Ghazi S. Alotaibi

Do women bleed more than men when prescribed novel oral anticoagulants for venous thromboembolism? A sex-based meta-analysis

INTRODUCTION Bleeding complications occur more frequently in women than men in clinical trials of warfarin and thrombolytics. It is unknown whether these sex-related differences exist for new oral anticoagulants, including dabigatran, rivaroxaban, and apixaban. To determine whether women suffer more bleeding complications with these agents, we conducted a systematic review and meta-analysis of randomized controlled trials on new oral anticoagulants for venous thromboembolism (VTE). MATERIALS AND METHODS Medline, Embase, and the Cochrane-controlled trial register on the Cochrane library were searched to identify studies that evaluated novel oral anticoagulants versus any comparator, and reported outcomes, including major bleeding and recurrent VTE, stratified by sex. No language restrictions were applied. Studies were evaluated according to a priori inclusion criteria and critically appraised using established internal validity criteria. Pooled relative risk was estimated using a random effects model. RESULTS Eight studies were eligible, comprising 9417 patients. There was no difference in the primary efficacy outcome of recurrent VTE between men and women [Relative Risk (RR) 1.02, 95% confidence interval (CI) 0.74-1.39]. However, men had less major bleeding with novel oral anticoagulants compared to women [RR 0.79, 95% CI 0.66-0.97, p=0.03]. All-cause mortality was not reported by sex in any of the studies. CONCLUSION Women suffer more bleeding complications than men when receiving novel oral anticoagulants for VTE. Future clinical trials should report outcomes stratified by sex, and further studies are needed to investigate the clinical impact of this sex-related safety difference.

Secular Trends in Incidence and Mortality of Acute Venous Thromboembolism: The AB-VTE Population-Based Study

BACKGROUND Venous thromboembolism is a major cause of morbidity and mortality, and comprehensive studies profiling the epidemiology and pattern of health services use are needed. In this study we provide contemporary estimates of venous thromboembolism incidence and case fatality over the past decade. METHODS We developed a population-based venous thromboembolism dataset by linking 6 administrative health databases in Alberta, Canada from April 1, 2002 to March 31, 2012. We defined acute symptomatic cases using a validated algorithm and used Poisson regression to model annual venous thromboembolism counts. RESULTS We identified 31,656 cases of acute symptomatic venous thromboembolism between April 1, 2002 and March 31, 2012. The age- and sex-adjusted incidence rate of venous thromboembolism was 1.38 (95% confidence interval [CI], 1.37-1.40) per 1000 person-years. For pulmonary embolism it was 0.38 (95% CI, 0.36-0.40) per 1000 person-years, and for deep vein thrombosis it was 1.0 (95% CI, 0.99-1.1) per 1000 person-years. The adjusted model showed no significant change in the incidence of venous thromboembolism during the study period. The 30-day case fatality rate of venous thromboembolism was 2.0% (95% CI, 1.89-2.21) and was almost doubled in patients with pulmonary embolism: 3.9% (95% CI, 3.50-4.33). The 1-year case fatality rate was 9.2% (95% CI, 8.88-9.52) for venous thromboembolism and 12.9% (95% CI, 12.2-13.6) for patients with pulmonary embolism. The case fatality rate increased with increasing subject age. The 1-year and 5-year survivals after first acute venous thromboembolism were similar in patients with unprovoked and provoked events. However, in patients with cancer-associated thrombosis, the 1-year and 5-year survival rate was 66% (95% CI, 64.71%-67.29%) and 46% (95% CI, 43.28%-48.72%), respectively. CONCLUSION The incidence of acute venous thromboembolism remained unchanged over a 10-year period. However, the case fatality of venous thromboembolism is substantial.

The validity of ICD codes coupled with imaging procedure codes for identifying acute venous thromboembolism using administrative data.

The purpose of this study was to evaluate the accuracy of using a combination of International Classification of Diseases (ICD) diagnostic codes and imaging procedure codes for identifying deep vein thrombosis (DVT) and pulmonary embolism (PE) within administrative databases. Information from the Alberta Health (AH) inpatients and ambulatory care administrative databases in Alberta, Canada was obtained for subjects with a documented imaging study result performed at a large teaching hospital in Alberta to exclude venous thromboembolism (VTE) between 2000 and 2010. In 1361 randomly-selected patients, the proportion of patients correctly classified by AH administrative data, using both ICD diagnostic codes and procedure codes, was determined for DVT and PE using diagnoses documented in patient charts as the gold standard. Of the 1361 patients, 712 had suspected PE and 649 had suspected DVT. The sensitivities for identifying patients with PE or DVT using administrative data were 74.83% (95% confidence interval [CI]: 67.01–81.62) and 75.24% (95% CI: 65.86–83.14), respectively. The specificities for PE or DVT were 91.86% (95% CI: 89.29–93.98) and 95.77% (95% CI: 93.72–97.30), respectively. In conclusion, when coupled with relevant imaging codes, VTE diagnostic codes obtained from administrative data provide a relatively sensitive and very specific method to ascertain acute VTE.

