High-dose Aspirin Research Articles

Concordance Between Patient-Reported Health Data and Electronic Health Data in the ADAPTABLE Trial

Patient-reported health data can facilitate clinical event capture in pragmatic clinical trials. However, few data are available on the fitness for use of patient-reported data in large-scale health research. To evaluate the concordance of a set of variables reported by patients and available in the electronic health record as part of a pragmatic clinical trial. Data from ADAPTABLE (Aspirin Dosing: A Patient-Centric Trial Assessing Benefits and Long-term Effectiveness), a pragmatic clinical trial, were used in a concordance substudy of a comparative effectiveness research trial. The trial randomized 15 076 patients with existing atherosclerotic cardiovascular disease in a 1:1 ratio to low- or high-dose aspirin from April 2016 through June 30, 2019. Concordance of data was evaluated from 4 domains (demographic characteristics, encounters, diagnoses, and procedures) present in 2 data sources: patient-reported data captured through an online portal and data from electronic sources (electronic health record data). Overall agreement, sensitivity, specificity, positive predictive value, negative predictive value, and κ statistics with 95% CIs were calculated using patient report as the criterion standard for demographic characteristics and the electronic health record as the criterion standard for clinical outcomes. Of 15 076 patients with complete information, the median age was 67.6 years (range, 21-99 years), and 68.7% were male. With the use of patient-reported data as the criterion standard, agreement (κ) was high for Black and White race and ethnicity but only moderate for current smoking status. Electronic health record data were highly specific (99.6%) but less sensitive (82.5%) for Hispanic ethnicity. Compared with electronic health record data, patient report of clinical end points had low sensitivity for myocardial infarction (33.0%), stroke (34.2%), and major bleeding (36.6%). Positive predictive value was similarly low for myocardial infarction (40.7%), stroke (38.8%), and major bleeding (21.9%). Coronary revascularization was the most concordant event by data source, with only moderate agreement (κ = 0.54) and positive predictive value. Agreement metrics varied by site for all demographic characteristics and several clinical events. In a concordance substudy of a large, pragmatic comparative effectiveness research trial, sensitivity and chance-corrected agreement of patient-reported data captured through an online portal for cardiovascular events were low to moderate. Findings suggest that additional work is needed to optimize integration of patient-reported health data into pragmatic research studies. ClinicalTrials.gov Identifier: NCT02697916.

High-Dose or Low-Dose Aspirin Application in the Initial Phase of Kawasaki Disease: A Meta-Analysis and Systematic Review

The initial dose of aspirin for Kawasaki disease (KD) is controversial to a great extent. In order to compare the efficacy of high-dose and low-dose aspirin in the treatment of KD, this study included articles containing information on the treatment of KD with aspirin before August 2021, which were collected from public databases. The results of different studies were summarized and weighted by an inverse variance model, and heterogeneity was assessed using the Q-test and I2. A meta-analysis of 12258 patients from nine retrospective studies was conducted. In general, no significant differences between high-dose and low-dose groups were found in the incidence of coronary artery abnormality (CAA) (RR = 1.154; 95% CI = 1.027–1.316) and the incidence of intravenous immunoglobulin (RR = 0.926; 95% CI = 0.594–1.441). But high-dose aspirin might be linked to the shortened duration of fever (RR = −0.134; 95% CI = −0.203–0.064) as well as hospitalized stay (RR = −1.263; 95% CI = −1.392–1.122). Conclusion. For the treatment of the acute phase of KD, low-dose aspirin plus intravenous immunoglobulin could be as effective as high-dose aspirin in preventing CAA. Nonetheless, high-dose aspirin might be related to reducing fever time and hospitalization time.

Antiplatelet agents aspirin and dipyridamole, and the risk of different carcinoma in patients with type 2 diabetes mellitus: A Taiwan retrospective cohort study.

Studies have shown aspirin decreases the risk of some cancers. However, the evidence reported the association between aspirin and cancer risk in the diabetic population. In this study, we investigate whether aspirin and dipyridamole decrease the risk of cancer in patients with type 2 diabetes. A total of 5308 patients with type 2 diabetes were identified by the National Health Insurance from 1998 to 2000 and followed up until 2013. The demographic characteristics among nondipyridamole nor aspirin, aspirin, and dipyridamole users were analyzed by using the χ(2) test. Cox proportional hazard regression models were used to determine the independent effects of no aspirin nor dipyridamole, aspirin, and dipyridamole users on the risk of different cancer. After adjustment with multiple covariates, both low and high doses of aspirin and dipyridamole decrease liver cancer with risk ratios of 0.56 (95% CI, 0.37–0.83), 0.14 (95% CI, 0.05–0.39), 0.61 (95% CI, 0.38–0.99), and 0.28 (95% CI, 0.12–0.66), respectively. Both low and high doses of aspirin decrease any types of cancer with risk ratios of 0.79 (95% CI, 0.64–0.98) and 0.49 (95% CI, 0.34–0.70), respectively. Therefore, we conclude aspirin may decrease any types of cancer and liver cancer, and dipyridamole may decrease the risk of liver cancer in patients with type 2 diabetes.

