VTE-related Mortality Research Articles

Subcutaneous unfractionated heparin for the initial treatment of venous thromboembolism.

Venous thromboembolism (VTE) is a prevalent and serious condition. Its medical treatment requires anticoagulation, usually with either unfractionated or low molecular weight heparin (LMWH). Administration of unfractionated heparin (UFH) is usually intravenous (IV) but can be subcutaneous as well. This is an update of a review first published in 2009. To assess the effects of subcutaneous UFH versus intravenous UFH, subcutaneous LMWH or any other anticoagulant drug for the initial treatment of venous thromboembolism. For this update, the Cochrane Vascular Information Specialist searched the Specialised Register (last searched 30 November 2016) and CENTRAL (2016, Issue 10). The Cochrane Vascular Information Specialist also searched trials registries for details of ongoing or unpublished studies. Randomised controlled trials comparing subcutaneous UFH to control, such as subcutaneous LMWH, continuous intravenous UFH or other anticoagulant drugs in participants with acute venous thromboembolism. Two review authors (JS and LR) independently extracted data and assessed the risk of bias in the trials. We used meta-analyses when we considered heterogeneity low. The primary outcomes were symptomatic recurrent venous thromboembolism (deep vein thrombosis and/or pulmonary embolism), VTE-related mortality, adverse effects of treatment including major bleeding, and all-cause mortality. We calculated all outcomes using an odds ratio (OR) with a 95% confidence interval (CI). We included one additional study in this update, bringing the total number of studies in the review to 16 randomised controlled trials, with a total of 3593 participants (1745 participants in the intervention group and 1848 participants in the control group). Eight trials used intravenous UFH as the control treatment, seven trials used LMWH, and one trial had three arms with both drugs as the controls. We did not identify trials comparing subcutaneous UFH with other anticoagulant drugs. We downgraded the quality of the evidence to low due to lack of blinding in studies, which led to a risk of performance bias, and also for imprecision, as reflected by the wide confidence intervals.When comparing subcutaneous versus IV UFH, there was no difference in the incidence of symptomatic recurrent VTE at three months (odds ratio (OR) 1.66, 95% confidence interval (CI) 0.89 to 3.10; 8 studies; N = 965; low-quality evidence), symptomatic recurrent deep vein thrombosis (DVT) at three months (OR 3.29, 95% CI 0.64 to 17.06; 1 study; N = 115; low-quality evidence), pulmonary embolism (PE) at three months (OR 1.44, 95% CI 0.73 to 2.84; 9 studies; N = 1161; low-quality evidence), VTE-related mortality at three months (OR 0.98, 95% CI 0.20 to 4.88; 9 studies; N = 1168; low-quality evidence), major bleeding (OR 0.91, 95% CI 0.42 to 1.97; 4 studies; N = 583; low-quality evidence) or all-cause mortality (OR 1.74, 95% CI 0.67 to 4.51; 8 studies; N = 972; low-quality evidence). There were no episodes of asymptomatic VTE occurring within three months of the commencement of treatment.When comparing subcutaneous UFH versus LMWH, there was no difference in the incidence of recurrent VTE at three months (OR 1.01, 95% CI 0.63 to 1.63; 5 studies; N = 2156; low-quality evidence), recurrent DVT at three months (OR 1.38, 95% CI 0.73 to 2.63; 3 studies; N = 1566; low-quality evidence), PE (OR 0.84, 95% CI 0.36 to 1.96; 5 studies, N = 1819; low-quality evidence), VTE-related mortality (OR 0.53, 95% CI 0.17 to 1.67; 8 studies; N = 2469; low-quality evidence), major bleeding (OR 0.72, 95% CI 0.43 to 1.20; 5 studies; N = 2300; low-quality evidence) or all-cause mortality (OR 0.73, 95% CI 0.50 to 1.07; 7 studies; N = 2272; low-quality evidence). There were no episodes of asymptomatic VTE occurring within three months of the commencement of treatment. There is no evidence of a difference between subcutaneous versus intravenous UFH for preventing VTE recurrence, VTE-related or all-cause mortality, and major bleeding. According to GRADE criteria, the quality of the evidence was low. There is also no evidence of a difference between subcutaneous UFH and LMWH for preventing VTE recurrence, VTE-related or all-cause mortality or major bleeding.

Assessment of the Safety and Efficacy of Edoxaban for the Treatment of Venous Thromboembolism Secondary to Active Malignancy.

Objective: To assess the safety and efficacy of edoxaban for the treatment of venous thromboembolism (VTE) secondary to active malignancy.Materials and Methods: We enrolled 48 patients with newly diagnosed VTE secondary to active malignancy that was treated with oral edoxaban for 1 year between September 2014 and August 2015. We retrospectively examined the presence or absence of recurrent symptomatic VTE, VTE-related mortality, and bleeding events.Results: No recurrent symptomatic VTE or VTE-related deaths were recorded, enabling efficient assessment. Treatment safety was determined based on the reports of bleeding. Bleeding was reported in two patients, with serious bleeding in one of them.Conclusion: Edoxaban is safe and effective for the treatment of VTE secondary to active malignancy.

Efficacy and safety of extended thromboprophylaxis for medically ill patients. A meta-analysis of randomised controlled trials.

