Direct Oral Anticoagulants: New Drugs and New Concepts

Direct oral anticoagulants (DOACs) are approved for multiple thromboembolic disorders and provide advantages over existing agents. As with all anticoagulants, management protocols for the eventuality of bleeding are important. Randomized phase III studies generally show that DOACs have a similar risk of clinically relevant bleeding compared with standard anticoagulants, with reductions in major bleeding in some cases. This may be particularly important in patients with atrial fibrillation, for whom the rate of intracranial hemorrhage was approximately halved with DOACs compared with warfarin. Conversely, the risk of gastrointestinal bleeding may be increased. Specific patient characteristics, such as renal impairment, comedications, and particular aspects of each drug, including the proportion eliminated by the kidneys, must be taken into account when assessing the risk of bleeding. Although routine coagulation monitoring of DOACs is not required, it may be useful under some circumstances. Of the traditional clotting assays, a sensitive and calibrated prothrombin time may be useful for detecting the presence or absence of clinically relevant factor Xa inhibitor concentrations (rivaroxaban or apixaban), but specific anti–factor Xa assays can measure drug levels quantitatively. For dabigatran, the results of an activated partial thromboplastin time test may exclude a clinically relevant pharmacodynamic effect, but a calibrated dilute thrombin time assay can be used for quantification of drug levels. In the event of mild or moderate bleeding, normal hemostatic support measures are recommended. For life-threatening bleeding, use of nonspecific prohemostatic agents may be considered, although clinical evidence is scarce. Specific antidotes are in development.     

Increased Risk of Deep Vein Thrombosis and Pulmonary Thromboembolism in Patients with Spinal Cord Injury: A Nationwide Cohort Prospective Study

Background

We investigated the effect of spinal cord injury (SCI) on the development of deep vein thrombosis (DVT) and pulmonary thromboembolism (PE) by conducting a nationwide longitudinal cohort study.

Methods

We studied the entire hospitalized population in Taiwan for the 1998–2008 period, with a follow-up period extending to the end of 2010. We identified SCI patients using the Taiwan National Health Insurance Research Database (NHIRD), and selected a cohort that was 1:4 frequency-matched by age (5-y span), sex, and index year from the general population. We analyzed the risks of DVT and PE using Cox proportional-hazards regression models, which included the demographic variables of sex, age, and comorbidities.

Results

A total of 47,916 SCI patients (62.7% men, mean age of 50.0 y) and 191,664 controls were followed for 308,266 and 1,341,169 person-years, respectively. The adjusted hazard ratio (HR) of DVT and PE development was 2.46-fold and 1.57-fold among the SCI patients, respectively. The highest risk of DVT and PE developed within 3 months after an SCI occurred (HR: 16.9 and 3.64, respectively). The adjusted HR of DVT and PE rose markedly with increasing age. The adjusted HR of DVT was highest among C-spine SCI patients, and the adjusted HR of PE was highest among T-spine SCI patients.

Conclusion

This nationwide prospective cohort study demonstrated that the risk of DVT and PE increased significantly in SCI patients compared with that of the general population. The highest risk of DVT and PE developed within 3 months after an SCI occurred.     

Improvement of anticoagulant treatment using a dynamic decision support algorithm: A Danish Cohort study

Introduction

Warfarin is the most widely prescribed vitamin K antagonist and in the United States and Europe more than 10 million people are currently in long-term oral anticoagulant treatment. This study aims to retrospectively validate a dynamic statistical model providing dosage suggestions to patients in warfarin treatment.

Materials and methods

The model was validated on a cohort of 553 patients with a mean TTR of 83%. Patients in the cohort were self-monitoring and managed by a highly specialised anticoagulation clinic. The predictive model essentially consists of three parts handling INR history, warfarin dosage and biological noise, which allows for prediction of future INR values and optimal warfarin dose to stay on INR target. Further, the model is based on parameters initially being set to population values and gradually individualised during monitoring of patients.

Primary outcome

Time in therapeutic range was used as surrogate quality measure of the treatment, and model-suggested dosage of warfarin was used to assess the accuracy of the model performance.

Results

The accuracy of the model predictions measured as median absolute error was 0.53 mg/day (interquartile range from 0.25 to 1.0). The model performance was evaluated by the difference between observed and predicted warfarin intake in the preceding week of an INR measurement. In more than 70% of the cases where INR measurements were outside the therapeutic range, the model suggested a more reasonable dose than the observed intake.

Conclusion

Applying the proposed dosing algorithm can potentially further increase the time in INR target range beyond 83%.     

Indirect treatment comparison of new oral anticoagulants for the treatment of acute venous thromboembolism

Background

Numerous new oral anticoagulants (NOACs) have been compared to a parenteral anticoagulant/oral vitamin K antagonist (VKA) for the treatment of acute venous thromboembolism (VTE). We aimed to conduct a systematic review and adjusted indirect comparison meta-analysis to compare the efficacy and safety of NOACs for this indication.

Methods

We conducted a systematic literature search through November 2013 for randomized trials that evaluated treatment of acute VTE with a NOAC including rivaroxaban, apixaban, dabigatran and edoxaban. Trials had to report at least one of the following outcomes of interest: mortality, recurrent VTE, recurrent pulmonary embolism (PE), recurrent deep vein thrombosis (DVT), or major bleeding. Included trials were evaluated for quality using the Cochrane Risk of Bias tool. We performed an adjusted indirect comparison meta-analysis to evaluate the comparative efficacy and safety of NOACs, reporting relative risks (RRs) and 95% confidence intervals for each outcome.

