Thromboprophylaxis – A Neglected Front in Hospitalised Patients with COVID-19 in Pakistan

SummaryBackgroundMany international guidelines on the prevention of venous thromboembolism recommend targeting heparin treatment at patients with stroke who have a high risk of venous thrombotic events or a low risk of haemorrhagic events. We sought to identify reliable methods to target anticoagulant treatment and so improve the chance of avoiding death or dependence after stroke.MethodsWe obtained individual patient data from the five largest randomised controlled trials in acute ischaemic stroke that compared heparins (unfractionated heparin, heparinoids, or low-molecular-weight heparin) with aspirin or placebo. We developed and evaluated statistical models for the prediction of thrombotic events (myocardial infarction, stroke, deep vein thrombosis, or pulmonary embolism) and haemorrhagic events (symptomatic intracranial or significant extracranial) in the first 14 days after stroke. We calculated the absolute risk difference for the outcome “dead or dependent” in patients grouped by quartiles of predicted risk of thrombotic and haemorrhagic events with random effect meta-analysis.FindingsPatients with ischaemic stroke who were of advanced age, had increased neurological impairment, or had atrial fibrillation had a high risk of both thrombotic and haemorrhagic events after stroke. Additionally, patients with CT-visible evidence of recent cerebral ischaemia were at increased risk of thrombotic events. In evaluation datasets, the area under a receiver operating curve for prediction models for thrombotic events was 0·63 (95% CI 0·59–0·67) and for haemorrhagic events was 0·60 (0·55–0·64). We found no evidence that the net benefit from heparins increased with either increasing risk of thrombotic events or decreasing risk of haemorrhagic events.InterpretationThere was no evidence that patients with ischaemic stroke who were at higher risk of thrombotic events or lower risk of haemorrhagic events benefited from heparins. We were therefore unable to define a targeted approach to select the patients who would benefit from treatment with early anticoagulant therapy. We recommend that guidelines for routine or selective use of heparin in stroke should be revised.FundingMRC.

Systemic Arterial and Venous Thrombotic Events Associated With Anti–Vascular Endothelial Growth Factor Injections: A Meta-Analysis

Severe bleeding accounts for about one-third of in-hospital trauma deaths. Patients with a high baseline risk of death have the most to gain from the use of life-saving treatments. An accurate and user-friendly prognostic model to predict mortality in bleeding trauma patients could assist doctors and paramedics in pre-hospital triage and could shorten the time to diagnostic and life-saving procedures such as surgery and tranexamic acid (TXA). The aim of the study was to develop and validate a prognostic model for early mortality in patients with traumatic bleeding and to examine whether or not the effect of TXA on the risk of death and thrombotic events in bleeding adult trauma patients varies according to baseline risk. Multivariable logistic regression and risk-stratified analysis of a large international cohort of trauma patients. Two hundred and seventy-four hospitals in 40 high-, medium- and low-income countries. We derived prognostic models in a large placebo-controlled trial of the effects of early administration of a short course of TXA [Clinical Randomisation of an Antifibrinolytic in Significant Haemorrhage (CRASH-2) trial]. The trial included 20,127 trauma patients with, or at risk of, significant bleeding, within 8 hours of injury. We externally validated the model on 14,220 selected trauma patients from the Trauma Audit and Research Network (TARN), which included mainly patients from the UK. We examined the effect of TXA on all-cause mortality, death due to bleeding and thrombotic events (fatal and non-fatal myocardial infarction, stroke, deep-vein thrombosis and pulmonary embolism) within risk strata in the CRASH-2 trial data set and we estimated the proportion of premature deaths averted by applying the odds ratio (OR) from the CRASH-2 trial to each of the risk strata in TARN. For the stratified analysis according baseline risk we considered the intervention TXA (1 g over 10 minutes followed by 1 g over 8 hours) or matching placebo. For the prognostic models we included predictors for death in hospital within 4 weeks of injury. For the stratified analysis we reported ORs for all causes of death, death due to bleeding, and fatal and non-fatal thrombotic events associated with the use of TXA according to baseline risk. A total of 3076 (15%) patients died in the CRASH-2 trial and 1705 (12%) in the TARN data set. Glasgow Coma Scale score, age and systolic blood pressure were the strongest predictors of mortality. Discrimination and calibration were satisfactory, with C-statistics > 0.80 in both CRASH-2 trial and TARN data sets. A simple chart was constructed to readily provide the probability of death at the point of care, while a web-based calculator is available for a more detailed risk assessment. TXA reduced all-cause mortality and death due to bleeding in each stratum of baseline risk. There was no evidence of heterogeneity in the effect of TXA on all-cause mortality (p-value for interaction = 0.96) or death due to bleeding (p= 0.98). There was a significant reduction in the odds of fatal and non-fatal thrombotic events with TXA (OR = 0.69, 95% confidence interval 0.53 to 0.89; p= 0.005). There was no evidence of heterogeneity in the effect of TXA on the risk of thrombotic events (p= 0.74). This prognostic model can be used to obtain valid predictions of mortality in patients with traumatic bleeding. TXA can be administered safely to a wide spectrum of bleeding trauma patients and should not be restricted to the most severely injured. Future research should evaluate whether or not the use of this prognostic model in clinical practice has an impact on the management and outcomes of trauma patients.

