebo (1.4% placebo versus 3.4% ticagrelor). The bleeding excess was driven primarily by spontaneous gastrointestinal bleeds. A history of spontaneous bleeding requiring hospitalization and the presence of anemia were independent predictors of bleeding but not of ischemic risk. Patients with at least 1 risk predictor had 3‐fold higher rates of bleeding with ticagrelor 60 mg versus those who had neither (absolute risk increase, 4.4% versus 1.5%; P =0.01). Patients with neither predictor had a more favorable benefit profile with ticagrelor 60 mg versus placebo including lower mortality (hazard ratio, 0.79; 95% CI, 0.65–0.96; P interaction = 0.03). Conclusions In patients with prior myocardial infarction, bleeding with ticagrelor 60 mg twice daily is predominantly spontaneous gastrointestinal. A history of spontaneous bleeding requiring hospitalization or the presence of anemia identifies patients at higher risk of bleeding, and the absence of either identifies patients likely to have a more favorable net benefit with ticagrelor. Registration URL https://www.clinicaltrials.gov/ . Unique identifier: NCT01225562.

In the search to rapidly identify effective therapies that will mitigate the morbidity and mortality of COVID-19, attention has been directed towards the repurposing of existing drugs. Candidates for repurposing include drugs that target COVID-19 pathobiology, including agents that alter angiotensin signalling. Recent data indicate that key findings in COVID-19 patients include thrombosis and endotheliitis. Activation of proteinase-activated receptor 1 (PAR1), in particular by the serine protease thrombin, is a critical element in platelet aggregation and coagulation. PAR1 activation also impacts on the actions of other cell types involved in COVID-19 pathobiology, including endothelial cells, fibroblasts and pulmonary alveolar epithelial cells. Vorapaxar is an approved inhibitor of PAR1, used for treatment of patients with myocardial infarction or peripheral arterial disease. We discuss evidence for a possible beneficial role for vorapaxar in the treatment of COVID-19 patients and other as-yet non-approved antagonists of PAR1 and proteinase-activated receptor 4 (PAR4). LINKED ARTICLES: This article is part of a themed issue on The Pharmacology of COVID-19. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v177.21/issuetoc.

Chronic kidney disease (CKD) is associated with worse clinical outcomes in patients with acute coronary syndrome. However, they are underrepresented in clinical trials. We aimed to investigate differences in prognosis of acute coronary syndrome patients with and without CKD, focusing on the use of novel P2Y12 receptor inhibitors. This multicenter registry involved patients with acute coronary syndrome from 3 tertiary institutions. After excluding anticoagulated patients and patients on antiplatelet monotherapy, 1280 patients remained. During 1 year of follow-up, we recorded all major adverse cardiovascular events (composite of cardiovascular death, nonfatal myocardial infarction, and nonfatal ischemic stroke), bleeds (Bleeding Academic Research Consortium classification) and deaths. Of 1280 patients, 325 (25.4%) had CKD; 55.5% of non-CKD patients and 22.7% of CKD patients were prescribed novel P2Y12 inhibitors. During follow-up, CKD patients under novel P2Y12 inhibitors showed a not statistically significant lower mortality and incidence of thrombotic events than clopidogrel-treated ones. In contrast, non-CKD patients taking novel P2Y12 inhibitors had better outcomes in terms of major adverse cardiovascular events (4.72 vs 9.41; P = .006), all-cause mortality (1.32 vs 4.24; P = .006), and severe bleeding events (Bleeding Academic Research Consortium 3-5) (0.94 vs 2.82; P = .030), without differences for any bleeding (8.11 vs 8.47; P = .849). Bleeding risk was not increased by using third-generation P2Y12 inhibitors in either group of patients. In conclusion, the use of third-generation P2Y12 inhibitors among non-CKD patients was associated with better outcomes. CKD patients receiving third-generation P2Y12 inhibitors treatment showed no statistically significant lower mortality and thrombotic events. Bleeding risk was not increased with the use of third-generation P2Y12 inhibitors in either group of patients.

Author(s): Di Tullio, Marco R; Qian, Min; Thompson, John LP; Labovitz, Arthur J; Mann, Douglas L; Sacco, Ralph L; Pullicino, Patrick M; Freudenberger, Ronald S; Teerlink, John R; Graham, Susan; Lip, Gregory YH; Levin, Bruce; Mohr, Jay P; Buchsbaum, Richard; Estol, Conrado J; Lok, Dirk J; Ponikowski, Piotr; Anker, Stefan D; Homma, Shunichi; WARCEF Investigators | Abstract: AimsLeft atrium (LA) dilation is associated with adverse cardiovascular (CV) outcomes. Blood stasis, thrombus formation and atrial fibrillation may occur, especially in heart failure (HF) patients. It is not known whether preventive antithrombotic treatment may decrease the incidence of CV events in HF patients with LA enlargement. We investigated the relationship between LA enlargement and CV outcomes in HF patients and the effect of different antithrombotic treatments.Methods and resultsTwo-dimensional echocardiography with LA volume index (LAVi) measurement was performed in 1148 patients with systolic HF from the Warfarin versus Aspirin in Reduced Ejection Fraction (WARCEF) trial. Patients were randomized to warfarin or aspirin and followed for 3.4 ± 1.7 years. While the primary aim of the trial was a composite of ischaemic stroke, death, and intracerebral haemorrhage, the present report focuses on the individual CV events, whose incidence was compared across different LAVi and treatment subgroups. After adjustment for demographics and clinical covariates, moderate or severe LA enlargement was significantly associated with total death (hazard ratio 1.6 and 2.7, respectively), CV death (HR 1.7 and 3.3), and HF hospitalization (HR 2.3 and 2.6) but not myocardial infarction (HR 1.0 and 1.4) or ischaemic stroke (1.1 and 1.5). The increased risk was observed in both patients treated with warfarin or aspirin. In warfarin-treated patients, a time in therapeutic range g60% was associated with lower event rates, and an interaction between LAVi and time in therapeutic range was observed for death (P = 0.034).ConclusionsIn patients with systolic HF, moderate or severe LA enlargement is associated with death and HF hospitalization despite treatment with antithrombotic medications. The possibility that achieving a more consistent therapeutic level of anticoagulation may decrease the risk of death requires further investigation.

We studied the influence of cardiovascular (CV) risk factors, previous CV events, and cotreatments with preventive medicines, on residual platelet thromboxane (TX)B2 production in 182 patients chronically treated with enteric coated (EC)-aspirin (100 mg/day). The response to aspirin was also verified by assessing arachidonic acid-induced platelet aggregation and urinary 11-dehydro-TXB2 levels. Residual serum TXB2 levels exceeded the upper limit value for an adequate aspirin response in 14% of individuals. This phenomenon was detected at 12 hours after dosing with aspirin. The coadministration of statins (mostly atorvastatin) was an independent predictor of residual serum TXB2 levels, and the percentage of patients with enhanced values was significantly lower in statin users vs. nonusers. We provide evidence in vitro that atorvastatin reduced residual TXB2 generation by increasing the extent of acetylation of platelet COX-1 by aspirin. In conclusion, the coadministration of statins may counter the mechanisms associated with reduced bioavailability of aspirin detected in some individuals with CV disease.