Burning urticarial plaques in a middle-aged woman

Burning urticarial plaques in a middle-aged woman

A Comprehensive Review of the Pleiotropic Effects of Ticagrelor.

This review summarizes the findings of preclinical studies evaluating the pleiotropic effects of ticagrelor. These include attenuation of ischemia-reperfusion injury (IRI), inflammation, adverse cardiac remodeling, and atherosclerosis. In doing so, it aims to provide novel insights into ticagrelor's mechanisms and benefits over other P2Y12 inhibitors. It also generates viable hypotheses for the results of seminal clinical trials assessing ticagrelor use in acute and chronic coronary syndromes. A comprehensive review of the preclinical literature demonstrates that ticagrelor protects against IRI in the setting of both an acute myocardial infarction (MI), and when MI occurs while on chronic treatment. Maintenance therapy with ticagrelor also likely mitigates adverse inflammation, cardiac remodeling, and atherosclerosis, while improving stem cell recruitment. These effects are probably mediated by ticagrelor's ability to increase local interstitial adenosine levels which activate downstream cardio-protective molecules. Attenuation and augmentation of these pleiotropic effects by high-dose aspirin and caffeine, and statins respectively may help explain variable outcomes in PLATO and subsequent randomized controlled trials (RCTs). Most RCTs and meta-analyses have not evaluated the pleiotropic effects of ticagrelor. We need further studies comparing cardiovascular outcomes in patients treated with ticagrelor versus other P2Y12 inhibitors that are mindful of the unique pleiotropic advantages afforded by ticagrelor, as well as possible interactions with other therapies (e.g., aspirin, statins, caffeine).

Kawasaki disease: a comprehensive review

Introduction and purpose: Kawasaki disease is an acute, self-limited vasculitis of medium arteries, and it affects children under 5 years old. It can lead to coronary artery aneurysms.
 Brief description of the state of knowledge: Pathogenesis of Kawasaki disease is unclear. The diagnosis is based on the clinical findings. The characteristic symptoms are polymorphous skin rashes, conjunctivitis, erythema, dryness, cracking and bleeding of the lips, erythema and swelling of palms and soles and cervical lymphadenopathy. Kawasaki disease is defined as a fever for 5 days accompanied by 4 or more of the diagnostic symptoms described above. The classic diagnosis is based on the exclusion of other diseases too. The diagnosis of incomplete Kawasaki disease is suggested if less than 4 main clinical features are found. It is the most common cause of acquired heart disease in children. Kawasaki disease can lead to coronary artery aneurysm, myocarditis and pericarditis so it is very important to treat this illness correctly. Basic treatment is a single infusion of intravenous immunoglobulin and high-dose aspirin. Recurrent Kawasaki disease (persistent fever after first line treatment with IVIG and aspirin) requires the same treatment as used for the first episode. Corticosteroids and immune-modulating therapies can be used as second and third line options. Quick recognition and early treatment result in a reduction of coronary artery abnormalities.
 Conclusion: This article reviews basic informations, history, epidemiology, pathophysiology, clinical presentation, diagnostic criteria, complications and treatment of Kawasaki disease.

Aspirin-Mediated Reset of Preeclamptic Placental Stem Cell Transcriptome - Implication for Stabilized Placental Function.

Preeclampsia (PE) is a pregnancy-specific disease, occurring in ~ 2-10% of all pregnancies. PE is associated with increased maternal and perinatal morbidity and mortality, hypertension, proteinuria, disrupted artery remodeling, placental ischemia and reperfusion, and inflammation. The mechanism of PE pathogenesis remains unresolved explaining limited treatment. Aspirin is used to reduce the risk of developing PE. This study investigated aspirin's effect on PE-derived placenta mesenchymal stem cells (P-MSCs). P-MSCs from chorionic membrane (CM), chorionic villi, membranes from the maternal and amniotic regions, and umbilical cord were similar in morphology, phenotype and multipotency. Since CM-derived P-MSCs could undergo long-term passages, the experimental studies were conducted with this source of P-MSCs. Aspirin (1mM) induced significant functional and transcriptomic changes in PE-derived P-MSCs, similar to healthy P-MSCs. These include cell cycle quiescence, improved angiogenic pathways, and immune suppressor potential. The latter indicated that aspirin could induce an indirect program to mitigate PE-associated inflammation. As a mediator of activating the DNA repair program, aspirin increased p53, and upregulated genes within the basic excision repair pathway. The robust ability for P-MSCs to maintain its function with high dose aspirin contrasted bone marrow (M) MSCs, which differentiated with eventual senescence/aging with 100 fold less aspirin. This difference cautions how data from other MSC sources are extrapolated to evaluate PE pathogenesis. Dysfunction among P-MSCs in PE involves a network of multiple pathways that can be restored to an almost healthy functional P-MSC. The findings could lead to targeted treatment for PE.