Compelling evidence suggests that the risk of pulmonary embolism (PE) and deep-vein thrombosis (DVT) persists after hospital discharge in acutely-ill medical patients. However, no studies consistently supported the routine use of extended-duration thromboprophylaxis (ET) in this setting. We performed a meta-analysis to assess efficacy and safety of ET in acutely-ill medical patients. Efficacy outcome was defined by the prevention of symptomatic DVT, PE, venous thromboembolism (VTE) and VTE-related mortality. Safety outcome was the occurrence of major bleeding (MB) and fatal bleeding (FB). Pooled odds ratios (ORs) and 95 % confidence intervals (95 %CI) were calculated for each outcome using a random effects model. Four RCTs for a total of 28,105 acutely-ill medical patients were included. ET was associated with a significantly lower risk of DVT (0.3 % vs 0.6 %, OR 0.504, 95 %CI: 0.287-0.885) and VTE (0.5 % vs 1.0 %, OR: 0.544, 95 %CI: 0.297-0.997); a non-significantly lower risk of PE (0.3 % vs 0.4 %, OR 0.633, 95 %CI: 0.388-1.034) and of VTE-related mortality (0.2 % vs 0.3 %, OR 0.687, 95 %CI: 0.445-1.059) and with a significantly higher risk of MB (0.8 % vs 0.4 %, OR 2.095, 95 %CI: 1.333-3.295). No difference in FB was found (0.06 % vs 0.03 %, OR 1.79, 95 %CI: 0.384-8.325). The risk benefit analysis showed that the NNT for DVT was 339, for VTE was 239, and the NNH for MB was 247. Results of our meta-analyses focused on clinical important outcomes did not support a general use of antithrombotic prophylaxis beyond the period of hospitalization in acutely-ill medical patients.

Thromboprophylaxis With Apixaban in Patients Undergoing Major Orthopedic Surgery: Meta-Analysis and Trial-Sequential Analysis.

BACKGROUNDVenous thromboembolism (VTE) is a potentially fatal complication of orthopedic surgery, and until recently, few antithrombotic compounds were available for postoperative thromboprophylaxis. The introduction of the non–vitamin K antagonists oral anticoagulants (NOAC), including apixaban, has extended the therapeutic armamentarium in this field. Therefore, estimation of NOAC net clinical benefit in comparison with the established treatment is needed to inform clinical decision making.OBJECTIVESSystematic review to assess the efficacy and safety of apixaban 2.5 mg twice a day versus low-molecular-weight heparins (LMWH) for thromboprophylaxis in patients undergoing knee or hip replacement.DATA SOURCESMEDLINE, Embase, and CENTRAL were searched from inception to September 2016, other systematic reviews, reference lists, and experts were consulted.STUDY ELIGIBILITY CRITERIA, PARTICIPANTS, AND INTERVENTIONAll major orthopedic surgery randomized controlled trials comparing apixaban 2.5 mg twice daily with LMWH, reporting thrombotic and bleeding events.DATA EXTRACTIONTwo independent reviewers, using a predetermined form.STUDY APPRAISAL AND SYNTHESIS METHODSThe Cochrane tool to assess risk bias was used by two independent authors. RevMan software was used to estimate pooled risk ratio (RR) and 95% confidence intervals (95% CI) using random-effects meta-analysis. Trial sequential analysis (TSA) was performed in statistical significant results to evaluate whether cumulative sample size was powered for the obtained effect. Overall confidence in cumulative evidence was assessed using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) Working Group methodology.RESULTSFour studies comparing apixaban 2.5 mg twice daily with LMWH were included, with a total of 11.828 patients (55% undergoing knee and 45% hip replacement). The overall risk of bias across studies was low. In comparison with LMWH (all regimens), apixaban showed a significantly lower risk of VTE events and overall mortality combined (RR: 0.63, 95% CI: 0.42–0.95, I2 = 84%, n = 8346), but not of major VTE events (RR: 0.62, 95% CI: 0.32–1.19, I2 = 63%, n = 9493), or of symptomatic VTE events and VTE-related mortality combined (RR: 1.14, 95% CI: 0.68–1.90, I2 = 0%, n = 11 879). Trial sequential analysis showed that the risk reduction obtained for VTE and mortality was based on underpowered cumulative sample size and effect dimension. Subgroup analysis according to LMWH regimens showed that apixaban reduced the risk of VTE events and overall mortality, and major VTE events, when compared with LMWH once daily, without differences between apixaban and LMWH twice daily.CONCLUSIONSThere is low to moderate evidence that in patients undergoing knee or hip replacement, apixaban seems equally effective and safe to LMWH twice a day. When compared with LMWH once a day, apixaban seems a superior thromboprophylaxis option. However, the results are underpowered which precludes definite answers regarding the true net clinical benefit of apixaban versus LMWH in this clinical context.

Rationale and Design of a Phase IIb/III Open-Label, Multicenter Study of Dabigatran Etexilate for Venous Thromboembolism in Children: The Diversity Study