Aim The effects of sevoflurane on microglia/macrophages, promoting or suppressing their activation, remains controversy. We aimed to determine whether sevoflurane preconditioning can protect brain via changing microglia/macrophage dynamics and phagocytosis profile after ischemia. Methods The impact of sevoflurane preconditioning was evaluated on microglia/macrophage migration, phagocytosis and proliferation altogether from day 1 to day 7 after transient middle cerebral arterial occlusion (tMCAO) in rats. Results Sevoflurane preconditioning was identified to accelerate microglia/macrophage migrating to and invasion in the ischemic core from day 1 to day 5 after damage. Significant accumulation of amoeboid and phagocytic microglia/macrophages was observed in sevoflurane group from day 3 to day 5 after ischemia injury. In addition, sevoflurane pretreatment also promoted the proliferation of microglia/macrophage (Iba1+ /Ki67+ ) dramatically in ischemic core on day 3 postinsult. Conclusions Our current study has identified the impact of sevoflurane preconditioning on microglia/macrophage dynamics, including its migration, phagocytosis, and proliferation at early stage after brain ischemia and reperfusion. Sevoflurane might enhance microglia/macrophage activation and promote brain repair. These results could help to approach more relevant microglia/macrophage cell-based strategy for human stroke therapy.

Objectives We aimed to assess the prognostic ability of the ST score, DAPT score, and PARIS score in a Chinese population. Background Recently, several risk scores predicting the long-term risk of coronary thrombotic events [CTE, defined as the composite of definite or probable stent thrombosis (ST) and myocardial infarction] and bleeding have been developed and initially validated in Western populations. Methods A total of 6,088 consecutive patients with acute coronary syndrome (mean age 58.3 ± 10.4; women 23.1%) treated with drug-eluting stents in 2013 at our single institution were enrolled. We calculated risk scores and evaluated their performance for predicting definite or probable ST, CTE and major bleeding (MB, defined as the occurrence of a Bleeding Academic Research Consortium type 3 or 5 bleed). The prognostic value of risk scores was assessed by receiver-operating characteristic curves. Results The ST score, DAPT score, and PARIS score all showed unsatisfactory discrimination to predict 2-year or 1- to 2-year ST and CTE (c-statistic = 0.51-0.59). With respect to bleeding outcomes, the PARIS score showed unsatisfactory discrimination in predicting 2-year MB (c-statistic = 0.56); the DAPT score performed slightly better than the PARIS score in predicting occurrence of later MB events between 1 and 2 years, whereas its discriminative capacity was only modest (c-statistic = 0.71). Conclusions The current three risk scores, derived and initially validated in Western populations, may not be applicable to the Chinese population, although DAPT score was determined to be a modestly accurate quantitative tool for prediction of later MB.

A 56-year-old woman was admitted to our hospital because of amaurosis fugax. The carotid angiogram showed irregularly stenotic lesions of the left and right internal carotid arteries (ICAs), suggestive of dissection. Follow-up evaluation was performed by transoral carotid ultrasonography (TOCU) with contrast enhancement (CE), which yielded better vessel lumen and intramural hematoma visualization than color Doppler imaging. CE-TOCU is useful for evaluating ICA dissections that extends to the high cervical portion.

Objectives: To understand the optimal timing of adenosine diphosphate (ADP) receptor inhibitor pretreatment prior to percutaneous coronary intervention (PCI) among acute myocardial infarction (MI) patients. Background: The role of ADP receptor inhibitor pretreatment in this population is unclear. Methods: A total of 9,251 ADP receptor inhibitor-naive MI patients undergoing PCI at 229 TRANSLATE-ACS sites were evaluated. Adjusted risks of in-hospital major adverse cardiovascular events (MACE) and major bleeding were compared among patients with and without pretreatment using inverse probability-weighted propensity adjustment. Results: Of 9,251 patients treated with either prasugrel or clopidogrel during the index MI hospitalization, 4,056 (44%) received pretreatment (ST-segment elevation MI [STEMI] 54.9%, non-STEMI 45.1%); pretreatment was used more commonly among those receiving clopidogrel than prasugrel (52% vs. 20%, P < 0.0001). MACE risks were not significantly different between patients with and without pretreatment (clopidogrel 2.1% vs. 2.2%, adjusted hazard ratio [HR] 1.00, 95% confidence interval [CI] 0.70–1.43; prasugrel 2.1% vs. 2.3%, adjusted odds ratio [OR] 0.82, 95% CI 0.42–1.60). No differences in major bleeding were observed among those receiving versus not receiving pretreatment (clopidogrel 3.1% vs. 3.5%, adjusted HR 0.94, 95% CI 0.65–1.36; prasugrel 2.5% vs. 2.7%, adjusted OR 0.93, 95% CI 0.42–2.02); results were similar when stratified by MI type. Conclusions: ADP receptor inhibitor pretreatment (44%) is commonly used among acute MI patients undergoing PCI in contemporary practice, but no significant differences were found in in-hospital MACE and/or bleeding risks between patients receiving versus not receiving pretreatment, regardless of ADP receptor inhibitor type.

Background Early stent thrombosis (ST) remains an important complication of primary percutaneous intervention (PCI). To date, our information on angiographic and clinical predictors of early ST in ST-segment elevation myocardial infarction (STEMI) patients treated with primary PCI is limited. Methods We tried to evaluate the incidence, predictors, and outcomes of early ST in real-world patients treated with primary PCI. We identified all the patients presenting with STEMI between June 2004 and January 2011 who underwent primary PCI as the primary mode of revascularization. Diagnosis of ST was made as per the standard definition proposed by the Academic Research Consortium. Results The incidence of early ST was 1% among 2,303 patients treated with primary PCI. Definite and probable early ST occurred in 22 and 2 patients, respectively. Patients with early ST had higher in-hospital (P = 0.03) and 30-day mortality (P = 0.048). The rate of cardiogenic shock (P = 0.0006) and cerebrovascular accident (P = 0.0004) was also greater in the early ST group. Smaller stent diameter and lower use of intracoronary glycoprotein IIb/IIIa inhibitor were associated with higher rate of early ST. There was a trend of higher bivalirudin use in ST group, which did not reach significance (P = 0.07) On IVUS imaging, stent malapposition and uncovered plaque area were noted in 6 out of 11 cases. Conclusion The incidence of early ST in primary PCI cohort is low. However, it is still associated with higher mortality and morbidity. Small stent diameter and disuse of intracoronary glycoprotein IIb/IIIa inhibitor may be associated with early ST.

Objectives To explore the role of ticagrelor versus clopidogrel in coronary blood flow normalization immediately after chronic coronary total occlusion (CTO) recanalization. Background Coronary vascular function of a CTO immediately after recanalization is demonstrated to be poor. Methods The TIGER BVS is a prospective, double-randomized, open-label, two parallel-group controlled clinical trial to evaluate efficacy of ticagrelor versus clopidogrel in improving vascular function of coronary segment distal to CTO immediately after CTO recanalization. A total of 50 patients who receive CTO PCI will be randomized 1:1 to receive ticagrelor versus clopidogrel at least 3 days before the procedure. Immediately after CTO recanalization with Absorb BVS implantation, a specific study of vascular function under adenosine infusion will be performed. Patients will be therefore randomized 1:1 to receive angiographic follow-up with vascular function and optical coherence tomography analyses at 1- or 3-year follow-up. This study is registered on ClinicalTrials.gov with number NCT02211066. Conclusions The TIGER BVS trial will provide the first randomized comparison between ticagrelor versus clopidogrel in recovering vascular function in CTO patients. It will also provide important data on vascular restoration therapy of Absorb BVS in this scenario.