Association of Genetic Polymorphisms in Kawasaki Disease with the Response to Intravenous Immunoglobulin Therapy.

Kawasaki disease (KD) is an acute febrile and systemic vasculitis disease mainly affecting children < 5years old. Although the first case of KD was reported in 1967 and despite extensive research on KD since then, the cause of the disease remains largely unknown. The most common complications of KD are coronary artery lesions (CAL), which significantly increase the risk of coronary heart disease. The standard treatment for KD is high-dose intravenous immunoglobulin (IVIG) plus aspirin within 10days from symptoms' appearance, which has been shown to decrease the incidence of CAL to 5-7%. Despite the benefits of IVIG, about 25% of the patients treated with IVIG develop resistance or are unresponsive to the therapy, which represents an important risk factor for CAL development. The cause of IVIG unresponsiveness has not been fully elucidated. However, the role of gene polymorphisms in IVIG response has been suggested. Herein, we comprehensively review genetic polymorphisms in KD that have been associated with IVIG resistance/unresponsiveness and further discuss available models to predict IVIG unresponsiveness.Kindly check and confirm inserted city in affiliation [1] is correctly identified.confirm.

Fatal adverse events of rivaroxaban combined with aspirin: an analysis using data from VigiBase

PurposeThe aim of this study was to analyze the clinical characteristics of fatal adverse events (AEs) of rivaroxaban combined with aspirin and to underline the importance of the rational use of drugs.MethodsThe WHO global database of reported potential side effects of medicinal products (VigiBase) was searched for fatal AEs in the combined use of rivaroxaban and aspirin, and the clinical characteristics of those cases with sufficient information (vigiGrade completeness score ≥ 0.80) were analyzed.ResultsBy January 19, 2020, 2309 fatal adverse event reports of rivaroxaban combined with aspirin from 21 countries were entered in VigiBase. One hundred and twenty cases contained further information, of which 42 were female (35%) and 78 were male (65%). The median age was 75 (range 34 to 93) years, and 109 cases (91%) were elderly patients (≥ 65 years). The AEs listed in the fatal case reports included bleeding in 114 cases (mainly intracranial hemorrhage and gastrointestinal hemorrhage, 59 and 46 respectively, accounting for 88%) and ischemic events in six cases (ischemic stroke in three, acute myocardial infarction in two, myocardial infarction combined with acute liver failure in one). Among the patients with bleeding events, 108 (95%) had existing risk factors for bleeding or for interacting with aspirin or rivaroxaban. These may be divided into the following: diseases (hypertension, renal impairment, history of stroke, peptic ulcer, or previous bleeding), drugs (high dose aspirin, antiplatelet drugs, anticoagulants, P-gp inhibitors/CYP3A4 inhibitors, non-steroidal anti-inflammatory drugs, steroids, and selective serotonin reuptake inhibitors), or other factors (e.g., elderly, low body weight, or excessive intake of ginger, fish oil, or alcohol). There were 45 cases with two or more of these risk factors in addition to rivaroxaban and aspirin. Patients with ischemic events are often in very high-risk groups of atherosclerotic cardiovascular disease (ASCVD) or self-discontinuation of treated drugs. Medication errors occurred in 24 patients (20%): excessive treatment in 17 cases, contraindication in three, frequency error in two, excessive treatment combined with contraindication in one, and self-discontinuation in one.ConclusionsFatal AEs related to rivaroxaban combined with aspirin, including bleeding and ischemic events, have been reported mostly in the elderly, and sometimes involved medication errors. The fatal AEs mainly manifested as serious bleeding, and most of them occurred in patients with concurrent multiple risk factors. Monitoring coagulation during rivaroxaban treatment is recommended in very high-risk ASCVD populations, and attention should be paid to prevention of medication errors.

