Lack of extended venous thromboembolism prophylaxis in high-risk patients undergoing major orthopaedic or major cancer surgery. Electronic Assessment of VTE Prophylaxis in High-Risk Surgical Patients at Discharge from Swiss Hospitals (ESSENTIAL)

Extended pharmacological venous thromboembolism (VTE) prophylaxis beyond discharge is recommended for patients undergoing high-risk surgery. We prospectively investigated prophylaxis in 1,046 consecutive patients undergoing major orthopaedic (70%) or major cancer surgery (30%) in 14 Swiss hospitals. Appropriate in-hospital prophylaxis was used in 1,003 (96%) patients. At discharge, 638 (61%) patients received prescription for extended pharmacological prophylaxis: 564 (77%) after orthopaedic surgery, and 74 (23%) after cancer surgery (p < 0.001). Patients with knee replacement (94%), hip replacement (81%), major trauma (80%), and curative arthroscopy (73%) had the highest prescription rates for extended VTE prophylaxis; the lowest rates were found in patients undergoing major surgery for thoracic (7%), gastrointestinal (19%), and hepatobiliary (33%) cancer. The median duration of prescribed extended prophylaxis was longer in patients with orthopaedic surgery (32 days, interquartile range 14-40 days) than in patients with cancer surgery (23 days, interquartile range 11-30 days; p<0.001). Among the 278 patients with an extended prophylaxis order after hip replacement, knee replacement, or hip fracture surgery, 120 (43%) received a prescription for at least 35 days, and among the 74 patients with an extended prophylaxis order after major cancer surgery, 20 (27%) received a prescription for at least 28 days. In conclusion, approximately one quarter of the patients with major orthopaedic surgery and more than three quarters of the patients with major cancer surgery did not receive prescription for extended VTE prophylaxis. Future effort should focus on the improvement of extended VTE prophylaxis, particularly in patients undergoing major cancer surgery.

Design and establishment of a biobank in a multicenter prospective cohort study of elderly patients with venous thromboembolism (SWITCO65+)

In the field of thrombosis and haemostasis, many preanalytical variables influence the results of coagulation assays and measures to limit potential results variations should be taken. To our knowledge, no paper describing the development and maintenance of a haemostasis biobank has been previously published. Our description of the biobank of the Swiss cohort of elderly patients with venous thromboembolism (SWITCO65+) is intended to facilitate the set-up of other biobanks in the field of thrombosis and haemostasis. SWITCO65+ is a multicentre cohort that prospectively enrolled consecutive patients aged ≥65 years with venous thromboembolism at nine Swiss hospitals from 09/2009 to 03/2012. Patients will be followed up until December 2013. The cohort includes a biobank with biological material from each participant taken at baseline and after 12 months of follow-up. Whole blood from all participants is assayed with a standard haematology panel, for which fresh samples are required. Two buffy coat vials, one PAXgene Blood RNA System tube and one EDTA-whole blood sample are also collected at baseline for RNA/DNA extraction. Blood samples are processed and vialed within 1 h of collection and transported in batches to a central laboratory where they are stored in ultra-low temperature archives. All analyses of the same type are performed in the same laboratory in batches. Using multiple core laboratories increased the speed of sample analyses and reduced storage time. After recruiting, processing and analyzing the blood of more than 1,000 patients, we determined that the adopted methods and technologies were fit-for-purpose and robust.

Adjudication-related processes are underreported and lack standardization in clinical trials of venous thromboembolism: a systematic review

OBJECTIVES Although the use of an adjudication committee (AC) for outcomes is recommended in randomized controlled trials, there are limited data on the process of adjudication. We therefore aimed to assess whether the reporting of the adjudication process in venous thromboembolism (VTE) trials meets existing quality standards and which characteristics of trials influence the use of an AC. STUDY DESIGN AND SETTING We systematically searched MEDLINE and the Cochrane Library from January 1, 2003, to June 1, 2012, for randomized controlled trials on VTE. We abstracted information about characteristics and quality of trials and reporting of adjudication processes. We used stepwise backward logistic regression model to identify trial characteristics independently associated with the use of an AC. RESULTS We included 161 trials. Of these, 68.9% (111 of 161) reported the use of an AC. Overall, 99.1% (110 of 111) of trials with an AC used independent or blinded ACs, 14.4% (16 of 111) reported how the adjudication decision was reached within the AC, and 4.5% (5 of 111) reported on whether the reliability of adjudication was assessed. In multivariate analyses, multicenter trials [odds ratio (OR), 8.6; 95% confidence interval (CI): 2.7, 27.8], use of a data safety-monitoring board (OR, 3.7; 95% CI: 1.2, 11.6), and VTE as the primary outcome (OR, 5.7; 95% CI: 1.7, 19.4) were associated with the use of an AC. Trials without random allocation concealment (OR, 0.3; 95% CI: 0.1, 0.8) and open-label trials (OR, 0.3; 95% CI: 0.1, 1.0) were less likely to report an AC. CONCLUSION Recommended processes of adjudication are underreported and lack standardization in VTE-related clinical trials. The use of an AC varies substantially by trial characteristics.

