The impact of long-term aspirin use on the patients undergoing shoulder arthroplasty.

BACKGROUND: Although aspirin is increasingly utilized to reduce the event of severe perioperative complications, the effect of long-term aspirin use (L-AU) on perioperative complications in patients undergoing shoulder arthroplasty (SA) has not been well studied. The goal of the present study is to identify the influence of L-AU on perioperative complications in individuals undergoing SA. METHODS: We selected data from the National Inpatient Sample database between 2010 and 2019, to identify adult patients with SA. Patients were subsequently categorized into L-AU and whole non-L-AU cohorts according to the presence of aspirin use. The demographic and comorbidity characteristics were matched using propensity score matching (PSM). The Pearson chi-square test, Wilcoxon rank test and logistic regression were utilized to assess the association of L-AU with perioperative complications. RESULTS: From 2010 to 2019, a total of 162,418 SA patients satisfied the inclusion criteria, with 22,659 (13.95%) using aspirin on a long-term basis. The vast majority of the patients with pre-existing L-AU were aged 65-74 years, female, White and had Medicare insurance. L-AU before surgery was linked to increased risks of perioperative complications, such as blood transfusion (adjusted odds ratio [aOR]: 1.339), genitourinary disease (aOR: 1.349), acute renal failure (aOR: 1.292), acute myocardial infarction (aOR: 1.494), higher total charge (L-AU vs. the whole non-L-AU vs. matched non-L-AU: $66,727.15 vs. $59,697.08 vs. $59,926.32), and prolonged hospitalization stay (LOS) (aOR: 0.837). However, L-AU was considered a protective factor of acute cerebrovascular disease (aOR: 0.722) and stroke (aOR: 0.725). CONCLUSIONS: Our study is based on the largest open-access all-payer inpatient database, revealing a noteworthy finding of aspirin's protective and adverse impact on different postoperative complications in the US population, such as acute cardiovascular disease, and stroke, etc. Further studies assessing the optimum preoperative aspirin duration and dosage to meet the best benefit quantity for patients with planned joint arthroplasties are suggested.

Trends in Upper Gastrointestinal Bleeding in Patients on Primary Prevention Aspirin: A Nationwide Emergency Department Sample Analysis, 2016-2020.

BACKGROUND: Recent guidelines do not recommend routine use of aspirin for primary cardiovascular prevention (ppASA) and suggest avoidance of ppASA in older individuals due to bleeding risk. However, ppASA is frequently taken without an appropriate indication. Estimates of the incidence of upper gastrointestinal bleeding due to ppASA in the United States are lacking. In this study, we provide national estimates of upper gastrointestinal bleeding incidence, characteristics, and costs in ppASA users from 2016-2020. METHODS: Primary cardiovascular prevention users (patients on long-term aspirin therapy without cardiovascular disease) presenting with upper gastrointestinal bleeding were identified in the Nationwide Emergency Department Sample using International Statistical Classification of Diseases and Related Health Problems, 10th revision codes. Trends in upper gastrointestinal bleeding incidence, etiology, severity, associated Medicare reimbursements, and the impact of ppASA on bleeding outcomes were assessed with regression models. RESULTS: From 2016-2020, adjusted incidence of upper gastrointestinal bleeding increased 29.2% among ppASA users, with larger increases for older patients (increase of 41.6% for age 65-74 years and 36.0% for age ≥75 years). The most common etiology among ppASA users was ulcer disease but increases in bleeding incidence due to angiodysplasias were observed. The proportion of hospitalizations with major complications or comorbidities increased 41.5%, and Medicare reimbursements increased 67.6%. Among patients without cardiovascular disease, ppASA was associated with increased odds of hospital admission, red blood cell transfusion, and endoscopic intervention as compared to no ppASA use. CONCLUSIONS: Considering recent guideline recommendations, the rising incidence, severity, and costs associated with upper gastrointestinal bleeding among patients on ppASA highlights the importance of careful assessment for appropriate ppASA use.

Bleeding risk in patients prescribed dual antiplatelet therapy and triple therapy after coronary interventions: the ADAPTT retrospective population-based cohort studies.