A novel family of potent and broad-spectrum antiplatelet agents has been discovered by exploration of a library of 3-oxopyridazin-5-yl-chalcone hybrids. The pharmacological evaluation of the collec ...

Objective Anticoagulant and antiplatelet (ACAP) drugs are associated with increased mortality in trauma patients, therefore medication history on admission is important. Whether these medications are recorded on trauma admission has not been investigated, nor if absence of a medication history is associated with worse patient outcomes. Methods We conducted a retrospective database review combining demographic and outcome data from the St George Hospital (Sydney) trauma registry with admission medication history in the electronic record. To contrast medications with a known increased risk (ACAP) to patients with unknown risk, patients were divided into three groups: those on ACAPs, no-ACAP if medication history was present and no-ACAP documented, or no-Hx if no medication history recorded. Inclusion criteria were aged >16 and Injury Severity Score (ISS) >12. Admission demographic data and outcome data were compared between all three groups. Results Of 533 consecutive patients, 21% comprised the no-Hx group, while 22% were on an ACAP and 57% not on an ACAP. No-Hx patients had more severe head injuries and a younger median age compared to ACAP patients (42 vs 82 years old, P

Precision medicine entails tailoring treatment based on patients' unique characteristics. As drug therapy constitutes the cornerstone of treatment for most chronic diseases, pharmacogenomics (PGx), the study of genetic variation influencing individual response to drugs, is an important component of precision medicine. Over the past decade investigations have identified genes and single-nucleotide polymorphisms (SNPs) and quantified their effect on drug response. Parallel development of point-of-care (POC) genotyping platforms has enabled the interrogation of the genes/SNPs within a timeline conducive to the provision of care. Despite these advances, the pace of integration of genotype-guided drug therapy (GGTx) into practice has faced significant challenges. These include difficulty in identifying SNPs with sufficiently robust evidence to guide clinical decision making, lack of clinician training on how to order and use genotype data, lack of clinical decision support (CDS) to guide treatment, and limited reimbursement. The University of Alabama at Birmingham's (UAB) efforts in precision medicine were initiated to address these challenges and improve the health of the racially diverse patients we treat.

Background Patients with acute myocardial infarction (AMI) and nonobstructive coronary artery disease (nonobCAD) may be perceived to be at lower risk for cardiac events, relative to those with obstructive CAD (obCAD), and thus less likely to receive optimal preventive medications in the year following AMI. Hypothesis We aimed to determine if AMI patients with nonobCAD, compared to obCAD, received lower rates of prevention medications in the year following AMI. Methods We compared optimal prevention medication use at hospital discharge, 1, 6, and 12 months after hospitalization. Optimal medication use was defined as the receipt of all prevention medications for which that patient was eligible (eg, aspirin, clopidogrel, statins, β-blockers, and angiotensin-converting enzyme inhibitors/angiotensin receptor blockers). We used multivariable logistic regression analyses to determine the association between nonobCAD to medication use and adjusted for potential confounders. Results Three thousand six hundred thirty AMI patients were studied, of whom 200 (5.2%) had nonobCAD. Fewer nonobCAD patients received optimal medication use compared to obCAD patients at discharge (31% vs 65%, P < 0.001), driven primarily by lower rates of clopidogrel use (40.5% vs 83.3%, P < 0.001). After adjustment for percutaneous coronary intervention (PCI), differences in medication use were similar at discharge and 1 year after hospitalization. Stratified analyses by receipt of PCI suggested patients confined to medical management had less optimal medication use, regardless of their CAD burden. Conclusions Lower rates of unadjusted optimal medication use were seen in nonobCAD patients, driven by low clopidogrel use among medically managed patients, suggesting improvement efforts should focus on these patients.

Objectives We compared the complications and diagnostic adequacy of ultrasound (US)-guided core needle biopsy (CNB) for head and neck mass lesions between patients who did and did not receive antiplatelet/anticoagulation therapy. Methods This study was designed as a prospective case study including 146 consecutive patients who underwent US-guided CNB for head and neck mass lesions. Of these, 32 patients were undergoing antiplatelet/anticoagulation therapy involving aspirin, clopidogrel, cilostazol, and warfarin. Results None of the patients had clinical bleeding/hematoma in either group. Subclinical bleeding/hematoma recognized only by a US examination was not significantly different between the groups (P = .229). No other complications were noticed. The rate of unsatisfactory sampling was also not different between the groups (P > .999). Furthermore, when patients receiving aspirin (n = 18) were reclassified into the no–antiplatelet/anticoagulation therapy group, there was still no significant difference in the incidences of complications compared with the patients receiving clopidogrel, cilostazol, or warfarin (n = 14). Conclusions Our study suggests that US-guided CNB is safe and provides good diagnostic results without necessitating the discontinuation of antiplatelet/anticoagulation therapy in patients with head and neck mass lesions. However, as this was a preliminary study, the cohort was relatively small. Larger studies are needed to confirm our findings.

Aim Direct-acting oral anticoagulants (DOACs) have become available for the prevention of stroke in patients with atrial fibrillation (AF). Conflicting results have been published on the risk of acute myocardial infarction (AMI) with the use of DOACs in comparison with vitamin K antagonists (VKAs). The objective of the present study was to evaluate the risk of AMI in patients with AF who are exposed to either VKAs, DOACs or low-dose (< 325 mg) aspirin. Methods We conducted a population-based cohort study using data from the Clinical Practice Research Datalink (2008–2014). The study population (n = 30 146) consisted of all patients ≥18 years with a diagnosis of AF who were new users of VKAs, DOACs (rivaroxaban and dabigatran) or aspirin. Cox proportional hazards models were used to estimate the hazard ratio (HR) of AMI for users of DOACs or aspirin vs. VKA. Adjustments were made for age, gender, lifestyle, risk factors, comorbidity and other drugs. Results The risk of AMI was doubled when we compared current use of DOACs with current use of VKAs [adjusted HR 2.11; 95% confidence interval (CI) 1.08, 4.12] and for current users of aspirin vs. current VKA users (adjusted HR 1.91; 95% CI 1.45, 2.51). Conclusions There is a twofold increase in the risk of AMI for users of DOACs, in comparison with VKAs, in AF therapy. In addition, the results suggested that in patients with AF, the incidence of AMI is higher during aspirin monotherapy than during the use of VKAs.