BackgroundVenous thromboembolism (VTE) is increasing in children. The current standard of care comprises unfractionated heparin (UFH) or low-molecular-weight heparin (LMWH) for at least 5 days followed by UFH, LMWH or Vitamin K antagonists (VKA) for approximately 3 months in general. All of the current options have limitations: UFH and LMWH require parenteral administration; VKA requires frequent international normalized ratio (INR) monitoring and is associated with multiple food and drug interactions. The direct thrombin inhibitor, dabigatran, which is orally administered as the prodrug, dabigatran etexilate (DE) is effective for the treatment of VTE in adults and may overcome some of the limitations associated with standard of care.ObjectiveTo describe the design of a study evaluating the appropriateness of a proposed DE dosing algorithm and assessing the safety and efficacy of DE versus standard of care in pediatric patients with VTE.MethodsThis open-label, randomized, parallel-group, active-controlled, multi-center, non-inferiority study (NCT01895777) will be conducted in approximately 100 sites in approximately 30 countries. Patients aged 0 to < 18 years with an imaging-confirmed diagnosis of VTE initially receiving parenteral treatment with UFH or LMWH for 5-7 days (but no more than 21 days) who are expected to require anticoagulation therapy for at least 3 months will be eligible for inclusion. Main exclusion criteria include conditions associated with an increased risk of bleeding, renal dysfunction, active infective endocarditis, mechanical or biological heart valve prosthesis, hepatic disease and anemia or thrombocytopenia.Patients will be stratified into three age groups: stratum 1 (12 to < 18 years), stratum 2 (2 to < 12 years) and stratum 3 (birth to < 2 years). Recruitment will begin in stratum 1, being subsequently escalated to strata 2 and 3, respectively based on recommendations from the Data Monitoring Committee.Patients will be randomized (2:1) to receive DE versus standard of care (LMWH or VKA). DE will be administered twice daily as capsules, pellets or an oral liquid formulation depending on patient age and the patient's ability to swallow pellets or capsules. Upon completion of a 3-month treatment period (including the initial parenteral treatment phase) patients will be followed off-study drug for any adverse events.DE will be dosed to achieve steady-state measured trough circulating plasma concentrations (≥50 and < 250 ng/mL); the initial dose required will be calculated using a nomogram, which adjusts dosing according to the age and weight of the child. Dabigatran plasma concentrations will be evaluated at all study visits (7 scheduled during treatment period); DE will be up- or down-titrated as required.ResultsIn terms of efficacy, the study will evaluate the proportion of patients with complete thrombus resolution, freedom from recurrent VTE (including symptomatic and asymptomatic, contiguous progression or non-contiguous new thrombus, deep vein thrombosis, pulmonary and paradoxical embolism, and thrombus progression) and freedom from VTE-related mortality. With regards to safety, the key endpoint will be freedom from major bleeding events, as per International Society on thrombosis and Haemostasis (ISTH) pediatric-specific criteria. All components of the primary efficacy and key safety endpoints will be adjudicated by an independent blinded committee.ConclusionThis study, one of the largest controlled pediatric studies for VTE, will provide data on the safety and efficacy of DE compared with standard of care for the treatment of VTE in children aged 0 to < 18 years. DisclosuresAlbisetti:Boehringer Ingelheim: Other: Pediatric Expert Working Group. Manastirski:Boehringer Ingelheim: Employment. Brueckmann:Boehringer Ingelheim: Employment. Gropper:Boehringer Ingelheim: Employment. Wang:Boehringer Ingelheim: Employment. Tartakovsky:Boehringer Ingelheim: Employment. Biss:Boehringer Ingelheim: Employment. Huang:Boehringer Ingelheim: Employment. Mitchell:Boehringer Ingelheim: Consultancy; Pfizer: Consultancy; Bristol Myers Squibb: Consultancy. Halton:Boehringer Ingelheim: Other: Pediatric Expert Working Group for Boehringer Ingelheim.

Venous thromboembolism after lower limb arthroplasty: is chemical prophylaxis still needed?

Venous thromboembolism (VTE) is a significant complication of lower limb arthroplasty. The National Institute for Health and Care Excellence recommends routine use of chemical and mechanical prophylaxis to prevent VTE. Our high-volume, elective, arthroplasty unit adopted this guidance in 2008. We examined our incidence of VTE before and after introduction of chemical thromboprophylaxis to determine whether the incidence of VTE reduced. We retrospectively gathered data on 2 cohorts of patients-from January 2004 to August 2007 (Group 1) and January 2010 to December 2012 (Group 2). Patients in Group 1 received mechanical prophylaxis only (unless particularly high risk for VTE), and patients in Group 2 received mechanical and chemical prophylaxis. We recorded VTE occurring within 6months of surgery. Patients in Group 1 receiving chemical prophylaxis were excluded. Group 1 had 2320 cases of primary and revision lower limb arthroplasty, and Group 2 had 1430 cases. VTE occurred in 37 cases in Group 1 (1.6%), and in 17 cases in Group 2 (1.2%). This difference was not statistically significant (p=0.26). In Group 1, 1 patient died within 6months due to pulmonary embolism (0.04%); there were no VTE-related deaths in Group 2 (0%). This was also not statistically significant (p=0.06). Although our VTE rate reduced by 0.4% and our VTE-related mortality reduced by 0.04% after introduction of chemical thromboprophylaxis, these differences were not statistically significant. Chemical thromboprophylaxis may not be required in all patients undergoing arthroplasty providing appropriate mechanical prophylaxis is used.

Thromboprophylaxis with dabigatran after total hip arthroplasty in Indian patients: A subanalysis of a double-blind, double-dummy, randomized RE-NOVATE II study

In the Re-NOVATE II study, oral dabigatran provided thromboprophylaxis after total hip arthroplasty and improved compliance postdischarge in a global population. This article aims to identify trends (if any) in the Indian population. In this prospective, double-blind, double-dummy study, patients scheduled for primary, unilateral, elective total hip arthroplasty were randomized to 220mg oral dabigatran once daily, starting with a 110mg half-dose, 1-4hours after surgery, or subcutaneous enoxaparin 40mg once daily, starting the evening before surgery. Each group received a placebo of the other study drug. The primary efficacy outcome was the composite of total venous thromboembolism (VTE) and all-cause mortality. Secondary outcome measures were composite of major VTE and VTE-related mortality during the treatment period. The major safety outcome was incidence of bleeding events. Of the 179 Indian patients randomized, 91 received oral dabigatran and 88 received subcutaneous enoxaparin for 28-35days. Total VTE and all-cause mortality occurred in 18.7% of patients in the dabigatran group and 13.7% in the enoxaparin group [odds ratio=1.4 (95% confidence interval 0.6, 3.5)]. Major VTE and VTE-related mortality was numerically lower in the dabigatran group (7.9%) compared with the enoxaparin group (9.9%). Safety outcomes were comparable between both groups. Dabigatran is an effective oral alternative to enoxaparin for thromboprophylaxis as demonstrated by the RE-NOVATE II study global results. Data analyzed in Indian patients indicate comparable effects of dabigatran etexilate for major efficacy and safety outcomes.

