Clinical relevance of symptomatic superficial-vein thrombosis extension: lessons from the CALISTO study.

The clinical relevance of symptomatic extension of spontaneous, acute, symptomatic, lower-limb superficial-vein thrombosis (SVT) is debated. We performed a post hoc analysis of a double-blind trial comparing fondaparinux with placebo. The main study outcome was SVT extension by day 77, whether to ≤ 3 cm or > 3 cm from the sapheno-femoral junction (SFJ). All events were objectively confirmed and validated by an adjudication committee. With placebo (n = 1500), symptomatic SVT extension to ≤ 3 cm or > 3 cm from the SFJ occurred in 54 (3.6%) and 56 (3.7%) patients, respectively, inducing comparable medical resource consumption (eg, anticoagulant drugs and SFJ ligation); subsequent deep-vein thrombosis or pulmonary embolism occurred in 9.3% (5/54) and 8.9% (5/56) of patients, respectively. Fondaparinux was associated with lower incidences of SVT extension to ≤ 3 cm (0.3%; 5/1502; P < .001) and > 3 cm (0.8%; 12/1502; P < .001) from the SFJ and reduced related use of medical resources; no subsequent deep-vein thrombosis or pulmonary embolism was observed in fondaparinux patients. Thus, symptomatic extensions are common SVT complications and, whether or not reaching the SFJ, are associated with a significant risk of venous thromboembolic complications and medical resource consumption, all reduced by fondaparinux.

Effect of a retrievable inferior vena cava filter plus anticoagulation vs anticoagulation alone on risk of recurrent pulmonary embolism: a randomized clinical trial.

IMPORTANCE: Although retrievable inferior vena cava filters are frequently used in addition to anticoagulation in patients with acute venous thromboembolism, their benefit-risk ratio is unclear. OBJECTIVE: To evaluate the efficacy and safety of retrievable vena cava filters plus anticoagulation vs anticoagulation alone for preventing pulmonary embolism recurrence in patients presenting with acute pulmonary embolism and a high risk of recurrence. DESIGN, SETTING, AND PARTICIPANTS: Randomized, open-label, blinded end point trial (PREPIC2) with 6-month follow-up conducted from August 2006 to January 2013. Hospitalized patients with acute, symptomatic pulmonary embolism associated with lower-limb vein thrombosis and at least 1 criterion for severity were assigned to retrievable inferior vena cava filter implantation plus anticoagulation (filter group; n = 200) or anticoagulation alone with no filter implantation (control group; n = 199). Initial hospitalization with ambulatory follow-up occurred in 17 French centers. INTERVENTIONS: Full-dose anticoagulation for at least 6 months in all patients. Insertion of a retrievable inferior vena cava filter in patients randomized to the filter group. Filter retrieval was planned at 3 months from placement. MAIN OUTCOMES AND MEASURES: Primary efficacy outcome was symptomatic recurrent pulmonary embolism at 3 months. Secondary outcomes were recurrent pulmonary embolism at 6 months, symptomatic deep vein thrombosis, major bleeding, death at 3 and 6 months, and filter complications. RESULTS: In the filter group, the filter was successfully inserted in 193 patients and was retrieved as planned in 153 of the 164 patients in whom retrieval was attempted. By 3 months, recurrent pulmonary embolism had occurred in 6 patients (3.0%; all fatal) in the filter group and in 3 patients (1.5%; 2 fatal) in the control group (relative risk with filter, 2.00 [95% CI, 0.51-7.89]; P = .50). Results were similar at 6 months. No difference was observed between the 2 groups regarding the other outcomes. Filter thrombosis occurred in 3 patients. CONCLUSIONS AND RELEVANCE: Among hospitalized patients with severe acute pulmonary embolism, the use of a retrievable inferior vena cava filter plus anticoagulation compared with anticoagulation alone did not reduce the risk of symptomatic recurrent pulmonary embolism at 3 months. These findings do not support the use of this type of filter in patients who can be treated with anticoagulation. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00457158.

Apixaban versus enoxaparin for thromboprophylaxis in medically ill patients.