Drug-eluting stents (DES) reduce risk of in-stent restenosis after percutaneous coronary intervention (PCI) but require dual antiplatelet therapy (DAPT) for a longer term than bare-metal stents (BMS). Few studies have examined clinical predictors of DES vs BMS, and variability in provider selection between DES and BMS in clinical practice has not been well described. These insights can inform our understanding of current practice and may identify opportunities to improve decision-making stent selection decinsion-making. In a multicenter registry, 3295 consecutive patients underwent PCI by 158 interventional cardiologists across 10 US sites. Eighty percent of patients with treated with DES. Using hierarchical regression, diabetes mellitus, multivessel disease, health insurance, and white race were independently associated with greater DES use, whereas increasing age, history of hypertension, anticipated surgery, use of warfarin, lower hemoglobin, prior history of bleeding, and treatment of right coronary and left circumflex artery lesions as compared with PCI of left anterior descending artery were associated with lower likelihood of receiving DES. Adjusted rates of DES use across providers varied from 52.3% to 94.6%, and adjusted median odds ratio for DES selection was 1.69. DES selection appeared to reflect physicians’ attempts to balance benefits of DES against risks of prolonged DAPT. Nevertheless, marked residual variability in DES selection across providers persisted after adjusting for predictors of restenosis, bleeding, and other factors. Further studies are needed to better understand drivers of this variability and identify the impact of patient and provider preferences on stent selection at the time of PCI.

Background The optimal duration of dual antiplatelet therapy (DAPT) after drug-eluting stent (DES) implantation remains undetermined, especially for those at high risk of cardiac events postprocedure. Objectives This study was aimed to investigate the impact of 6 versus 12 months of DAPT after DES implantation based on risk stratification with the residual SYNTAX score (rSS). Methods A total of 2737 patients in the I-LOVE-IT 2 trial were grouped according to rSS status (low rSS [rSS = 0, n = 1474] versus high rSS [rSS > 0, n = 1263]) and DAPT duration (6 months vs. 12 months). The primary endpoint was 12-month target lesion failure (TLF), and the major secondary endpoints were 12-month net adverse clinical events (NACE) and major bleeding. Results Incidences of TLF (5.2 vs. 7.4%, P = 0.01) and NACE (9.2 vs. 13.4%, P

BACKGROUND Degenerated surgical mitral valve repairs or surgical prostheses are currently being treated with transcatheter mitral valve replacement (TMVR). We report the procedural and mid-term assessment of thirteen cases. METHODS From 12/2013 to 12/2015, 13 consecutive patients with degenerated mitral valve repair or valve replacement were treated. Patients were assessed for mitral valve academic valve consortium (MVARC) defined outcomes. RESULTS Immediate procedural MVARC defined technical success was 92%. At 30 days MVARC device and procedure success were 61% and 84%, respectively. Mean follow-up was 150 days [IQR 40-123 days]. There were 2 late major adverse outcomes, a noncardiac related death (628 days) and a stroke (382 days). The mean mitral gradient decreased from 9.5 ± 3.4 to 5.5 ± 2.6 mm Hg (P

Background Patients presenting with acute coronary syndrome (ACS) are at increased risk of complications after percutaneous coronary intervention with stent placement compared to patients with stable angina (SA) treated in an elective setting. The novel pro-healing COMBO stent is a bio-engineered drug eluting stent designed to promote vessel healing. Therefore, the stent may reduce this difference in clinical outcomes between elective and ACS-patients and prevent late stent thrombosis. Methods and Results The European, prospective, multicenter, 1000 all-comers patient REMEDEE registry evaluates clinical outcomes after COMBO stent placement in ACS- and elective patients. The primary endpoint at 12 months is target lesion failure (TLF), a composite of cardiac death, target-vessel myocardial infarction and target lesion revascularization. A total of 49.9% (n = 498) of patients presented with acute coronary syndrome. TLF was 7.1% in ACS patients, definite and probable stent thrombosis was observed in 0.5% of ACS patients and in all within 9 days post stenting. We found no significant difference in TLF between ACS and non-ACS patients and a low overall rate of TLF. Conclusions The COMBO stent is a safe and efficient device for patients presenting with ACS. Low ST rate and only early stent thrombosis were observed. © 2017 Wiley Periodicals, Inc.

Purpose To describe the characteristics of new users of cilostazol in Europe with the aim to support the evaluation of its benefit/risk as used in regular clinical practice before the implementation of labeling changes recommended by the European Medicines Agency. Methods New users of cilostazol were identified in populations enrolled in five European health automated databases in the UK (The Health Improvement Network [THIN]), Spain (EpiChron cohort and Information System for the Improvement of Research in Primary Care [SIDIAP]), Sweden (National Registers), and Germany (German Pharmacoepidemiological Research Database [GePaRD]) between 2002 and 2012. New users were characterized according to the prevalence of cardiovascular disease and other comorbidities, concurrent use of interacting medications, new contraindications, duration of use, and potential off-label prescribing. Results We identified 22 593 new users of cilostazol. The median age was between 68.0 (THIN) and 73.7 (Sweden) years. More than 78% of users had concomitant cardiovascular disease, and between 78.8% (GePaRD) and 91.6% (THIN) were treated with interacting medications. Prevalence of new cardiovascular contraindications ranged from 1.5% (THIN) to 11.6% (GePaRD), and concurrent use of two or more antiplatelet drugs ranged from 6.3% (SIDIAP) to 13.5% (EpiChron cohort). Between 39.4% (Sweden) and 52.9% (THIN) of users discontinued cilostazol in the first 3 months. Between 41.0% (SIDIAP) and 93.4% (THIN) were considered to have received cilostazol according to the European Medicines Agency labeling. Conclusions In this collaborative European study, most cilostazol users were elderly patients with a high prevalence of cardiovascular diseases and other comorbidity and concurrent use of interacting drugs, indicating that this is a vulnerable population at high risk of complications, especially cardiovascular events. © 2017 The Authors. Pharmacoepidemiology and Drug Safety Published by John Wiley & Sons Ltd.

We recently demonstrated that ischemic tolerance was dependent on astrocytes, for which HIF-1α had an essential role. The mild ischemia (preconditioning; PC) increased HIF-1α in a biphasic pattern, that is, a quick and transient increase in neurons, followed by a slow and sustained increase in astrocytes. However, mechanisms underlying such temporal difference in HIF-1α increase remain totally unknown. Here, we show that unlike a hypoxia-dependent mechanism in neurons, astrocytes increase HIF-1α via a novel hypoxia-independent but P2X7-dependent mechanism. Using a middle cerebral artery occlusion (MCAO) model of mice, we found that the PC (a 15-min MCAO period)-evoked increase in HIF-1α in neurons was quick and transient (from 1 to 3 days after PC), but that in astrocytes was slow-onset and long-lasting (from 3 days to at least 2 weeks after PC). The neuronal HIF-1α increase was dependent on inhibition of PHD2, an oxygen-dependent HIF-1α degrading enzyme, whereas astrocytic one was independent of PHD2. Astrocytes even do not possess this enzyme. Instead, they produced a sustained increase in P2X7 receptors, activation of which resulted in HIF-1α increase. The hypoxia-independent but P2X7-receptor-dependent mechanism could allow astrocytes to cause long-lasting HIF-1α expression, thereby leading to induction of ischemic tolerance efficiently. GLIA 2017;65:523-530.