DVT Management and Outcome Trends, 2001 to 2014

A comprehensive evaluation of temporal trends in the treatment of patients who have DVT may assist with identification of modifiable factors that contribute to short-term outcomes. We assessed temporal trends in length of hospital stay and use of pharmacological and interventional therapies among 26,695 adults with DVT enrolled in the Registro Informatizado de la Enfermedad TromboEmbólica registry between 2001 and 2014. We also examined temporal trends in risk-adjusted rates of all-cause, pulmonary embolism-related, and bleeding-related death to 30days after diagnosis. The mean length of hospital stay decreased from 9.0days in 2001 to 2005 to 7.6days in 2010 to 2014 (P< .01). For initial DVT treatment, the use of low-molecular-weight heparin decreased from 98%to 90%(P< .01). Direct oral anticoagulants use increased from 0.5%in 2010 to 13.4%in 2014 (P< .001). Risk-adjusted rates of 30-day all-cause mortality decreased from 3.9%in 2001 to 2005 to 2.7%in 2010 to 2014 (adjusted rate ratio per year, 0.84; 95%CI, 0.74-0.96; P< .01). VTE-related mortality showed a nonstatistically significant downward trend (adjusted rate ratio per year, 0.70; 95%CI, 0.44-1.10; P= .13), whereas 30-day bleeding-related mortality significantly decreased from 0.5%in 2001 to 2005 to 0.1%in 2010-2014 (adjusted rate ratio per year, 0.55; 95%CI, 0.40-0.77; P<.01). This international registry-based temporal analysis identified reductions in length of stay for adults hospitalized for DVT. The study also found a decreasing trend in adjusted rates of all-cause and bleeding-related mortality.

Mortality Associated with Venous Thromboembolism in Hospitalized Pediatric Patients: A Single Tertiary Care Institute Experience

▪Background: Hospital-associated venous thromboembolism (HA-VTE) is a major cause of morbidity and mortality in adults; there is a paucity of data about mortality risk in children.Objective: To determine clinical factors associated with mortality in children with HA-VTE.Methods: We conducted retrospective chart review of patients <=21 years with HA-VTE admitted to the Johns Hopkins Hospital from 1992-2013. ICD-9 codes were used to identify cases with deep venous thrombosis and pulmonary embolism; diagnosis was verified by reviewing hospital records and radiologic imaging. HA-VTE was defined as 1) VTE diagnosed ≥48 hours after hospital admission or 2) VTE diagnosed within 90 days of hospital discharge. Univariate and conditional multivariable logistic regression analyses with backward elimination were used to estimate the risk factors for mortality and adjusted Odds Ratios (adjOR) calculated.Results: Of 330 HA-VTE cases, there were 55 deaths (16.7%); 18 deaths (5.5%) were attributable to VTE. Median follow up was 2.9 years. Within 30 days of VTE diagnosis, all-cause mortality was 4.2% and VTE-attributable mortality was 1.8%. Acute systemic infection (adjOR 11.3; 95%CI 4.7-26.8) and malignancy (adjOR 3.9; 95%CI 1.6-9.5) were associated with increased adjusted odds of all-cause mortality (Table 1). For deaths specifically attributable to VTE, acute systemic infection (adjOR 18.6; 95%CI 4.9-71.4) was associated with increased adjusted odds of mortality.Conclusion: The majority of VTE-attributable deaths occurred over 30 days from VTE diagnosis. Acute systemic infection was a significant predictor of VTE-related mortality in HA-VTE. Further studies are warranted to identify additional risks for VTE-related mortality to develop prevention strategies.Table 1Odds Ratio Estimates of All-cause Mortality in Hospital Associated Venous Thromboembolism in Children in a Tertiary Care Hospital.Putative Risk FactorOdds Ratio95% WaldConfidence Limits*Systemic Infection11.34.726.8Cancer3.91.69.5Pulmonary Embolism0.70.32.0Age (each year increase)0.90.91.1Male gender versus female0.70.31.5Central Venous Catheter1.40.63.2Hospital readmission within 90 days1.50.63.7*Meningitis, abscess, pneumonia, osteomyelitis, bacteremia, fungemia, and pyelonephritis DisclosuresTakemoto:Novo Nordisk: Research Funding; Mast Therapeutics: Speakers Bureau.

Implementing an evidence-based computerized decision support system to improve patient care in a general hospital: the CODES study protocol for a randomized controlled trial.

BackgroundComputerized decision support systems (CDSSs) are information technology-based software that provide health professionals with actionable, patient-specific recommendations or guidelines for disease diagnosis, treatment, and management at the point-of-care. These messages are intelligently filtered to enhance the health and clinical care of patients. CDSSs may be integrated with patient electronic health records (EHRs) and evidence-based knowledge.Methods/designWe designed a pragmatic randomized controlled trial to evaluate the effectiveness of patient-specific, evidence-based reminders generated at the point-of-care by a multi-specialty decision support system on clinical practice and the quality of care. We will include all the patients admitted to the internal medicine department of one large general hospital. The primary outcome is the rate at which medical problems, which are detected by the decision support software and reported through the reminders, are resolved (i.e., resolution rates). Secondary outcomes are resolution rates for reminders specific to venous thromboembolism (VTE) prevention, in-hospital all causes and VTE-related mortality, and the length of hospital stay during the study period.DiscussionThe adoption of CDSSs is likely to increase across healthcare systems due to growing concerns about the quality of medical care and discrepancy between real and ideal practice, continuous demands for a meaningful use of health information technology, and the increasing use of and familiarity with advanced technology among new generations of physicians. The results of our study will contribute to the current understanding of the effectiveness of CDSSs in primary care and hospital settings, thereby informing future research and healthcare policy questions related to the feasibility and value of CDSS use in healthcare systems. This trial is seconded by a specialty trial randomizing patients in an oncology setting (ONCO-CODES).Trial registrationClinicalTrials.gov, https://clinicaltrials.gov/ct2/show/NCT02577198?term=NCT02577198&rank=1

Oral dabigatran etexilate versus enoxaparin for venous thromboembolism prevention after total hip arthroplasty: pooled analysis of two phase 3 randomized trials.