BACKGROUND: The efficacy and safety of prolonging prophylaxis for venous thromboembolism in medically ill patients beyond hospital discharge remain uncertain. We hypothesized that extended prophylaxis with apixaban would be safe and more effective than short-term prophylaxis with enoxaparin. METHODS: In this double-blind, double-dummy, placebo-controlled trial, we randomly assigned acutely ill patients who had congestive heart failure or respiratory failure or other medical disorders and at least one additional risk factor for venous thromboembolism and who were hospitalized with an expected stay of at least 3 days to receive apixaban, administered orally at a dose of 2.5 mg twice daily for 30 days, or enoxaparin, administered subcutaneously at a dose of 40 mg once daily for 6 to 14 days. The primary efficacy outcome was the 30-day composite of death related to venous thromboembolism, pulmonary embolism, symptomatic deep-vein thrombosis, or asymptomatic proximal-leg deep-vein thrombosis, as detected with the use of systematic bilateral compression ultrasonography on day 30. The primary safety outcome was bleeding. All efficacy and safety outcomes were independently adjudicated. RESULTS: A total of 6528 subjects underwent randomization, 4495 of whom could be evaluated for the primary efficacy outcome--2211 in the apixaban group and 2284 in the enoxaparin group. Among the patients who could be evaluated, 2.71% in the apixaban group (60 patients) and 3.06% in the enoxaparin group (70 patients) met the criteria for the primary efficacy outcome (relative risk with apixaban, 0.87; 95% confidence interval [CI], 0.62 to 1.23; P=0.44). By day 30, major bleeding had occurred in 0.47% of the patients in the apixaban group (15 of 3184 patients) and in 0.19% of the patients in the enoxaparin group (6 of 3217 patients) (relative risk, 2.58; 95% CI, 1.02 to 7.24; P=0.04). CONCLUSIONS: In medically ill patients, an extended course of thromboprophylaxis with apixaban was not superior to a shorter course with enoxaparin. Apixaban was associated with significantly more major bleeding events than was enoxaparin. (Funded by Bristol-Myers Squibb and Pfizer; ClinicalTrials.gov number, NCT00457002.).

Fondaparinux for the treatment of superficial-vein thrombosis in the legs.

BACKGROUND: The efficacy and safety of anticoagulant treatment for patients with acute, symptomatic superficial-vein thrombosis in the legs, but without concomitant deep-vein thrombosis or symptomatic pulmonary embolism at presentation, have not been established. METHODS: In a randomized, double-blind trial, we assigned 3002 patients to receive either fondaparinux, administered subcutaneously at a dose of 2.5 mg once daily, or placebo for 45 days. The primary efficacy outcome was a composite of death from any cause or symptomatic pulmonary embolism, symptomatic deep-vein thrombosis, or symptomatic extension to the saphenofemoral junction or symptomatic recurrence of superficial-vein thrombosis at day 47. The main safety outcome was major bleeding. The patients were followed until day 77. RESULTS: The primary efficacy outcome occurred in 13 of 1502 patients (0.9%) in the fondaparinux group and 88 of 1500 patients (5.9%) in the placebo group (relative risk reduction with fondaparinux, 85%; 95% confidence interval [CI], 74 to 92; P<0.001). The incidence of each component of the primary efficacy outcome was significantly reduced in the fondaparinux group as compared with the placebo group, except for the outcome of death (0.1% in both groups). The rate of pulmonary embolism or deep-vein thrombosis was 85% lower in the fondaparinux group than in the placebo group (0.2% vs. 1.3%; 95% CI, 50 to 95; P<0.001). Similar risk reductions were observed at day 77. A total of 88 patients would need to be treated to prevent one instance of pulmonary embolism or deep-vein thrombosis. Major bleeding occurred in one patient in each group. The incidence of serious adverse events was 0.7% with fondaparinux and 1.1% with placebo. CONCLUSIONS: Fondaparinux at a dose of 2.5 mg once a day for 45 days was effective in the treatment of patients with acute, symptomatic superficial-vein thrombosis of the legs and did not have serious side effects. (Funded by GlaxoSmithKline; ClinicalTrials.gov number, NCT00443053.)