The clinical impact of concurrently administered morphine and P2Y12 inhibitors in primary percutaneous coronary intervention (PCI) is not well understood. Large, randomized clinical trials are required to assess clinical outcomes with concurrent morphine and P2Y12 inhibitor use in ST-segment elevation myocardial infarction patients undergoing PCI. Based on the currently available pharmacologic data, cautious use of morphine in primary PCI would seem prudent.

Background The continuation of preventive drugs among older patients with advanced cancer has come under scrutiny because these drugs are unlikely to achieve their clinical benefit during the patients' remaining lifespan. Methods A nationwide cohort study of older adults (those aged ≥65 years) with solid tumors who died between 2007 and 2013 was performed in Sweden, using routinely collected data with record linkage. The authors calculated the monthly use and cost of preventive drugs throughout the last year before the patients' death. Results Among 151,201 older persons who died with cancer (mean age, 81.3 years [standard deviation, 8.1 years]), the average number of drugs increased from 6.9 to 10.1 over the course of the last year before death. Preventive drugs frequently were continued until the final month of life, including antihypertensives, platelet aggregation inhibitors, anticoagulants, statins, and oral antidiabetics. Median drug costs amounted to $1482 (interquartile range [IQR], $700-$2896]) per person, including $213 (IQR, $77-$490) for preventive therapies. Compared with older adults who died with lung cancer (median drug cost, $205; IQR, $61-$523), costs for preventive drugs were higher among older adults who died with pancreatic cancer (adjusted median difference, $13; 95% confidence interval, $5-$22) or gynecological cancers (adjusted median difference, $27; 95% confidence interval, $18-$36). There was no decrease noted with regard to the cost of preventive drugs throughout the last year of life. Conclusions Preventive drugs commonly are prescribed during the last year of life among older adults with cancer, and often are continued until the final weeks before death. Adequate deprescribing strategies are warranted to reduce the burden of drugs with limited clinical benefit near the end of life.

Optically pure 2-chloromandelic acid (ClMA) is a very important chiral drug intermediate for synthesis of (S)-clopidogrel, belonging to the platelet aggregation inhibitor. Enantioselective resolution of (R,S)-2-chloromandelic acid was carried out in organic solvent through irreversible transesterification catalyzed by lipase AK with vinyl acetate acting as the acyl donor. Effects of various conditions on enantioselectivity and activity of lipase were investigated, including organic solvents, temperature, water content, substrate ratio, enzyme loading, and reaction time. Based on homogeneous reaction and Ping-Pong bi-bi mechanism, a quantitative model was constructed to simulate and optimize the reaction process. Under the optimal conditions, excellent results were obtained with high conversion of (R)-2-ClMA (c R , ≥98.85%) and large enantiomeric excess of substrate (ee s , ≥98.15%). There is a good agreement between predicted values and experiment data, which indicates that the established method is a powerful tool for optimization of the enantioselective transesterification process for enantiomers separation.

Background Several clinical and laboratory variables have an impact on the prognosis of STEMI patients undergoing PPCI; however, little is known about the role of ongoing DAPT at the time of the event and the smoking status as prognostic factors affecting the outcome of these patients. Methods and Results Seven-hundred and thirteen consecutive STEMI patients undergoing PPCI, admitted to the S. Anna and S. Sebastiano Hospital (Caserta, Italy) and to the OLV Clinic (Aalst, Belgium), between March 2009 and December 2011, were retrospectively enrolled. Rescue PCI was the only exclusion criterion. Primary end-point was the combination of death for all causes, re-infarction, stroke, and target lesion revascularization (TLR). Patients already on DAPT at admission (26.4%) showed a significant increase in the event rate at univariate analysis (HR 2.34, CI 1.62–3.75, P 1 were more frequently present than in patients not on DAPT), Cox regression analysis confirmed that both DAPT (HR 1.74, 95%CI 1.20–2.53, P

Purpose The aim of this study was to assess effectiveness and safety of antithrombotics for stroke prevention in non-valvular atrial fibrillation in real-use conditions. Methods We used a population-based retrospective cohort study. Information emerges from SIDIAP, a database containing anonymized information from electronic health records from 274 primary healthcare centres of the Catalan Health Institute, Catalonia (Spain), with a reference population of 5 835 000 people. Population includes all adults with a new diagnosis of non-valvular atrial fibrillation registered in SIDIAP from 2007 to 2012. The main outcome of antithrombotics' effectiveness was stroke. The main outcomes of safety were cerebral and gastrointestinal haemorrhages. We also estimated all-cause mortality. We used multivariable Cox proportional hazard models to examine association between antithrombotic treatment and main outcomes. Results We included 22 205 subjects with non-valvular atrial fibrillation; 40.8% initiated on vitamin K antagonists (VKA), 33.4% on antiplatelets and 25.8% untreated. We found stroke-risk reduction with VKA, hazard ratio (HR) 0.72 (95% confidence interval (CI), 0.58–0.91), also seen in patients with CHADS2 ≥ 2, HR 0.65 (95%CI, 0.49–0.86), and CHA2DS2-VASc ≥ 2, HR 0.66 (95%CI, 0.52–0.84). We observed a higher risk of digestive bleeding with antiplatelets, HR 1.32 (95%CI, 1.01–1.73). Both VKA and antiplatelets were associated with reduction of all-cause mortality risk; HR 0.55 (95%CI, 0.49–0.62) and HR 0.89 (95%CI, 0.80–0.97), respectively. Conclusions This study found a stroke-risk reduction associated with VKA and an increased risk of gastrointestinal bleeding associated with platelet-aggregation inhibitors in comparison with untreated patients. Both antithrombotic groups showed a reduction in all-cause mortality. Copyright © 2016 John Wiley & Sons, Ltd.

SummaryObjectives To investigate safety and efficacy of policosanol in patients with high on-treatment platelet reactivity after drug-eluting stent implantation. Background Certain number of patients has high residual platelet reactivity on clopidogrel after coronary intervention, and their risk of thrombotic events is high. Method In this prospective, randomized trial conducted in four Chinese sites, 350 patients with high on-treatment platelet reactivity (HPR, defined as platelet aggregation >65%) were randomized by the ratio of 1:3:3 to: group A, clopidogrel 75 mg/d for 1 year (n=50); group B, clopidogrel 150 mg/d for 30 days followed by 75 mg/d until 1 year (n=150); or group C, policosanol 40 mg/d for 6 month and clopidogrel 75 mg/d for 1 year (n=150). All of them were treated with aspirin. The primary endpoint was the reversion rate of HPR at 1 month (reversion was defined as platelet aggregation

SummaryAims To compare three glycoprotein IIb/IIIa receptor antagonists (GPIs) in terms of platelet inhibition and major adverse cardiac events (MACEs), and assess the rate of bleeding and MACEs between GPIs and coadministered P2Y12 agents. Methods Eighty-three acute coronary syndrome (ACS) patients undergoing percutaneous coronary intervention (PCI) with planned GPI use were randomized to receive high-dose bolus tirofiban, double-bolus eptifibatide, or abciximab followed by a 12-hour infusion. Glycoprotein IIb/IIIa platelet receptor inhibition was measured at baseline and at 10 minutes, 1 hour, and 24 hours postbolus dose. Major adverse cardiac events and bleeding complications at 30 days were documented. The incidence of MACEs and bleeding in patients receiving ticagrelor or prasugrel were compared to those given clopidogrel. Results There were no statistically significant differences in platelet inhibition between GPIs at 10 minutes (P=.085) and 1 hour (P=.337). At 24 hours, abciximab achieved statistically significantly higher median [interquartile range] platelet inhibition (75 [65–88]%) compared to tirofiban (28 [3–56]%; P