Background: Bleeding among populations undergoing percutaneous coronary intervention or coronary artery bypass grafting and among conservatively managed patients with acute coronary syndrome exposed to different dual antiplatelet therapy and triple therapy (i.e. dual antiplatelet therapy plus an anticoagulant) has not been previously quantified. Objectives: The objectives were to estimate hazard ratios for bleeding for different antiplatelet and triple therapy regimens, estimate resources and the associated costs of treating bleeding events, and to extend existing economic models of the cost-effectiveness of dual antiplatelet therapy. Design: The study was designed as three retrospective population-based cohort studies emulating target randomised controlled trials. Setting: The study was set in primary and secondary care in England from 2010 to 2017. Participants: Participants were patients aged ≥ 18 years undergoing coronary artery bypass grafting or emergency percutaneous coronary intervention (for acute coronary syndrome), or conservatively managed patients with acute coronary syndrome. Data sources: Data were sourced from linked Clinical Practice Research Datalink and Hospital Episode Statistics. Interventions: Coronary artery bypass grafting and conservatively managed acute coronary syndrome: aspirin (reference) compared with aspirin and clopidogrel. Percutaneous coronary intervention: aspirin and clopidogrel (reference) compared with aspirin and prasugrel (ST elevation myocardial infarction only) or aspirin and ticagrelor. Main outcome measures: Primary outcome: any bleeding events up to 12 months after the index event. Secondary outcomes: major or minor bleeding, all-cause and cardiovascular mortality, mortality from bleeding, myocardial infarction, stroke, additional coronary intervention and major adverse cardiovascular events. Results: The incidence of any bleeding was 5% among coronary artery bypass graft patients, 10% among conservatively managed acute coronary syndrome patients and 9% among emergency percutaneous coronary intervention patients, compared with 18% among patients prescribed triple therapy. Among coronary artery bypass grafting and conservatively managed acute coronary syndrome patients, dual antiplatelet therapy, compared with aspirin, increased the hazards of any bleeding (coronary artery bypass grafting: hazard ratio 1.43, 95% confidence interval 1.21 to 1.69; conservatively-managed acute coronary syndrome: hazard ratio 1.72, 95% confidence interval 1.15 to 2.57) and major adverse cardiovascular events (coronary artery bypass grafting: hazard ratio 2.06, 95% confidence interval 1.23 to 3.46; conservatively-managed acute coronary syndrome: hazard ratio 1.57, 95% confidence interval 1.38 to 1.78). Among emergency percutaneous coronary intervention patients, dual antiplatelet therapy with ticagrelor, compared with dual antiplatelet therapy with clopidogrel, increased the hazard of any bleeding (hazard ratio 1.47, 95% confidence interval 1.19 to 1.82), but did not reduce the incidence of major adverse cardiovascular events (hazard ratio 1.06, 95% confidence interval 0.89 to 1.27). Among ST elevation myocardial infarction percutaneous coronary intervention patients, dual antiplatelet therapy with prasugrel, compared with dual antiplatelet therapy with clopidogrel, increased the hazard of any bleeding (hazard ratio 1.48, 95% confidence interval 1.02 to 2.12), but did not reduce the incidence of major adverse cardiovascular events (hazard ratio 1.10, 95% confidence interval 0.80 to 1.51). Health-care costs in the first year did not differ between dual antiplatelet therapy with clopidogrel and aspirin monotherapy among either coronary artery bypass grafting patients (mean difference £94, 95% confidence interval -£155 to £763) or conservatively managed acute coronary syndrome patients (mean difference £610, 95% confidence interval -£626 to £1516), but among emergency percutaneous coronary intervention patients were higher for those receiving dual antiplatelet therapy with ticagrelor than for those receiving dual antiplatelet therapy with clopidogrel, although for only patients on concurrent proton pump inhibitors (mean difference £1145, 95% confidence interval £269 to £2195). Conclusions: This study suggests that more potent dual antiplatelet therapy may increase the risk of bleeding without reducing the incidence of major adverse cardiovascular events. These results should be carefully considered by clinicians and decision-makers alongside randomised controlled trial evidence when making recommendations about dual antiplatelet therapy. Limitations: The estimates for bleeding and major adverse cardiovascular events may be biased from unmeasured confounding and the exclusion of an eligible subgroup of patients who could not be assigned an intervention. Because of these limitations, a formal cost-effectiveness analysis could not be conducted. Future work: Future work should explore the feasibility of using other UK data sets of routinely collected data, less susceptible to bias, to estimate the benefit and harm of antiplatelet interventions. Trial registration: This trial is registered as ISRCTN76607611. Funding: This project was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 27, No. 8. See the NIHR Journals Library website for further project information.

People who have a heart attack are treated with a stent to open up the blocked artery that caused the heart attack, with surgery to bypass the blocked artery or with medication only. Whatever the treatment, they are prescribed one or more antiplatelet drugs, either aspirin only or aspirin and an additional antiplatelet (clopidogrel, prasugrel or ticagrelor), for 12 months after the heart attack. Antiplatelets are given to prevent another heart attack, but increase the risk of bleeding. We used a large general practice database and a database describing patients' attendances and admissions to hospital to determine how many people bleed with different antiplatelet combinations. We found that, overall, up to 1 in 10 people taking antiplatelets (rising to 2 in 10 if also taking an anticoagulant such as warfarin or dabigatran) reported a bleed. Among patients treated with surgery or medication only, we compared aspirin only (which is a less potent therapy) with aspirin and clopidogrel (a more potent therapy). Among patients treated with stents, we compared aspirin and clopidogrel (less potent therapy) with aspirin and prasugrel or ticagrelor (more potent therapy). In all three populations, the more potent therapy increased the risk of bleeding by about one and a half times, but this was not offset by a reduced risk of having a subsequent heart attack. This may be explained by low adherence to the medication: between one-third and almost half of all patients did not adhere to their regimen, and non-adherence was generally higher among patients taking a more potent therapy. It may also be explained by bias inherent in the study, for example if the groups prescribed different antiplatelet regimens had different risks of having another heart attack. Nevertheless, the results show that doctors should be cautious about prescribing more potent antiplatelet therapy because it may increase serious bleeds without necessarily reducing the number of heart attacks.

Does use of long-term aspirin impact outcomes in patients with acute pancreatitis?