The risk of subsequent cancer and arterial cardiovascular events in patients with superficial vein thrombosis in the legs.

Although it has been clearly demonstrated that venous thromboembolism is associated with an increased risk of subsequent overt cancer and arterial cardiovascular events in comparison with control populations, whether this association also applies to patients with isolated (ie, without concomitant involvement of the deep vein system) superficial vein thrombosis (SVT) in the legs is unknown. In 737 consecutive patients with isolated SVT not involving the sapheno-femoral junction, we conducted a retrospective investigation to assess the rate of cancer and that of arterial cardiovascular events occurring during follow-up. The event rates were compared with those occurring in 1438 controls having comparable characteristics. Both cases and controls were followed-up for an average period of 26 ± 8 months (range, 3-45). Malignancy was diagnosed in 26 cases (3.5%) and 56 controls (3.9%), leading to a hazard ratio of 0.86 (95% confidence interval, 0.55%-1.35%). Arterial cardiovascular events occurred in 32 cases (4.3%) and 63 controls (4.4%), leading to a hazard ratio of 0.97 (95% confidence interval, 0.63%-1.50%). We conclude that the occurrence of isolated SVT in the legs does not place patients at an increased risk of malignancies or arterial cardiovascular events. Whether this conclusion also applies to patients whose thrombosis involves the sapheno-femoral junction remains to be demonstrated.

[ECRIN standard requirements for good clinical practices-compliant data management in multinational clinical trials]. / Référentiel ECRIN pour la conformité aux bonnes pratiques de gestion des données des essais cliniques multinationaux.

CONTEXT: Clinical studies involve an increasing amount of data collection and management. However, there is no specific quality standard sufficiently practical, in free access, and open for data management and the underlying IT-infrastructure in academic units. European Clinical Research Infrastructures Network (ECRIN) published standard requirements for certified data management units. We present a French version of these standards. METHODS: A group of experts produced the standards, by consensus. The first version was revised after two pilot audits for data centre certification were performed. RESULTS: The revised version includes 21 lists of five to ten standards, in three groups: information technologies, data management (DM) and "general". CONCLUSIONS: These standards offer a clear description of DM and IT requirements for clinical studies. Initially created for ECRIN certification purposes, they offer a very useful reference for academic DM structures.

A randomized double-blind trial of upward progressive versus degressive compressive stockings in patients with moderate to severe chronic venous insufficiency.

BACKGROUND: The present randomized double-blind multicenter study was designed to assess the efficacy of a progressive compressive stocking (new concept with maximal pressure at calf), compared to a degressive compressive stocking graded 30 mm Hg, evaluating the improvement of lower leg symptoms of chronic venous insufficiency (CVI) in ambulatory patients with moderate to severe chronic venous disease. METHODS: Both gender outpatients presenting symptomatic moderate to severe CVI were eligible for a treatment by compressive stockings. Patients were randomly assigned to receive either degressive compressive stockings (30 mm Hg at ankle, 21 mm Hg at upper calf) or progressive compressive stockings (10 mm Hg at ankle, 23 mm Hg at upper calf). The primary outcome, evaluated after 3 months, was a composite success outcome, including improvement of pain or heavy legs without onset of either ulcer, deep or superficial vein thrombosis of the lower limbs, or pulmonary embolism. The ease of application of the compressive stockings reported by patients was one of secondary outcome. RESULTS: Overall, 401 patients (199 in the progressive compressive stocking group and 202 in the degressive compressive stocking group) were randomized by 44 angiologists in France. Among them, 66% were classified in the C3 CEAP category. The rate of success was significantly higher in the progressive compressive stocking group compared to the degressive compressive stocking group (70.0% vs 59.6%; relative risk, 1.18; 95% confidence interval, 1.02-1.37; P = .03). This was mainly due to more frequent symptom improvement in the progressive compressive stocking group. The compressive stockings were considered easy to apply by 81.3% of patients in the progressive compressive stocking group vs 49.7% of patients in the degressive compressive stocking group (P < .0001). The rate of related serious adverse events was low and similar in both groups. CONCLUSIONS: This trial has demonstrated that progressive compressive stockings are more effective than usual degressive compressive stockings in the improvement of pain and lower leg symptoms in patients with CVI. Moreover, progressive compressive stockings were easier to apply, raising no safety concern at 3 months.