Case-fatality of recurrent venous thromboembolism and major bleeding associated with aspirin, warfarin, and direct oral anticoagulants for secondary prevention

INTRODUCTION The duration of anticoagulation after venous thromboembolic events (VTE) is based on the balance between the risk of recurrent VTE and bleeding. The purpose of this study was to estimate the frequency and case-fatality rate of major bleeding and recurrent VTE during secondary prevention of VTE. MATERIALS AND METHODS MEDLINE, EMBASE, and Cochrane Central Register of Controlled Trials databases were searched through September 2014. Two reviewers independently screened citations to identify trials that enrolled patients for secondary prevention of VTE with direct oral anticoagulants (DOACs), vitamin K antagonists (VKAs), aspirin or placebo. Two reviewers independently extracted data onto standardized forms. RESULTS Twelve RCTs that enrolled 10,542 patients were included. The rate of major bleeding was 1.6 per 100 patient-years (95% CI, 1.2-2.1), and 0.58 per 100 patient-years (95% CI, 0.24-1.1) on VKAs and DOACs, respectively, with an incidence rate ratio of 0.35 (95% CI, 0.17-0.68, p=0.0023). The case-fatality rates for DOACs and VKAs were not significantly different at 0% (95% CI, 0.0-15.4) and 6.8% (95% CI, 1.4-18.6), respectively. The rate of recurrent VTE was not different between DOACs and VKA, IRR 0.88 (95% CI, 0.15-4.8, p=0.88). Case-fatality rates for recurrent VTE for DOAC and VKAs were 10.8% (95% CI, 4.4-20.9) and 5.6% (95% CI, 1.2-15.4), respectively. Only DOACs showed a significant reduction in the composite outcome of fatal recurrent VTE and fatal bleeding when compared to placebo, IRR 0.40 (95% CI, 0.14-1.0, p=0.03). CONCLUSION Case-fatality rates for major bleeding and recurrent VTE for DOACs appear to be similar to those for VKA and the composite of fatal events is lower for DOACs than placebo. Overall, given the favorable safety profile and comparable efficacy of DOAC therapy, the threshold to continue anticoagulation with DOACs after unprovoked VTE should be low if the baseline risk of anticoagulation-related bleeding is not high.

Case fatality of bleeding and recurrent venous thromboembolism during, initial therapy with direct oral anticoagulants: a systematic review.

INTRODUCTION The frequency and case fatality of venous thromboembolism (VTE) and major bleeding during the initial 3 months of therapy in those treated for symptomatic VTE with either direct oral anticoagulants (DOACs) or vitamin K antagonists (VKA) are important clinically relevant outcomes. We sought to measure it during the initial months of anticoagulation for symptomatic VTE. MATERIAL AND METHODS We searched MEDLINE, EMBASE, and CENTRAL to identify studies that enrolled patients with acute symptomatic VTE treated with DOACs or VKA and reported data on bleeding, VTE recurrence and death. Studies were evaluated according to a priori inclusion criteria and critically appraised using established internal validity criteria. Single-proportion random-effects models were used to pool estimates. RESULTS Of the 2453 citations retrieved, 5 RCTs that enrolled 24,507 patients were included. The rate of major bleeding was 1.8 (95% CI: 1.3-2.5) and 3.1 (95% CI: 2.4-3.9) per 100 patient-years in DOAC and VKA arms, respectively. The rate of VTE recurrence was 3.7 (95% CI: 2.7-4.7) and 4.1 (95% CI: 3.0-5.4) per 100 patient-years of DOAC and VKA, respectively. The case fatality rate of bleeding was significantly higher in the VKA arms 10.4% (95% CI: 6.6-15.4) compared to DOACs 6.1% (95% CI: 2.7-11.7; p value for difference=0.029) with no statistical difference between the case fatalities for recurrent VTE. The rate of death from either definite major bleeding or definite recurrent VTE was 0.27 (95% CI: 0.16-0.40) and 0.46 (95% CI: 0.32-0.63) per 100 patient-years for DOACs and VKAs respectively, resulting in a number needed to treat of 875 for DOACs to prevent one death. CONCLUSION DOACs are attractive alternatives to VKAs for initial treatment of symptomatic VTE, with lower frequency and case fatality for major bleeding. However, the incremental safety benefit of DOACs over VKAs is small, with large numbers needed to treat.

