Fatal pulmonary embolism and fatal bleeding in cancer patients with venous thromboembolism: findings from the RIETE registry

OBJECTIVES: To examine the clinical characteristics and outcomes of cancer patients with venous thromboembolism (VTE) in order to identify factors that place these patients at an increased risk for fatal pulmonary embolism (PE) or fatal bleeding. PATIENTS AND METHODS: Registro Informatizado de la Enfermedad Trombo Embólica (RIETE) is a prospective registry of consecutive patients with symptomatic, objectively confirmed, acute VTE. RESULTS: Up to January 2006, a total of 14 391 patients with symptomatic acute VTE were enrolled in RIETE, of whom 2945 (20%) had cancer. During the 3-month follow-up period the frequency of fatal PE in cancer patients was 2.6%, and that of fatal bleeding 1.0%. These frequencies were significantly higher than in VTE patients without cancer (1.4% and 0.3%, respectively). In patients with cancer, abnormal renal function, metastatic disease, recent major bleeding and recent immobility for >or= 4 days (42% of the 108 patients who died from PE or bleeding had recent immobility) were factors independently associated with an increased risk for both fatal PE and fatal bleeding. In addition, PE diagnosis on admission was an independent risk factor for fatal PE, while body weight < 60 kg was an independent risk factor for fatal bleeding. CONCLUSIONS: Both fatal PE and fatal bleeding are more common in cancer patients with VTE than in those patients without cancer. In cancer patients, abnormal renal function, metastatic disease, recent major bleeding and recent immobility for >or= 4 days are associated with an increased risk for both fatal PE and fatal bleeding.     

Acute venous thromboembolism in patients with recent major bleeding. The influence of the site of bleeding and the time elapsed on outcome

BACKGROUND: Patients with major bleeding who subsequently develop clinically apparent venous thromboembolism (VTE) present a particularly difficult therapeutic dilemma. METHODS: RIETE is a prospective registry of consecutive patients with symptomatic, objectively confirmed, acute VTE. We retrospectively studied those who had experienced recent major bleeding (<30 days prior to VTE) to assess the influence of the site of bleeding and the time elapsed to VTE on their 3 month outcome. RESULTS: Of 12,294 patients enrolled up to July 2005, 306 (2.5%) had recent major bleeding: gastrointestinal (GI) tract, 116 (38%); intracranial, 94 (31%); other, 96 (31%). During the study period, 19 patients [6.2%; 95% confidence interval (CI) 3.5-8.9] with recent bleeding rebled (eight died): 13 of them (68%) during the first 2 weeks. Multivariate analysis confirmed that patients with recent GI bleeding had an increased risk for both major rebleeding (hazard ratio 2.8; 95% CI 1.4-5.3) and death (hazard ratio 1.9; 95% CI 1.2-3.1) compared to those with no recent bleeding. Those who bled in other sites had an increased risk only for death (hazard ratio 2.0; 95% CI 1.2-3.3). An elapsed time of <2 weeks from bleeding to the index VTE event was also associated with an increased risk for major rebleeding (hazard ratio 2.4; 95% CI 1.2-5.0) and death (hazard ratio 2.8; 95% CI 1.8-4.5). CONCLUSION: The incidence of new bleeding or death depends on the site of prior bleeding and the time elapsed until VTE. This information may help to identify the best therapeutic approach for these high-risk patients.     

The outcome after treatment of venous thromboembolism is different in surgical and acutely ill medical patients. Findings from the RIETE registry

