Clot resolution after 3 weeks of anticoagulant treatment for pulmonary embolism: comparison of computed tomography and perfusion scintigraphy.

INTRODUCTION: Little is known about the natural history of clot resolution in the initial weeks of anticoagulant therapy in patients with acute pulmonary embolism (PE). Clot resolution of acute PE was assessed with either computed tomography pulmonary angiography scan (CT-scan) or perfusion scintigraphy scan (Q-scan) after 3 weeks of treatment. METHODS: This was a predefined safety analysis of the Einstein PE study, including PE patients, randomized to either enoxaparin with vitamin K antagonist (VKA) or rivaroxaban. A similar scan as at baseline was repeated after 3 weeks. The percentage of vascular obstruction (PVO) was calculated on the basis of a weighted semiquantitative estimation of obstruction. Clot resolution was assessed blindly by calculating the relative change after 3 weeks. RESULTS: PE was diagnosed in 264 patients with CT-scan and in 83 with Q-scan. Baseline characteristics were similar. At baseline, the mean PVO assessed with CT-scan (PVO-CT) and the mean PVO assessed with Q-scan (PVO-Q) were both 21% (standard deviation [SD] 13%) (P = 0.9). The mean relative decrease in PVO was 71% (SD 33%) for PVO-CT, and 62% (SD 36%) for PVO-Q (P = 0.02); complete resolution was observed in 44% (116/264; 95% confidence interval [CI] 38-50%) and 31% (26/83; 95% CI 22-42%) with CT-scan and Q-scan, respectively (P = 0.04). No difference in clot resolution between enoxaparin/VKA and rivaroxaban was found. CONCLUSION: In patients with acute PE, only 3 weeks of anticoagulant treatment leads to complete clot resolution in a considerable proportion of patients, and normalization is more often observed with CT-scan than with Q-scan.

Effect of obesity on outcomes after fondaparinux, enoxaparin, or heparin treatment for acute venous thromboembolism in the Matisse trials.

BACKGROUND: Selecting initial anticoagulant dose by patient weight for acute pulmonary embolism and deep vein thrombosis has clinical credibility; however, uncertainty remains regarding how to dose obese patients with newer anticoagulants because outcome data are sparse. OBJECTIVES: To use the Matisse trials' comparison of sc fondaparinux once daily with control heparin therapies (intravenous unfractionated heparin for pulmonary embolism, sc enoxaparin 1 mg/kg b.i.d. for deep vein thrombosis) for initial treatment in order to compare primary outcomes (venous thromboembolism recurrence and major bleeding) in obese patients. PATIENTS AND METHODS: Primary outcomes were compared in subsets composed of patients weighing < or = and > 100 kg and with body mass index (BMI) < 30 and > or = 30 kg/m(2). Medians and ranges for weight and BMI were compared for patients suffering either recurrence or major bleeding. RESULTS: Twenty-two thousand and one patients received fondaparinux and 2217 received enoxaparin or unfractionated heparin. Four hundred and ninety-six patients (11%) weighed > 100 kg and 1216 (28%) had a BMI > or = 30. Treatment groups had similar characteristics. The upper limit in subject weight for recurrence was 166 kg (BMI 58), and for major bleeding 120 kg (BMI 39). The incidences of recurrence and major bleeding were similar for each patient subset of weight and BMI for both fondaparinux and heparin treatment groups. Among patients with a primary outcome, median weights and BMIs were also similar. CONCLUSIONS: The current recommended doses of fondaparinux and heparins for the treatment of venous thromboembolism appear to provide similar protection against recurrence and major bleeding to one another and to obese and non-obese patients.

Venous thromboembolism and the risk of subsequent symptomatic atherosclerosis.