Platelet count and outcome in patients with acute venous thromboembolism

The relationship between platelet count and outcome in patients with acute venous thromboembolism (VTE) has not been consistently explored. RIETE is an ongoing registry of consecutive patients with acute VTE. We categorised patients as having very low- (<80,000/µl), low- (80,000/µl to 150,000/µl), normal- (150,000/µl to 300,000/µl), high- (300,000/µl to 450,000/µl), or very high (>450,000/µl) platelet count at baseline, and compared their three-month outcome. As of October 2012, 43,078 patients had been enrolled in RIETE: 21,319 presenting with pulmonary embolism and 21,759 with deep-vein thrombosis. In all, 502 patients (1.2%) had very low-; 5,472 (13%) low-; 28,386 (66%) normal-; 7,157 (17%) high-; and 1,561 (3.6%) very high platelet count. During the three-month study period, the recurrence rate was: 2.8%, 2.2%, 1.8%, 2.1% and 2.2%, respectively; the rate of major bleeding: 5.8%, 2.6%, 1.7%, 2.3% and 4.6%, respectively; the rate of fatal bleeding: 2.0%, 0.9%, 0.3%, 0.5% and 1.2%, respectively; and the mortality rate: 29%, 11%, 6.5%, 8.8% and 14%, respectively. On multivariate analysis, patients with very low-, low-, high- or very high platelet count had an increased risk for major bleeding (odds ratio [OR]: 2.70, 95% confidence interval [CI]: 1.85-3.95; 1.43 [1.18-1.72]; 1.23 [1.03-1.47]; and 2.13 [1.65-2.75]) and fatal bleeding (OR: 3.70 [1.92-7.16], 2.10 [1.48-2.97], 1.29 [0.88-1.90] and 2.49 [1.49-4.15]) compared with those with normal count. In conclusion, we found a U-shaped relationship between platelet count and the three-month rate of major bleeding and fatal bleeding in patients with VTE.

Multicentre validation of the Geneva Risk Score for hospitalised medical patients at risk of venous thromboembolism. Explicit ASsessment of Thromboembolic RIsk and Prophylaxis for Medical PATients in SwitzErland (ESTIMATE).

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.

The adherence to initial processes of care in elderly patients with acute venous thromboembolism.

BACKGROUND We aimed to assess whether elderly patients with acute venous thromboembolism (VTE) receive recommended initial processes of care and to identify predictors of process adherence. METHODS We prospectively studied in- and outpatients aged ≥65 years with acute symptomatic VTE in a multicenter cohort study from nine Swiss university- and non-university hospitals between September 2009 and March 2011. We systematically assessed whether initial processes of care, which are recommended by the 2008 American College of Chest Physicians guidelines, were performed in each patient. We used multivariable logistic models to identify patient factors independently associated with process adherence. RESULTS Our cohort comprised 950 patients (mean age 76 years). Of these, 86% (645/750) received parenteral anticoagulation for ≥5 days, 54% (405/750) had oral anticoagulation started on the first treatment day, and 37% (274/750) had an international normalized ratio (INR) ≥2 for ≥24 hours before parenteral anticoagulation was discontinued. Overall, 35% (53/153) of patients with cancer received low-molecular-weight heparin monotherapy and 72% (304/423) of patients with symptomatic deep vein thrombosis were prescribed compression stockings. In multivariate analyses, symptomatic pulmonary embolism, hospital-acquired VTE, and concomitant antiplatelet therapy were associated with a significantly lower anticoagulation-related process adherence. CONCLUSIONS Adherence to several recommended processes of care was suboptimal in elderly patients with VTE. Quality of care interventions should particularly focus on processes with low adherence, such as the prescription of continued low-molecular-weight heparin therapy in patients with cancer and the achievement of an INR ≥2 for ≥24 hours before parenteral anticoagulants are stopped.

Primary prophylaxis for venous thromboembolism in ambulatory cancer patients receiving chemotherapy.