Superficial venous thrombosis and compression ultrasound imaging.

BACKGROUND: A current debate concerning suspected superficial vein thrombosis (SVT) focuses on the need of performing a compression ultrasound (CUS) exploration for confirming the diagnosis of SVT. This study was conducted to determine the clinical relevance and optimal CUS exploration in patients with symptomatic SVT. METHODS: We analyzed the characteristics of SVT and concomitant deep vein thrombosis (DVT) in patients included in the Prospective Observational Superficial Thrombophlebitis (POST) multicenter, observational prospective study. All patients underwent complete bilateral lower limb CUS, exploring both the superficial and deep venous systems. RESULTS: A total of 844 patients with clinical symptoms of SVT were recruited, of which 99 isolated SVTs (21.4%) had saphenofemoral/popliteal junction involvement, and 198 (23.5%) had a concomitant DVT, with 41.8% of them proximal DVTs. In 83 patients (41.9%), DVT and SVT were not contiguous. Five of 639 patients (1%) had an isolated contralateral DVT (ie, not bilateral). Age ≥ 75 years (odds ratio [OR], 2.3; 95% confidence interval [CI], 1.6-3.4), inpatient status (OR, 5.4; 95% CI, 3.4-8.7), a personal history of DVT or pulmonary embolism (OR, 1.8; 95% CI, 1.2-2.8), and SVT on nonvaricose veins (OR, 3.3; 95% CI, 2.1-5.0) were significantly and independently associated with an increased risk of concomitant DVT. Half of the patients exhibited none of these risk factors, and the prevalence of concomitant DVT dropped to 11%. CONCLUSIONS: In patients with symptomatic SVT, a CUS exploration screening the whole venous system of the affected limb is useful because it provides information that has important consequences for the management of these patients.

Superficial venous thrombosis and venous thromboembolism: a large, prospective epidemiologic study.

BACKGROUND: Superficial venous thrombosis (SVT) is perceived to have a benign prognosis. OBJECTIVE: To assess the prevalence of venous thromboembolism in patients with SVT and to determine the 3-month incidence of thromboembolic complications. DESIGN: National cross-sectional and prospective epidemiologic cohort study. (ClinicalTrials.gov registration number: NCT00818688) SETTING: French office- and hospital-based vascular medicine specialists. PATIENTS: 844 consecutive patients with symptomatic SVT of the lower limbs that was at least 5 cm on compression ultrasonography. MEASUREMENTS: Incidence of venous thromboembolism and extension or recurrence of SVT in patients with isolated SVT at presentation. RESULTS: Among 844 patients with SVT at inclusion (median age, 65 years; 547 women), 210 (24.9%) also had deep venous thrombosis (DVT) or symptomatic pulmonary embolism. Among 600 patients without DVT or pulmonary embolism at inclusion who were eligible for 3-month follow-up, 58 (10.2%) developed thromboembolic complications at 3 months (pulmonary embolism, 3 [0.5%]; DVT, 15 [2.8%]; extension of SVT, 18 [3.3%]; and recurrence of SVT, 10 [1.9%]), despite 540 patients (90.5%) having received anticoagulants. Risk factors for complications at 3 months were male sex, history of DVT or pulmonary embolism, previous cancer, and absence of varicose veins. LIMITATION: The findings are from a specialist referral setting, and the study was terminated before the target patient population was reached because of slow recruitment. CONCLUSION: A substantial number of patients with SVT exhibit venous thromboembolism at presentation, and some that do not can develop this complication in the subsequent 3 months. PRIMARY FUNDING SOURCE: GlaxoSmithKline, sanofi-aventis, and the Ministère Francais de la Santé et des Sports (Programme Hospitalier de Recherche Clinique).