INTRODUCTION: Although the effect of rectal indomethacin in post-endoscopic retrograde cholangiopancreatography pancreatitis is well established, the effect of aspirin on acute pancreatitis (AP) is not well studied. We investigate the effect of aspirin on AP. METHODS: We collected data from the National Inpatient Sample database from 2016 to 2020, to identify adult patients with acute pancreatitis. Patients were stratified into 2 groups, based on the presence of aspirin use. The primary outcome was mortality, while other outcomes were sepsis, shock, acute kidney injury (AKI), ICU admission, deep venous thrombosis (DVT), pulmonary embolism (PE), portal vein thrombosis (PVT), pseudocyst and ileus. RESULTS: A total of 2.09 million patients met the inclusion criteria, of which 197 170 (9.41%) had long-term aspirin use. The majority of the patients with aspirin use were aged >65 years, male, White and had Medicare insurance. There was a higher incidence of biliary pancreatitis while rates of alcohol-induced pancreatitis were lower in patients with aspirin use. There was a lower incidence of mortality, sepsis, shock, PE, DVT, PVT and pseudocyst in patients with aspirin use. There was no difference in the incidence of ileus, while the incidence of AKI was higher. After adjusting for confounding factors, patients with aspirin use had a 23.6% lower risk of mortality. DISCUSSION: Our results reveal a significant finding of aspirin's protective effect on AP in the US population. Our study is the largest study revealing an association between aspirin and AP. Further studies assessing the role of aspirin use in AP are warranted.

Thromboelastography 6s for assessment of platelet function during coil embolization of unruptured intracranial aneurysms.

OBJECTIVES: Methods for assessing platelet function in patients with neurovascular disease remain controversial and poorly studied. This study aimed to assess associations between thromboelastography 6s (TEG6s) measurements and postoperative ischemic complications in patients with unruptured intracranial aneurysms (UIAs) treated by coil embolization. METHODS: Eighty-four patients with UIAs taking a combined aspirin and clopidogrel protocol were retrospectively reviewed from January 2021 to May 2022. Blood samples were obtained for TEG6s to assess platelet function on the day of coil embolization. To identify acute ischemic complications, diffusion-weighted imaging (DWI) was performed within 24 h after coil embolization. Multivariate logistic regression analysis was conducted to identify potential risk factors for postoperative positive DWI (DWI (+)) lesions. RESULTS: Forty-three of the 84 patients (51%) with DWI (+) lesions were identified. Compared with patients without DWI (+) lesions, Adenosine diphosphate (ADP)-induced platelet-fibrin clot strength (MAADP) was significantly higher (53.6 mm [Interquartile range (IQR): 48.3-58.3 mm] vs 46.7 mm [IQR: 36.8-52.2 mm]; p=0.001) and ADP inhibition rate (ADP%) was significantly lower (19% [IQR: 11-31%] vs 31% [IQR: 21-44%]; p=0.001) in DWI (+) patients. Multivariate analysis identified MAADP, ADP%, and procedure time as significant independent predictors of subsequent DWI (+) lesions (odds ratios: 1.07, 0.96, and 1.02, respectively). Based on receiver operating characteristic curve analysis, MAADP >50.9 mm and ADP% <28.8% were associated with postoperative DWI (+) lesions in patients undergoing coil embolization for UIAs. CONCLUSIONS: MAADP and ADP% as assessed by TEG6s can offer reliable parameters to predict postoperative ischemic complications after coil embolization of UIAs. Lower MAADP values and higher ADP% may decrease the risk of postoperative ischemic complications.

Cost-Effectiveness of Vonoprazan Compared With Proton Pump Inhibitors in Patients Taking Low-Dose Aspirin for Secondary Prevention of Cardiovascular Events in Japan.

BACKGROUND: Low-dose aspirin (LDA) is used to prevent recurrent cardiovascular (CV) events, but is associated with upper gastrointestinal (GI) bleeding; concomitant use of a proton pump inhibitor (PPI) reduces this risk. This study aimed to assess the cost-effectiveness of vonoprazan compared with PPIs (lansoprazole and esomeprazole) in patients taking LDA for secondary prevention of CV events.Methods and Results: A Markov simulation model was developed to predict the number of GI bleeding and acute CV events using 3 strategies (vonoprazan+LDA, esomeprazole+LDA, and lansoprazole+LDA), which were translated into quality-adjusted life-years (QALYs) and costs. Transition probabilities and utilities were derived from the results of published literature, and medical costs were based on the Japanese National Health Insurance fee table and claims databases in 2020. Outcomes were projected over 30 years starting at age 65 years and discounted at 2% annually. Expected costs with esomeprazole 20 mg, lansoprazole 15 mg and vonoprazan 10 mg were JPY 1,225,657, JPY 943,930, and JPY 1,059,510, respectively. The QALY gain for vonoprazan vs. esomeprazole was 0.35, thus vonoprazan was dominant against esomeprazole. The QALY gain for vonoprazan vs. lansoprazole was 0.29 and the incremental cost-effectiveness ratio (ICER) was JPY 398,551, thus, vonoprazan was more cost-effective than lansoprazole. CONCLUSIONS: Vonoprazan is dominant or cost-effective compared with esomeprazole and lansoprazole in patients taking LDA for secondary prevention of CV events.

Helicobacter pylori eradication for primary prevention of peptic ulcer bleeding in older patients prescribed aspirin in primary care (HEAT): a randomised, double-blind, placebo-controlled trial.

