Alain Leizorovicz

A Clinical Trial of Vena Caval Filters in the Prevention of Pulmonary Embolism in Patients with Proximal Deep-Vein Thrombosis

BACKGROUND The efficacy and safety of vena caval filters in the prevention of pulmonary embolism in patients with proximal deep-vein thrombosis is still a matter of debate. METHODS Using a two-by-two factorial design, we randomly assigned 400 patients with proximal deep-vein thrombosis who were at risk for pulmonary embolism to receive a vena caval filter (200 patients) or no filter (200 patients), and to receive low-molecular-weight heparin (enoxaparin, 195 patients) or unfractionated heparin (205 patients). The rates of recurrent venous thromboembolism, death, and major bleeding were analyzed at day 12 and at two years. RESULTS At day 12, two patients assigned to receive filters (1.1 percent), as compared with nine patients assigned to receive no filters (4.8 percent), had had symptomatic or asymptomatic pulmonary embolism (odds ratio, 0.22; 95 percent confidence interval, 0.05 to 0.90). At two years, 37 patients assigned to the filter group (20.8 percent), as compared with 21 patients assigned to the no-filter group (11.6 percent), had had recurrent deep-vein thrombosis (odds ratio, 1.87; 95 percent confidence interval, 1.10 to 3.20). There were no significant differences in mortality or the other outcomes. At day 12, three patients assigned to low-molecular-weight heparin (1.6 percent), as compared with eight patients assigned to unfractionated heparin (4.2 percent), had had symptomatic or asymptomatic pulmonary embolism (odds ratio, 0.38; 95 percent confidence interval, 0.10 to 1.38). CONCLUSIONS In high-risk patients with proximal deep-vein thrombosis, the initial beneficial effect of vena caval filters for the prevention of pulmonary embolism was counterbalanced by an excess of recurrent deep-vein thrombosis, without any difference in mortality. Our data also confirmed that low-molecular-weight heparin was as effective and safe as unfractionated heparin for the prevention of pulmonary embolism.

A COMPARISON OF ENOXAPARIN WITH PLACEBO FOR THE PREVENTION OF VENOUS THROMBOEMBOLISM IN ACUTELY ILL MEDICAL PATIENTS

BACKGROUND The efficacy and safety of thromboprophylaxis in patients with acute medical illnesses who may be at risk for venous thromboembolism have not been determined in adequately designed trials. METHODS In a double-blind study, we randomly assigned 1102 hospitalized patients older than 40 years to receive 40 mg of enoxaparin, 20 mg of enoxaparin, or placebo subcutaneously once daily for 6 to 14 days. Most patients were not in an intensive care unit. The primary outcome was venous thromboembolism between days 1 and 14, defined as deep-vein thrombosis detected by bilateral venography (or duplex ultrasonography) between days 6 and 14 (or earlier if clinically indicated) or documented pulmonary embolism. The duration of follow-up was three months. RESULTS The primary outcome could be assessed in 866 patients. The incidence of venous thromboembolism was significantly lower in the group that received 40 mg of enoxaparin (5.5 percent [16 of 291 patients]) than in the group that received placebo (14.9 percent [43 of 288 patients]) (relative risk, 0.37; 97.6 percent confidence interval, 0.22 to 0.63; P< 0.001). The benefit observed with 40 mg of enoxaparin was maintained at three months. There was no significant difference in the incidence of venous thromboembolism between the group that received 20 mg of enoxaparin (43 of 287 patients [15.0 percent]) and the placebo group. The incidence of adverse effects did not differ significantly between the placebo group and either enoxaparin group. By day 110, 50 patients had died in the placebo group (13.9 percent), 51 had died in the 20-mg group (14.7 percent), and 41 had died in the 40-mg group (11.4 percent); the differences were not significant. CONCLUSIONS Prophylactic treatment with 40 mg of enoxaparin subcutaneously per day safely and effectively reduces the risk of venous thromboembolism in patients with acute medical illnesses.

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 ≥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 ≥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.

Heart Rate and Cardiac Rhythm Relationships With Bisoprolol Benefit in Chronic Heart Failure in CIBIS II Trial

Background —&bgr;-Blockade–induced benefit in heart failure (HF) could be related to baseline heart rate and treatment-induced heart rate reduction, but no such relationships have been demonstrated. Methods and Results —In CIBIS II, we studied the relationships between baseline heart rate (BHR), heart rate changes at 2 months (HRC), nature of cardiac rhythm (sinus rhythm or atrial fibrillation), and outcomes (mortality and hospitalization for HF). Multivariate analysis of CIBIS II showed that in addition to &bgr;-blocker treatment, BHR and HRC were both significantly related to survival and hospitalization for worsening HF, the lowest BHR and the greatest HRC being associated with best survival and reduction of hospital admissions. No interaction between the 3 variables was observed, meaning that on one hand, HRC-related improvement in survival was similar at all levels of BHR, and on the other hand, bisoprolol-induced benefit over placebo for survival was observed to a similar extent at any level of both BHR and HRC. Bisoprolol reduced mortality in patients with sinus rhythm (relative risk 0.58, P <0.001) but not in patients with atrial fibrillation (relative risk 1.16, P =NS). A similar result was observed for cardiovascular mortality and hospitalization for HF worsening. Conclusions —BHR and HRC are significantly related to prognosis in heart failure. &bgr;-Blockade with bisoprolol further improves survival at any level of BHR and HRC and to a similar extent. The benefit of bisoprolol is questionable, however, in patients with atrial fibrillation.

Primary angioplasty versus prehospital fibrinolysis in acute myocardial infarction: a randomised study.

BACKGROUND Although both prehospital fibrinolysis and primary angioplasty provide a clinical benefit over in-hospital fibrinolysis in acute myocardial infarction, they have not been directly compared. Our aim was to find out whether primary angioplasty was better than prehospital fibrinolysis. METHODS We did a randomised multicentre trial of 840 patients (of 1200 planned) who presented within 6 h of acute myocardial infarction with ST-segment elevation, initially managed by mobile emergency-care units. We assigned patients to prehospital fibrinolysis (n=419) with accelerated alteplase or primary angioplasty (n=421), and transferred all to a centre with access to emergency angioplasty. Our primary endpoint was a composite of death, non-fatal reinfarction, and non-fatal disabling stroke at 30 days. Analyses were by intention to treat. FINDINGS The median delay between onset of symptoms and treatment was 130 min in the prehospital-fibrinolysis group and 190 min (time to first balloon inflation) in the primary-angioplasty group. Rescue angioplasty was done in 26% of the patients in the fibrinolysis group. The rate of the primary endpoint was 8.2% (34 patients) in the prehospital-fibrinolysis group and 6.2% (26 patients) in the primary-angioplasty group (risk difference 1.96, 95% CI -1.53 to 5.46). 16 (3.8%) patients assigned prehospital fibrinolysis and 20 (4.8%) assigned primary angioplasty died (p=0.61). INTERPRETATION A strategy of primary angioplasty was not better than a strategy of prehospital fibrinolysis (with transfer to an interventional facility for possible rescue angioplasty) in patients presenting with early myocardial infarction.

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.)

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.

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).

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

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