BACKGROUND Venous thromboembolism (VTE) often complicates the clinical course of cancer. The risk is further increased by chemotherapy, but the safety and efficacy of primary thromboprophylaxis in cancer patients treated with chemotherapy is uncertain. This is an update of a review first published in February 2012. OBJECTIVES To assess the efficacy and safety of primary thromboprophylaxis for VTE in ambulatory cancer patients receiving chemotherapy compared with placebo or no thromboprophylaxis. SEARCH METHODS For this update, the Cochrane Peripheral Vascular Diseases Group Trials Search Co-ordinator searched the Specialised Register (last searched May 2013), CENTRAL (2013, Issue 5), and clinical trials registries (up to June 2013). SELECTION CRITERIA Randomised controlled trials (RCTs) comparing any oral or parenteral anticoagulant or mechanical intervention to no intervention or placebo, or comparing two different anticoagulants. DATA COLLECTION AND ANALYSIS Data were extracted on methodological quality, patients, interventions, and outcomes including symptomatic VTE and major bleeding as the primary effectiveness and safety outcomes, respectively. MAIN RESULTS We identified 12 additional RCTs (6323 patients) in the updated search so that this update considered 21 trials with a total of 9861 patients, all evaluating pharmacological interventions and performed mainly in patients with advanced cancer. Overall, the risk of bias varied from low to high. One large trial of 3212 patients found a 64% (risk ratio (RR) 0.36, 95% confidence interval (CI) 0.22 to 0.60) reduction of symptomatic VTE with the ultra-low molecular weight heparin (uLMWH) semuloparin relative to placebo, with no apparent difference in major bleeding (RR 1.05, 95% CI 0.55 to 2.00). LMWH, when compared with inactive control, significantly reduced the incidence of symptomatic VTE (RR 0.53, 95% CI 0.38 to 0.75; no heterogeneity, Tau(2) = 0%) with similar rates of major bleeding events (RR 1.30, 95% CI 0.75 to 2.23). In patients with multiple myeloma, LMWH was associated with a significant reduction in symptomatic VTE when compared with the vitamin K antagonist warfarin (RR 0.33, 95% CI 0.14 to 0.83), while the difference between LMWH and aspirin was not statistically significant (RR 0.51, 95% CI 0.22 to 1.17). No major bleeding was observed in the patients treated with LMWH or warfarin and in less than 1% of those treated with aspirin. Only one study evaluated unfractionated heparin against inactive control and found an incidence of major bleeding of 1% in both study groups while not reporting on VTE. When compared with placebo, warfarin was associated with a statistically insignificant reduction of symptomatic VTE (RR 0.15, 95% CI 0.02 to 1.20). Antithrombin, evaluated in one study involving paediatric patients, had no significant effect on VTE nor major bleeding when compared with inactive control. The new oral factor Xa inhibitor apixaban was evaluated in a phase-II dose finding study that suggested a promising low rate of major bleeding (2.1% versus 3.3%) and symptomatic VTE (1.1% versus 10%) in comparison with placebo. AUTHORS' CONCLUSIONS In this update, we confirmed that primary thromboprophylaxis with LMWH significantly reduced the incidence of symptomatic VTE in ambulatory cancer patients treated with chemotherapy. In addition, the uLMWH semuloparin significantly reduced the incidence of symptomatic VTE. However, the broad confidence intervals around the estimates for major bleeding suggest caution in the use of anticoagulation and mandate additional studies to determine the risk to benefit ratio of anticoagulants in this setting. Despite the encouraging results of this review, routine prophylaxis in ambulatory cancer patients cannot be recommended before safety issues are adequately addressed.

Polypharmacy is Associated with an Increased Risk of Bleeding in Elderly Patients with Venous Thromboembolism.

