Comparison of idraparinux with vitamin K antagonists for prevention of thromboembolism in patients with atrial fibrillation: a randomised, open-label, non-inferiority trial.

BACKGROUND: Vitamin K antagonists, the current standard treatment for prophylaxis against stroke and systemic embolism in patients with atrial fibrillation, require regular monitoring and dose adjustment; an unmonitored, fixed-dose anticoagulant regimen would be preferable. The aim of this randomised, open-label non-inferiority trial was to compare the efficacy and safety of idraparinux with vitamin K antagonists. METHODS: Patients with atrial fibrillation at risk for thromboembolism were randomly assigned to receive either subcutaneous idraparinux (2.5 mg weekly) or adjusted-dose vitamin K antagonists (target of an international normalised ratio of 2-3). Assessment of outcome was done blinded to treatment. The primary efficacy outcome was the cumulative incidence of all stroke and systemic embolism. The principal safety outcome was clinically relevant bleeding. Analyses were done by intention to treat; the non-inferiority hazard ratio was set at 1.5. This trial is registered with ClinicalTrials.gov, number NCT00070655. FINDINGS: The trial was stopped after randomisation of 4576 patients (2283 to receive idraparinux, 2293 to receive vitamin K antagonists) and a mean follow-up period of 10.7 (SD 5.4) months because of excess clinically relevant bleeding with idraparinux (346 cases vs 226 cases; 19.7 vs 11.3 per 100 patient-years; p<0.0001). There were 21 instances of intracranial bleeding with idraparinux and nine with vitamin K antagonists (1.1 vs 0.4 per 100 patient-years; p=0.014); elderly patients and those with renal impairment were at greater risk of such complications. There were 18 cases of thromboembolism with idraparinux and 27 cases with vitamin K antagonists (0.9 vs 1.3 per 100 patient-years; hazard ratio 0.71, 95% CI 0.39-1.30; p=0.007), satisfying the non-inferiority criterion. There were 62 deaths with idraparinux and 61 with vitamin K anatagonists (3.2 vs 2.9 per 100 patient-years; p=0.49). INTERPRETATION: In patients with atrial fibrillation at risk for thromboembolism, long-term treatment with idraparinux was no worse than vitamin K antagonists in terms of efficacy, but caused significantly more bleeding.

Safety assessment of new antithrombotic agents: lessons from the EXTEND study on ximelagatran.

BACKGROUND: Ximelagatran, the first oral direct thrombin inhibitor, was shown to be an effective antithrombotic agent but was associated with potential liver toxicity after prolonged administration. OBJECTIVES AND METHODS: The aim of the EXTEND study was to assess safety and efficacy of extended administration (35 days) of ximelagatran or enoxaparin for the prevention of venous thromboembolism after elective hip replacement and hip fracture surgery. A follow-up period, including assessment of liver enzymes (in particular alanine aminotransferase; ALAT), until post-operative day 180 was planned, with visits at days 56 and 180. RESULTS: Randomization and administration of study drugs were stopped following a report of serious liver injury occurring 3 weeks after completion of ximelagatran treatment. At the time of study termination, 1158 patients had been randomized and 641 had completed the 35-day treatment; with 303 ximelagatran and 265 enoxaparin patients remaining in the study through to the day 56 follow-up visit. Overall, 58 patients showed an ALAT increase to >2x upper limit of normal: 31 treated with enoxaparin, 27 with ximelagatran. Three ximelagatran patients also showed symptoms potentially related to liver toxicity. Eleven ximelagatran patients showed an ALAT increase after study treatment ended. The clinical development of ximelagatran was terminated and the drug withdrawn from the market. Evaluation of the relative efficacy of the two treatments as specified in the protocol was impossible due to the premature termination of the study. CONCLUSIONS: Prolonged administration of ximelagatran was associated with an increased risk of liver toxicity. In a substantial proportion of patients, ALAT increase occurred after treatment withdrawal. The findings seen with ximelagatran should be considered when designing studies with new antithrombotic agents.