BACKGROUND: The history of venous thromboembolism (VTE), and the rationale for thromboprophylaxis in surgical patients are well understood. The situation is less clear for acutely ill medical patients. OBJECTIVES: To compare the clinical presentation of VTE and clinical outcomes of immobile acutely ill medical patients with surgical patients. PATIENTS: RIETE (Registro Informatizado de la Enfermedad TromboEmbolica) is a Spanish registry of consecutively enrolled patients with objectively confirmed, symptomatic acute VTE. In this analysis, clinical characteristics of patients, details of anticoagulant therapy, and outcomes of all enrolled acutely ill medical patients with immobility >/= 4 days, and surgical patients are included. RESULTS: Of 6160 patients enrolled up to December 2003, 756 (12%) were acutely ill medical patients with immobility >/= 4 days, and 884 (14%) were surgical patients who developed VTE within 2 months of surgical intervention. Only 28% of acutely ill medical patients had received thromboprophylaxis, compared with 67% of surgical patients. During the 3-month follow-up period, both fatal pulmonary embolism (PE) and fatal bleeding occurred more frequently in acutely ill medical patients. Immobility in acutely ill medical patients, cancer, and PE were associated with a significantly higher risk of fatal PE or bleeding. CONCLUSIONS: In patients treated for VTE, the incidences of fatal PE, fatal bleeding, and major bleeding were significantly higher in acutely ill medical patients compared with surgical patients. Given the low percentage of acutely ill medical patients who had received thromboprophylaxis, increasing its use appropriately may reduce the incidence of VTE and associated complications.     

The influence of extreme body weight on clinical outcome of patients with venous thromboembolism: findings from a prospective registry (RIETE)

BACKGROUND: Data evaluating the safety of using weight-based dosing of low-molecular-weight heparin (LMWH) in either underweight or obese patients with venous thromboembolism (VTE) are limited. Thus, recommendations based on evidence from clinical trials might not be suitable for patients with extreme body weight. PATIENTS AND METHODS: Patients with objectively confirmed, symptomatic acute VTE are consecutively enrolled into the Registro Informatizado de la Enfermedad TromboEmbólica (RIETE) registry. For this analysis, data from patients in the following ranges of body weight were examined: <50, 50-100, and >100 kg. Patient characteristics, underlying conditions, treatment schedules and clinical outcomes during the first 15 days of treatment were compared. RESULTS: As of August 2004, 8845 patients with acute VTE were enrolled from 94 participating centers. Of these, 169 (1.9%) weighed <50 kg, 8382 (95%) weighed 50-100 kg and 294 (3.3%) weighed >100 kg. Patients weighing <50 kg were more commonly females, were taking non-steriodal antiinflammatory drugs (NSAIDs), and had severe underlying diseases more often than patients weighing 50-100 kg. Their incidence of overall bleeding complications was significantly higher than in patients weighing 50-100 kg (odds ratio 2.2; 95% CI: 1.2-4.0). Patients weighing >100 kg were younger, most commonly males, and had cancer less often than those weighing 50-100 kg. Incidences of recurrent VTE, fatal pulmonary embolism or major bleeding complications were similar in both groups. CONCLUSIONS: Patients with VTE weighing <50 kg have a significantly higher rate of bleeding complications. The clinical outcome of patients weighing over 100 kg was not significantly different from that in patients weighing 50-100 kg.     

Safety of the pulmonary embolism rule-out criteria rule: Findings from the Registro Informatizado de la Enfermedad TromboEmbolica venosa (RIETE) registry

Background

The diagnostic strategy for pulmonary embolism (PE) includes a D-dimer test when PE probability is low or intermediate, but false-positive D-dimer results are frequent and can result in an unnecessary computed tomography pulmonary angiogram. The PE rule-out criteria (PERC) rule excludes PE without D-dimer testing when pretest probability is <15%. The aim of this study was to assess the safety of the PERC rule strategy in patients included in the Registro Informatizado de la Enfermedad TromboEmbolica venosa (RIETE) registry.

Methods

This retrospective cohort study used data from the RIETE registry, an ongoing, international prospective registry of patients with objectively confirmed venous thromboembolism. The primary outcome was the failure rate of the PERC strategy, represented by the proportion of PERC-negative (PERC-N) patients with a PE included in the registry. Secondary outcomes were a comparison of the clinical characteristics, treatment strategy, and outcome of PERC-N versus PERC-positive (PERC-P) patients at 3 months.

Results

From 2001 to 2021, a total of 49,793 patients with acute PE were enrolled in the RIETE registry. We included 48,903 in the final analysis after exclusion of 890 patients with an undetermined PERC status. Only 346 patients were PERC-N with a failure rate of 0.7% (95% confidence interval 0.6%–0.8%). PERC-N patients presented more frequently with chest pain but less often with dyspnea, syncope, or hypotension. They also had subsegmental or segmental PE more frequently, were more often treated with direct oral anticoagulants, and received mechanical or pharmacological thrombolysis less often. In addition, PERC-N patients had a lower incidence of recurrent deep vein thrombosis, major bleeding, and death attributed to PE during the 3-month follow-up.