P-427 Pregnancy outcomes following recurrent first-trimester miscarriage: a retrospective cohort study

Abstract Study question What are the subsequent pregnancy outcomes (livebirths, miscarriages or other adverse pregnancy outcomes) in a cohort of women with recurrent miscarriage (RM)? Summary answer The overall live birth rate in women with RM was 62% (466/748), falling to 44% in women aged &amp;gt;40 and 54% in women with infertility. What is known already RM affects approximately 1% of women of reproductive age. RM is recognized as a prognostic indicator for subsequent pregnancies and adverse pregnancy outcomes including ante-partum hemorrhage, diabetes, preterm birth, small for gestational age and perinatal death. While RM has known associations with advanced maternal age, obesity, diabetes, thyroid dysfunction and endometriosis, approximately 50% of women/couples will be left without an explanation for their pregnancy loss, even after completing investigations. Study design, size, duration A retrospective cohort study was undertaken to identify subsequent pregnancy outcomes in women with RM, where RM referral criteria are 3 consecutive first-trimester miscarriages. Women attending the pregnancy loss clinic at a tertiary university hospital in the Republic of Ireland over a 12-year period (2008 - 2020) with a confirmed diagnosis of primary or secondary first-trimester RM were eligible for inclusion. In total, 923 charts were identified for review against the eligibility criteria. Participants/materials, setting, methods Women with non-consecutive first trimester miscarriages or ectopic pregnancy were excluded. Epidemiological and clinical information was gathered from paper and electronic medical records. Data were analysed descriptively using SPSS (Version 27). Main results and the role of chance Of 748 women identified, 332(44%) had primary RM, 416(56%) had secondary RM. The median age was 36(range 19-47) years with 12% aged under 29 and 64% of women aged ≥35. 142(19%) had a history of infertility with 43(5.7%) attending for ART. 12% of women had anti-nuclear antibodies(89/742), 8% had abnormal thyroid function tests(60/742), 4.7% were heterozygous carriers of the Factor V Leiden gene mutation(35/737), 1.5% had positive anti-cardiolipin antibodies(11/733), 2% were carriers of a Prothrombin gene mutation(7/343) and 1% had elevated HbA1c levels(7/742). Fetal karyotype was recorded in 141 pregnancies, with 111 abnormal results(78%;111/141). Trisomy(T) 16 was most common(17/111; 15%) followed by T21 and T22(n = 14; 13%). Parental karyotyping of 697 sets of parents identified 28 balanced translocations(4%; 28/697). Prescribed pharmacological treatments included high dose folic acid(75%; n = 548/728), aspirin(96%; 696/726), progesterone (52%; 389/728), tinzaparin(24%; 175/727), prednisolone(4%; 28/726), metformin(2%; 12/727) and hydroxychloroquine(1%; 7/727). 573 women had a subsequent pregnancy (76.6%); 359(62%; 359/573) had a live birth, 190 had a miscarriage(33%) and 18(3%) had an adverse pregnancy outcome such as ectopic pregnancy, stillbirth or second-trimester miscarriage. Including successive pregnancies over the study period, the overall live birth rate was 62%(466/748), falling to 44% in women aged &amp;gt;40 and 54% in women with infertility. Limitations, reasons for caution This work covers a 12-year period, and while the RM clinic staffing is largely unchanged, some changes in management of RM patients has occurred in this time, reflecting up-to-date evidence and greater public awareness. Furthermore, the adoption of an electronic health chart in 2017 may have affected data availability. Wider implications of the findings Our findings confirm RM occurs more frequently in women aged &amp;gt;35. Aneuploidy remains a leading cause of miscarriage. Age is a prognostic indicator for livebirth after RM. These findings will facilitate counselling in this cohort. The substantial rates of prescribed medications and infertility in women with RM merit further exploration. Trial registration number N/A

Early and mid-term results of transcatheter closure of perimembranous ventricular septal defect using Amplatzer Ductal Occluder type 1

Objectives: To study the early and midterm results of transcatheter closure of perimembranous VSD using Amplatzer Ductal Occluder type 1.&#x0D; Methods: Prospective study of one hundred thirteen patients with perimembranous VSD (PMVSD) who referred to catheterization laboratory and underwent transcatheter closure of their defects by using Amplatzer Ductal Occluder type 1 device. Routine right and left heart catheterization was performed with evaluation of the pulmonary and systemic pressure. All the procedures were done under fluoroscopy and transthoracic echocardiography guide. Follow up evaluations were done between 1 month and 12 months after discharge (mean 4.5 ± 1.13 months) with transthoracic echocardiography and 12 lead electrocardiography.&#x0D; Results: The age of patients range from 2 to 34 years at procedure (mean 10.60 ± 7.31 years), weight range from 10 to 85 kg (mean 32.38 ± 19.70 kg). The mean echocardiographic defect size was 5.69 ± 1.63 mm and the mean angiographic size was 5.89 ± 1.70 mm. The devices size used range from 6/4 – 16/14 mm. The most common device used was 10/8. The ADOs were successfully implanted in 108 patients (95.6 %). The VSD occlusion rate was 85.2% at completion of the procedure, rising up to 90.7 % next day at discharge, 93.5% at one month and 97.2% at 6 months during follow-up. Two patients (1.9%) developed CAVB, one case within 24 hours and the other case after 2 days of the procedure, they were admitted in hospital treated by temporary pacemaker implantation, steroids and NSAIDs (high dose aspirin) with complete remission within 5 days. Conclusion: Transcatheter closure of PMVSD with ADO1 in children is a safe and effective treatment associated with excellent success and closure rates and with no significant adverse events, but long-term follow-up in a large number of patients would be warranted.

