Circulating Blood Biomarkers and Risk of Venous Thromboembolism in Cancer Patients: A Systematic Review and Meta-Analysis.

BACKGROUND: Cancer patients have an increased risk of venous thromboembolism (VTE). Currently, the availability of highly discriminatory prediction models for VTE in cancer patients is limited. The implementation of biomarkers in prediction models might lead to refined VTE risk prediction. In this systematic review and meta-analysis, we aimed to evaluate candidate biomarkers and their association with cancer-associated VTE. METHODS: We searched Medline, EMBASE and Cochrane Central for studies that evaluated biomarkers in adult cancer patients from inception to September 2022. We included studies reporting on VTE after a cancer diagnosis with biomarker measurements performed at a defined timepoint. Median/Mean differences (for continuous measures) and Odds Ratios (for dichotomous measures) with 95% confidence intervals were estimated and pooled using random-effects models. RESULTS: We included 114 studies in the systematic review. Of these, 50 studies were included in the meta-analysis. We identified two biomarkers at cancer diagnosis (factor VIII and time to peak thrombin), three biomarkers pre-chemotherapy (d-dimer, fibrinogen and mean platelet volume) and, one biomarker preoperatively (platelet count) that had significant median or mean differences. Additionally, we found that hemoglobin <100g/L and white blood count >11 x 109/L were significantly associated with future VTE risk only when measured at cancer diagnosis. Pre-chemotherapy neutrophil lymphocyte ratio >3 and preoperative platelet count ≥400 x 109/L were also found to be associated with future VTE risk. CONCLUSIONS: In conclusion, this study identified nine candidate blood biomarkers that may help in optimizing VTE prediction in cancer patients that should be further explored in future studies.

Does celecoxib prescription for pain management impact post-tonsillectomy hemorrhage requiring surgery? A retrospective observational cohort study.

BACKGROUND: Adenotonsillectomy and tonsillectomy (now referred to as tonsillectomy thereafter) are common pediatric surgeries. Postoperative complications include hemorrhage requiring surgery (2-3% of cases) and pain. While non-steroidal anti-inflammatory drugs are commonly administered for post-surgical pain, controversy exists regarding bleeding risk with cyclo-oxygenase-1 inhibition and associated platelet dysfunction. Preliminary evidence suggests selective cyclo-oxygenase-2 inhibitors, for example celecoxib, effectively manage pain without adverse events including bleeding. Given the paucity of data for routine celecoxib use after tonsillectomy, we investigated the association between post-operative celecoxib prescription and post-tonsillectomy hemorrhage requiring surgery using chart-review data from the Children's Hospital of Eastern Ontario, Canada. METHODS: After ethics approval we performed a retrospective single-center observational cohort study in children <18 yrs undergoing tonsillectomy from January 2007 to December 2017. Cases of adenoidectomy alone were excluded due to low bleed rates. The primary outcome was the proportion of patients with post-tonsillectomy hemorrhage requiring surgery. The association between a celecoxib prescription and post-tonsillectomy hemorrhage requiring surgery was estimated using inverse probability of treatment weighting based on propensity scores and using generalized estimating equations to accommodate clustering by surgeon. RESULTS: An initial patient cohort of 6468 was identified and 5846 children with complete data were included in analyses. Median (interquartile range) age was 6.10 (4.40, 9.00) years and 46% were female. In our cohort, 28.1% (n=1644) were prescribed celecoxib. Among the 4996 tonsillectomy patients, 1.7% (n=86) experienced post-tonsillectomy hemorrhage requiring surgery. The proportion with post-tonsillectomy hemorrhage requiring surgery among patients who had a tonsillectomy and were or were not prescribed celecoxib was 1.94% (30/1548; 95% CI: 1.36-2.75) and 1.62% (56/3448; 95% CI: 1.25-2.10), respectively. Modelling did not identify an association between celecoxib prescription and increased odds of post-tonsillectomy hemorrhage requiring surgery (OR=1.4, 95% CI: 0.85-2.31, p=0.20). CONCLUSIONS: Celecoxib does not significantly increase the odds of post-tonsillectomy hemorrhage requiring surgery, after adjusting for covariates. This large pediatric cohort study of celecoxib administered after tonsillectomy provides compelling evidence for safety but requires confirmation with a multi-site randomized controlled trial.

Inherited thrombophilia gene mutations and risk of venous thromboembolism in patients with cancer: A systematic review and meta-analysis.