Conclusions

A low failure rate of the PERC rule was observed in the RIETE registry, thus supporting its use to safely identify patients with an unlikely probability of PE.     

Clinical outcome in patients with venous thromboembolism and hidden cancer: findings from the RIETE Registry

Summary.  Introduction:  Although extensive screening in patients with venous thromboembolism (VTE) may result in early identification of hidden cancer, it is unknown whether the prognosis of these patients may be favorably influenced. Patients and methods:  RIETE is an ongoing, prospective registry of consecutive patients with objectively confirmed, symptomatic, acute VTE. We compared the 3-month outcome of patients with hidden cancer with that in patients in whom no symptoms of cancer were noted. Results:  Of 17 475 patients with acute VTE, 2852 (16%) had cancer diagnosed before VTE or during admission. Hidden cancer was detected in 178 (1.2%) of the remaining 14 623 patients. The most common sites were lung, prostate, colorectum, or hematologic, and 51% had metastases. As compared with patients in whom no symptoms of cancer were noted, those with hidden cancer had an increased incidence of recurrent VTE (11.4% vs. 2.1%; P  <   0.001), major bleeding (5.1% vs. 2.1%; P  =   0.007), and mortality (20% vs. 5.4%; P  <   0.001). In the multivariate analysis, patients aged 60–75 years [odds ratio 1.8; 95% CI 1.2–2.7], with idiopathic VTE (odds ratio 3.0; 95% CI 2.2–4.2), with bilateral thrombosis (odds ratio 2.3; 95% CI 1.3–4.1) or with anemia (odds ratio 1.9; 95% CI 1.4–2.6) were at an increased risk for hidden cancer. Conclusions:  VTE patients with hidden cancer have an increased incidence of recurrences, major bleeding or death during the first 3 months of therapy. With four simple, easily obtainable variables, it is possible to identify a subgroup of VTE patients with a higher risk for hidden cancer.     

Body mass index and mortality in patients with acute venous thromboembolism: findings from the RIETE registry

Summary.  Background:  There is little information on the influence of body mass index (BMI) on mortality in patients with acute venous thromboembolism (VTE). Patients and methods:  RIETE is an ongoing registry of consecutive patients with symptomatic, objectively confirmed, acute VTE. We examined the association between BMI and mortality during the first 3 months of therapy. Results:  Of the 10 114 patients enrolled as of March 2007: 153 (1.5%) were underweight (BMI < 18.5); 2882 (28%) had a normal weight (BMI 18.5–24.9); 4327 (43%) were overweight (BMI 25.0–30); and 2752 (27%) were obese (BMI > 30). The overweight and obese patients were significantly older, and were less likely to have had cancer, recent immobility or renal insufficiency. After 3 months of therapy their death rates were 28%, 12%, 6.2% and 4.2%, respectively. In multivariate analysis, the relative risks for death after adjusting for confounding variables including age, cancer, renal insufficiency or idiopathic VTE were: 2.1 (95% CI, 1.5–2.7); 1.0 (reference); 0.6 (95% CI, 0.5–0.7); and 0.5 (95% CI, 0.4–0.6), respectively. The rates of fatal pulmonary embolism (2.0%, 2.1%, 1.2% and 0.8%, respectively) also decreased with BMI. There were no differences in the rate of fatal bleeding, but patients who were underweight had an increased incidence of major bleeding complications (7.2% vs. 2.7%; odds ratio, 2.7; 95% CI, 1.4–5.1). Conclusions:  Obese patients with acute VTE have less than half the mortality rate when compared with normal BMI patients. This reduction in mortality rates was consistent among all subgroups and persisted after multivariate adjustment.     