CYCLOOXYGENASE-2 INHIBITION AS A NEW TOOL TO COMBAT ANGIOGENESIS INHIBITOR-INDUCED HYPERTENSION AND RENAL TOXICITY

Objective: Angiogenesis inhibitors are effective anti-cancer agents, but also cause hypertension and renal injury. Earlier, we observed in rats that high-dose aspirin (capable of blocking cyclooxygenase (COX)-1 and -2) prevented these side effects better than low-dose aspirin (blocking COX-1 only). Therefore, we hypothesized that selective COX-2 inhibition would prevent toxicity during angiogenesis inhibition, and that this toxicity involves a reduced ratio of vasodilator/constrictor COX-derived prostanoids, i.e., prostacyclin (PGI2) and thromboxane (TXA2). Design and method: Male WKY rats received vehicle, angiogenesis inhibition (sunitinib (SU), 14 mg/kg/day) alone or combined with COX-2 inhibition (celecoxib, 10 mg/kg/day), a PGI2 analogue (iloprost 100 mcg/kg/day), or a dual TXA2 synthase/receptor antagonist (picotamide, 2.5 mg/kg/day) for 8 days (n = 7–8/group). Mean arterial pressure (MAP) was measured via radiotelemetry, vascular function was assessed via wire myography, and biochemical measurements were performed by ELISA. Results: SU induced a rapid increase in MAP (16 ± 2 vs. 3 ± 1 mmHg after vehicle on day 6, P &lt; 0.001), which was blunted by celecoxib (10 ± 2 mmHg on day 6, P = 0.06 versus SU), temporarily attenuated by iloprost (on treatment days 1–2) and unaffected by picotamide. Wire myography demonstrated a trend towards increased vasoconstrictor response to endothelin-1 in iliac arteries after SU, which was prevented by celecoxib (P &lt; 0.001). SU increased albuminuria (0.6 ± 0.1 vs. 0.3 ± 0.1 mg/24 h after vehicle; P &lt; 0.001), and this was prevented by celecoxib only (0.4 ± 0.1 mg/24 h, P = 0.01 vs. SU). SU increased the PGI2/TXA2 ratio in both plasma (3.0 ± 1.1 vs. 0.6 ± 0.2 after vehicle, P = 0.02) and urine (23 ± 2.1 vs. 0.9 ± 0.2 after vehicle, P &lt; 0.0001). Conclusions: In conclusion, selective COX-2 inhibition combats angiogenesis inhibitor-induced hypertension and renal toxicity. SU paradoxically increases the PGI2/TXA2 ratio, particularly in the kidney. Although this upregulation might initially be protective, it could eventually contribute to renal toxicity, most likely because PGI2 exerts deleterious effects in excessive concentrations. Targeting excessive renal PGI2 production might be another promising strategy to prevent renal toxicity during angiogenesis inhibition.

Fixed-dose aspirin monotherapy compared with thromboelastography directed antiplatelet therapy in long-term management of left ventricular assist devices.

The role of thromboelastography (TEG) in managing antiplatelet therapy (APT) in left ventricular assist devices (LVADs) is controversial. Our aim was to determine whether removal of TEG from an LVAD-specific APT protocol reduced late-onset bleeding without increasing thromboembolic complications. We performed a single-center, retrospective cohort study including all recipients of a continuous-flow LVAD between April 2005 and November 2019 (n = 293). LVAD recipients before June 1, 2017 (n = 221) whose APT was monitored and adjusted using TEG were compared with LVAD recipients after June 1,2017 (n = 72) where TEG was not utilized. Occurrence of late-onset bleeding events after postoperative Day 7 and thromboembolic events were collected. APT doses, warfarin use and International normalized ratio (INR) values were collected at discharge and at 1, 3, 6, and 12-months postimplantation. Over a median 12-month follow-up, INTERMACS major bleeding events occurred in 35% of patients where TEG was utilized compared with 29% where TEG was not utilized (p = 0.375), and procedural intervention was required in 29% compared with 18%, respectively (p = 0.058). Use of TEG was associated with higher doses of aspirin (>325 mg) (41% compared with none) and use of a second antiplatelet (dipyridamole) (43% compared to 1%). Despite this, there was no significant difference in thromboembolic events (15% in each). Our study suggests the use of TEG led to increased doses of aspirin as well as adding a second antiplatelet agent, without improving outcomes in LVAD recipients. Furthermore, the removal of TEG from an LVAD-specific APT protocol did not worsen thromboembolic outcomes.

