Usefulness of D-dimer testing in predicting recurrence in elderly patients with unprovoked venous thromboembolism.

BACKGROUND Whether post-anticoagulation D-dimer levels are useful in predicting recurrence in elderly patients with unprovoked venous thromboembolism is unknown. METHODS We followed-up 157 patients aged ≥65 years with acute symptomatic unprovoked venous thromboembolism in a prospective multicenter cohort study. All patients completed 3-12 months of anticoagulation and then underwent quantitative D-dimer testing (ELISA, VIDAS DD) 12 months after the index venous thromboembolism. The outcome was recurrent symptomatic venous thromboembolism after D-dimer measurement. We examined associations between log-transformed and dichotomized D-dimer values and the time to venous thromboembolism recurrence using competing risk regression, adjusting for age, sex and overt pulmonary embolism. RESULTS There was no statistically significant association between quantitative or dichotomized D-dimer levels and venous thromboembolism recurrence. The area under the receiver operating characteristic curve for predicting recurrent venous thromboembolism was moderate (0.66, 95% confidence interval [CI] 0.51-0.82). The negative likelihood ratios were 0.34 (95% CI 0.05-2.38) at the usual and 0.34 (95% CI 0.09-1.29) at the age-adjusted cutoff values. Among patients with normal D-dimer results, venous thromboembolism recurrence rates were 6.8 (95% CI 2.2-21.2) per 100 patient-years using the usual and 7.1 (95% CI 3.2-15.8) per 100 patient-years using the age-adjusted cutoff values. CONCLUSION D-dimer testing alone may not be useful in identifying elderly patients with unprovoked venous thromboembolism who are at low risk of recurrent venous thromboembolism and in whom anticoagulants may be safely stopped

All-cause mortality after major gastrointestinal bleeding among patients receiving direct oral anticoagulants: a protocol for a systematic review and meta-analysis.

BACKGROUND Gastrointestinal (GI) bleeding represents the single most frequent site of anticoagulant-related bleeding. Adverse outcomes after major GI bleeding including mortality are not well characterized and, as a result, may be underappreciated in clinical practice. We aim to conduct a systematic review and meta-analysis of the risk for 30-day all-cause mortality after major GI bleeding among patients receiving DOACs. METHODS Electronic databases including MEDLINE, EMBASE, and Cochrane CENTRAL will be systematically searched to identify randomized controlled trials and prospective and retrospective cohort studies reporting 30-day all-cause mortality in adults with DOAC-related major GI bleeding. At least two investigators will independently perform study selection, risk of bias assessment, and data extraction. The proportion of deaths following a major GI event relative to the number of major GI bleeding events will be calculated for each individual study, and results across studies will be pooled using random-effects meta-analysis. We will assess risk of bias using criteria proposed by the GRADE group for prognostic studies. DISCUSSION The findings of this systematic review and meta-analysis will provide clinicians and patients with estimates of mortality after the most common major bleeding event to support shared decision making about anticoagulation management. TRIAL REGISTRATION PROSPERO CRD42022295815

Protocol for a modelling study to assess the clinical and cost-effectiveness of indefinite anticoagulant therapy for first unprovoked venous thromboembolism.

INTRODUCTION Deciding whether to stop or extend anticoagulant therapy indefinitely after completing at least 3 months of initial treatment for a first unprovoked venous thromboembolism (VTE) remains a challenge for clinicians, patients and policy makers. Guidelines suggest an indefinite duration of anticoagulant therapy in these patients, yet its benefits, harms and costs have not been formally assessed. The aim of this proposed modelling study is to assess the differences in clinical benefits, harms and costs of stopping versus continuing anticoagulant therapy indefinitely for a first unprovoked VTE. METHODS AND ANALYSIS We will develop a probabilistic Markov model, adopting a 1-month cycle length and a lifetime horizon, to estimate life-years, quality-adjusted life-years, costs and the incremental cost-effectiveness ratios for a simulated population of patients with a first unprovoked VTE who will receive indefinite duration of anticoagulant therapy versus a population who will not receive extended treatment after completing 3 months of initial anticoagulant therapy. The economic evaluation will adopt a third-party payer perspective relating to a Canadian publicly funded healthcare system. Estimates for the probability of relevant clinical events will be informed by systematic reviews and meta-analyses, while costs and utility values will be obtained from published Canadian sources. Stratified analyses based on sex, age and site of initial VTE will also be performed to identify subgroups of patients with a first unprovoked VTE in whom continuing anticoagulant therapy indefinitely might prove to be clinically beneficial and cost-effective over stopping treatment. We will also conduct sensitivity and scenario analyses to assess robustness of study findings to changes in individual or groups of key parameters. ETHICS AND DISSEMINATION Ethical approval is not applicable for this study. The results will be disseminated through presentations at relevant conferences and in a manuscript that will be submitted to a peer-reviewed journal

ISTH definition of pulmonary embolism-related death and classification of the cause of death in venous thromboembolism studies: validation in an autopsy cohort.