Safety and efficacy of low‐dose fondaparinux (1.5 mg) for the prevention of venous thromboembolism in acutely ill medical patients with renal impairment: the FONDAIR study

Summary. Background: Renal impairment is common, affecting around 40% of acutely ill medical patients, and is associated with an increased risk of both venous thromboembolism (VTE) and bleeding. The clinical benefit of effective thromboprophylactic strategies may be outweighed in these patients by an excessive rate of hemorrhage. Objective: To assess the safety and efficacy of lower prophylactic doses of fondaparinux in acutely ill medical patients with renal impairment. Patients/Methods: We carried out a multicenter, investigator‐initiated, prospective cohort study. Patients at risk of VTE with a creatinine clearance between 20 and 50 mL min^?1 were treated with fondaparinux 1.5 mg qd for a minimum of 6 to a maximum of 15 days. The primary outcome was the incidence of major bleeding; secondary outcomes were clinically relevant non‐major bleeding (CRNMB) and symptomatic VTE. Results: We enrolled 206 patients with a mean age of 82 years, mean creatinine clearance of 33 mL min^?1, and a mean Charlson co‐morbidity index of 8.2. One patient had major bleeding (0.49%, 95% confidence interval [CI] 0.03–3.10), eight had CRNMB (3.88%, 95% CI 1.81–7.78) and three developed symptomatic VTE (1.46%, 0.38–4.55). Twenty‐three patients (11.17%, 7.36–16.48) died. No independent predictors of bleeding were found at univariate analysis. Conclusions: The addition of moderate to severe renal impairment to patients with traditional risk factors for VTE identified a population of very elderly acutely ill medical patients potentially at high risk of both VTE and bleeding complications. The recently approved lower prophylactic dose of fondaparinux appears to be a safe and relatively effective strategy in these patients.     

Guidelines and the use of inferior vena cava filters: a review of an institutional experience

Summary.  Background and objectives:  Based on the American College of Chest Physicians 2004 antithrombotic therapy for venous thromboembolism (VTE) and the Eastern Association for the Surgery of Trauma 2002 guidelines, placement of an inferior vena cava (IVC) filter is indicated in patients who either have, or are at high risk for, VTE, but have a contraindication or failure of anticoagulation. Our aim is to compare clinical characteristics and outcomes of patients receiving IVC filters within-guidelines (WG) and outside-of-guidelines (OOG). Methods:  The 558 patients who received an IVC filter were divided into two groups called WG or OOG. The WG group met the criteria described above and the OOG group did not have a contraindication to or a failure of anticoagulation. Results:  The WG group had 362 patients and the OOG group had 196 patients. The OOG group had one (0.5%) patient with post-filter pulmonary embolism (PE), two (1%) with IVC thrombosis, and seven (3.6%) with deep vein thrombosis (DVT). The WG group had five (1.4%) patients with post-filter PE, 13 (3.6%) with IVC thrombosis, and 34 (9.4%) with DVT. All patients who developed post-filter PE had a DVT before filter placement, and patients who did not have a prior VTE event were at a significantly lower risk of developing post-filter IVC thrombosis and PE. Conclusion:  Our data do not support the use of an IVC filter outside of guidelines in patients without prior VTE who can tolerate anticoagulation because of the low risk of developing PE.     

Tinzaparin in outpatients with pulmonary embolism or deep vein thrombosis

BACKGROUND: The low-molecular-weight heparins (LMWHs) have been shown to be effective in the outpatient treatment of deep vein thrombosis (DVT). Data regarding outpatient use of any LMWH in pulmonary embolism (PE) or tinzaparin in DVT while transitioning therapy to a vitamin K antagonist are limited. OBJECTIVE: To determine the safety and efficacy of tinzaparin in patients with either DVT or PE being transitioned to warfarin during LMWH therapy in the outpatient setting. METHODS: All patients who were treated with at least one outpatient dose of tinzaparin for venous thromboembolism (VTE) were identified. Charts of all patients followed within the University of California Davis healthcare system were reviewed. The incidence of bleeding and recurrent thromboembolism over a minimum of the first 4 weeks to a maximum of 12 weeks after initiating anticoagulation was assessed. RESULTS: A total of 178 patients with acute VTE were treated with tinzaparin, and outcomes could be determined in 140 cases. Forty-seven percent of these patients had objectively documented PE. Only one (0.7%) case of recurrent VTE was observed. Major bleeding was documented in 5 (3.6%) and minor bleeding in 8 (5.8%) patients. Two bleeding events, both major, occurred during tinzaparin therapy. CONCLUSIONS: Outpatient use of tinzaparin during transition to warfarin therapy in the treatment of VTE, including PE, appears to be feasible in patients who are judged candidates for home therapy.     