Differential effects of cyclo-oxygenase 1 and 2 inhibition on angiogenesis inhibitor-induced hypertension and kidney damage.

Vascular endothelial growth factor antagonism with angiogenesis inhibitors in cancer patients induces a ‘preeclampsia-like’ syndrome including hypertension, proteinuria and elevated endothelin (ET)-1. Cyclo-oxygenase (COX) inhibition with aspirin is known to prevent the onset of preeclampsia in high-risk patients. In the present study, we hypothesised that treatment with aspirin would prevent the development of angiogenesis inhibitor-induced hypertension and kidney damage. Our aims were to compare the effects of low-dose (COX-1 inhibition) and high-dose (dual COX-1 and COX-2 inhibition) aspirin on blood pressure, vascular function, oxidative stress, ET-1 and prostanoid levels and kidney damage during angiogenesis-inhibitor therapy in rodents. To this end, Wistar Kyoto rats were treated with vehicle, angiogenesis inhibitor (sunitinib) alone or in combination with low- or high-dose aspirin for 8 days (n=5–7/group). Our results demonstrated that prostacyclin (PGI2) and ET-1 were increased during angiogenesis-inhibitor therapy, while thromboxane (TXA2) was unchanged. Both low- and high-dose aspirin blunted angiogenesis inhibitor-induced hypertension and vascular superoxide production to a similar extent, whereas only high-dose aspirin prevented albuminuria. While circulating TXA2 and prostaglandin F2α levels were reduced by both low- and high-dose aspirin, circulating and urinary levels PGI2 were only reduced by high-dose aspirin. Lastly, treatment with aspirin did not significantly affect ET-1 or vascular function. Collectively our findings suggest that prostanoids contribute to the development of angiogenesis inhibitor-induced hypertension and renal damage and that targeting the prostanoid pathway could be an effective strategy to mitigate the unwanted cardiovascular and renal toxicities associated with angiogenesis inhibitors.

Both G protein–coupled and immunoreceptor tyrosine-based activation motif receptors mediate venous thrombosis in mice

AbstractPlatelets are critical in hemostasis and a major contributor to arterial thrombosis (AT). (Pre)clinical studies suggest platelets also contribute to venous thrombosis (VT), but the mechanisms are largely unknown. We hypothesized that in VT, platelets use signaling machinery distinct from AT. Here we aimed to characterize the contributions of platelet G protein–coupled (GPCR) and immunoreceptor tyrosine-based activation motif (ITAM) receptor signaling to VT. Wild-type (WT) and transgenic mice were treated with inhibitors to selectively inhibit platelet-signaling pathways: ITAM-CLEC2 (Clec2mKO), glycoprotein VI (JAQ1 antibody), and Bruton's tyrosine kinase (ibrutinib); GPCR-cyclooxygenase 1 (aspirin); and P2Y12 (clopidogrel). VT was induced by inferior vena cava stenosis. Thrombin generation in platelet-rich plasma and whole-blood clot formation were studied ex vivo. Intravital microscopy was used to study platelet–leukocyte interactions after flow restriction. Thrombus weights were reduced in WT mice treated with high-dose aspirin + clopidogrel (dual antiplatelet therapy [DAPT]) but not in mice treated with either inhibitor alone or low-dose DAPT. Similarly, thrombus weights were reduced in mice with impaired ITAM signaling (Clec2mKO + JAQ1; WT + ibrutinib) but not in Clec2mKO or WT + JAQ1 mice. Both aspirin and clopidogrel, but not ibrutinib, protected mice from FeCl3-induced AT. Thrombin generation and clot formation were normal in blood from high-dose DAPT- or ibrutinib-treated mice; however, platelet adhesion and platelet–neutrophil aggregate formation at the vein wall were reduced in mice treated with high-dose DAPT or ibrutinib. In summary, VT initiation requires platelet activation via GPCRs and ITAM receptors. Strong inhibition of either signaling pathway reduces VT in mice.