[Epidemiologic and therapeutic advances in superficial venous thrombosis of the legs]. / Epidémiologie et traitement des thromboses veineuses superficielles des membres inférieurs.

Thromboses affecting venous superficial system have been considered as benign diseases. Recent studies demonstrate that they might be associated with more severe venous events (as deep venous thrombosis [DVT] or pulmonary embolism [PE]), initially or during 3-month followup. The POST study presents clinical evolution of 844 patients with superficial venous thrombosis (SVT) of lower limbs. Of note, concomitant DVT and/or symptomatic PE were initially found in one quarter of them. Among the 586 patients with isolated SVT (i. e. without DVT or symptomatic PE, and at more than 3 cm of the saphenofemoral junction), 10% presented with DVT, PE, recurrent or extensive SVT during the 3-month follow-up. These results, as the heterogeneous therapeutic management, were confirmed by another cohort study (OPTIMEV). In the CALISTO study, Fondaparinux, at a dose of 2.5 mg once a day for 45 days was effective in the treatment of patients with isolated SVT of the legs and did not have serious side effects. In absence of contra-indication, this treatment may be preferred in patients with confirmed isolated SVT of lower limb.

New insights on the relation between untreated and treated outcomes for a given therapy effect model is not necessarily linear.

BACKGROUND AND OBJECTIVES: A relation between the size of treatment efficacy and severity of the disease has been postulated and observed as linear for a few therapies. We have called this relation the effect model. Our objectives were to demonstrate that the relation is general and not necessarily linear. STUDY DESIGN AND SETTING: We extend the number of observed effect model. Then we established three numerical models of treatment activity corresponding to the three modes of action we have identified. Using these models, we simulated the relation. RESULTS: Empirical evidence confirms the effect model and suggests that it may be linear over a short range of event frequency. However, it provides an incomplete understanding of the phenomenon because of the inescapable limitations of data from randomized clinical trials. Numerical modeling and simulation show that the real effect model is likely to be more complicated. It is probably linear only in rare instances. The effect model is general. It depends on factors related to the individual, disease and outcome. CONCLUSION: Contrarily to common, assumption, since the effect model is often curvilinear, the relative risk cannot be granted as constant. The effect model should be taken into account when discovering and developing new therapies, when making, health care policy decisions or adjusting clinical decisions to the patient risk profile.

Epidemiology of post-operative venous thromboembolism in Asian patients. Results of the SMART venography study.

BACKGROUND AND OBJECTIVES: The rate of post-operative asymptomatic deep-vein thrombosis in Asian patients remains uncertain. The aim of this study was to estimate the rate of venous thromboembolism, including asymptomatic deep-vein thrombosis, undergoing hip or knee surgery and not receiving pharmacological thromboprophylaxis. DESIGN AND METHODS: This was a prospective observational study of a cohort of consecutive Asian patients. The primary study outcome was the composite of venographically detected asymptomatic, or confirmed symptomatic venous thromboembolism, or sudden death at hospital discharge. Bilateral venography was to be performed in all patients between days 5 and 14 after surgery. Follow-up lasted 1 month. RESULTS: A total of 386 patients (median age: 65 years, female: 63.7%, body-mass index > or = 30 kg/m2: 15.4%) undergoing hip (n=160) or knee (n=226) replacement surgery satisfied the study selection criteria and 326 (84.5%) had evaluable venograms. The rate of the primary outcome was 36.5% (119 patients, 99% confidence interval: 29.7 to 43.7). The rate of symptomatic venous thromboembolism was 0.9% (3 patients, 99% confidence interval: 0.1 to 3.3). During follow-up (358 patients for a median duration of 33 days after surgery), two additional episodes of symptomatic venous thromboembolism occurred. Multivariate analysis identified that knee replacement surgery, duration of surgery and treatment with antibiotics within 1 week before surgery were independent risk factors (p<0.05) for venous thromboembolism or sudden death at hospital discharge. INTERPRETATION AND CONCLUSIONS: In Asian patients, the incidence of asymptomatic and symptomatic venous thromboembolism after major orthopedic surgery is high. These results suggest that thromboprophylaxis should be considered in these patients.