Deep Vein Thrombosis in Europe-Health-Related Quality of Life and Mortality.

OBJECTIVES: Deep vein thrombosis (DVT) is a major health-care burden in Europe, but exact estimates are lacking. This study reports results from the PREFER venous thromboembolism (VTE) study concerning health-related quality of life (HrQoL) and mortality of patients with DVT. METHODS: PREFER VTE was a prospective, observational study, conducted in 7 European countries, designed to provide data concerning treatment patterns, resource utilization, mortality, and QoL. First-time or recurrent patients with DVT were followed at 1, 3, 6, and 12 months. Health-related QoL-as measured by the EuroQoL 5-Dimension 5-Level instrument ( EQ-5D-5L)-was analyzed using Tobit regression with repeated measures, assessing the impact of baseline characteristics stratified by cancer activity. Mortality was analyzed using logistic regression. RESULTS: At baseline, patients with DVT had a 0.14 lower EQ-5D-5L index score (0.72 for total sample) compared to the reference UK population (0.85). The EQ-5D-5L index score improved from baseline to 12 months in patients with active cancer (from 0.70 to 0.79) and those without (0.72-0.87); 7.3% died within a year, a 5.2% excess mortality compared to the age- and gender-adfjusted general population. The 12-month mortality rate of DVT varied between 2.9% in the pooled data from Germany, Switzerland, or Austria and 15.4% in Italy. Furthermore, the mortality rate differed between patients with active cancer and those without (42.9% vs 4.7%). CONCLUSIONS: Deep vein thrombosis is associated with a substantial burden of illness in terms of HrQoL at baseline, which following treatment normalizes after 12 months and has a significant mortality rate. In addition, active cancer has a significant impact on mortality and the HrQoL of patients with DVT.

Incidence and risk factors of chronic thromboembolic pulmonary hypertension following venous thromboembolism, a population-based cohort study in England.

Chronic thromboembolic pulmonary hypertension (CTEPH) is a complication of unresolved organised pulmonary emboli/thrombi obstructing the major pulmonary arteries. The aim of this study was to estimate the incidence and risk factors of CTEPH in a cohort with first venous thromboembolism (VTE). This was a population-based cohort study of patients with first VTE and no active cancer in England between 2001 and 2012. CTEPH was assessed using a rigorous case-ascertainment algorithm. Risk factors for CTEPH were studied using a nested case-control approach by matching CTEPH cases to VTE patients without CTEPH. Adjusted odds ratios (OR) of comorbidities were estimated from conditional logistic regression. During 81,413 person-years of follow-up among 23,329 patients with first VTE (mean follow-up 3.5 years; maximum 11.0 years) 283 patients were diagnosed with CTEPH (incidence rate 3.5 per 1000 person-years); cumulative incidence was 1.3% and 3.3% at 2 and 10 years after pulmonary embolism, and 0.3% and 1.3% following deep vein thrombosis (DVT), respectively. Risk factors for CTEPH included age over 70, OR 2.04 (95% CI 1.23 to 3.38), female gender, 1.44 (1.06 to 1.94), pulmonary embolism at first VTE, 3.11 (2.23 to 4.35), subsequent pulmonary embolism and DVT, 3.17 (2.02 to 4.96) and 2.46 (1.34 to 4.51) respectively, chronic obstructive pulmonary disease 3.17 (2.13 to 4.73), heart failure 2.52 (1.76 to 3.63) and atrial fibrillation, 2.42 (1.71 to 3.42). CTEPH develops most commonly after pulmonary embolism and less frequently after DVT. Awareness of risk factors may increase referrals to specialised centres for confirmation of CTEPH and initiation of specific treatment.

A systematic review of network meta-analyses among patients with nonvalvular atrial fibrillation: A comparison of efficacy and safety following treatment with direct oral anticoagulants.