BACKGROUND: Peptic ulcers in patients receiving aspirin are associated with Helicobacter pylori infection. We aimed to investigate whether H pylori eradication would protect against aspirin-associated ulcer bleeding. METHODS: We conducted a randomised, double-blind, placebo-controlled trial (Helicobacter Eradication Aspirin Trial [HEAT]) at 1208 primary care centres in the UK, using routinely collected clinical data. Eligible patients were aged 60 years or older who were receiving aspirin at a daily dose of 325 mg or less (with four or more 28-day prescriptions in the past year) and had a positive C13 urea breath test for H pylori at screening. Patients receiving ulcerogenic or gastroprotective medication were excluded. Participants were randomly assigned (1:1) to receive either a combination of oral clarithromycin 500 mg, metronidazole 400 mg, and lansoprazole 30 mg (active eradication), or oral placebo (control), twice daily for 1 week. Participants, their general practitioners and health-care providers, and the research nurses, trial team, adjudication committee, and analysis team were all masked to group allocation throughout the trial. Follow-up was by scrutiny of electronic data in primary and secondary care. The primary outcome was time to hospitalisation or death due to definite or probable peptic ulcer bleeding, and was analysed by Cox proportional hazards methods in the intention-to-treat population. This trial is registered with EudraCT, 2011-003425-96. FINDINGS: Between Sept 14, 2012, and Nov 22, 2017, 30 166 patients had breath testing for H pylori, 5367 had a positive result, and 5352 were randomly assigned to receive active eradication (n=2677) or placebo (n=2675) and were followed up for a median of 5·0 years (IQR 3·9-6·4). Analysis of the primary outcome showed a significant departure from proportional hazards assumptions (p=0·0068), requiring analysis over separate time periods. There was a significant reduction in incidence of the primary outcome in the active eradication group in the first 2·5 years of follow-up compared with the control group (six episodes adjudicated as definite or probable peptic ulcer bleeds, rate 0·92 [95% CI 0·41-2·04] per 1000 person-years vs 17 episodes, rate 2·61 [1·62-4·19] per 1000 person-years; hazard ratio [HR] 0·35 [95% CI 0·14-0·89]; p=0·028). This advantage remained significant after adjusting for the competing risk of death (p=0·028) but was lost with longer follow-up (HR 1·31 [95% CI 0·55-3·11] in the period after the first 2·5 years; p=0·54). Reports of adverse events were actively solicited; taste disturbance was the most common event (787 patients). INTERPRETATION: H pylori eradication protects against aspirin-associated peptic ulcer bleeding, but this might not be sustained in the long term. FUNDING: National Institute for Health and Care Research Health Technology Assessment.

Assessment of adherence to aspirin for preeclampsia prophylaxis and reasons for nonadherence.

BACKGROUND: Preeclampsia is a hypertensive disease unique to pregnancy and has a significant impact on maternal and neonatal morbidity and mortality. Daily aspirin has been demonstrated to reduce the risk of preeclampsia. The American College of Obstetricians and Gynecologists recommends daily low-dose aspirin, ideally before 16 weeks' gestation, in at-risk patients for preeclampsia risk reduction. This study examined whether patients at-risk for preeclampsia by the American College of Obstetricians and Gynecologists criteria recalled aspirin recommendation and factors associated with treatment adherence. OBJECTIVE: This study examined whether patients at-risk for preeclampsia by the American College of Obstetricians and Gynecologists criteria recalled aspirin recommendation and factors associated with treatment adherence. STUDY DESIGN: This study used an anonymous written survey. Pregnant patients were asked to record self-reported risk factors and to recall recommendation to take aspirin for preeclampsia prophylaxis. Participants were then determined to be high-, moderate-, or low-risk on the basis of the American College of Obstetricians and Gynecologists guidelines. Self-reported adherence to recommendations and factors contributing to the patients' decisions to take or decline aspirin were assessed. Secondary outcomes included demographic characteristics of adherent patients and patients who did not recall aspirin recommendation. RESULTS: A total of 544 surveys were distributed and 500 were returned (91.9% response rate). Of the 104 high-risk pregnancies identified, aspirin was recommended in 60 (57.7%; 95% confidence interval, 0.48-0.67). Of the 269 patients with 2 or more moderate-risk factors, aspirin was recommended for 13 (4.8%; 95% confidence interval, 0.03-0.08). Among the participants who recalled aspirin recommendation, adherence was similar between high-risk (81.7%) and moderate-risk (76.9%) groups (P=.69). Patients with chronic hypertension, a history of preeclampsia or gestational hypertension in a previous pregnancy, and pregestational diabetes mellitus were most likely to report receiving aspirin recommendation (78.8%, 76.5%, 63.8%, and 53.3%, respectively). No high-risk factor was associated with a decreased likelihood of adherence. Nonadherent patients rarely discussed their decision with their medical provider (5.9%). In the 42.3% of high-risk participants who did not recall aspirin recommendation, autoimmune disease, multiple gestation, and kidney disease were the most prevalent risk factors (42.9%, 35.7%, and 25.0%, respectively). CONCLUSION: In the population studied, many at-risk patients, as defined by the American College of Obstetricians and Gynecologists criteria, did not recall recommendations to take aspirin for preeclampsia prophylaxis. This raises concerns for absent or ineffective counseling. Of the patients who recalled aspirin recommendation, most reported adherence, and a history of hypertensive disorders or preeclampsia, autoimmune disease, and pregestational diabetes mellitus were most often associated with adherence. There was no single factor most strongly associated with intentional nonadherence.

Impact of prior oral anticoagulant use and outcomes on patients from secondary analysis in the AUGUSTUS trial.