A Nordic Population-Based Cohort Study of Risk of Arterial Thrombotic and Venous Thromboembolic Events in Patients with Primary Chronic Immune Thrombocytopenia (cITP)

Risk of death, thrombotic and hemorrhagic events in patients with atrial fibrillation and systemic autoimmune diseases

Objectives To examine whether the effect of tranexamic acid on the risk of death and thrombotic events in patients with traumatic bleeding varies according to baseline risk of death. To...

The aim of the study was to evaluate the efficacy and safety of increased doses of anticoagulants in comparison with standard doses in inpatients with COVID-19. A systematic review was carried out in October 2021 using the PubMed database. The analysis included only randomized clinical trials (RCTs) with ≥ 200 participants that reported the rate of death as the total number of cases or the percentage of patients. The primary outcome was all-cause mortality within the observational period. In addition, the risk of arterial and venous thrombotic events and major and clinically relevant nonmajor (CRNM) bleeding was assessed. Searching of Pubmed identified 8903 references. The final qualitative and quantitative analysis included the results of 6 RCTs that covered 5228 patients. Among all patients, 2660 received increased and 2568 standard doses of anticoagulants. The follow-up period varied from 21 to 30 days. The administration of increased doses did not affect the risk of death (odds ratio [OR], 0.95; 95% confidence interval [CI], 0.73–1.25; I2 = 59.5%), was associated with a reduced risk of thrombotic events (OR, 0.56; 95% CI, 0.43–0.73; I2 = 20.6%), and increased risk of major bleeding (OR, 1.86; 95% CI, 1.23–2.80; I2 = 0%) or CRNM bleeding (OR, 3.65; 95% CI, 1.65–8.09; I2 = 0%). Within the sensitivity analysis, similar results were obtained in the subgroups of critically ill or stable patients and individuals with increased D-dimer. The maximal reduction in the risk of thrombotic events was found for the subgroup of patients with increased D-dimer (OR, 0.48; 95% CI, 0.32–0.70; I2 = 36.4%). The use of increased doses of anticoagulants in inpatients with COVID-19 does not reduce the risk of death. Still, it is associated with a decrease in the risk of thrombotic events and increased risk of major bleeding.

Red cells play a key role in normal haemostasis in vitro but their importance clinically is less clear. The objective of this meta-analysis was to assess if correction of anaemia by transfusing red cells at a high haemoglobin threshold (liberal transfusion) is superior to transfusion at a lower haemoglobin threshold (restrictive transfusion) for reducing the risk of bleeding or thrombotic events. We searched for randomised controlled trials in any clinical setting that compared two red cell transfusion thresholds and investigated the risk of bleeding. We searched for studies published up to October 19, 2016 in The Cochrane Central Register of Controlled Trials, MEDLINE, PubMed, Embase, and the Transfusion Evidence Library and ISI Web of Science. Relative risks (RR) or Peto Odds Ratios (pOR) were pooled using a random-effect model. Nineteen randomised trials with 9852 participants were eligible for inclusion in this review. Overall there was no difference in the risk of any bleeding between transfusion strategies (RR 0.91, 95 % confidence interval [CI] 0.74 to 1.12). The risk of severe or life-threatening bleeding was lower with a restrictive strategy (RR 0.75, 95 % CI 0.57 to 0.99). There was no difference in the risk of thrombotic events (RR 0.83, 95 % CI 0.61 to 1.13). The risk of any bleeding was not reduced with liberal transfusion and there was no overall difference in the risk of thrombotic events. Data from the included trials do not support aiming for a high haemoglobin threshold to improve haemostasis. PROSPERO registration number CRD42016035519.