Purpose The purpose of this study was to compare the predictive accuracy of different methods suggested for approximation of drug prescription durations in claims data. Methods We expanded a well-established modeling and simulation framework to compare approximated drug prescription durations with ‘true’ (i.e., simulated) durations. Real claims data of persons aged ≥65 years insured by the German nationwide ‘Statutory Health Insurance Fund’ AOK between 2010 and 2012 provided empiric input parameters that were completed with missing information on actual dosing patterns from an observational cohort. The distinct approximation methods were based on crude measures (one tablet a day), population-averaged measures (defined daily doses), or individually-derived measures (longitudinal coverage approximation of the applied dose, COV). As a proof-of-principle, we assessed the methods' performance to predict the well-characterized bleeding risks of anticoagulant, antiplatelet, and/or non-steroidal anti-inflammatory drugs. Results When applied to modeling and simulation data sets, the closest, least biased, and thus most accurate approximation was observed using the COV approximation. In a real-data example, rather similar results to an external reference were obtained for all methods. However, some of the differences between methods were meaningful, and the most reasonable and consistent results were obtained with the COV approach. Conclusion Based on theoretically most accurate approximations and practically reasonable estimates, the individual COV approach was preferable over the population-averaged defined daily dose technique, although the latter might be justified in certain situations. Advantages of the COV approach are expected to be even bigger for drug therapies with particularly large dosing heterogeneity. Copyright © 2016 John Wiley & Sons, Ltd.

Aims The biological response to clopidogrel is highly variable and a poor responsiveness is associated with major adverse cardiac events. Adherence to therapy is a major cause of poor responsiveness but its impact on long-term platelet inhibition is unknown. The objective of the present study was to evaluate the effect of different programmes monitoring adherence to clopidogrel on platelet reactivity. Methods The study took the form of a monocentric, parallel group, randomized controlled trial. Adults treated with clopidogrel 75 mg after elective coronary stenting were randomized into one of three groups: (i) a standard of care group; (ii) a standard of care + adherence electronic monitoring group, in which drug intake was recorded but kept blinded until the study end; or (iii) an integrated care group, with regular feedback on recorded adherence. Clopidogrel response was assessed with the vasodilator-stimulated phosphoprotein–platelet reactivity index (VASP-PRI) at randomization, 3 months and 6 months. Results A total of 123 adults were enrolled and randomized. Baseline VASP-PRI was highly variable, with a mean of 48 ± 18.8%. No difference between groups in VASP-PRI was found at 6 months (P = 0.761), despite better adherence to clopidogrel in the integrated care group. However, adherence (P = 0.035) and baseline VASP-PRI (P = 0.015) were associated with VASP-PRI at 3 months and 6 months. The association between adherence and VASP-PRI was lost in patients with baseline VASP-PRI > 50%. Diabetes, CYP2C19*2 carrier status and body mass index were significant predictors of VASP-PRI. Conclusions The platelet response to clopidogrel during chronic therapy remained highly variable, despite high adherence. Different adherence monitoring programmes did not affect VASP-PRI at 6 months. Poor adherence is associated with lower VASP-PRI only in initial good responders to clopidogrel.

BACKGROUND Whether the efficacy and safety of dual antiplatelet therapy (DAPT) are uniform between sexes is unclear. We sought to compare clinical outcomes between short- (≤6 months) versus long-term (≥1 year) DAPT after drug-eluting stent (DES) placement in women and men. METHODS AND RESULTS We pooled individual patient data from 6 randomized trials of DAPT (EXCELLENT, OPTIMIZE, PRODIGY, RESET, SECURITY, ITALIC PLUS). The primary outcome was 1-year risk of major adverse cardiac events (MACE). The main secondary outcome was 1-year risk of any bleeding. Out of the 11,473 randomized patients included in the pooled dataset, 3,454 (30%) were females. At 1-year follow-up, women had higher risk of MACE (3.6% vs. 2.8%; P = 0.01) but similar risk of bleeding (1.9% vs. 1.6%; P = 0.16) as compared with men. Compared with long-term DAPT, short-term DAPT was associated with similar rates of MACE in both women (HR 0.88; 95% CI 0.62-1.25) and men (HR 1.25; 95% CI 0.95-1.6; P interaction = 0.08)]. At 1-year follow-up, short-term DAPT was associated with lower rates of bleeding as compared with long-term DAPT in both women (HR 0.84; 95% CI 0.51-1.37) and men (HR 0.58; 95% CI 0.40-0.84; P-interaction = 0.25). The presence of MVD was associated with higher MACE rates in the short-term DAPT group in women (HR: 1.16; CI 0.60-2.23) and men (HR: 2.29; CI 1.22-4.29; P interaction = 0.25). CONCLUSIONS Short-term DAPT is associated with similar rates of MACE but lower risk of bleeding when as compared with prolonged DAPT. There was no significant difference between sexes in the population studied. © 2016 Wiley Periodicals, Inc.

Objectives The aim of the present study was to define the feasibility and clinical impact of complying with national consensus recommendations on perioperative management of antiplatelet therapy in patients with coronary stents undergoing cardiac and noncardiac surgery. Background There are limited evidence-based recommendations on the perioperative management of antiplatelet therapy in stented patients undergoing surgery. Methods The recommendations provided by the national consensus document were applied in a multicenter, prospective registry of consecutive patients with prior coronary stenting undergoing any type of surgery at 19 hospitals in Italy. The primary end-point was in-hospital net adverse clinical events (NACE) represented by the composite of all-cause death, myocardial infarction, probable/definite stent thrombosis and Bleeding Academic Research Consortium (BARC) grade ≥3 bleeding. Patients were followed for 30 days. Results A total of 1,082 patients were enrolled. Adherence to consensus recommendations occurred in 85% of the cases. Perioperative aspirin and dual antiplatelet therapy were maintained in 69.7 and 10.5% of the cases, respectively. In-hospital NACE rate was 12.7%, being significantly higher in patients undergoing cardiac surgery (36.3% vs. 7.3%, P

Background Hypertensive disorders are among the most common medical problems in pregnancy. Compliance with clinical practice guidelines has potential to translate to significant maternal and perinatal health benefits. Aims To evaluate compliance with Society of Obstetric Medicine of Australia and New Zealand (SOMANZ) clinical guidelines for management of hypertension during pregnancy. Methods Inclusion criteria: women with hypertension in pregnancy who gave birth at a tertiary obstetric centre in 2010. Compliance with SOMANZ guidelines was assessed, as well as uptake of findings from the ‘Induction of labour versus expectant monitoring for mild gestational hypertension/pre-eclampsia after 36 weeks’ gestation’ (HYPITAT) trial. Results Of 5624 women, 516 (9.2%) were identified with hypertension (49 chronic hypertension (CH); 457 gestational hypertension (GH) or pre-eclampsia (PE)). Thresholds to diagnose hypertension and initiate anti-hypertensive treatment were consistent with SOMANZ recommendations. Among women with CH, only 12.2% were prescribed aspirin prior to 16 weeks as PE prophylaxis. Of women with PE, 37 (18.6%) had known risk factors for development of PE at the initial visit yet only nine (24.3%) received aspirin. Of the 244 women who met HYPITAT inclusion criteria at 36 weeks, 174 (77.7%) were managed expectantly; nine (5.2%) developed severe adverse outcomes. Conclusion Current management guidelines for hypertension treatment were generally followed, although aspirin prophylaxis was frequently overlooked, resulting in up to 19 excess PE cases. Uptake of recommendations from the HYPITAT trial was low; however, severe complications were fewer than expected. Overall, this suggests that clinicians appropriately weigh up the likely maternal risk compared to infant benefits of deferred delivery in each case, a key recommendation of HYPITAT-II.