Primary angioplasty is cost-minimizing compared with pre-hospital thrombolysis for patients within 60 min of a percutaneous coronary intervention center: the Comparison of Angioplasty and Pre-hospital Thrombolysis in Acute Myocardial Infarction (CAPTIM) cost-efficacy sub-study.

OBJECTIVES: This ancillary study of the Comparison of Angioplasty and Pre-hospital Thrombolysis in Acute Myocardial Infarction (CAPTIM) trial sought to assess the cost-efficacy ratio of primary coronary angioplasty (PCA) and pre-hospital thrombolysis (PHT) in patients suffering from an acute myocardial infarction (AMI) (<6 h) close to (<60 min journey) a percutaneous coronary intervention (PCI) center. BACKGROUND: In the CAPTIM study, at 30 days follow-up PCA was as equally effective as PHT with rescue angioplasty if needed. The cost efficacy of these two strategies has not yet been compared. METHODS: Data were prospectively collected for 299 patients in three centers. The efficacy analysis was extended at one-year follow-up for those patients. Direct fixed and variable actual costs were assessed with a piggyback data collection. RESULTS: The one-year primary end point event-rate (death, non-fatal myocardial infarction, and stroke) was not different after PCA or PHT (14% vs. 16. 4%, p = NS). Costs were lower in the PCA group either during the in-hospital period (8,287 vs. 9,170 $, p = 0.0001) and after one-year follow-up, in relation to a higher rate of subsequent revascularizations in the PHT group (49% vs. 23%, p < 0. 01), leading to a longer hospital stay (10 vs. 9.1 days, p = 0. 03). CONCLUSIONS: After AMI in patients less than 1 h from a PCI center, PCA is as effective and less costly than a combined strategy of PHT followed by rescue angioplasty.

Prevention of venous thromboembolism in medically ill patients: a clinical update.

The risk of venous thromboembolism (VTE) in hospitalised medically ill patients is often underestimated, despite the fact that it remains a major cause of preventable morbidity and mortality in this group. It is not well recognised that the risk of VTE in many hospitalised medically ill patients is at least as high as in populations after surgery. This may partly be attributed to the clinically silent nature of VTE in many patients, and the difficulty in predicting which patients might develop symptoms or fatal pulmonary embolism. Two large studies, Prospective Evaluation of Dalteparin Efficacy for Prevention of VTE in Immobilized Patients Trial and prophylaxis in MEDical patients with ENOXaparin, have shown that low-molecular-weight heparins provide effective thromboprophylaxis in medically ill patients, without increasing bleeding risk. Recent guidelines from the American College of Chest Physicians recommend that acutely medically ill patients admitted with congestive heart failure or severe respiratory disease, or those who are confined to bed and have at least one additional risk factor for VTE, should receive thromboprophylaxis.

Efficacy and safety of fixed low-dose dalteparin in preventing venous thromboembolism among obese or elderly hospitalized patients: a subgroup analysis of the PREVENT trial.

BACKGROUND: We were concerned that a fixed rather than a weight-based dosing regimen of dalteparin sodium to prevent venous thromboembolism (VTE) might result in decreased efficacy in obese patients and decreased safety in elderly patients. METHODS: We retrospectively performed subgroup analyses using the database from the Prospective Evaluation of Dalteparin Efficacy for Prevention of VTE in Immobilized Patients (PREVENT) Trial, a study of 3706 hospitalized, medically ill patients randomized to receive either dalteparin sodium, 5000 U/d, or placebo. The primary end point was a composite of symptomatic VTE, fatal pulmonary embolism, sudden death, or asymptomatic proximal deep venous thrombosis by day 21. Obesity was defined as a body mass index (calculated as weight in kilograms divided by the square of height in meters) of 30 or greater for men and 28.6 or greater for women. RESULTS: Overall, 1118 patients (30.4%) were obese and 1226 (33.3%) were 75 years or older. In obese patients, the primary end point occurred in 2.8% of the dalteparin and in 4.3% of the placebo groups (relative risk, 0.64; 95% confidence interval [CI], 0.32-1.28). In patients 75 years or older, the primary end point was reported in 4.2% of the dalteparin and in 8.0% of the placebo groups (relative risk, 0.52; 95% CI, 0.31-0.87). The dalteparin effect for the primary end point (odds ratio, 0.51; 95% CI, 0.32-0.82) was not attenuated when adjusted for age, sex, obesity, history of VTE, and varicose veins. Dalteparin was not associated with an increase in major hemorrhage by day 21 in obese (0% vs 0.7% placebo; P>.99) and in elderly (1.1% vs 0.7%; P=.12) patients. CONCLUSION: Our findings suggest that a fixed low dose of dalteparin sodium of 5000 U/d is effective and safe in preventing VTE in obese and elderly hospitalized medical patients.