OBJECTIVE: Managing antithrombotic therapy in patients with atrial fibrillation (AF) and an acute coronary syndrome (ACS) and/or percutaneous coronary intervention (PCI) is challenging and can be affected by prior oral anticoagulant (OAC) treatment. We examined the relationship between prior OAC use and outcomes in the AUGUSTUS trial. METHODS: This prespecified secondary analysis is from AUGUSTUS, an open-label, 2-by-2 factorial, RCT to evaluate the safety of apixaban versus vitamin K antagonist (VKA) and aspirin versus placebo in patients with AF and ACS and/or PCI. The primary endpoint, major or clinically relevant non-major bleeding and clinical outcomes were compared in patients receiving (n=2262) or not receiving (n=2352) an OAC prior to enrolment. RESULTS: Patients with prior OAC use had more comorbidities, higher CHA2DS2-VASC and HAS-BLED scores, and were more likely enrolled following elective PCI. There was no difference in major or clinically relevant non-major bleeding with or without prior OAC (30 days: 5.1% vs 5.9% (adjusted HR (aHR) 0.82, 95% CI 0.63 to 1.06); 180 days: 13.5% vs 13.5% (aHR 0.98, 95% CI 0.83 to 1.16)). Patients with prior OAC use had a lower risk of death or ischaemic events (30 days: 1.7% vs 2.8% (aHR 0.61, 95% CI 0.41 to 0.92); 180 days: 5.4% vs 7.6% (aHR 0.70, 95% CI 0.55 to 0.88)). No interactions between randomised treatment (apixaban vs VKA, aspirin vs placebo) and prior OAC status were observed for outcomes, apart from apixaban (vs VKA) being associated with a lower risk of myocardial infarction with prior OAC use (180 days: 2.0% vs 3.7% (aHR 0.56, 95% CI 0.33 to 0.91(). CONCLUSIONS: In AUGUSTUS, prior OAC use was associated with fewer ischaemic events but not more bleeding. In patients with AF and ACS and/or undergoing PCI, clinicians can be assured that the trial results can be applied to patients regardless of their prior OAC status. TRIAL REGISTRATION NUMBER: NCT02415400.

Hospitalisation and associated costs of gastrointestinal bleeding from primary prevention aspirin use in South Australia: a retrospective case series analysis.

We assessed hospitalisations for gastrointestinal bleeding directly related to primary prevention aspirin in lower risk patients for a 6-month period in three South Australian hospitals. Those with related underlying pathology or concurrent causative medication were excluded. Identified patients (n = 22) carried little co-morbidity, 41% received prior proton-pump inhibitors and 68% were aged >70 years. Mean hospital admission cost was $6769 (95% confidence interval $5198-$8340), with projected state and national annual costs of $0.57 and $8.12 million respectively. In light of recent guideline changes, clinicians need to vigorously assess the need for primary prevention aspirin.

Effect of postoperative antithrombotic therapy on lower extremity outcomes after infrapopliteal bypass for chronic limb-threatening ischemia.

OBJECTIVE: Although the current guidelines have recommended single antiplatelet therapy (SAPT) for patients undergoing revascularization for chronic limb-threatening ischemia (CLTI), antithrombotic management has varied by patient and provider. Our aim was to examine the effects of different postoperative antithrombotic regimens on 3-year clinical outcomes after infrapopliteal bypass for CLTI. METHODS: We identified patients who had undergone infrapopliteal bypass for CLTI in the Vascular Quality Initiative (VQI) registry from 2003 to 2017 with linkage to Medicare claims for long-term outcomes. We divided the patients into three cohorts according to the discharge antithrombotic regimen: SAPT (aspirin or clopidogrel), dual antiplatelet therapy (DAPT; aspirin and clopidogrel), or anticoagulation (AC) plus any antiplatelet (AP) agent. To reduce selection bias, we restricted the analysis cohorts to patients treated by providers who discharged >50% of patients with each antithrombotic regimen. Our primary outcome was 3-year major adverse limb events (MALE; major amputation or reintervention). The secondary outcomes included 3-year major amputation, reintervention, and mortality. We used Kaplan-Meier and Cox regression analyses to assess these outcomes stratified by antithrombotic regimen and adjusted for demographic, comorbid, clinical, and operative differences between the treatment groups with clustering at the center level. RESULTS: Among 1812 patients (median follow-up, >2 years), 693 (38%) were discharged with SAPT, 544 (30%) with DAPT, and 575 (32%) with AC+AP. At 3 years, the MALE rates were 75% with DAPT, 74% with AC+AP, and 68% with SAPT. In adjusted analyses with SAPT as the reference group, no differences were found in 3-year MALE with DAPT (adjusted hazard ratio [aHR], 1.0; 95% confidence interval [CI], 0.85-1.3; P = .71) or AC+AP (aHR, 1.1; 95% CI, 0.96-1.3; P = .14). Across the treatment groups, we also found no differences in the individual end points of 3-year major amputation (DAPT: aHR, 0.98; 95% CI, 0.72-1.3; AC+AP: aHR, 1.3; 95% CI, 0.96-1.7), reintervention (DAPT: aHR, 1.0; 95% CI, 0.84-1.3; AC+AP: aHR, 1.1; 95% CI, 0.96-1.3), or mortality (DAPT: aHR, 1.1; 95% CI, 0.88-1.4; AC+AP: aHR, 0.95; 95% CI, 0.74-1.2). In a sensitivity analysis evaluating patients treated by providers who discharged >60%, >70%, or >80% of patients with these regimens, the association between antithrombotic regimen and MALE was unchanged. CONCLUSIONS: Compared with SAPT, DAPT and anticoagulation therapy were not associated with improved outcomes among Medicare beneficiaries who had undergone infrapopliteal bypass for CLTI at VQI participating centers. These findings support current guidelines recommending SAPT after lower extremity bypass and suggest that the routine use of DAPT or anticoagulation therapy might not provide clinical benefit in this high-risk, elderly population. However, further evaluation of the risks and benefits of various antithrombotic regimens in relevant subgroups is warranted.