BACKGROUND The International Society on Thrombosis and Haemostasis (ISTH)'s Scientific and Standardization Committee (SSC) recently proposed a definition of pulmonary embolism (PE)-related death. We aimed to evaluate the accuracy and interrater reliability of the definition in an autopsy cohort. METHODS We reviewed reports of 1,064 consecutive adult autopsies that were performed at the NewYork-Presbyterian Hospital from 01/2010 until 07/2019. We included all patients with autopsy-confirmed PE-related death (cases) during that time frame, combined with patients who died in 2018 from a cause other than PE (controls). Based on clinical summaries, two adjudicators independently adjudicated the cause of death in each patient using the ISTH classification for the cause of death, blinded to the case/control status and ratio. The primary outcome was autopsy-confirmed PE-related death. We determined the sensitivity and specificity of the ISTH definition to identify autopsy-confirmed PE-related death, and its interrater reliability using the percentage agreement and Cohen's kappa. RESULTS A total of 126 patients who underwent autopsy were included in the analysis (median age, 68 years [range, 21-94], 60 [48%] women), of which 29 (23%) had died from PE as confirmed by autopsy. The ISTH definition's sensitivity and specificity for autopsy-confirmed PE-related death were 45% (95% CI, 26-64) and 99% (95% CI, 94-100), respectively. Interrater reliability for PE-related death was substantial (percentage agreement, 94% [95% CI, 89-97]; kappa, 0.73 [95% CI, 0.55-0.97]). CONCLUSION Adjudication of the cause of death using the ISTH definition resulted in very high specificity, moderate sensitivity, and good interrater reliability for PE-related death

Prediction of in-hospital bleeding in acutely ill medical patients: External validation of the IMPROVE bleeding risk score.

INTRODUCTION Pharmacological thromboprophylaxis slightly increases bleeding risk. The only risk assessment model to predict bleeding in medical inpatients, the IMPROVE bleeding risk score, has never been validated using prospectively collected outcome data. METHODS We validated the IMPROVE bleeding risk score in a prospective multicenter cohort of medical inpatients. Primary outcome was in-hospital clinically relevant bleeding (CRB) within 14 days of admission, a secondary outcome was major bleeding (MB). We classified patients according to the score in high or low bleeding risk. We assessed the score's predictive performance by calculating subhazard ratios (sHRs) adjusted for thromboprophylaxis use, positive and negative predictive values (PPV, NPV), and the area under the receiver operating characteristic curves (AUC). RESULTS Of 1155 patients, 8 % were classified as high bleeding risk. CRB and MB within 14 days occurred in 0.94 % and 0.47 % of low-risk and in 5.6 % and 3.4 % of high-risk patients, respectively. Adjusted for thromboprophylaxis, classification in the high-risk group was associated with an increased risk of 14-day CRB (sHR 4.7, 95 % confidence interval [CI] 1.5-14.5) and MB (sHR 4.9, 95%CI 1.0-23.4). PPV was 5.6 % and 3.4 %, while NPV was 99.1 % and 99.5 % for CRB and MB, respectively. The AUC was 0.68 (95%CI 0.66-0.71) for CRB and 0.73 (95%CI 0.71-0.76) for MB. CONCLUSION The IMPROVE bleeding risk score showed moderate to good discriminatory power to predict bleeding in medical inpatients. The score may help identify patients at high risk of in-hospital bleeding, in whom careful assessment of the risk-benefit ratio of pharmacological thromboprophylaxis is warranted

Overuse and underuse of thromboprophylaxis in medical inpatients.