Results

Six trials (n = 27,069) met inclusion criteria, one each evaluating apixaban and edoxaban and two trials each evaluating rivaroxaban and dabigatran. Risk of bias was low for all trials. NOACS did not differ significantly in the risk of mortality, recurrent VTE, recurrent PE or recurrent DVT. Dabigatran increased major bleeding risk compared to apixaban [RR 2.69 (1.19 to 6.07)] as did edoxaban compared to apixaban [RR 2.74 (1.40 to 5.39)].

Conclusion

Although NOACs do not appear to differ in the efficacy of treating acute VTE, data suggests apixaban to be the safer than some of its competitors.     

Increased activation of blood coagulation in pregnant women with the Factor V Leiden mutation

Background

The risk of venous thromboembolism is enhanced in pregnant carriers of the Factor V Leiden mutation. The primary aim of the study was to compare prothrombin fragments 1 + 2, soluble fibrin and D-dimer levels in pregnant Factor V Leiden mutation carriers with those in non-carriers. Secondary aims were to evaluate whether these biomarkers could predict placenta-mediated complications or venous thromboembolism, and to study blood coagulation after caesarean section with thromboprophylaxis and after vaginal delivery without thromboprophylaxis.

Material/Methods

Prothrombin fragments 1 + 2, soluble fibrin and D-dimer levels were studied longitudinally in 476 carriers with singleton pregnancies from gestational weeks 23–25 until 8–10 weeks postpartum.

Results

Prothrombin fragments 1 + 2 and D-dimer levels gradually increased during pregnancy. D-dimer levels were higher in carriers, both during pregnancy and puerperium, compared to non-carriers. D-dimer levels above 0.5 mg/l were found in about 30% and 20% of the heterozygous carriers at 4–5 and 8–10 weeks postpartum, respectively. Soluble fibrin levels were mainly unchanged during pregnancy, with no difference between carriers and non-carriers. Biomarker levels were similar in carriers with uncomplicated and complicated pregnancies.

Conclusion

Higher D-dimer levels indicate increased blood coagulation and fibrinolysis activity in carriers. The high proportion of carriers with D-dimer levels exceeding 0.5 mg/l postpartum must be considered when assessing the probability of venous thromboembolism. Large overlaps in biomarker levels in normal and complicated pregnancies suggest that these biomarkers cannot be used as predictors. Thromboprophylaxis following caesarean section may prevent increased activation of blood coagulation.     

Outpatient treatment of symptomatic pulmonary embolism: A systematic review and meta-analysis

Background

Patients with acute deep vein thrombus (DVT) can safely be treated as outpatients. However the role of outpatient treatment in patients diagnosed with a pulmonary embolism (PE) is controversial. We sought to determine the safety of outpatient management of patients with acute symptomatic PE.

Materials and Methods

A systematic literature search strategy was conducted using MEDLINE, EMBASE, the Cochrane Register of Controlled Trials and all EBM Reviews. Pooled proportions for the different outcomes were calculated.

Results

A total of 1258 patients were included in the systematic review. The rate of recurrent venous thromboembolism (VTE) in patients with PE managed as outpatients was 1.47% (95% CI: 0.47 to 3.0%; I²: 65.4%) during the 3 month follow-up period. The rate of fatal PE was 0.47% (95% CI: 0.16 to 1.0%; I²: 0%). The rates of major bleeding and fatal intracranial hemorrhage were 0.81% (95% CI: 0.37 to 1.42%; I²: 0%) and 0.29% (95% CI: 0.06 to 0.68%; I²: 0%), respectively. The overall 3 month mortality rate was 1.58% (95% CI: 0.71 to 2.80%; I²: 45%). The event rates were similar if employing risk stratification models versus using clinical gestalt to select appropriate patients for outpatient management.

Conclusions

Independent of the risk stratification methods used, the rate of adverse events associated with outpatient PE treatment seems low. Based on our systematic review and pooled meta-analysis, low-risk patients with acute PE can safely be treated as outpatients if home circumstances are adequate.     

Thromboprophylaxis patterns,risk factors,and outcomes of care in the medically ill patient population

Introduction

Medically ill, hospitalized patients are at increased risk for venous thromboembolism (VTE) after discharge. This study aimed to examine thromboprophylaxis patterns, risk factors, and post-discharge outcomes.

Methods

This was a retrospective claims analysis involving administrative claims data and in-patient data abstracted from a sample of hospital charts. Patients aged ≥ 40 years hospitalized for ≥ 2 days for nonsurgical reasons between 2005 and 2009 were included. Hospital chart data were abstracted for a random sample of patients without evidence of anticoagulant use at 30 days post-discharge. The combined data determined whether in-patient thromboprophylaxis (anticoagulant or mechanical prophylaxis) reduces risk of VTE at 90 days post-discharge. Hazard ratios (HR) and odds ratios (OR) were calculated using Cox proportional hazard models and logistic regression.

Results

Of 141,628 patients in the claims analysis, 3.9% received anticoagulants (3.6% warfarin). VTE, rehospitalization, and mortality rates were 1.9%, 17.2%, and 6.2%, respectively. The strongest predictors of post-discharge VTE were history of VTE (HR = 4.0, 95% confidence interval [CI]: 3.3-4.8), and rehospitalization (HR = 3.9, 95% CI: 3.6-4.3). Of 504 medical charts, 209 (41.5%) reported in-patient thromboprophylaxis. There was no statistically significant difference in post-discharge VTE rates between patients who did and did not receive in-patient thromboprophylaxis. All-cause mortality was greater among patients without use of VTE prophylaxis.

Conclusion

Utilization rates of in-hospital and post-discharge VTE prophylaxis were low. In-hospital VTE prophylaxis did not reduce the risk of post-discharge VTE in the absence of post-discharge anticoagulation. Combined in-patient and post-discharge thromboprophylaxis lowered the odds of short-term, all-cause post-discharge mortality.