Impact of stage 3B chronic kidney disease on thrombosis and bleeding outcomes after orthopedic surgery in patients treated with desirudin or enoxaparin: insights from a randomized trial

Summary. Background: Venous thromboembolism (VTE) remains a significant complication of major orthopedic surgery, and chronic kidney disease (CKD) is common among elderly patients undergoing total hip replacement (THR). Objectives: The purpose of this study was to evaluate thrombosis and bleeding outcomes in patients with stage 3B CKD treated with either desirudin or enoxaparin after elective THR. Patients/Methods: This was a post hoc subgroup analysis of a randomized, multicenter, double‐blind study of desirudin vs. enoxaparin in patients undergoing elective THR. Results: Patients received either subcutaneous desirudin 15 mg twice daily or subcutaneous enoxaparin 40 mg once daily. Of the 2078 randomized patients who received study medication, 577 had stage 3B CKD or worse (27.8%), and the proportion of these patients who experienced a major VTE in the enoxaparin treatment group was found to be much higher than in the desirudin treatment group (11.1% vs. 3.4%, model‐adjusted odds ratio 3.52, 95% confidence interval 1.48–8.40, P = 0.004). There was no statistically significant difference between treatment groups in terms of rates of major bleeding, regardless of stage of renal function. Conclusions: CKD has been reported previously to increase the risk of bleeding with anticoagulants, and these findings suggest that CKD may also increase the risk of major VTE for patients treated with enoxaparin, but not for patients treated with desirudin. Clinicians should consider the impact of CKD on the risk of VTE when choosing a prophylaxis agent.     

Management patterns and outcomes of patients with venous thromboembolism in the usual community practice setting

OBJECTIVE: The objectives of this study were to observe a commercially insured sample diagnosed with a venous thromboembolism (VTE) event and treated postevent with warfarin and to detail the thromboembolic and bleeding outcomes in the time periods during warfarin therapy and after discontinuation of such therapy. METHODS: This retrospective, observational cohort study used medical, pharmacy, and eligibility data from 2 US health plans. Study inclusion required an inpatient diagnosis of deep venous thrombosis (DVT) or pulmonary embolism (PE) between January 1, 1998, and December 31, 2000; warfarin, heparin, or low-molecular-weight heparin within 30 days after diagnosis; no VTE diagnosis; and no anticoagulant use for 3 months preceding diagnosis. A random sample of medical charts was abstracted to validate VTE events and collect prothrombin time/international normalized ratio (INR) result data. Recurrent VTE events, bleeding events, and proportion of time within INR range were captured in the postindex VTE event time period. Univariate and multivariate statistical techniques were used to assess outcomes. RESULTS: A total of 2,090 patients were identified with a newly diagnosed VTE event (DVT only, 1450; PE with or without DVT, 640). Mean (SD) age was 61.7 (16) years; mean (SD) follow-up time after the index diagnosis was 21.3 (10) months. Overall mean (SD) length of warfarin therapy was 6.6 (6) months. During the follow-up period, 224 patients (10.7%) experienced a recurrent VTE event and 122 patients (5.8%) experienced a bleeding event requiring hospitalization. The cumulative incidence of recurrent VTE events over 3 and 6 months was 9.0% and 10.9%, respectively. Using the chart abstraction subset, patients were within the appropriate INR range 37.7% of the time while receiving warfarin. CONCLUSIONS: Negative outcomes associated with warfarin therapy-recurrent VTE events and bleeding requiring hospitalization-were experienced by 10.7% and 5.8% of patients, respectively. These data suggest that negative outcomes may be more prevalent in usual community medical practice compared with rates observed in the controlled environment of the clinical trial or specialized anticoagulation clinic.     