BACKGROUND: Direct oral anticoagulants (DOACs) are indicated for the prevention of stroke and systemic embolism (SE) in patients with nonvalvular atrial fibrillation. While no head-to-head randomized controlled trials (RCTs) exist that evaluate the efficacy and safety of DOACs, network meta-analyses (NMAs) based mainly on RCTs for each DOAC and using various methodologies have been published. This systematic literature review summarizes the evidence on stroke/SE bleeding events, mortality, and other adverse events from NMAs that reported indirect comparisons of DOACs. METHODS: Searches were conducted in PubMed, Embase, and the Cochrane Database of Systematic Reviews to identify NMAs published between January 2010 and March 2017 that compared vitamin K antagonists or DOACs using RCT data. Comparisons on stroke/SE and major bleeding (MB), as well as secondary outcomes, for DOAC versus DOAC comparisons were extracted and summarized using apixaban as the reference. RESULTS: Twenty-two NMAs were included in the final summary: All assessed MB; 15 assessed stroke/SE. No statistically significant differences were observed for apixaban compared with any DOAC in the 15 NMAs that assessed stroke/SE. Apixaban was associated with a lower risk for MB compared with rivaroxaban in 16 of 20 NMAs and dabigatran 150 mg in 13 of 16 NMAs. Four of 6 NMAs showed lower risk for GI bleeding for apixaban compared with rivaroxaban and dabigatran 150 mg; however, this outcome was not assessed by most NMAs. CONCLUSION: This systematic literature review of NMAs showed varying levels of bleeding risk among DOACs, with apixaban generally having a lower risk than rivaroxaban and dabigatran 150 mg.

Deep-vein thrombosis in Europe - Burden of illness in relationship to healthcare resource utilization and return to work.

OBJECTIVES: Deep-vein thrombosis (DVT) forms a major healthcare burden in Europe, but exact estimates concerning the economic burden on society are lacking. This study reports results from the PREFER in VTE study concerning resource utilization and absence from work in DVT patients. METHODS: The PREFER in VTE registry was a prospective, observational, multicenter study carried out in Europe (France, Italy, Spain, the UK, and DACH [Germany, Switzerland and Austria]), designed to provide data concerning treatment patterns, resource utilization, mortality and quality of life. Patients with a first-time and/or recurrent DVT, were recruited and followed for 12 months. Data about resource utilization concerns resource utilization related to DVT. Specifically, treatment pattern, re-hospitalization rate, length of hospital stay, ambulatory/office visit, and proportion of patients returning to work, were analyzed and presented. Subgroup analysis by country and active cancer were also conducted. The length of hospital stay was analyzed as a function of demographics, previous events and co-morbidities using zero-inflated binomial negative regression. Similarly, time until return to work was analyzed using Cox regression. RESULTS: A total of 2056 patients with DVT were recruited, with an average age of 60 years. Patients with active cancer were mostly treated with heparin (83.9%), while patients without active cancer were treated with combinations of heparin, VKA and DOACs. DOACs were less often used in Spain and Italy (<7.0%). Following the management of their initial DVT 20.5% of the patients with and 12.2% of patients without active cancer (n = 88; n = 1462) were hospitalized for on average 8.2 and 10.1 days, respectively. The hospitalization-rate was highest in Italy (16.7%) and lowest in France (7.7%). Furthermore, the average length of stay was highest in Italy (16.6 days) and lowest in DACH (5.2 days). Physician visits were highest in DACH (9.3), lowest in the UK (2.6). Of those working, 50% returned to work at 1 month; >30% did not return to work within the year. CONCLUSIONS: Medical treatment of DVT differed between patients with active cancer and those without. Post-VTE or VTE-related resource utilization differs remarkably between countries. Work-loss seems high, but questions may be raised concerning the causality due to the presence of co-morbidities.

State of play and future direction with NOACs: An expert consensus.