Trends in admission rates and in-hospital stay for venous thromboembolism☆

BACKGROUND Acute venous thromboembolism leads to significant morbidity and mortality. Advances in pharmacotherapy facilitate outpatient care in low-risk acute venous thromboembolism. The proportion of hospitalized acute venous thromboembolism cases and the average length of stay are not known. We sought to identify predictors of hospitalization, changes in hospitalization rates and length of stay of acute venous thromboembolism over a decade in Alberta, Canada. METHODS Using linked administrative health databases, we identified adult patients diagnosed primarily with acute venous thromboembolism between April 2002 and March 2012. We measured trends using Poisson regression, adjusted length of stay using analysis of covariance. We identified predictors of hospitalization using multivariate logistic regression. RESULTS 8198 out of 31,656 acute venous thromboembolism cases were hospitalized. The overall venous thromboembolism admission rates ranged between 23.7% and 27.8% with no evident temporal trend (P=0.10). The average admission rate was 51.9% for pulmonary embolism and 16.1% for deep vein thrombosis. The mean length of stay for deep vein thrombosis and pulmonary embolism remained unchanged with an adjusted mean for venous thromboembolism of 6.9±1.0days. Higher Charlson index, older age, male gender, pulmonary embolism at presentation and multiple comorbidities were associated with hospitalization. Hospitalization was associated with 30-day mortality (odds ratio:2.8, 95% CI: 2.2-3.5) whereas the length of stay was not (odds ratio:1.0, 95% CI: 0.99-1.0). CONCLUSION Hospitalization rates and mean length of stay for acute venous thromboembolism did not change significantly between 2002 and 2012. Advances in pharmacotherapy have not yet reduced hospitalization rates or length of stay for venous thromboembolism.

Sex disparities in hospitalization and mortality rates for venous thromboembolism

Venous thromboembolism (VTE) is a major health problem for both men and women. Whether sex disparities exist for outcomes after acute VTE is unknown. We sought to measure sex-specific rates of hospitalization for and mortality from acute VTE. We used a population-based administrative dataset from Alberta, Canada, covering the years 2002 to 2012. We used Poisson regression to measure the incidence rate ratio for hospitalization and Cox regression to test for sex disparities in short-term all-cause mortality after adjusting for potential confounders. Of those diagnosed with VTE, 55.9% were women. The proportion of hospitalized women for VTE was 24.4 versus 27.8% in men (p < 0.001). The risk adjusted incidence rate ratio for VTE hospitalization increased with age for both sex. While women younger than 80 years old were less likely to be hospitalized than men, sex disparities for the risk of hospitalization were not significant after age 80 (p = 0.93). The adjusted 90-day all-cause mortality rate for women was 4.0% compared to 4.9% in men (adjusted HR = 1.0, p = 0.49). Women with acute VTE were less likely than men to be hospitalized in most age groups, but sex disparities in short-term all-cause mortality were not found.

Effect of anticoagulants on admission rates and length of hospital stay for acute venous thromboembolism: A systematic review of randomized control trials

BACKGROUND There is a paucity of data available on hospitalization and length of stay (LOS) for different anticoagulant therapies. We sought to compare and summarize admission rates and LOS, and describe the frequency of reporting these two outcomes in randomized control trials (RCTs) comparing different anticoagulant therapies for venous thromboembolism (VTE). METHODS A literature search was conducted from inception to August 15, 2016 on RCTs of anticoagulant therapy for patients with VTE. Study selection, data extraction and risk of bias analysis were done by two reviewers independently. Meta-analyses were conducted for admission rates and LOS. RESULTS A total of 4064 articles were identified. There were 74 articles of 70 studies included in the analysis. Hospitalization rates and LOS were reported in 13 (18.6%) and 12 (17.1%) of the 70 included studies, respectively. Low-molecular-weight heparin (LMWH)-treated patients were 33.0% less likely to be admitted to hospitals compared to unfractionated heparin (UFH) (RR = 0.67, 95% CI [0.58, 0.78]). The mean difference in LOS between LMWH and UFH was 2.54 days in favor of LMWH (95% CI [-4.94, -0.14]). Compared to parenteral therapy, using rivaroxaban was associated with a lower admission rate for a difference of 1.4-5.1% in VTE, 2.5% in DVT and 0.2% in PE. The LOS of patients receiving rivaroxaban was significant shorter than the LOS in parenteral therapy group for a difference of 1-5 days in VTE, 3 days in DVT and 1 day in PE. CONCLUSION Admission rates were lower and LOS was shorter using LMWH compared to UFH and oral therapy compared to parenteral therapy for acute VTE treatment in RCTs, based on limited eligible RCTs. These crucial clinically relevant outcomes are underreported in the existing VTE clinical trials.