Background Thromboprophylaxis (TPX) prescription is recommended in medical inpatients categorized as high risk of venous thromboembolism (VTE) by validated risk assessment models (RAMs), but how various RAMs differ in categorizing patients in risk groups, and whether the choice of RAM influences estimates of appropriate TPX use is unknown. Objectives To determine the proportion of medical inpatients categorized as high or low risk according to validated RAMs, and to investigate the appropriateness of TPX prescription. Methods This is a prospective cohort study of acutely ill medical inpatients from three Swiss university hospitals. Participants were categorized as high or low risk of VTE by validated RAMs (i.e., the Padua, IMPROVE, simplified, and original Geneva score). We assessed prescription of any TPX at baseline. We considered TPX prescription in high-risk and no TPX prescription in low-risk patients as appropriate. Results Among 1352 medical inpatients, the proportion categorized as high risk ranged from 29.8% with the IMPROVE to 66.1% with the original Geneva score. Overall, 24.6% were consistently categorized as high risk, and 26.3% as low risk by all four RAMs. Depending on the RAM used, TPX prescription was appropriate in 58.7-63.3% of high-risk (i.e., 36.7-41.3% underuse) and 52.4-62.8% of low-risk patients (i.e., 37.2-47.6% overuse). Conclusion The proportion of medical inpatients considered as high or low VTE risk varied widely according to different RAMs. Only half of patients were consistently categorized in the same risk group by all RAMs. While TPX remains underused in high-risk patients, overuse in low-risk patients is even more pronounced

Adherence to thrombophilia testing guidelines and its influence on anticoagulation therapy: A single-center cross-sectional study.

INTRODUCTION The collected evidence on thrombophilia guidelines is scarce and data about their impact on clinical decisions are unknown. We aimed to investigate the adherence to thrombophilia testing guidelines, its therapeutic impact in patients with guideline-adherent and non-adherent testing and identify the patients' clinical characteristics mostly associated with treatment decisions. MATERIALS AND METHODS We conducted a single-center cross-sectional study of patients referred for thrombophilia testing at the outpatient clinic of a tertiary hospital between 01/2010-10/2020. We systematically evaluated the adherence of thrombophilia testing to internal guidelines and the influence of test results on anticoagulation therapy. Using multivariable logistic regression, we evaluated the association between clinical characteristics and influence of thrombophilia tests on anticoagulation therapy in the entire cohort and by indication for referral. RESULTS Of 3686 included patients, mostly referred for venous thromboembolism (2407, 65 %) or arterial thrombosis (591, 16 %), 3550 patients (96 %) underwent thrombophilia testing. Indication for testing was according to guidelines in 1208 patients (33 %). Test results influenced treatment decisions in 56 of 1102 work-ups (5.1 %) that were adherent to guidelines, and in 237 of 2448 (9.7 %) non-adherent work-ups (absolute difference, 4.3 %; 95 % confidence interval, 2.9-6.3 %). Age < 50 years, female sex, absence of risk factors and co-morbidities, weakly provoked venous thromboembolism and referral indication other than venous thromboembolism were associated with influence on anticoagulation therapy. CONCLUSIONS Adherence to guidelines for thrombophilia testing was poor and did not have an impact on treatment decisions. Refinement of selection criteria is needed to increase the therapeutic impact of thrombophilia testing

Thrombophilia Impact on Treatment Decisions, Subsequent Venous or Arterial Thrombosis and Pregnancy-Related Morbidity: A Retrospective Single-Center Cohort Study.

(1) Background: Thrombophilia testing utility has remained controversial since its clinical introduction, because data on its influence on treatment decisions are limited. (2) Methods: We conducted a single-center retrospective cohort study of 3550 unselected patients referred for thrombophilia consultation at the Bern University Hospital in Switzerland from January 2010 to October 2020. We studied the influence of thrombophilia testing results on treatment decisions and evaluated the association between thrombophilia and thromboembolic and pregnancy-related morbidity events after testing up to 03/2021. (3) Results: In 1192/3550 patients (34%), at least one case of thrombophilia was found and 366 (10%) had high-risk thrombophilia. A total of 211/3550 (6%) work-ups (111/826 (13%) with low-risk thrombophilia and 100/366 (27%) with high-risk thrombophilia) led to an appropriate decision to extend or initiate anticoagulation, and 189 (5%) negative results led to the withholding of anticoagulation therapy inappropriately. A total of 2492 patients (69%) were followed up for &gt;30 days, with a median follow-up of 49 months (range, 1-183 months). Patients with high-risk thrombophilia had a higher risk of subsequent venous thromboembolic events and pregnancy-related morbidity compared to those without thrombophilia. (4) Conclusions: Our study demonstrated the limited usefulness of thrombophilia work-up in clinical decision-making. High-risk thrombophilia was associated with subsequent venous thromboembolism and pregnancy-related morbidity