D-dimer levels and 15-day outcome in acute pulmonary embolism. Findings from the RIETE Registry

Summary.  Background:  A number of variables have been evaluated for risk stratification in patients with acute pulmonary embolism (PE). Whereas increased D-dimer levels have been associated with mortality at 3 months, its role in predicting short-term outcome (the period of time during which any therapeutic decision has to be taken) remains unclear. Methods:  RIETE is an ongoing, prospective registry of consecutive patients with acute venous thromboembolism. We assessed the prognostic value of D-dimer levels at baseline, measured with an automated latex agglutination test (IL Test D-dimer^®), on the 15-day outcome in patients with acute PE. Overall mortality, fatal PE and major bleeding rates were compared by quartile. Results:  As of February 2008, 1707 patients with acute PE underwent D-dimer testing. Of these, 72 patients (4.2%) died during the first 15 days, 11 (0.6%) had recurrent PE, and 29 (1.7%) had major bleeding. Overall mortality increased with increasing D-dimer levels, from 2.7% in the first quartile (< 1050 ng mL⁻¹) to 7.0% in the fourth quartile (≥ 4200 ng mL⁻¹). The rates of fatal PE and major bleeding also increased. On multivariate analysis, patients with D-dimer levels in the fourth quartile had an increased risk for overall death (odds ratio, 1.8; 95% CI, 1.1–3.2), fatal PE (odds ratio, 2.0; 95% CI, 1.0–3.8) or major bleeding (odds ratio, 3.2; 95% CI, 1.5–7.0). Conclusions:  PE patients with D-dimer levels in the fourth quartile had an increased incidence of overall death, fatal PE and major bleeding within 15 days both before and after multivariate adjustment.     

Fatal bleeding in patients receiving anticoagulant therapy for venous thromboembolism: findings from the RIETE registry

Summary. Background: Fatal bleeding is a serious consequence of anticoagulant therapy, but factors associated with fatal bleeding during the first 3 months of treatment of venous thromboembolism (VTE) are uncertain. Methods: Using data from RIETE, an ongoing registry of consecutive patients with acute VTE, we assessed risk factors for fatal bleeding among all patients. We then used this information to derive a clinical model that would stratify a patient’s risk of fatal bleeding during the first 3 months of treatment. Results: Of 24 395 patients, 546 (2.24%) had a major bleed and 135 (0.55%) had a fatal bleed. The gastrointestinal tract was the most common site (40% of fatal bleeds), followed by intracranial bleeding (25%). Fatal bleeding was independently associated with the following factors at the time of VTE diagnosis: age >75 years (OR, 2.16), metastatic cancer (OR, 3.80), immobility ≥ 4 days (OR, 1.99), a major bleed within the past 30 days (OR, 2.64), an abnormal prothrombin time (OR, 2.09), a platelet count < 100 × 10⁹ L⁻¹ (OR, 2.23), creatinine clearance < 30 mL min⁻¹ (OR, 2.27), anemia (OR, 1.54), and distal deep vein thrombosis (OR, 0.39). INR at the time of bleeding is not known. A clinical prediction rule for risk of fatal bleeding that included nine baseline factors was derived. Fatal bleeding occurred in 0.16% (95% CI, 0.11–0.23) of the low‐risk, 1.06% (95% CI, 0.85–1.30) of the moderate‐risk, and 4.24% (95% CI, 2.76–6.27) of the high‐risk category. Conclusions: Patient characteristics and laboratory variables can identify patients at high risk for fatal bleeding during treatment of VTE.     

Silent pulmonary embolism in patients with proximal deep vein thrombosis in the lower limbs