BACKGROUND: Recently, we reported an association between asymptomatic carotid atherosclerosis and venous thromboembolism (VTE) of unknown origin. We hypothesized that patients with VTE of unknown origin would be at a higher risk of developing symptomatic atherosclerosis than patients with VTE induced by known risk factors. METHODS: To examine this hypothesis, we studied 1,919 consecutive patients followed prospectively after their first VTE episode. The primary outcome was non-fatal and fatal symptomatic atherosclerotic disease in patients with VTE of unknown origin as compared to those with secondary VTE. An independent committee assessed all study outcomes, and adjusted hazard ratios (HR) were calculated using the Cox's proportional hazards model. RESULTS: After a median follow-up of 48 and 51 months, respectively, at least one symptomatic atherosclerotic complication was detected in 160 of the 1,063 patients (15.1%) with VTE of unknown origin, and in 73 of the 856 (8.5%) with secondary VTE. After adjusting for age and other risk factors of atherosclerosis, the HR for symptomatic atherosclerotic complications in patients with VTE of unknown origin compared to those with secondary VTE was 1.6 (95% confidence intervals; CI: 1.2-2.0). When the analysis was restricted to patients without previous symptomatic atherosclerosis, the HR became 1.7 (95% CI: 1.1-2.4). CONCLUSIONS: Patients with VTE of unknown origin have a 60% higher risk of developing symptomatic atherosclerotic disease than do patients with secondary venous thrombosis.

Decision analysis for cancer screening in idiopathic venous thromboembolism.

BACKGROUND: The SOMIT trial randomized patients with idiopathic venous thromboembolism (IVTE) and without signs of cancer at routine medical examination, to extensive screening for cancer plus 2 years of follow-up or to just 2-year follow-up. METHODS: The data of the SOMIT-trial were used to perform a decision analysis. The screening tests were divided in several possible strategies. The number of detected cancer patients and the number of patients investigated further for an eventually benign condition were calculated for each strategy. The total costs for the screening strategy and for each detected cancer patient were determined. Based on the tumor type, stage, age and gender of the individual cancer patient, the difference in live years gained (LYG) was calculated between the two study groups. RESULTS: Computed tomography (CT) of the abdomen combined with sputum cytology and mammography detected 12 of the 14 patients with cancer and had one false-positive result. In general, screening strategies including abdominal/pelvic ultrasonography (US) or tumor markers yielded a higher number of patients needed to screen in comparison with those using abdominal/pelvic CT. Furthermore, the strategies which included colonoscopy, tumor markers, and abdominal/pelvic US were significantly more costly, had inferior LYG and higher costs per LYG, when compared with strategies using abdominal/pelvic CT. CONCLUSIONS: Despite the limitations of this analysis, the screening for cancer with a strategy including abdominal/pelvic CT with or without mammography and/or sputum cytology appears potentially useful for cancer screening in patients with IVTE. The cost-effectiveness analysis of this strategy needs confirmation in a large trial.

Fixed dose subcutaneous low molecular weight heparins versus adjusted dose unfractionated heparin for venous thromboembolism.

BACKGROUND: Low molecular weight heparins (LMWH) have been shown to be effective and safe in preventing venous thromboembolism (VTE), and may also be effective for the initial treatment of VTE. OBJECTIVES: To determine the effect of LMWH compared with unfractionated heparin (UFH) for the initial treatment of VTE. SEARCH STRATEGY: Trials were identified from the Cochrane Peripheral Vascular Diseases Group's Specialised Register, CENTRAL and LILACS. Colleagues and pharmaceutical companies were contacted for additional information. SELECTION CRITERIA: Randomised controlled trials comparing fixed dose subcutaneous LMWH with adjusted dose intravenous or subcutaneous UFH in people with VTE. DATA COLLECTION AND ANALYSIS: At least two reviewers assessed trials for inclusion and quality, and extracted data independently. MAIN RESULTS: Twenty-two studies were included (n = 8867). Thrombotic complications occurred in 151/4181 (3.6%) participants treated with LMWH, compared with 211/3941 (5.4%) participants treated with UFH (odds ratio (OR) 0.68; 95% confidence intervals (CI) 0.55 to 0.84, 18 trials). Thrombus size was reduced in 53% of participants treated with LMWH and 45% treated with UFH (OR 0.69; 95% CI 0.59 to 0.81, 12 trials). Major haemorrhages occurred in 41/3500 (1.2%) participants treated with LMWH, compared with 73/3624 (2.0%) participants treated with UFH (OR 0.57; 95% CI 0.39 to 0.83, 19 trials). In eighteen trials, 187/4193 (4.5%) participants treated with LMWH died, compared with 233/3861 (6.0%) participants treated with UFH (OR 0.76; 95% CI 0.62 to 0.92). Nine studies (n = 4451) examined proximal thrombosis; 2192 participants treated with LMWH and 2259 with UFH. Subgroup analysis showed statistically significant reductions favouring LMWH in thrombotic complications and major haemorrhage. By the end of follow up, 80 (3.6%) participants treated with LMWH had thrombotic complications, compared with 143 (6.3%) treated with UFH (OR 0.57; 95% CI 0.44 to 0.75). Major haemorrhage occurred in 18 (1.0%) participants treated with LMWH, compared with 37 (2.1%) treated with UFH (OR 0.50; 95% CI 0.29 to 0.85). Nine studies (n = 4157) showed a statistically significant reduction favouring LMWH with respect to mortality. By the end of follow up, 3.3% (70/2094) of participants treated with LMWH had died, compared with 5.3% (110/2063) of participants treated with UFH (OR 0.62; 95% CI 0.46 to 0.84). REVIEWERS' CONCLUSIONS: LMWH is more effective than UFH for the initial treatment of VTE. LMWH significantly reduces the occurrence of major haemorrhage during initial treatment and overall mortality at follow up.