Background The postpartum state is associated with a substantially increased risk of thrombosis. It is uncertain to what extent this heightened risk persists beyond the conventionally defined 6-week postpartum period. Methods Using claims data on all discharges from nonfederal emergency departments and acute care hospitals in California, we identified women who were hospitalized for labor and delivery between January 1, 2005, and June 30, 2010. We used validated diagnosis codes to identify a composite primary outcome of ischemic stroke, acute myocardial infarction, or venous thromboembolism. We then used conditional logistic regression to assess each patient’s likelihood of a first thrombotic event during sequential 6-week periods after delivery, as compared with the corresponding 6-week period 1 year later. Results Among the 1,687,930 women with a first recorded delivery, 1015 had a thrombotic event (248 cases of stroke, 47 cases of myocardial infarction, and 720 cases of venous thromboembolism) in the period of 1 year plus up to 24 weeks after delivery. The risk of primary thrombotic events was markedly higher within 6 weeks after delivery than in the same period 1 year later, with 411 events versus 38 events, for an absolute risk difference of 22.1 events (95% confidence interval [CI], 19.6 to 24.6) per 100,000 deliveries and an odds ratio of 10.8 (95% CI, 7.8 to 15.1). There was also a modest but significant increase in risk during the period of 7 to 12 weeks after delivery as compared with the same period 1 year later, with 95 versus 44 events, for an absolute risk difference of 3.0 events (95% CI, 1.6 to 4.5) per 100,000 deliveries and an odds ratio of 2.2 (95% CI, 1.5 to 3.1). Risks of thrombotic events were not significantly increased beyond the first 12 weeks after delivery. Conclusions Among patients in our study, an elevated risk of thrombosis persisted until at least 12 weeks after delivery. However, the absolute increase in risk beyond 6 weeks after delivery was low. (Funded by the National Institute of Neurological Disorders and Stroke.)

BackgroundThe postpartum state is associated with a substantially increased risk of thrombosis. It is uncertain to what extent this heightened risk persists beyond the conventionally defined 6-week postpartum period.MethodsUsing claims data on all discharges from nonfederal emergency departments and acute care hospitals in California, we identified women who were hospitalized for labor and delivery between January 1, 2005, and June 30, 2010. We used validated diagnosis codes to identify a composite primary outcome of ischemic stroke, acute myocardial infarction, or venous thromboembolism. We then used conditional logistic regression to assess each patient's likelihood of a first thrombotic event during sequential 6-week periods after delivery, as compared with the corresponding 6-week period 1 year later.ResultsAmong the 1,687,930 women with a first recorded delivery, 1015 had a thrombotic event (248 cases of stroke, 47 cases of myocardial infarction, and 720 cases of venous thromboembolism) in the period of 1 year plus up to 24 weeks after delivery. The risk of primary thrombotic events was markedly higher within 6 weeks after delivery than in the same period 1 year later, with 411 events versus 38 events, for an absolute risk difference of 22.1 events (95% confidence interval [CI], 19.6 to 24.6) per 100,000 deliveries and an odds ratio of 10.8 (95% CI, 7.8 to 15.1). There was also a modest but significant increase in risk during the period of 7 to 12 weeks after delivery as compared with the same period 1 year later, with 95 versus 44 events, for an absolute risk difference of 3.0 events (95% CI, 1.6 to 4.5) per 100,000 deliveries and an odds ratio of 2.2 (95% CI, 1.5 to 3.1). Risks of thrombotic events were not significantly increased beyond the first 12 weeks after delivery.ConclusionsAmong patients in our study, an elevated risk of thrombosis persisted until at least 12 weeks after delivery. However, the absolute increase in risk beyond 6 weeks after delivery was low. (Funded by the National Institute of Neurological Disorders and Stroke.)

Aspirin prevents thrombotic events by inhibiting platelet cyclooxygenase-1 (COX-1), thus reducing thromboxane A2 formation and platelet aggregation. The C50T polymorphism of COX-1 is associated with an impaired inhibition of both thromboxane production and in-vitro platelet aggregation by aspirin. We studied whether this polymorphism is also associated with the risk of clinical thrombotic events in patients using aspirin. We included 496 patients admitted to our Coronary Care Unit for various indications treated with aspirin 80 mg daily. Genotyping for the C50T polymorphism demonstrated that 86.7% of the patients had the common genotype, and 13.3% had the variant (12.5% heterozygous, 0.8% homozygous). Baseline variables were well balanced, except that patients with the common genotype more frequently used aspirin prior to admission compared to those patients with the variant genotype. The composite primary endpoint of myocardial infarction, stroke, and/or cardiovascular death occurred in 98 patients (19.8%). Myocardial infarction occurred in 9.6% of patients, stroke in 1.6%, and cardiovascular death in 12.1%. The unadjusted hazard ratio (95% CI) for the primary endpoint for patients with the variant versus the common genotype was 1.07 (0.62-1.85), p = 0.8. The adjusted hazard ratio was 0.86 (0.49-1.50), p = 0.6. In prior laboratory studies the COX-1 C50T polymorphism was associated with an impaired inhibitory effect of aspirin on thromboxane production and platelet function. However, in this cohort of patients using low-dose aspirin for secondary prevention the polymorphism was not associated with a higher risk of atherothrombotic events.