Summary. Background: One in every three patients with deep vein thrombosis (DVT) in the lower limbs may have silent pulmonary embolism (PE), but its clinical relevance has not been thoroughly studied. Methods: We used the RIETE Registry data to study patients with proximal DVT and no PE symptoms, but with a systematic search for PE. We compared the outcome of DVT patients with silent PE and those with no PE. Results: Of 2375 patients with DVT, 842 (35%) had silent PE and 1533 had no PE. During the first 15 days of anticoagulation, patients presenting with silent PE had a higher incidence of symptomatic PE events than those with no PE (0.95% vs. 0.13%; P = 0.015), with a similar incidence of major bleeding (0.95% vs. 1.63%; P = 0.09). In patients with silent PE, the incidence of PE events during the first 15 days was equal to the incidence of major bleeding (eight events each), but in those with no PE the incidence of PE events was eight times lower (3 vs. 25 bleeding events). Multivariate analysis confirmed that DVT patients with silent PE had a higher incidence of symptomatic PE events during the first 15 days than those with no PE (odds ratio, 4.80; 95% CI, 1.27–18.1), with no differences in bleeding. Conclusions: DVT patients with silent PE at baseline had an increased incidence of symptomatic PE events during the first 15 days of anticoagulant therapy. This effect disappeared after 3 months of anticoagulation.     

Apixaban and Rivaroxaban in Patients With Acute Venous Thromboembolism

ObjectiveTo compare the clinical efficacy and safety of apixaban with those of rivaroxaban for the treatment of acute venous thromboembolism (VTE).Patients and MethodsConsecutive patients enrolled in the Mayo Thrombophilia Clinic Registry (between March 1, 2013, and January 30, 2018) and treated with apixaban or rivaroxaban for acute VTE were followed forward in time. The primary efficacy outcome was VTE recurrence. The primary safety outcome was major bleeding; the second safety outcome was clinically relevant nonmajor bleeding (CRNMB); and the third was a composite of major bleeding or CRNMB.ResultsWithin the group of 1696 patients with VTE enrolled, 600 (38%) were treated either with apixaban (n=302, 50%) or rivaroxaban (n=298, 50%) within the first 14 days of VTE diagnosis and who completed at least 3 months of therapy or had a study event. Recurrent VTE was diagnosed in 7 patients (2.3%) treated with apixaban and in 6 (2%) treated with rivaroxaban (adjusted hazard ratio [aHR], 1.4; 95% CI, 0.5-3.8). Major bleeding occurred in 11 patients (3.6%) receiving apixaban and in 9 patients (3.0%) receiving rivaroxaban (aHR, 1.2; 95% CI, 0.5-3.2). Clinically relevant nonmajor bleeding was diagnosed in 7 patients (2.3%) receiving apixaban and in 20 (6.7%) receiving rivaroxaban (aHR, 0.4; 95% CI, 0.2-0.9). The rates of composite major bleeding or CRNMB were similar (aHR, 0.6; 95% CI, 0.3-1.2). Most study events occurred in patients with cancer.ConclusionIn the setting of a standardized, guideline-directed, patient-oriented clinical practice, the efficacy and safety of apixaban and rivaroxaban for the treatment of acute VTE were comparable.     

Comparison of the clinical history of symptomatic isolated distal deep‐vein thrombosis vs. proximal deep vein thrombosis in 11 086 patients

Background: The clinical significance of symptomatic isolated distal deep vein thrombosis (DVT) is uncertain. Consequently, this leads to important disparities in its management. Objective: To examine the clinical history of isolated distal DVT and to compare it with that of proximal DVT. Methods: Using data from the international, prospective, RIETE registry on patients with confirmed symptomatic venous thromboembolism (VTE), we compared the risk factors and 3‐month outcome in patients with isolated distal DVT vs. proximal DVT. Results: Eleven thousand and eighty‐six patients with symptomatic DVT, but without pulmonary embolism, were included between 2001 and 2008; 1921 (17.3%) exhibited isolated distal DVT. Anticoagulant treatment was received by 89.1% (1680/1885) of isolated distal DVT and 91.8% (7911/8613) of proximal DVT patients for the entire follow‐up period. Isolated distal DVTs were more associated with transient risk factors (i.e. recent travel, hospitalization, recent surgery), whereas proximal DVTs were more associated with chronic states (i.e. ≥75 years or with active cancer). At 3 months, major bleeding rate was lower in patients with isolated distal DVT (1.0% vs. 2.2%, P < 0.01), whereas VTE recurrence rate was equivalent (2.0% vs. 2.7%, P = 0.07). The mortality rate was lower in patients with isolated distal DVT (2.7% vs. 7.5%; P < 0.001); this was mainly due to a lower rate of non‐VTE‐related deaths (2.2% vs. 6.3%; P < 0.001). Active cancer was the main predictive factor of death in patients with isolated distal DVT. Conclusions: Proximal and isolated distal DVT patients differ in terms of risk factors and clinical outcomes, suggesting different populations. In the short term, the life expectancy of patients with isolated distal DVT depended chiefly on their cancer status.     