Assessment of embryo morphology following perinatal exposure to aspirin, ibuprofen and paracetamol using whole embryo culture system.

BACKGROUND: Recent evidence from a meta-analysis indicates that maternal prenatal exposure, single or repeated, to non-steroidal anti-inflammatory drugs (NSAIDs) or non-opioid painkillers, is associated with increased risk of cerebral palsy and cognitive-behavioral disorders in offspring. One potential route of action is interference with the neurulation process and hence early brain development. OBJECTIVE: To examine the effect of prenatal exposure to common NSAIDs and non-opioid drugs on neurulation using an in vitro whole embryo culture system. METHODS: Mouse embryos from in-bred Institute of Cancer Research albino strain mice were exteriorized on embryonic day 7.5 and cultured for 48 h in either 1 mL heat-inactivated rat serum + 0.1% dimethyl sulfoxide ("Control") or 1 mL of rat serum supplemented with six increasing concentrations of laboratory-grade aspirin, paracetamol, and ibuprofen ("Experimental"). After culture, embryo morphological and developmental parameters were documented using standardized scoring systems at each dosage concentration. The assessed concentration in rat serum culture ranged from 1.23 to 13.57 mg/mL for aspirin and 0.06-4.93 mg/mL for paracetamol and ibuprofen. The equivalent respective human dosages were 600-6600 mg and 30-2400 mg. RESULTS: Between-group comparisons ("Control" vs "Experimental") and post-hoc pair-wise tests, adjusted for multiple comparisons, indicating no statistically significant effect on crown-rump length (p > .21), head length (p > .28), somite number (p > .25), incidence of absent hindlimb buds (p > .18), yolk sac circulation score (p > .07) and posterior neuropore closure (p > .35) in the aspirin, paracetamol and ibuprofen experiments. All embryos had forelimb buds, closed anterior neuropores and none had neural tube defects. CONCLUSION: This study has demonstrated that there are no safety concerns regarding high-dose aspirin, ibuprofen, and paracetamol on mice's embryonic development.

Magnetically Controlled Capsule Endoscopy for Assessment of Antiplatelet Therapy-Induced Gastrointestinal Injury.

BACKGROUND: Gastrointestinal bleeding is the most frequent major complication of antiplatelet therapy. In patients at low bleeding risk, however, clinically overt gastrointestinal bleeding is relatively uncommon. OBJECTIVES: The authors sought to assess the effects of different antiplatelet regimens on gastrointestinal mucosal injury by means of a novel magnetically controlled capsule endoscopy system in patients at low bleeding risk. METHODS: Patients (n = 505) undergoing percutaneous coronary intervention in whom capsule endoscopy demonstrated no ulcerations or bleeding (although erosions were permitted) after 6 months of dual antiplatelet therapy (DAPT) were randomly assigned to aspirin plus placebo (n = 168), clopidogrel plus placebo (n = 169), or aspirin plus clopidogrel (n = 168) for an additional 6 months. The primary endpoint was the incidence of gastrointestinal mucosal injury (erosions, ulceration, or bleeding) at 6-month or 12-month capsule endoscopy. RESULTS: Gastrointestinal mucosal injury through 12 months was less with single antiplatelet therapy (SAPT) than with DAPT (94.3% vs 99.2%; P = 0.02). Aspirin and clopidogrel monotherapy had similar effects. Among 68 patients without any gastrointestinal injury at randomization (including no erosions), SAPT compared with DAPT caused less gastrointestinal injury (68.1% vs 95.2%; P = 0.006), including fewer new ulcers (8.5% vs 38.1%; P = 0.009). Clinical gastrointestinal bleeding from 6 to 12 months was less with SAPT than with DAPT (0.6% vs 5.4%; P = 0.001). CONCLUSIONS: Despite being at low risk of bleeding, nearly all patients receiving antiplatelet therapy developed gastrointestinal injury, although overt bleeding was infrequent. DAPT for 6 months followed by SAPT with aspirin or clopidogrel from 6 to 12 months resulted in less gastrointestinal mucosal injury and clinical bleeding compared with DAPT through 12 months. (OPT-PEACE [Optimal Antiplatelet Therapy for Prevention of Gastrointestinal Injury Evaluated by Ankon Magnetically Controlled Capsule Endoscopy]; NCT03198741).

Primary care providers should prescribe aspirin to prevent cardiovascular disease based on benefit-risk ratio, not age.

Recent guidelines restricted aspirin (ASA) in primary prevention of cardiovascular disease (CVD) to patients <70 years old and more recent guidance to <60.In the most comprehensive prior meta-analysis, the Antithrombotic Trialists Collaboration reported a significant 12% reduction in CVD with similar benefit-risk ratios at older ages. Using Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, four trials were added to an updated meta-analysis.ASA produced a statistically significant 13% reduction in CVD with 95% confidence limits (0.83 to 0.92) with similar benefits at older ages in each of the trials.Primary care providers should make individual decisions whether to prescribe ASA based on benefit-risk ratio, not simply age. When the absolute risk of CVD is >10%, benefits of ASA will generally outweigh risks of significant bleeding. ASA should be considered only after implementation of therapeutic lifestyle changes and other drugs of proven benefit such as statins, which are, at the very least, additive to ASA. Our perspective is that individual clinical judgements by primary care providers about prescription of ASA in primary prevention of CVD should be based on our evidence-based solution of weighing all the absolute benefits and risks rather than age. This strategy would do far more good for far more patients as well as far more good than harm in both developed and developing countries. This new and novel strategy for primary care providers to consider in prescribing ASA in primary prevention of CVD is the same as the general approach suggested by Professor Geoffrey Rose decades ago.