Preventing venous thromboembolism in medical patients.

Given the increased number of patients hospitalized for acute medical illnesses and the associated risk of venous thromboembolism (VTE), the use of prophylaxis has become a public health matter. Thromboprophylaxis is not widely practiced in acutely ill medical patients, due in part to the heterogeneity of this group and the perceived difficulty in assessing those who would most benefit from treatment. Nevertheless, the results of recent well-conducted clinical trials support the evidence-based recommendations for more widespread systematic use of low-dose low-molecular-weight heparin (LMWH) or unfractionated heparin (UFH) in this population. Three large well-controlled studies (MEDENOX, PREVENT, and ARTEMIS) in acutely ill medical patients confirm previous findings that different at-risk patient populations show a consistent 50% reduction in VTE events with LMWH and fondaparinux. A meta-analysis in nearly 5000 patients in internal medicine comparing UFH and LMWH revealed a trend for reduction of deep vein thrombosis and pulmonary embolism with LMWH. Based on duration of use in clinical trials in acutely ill medical patients, prophylactic treatment with UFH and LMWH is recommended for 2 weeks.

Impact of time to treatment on mortality after prehospital fibrinolysis or primary angioplasty: data from the CAPTIM randomized clinical trial.

BACKGROUND: CAPTIM was a randomized trial comparing prehospital thrombolysis with transfer to an interventional facility (and, if needed, percutaneous intervention) with primary percutaneous coronary intervention (PCI) in patients with ST-segment-elevation myocardial infarction (STEMI). Because the benefit of thrombolysis is maximal during the first 2 hours after symptom onset, and because prehospital thrombolysis can be implemented earlier than PCI, this analysis studied the relationship between the effect of assigned treatment and the time elapsed from symptom onset. METHODS AND RESULTS: Randomization within 2 hours (n=460) or > or =2 hours (n=374) after symptom onset had no impact on the effect of treatment on the 30-day combined primary end point of death, nonfatal reinfarction, and disabling stroke. However, patients randomized <2 hours after symptom onset had a strong trend toward lower 30-day mortality with prehospital thrombolysis compared with those randomized to primary PCI (2.2% versus 5.7%, P=0.058), whereas mortality was similar in patients randomized > or =2 hours (5.9% versus 3.7%, P=0.47). There was a significant interaction between treatment effect and delay with respect to 30-day mortality (hazard ratio 4.19, 95% CI 1.033 to 17.004, P=0.045). Among patients randomized in the first 2 hours, cardiogenic shock was less frequent with lytic therapy than with primary PCI (1.3% versus 5.3%, P=0.032), whereas rates were similar in patients randomized later. CONCLUSIONS: Time from symptom onset should be considered when one selects reperfusion therapy in STEMI. Prehospital thrombolysis may be preferable to primary PCI for patients treated within the first 2 hours after symptom onset.

Randomized, placebo-controlled trial of dalteparin for the prevention of venous thromboembolism in acutely ill medical patients.