Outpatient treatment in patients with acute pulmonary embolism: the Hestia Study

Summary. Background: Traditionally, patients with pulmonary embolism (PE) are initially treated in the hospital with low molecular weight heparin (LMWH). The results of a few small non‐randomized studies suggest that, in selected patients with proven PE, outpatient treatment is potentially feasible and safe. Objective: To evaluate the efficacy and safety of outpatient treatment according to predefined criteria in patients with acute PE. Patients and Methods: A prospective cohort study of patients with objectively proven acute PE was conducted in 12 hospitals in The Netherlands between 2008 and 2010. Patients with acute PE were triaged with the predefined criteria for eligibility for outpatient treatment, with LMWH (nadroparin) followed by vitamin K antagonists. All patients eligible for outpatient treatment were sent home either immediately or within 24 h after PE was objectively diagnosed. Outpatient treatment was evaluated with respect to recurrent venous thromboembolism (VTE), including PE or deep vein thrombosis (DVT), major hemorrhage and total mortality during 3 months of follow‐up. Results: Of 297 included patients, who all completed the follow‐up, six (2.0%; 95% confidence interval [CI] 0.8–4.3) had recurrent VTE (five PE [1.7%] and one DVT [0.3%]). Three patients (1.0%, 95% CI 0.2–2.9) died during the 3 months of follow‐up, none of fatal PE. Two patients had a major bleeding event, one of which was fatal intracranial bleeding (0.7%, 95% CI 0.08–2.4). Conclusion: Patients with PE selected for outpatient treatment with predefined criteria can be treated with anticoagulants on an outpatient basis. (Dutch Trial Register No 1319; http://www.trialregister.nl/trialreg/index.asp ).     

AVE5026, a new hemisynthetic ultra-low-molecular-weight heparin for the prevention of venous thromboembolism in patients after total knee replacement surgery – TREK: a dose-ranging study

Summary.  Background: AVE5026 is a new hemisynthetic ultra-low-molecular-weight heparin, with a novel anti-thrombotic profile resulting from high anti-factor (F)Xa activity and residual anti-FIIa activity. AVE5026 is in clinical development for venous thromboembolism (VTE) prevention, a frequent complication after total knee replacement (TKR) surgery. Objectives: This study evaluated the dose-response of AVE5026 for the prevention of VTE in patients undergoing TKR surgery. Patients/methods: In this parallel-group, double-blind, double-dummy study, 690 patients were randomized, and 678 treated with once-daily doses of AVE5026 (5, 10, 20, 40, or 60 mg) or enoxaparin 40 mg in the calibrator arm. The primary efficacy end point was VTE until post-operative day 11, defined as deep vein thrombosis (DVT) detected by bilateral venography, symptomatic DVT, non-fatal pulmonary embolism (PE) and VTE-related death. The primary safety outcome was the incidence of major bleeding. Results: The primary efficacy outcome was assessed in 464 patients. There was a significant dose-response across the five AVE5026 groups for VTE prevention ( P  <   0.0001), with the incidence of VTE ranging from 5.3% to 44.1% compared with 35.8% in the enoxaparin group and for proximal DVT ( P  =   0.0002). Also, a significant dose-response for AVE5026 was seen for major bleeding ( P  =   0.0231) and any bleeding ( P  =   0.0003). Six patients in the AVE5026 groups, four in the 60 mg group, experienced major bleeding; none did in the enoxaparin group. Conclusions: The safety and efficacy results of this study suggest that a AVE5026 dose of between 20 and 40 mg presents an adequate benefit-to-risk ratio.     

Family history of venous thromboembolism predicts the diagnosis of acute pulmonary embolism in the emergency department

Background

Pulmonary embolism (PE) clinical decision rules do not consider a patient's family history of venous thromboembolism (VTE). We evaluated whether a family history of VTE predicts acute PE in the emergency department (ED).