BACKGROUND Polypharmacy, defined as the concomitant use of multiple medications, is very common in the elderly and may trigger drug-drug interactions and increase the risk of falls in patients receiving vitamin K antagonists. OBJECTIVE To examine whether polypharmacy increases the risk of bleeding in elderly patients who receive vitamin K antagonists for acute venous thromboembolism (VTE). DESIGN We used a prospective cohort study. PARTICIPANTS In a multicenter Swiss cohort, we studied 830 patients aged ≥ 65 years with VTE. MAIN MEASURES We defined polypharmacy as the prescription of more than four different drugs. We assessed the association between polypharmacy and the time to a first major and clinically relevant non-major bleeding, accounting for the competing risk of death. We adjusted for known bleeding risk factors (age, gender, pulmonary embolism, active cancer, arterial hypertension, cardiac disease, cerebrovascular disease, chronic liver and renal disease, diabetes mellitus, history of major bleeding, recent surgery, anemia, thrombocytopenia) and periods of vitamin K antagonist treatment as a time-varying covariate. KEY RESULTS Overall, 413 (49.8 %) patients had polypharmacy. The mean follow-up duration was 17.8 months. Patients with polypharmacy had a significantly higher incidence of major (9.0 vs. 4.1 events/100 patient-years; incidence rate ratio [IRR] 2.18, 95 % confidence interval [CI] 1.32-3.68) and clinically relevant non-major bleeding (14.8 vs. 8.0 events/100 patient-years; IRR 1.85, 95 % CI 1.27-2.71) than patients without polypharmacy. After adjustment, polypharmacy was significantly associated with major (sub-hazard ratio [SHR] 1.83, 95 % CI 1.03-3.25) and clinically relevant non-major bleeding (SHR 1.60, 95 % CI 1.06-2.42). CONCLUSIONS Polypharmacy is associated with an increased risk of both major and clinically relevant non-major bleeding in elderly patients receiving vitamin K antagonists for VTE.

Risk of falls and bleeding in elderly patients with acute venous thromboembolism.

OBJECTIVE Whether or not a high risk of falls increases the risk of bleeding in patients receiving anticoagulants remains a matter of debate. METHODS We conducted a prospective cohort study involving 991 patients ≥ 65 years of age who received anticoagulants for acute venous thromboembolism (VTE) at nine Swiss hospitals between September 2009 and September 2012. The study outcomes were as follows: the time to a first major episode of bleeding; and clinically relevant nonmajor bleeding. We determined the associations between the risk of falls and the time to a first episode of bleeding using competing risk regression, accounting for death as a competing event. We adjusted for known bleeding risk factors and anticoagulation as a time-varying covariate. RESULTS Four hundred fifty-eight of 991 patients (46%) were at high risk of falls. The mean duration of follow-up was 16.7 months. Patients at high risk of falls had a higher incidence of major bleeding (9.6 vs. 6.6 events/100 patient-years; P = 0.05) and a significantly higher incidence of clinically relevant nonmajor bleeding (16.7 vs. 8.3 events/100 patient-years; P < 0.001) than patients at low risk of falls. After adjustment, a high risk of falls was associated with clinically relevant nonmajor bleeding [subhazard ratio (SHR) = 1.74, 95% confidence interval (CI) = 1.23-2.46], but not with major bleeding (SHR = 1.24, 95% CI = 0.83-1.86). CONCLUSION In elderly patients who receive anticoagulants because of VTE, a high risk of falls is significantly associated with clinically relevant nonmajor bleeding, but not with major bleeding. Whether or not a high risk of falls is a reason against providing anticoagulation beyond 3 months should be based on patient preferences and the risk of VTE recurrence.

Survival effects of inferior vena cava filter in patients with acute symptomatic venous thromboembolism and a significant bleeding risk.

OBJECTIVES The purpose of this study was to investigate the survival effects of inferior vena cava filters in patients with venous thromboembolism (VTE) who had a significant bleeding risk. BACKGROUND The effectiveness of inferior vena cava filter use among patients with acute symptomatic VTE and known significant bleeding risk remains unclear. METHODS In this prospective cohort study of patients with acute VTE identified from the RIETE (Computerized Registry of Patients With Venous Thromboembolism), we assessed the association between inferior vena cava filter insertion for known significant bleeding risk and the outcomes of all-cause mortality, pulmonary embolism (PE)-related mortality, and VTE rates through 30 days after the initiation of VTE treatment. Propensity score matching was used to adjust for the likelihood of receiving a filter. RESULTS Of the 40,142 eligible patients who had acute symptomatic VTE, 371 underwent filter placement because of known significant bleeding risk. A total of 344 patients treated with a filter were matched with 344 patients treated without a filter. Propensity score-matched pairs showed a nonsignificant trend toward lower risk of all-cause death for filter insertion compared with no insertion (6.6% vs. 10.2%; p = 0.12). The risk-adjusted PE-related mortality rate was lower for filter insertion than no insertion (1.7% vs. 4.9%; p = 0.03). Risk-adjusted recurrent VTE rates were higher for filter insertion than for no insertion (6.1% vs. 0.6%; p < 0.001). CONCLUSIONS In patients presenting with VTE and with a significant bleeding risk, inferior vena cava filter insertion compared with anticoagulant therapy was associated with a lower risk of PE-related death and a higher risk of recurrent VTE. However, study design limitations do not imply a causal relationship between filter insertion and outcome.