Pharmacologic interventions for Kawasaki disease in children: A network meta-analysis of 56 randomized controlled trials

SummaryBackgroundAlthough the current consensus recommends a standard treatment of high-dose intravenous immunoglobulin with high-dose aspirin to manage Kawasaki disease (KD), the use of different adjunctive therapies remains controversial. The aim of the current network meta-analysis (NMA) was to compare the efficacy and tolerability of different existing interventions for the initial and refractory stages of KD.MethodsAn NMA of randomised controlled trials (RCTs) was conducted using the frequentist model applied after electronic searches in PubMed, Embase, ScienceDirect, ProQuest, ClinicalTrials.gov, ClinicalKey, Cochrane CENTRAL, and Web of Science. The main outcomes were reduced fever duration/diminished severity of fever subsided. The initial stage of KD was defined as the first stage to treat patients with KD; the refractory stage of KD represents KD patients who failed to respond to standard KD treatment. The cut-off points for intravenous immunoglobulin (IVIG) were low (100–400 mg), medium (1 g), and high (at least 2 g).FindingsA total of fifty-six RCTs with 6486 participants were included. NMA demonstrated that the medium-dosage IVIG + aspirin + infliximab [mean difference=−1.76 days (95% confidence intervals (95% CIs): −3.65 to 0.13 days) compared to high-dosage IVIG + aspirin] exhibited the shortest fever duration; likewise, the medium-dosage IVIG + aspirin + infliximab [odds ratio (OR)=0.50, 95% CIs: 0.18–1.37 compared to high-dosage IVIG + aspirin] exhibited the smallest incidence of coronary artery lesion (CAL) in the initial-stage KD. In the refractory-stage KD, the high-dosage IVIG + pulse steroid therapy (OR=0.04, 95% CIs: 0.00–0.43 compared to the high-dosage IVIG only) had the best rate of decline of fever; likewise, the high-dosage IVIG + ciclosporin [OR=0.05 (95% CIs: 0.00–1.21) compared to the high-dosage IVIG only] exhibited the smallest incidence of CAL. Infliximab significantly improved resolution compared to the high-dosage IVIG only group (OR=0.20, 95%CIs: 0.07–0.62) in refractory-stage KD.InterpretationThe NMA demonstrated that the combination therapy with the standard therapy of IVIG and aspirin might have an additional effect on shortening the duration of fever and lowering the CAL incidence rate in patients with acute KD. Moreover, the combination therapy with high-dose IVIG and pulse steroid therapy or cyclosporine therapy might have an additional effect on improving the rate of decline of fever and lowering the incidence rate of CAL in children with refractory KD. Because some of the findings of this NMA should be considered hypothesis-generating rather than confirmatory, further evidence from de novo randomised trials is needed to support our results.FundingNone.

Clinical Profile and Outcome and Risk Factors of Cardiovascular Involvement in Hospitalized Children with Kawasaki Disease

Kawasaki disease (KD), also known as Kawasaki syndrome, is an acute febrile illness of unknown cause that primarily affects children younger than 5 years of age. The present study was conducted to study the clinical profile and outcome and risk factors of Kawasaki disease in children. This observational prospective study was conducted in cardiology ward with a diagnosis of Kawasaki disease from 1st June 2020 to 31 July 2021 in Bangabandhu Sheikh Mujib Medical University Hospital Dhaka, Bangladesh. Forty five (45) children aged between 3 months to 10 years were studied. Kawasaki disease is more prevalent among male child (73.33%). Most commonly encountered risk factor for cardiovascular involvement especially coronary dilatation or aneurysmal change is more observed in younger age of presentation. Fever, rash, conjunctivitis, erythema and edema of limbs, periungual skin desquamations are the presenting features. Cardiovascular involvement of left main coronary artery dilation is the most frequently observed aneurismal change observed among study population which was evident in 68% of the children having coronary involvement. All the study patient received high dose aspirin (100%) and 93% received IVIG of whom 6.66% had IVIG- resistant Kawasaki disease. Commonly occurring complication is uveitis (17.77%). Among the total 45 study population 1 patient expired (2.22%).Clinicians should have a high index of suspicion of Kawasaki disease in persistently febrile patients and once clinically diagnosed, echocardiography should be done and IVIG therapy along with aspirin should be started, specially in infants (&lt;6 months) as they have the higher tendency to develop coronary aneurysm.

Longitudinal Study of Analgesic Use and Risk of Incident Persistent Tinnitus.