BACKGROUND: Considerable variability exists in the use of pharmacological thromboprophylaxis among acutely ill medical patients, partly because clinically relevant end points have not been fully assessed in this population. We undertook an international, multicenter, randomized, double-blind, placebo-controlled trial using clinically important outcomes to assess the efficacy and safety of dalteparin in the prevention of venous thromboembolism in such patients. METHODS AND RESULTS: Patients (n=3706) were randomly assigned to receive either subcutaneous dalteparin 5000 IU daily or placebo for 14 days and were followed up for 90 days. The primary end point was venous thromboembolism, defined as the combination of symptomatic deep vein thrombosis, symptomatic pulmonary embolism, and asymptomatic proximal deep vein thrombosis detected by compression ultrasound at day 21 and sudden death by day 21. The incidence of venous thromboembolism was reduced from 4.96% (73 of 1473 patients) in the placebo group to 2.77% (42 of 1518 patients) in the dalteparin group, an absolute risk reduction of 2.19% or a relative risk reduction of 45% (relative risk, 0.55; 95% CI, 0.38 to 0.80; P=0.0015). The observed benefit was maintained at 90 days. The overall incidence of major bleeding was low but higher in the dalteparin group (9 patients; 0.49%) compared with the placebo group (3 patients; 0.16%). CONCLUSIONS: Dalteparin 5000 IU once daily halved the rate of venous thromboembolism with a low risk of bleeding.

Mortality rates and risk factors for asymptomatic deep vein thrombosis in medical patients.

The clinical importance of asymptomatic proximal and distal deep vein thrombosis (DVT) remains uncertain and controversial. The aim of this retrospective, post-hoc analysis was to examine mortality and risk factors for development of proximal DVT in hospitalized patients with acute medical illness who were recruited into a randomized, prospective clinical trial of thromboprophylaxis with dalteparin (PREVENT). We analyzed 1738 patients who had not sustained a symptomatic venous thromboembolic event by Day 21 and who had a complete compression ultrasound of the proximal and distal leg veins on Day 21. We examined the 90-day mortality rates in patients with asymptomatic proximal DVT (Group I, N=80), asymptomatic distal DVT (Group II, N=118) or no DVT (Group III, N=1540). The 90-day mortality rates were 13.75%, 3.39%, and 1.92% for Groups I-III, respectively. The difference in mortality between Group I and Group III was significant (hazard ratio 7.63, 95% CI=3.8-15.3; p <0.0001), whereas the difference between Groups II and III did not reach significance (hazard ratio 1.36, 95% CI=0.41-4.45). The association of asymptomatic proximal DVT with increased mortality remained highly significant after adjusting for differences in baseline demographics and clinical variables. Risk factors significantly associated with the development of proximal DVT included advanced age (p=0.0005), prior DVT (p=0.001), and varicose veins (p=0.04). In conclusion, the high mortality rate in patients with asymptomatic proximal DVT underscores its clinical relevance and supports targeting of asymptomatic proximal DVT as an appropriate endpoint in clinical trials of thromboprophylaxis.

Risk factors for venous thromboembolism in hospitalized patients with acute medical illness: analysis of the MEDENOX Study.

BACKGROUND: There is limited information about risk factors for venous thromboembolism (VTE) in acutely ill hospitalized general medical patients. METHODS: An international, randomized, double-masked, placebo-controlled trial (MEDENOX) has previously been conducted in 1102 acutely ill, immobilized general medical patients and has shown the efficacy of using a low-molecular-weight heparin, enoxaparin sodium, in preventing thrombosis. We performed logistic regression analysis to evaluate the independent nature of different types of acute medical illness (heart failure, respiratory failure, infection, rheumatic disorder, and inflammatory bowel disease) and predefined factors (chronic heart and respiratory failure, age, previous VTE, and cancer) as risk factors for VTE. RESULTS: The primary univariate analysis showed that the presence of an acute infectious disease, age older than 75 years, cancer, and a history of VTE were statistically significantly associated with an increased VTE risk. Multiple logistic regression analysis indicated that these factors were independently associated with VTE. CONCLUSIONS: Several independent risk factors for VTE were identified. These findings allow recognition of individuals at increased risk of VTE and will contribute to the formulation of an evidence-based risk assessment model for thromboprophylaxis in hospitalized general medical patients.