BackgroundTwo phase 3 trials compared 28–35 days of treatment with oral dabigatran 220 mg or 150 mg (RE-NOVATE) or 220 mg (RE-NOVATE II) once daily with subcutaneous enoxaparin 40 mg once daily for prevention of venous thromboembolism (VTE) after elective total hip arthroplasty.MethodsThis prespecified pooled analysis compared the outcomes for the dabigatran 220 mg dose with enoxaparin, which included 4,374 patients. Total VTE (venographic and symptomatic) plus all-cause mortality (primary efficacy), major VTE (proximal deep vein thrombosis [DVT] or non-fatal pulmonary embolism) plus VTE-related death, and bleeding events were evaluated. Efficacy analysis was based on the modified intention-to-treat (ITT) population and safety analysis was based on all treated patients. The common risk difference (RD) for dabigatran versus enoxaparin was estimated using a fixed effects model.ResultsTotal VTE and all-cause mortality occurred in 6.8 % (114/1,672) and 7.7 % (129/1,682) (RD:–0.8 %, 95 % confidence interval [CI] –2.6 to 0.9) for dabigatran and enoxaparin, respectively. Major VTE plus VTE-related mortality occurred in 2.7 % (46/1,714) and 4.0 % (69/1,711) (RD: –1.4 %, 95 % CI –2.6 to –0.2) of patients receiving dabigatran 220 mg and enoxaparin, respectively. Major bleeding occurred in 1.7 % (37/2,156) and 1.3 % (27/2,157) (RD: 0.5 %, 95 % CI –0.2 to 1.2), for dabigatran and enoxaparin respectively.ConclusionsExtended prophylaxis with oral dabigatran 220 mg once daily was as effective as enoxaparin 40 mg once daily in reducing the risk of total VTE and all-cause mortality after total hip arthroplasty, with a similar bleeding profile. The clinically relevant outcome of major VTE and VTE-related death was significantly reduced with dabigatran versus enoxaparin.Trial registrationNCT00657150 and NCT00168818

The design and implementation of a new surveillance system for venous thromboembolism using combined active and passive methods

Estimates of venous thromboembolism (VTE) incidence in the United States are limited by lack of a national surveillance system. We implemented a population-based surveillance system in Oklahoma County, OK, for April 1, 2012 to March 31, 2014, to estimate the incidences of first-time and recurrent VTE events, VTE-related mortality, and the proportion of case patients with provoked versus unprovoked VTE. The Commissioner of Health made VTE a reportable condition and delegated surveillance-related responsibilities to the University of Oklahoma, College of Public Health. The surveillance system included active and passive methods. Active surveillance involved reviewing imaging studies (such as chest computed tomography and compression ultrasounds) from all inpatient and outpatient facilities. Interrater agreement between surveillance officers collecting data was assessed using κ. Passive surveillance used International Classification of Disease, Ninth Revision (ICD-9) codes from hospital discharge data to identify cases. The sensitivity and specificity of various ICD-9-based case definitions will be assessed by comparison with cases identified through active surveillance. As of February 1, 2015, we screened 54,494 (99.5%) of the imaging studies and identified 2,725 case patients, of which 91.6% were from inpatient facilities, and 8.4% were from outpatient facilities. Agreement between surveillance officers was high (κ ≥0.61 for 93.2% of variables). Agreement for the diagnosis of pulmonary embolism and diagnosis of deep vein thrombosis was κ = 0.92 (95% CI 0.74-1.00) and κ = 0.89 (95% CI 0.71-1.00), respectively. This surveillance system will provide data on the accuracy of ICD-9-based case definitions for surveillance of VTE events and help the Centers for Disease Control and Prevention develop a national VTE surveillance system.

Effect of testing for cancer on cancer- and venous thromboembolism (VTE)-related mortality and morbidity in patients with unprovoked VTE.

Venous thromboembolism (VTE) is a collective term for two conditions: deep vein thrombosis (DVT) and pulmonary embolism (PE). A proportion of patients with VTE have no underlying or immediately predisposing risk factors and the VTE is referred to as unprovoked. Unprovoked VTE can often be the first clinical manifestation of an underlying malignancy. This has raised the question of whether patients with an unprovoked VTE should be investigated for an underlying cancer. Treatment for VTE is different in cancer and non-cancer patients and a correct diagnosis would ensure that patients received the optimal treatment for VTE to prevent recurrence and further morbidity. Furthermore, an appropriate cancer diagnosis at an earlier, potentially curative stage could avoid the risk of cancer progression and thus lead to improvements in cancer-related mortality and morbidity. To determine whether testing for undiagnosed cancer in patients with a first episode of unprovoked VTE (DVT or PE) is effective in reducing cancer and VTE-related mortality and morbidity and to establish which tests for cancer are most useful. The Cochrane Peripheral Vascular Diseases Group Trials Search Co-ordinator searched the Specialised Register (last searched January 2015) and the Cochrane Register of Studies (CRS) (2014, Issue 12). Clinical trials databases were searched. The reference lists of relevant articles were also checked. Randomised and quasi-randomised trials in which patients with an unprovoked VTE were allocated to receive specific tests for cancer or clinically indicated tests only were eligible for inclusion in this review. Primary outcomes included all-cause mortality, cancer-related mortality and VTE-related mortality. Selection of the studies, quality assessment and data extraction were completed independently by two review authors. Any disagreements were resolved by discussion. Two studies with a combined total of 396 patients met the inclusion criteria for this review. Both studies assessed the effect of testing for cancer versus clinically indicated tests only in patients with an unprovoked VTE. The quality of the evidence was moderate because although the studies were judged to be at low or unclear risk of bias, there was concern that the studies were small as reflected in the wide confidence intervals (CIs). Pooled analysis showed that testing for cancer was consistent with either a benefit or no benefit on cancer-related mortality (odds ratio (OR) 0.49, 95% CI 0.15 to 1.67, P = 0.26). One study showed that, overall, malignancies were less advanced in patients belonging to the extensive screening group than in patients of the control group (64% versus 20%, P = 0.047) and that tested patients were diagnosed earlier than untested patients (mean 1 month versus 11.6 months to cancer diagnosis from the time of diagnosis of VTE). Standard deviations were not provided for time to diagnosis, so it was not possible to perform an independent statistical analysis on this association. Neither study measured all-cause mortality, VTE-related morbidity and mortality, side effects of anticoagulation, side effects of cancer tests or patient satisfaction. Testing for cancer in patients with idiopathic VTE leads to earlier diagnosis of cancer at an earlier stage of the disease. However, there is currently insufficient evidence to draw definitive conclusions concerning the effectiveness of testing for undiagnosed cancer in patients with a first episode of unprovoked VTE (DVT or PE) in reducing cancer and VTE-related morbidity and mortality. The results are imprecise and could be consistent with either harm or benefit. Further good-quality large-scale randomised controlled trials are required before firm conclusions can be made.