Background Although low platelet reactivity (LPR) is commonly detected during bleeding, a validated threshold for reliable DAPT bleeding risk stratification is lacking. We tested the diagnostic utility of 3 conventional platelet-activity assays to define the predictive value (if any) of LPR for bleeding. Hypothesis We hypothesized whether one of these tests be better than any others for predicting bleeding events. Methods Patients (n = 800) following drug-eluting stent implantation received DAPT. Bleeding was assessed by Bleeding Academic Research Consortium (BARC) classification and events were collected for 1 year after stenting. Platelet reactivity was measured by light transmittance aggregometry (LTA), VerifyNow, and multiple electrode aggregometry (MEA). The LPR values for bleeding event stratification were defined as ≤15% for LTA, ≤139 PRU for VerifyNow, and ≤25 U for MEA. Results Bleeding events occurred in 18 patients (2.3%). All tests distinguished LPR as an independent predictor for bleeding by univariate analysis ([HR]: 5.00, 95% [CI]: 1.8-14.0, P = 0.002 for LTA; HR: 21.3, 95% CI: 6.2-73.0, P < 0.0001 for VerifyNow; and HR: 7.4, 95% CI: 2.2-25.5, P = 0.002 for MEA). Multivariate analysis revealed that only VerifyNow (HR: 11.5, 95% CI: 2.9-45.7, P < 0.0004) remained an independent predictor for bleeding. However, the specificity (81.5%, 60.2%, and 81.7%, respectively) and sensitivity (61.1%, 83.3%, and 83.2%, respectively) of all 3 tests were quite low. Conclusions Among 3 conventional platelet-activity assays, VerifyNow was better than LTA or MEA for triaging future bleeding risks. However, all 3 tests failed to reliably predict future bleeding.

Aim The aim of the study was to assess ticagrelor's effects on inhibition of platelet aggregation (IPA), P2Y12 reaction units (PRU, measure of platelet P2Y12 receptor blockade), pharmacokinetic (PK) parameters and safety in Chinese patients with stable coronary artery disease (CAD). Methods This was an open label, single centre, randomized study. Thirty-six patients on low dose aspirin (75–100 mg day–1) received ticagrelor 45, 60 or 90 mg (single dose, days 1 and 7; twice daily, days 3–6). IPA (final extent), PRU and ticagrelor and AR-C124910XX plasma concentrations were determined. Results On day 1, peak IPA >80% occurred 2–6 h post-dose (all doses). PRU was markedly reduced at 1 h vs. baseline (all doses). With ticagrelor 45 and 90 mg twice daily, maximum IPA (mean, SD) was 91% (13%), and 99% (3%), and maximum PRU reduction from baseline (mean, SD) was 82% (17%) and 92% (9%), respectively. Approximate dose-proportional increases (mean [%CV]; 45 vs. 90 mg twice daily) in ticagrelor Cmax (616 [37] vs. 1273 [43] ng ml–1) and AUC (3882 [42] vs. 8206 [51] ng ml–1 h) and AR-C124910XX parameters were seen. Pharmacodynamic and PK differences between 45 and 60 mg were small. No safety issues were identified. Conclusions In Chinese patients with CAD, ticagrelor (45, 60 and 90 mg) markedly reduced platelet aggregation. The IPA and PRU magnitude increased generally with increasing doses. However, the mean pharmacodynamic differences between 45 and 60 mg doses were small. Following single and multiple doses, the mean Cmax and AUC values of ticagrelor and AR-C124910XX increased approximately dose proportionally between 45 and 90 mg doses.

This study aimed to describe the impact of implementing a protocol on the perioperative management of patients admitted for hip fracture treated with antithrombotics. A protocol was designed based on the recommendations from the American College of Chest Physicians (ACCP). After its implementation (May 2012), information on antithrombotic management was collected from admission to 3 months after surgery in retrospective (October 2011-March 2012) and prospective (October 2012-March 2013) cohorts. Patients' thromboembolic risk was classified into high, moderate or low according to the ACCP categories. A total of 113 and 101 cases were included in the retrospective and prospective cohorts, respectively. No differences in age, gender, American Society of Anaesthesiology score or thrombotic risk categories were observed between cohorts. Most patients were treated with aspirin or triflusal (55.1% and 48.1% in each cohort, respectively), clopidogrel (24.5% and 26.6%) or acenocoumarol (16.3% and 20.2%). In moderate to high thromboembolic risk patients, a higher rate of bridging therapy with full doses of enoxaparin (18.5% and 50%, p = 0.04 before and 9.1% and 43.7%, p = 0.02 after surgery) and a lower rate of aspirin discontinuation (76% and 55.3%, p = 0.03) were observed in the prospective cohort. Both cohorts had a similar percentage of cases with bleeding (68.1% and 68.3%) and thrombotic events (11.5% and 13%). No differences in the timing between surgery and the discontinuation or resumption of antithrombotics were noted. After the protocol implementation, aspirin was less often stopped and bridging therapy with therapeutic doses of enoxaparin was used more often. However, interruption and resumption times of antithrombotics remained almost unchanged. In order to achieve these goals, more efforts should be made to implement the protocol in clinical practice.

Introduction Current guidelines recommend continuation of dual anti-platelet therapy (DAPT) for 12 months after percutaneous coronary intervention (PCI). Recent studies have shown benefit in continuing DAPT beyond 12 months but at the risk of increase bleeding. To date, there has been little data on risk stratifying patients to determine who can continue DAPT beyond 12 months at minimal bleeding risk. Methods All patients who underwent drug-eluting stent (DES) placement from January 1, 2013 to September 30, 2014 were reviewed. Patients who had follow-up for at least 12 months, placement of 2nd generation everolimus-coated DES, and were on DAPT for at least 12 months were included. Patients with a history of atrial fibrillation, follow-up time less than 12 months, or were on concurrent oral anticoagulation therapy were excluded. Results Five hundred thirty-one patients were analyzed as described above. Two hundred two patients included in our study with 7 patients in the bleeding cohort and 195 patients in no-bleed cohort. The HAS-BLED score in patients who had a bleeding episode vs. those who did not was 3.29 vs. 2.24 (P value of 0.0009). Although not statistically significant, patients who had a bleeding episode were more likely to have renal dysfunction, alcohol use, be on prasugrel, and be on 325mg of aspirin. Conclusion The study shows that the HAS-BLED score can be of utility in risk stratifying patients in determining who can continue DAPT beyond 12 months. Furthermore, a HAS-BLED score of less than 2 may help guide extended DAPT beyond 12 months at minimal bleeding risk. © 2016 Wiley Periodicals, Inc.