In the general population, individuals with an inherited thrombophilia have a higher risk of thrombosis, but the effect of inherited thrombophilia on the risk of cancer-associated venous thromboembolism (VTE) remains controversial. Our objective was to determine the risk of VTE in cancer patients with inherited thrombophilia. We conducted a systematic review and meta-analysis of studies reporting on VTE after a cancer diagnosis in adult patients who were tested for inherited thrombophilia. In September 2022, we searched Medline, EMBASE, and Cochrane Central. Two reviewers screened the abstracts/full texts and assessed study quality using the Quality in Prognostic Studies tool. We used Mantel-Haenszel random-effects models to estimate pooled odds ratios (OR) of VTE and 95% confidence intervals (95%CI). We included 37 and 28 studies in the systematic review and meta-analysis, respectively. Most studies focused on specific cancer types and hematologic malignancies were rare. The risk of VTE was significantly higher in cancer patients with non-O (compared with O) blood types (OR: 1.56 [95% CI: 1.28-1.90]), Factor V Leiden, and Prothrombin Factor II G20210A mutations compared with wild types (OR: 2.28 [95% CI: 1.51-3.48] and 2.14 [95% CI: 1.14-4.03], respectively). Additionally, heterozygous and homozygous methylenetetrahydrofolate reductase C677T had ORs of 1.50 (95% CI: 1.00-2.24) and 1.38 (95% CI: 0.87-2.22), respectively. Among those with Plasminogen-Activator Inhibitor-1 4G/5G, Vascular Endothelial Growth Factor (VEGF) A C634G, and VEGF C2578A mutations, there was no significant association with VTE. In conclusion, this meta-analysis provided evidence that non-O blood types, Factor V Leiden, and Prothrombin Factor II G20210A mutations are important genetic risk factors for VTE in cancer patients.

Network meta-analysis can inform the ethical evaluation of trials that randomise away from standard of care: The case of symptomatic carotid stenosis.

OBJECTIVE: Little guidance exists on the conduct of randomised clinical trials (RCT) that seek to randomise patients away from standard of care. We sought to test the technique of network meta-analysis (NMA) to ascertain best available evidence for the purposes of informing the ethical evaluation of RCTs under these circumstances. We used the example of RCTs for patients with symptomatic, moderate to severe carotid stenosis that seek to compare surgical intervention plus medical therapy (standard of care) versus medical therapy (less than standard of care). STUDY DESIGN AND SETTING: Network meta-analysis of RCTs of adults with symptomatic carotid artery stenosis of 50%-99% who were treated with carotid endarterectomy (CEA), carotid artery stenting (CAS), or medical therapy (MT). The primary outcome was any stroke or death until end of follow-up, and secondary outcome was 30-day risk of ipsilateral stroke/death. RESULTS: We analysed eight studies, with 7187 subjects with symptomatic moderate/severe stenosis (50%-99%). CEA was more efficacious than MT (HR = 0.82, 95% credible intervals [95% CrI] = 0.73-0.92) and CAS (HR 0.73, 95% CrI = 0.62-0.85) for the prevention of any stroke/death. At 30 days, the odds of experiencing an ipsilateral stroke/death were significantly lower in the CEA group compared to both MT (OR = 0.58, 95% CrI = 0.47-0.72) and CAS (OR = 0.68, 95% CrI = 0.55-0.83). CONCLUSION: Our results support the feasibility of using NMA to assess best available evidence to inform the ethical evaluation of RCTs seeking to randomise patients away from standard of care. Our results suggest that a strong argument is required to ethically justify the conduct of RCTs that seek to randomise patients away from standard of care in the setting of symptomatic moderate to severe carotid stenosis.

Dual Antiplatelet Therapy in Minor Stroke/Transient Ischemic Attack - An Updated Network Meta-Analysis.

We previously analyzed five trials on ticagrelor/aspirin versus clopidogrel/aspirin in patients with minor stroke/ TIA in a network meta-analysis. We updated our search and identified 311 new citations with one study for inclusion: CHANCE2 enrolled patients with CYP2C19 loss-of-function alleles and randomized them to ticagrelor/aspirin or clopidogrel/aspirin. Pooling of CHANCE2 with the original studies could not be completed due to violation of NMA assumptions, due to significant inconsistency. This suggests patients with CYP2C19 loss-of-function alleles represent a subpopulation that is inherently different from the general stroke population in their antiplatelet response. Results from CHANCE-2 may not be generalizable without genotype testing.

Pharmacologic Interventions to Prevent Delirium in Trauma Patients: A Systematic Review and Network Meta-Analysis of Randomized Controlled Trials.

To compare the relative efficacy of pharmacologic interventions in the prevention of delirium in ICU trauma patients. DATA SOURCES: We searched Medical Literature Analysis and Retrieval System Online, Embase, and Cochrane Registry of Clinical Trials from database inception until June 7, 2022. We included randomized controlled trials comparing pharmacologic interventions in critically ill trauma patients. STUDY SELECTION: Two reviewers independently screened studies for eligibility, extracted data, and assessed risk of bias. DATA EXTRACTION: Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines for network analysis were followed. Random-effects models were fit using a Bayesian approach to network meta-analysis. Between-group comparisons were estimated using hazard ratios (HRs) for dichotomous outcomes and mean differences for continuous outcomes, each with 95% credible intervals. Treatment rankings were estimated for each outcome in the form of surface under the cumulative ranking curve values. DATA SYNTHESIS: A total 3,541 citations were screened; six randomized clinical trials (n = 382 patients) were included. Compared with combined propofol-dexmedetomidine, there may be no difference in delirium prevalence with dexmedetomidine (HR 1.44, 95% CI 0.39-6.94), propofol (HR 2.38, 95% CI 0.68-11.36), nor haloperidol (HR 3.38, 95% CI 0.65-21.79); compared with dexmedetomidine alone, there may be no effect with propofol (HR 1.66, 95% CI 0.79-3.69) nor haloperidol (HR 2.30, 95% CI 0.88-6.61). CONCLUSIONS: The results of this network meta-analysis suggest that there is no difference found between pharmacologic interventions on delirium occurrence, length of ICU stay, length of hospital stay, or mortality, in trauma ICU patients.