Atrial fibrillation (AF) and venous thromboembolism (VTE) are cardiovascular conditions significant in contemporary practice. In both, the use of anticoagulation with vitamin K antagonists (VKAs) has been traditionally used to prevent adverse events. However, VKA therapy is associated with challenges relating to dose maintenance, the need to monitor anticoagulation, and bleeding risks. The non-vitamin K oral anticoagulants (NOACs) are becoming accepted as a clear alternative to VKA therapy for both AF and VTE management. The aim of this paper was to review contemporary evidence on the safety of NOACs in both conditions. A comprehensive literature review was conducted to explore key safety issues and expert consensus was achieved from eight professionals specialised in AF and VTE care. Consensus-based statements were formulated where available evidence was weak or contradictory. The expert statements in this paper form a key overview of the safety of NOACs compared with VKA therapy, and the comparative safety of different NOACs. It is apparent that a detailed patient work-up is required in order to identify and manage individual risk factors for bleeding and thrombosis prior to NOAC therapy. Additional measures, such as dose reductions, may also be used to maintain the safety of NOACs in practice.

The use of graduated compression stockings in association with fondaparinux in surgery of the hip. A multicentre, multinational, randomised, open-label, parallel-group comparative study.

Little is known about the efficacy of graduated compression stockings in preventing venous thromboembolism after hip surgery. We conducted a prospective, randomised single-blind study to determine whether the addition of compression stockings to fondaparinux conferred any additional benefit. The study included 874 patients, of whom 795 could be evaluated (400 in the fondaparinux group and 395 in the fondaparinux plus compression stocking group). Fondaparinux was given post-operatively for five to nine days, either alone or combined with wearing stockings, which were worn for a mean 42 days (35 to 49). The study outcomes were venous thromboembolism, or sudden death before day 42. Duplex ultrasonography was scheduled within a week of day 42. Safety outcomes were bleeding and death from venous thromboembolism. The prevalence of deep-vein thrombosis was similar in the two groups 5.5% (22 of 400) in the fondaparinux group and 4.8 (19 of 395) in the fondaparinux plus stocking group (odds ratio 0.88, 95% confidence interval 0.46 to 1.65, p = 0.69). Major bleeding occurred in only one patient. The addition of graduated compression stockings to fondaparinux appears to offer no additional benefit over the use of fondaparinux alone.

Effect of extended-duration thromboprophylaxis on venous thromboembolism and major bleeding among acutely ill hospitalized medical patients: a bivariate analysis.

Essentials Anticoagulants prevent venous thromboembolism but may be associated with greater bleeding risks. Bivariate analysis assumes a non-linear relationship between efficacy and safety outcomes. Extended full-dose betrixaban is favorable over standard enoxaparin in bivariate endpoint. Clinicians must weigh efficacy and safety outcomes in decision-making on thromboprophylaxis. SUMMARY: Background Among acutely ill hospitalized medical patients, extended-duration thromboprophylaxis reduces the risk of venous thromboembolism (VTE), but some pharmacologic strategies have been associated with greater risks of major bleeding, thereby offsetting the net clinical benefit (NCB). Methods To assess the risk-benefit profile of anticoagulation regimens, a previously described bivariate method that does not assume a linear risk-benefit tradeoff and can accommodate different margins for efficacy and safety was performed to simultaneously assess efficacy (symptomatic VTE) and safety (major bleeding) on the basis of data from four randomized controlled trials of extended-duration (30-46 days) versus standard-duration (6-14 days) thromboprophylaxis among 28 227 patients (EXCLAIM, ADOPT, MAGELLAN and APEX trials). Results Extended thromboprophylaxis with full-dose betrixaban (80 mg once daily) was superior in efficacy and non-inferior in safety to standard-duration enoxaparin, and showed a significantly favorable NCB, with a risk difference of - 0.51% (- 0.89% to - 0.10%) in the bivariate outcome. Extended enoxaparin was superior in efficacy and inferior in safety (bivariate outcome: 0.03% [- 0.37% to 0.43%]), whereas apixaban and rivaroxaban were non-inferior in efficacy and inferior in safety (- 0.20% [- 0.49% to 0.17%] and 0.23% [- 0.16% to 0.69%], respectively). Reduced-dose betrixaban did not show a significant difference in either efficacy or safety (0.41% [- 0.85% to 1.94%]). Conclusions In a bivariate analysis that assumes non-linear risk-benefit tradeoffs, extended prophylaxis with full-dose betrixaban was superior to standard-duration enoxaparin, whereas other regimens failed to simultaneously achieve both superiority and non-inferiority with respect to symptomatic VTE and major bleeding in the management of acutely ill hospitalized medical patients.