Cost-effectiveness analysis comparing dupilumab and aspirin desensitization therapy for chronic rhinosinusitis with nasal polyposis in aspirin-exacerbated respiratory disease.

BACKGROUND: Chronic rhinosinusitis with nasal polyposis (CRSwNP) in the setting of aspirin-exacerbated respiratory disease (AERD) is a disease that is difficult to treat and prone to recurrence. Dupilumab is a promising treatment for these patients, but its cost-effectiveness has not yet been compared with aspirin (acetylsalicyclic acid, or ASA) desensitization, a known and effective treatment. We aimed to compare the cost-effectiveness of ASA desensitization with dupilumab therapy for the treatment of CRSwNP in AERD. METHODS: Analyses of cost-effectiveness, as measured in quality-adjusted life years (QALYs), and cost-utility, as measured in number of required revision endoscopic sinus surgeries (ESSs), were conducted. RESULTS: ASA desensitization after ESS was cost-effective and dominated appropriate medical management. Adding salvage dupilumab was also cost-effective (incremental cost-effectiveness ratio [ICER] $135,517.33), and upfront dupilumab therapy was not cost-effective in any scenario (ICER $273,181.32). The cost-utility analysis demonstrated that, over a 10-year period per patient, appropriate medical management after ESS cost $54,125.31 and resulted in 2.25 revision ESSs, ASA desensitization after ESS cost $53,775.15 and resulted in 2.02 revision ESSs, ASA desensitization with salvage dupilumab cost $121,176.25 and resulted in 1.68 revision ESSs, and upfront dupilumab cost $185,950.34 and resulted in 1.51 revision ESSs. CONCLUSION: Dupilumab for the treatment of severe CRSwNP was found to be cost-effective as salvage therapy under the willingness-to-pay threshold of $150,000. Further analysis highlighted that the cost-effectiveness of dupilumab was most sensitive to drug price and expected gains in quality of life. This suggests that additional investigation into improving patient population selection and tailoring treatment algorithms may improve the cost-effectiveness of dupilumab in specific scenarios.

Burden of oral anticoagulation in embolic stroke of undetermined source without atrial fibrillation.

OBJECTIVE: Prevention of recurrent stroke in patients with embolic stroke of undetermined source (ESUS) is challenging. The advent of safer anticoagulation in the form of direct oral anticoagulants (DOACs) has prompted exploration of prophylactic anticoagulation for all ESUS patients, rather than anticoagulating just those with documented atrial fibrillation (AF). However, recent trials have failed to demonstrate a clinical benefit, while observing increased bleeding. We modeled the economic impact of anticoagulating ESUS patients without documented AF across multiple geographies. METHODS: CRYSTAL-AF trial data were used to assess ischaemic stroke event rates in ESUS patients confirmed AF-free after long-term monitoring. Anticipated bleeding event rates (including both minor and major bleeds) with aspirin, dabigatran 150 mg, and rivaroxaban 20 mg were sourced from published meta-analyses, whilst a 30% ischaemic stroke reduction for both DOACs was assumed. Cost data for clinical events and pharmaceuticals were collected from the local payer perspective. RESULTS: Compared with aspirin, dabigatran and rivaroxaban resulted in 17.9 and 29.9 additional bleeding events per 100 patients over a patient's lifetime, respectively. Despite incorporating into our model the proposed 30% reduction in ischaemic stroke risk, both DOACs were cost-additive over patient lifetime, as the costs of bleeding events and pharmaceuticals outweighed cost savings associated with the reduction in ischaemic strokes. DOACs added £5953-£7018 per patient (UK), €6683-€7368 (Netherlands), €4933-€9378 (Spain), AUD$5353-6539 (Australia) and $26,768-$32,259 (US) of payer cost depending on the agent prescribed. Additionally, in the U.S. patient pharmacy co-payments ranged from $2468-$12,844 depending on agent and patient plan. In all settings, cost-savings could not be demonstrated even when the modelling assumed 100% protection from recurrent ischaemic strokes, due to the very low underlying risk of recurrent ischaemic stroke in this population (1.27 per 100 patient-years). CONCLUSIONS: Anticoagulation of non-AF patients may cause excess bleeds and add substantial costs for uncertain benefits, suggesting a personalised approach to anticoagulation in ESUS patients.

Very-low-dose aspirin and surveillance colonoscopy is cost-effective in secondary prevention of colorectal cancer in individuals with advanced adenomas: network meta-analysis and cost-effectiveness analysis.