ANALYSIS OF THE BLEEDING AND THROMBOEMBOLIC RISK WITH CONCOMITANT USE OF ANTIPLATELET TREATMENT IN THE AMPLIFY TRIAL

The AMPLIFY trial compared apixaban with conventional anticoagulation consisting of enoxaparin followed by warfarin in patients with acute venous thromboembolism (VTE). In this analysis, we examined the impact of concomitant antiplatelet therapy on the risk of major bleeding, the primary safety endpoint, and recurrent VTE or VTE-related mortality, the primary efficacy endpoint, in patients enrolled in the trial. Patients who reported concomitant use of antiplatelet treatment at any time during the clinical trial were identified, and rates for the adjudicated primary safety and efficacy endpoints in these patients were compared with those in patients not taking antiplatelet drugs. Of the 2676 patients treated with apixaban and 2689 treated with conventional therapy, 402 (15%) and 411 (15%), respectively, reported concomitant antiplatelet drug use; primarily with aspirin. In patients taking concomitant antiplatelet therapy, major bleeds occurred in 5 patients in the apixaban group and in 17 patients in the conventional treatment group (relative risk, 0.30; 95% confidence interval, 0.11 to 0.81). In patients randomized to apixaban, the rate of major bleeding in those taking concomitant antiplatelet drugs was 3-fold higher than in those not taking these agents (1.2% and 0.4%, respectively), whereas in those randomized to conventional treatment, the rate of major bleeding in patients taking concomitant antiplatelet drugs was 2.9-fold higher than in those not taking these agents (4.1% and 1.4%, respectively). Rates of VTE or VTE-related death were similar in those taking or not taking concomitant antiplatelet drugs in both the apixaban group (3.6% and 2.0%, respectively) and the warfarin group (3.0% and 2.6%, respectively). Although concomitant administration of antiplatelet drugs produced a proportionally similar increase in the risk of major bleeding in patients randomized to apixaban or conventional treatment, there were fewer major bleeds with apixaban. Thus, the overall safety benefit of apixaban over conventional treatment was maintained in patients taking concomitant antiplatelet drugs. Concomitant administration of these drugs did not appear to influence the rates of VTE or VTE-related death.

Thromboembolic events in bariatric surgery: a large multi-institutional referral center experience

The risk of venous thromboembolic (VTE) events is increased in patients undergoing bariatric surgery. Population studies examining VTE rates after bariatric surgery often lack details and uniformity regarding the prophylactic regimens used. The aim of this study was to determine the incidence of VTE in patients undergoing laparoscopic bariatric surgery. Database searches from Cleveland Clinic bariatric surgery programs in Cleveland, OH, and Weston, FL, were conducted from January 2005 to January 2013. Mechanical and chemical prophylaxes were provided for all patients as per protocol. Data on age, gender, body mass index (BMI), interval between procedure and VTE, inpatient versus outpatient status, anticoagulation prophylaxis, type of surgery and mortality were collected. A total of 4,293 patients underwent primary or revisional bariatric surgery during this 8-year time period. VTE events were identified in 57 patients (1.3 %). Pulmonary embolism (PE) was identified in 39 patients (0.9 %), and 15 of these patients had negative duplex studies of the lower extremities. Deep venous thrombosis only was identified in 18 patients (0.4 %). VTE rates for gastric bypass (n = 2,945), sleeve gastrectomy (n = 709), gastric banding (n = 467) and revisional procedures (n = 171) were 1.1, 2.9, 0.2 and 6.4 %, respectively. Eight patients had VTE diagnosed during their inpatient stay. The mean time to VTE diagnosis after surgery was 24 days. Seventeen patients who developed VTE had been prescribed extended prophylaxis for 2-4 weeks after discharge. There was only one VTE-related mortality from PE reported in this cohort (0.02 %). Univariate and multivariate analyses revealed age, BMI, open and revisional surgery as predictive of VTE (p < 0.05). The risk of VTE among morbidly obese patients undergoing bariatric surgery is persistent despite use of laparoscopy and aggressive prophylactic anticoagulation policy. Patients with advanced age, higher BMI and those undergoing open or revisional surgery are at higher risk of postoperative VTE.

Multicentre validation of the Geneva Risk Score for hospitalised medical patients at risk of venous thromboembolism