Thromboprophylaxis in major abdominal surgery for cancer.

AIMS: To review the epidemiology and pathogenesis of venous thromboembolism (VTE) in surgical cancer patients, in addition to the use of thromboprophylaxis in major abdominal surgery, such as low-molecular-weight heparin (LMWH) and fondaparinux. METHODS: Systematic review of the literature, focussing on risk factors for VTE, parenteral methods of thromboprophylaxis, approaches to prolonged prophylaxis, and effects on patient survival. FINDINGS: Patients with cancer undergoing abdominal surgery are at substantially higher risk for VTE than patients without cancer. Furthermore, prolonged thromboprophylaxis for up to 4 weeks is more effective than short-term administration in these high-risk patients. The concurrent use of graduated compression stockings has a synergistic effect on the reduction in VTE risk. CONCLUSIONS: Thromboprophylaxis with LMWH has been shown to minimise the incidence of thromboembolic events, and is a well-established therapy worldwide. The American College of Chest Physicians recommends the routine use of thromboprophylaxis, with LMWH or unfractionated heparin, in patients with cancer who are undergoing surgical procedures, and the appropriate use of these thromboprophylactic agents has significant implications for the clinical care and quality of life of surgical patients with cancer.

Risk of recurrent venous thromboembolism after discontinuation of vitamin K antagonist treatment: a nested case-control study.

UNLABELLED: Essentials Vitamin K antagonists (VKA) in venous thromboembolism (VTE) lower the risk of recurrences. 41 841 VKA-treated VTE patients had 1242 recurrent VTEs on therapy or early after cessation. An increased risk of recurrence was found in the first 120 days after VKA cessation. Patient education for the early detection of recurrent VTE after VKA cessation is recommended. SUMMARY: Background The standard treatment for venous thromboembolism (VTE) and the prevention of recurrent VTE (rVTE) consists of anticoagulant therapy. The optimal duration of anticoagulation depends on the presence of risk factors for rVTE. Objectives To estimate the risk of rVTE in association with time since discontinuation of vitamin K antagonist (VKA) treatment. Methods From the UK Clinical Practice Research Datalink with linked information on hospitalization and cause of death, a cohort of patients with a first VTE receiving initial VKA treatment between 2001 and 2013 was formed. With a nested case-control approach, patients with incident rVTE (cases) were matched to patients with VTE but without rVTE (controls). Adjusted rate ratios (RRs) of rVTE associated with time since VKA discontinuation relative to current VKA use were estimated from conditional logistic regression. Results The VTE cohort comprised 41 841 patients with 1242 rVTEs and 6205 matched controls. The RR of rVTE was increased within 60 days following VKA discontinuation (RR 2.23, 95% confidence interval [CI] 1.71-2.91) and within 61-120 days following VKA discontinuation (RR 1.49, 95% CI 1.08-2.05) relative to current VKA use. The increased RR corresponded to excess incidence rates of 6.72 (95% CI 3.90-10.06) rVTE cases per 100 person-years within 60 days, and of 2.68 (95% CI 0.42-5.58) rVTE cases per 100 person-years within 61-120 days after VKA discontinuation. Conclusions VKA discontinuation results in a transient increased risk of rVTE, which peaks within 60 days and lasts for up to 120 days after VKA discontinuation. Specific patient education for increased vigilance for signs and symptoms of recurrences is recommended in this period.

Correction: Comparison of the Non-VKA Oral Anticoagulants Apixaban, Dabigatran, and Rivaroxaban in the Extended Treatment and Prevention of Venous Thromboembolism: Systematic Review and Network Meta-Analysis.

[This corrects the article DOI: 10.1371/journal.pone.0160064.].