Persistent tinnitus is common, disabling, and difficult to treat. High-dose aspirin may precipitate tinnitus, but longitudinal data on typical dose aspirin and other analgesics are scarce. To investigate independent associations of aspirin, NSAIDs, and acetaminophen and risk of incident persistent tinnitus. Longitudinal cohort study. Nurses' Health Study II (1995-2017). A total of 69,455 women, age 31-48 years, without tinnitus at baseline. Information on analgesic use and tinnitus obtained by biennial questionnaires. After 1,120,936 person-years of follow-up, 10,452 cases of incident persistent tinnitus were reported. For low-dose aspirin, the risk of developing persistent tinnitus was not elevated among frequent low-dose aspirin users. For moderate dose aspirin, frequent use was associated with higher risk of tinnitus among women aged < 60 years, but not among older women (p-interactionage = 0.003). Compared with women aged < 60 using moderate-dose aspirin < 1 day/week, the multivariable-adjusted hazard ratio (MVHR, 95% CI) among women using moderate-dose aspirin 6-7 days per week was 1.16 (1.03, 1.32). Among all women, frequent non-aspirin non-steroidal anti-inflammatory drug (NSAID) or acetaminophen use was associated with higher risk. Compared with women using NSAIDs <1 day/week, the MVHR for use 4-5days/week was 1.17 (1.08, 1.28) and for 6-7days/week was 1.07 (1.00, 1.16) (p-trend=0.001). For acetaminophen, compared with use <1 day/week, the MVHR for use 6-7days/week was 1.18 (1.07, 1.29) (p-trend=0.002). Information on tinnitus and analgesic use was self-reported. Information on indications for analgesic use was not available. Studies in non-White women and men are needed. The risk of developing persistent tinnitus was not elevated among frequent low-dose aspirin users. Among younger women, frequent moderate-dose aspirin use was associated with higher risk. Frequent NSAID use and frequent acetaminophen use were associated with higher risk of incident persistent tinnitus among all women, and the magnitude of the risks tended to be greater with increasing frequency of use. Our results suggest analgesic users are at higher risk for developing tinnitus and may provide insight into the precipitants of this challenging disorder, but additional investigation to determine whether there is a causal association is needed.

Aspirin Attenuates Hyperoxia-Induced Acute Respiratory Distress Syndrome (ARDS) by Suppressing Pulmonary Inflammation via the NF-κB Signaling Pathway.

Acute respiratory distress syndrome (ARDS) is a common destructive syndrome with high morbidity and mortality rates. Currently, few effective therapeutic interventions for ARDS are available. Clinical trials have shown that the effectiveness of aspirin is inconsistent. The contribution of platelets to the inflammatory response leading to the development of ARDS is increasingly recognized. The antiplatelet agent aspirin reportedly exerts a protective effect on acid- and hyperoxia-induced lung injury in murine models. Our previous study showed that pretreatment with aspirin exerts protective effects on hyperoxia-induced lung injury in mice. However, the mechanisms and therapeutic efficacy of aspirin in the posttreatment of hyperoxia-induced acute lung injury (ALI) remain unclear. In this study, we used a homozygous NF-κB-luciferase+/+ transgenic mouse model and treated mice with low-dose (25 μg/g) or high-dose (50 μg/g) aspirin at 0, 24, and 48 h after exposure to hyperoxia (inspired oxygen fraction (FiO2) > 95%). Hyperoxia-induced lung injury significantly increased the activation of NF-κB in the lung and increased the levels of macrophages infiltrating the lung and reactive oxygen species (ROS), increased the HO-1, NF-κB, TNF-α, IL-1β, and IL-4 protein levels, and reduced the CC10, SPC, eNOS, Nrp-1, and IκBα protein levels in the lung tissue. Pulmonary edema and alveolar infiltration of neutrophils were also observed in the lung tissue of mice exposed to hyperoxia. However, in vivo imaging revealed that posttreatment with aspirin reduced luciferase expression, suggesting that aspirin might reduce NF-κB activation. Posttreatment with aspirin also reduced hyperoxia-induced increases in the numbers of lung macrophages, intracellular ROS levels, and the expression of TNF-α, IL-1β, and IL-4; it also increased CC10, SPC and Nrp-1 levels compared with hyperoxia exposure alone. Lung histopathology also indicated that the aspirin posttreatment significantly reduced neutrophil infiltration and lung edema compared with hyperoxia exposure alone. Aspirin effectively induces an anti-inflammatory response in a model of hyperoxia-induced lung injury. Thus, aspirin may have potential as a novel treatment for hyperoxia-induced ALI.

Controversies in Allergy: Aspirin Desensitization or Biologics for Aspirin-Exacerbated Respiratory Disease—How to Choose

Aspirin-exacerbated respiratory disease (AERD) can be a frustratingly complex syndrome to treat. Until recently, standard medical and surgical therapies for patients' asthma and chronic rhinosinusitis with nasal polyposis were the primary treatment modalities available, combined with either complete avoidance of all aspirin and nonsteroidal anti-inflammatory medications, or aspirin desensitization and initiation of high-dose aspirin therapy. There are now several targeted respiratory biologics added to the available armament for patients with AERD and choosing between this ever-growing list of options can be daunting for both patients and their clinicians. This review includes our understanding and interpretation of the existing data for each option, along with our own approach to weighing the pros and cons of each treatment for individual patients.