Comparison of Ticagrelor vs Clopidogrel in Addition to Aspirin in Patients With Minor Ischemic Stroke and Transient Ischemic Attack: A Network Meta-analysis.

Importance: Dual antiplatelet therapy (DAPT) with clopidogrel and aspirin is effective in preventing recurrent strokes after minor ischemic stroke or transient ischemic attack (TIA). However, there is emerging evidence for the use of ticagrelor and aspirin, and the 2 DAPT regimens have not been compared directly. Objective: To compare ticagrelor and aspirin with clopidogrel and aspirin in patients with acute minor ischemic stroke or TIA in the prevention of recurrent strokes or death. Data Sources: MEDLINE, Embase, and Cochrane from database inception until February 2021. Study Selection: Randomized clinical trials that enrolled adults with acute minor ischemic stroke or TIA and provided the mentioned interventions within 72 hours of symptom onset, with a minimum follow-up of 30 days. Data Extraction and Synthesis: PRISMA guidelines for network meta-analyses were followed. Two reviewers independently extracted data and appraised risk of bias. Fixed-effects models were fit using a bayesian approach to network meta-analysis. Between-group comparisons were estimated using hazard ratios (HRs) with 95% credible intervals (95% CrIs). Surface under the cumulative rank curve plots were produced. Main Outcomes and Measures: The primary outcome was a composite of recurrent stroke or death up to 90 days. Secondary outcomes include major bleeding, mortality, adverse events, and functional disability. A sensitivity analysis was performed at 30 days for the primary outcome. Results: A total of 4014 citations were screened; 5 randomized clinical trials were included. Data from 22 098 patients were analyzed, including 5517 in the clopidogrel and aspirin arm, 5859 in the ticagrelor and aspirin arm, and 10 722 in the aspirin arm. Both clopidogrel and aspirin (HR, 0.74; 95% CrI, 0.65-0.84) and ticagrelor and aspirin (HR, 0.79; 95% CrI, 0.68-0.91) were superior to aspirin in the prevention of recurrent stroke and death. There was no statistically significant difference between clopidogrel and aspirin compared with ticagrelor and aspirin (HR, 0.94; 95% CrI, 0.78-1.13). Both DAPT regimens had higher rates of major hemorrhage than aspirin alone. Clopidogrel and aspirin was associated with a decreased risk of functional disability compared with aspirin alone (HR, 0.82; 95% CrI, 0.74-0.91) and ticagrelor and aspirin (HR, 0.85; 95% CrI, 0.75-0.97). Conclusions and Relevance: DAPT combining aspirin with either ticagrelor or clopidogrel was superior to aspirin alone, but there was no statistically significant difference found between the 2 regimens for the primary outcome.

Ticagrelor vs Clopidogrel in addition to Aspirin in minor ischemic stroke/ transient ischemic attack-Protocol for a systematic review and network meta-analysis.

INTRODUCTION: Patients with minor ischemic stroke or transient ischemic attack represent a high-risk population for recurrent stroke. No direct comparison exists comparing dual antiplatelet therapy regimens-namely, Ticagrelor and Aspirin versus Clopidogrel and Aspirin. This systematic review and network meta-analysis (NMA) will examine the efficacy of these two different antiplatelet regimens in preventing recurrent stroke and mortality up to 30 days. METHODS AND ANALYSIS: MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials (CENTRAL) will be searched with the assistance of a medical information specialist. Two independent reviewers will screen studies for inclusion; eligible studies will include randomized controlled trials that enrolled adults presenting with acute minor ischemic stroke or transient ischemic attack and compared one or more of the interventions against each other and/or a control. The primary outcomes will be recurrent ischemic stroke up to 30 days from symptom onset. Secondary outcomes will include safety outcomes (I.e. major bleeding and mortality), functional disability, and outcomes up to 90 days from symptom onset. A Bayesian approach to NMA will be implemented using the BUGSnet function in R Software. Between group comparisons for time-to-event (TTE) and dichotomous outcomes will be presented in terms of hazard ratios and odds ratios with 95% credible intervals, respectively. Secondary effect measures of treatment ranking will also be estimated. ETHICS AND DISSEMINATION: No formal research ethics approval are necessary. We will disseminate our findings through scientific conference presentations, peer-reviewed publications, and social media/the press. The findings from this review will aid clinicians in decision-making on the choice of antithrombotic therapy in a high-risk stroke population and could be important in the development of future treatment trials and guidelines. Registration ID with Open Science Framework: 10.17605/OSF.IO/XDJYZ.