Clinical decision rules and D-Dimer in venous thromboembolism: current controversies and future research priorities

Venous thromboembolism (VTE) is a potentially lethal clinical condition that is suspected in patients with common clinical complaints, in many and varied, clinical care settings. Once VTE is diagnosed, optimal therapeutic management (thrombolysis, IVC filters, type and duration of anticoagulants) and ideal therapeutic management settings (outpatient, critical care) are also controversial. Clinical prediction tools, including clinical decision rules and D-Dimer, have been developed, and some validated, to assist clinical decision making along the diagnostic and therapeutic management paths for VTE. Despite these developments, practice variation is high and there remain many controversies in the use of the clinical prediction tools. In this narrative review, we highlight challenges and controversies in VTE diagnostic and therapeutic management with a focus on clinical decision rules and D-Dimer.

How to avoid venous thromboembolism in women at increased risk--with special focus on low-risk periods

Venous thromboembolism (VTE) is a major cause of mortality during Western women's fertile life. Although half of thromboembolic events occur during times of low-risk situations, almost all our knowledge is focused on medical thromboprophylaxis during high-risk situations. Thus, since we only use medical thromboprophylaxis at high-risk periods, lifestyle advice could be an attractive complement both during high- and low-risk situations. The knowledge of how lifestyle factors affect VTE risk has grown in recent years, and women at high risk are often highly motivated to make changes in order to reduce their risk. This review is focused on modifiable risk factors for VTE and advice that may be given to women at increased risk of VTE.

Depressive symptoms as a novel risk factor for recurrent venous thromboembolism: a longitudinal observational study in patients referred for thrombophilia investigation.

BACKGROUND Increasing evidence suggests that psychosocial factors, including depression predict incident venous thromboembolism (VTE) against a background of genetic and acquired risk factors. The role of psychosocial factors for the risk of recurrent VTE has not previously been examined. We hypothesized that depressive symptoms in patients with prior VTE are associated with an increased risk of recurrent VTE. METHODS In this longitudinal observational study, we investigated 271 consecutive patients, aged 18 years or older, referred for thrombophilia investigation with an objectively diagnosed episode of VTE. Patients completed the depression subscale of the Hospital Anxiety and Depression Scale (HADS-D). During the observation period, they were contacted by phone and information on recurrent VTE, anticoagulation therapy, and thromboprophylaxis in risk situations was collected. RESULTS Clinically relevant depressive symptoms (HADS-D score ≥ 8) were present in 10% of patients. During a median observation period of 13 months (range 5-48), 27 (10%) patients experienced recurrent VTE. After controlling for sociodemographic and clinical factors, a 3-point increase on the HADS-D score was associated with a 44% greater risk of recurrent VTE (OR 1.44, 95% CI 1.02, 2.06). Compared to patients with lower levels of depressive symptoms (HADS-D score: range 0-2), those with higher levels (HADS-D score: range 3-16) had a 4.1-times greater risk of recurrent VTE (OR 4.07, 95% CI 1.55, 10.66). CONCLUSIONS The findings suggest that depressive symptoms might contribute to an increased risk of recurrent VTE independent of other prognostic factors. An increased risk might already be present at subclinical levels of depressive symptoms.

Predicting recurrence after unprovoked venous thromboembolism: prospective validation of the updated Vienna Prediction Model.

The updated Vienna Prediction Model for estimating recurrence risk after an unprovoked venous thromboembolism (VTE) has been developed to identify individuals at low risk for VTE recurrence in whom anticoagulation (AC) therapy may be stopped after 3 months. We externally validated the accuracy of the model to predict recurrent VTE in a prospective multicenter cohort of 156 patients aged ≥65 years with acute symptomatic unprovoked VTE who had received 3 to 12 months of AC. Patients with a predicted 12-month risk within the lowest quartile based on the updated Vienna Prediction Model were classified as low risk. The risk of recurrent VTE did not differ between low- vs higher-risk patients at 12 months (13% vs 10%; P = .77) and 24 months (15% vs 17%; P = 1.0). The area under the receiver operating characteristic curve for predicting VTE recurrence was 0.39 (95% confidence interval [CI], 0.25-0.52) at 12 months and 0.43 (95% CI, 0.31-0.54) at 24 months. In conclusion, in elderly patients with unprovoked VTE who have stopped AC, the updated Vienna Prediction Model does not discriminate between patients who develop recurrent VTE and those who do not. This study was registered at www.clinicaltrials.gov as #NCT00973596.