Background Low levels of high-density lipoprotein cholesterol (HDL-C

The dosing regimen of prasugrel adjusted for Japanese patients was compared with that of clopidogrel by analyzing the pharmacokinetics and pharmacodynamics in 40 healthy Japanese subjects in a randomized, single‐blind crossover study. In period 1, the subjects received either 300 mg clopidogrel or 20 mg prasugrel; after a >2‐week interval (period 2), the drug was switched. Blood samples of 36 of the 40 subjects were collected for analysis of pharmacokinetics, pharmacodynamics, and CYP2C19 genotypes. The plasma concentration of the active metabolite of prasugrel increased rapidly and reached its peak 30 minutes postadministration, whereas that of the active metabolite of clopidogrel reached its peak 1 hour postadministration. The mean AUC and Cmax of the active metabolite of clopidogrel, but not those of prasugrel, were CYP2C19 genotype dependent. Prasugrel rapidly inhibited platelet aggregation, reaching its maximum effect 1 hour postadministration. Clopidogrel, on the other hand, showed maximum inhibition 2 hours postadministration. Platelet aggregation inhibition by clopidogrel was significantly lower in the poor‐metabolizer subjects than in the extensive‐metabolizer subjects. Overall, prasugrel inhibited platelet aggregation more rapidly and more effectively in healthy Japanese subjects than was observed for clopidogrel.

Aims Heart failure (HF) and chronic obstructive pulmonary disease (COPD) frequently co-exist, and each is a major public health issue. In a large cohort of hospitalized HF patients, we evaluated: (i) the impact of COPD on clinical outcomes; (ii) whether outcomes and treatments changed from 2002 to 2009; and (iii) the relationship between outcomes and treatments focusing on beta-blockers (BBs) and bronchodilators (BDs). Methods and results From linkable Lombardy administrative health databases, we selected individuals with a discharge diagnosis of HF with or without concomitant COPD (HF yesCOPD and HF noCOPD) in 2002 and 2009. Patients were followed up for 4 years. Outcomes were total mortality, first readmission for HF, and their combination. Unadjusted and adjusted Cox proportional models and competing risk analyses were used. We identified 11 274 patients with HF noCOPD and 2837 with HF yesCOPD. HF yesCOPD patients in 2002 and 2009 had a 20% higher risk of the outcomes. From 2002 to 2009, BB and BD prescriptions increased significantly. In HF noCOPD patients, risks for mortality [adjusted hazard ratio (HR) 0.91, 95% confidence interval (CI) 0.86–0.97], first HF readmission (HR 0.79, 95% CI 0.74–0.85), and the combined endpoint (HR 0.88, 95% CI 0.84–0.92) declined (all P < 0.003) while in HF yesCOPD only the risk for first HF readmission dropped (HR 0.86, 95% CI 0.76–0.97; P = 0.018). BBs were associated with significantly lower mortality in both groups, but with a higher risk for first HF readmission in HF noCOPD. Outcomes did not significantly differ in HF yesCOPD treated or not with BDs. Conclusions The prognosis of patients hospitalized for HF, either with or without COPD, seemed to improve between 2002 and 2009, with possibly better survival of those on BBs. Because of residual confounding in observational studies, a randomized controlled trial should be considered to confirm these results.

Objectives To construct a model to predict long-term bleeding events following percutaneous coronary intervention (PCI). Background Treatment with dual antiplatelet therapy following PCI involves balancing the benefits of preventing ischemic events with the risks of bleeding. There are no models to predict long-term bleeding events after PCI. Methods We analyzed 1-year bleeding outcomes from 3,128 PCI procedures in the Patient Risk Information Services Manager (PRISM) observational study. Patient-reported bleeding events were categorized according to Bleeding Academic Research Consortium (BARC) definitions. Logistic regression analysis was used to develop a model predicting BARC ≥ 1 bleeding. Results BARC 0, 1, 2 or 3 bleeding was observed in 574 (18.4%); 2382 (76.2%); 114 (3.6%); and 58 (1.8%) patients, respectively. Compared to patients who had no bleeding, patients with BARC ≥ 1 bleeding were more often female (30 vs. 23%), Caucasian (94 vs. 83%), had a higher incidence of drug eluting stent (DES) implantation (83 vs. 76%) and warfarin therapy (7.4 vs. 3.9%), and a lower incidence of diabetes (31 vs. 45%; P-value

Background and purpose Dual antiplatelet therapy (DAPT) with aspirin and clopidogrel for 90 days was recommended as the secondary prevention of minor ischaemic strokes or transient ischaemic attacks (TIAs) in 2014. However, whether the duration of 90 days is optimal for each patient remains unclear. Therefore, the efficacy and safety of short-term (≤3 months) and prolonged (≥1 year) DAPT after stroke or TIA were assessed via a systematic review and meta-analysis. Methods The Cochrane Library, Clinical Trials.gov and PubMed were searched up to December 2014 and nine randomized controlled trials were included involving 21 923 patients. Results Short-term DAPT significantly reduced the risk of ischaemic stroke recurrence by 41% and major vascular events by 30%, without increasing the risk of intracranial haemorrhage. Prolonged DAPT reduced the risk of ischaemic stroke recurrence by 12% and major vascular events by 10%. However, the risk of major bleeding and intracranial haemorrhage increased. Conclusions Short-term DAPT appears to be superior to prolonged DAPT. However, the difference in efficacy outcome needs to be carefully explained and confirmed by further well-designed randomized controlled trials.

BACKGROUND AND OBJECTIVE: Severe idiopathic pulmonary fibrosis is associated with an increased risk of cardiovascular disease and gastro-oesophageal reflux, which may influence prognosis. We evaluated associations between cardiovascular and antacid medications, and mortality, in oxygen-dependent pulmonary fibrosis (PF) of unknown cause.METHODS: Prospective population-based study of adults starting long-term oxygen therapy (LTOT) for PF in Sweden 2005-2009. PF of unknown cause was defined by excluding patients with known or probable secondary PF. Time-dependent associations between medications and all-cause mortality were analysed using extended Cox regression, adjusting for potential confounders including age, sex, vital capacity, blood gases, body mass index, performance status, comorbidity and concurrent medications.RESULTS: Of 462 included patients, 329 (71%) died under observation. No patient was lost to follow-up. Angiotensin-converting enzyme inhibitors or angiotensin receptor blockers (ACEI/ARB) were associated with reduced adjusted mortality (HR 0.63; 0.47-0.85) and antiplatelet drugs with increased mortality (HR 1.49; 1.11-2.00), largely driven by higher mortality in women. There were no associations with mortality for antacid treatments, β-blockers, diuretics or statins.CONCLUSION: In oxygen-dependent PF, treatment with ACEI/ARB was associated with improved survival, antiplatelet drugs with decreased survival, whereas there was no association between antacid, β-blocker, diuretic or statin treatment and survival.