Patients with inflammatory bowel disease (IBD) are at increased risk of thrombotic events. Therapies for IBD have the potential to modulate this risk. The aims of this Evidence-Based Guideline were to summarize available evidence and to provide practical recommendations regarding epidemiological aspects, prevention and drug-related risks of venous and arterial thrombotic events in patients with IBD. A virtual meeting took place in May 2020 involving 14 international IBD experts and 3 thrombosis experts from 12 countries. Proposed statements were voted upon in an anonymous manner. Agreement was defined as at least 75% of participants voting as ‘fully agree’ or ‘mostly agree’ with each statement. For each statement, the level of evidence was graded according to the Scottish Intercollegiate Guidelines Network (SIGN) grading system. Consensus was reached for 19 statements. Patients with IBD harbour an increased risk of venous and arterial thrombotic events. Thromboprophylaxis is indicated during hospitalization of any cause in patients with IBD. Disease activity is a modifiable risk factor in patients with IBD, and physicians should aim to achieve deep remission to reduce the risk. Exposure to steroids should be limited. Antitumour necrosis factor agents might be associated with a reduced risk of thrombotic events.

BackgroundGrowing evidence showing that systemic autoimmune diseases (SADs) are associated with a high risk of atrial fibrillation (AF). However, the impact of SAD on the clinical course of AF patients is largely unknown.MethodsRetrospective cohort study within a federated healthcare network (TriNetX). Using ICD codes, AF patients on anticoagulant therapy were categorized according to the presence of SAD (M32: Systemic Lupus Erythematosus (SLE); M33: Dermato-polymyositis (DMP); M34: Systemic Sclerosis (SSc); M35: Sjogren syndrome). The primary outcomes were the 5-year risks of (1) all-cause death, (2) thrombotic events (ischemic stroke, acute myocardial infarction, deep vein thrombosis, and pulmonary embolism), and (3) bleeding (intracranial (ICH) and gastrointestinal (GI)). Secondary outcomes were each component of the primary outcomes. Cox regression analysis after propensity score matching (PSM) was used to estimate hazard ratio (HR) and 95% confidence interval (95%CI).ResultsWe identified 16,098 AF patients with SAD (68.2 ± 13.4 years; 71.0% female) and 828,772 AF controls (70.7 ± 12.9 years, 41.1% females). After PSM, AF patients with SAD were associated with a higher risk of all-cause death (HR 1.13, 95%CI 1.09–1.71), thrombotic events (HR 1.37, 95%CI 1.32–1.43), and hemorrhagic events (HR 1.41, 95%CI 1.33–1.50) compared to AF controls without SAD. The highest risk of all-cause death and GI bleeding was associated with SSc, while the highest risk of thrombotic events and ICH was associated with SLE.ConclusionAF patients with SAD are associated with a high risk of all-cause death, thrombotic, and hemorrhagic events. These patients merit careful follow-up and integrated care management to improve their prognosis.Graphical

The aim of the study was to evaluate the efficacy and safety of increased doses of anticoagulants in comparison with standard doses in inpatients with COVID-19. Material and methods. A systematic review was carried out in October 2021 using the Pubmed database. The analysis included only randomized clinical trials with ≥200 participants that reported the death rate as the total number of cases or the percentage of patients. The primary outcome was all-cause mortality within the observation period. Additionally, the risk of arterial and venous thrombotic events, major and clinically relevant non-major bleeding was assessed. Results. Searching of Pubmed identified 8,903 references, of which the results of 6 randomized clinical trials (INSPIRATION, 3 platforms study in REMAP-CAP, ACTIV-4a, and ATTACC including stable and unstable patients, RAPID, ACTION and HEP-COVID) with the total of 5,228 patients were included in the final qualitative analysis and quantitative synthesis. Among all the patients, 2,660 received increased doses and 2,568 — standard doses of anticoagulants. The follow-up period varied from 21 to 30 days. The administration of increased doses did not affect the risk of death (OR, 0.95; 95 % CI, 0.73–1.24; I² = 59.14 %), but was associated with a reduced risk of thrombotic events (OR, 0.56; 95 % CI, 0.43–0.73; I² = 24.90 %), and an increased risk of major bleeding (OR, 1.86; 95 % CI, 1.23–2.80; I² = 0.00 %) or clinically relevant non-major bleeding (OR, 3.66; 95 % CI, 1.65–8.10; I² = 0.00 %). Within the sensitivity analysis, similar results were obtained in the subgroups of critically ill or stable patients and individuals with increased D-dimer. The maximal reduction in the risk of thrombotic events was found for the subgroup of patients with increased D-dimer (OR, 0.48; 95 % CI, 0.34–0.70; I² = 36.38 %). Conclusions. The use of increased doses of anticoagulants in inpatients with COVID-19 does not reduce the risk of death. Still, it is associated with a decrease in the risk of arterial and venous thrombosis and an increased risk of major bleeding.

Mortality and complications in low-dose vs standard-dose unfractionated heparin anticoagulation for extracorporeal membrane oxygenation: a systematic review and meta-analysis