Comparison of the Non-VKA Oral Anticoagulants Apixaban, Dabigatran, and Rivaroxaban in the Extended Treatment and Prevention of Venous Thromboembolism: Systematic Review and Network Meta-Analysis.

BACKGROUND: Historically, warfarin or aspirin have been the recommended therapeutic options for the extended treatment (>3 months) of VTE. Data from Phase III randomised controlled trials (RCTs) are now available for non-VKA oral anticoagulants (NOACs) in this indication. The current systematic review and network meta-analysis (NMA) were conducted to compare the efficacy and safety of anticoagulants for the extended treatment of VTE. METHODS: Electronic databases (accessed July 2014 and updated April 2016) were systematically searched to identify RCTs evaluating apixaban, aspirin, dabigatran, edoxaban, rivaroxaban, and warfarin for the extended treatment of VTE. Eligible studies included adults with an objectively confirmed deep vein thrombosis, pulmonary embolism or both. A fixed-effect Bayesian NMA was conducted, and results were presented as relative risks (RRs). Sensitivity analyses examining (i) the dataset employed according to the time frame for outcome assessment (ii) the model used for the NMA were conducted. RESULTS: Eleven Phase III RCTs (examining apixaban, aspirin, dabigatran, rivaroxaban, warfarin and placebo) were included. The risk of the composite efficacy outcome (VTE and VTE-related death) was statistically significantly lower with the NOACs and warfarin INR 2.0-3.0 compared with aspirin, with no significant differences between the NOACs. Treatment with apixaban (RR 0.23, 95% CrI 0.10, 0.55) or dabigatran (RR 0.55, 95% Crl 0.43, 0.71) was associated with a statistically significantly reduced risk of 'major or clinically relevant non-major bleed' compared with warfarin INR 2.0-3.0. Apixaban also showed a significantly reduced risk compared with dabigatran (RR 0.42, 95% Crl 0.18, 0.97) and rivaroxaban (RR 0.23, 95% Crl 0.09, 0.59). Sensitivity analyses indicate that results were dependent on the dataset, but not on the type of NMA model employed. CONCLUSIONS: Results from the NMA indicate that NOACs are an effective treatment for prevention of VTE or VTE-related death) in the extended treatment setting. However, bleeding risk differs between potential treatments, with apixaban reporting the most favourable profile compared with other NOACs, warfarin INR 2.0-3.0, and aspirin.

Epidemiology of venous thromboembolism in Asian patients undergoing major orthopedic surgery without thromboprophylaxis. The SMART study.

BACKGROUND: In Asian patients undergoing surgery, the incidence of venous thromboembolism (VTE) is thought to be low relative to Western patients, and the routine use of thromboprophylaxis is controversial. OBJECTIVES: The aim of this work was to study the epidemiology of VTE in Asian patients undergoing orthopedic surgery without thromboprophylaxis. PATIENTS AND METHODS: We performed a prospective observational study of a cohort of consecutive Asian patients hospitalized for total hip or knee replacement or hip fracture surgery without thromboprophylaxis. The primary study outcome was the incidence of the composite of symptomatic VTE or sudden death at hospital discharge. This outcome was also assessed at 1 month's follow-up. RESULTS: Between April 2001 and July 2002, 2420 patients were enrolled. Median age was 68 years and the median duration of hospital stay was 13 days. The rate of symptomatic VTE or sudden death as notified by investigators was 2.3%[55 patients, 99% confidence interval (CI) 1.6, 3.2] and 1.2% (28 patients, 99% CI 0.7, 1.8) after adjudication by an independent committee. Chronic heart failure, varicose veins and a history of VTE were independent risk factors (P < 0.05) for the occurrence of the primary endpoint. At 1 month's follow-up, the incidence of adjudicated symptomatic VTE or sudden death was 1.5% (35/2264 patients). CONCLUSION: In Asian patients, the incidence of symptomatic VTE after major orthopedic surgery is not low, consistent with the rates observed in Western countries. The use of thromboprophylaxis should be considered in Asian patients undergoing such high-risk surgical procedures.