There is a need to validate risk assessment tools for hospitalised medical patients at risk of venous thromboembolism (VTE). We investigated whether a predefined cut-off of the Geneva Risk Score, as compared to the Padua Prediction Score, accurately distinguishes low-risk from high-risk patients regardless of the use of thromboprophylaxis. In the multicentre, prospective Explicit ASsessment of Thromboembolic RIsk and Prophylaxis for Medical PATients in SwitzErland (ESTIMATE) cohort study, 1,478 hospitalised medical patients were enrolled of whom 637 (43%) did not receive thromboprophylaxis. The primary endpoint was symptomatic VTE or VTE-related death at 90 days. The study is registered at ClinicalTrials.gov, number NCT01277536. According to the Geneva Risk Score, the cumulative rate of the primary endpoint was 3.2% (95% confidence interval [CI] 2.2-4.6%) in 962 high-risk vs 0.6% (95% CI 0.2-1.9%) in 516 low-risk patients (p=0.002); among patients without prophylaxis, this rate was 3.5% vs 0.8% (p=0.029), respectively. In comparison, the Padua Prediction Score yielded a cumulative rate of the primary endpoint of 3.5% (95% CI 2.3-5.3%) in 714 high-risk vs 1.1% (95% CI 0.6-2.3%) in 764 low-risk patients (p=0.002); among patients without prophylaxis, this rate was 3.2% vs 1.5% (p=0.130), respectively. Negative likelihood ratio was 0.28 (95% CI 0.10-0.83) for the Geneva Risk Score and 0.51 (95% CI 0.28-0.93) for the Padua Prediction Score. In conclusion, among hospitalised medical patients, the Geneva Risk Score predicted VTE and VTE-related mortality and compared favourably with the Padua Prediction Score, particularly for its accuracy to identify low-risk patients who do not require thromboprophylaxis.

Thrombo-Embolic Events in Cancer Patients with Impaired Renal Function

Venous Thromboembolism (VTE) is a frequent cause of mortality and morbidity in patients with malignancy. Thrombosis is one of the leading causes of death in patients with malignancy after cancer itself. As such, prompt recognition and treatment of VTE are required in order to reduce the risk of VTE-related mortality. This report reviews the interrelationship between cancer, renal insufficiency and VTE. The working group behind this review article concludes that Low Molecular Weight Heparins (LMWHs) decrease the risk of recurrent venous thrombosis in cancer patients without increasing major bleeding complications. LMWHs are therefore recommended as first line antithrombotic treatment in cancer patients with a clear clinical benefit. In patients with renal dysfunction, who are at both increased risk of bleeding and of thrombotic complications, preference should be given to unfractionated heparin or a LMWH with a mean molecular weight such as tinzaparin, having less risk of plasma accumulation and offering the possibility to maintain full therapeutic dose.

Thromboprophylaxis only during hospitalisation in fast-track hip and knee arthroplasty, a prospective cohort study

ObjectivesInternational guidelines recommend thrombosis prophylaxis after total hip arthroplasty (THA) and total knee arthroplasty (TKA) for up to 35 days. However, previous studies often have hospital stays (length of stay;...

Comparative Efficacy and Safety Of Dabigatran Etexilate and Rivaroxaban For The Treatment Of Deep Vein Thrombosis and Pulmonary Embolism

Objective Two novel oral anticoagulants recently have been investigated for the treatment of deep vein thrombosis and/or pulmonary embolism: dabigatran etexilate (dabigatran) and rivaroxaban. The aim of this analysis was to compare their efficacy and safety. Methods Randomized, controlled trials investigating dabigatran or rivaroxaban were identified by a systematic review. Direct meta-analyses and anchored (adjusted) indirect comparisons (AICs) were performed using aggregated results for the following endpoints for the overall treatment duration: first recurrent symptomatic venous thromboembolism (VTE) or VTE-related death, major bleeding events (MBEs), MBEs or clinically relevant bleeding events (CRBEs), and all-cause mortality. Results Four trials were identified; two compared dabigatran with warfarin and two compared rivaroxaban with vitamin K antagonists. The results of the trials, and the direct meta-analyses of the two dabigatran trials and the two rivaroxaban trials, are presented in Table 1. Overall, there was little evidence of heterogeneity in treatment effects among the RE-COVER trials (VTE or VTE-related death, MBEs, MBEs or CRBEs, all-cause mortality: P= 0.82, 0.67, 0.97, 0.97, respectively; I2= 0%). There was some evidence of heterogeneity among the EINSTEIN trials for VTE or VTE-related death (P=0.11; I2=61.9%) and all-cause mortality (P=0.16; I2=50%), but none for MBEs and MBEs/CRBEs with I2= 0% (P= 0.43, 0.47). In the AICs, sensitivity analyses were performed to explore potential trial heterogeneity arising from differences in the type of index VTE and time with an international normalized ratio between 2.0 and 3.0. AIC results suggested that dabigatran was associated with a lower risk of MBEs/CRBEs than rivaroxaban (upper 95% confidence limits for relative risks were less than 1.00). There was no evidence to suggest a difference between dabigatran and rivaroxaban with respect to prevention of recurrent symptomatic VTE or VTE-related death, MBEs, or all-cause mortality. Conclusions Dabigatran may be associated with a lower risk of major or clinically relevant bleeding; there was no evidence to suggest a difference among drugs in prevention of recurrent VTE, MBEs, or overall mortality. Disclosures: Clemens: Boehringer Ingelheim Pharma GmbH &amp; Co. KG: Employment. Off Label Use: Dabigatran etexilate, direct oral thrombin inhibitor, anticoagulant effect; indications for stroke prevention in atrial fibrillation patients in about 90 countries including US; indication for primary VTE prevention in total hip or knee replacement patients in about 100 countries excluding US. Abeysinghe:Boehringer Ingelheim International GmbH: Consultancy. Gonschior:Boehringer Ingelheim GmbH: Employment. Hösel:Boehringer Ingelheim GmbH: Consultancy. Lock:Boehringer Ingelheim International GmbH: Consultancy. Wolowacz:Boehringer Ingelheim International GmbH: Consultancy. Woods:Boehringer Ingelheim International GmbH: Consultancy. Zimovetz:Boehringer Ingelheim International GmbH: Consultancy.