BACKGROUND: Individuals with advanced colorectal adenomas (ACAs) are at high risk for colorectal cancer (CRC), and it is unclear which chemopreventive agent (CPA) is safe and cost-effective for secondary prevention. We aimed to determine, firstly, the most suitable CPA using network meta-analysis (NMA) and secondly, cost-effectiveness of CPA with or without surveillance colonoscopy (SC). METHODS: Systematic review and NMA of randomised controlled trials were performed, and the most suitable CPA was chosen based on efficacy and the most favourable risk-benefit profile. The economic benefits of CPA alone, 3 yearly SC alone, and a combination of CPA and SC were determined using the cost-effectiveness analysis (CEA) in the Malaysian health-care perspective. Outcomes were reported as incremental cost-effectiveness ratios (ICERs) in 2018 US Dollars ($) per quality-adjusted life-year (QALY), and life-years (LYs) gained. RESULTS: According to NMA, the risk-benefit profile favours the use of aspirin at very-low-dose (ASAVLD, ≤ 100 mg/day) for secondary prevention in individuals with previous ACAs. Celecoxib is the most effective CPA but the cardiovascular adverse events are of concern. According to CEA, the combination strategy (ASAVLD with 3-yearly SC) was cost-saving and dominates its competitors as the best buy option. The probability of being cost-effective for ASAVLD alone, 3-yearly SC alone, and combination strategy were 22%, 26%, and 53%, respectively. Extending the SC interval to five years in combination strategy was more cost-effective when compared to 3-yearly SC alone (ICER of $484/LY gain and $1875/QALY). However, extending to ten years in combination strategy was not cost-effective. CONCLUSION: ASAVLD combined with 3-yearly SC in individuals with ACAs may be a cost-effective strategy for CRC prevention. An extension of SC intervals to five years can be considered in resource-limited countries.

Platelet Reactivity in Patients With Acute Coronary Syndromes Awaiting Surgical Revascularization.

BACKGROUND: Dual antiplatelet therapy is recommended for patients with acute coronary syndromes (ACS). Approximately 10% to 15% of these patients will undergo coronary artery bypass graft (CABG) surgery for index events, and current guidelines recommend stopping clopidogrel at least 5 days before CABG. This waiting time has clinical and economic implications. OBJECTIVES: This study aimed to evaluate if a platelet reactivity-based strategy is noninferior to standard of care for 24-h post-CABG bleeding. METHODS: In this randomized, open label noninferiority trial, 190 patients admitted with ACS with indications for CABG and on aspirin and P2Y12 receptor inhibitors, were assigned to either control group, P2Y12 receptor inhibitor withdrawn 5 to 7 days before CABG, or intervention group, daily measurements of platelet reactivity by Multiplate analyzer (Roche Diagnostics GmbH, Vienna, Austria) with CABG planned the next working day after platelet reactivity normalization (pre-defined as ≥46 aggregation units). RESULTS: Within the first 24 h of CABG, the median chest tube drainage was 350 ml (interquartile range [IQR]: 250 to 475 ml) and 350 ml (IQR: 255 to 500 ml) in the intervention and control groups, respectively (p for noninferiority <0.001). The median waiting period between the decision to undergo CABG and the procedure was 112 h (IQR: 66 to 142 h) and 136 h (IQR: 112 to 161 h) (p < 0.001), respectively. In the intention-to-treat analysis, a 6.4% decrease in the median in-hospital expenses was observed in the intervention group (p = 0.014), with 11.2% decrease in the analysis per protocol (p = 0.003). CONCLUSIONS: A strategy based on platelet reactivity-guided is noninferior to the standard of care in patients with ACS awaiting CABG regarding peri-operative bleeding, significantly shortens the waiting time to CABG, and decreases hospital expenses. (Evaluation of Platelet Aggregability in the Release of CABG in Patients With ACS With DAPT; NCT02516267).

Efficacy and safety of rivaroxaban plus aspirin in women and men with chronic coronary or peripheral artery disease.

AIMS: The COMPASS trial demonstrated that the combination of rivaroxaban 2.5 mg twice daily and aspirin 100 mg once daily compared with aspirin 100 mg once daily reduced major adverse cardiovascular events (MACE) in patients with chronic coronary artery disease or peripheral artery disease by 24% during a mean follow-up of 23 months. We explored whether this effect varies by sex. METHODS AND RESULTS: The effects were examined in women and men using log-rank tests and Kaplan-Meier curve. Hazard ratios (HRs) and corresponding 95% confidence intervals (CIs) were obtained from stratified Cox proportional hazards models to explore subgroup effects including subgroup of women and men according to baseline modified REACH risk score. Of 27 395 patients randomized, 18 278 were allocated to receive rivaroxaban plus aspirin (n = 9152) or aspirin alone (n = 9126), and of these, 22.1% were women. Women compared with men had similar incidence rates for MACE and major bleeding but borderline lower rates for myocardial infarction (1.7% vs. 2.2%, P = 0.05). The effect of combination therapy compared with aspirin in women and men was consistent for MACE (women: 3.8% vs. 5.2%, HR 0.72, 95% CI 0.54-0.97; men: 4.2% vs. 5.5%, HR 0.76, 95% CI 0.66-0.89; P interaction 0.75) and major bleeding (women: 3.1% vs. 1.4%, HR 2.22, 95% CI 1.42-3.46; men: 3.2% vs. 2.0%, HR 1.60, 95% CI 1.29-1.97; P interaction 0.19). There was no significant interaction between randomized treatment and baseline modified REACH score above or below the median for MACE or major bleeding. CONCLUSION: In patients with stable coronary artery disease or peripheral artery disease, the combination of rivaroxaban (2.5 mg twice daily) and aspirin compared with aspirin alone appears to produce consistent benefits in women and men, independent of baseline cardiovascular risk.