Influence Of Concomitant NSAID Or ASA On The Efficacy and Safety Of Dabigatran Versus Warfarin For The Treatment Of Acute Venous Thromboembolism: A Pooled Analysis From RE-Cover and RE-Cover II

BackgroundIn two phase III trials, RE-COVER and RE-COVER II, dabigatran etexilate was as effective as warfarin for treatment of acute venous thromboembolism (VTE), with a lower risk of bleeding. However, some patients may already be taking non-steroidal anti-inflammatory drugs (NSAIDs) or acetylsalicylic acid (ASA), which can have antihemostatic effects. ObjectivesWe performed a prespecified subgroup analysis on pooled data from RE-COVER and RE-COVER II to investigate the efficacy and safety of dabigatran versus warfarin in patients with and without concomitant NSAIDs (half-life < 12 hours) or low-dose ASA. MethodsPatients with acute VTE received parenteral anticoagulation and were randomized to the addition of warfarin or warfarin-placebo for at least 5 days until the international normalized ratio (INR) was ≥ 2 at two consecutive measurements. This was followed (on discontinuation of parenteral therapy) by continued warfarin (target INR range 2.0–3.0) or dabigatran 150 mg twice daily (double-dummy; “oral only” treatment period) for 6 months. Concomitant use of ASA ≤ 100 mg/day or NSAIDs with a half-life ≤ 12 hours was permitted. Primary efficacy outcome: recurrent, symptomatic, objectively confirmed VTE, or VTE-related death from randomization (i.e., start of parenteral therapy plus either warfarin or warfarin-placebo) up to the end of the prespecified post-treatment follow-up. Safety: major bleeding events (MBEs), the composite of MBEs or clinically relevant bleeding events (CRBEs), and any bleeds, measured from the start of the double-dummy period (treatment with oral dabigatran or warfarin alone) up to the end of the 6-month study period. Thus, the safety analysis excludes events associated with parenteral therapy, either in combination with warfarin or with warfarin-placebo prior to commencing dabigatran treatment; it therefore compares dabigatran with warfarin at its full pharmacological potential. ResultsOverall, recurrent VTE or VTE-related death occurred in 68/2553 patients (2.7%) randomized to dabigatran and 62/2554 (2.4%) randomized to warfarin; hazard ratio (HR) 1.09 (95% confidence interval [CI] 0.77, 1.54). The Table shows event rates for dabigatran versus warfarin in subgroups with and without concomitant NSAIDs or low-dose ASA. Cox regression analysis showed no statistically significant interaction, indicating similar treatment effects regardless of presence or absence of these concomitant medications. Overall, MBEs were significantly less frequent with dabigatran than with warfarin during the oral only treatment (double dummy) period (HR 0.60; 95% CI 0.36, 0.99). Likewise, MBE/CRBE incidence overall was significantly lower with dabigatran versus warfarin overall (HR 0.56; 95% CI 0.45, 0.71). Results according to concomitant NSAID or low-dose ASA use at baseline are shown in the Table. There was no significant treatment interaction by concomitant medication status for either MBE or MBE/CRBE. Similarly, any bleeding events were significantly less frequent with dabigatran than with warfarin overall, and showed no treatment interaction by baseline NSAID or low-dose ASA use. ConclusionsThere was no apparent difference in recurrent VTE or VTE-related mortality across NSAID or low-dose ASA concomitant medication subgroups. The incidence of bleeding events was similar or numerically lower with dabigatran than with warfarin across subgroups. The results suggest that no increased bleeding risk exists when dabigatran is administered with NSAIDs with a half-life < 12 hours or low-dose ASA. Disclosures:Schulman:Bayer Healthcare: Consultancy, Honoraria, Research Funding; Boehringer Ingelheim: Consultancy, Honoraria, Research Funding. Off Label Use: Dabigatran etexilate is an oral direct thrombin inhibitor approved for the prevention of stroke in patients with atrial fibrillation and (outside the US) for prevention of venous thromboembolism in patients undergoing total hip or knee replacement. This presentation includes discussion of the following off-label use of dabigatran: treatment of venous thromboembolism. Eriksson:Boehringer Ingelheim: Consultancy; BMS: Consultancy; Pfizer: Consultancy. Goldhaber:Boehringer Ingelheim: Consultancy; Daiichi: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Janssen: Consultancy; Merck: Consultancy; Pfizer: Consultancy; Portola: Consultancy; Sanofi-Aventis: Consultancy. Kakkar:Boehringer Ingelheim: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding; Daiichi: Consultancy, Honoraria, Research Funding; Bayer: Consultancy, Honoraria, Research Funding; Sanofi: Consultancy, Honoraria, Research Funding; Eisai: Consultancy, Honoraria, Research Funding. Kearon:Bayer Healthcare Inc. : Consultancy; Boehringer Ingelheim (Canada) Ltd./Ltée : Consultancy. Schellong:Boehringer Ingelheim: Advisory Boards Other, Consultancy, Honoraria; Bayer Healthcare: Advisory Boards, Advisory Boards Other, Consultancy, Honoraria; BMS/Pfizer: Honoraria; Daiichi Sankyo: Advisory Boards, Advisory Boards Other, Honoraria. Feuring:Boehringer Ingelheim: Employment. Peter:Boehringer Ingelheim: Employment. Friedman:Boehringer Ingelheim: Employment.Table: Incidence of recurrent VTE/VTE-related deaths, MBEs, and MBEs/CRBEs in the dabigatran and warfarin groups by use of concomitant NSAID or ASA at baselineConcomitant medication statusVTE or VTE-related death Patients, n/N (%)MBEs Patients, n/N (%)MBEs or CRBEs Patients, n/N (%)DEWarfarinDEWarfarinDEWarfarinNSAID No52/1973 (2.6)51/2015 (2.5)18/1922 (0.9)35/1982 (1.8)87/1922 (4.5)163/1982 (8.2)NSAID Yes16/580 (2.8)11/539 (2.0)6/534 (1.1)5/480 (1.0)22/534 (4.1)26/480 (5.4)ASA No60/2294 (2.6)57/2340 (2.4)21/2163 (1.0)33/2227 (1.5)95/2163 (4.4)167/2227 (7.5)ASA Yes8/259 (3.1)5/214 (2.3)3/293 (1.0)7/235 (3.0)14/293 (4.8)22/235 (9.4)DE, dabigatran etexilate.