Screening for occult cancer in patients with acute deep vein thrombosis or pulmonary embolism.

Patients with acute venous thromboembolism have an increased risk for occult malignancy. Limited screening for these malignancies has become common practice but little is known about its usefulness. This is a prospective cohort follow-up study in consecutive patients with acute venous thromboembolism. All patients underwent a routine clinical evaluation for malignancy, if negative, followed by a limited diagnostic work-up consisting of abdominal and pelvic ultrasound and laboratory markers for malignancy. Clinical follow-up was conducted to detect screening failures. The routine clinical evaluation was performed in 864 patients and revealed malignancy in 34 (3.9%) of them. Among the remaining 830 patients the limited diagnostic work-up revealed 13 further malignancies. During follow-up, cancer became symptomatic in 14 patients who were negative for cancer at screening (sensitivity of limited diagnostic work-up, 48.1%). Malignancies that were identified by the limited diagnostic work-up were early stage in 61% of cases vs. 14% in cases occurring during follow-up. Most patients with occult cancer had idiopathic venous thromboembolism and were older than 70 years. A limited diagnostic work-up for occult cancer in patients with venous thromboembolism has the capacity to identify approximately one-half of the malignancies. Identified malignancies were predominantly in an early stage.

Extensive screening for occult malignant disease in idiopathic venous thromboembolism: a prospective randomized clinical trial.

Patients with symptomatic idiopathic venous thromboembolism and apparently cancer-free have an approximate 10% incidence of subsequent cancer. Apparently cancer-free patients with acute idiopathic venous thromboembolism were randomized to either the strategy of extensive screening for occult cancer or to no further testing. Patients had a 2-year follow-up period. Of the 201 patients, 99 were allocated to the extensive screening group and 102 to the control group. In 13 (13.1%) patients, the extensive screening identified occult cancer. In the extensive screening group, a single (1.0%) malignancy became apparent during follow-up, whereas in the control group a total of 10 (9.8%) malignancies became symptomatic [relative risk, 9.7 (95% CI, 1.3-36.8; P < 0.01]. Overall, malignancies identified in the extensive screening group were at an earlier stage and the mean delay to diagnosis was reduced from 11.6 to 1.0 months (P < 0.001). Cancer-related mortality during the 2 years follow-up period occurred in two (2.0%) of the 99 patients of the extensive screening group vs. four (3.9%) of the 102 control patients [absolute difference, 1.9% (95% CI, -5.5-10.9)]. Although early detection of occult cancers may be associated with improved treatment possibilities, it is uncertain whether this improves the prognosis.

Subcutaneous fondaparinux versus intravenous unfractionated heparin in the initial treatment of pulmonary embolism.

BACKGROUND: The standard initial treatment of hemodynamically stable patients with pulmonary embolism is intravenous unfractionated heparin, requiring laboratory monitoring and hospitalization. METHODS: We conducted a randomized, open-label trial involving 2213 patients with acute symptomatic pulmonary embolism to compare the efficacy and safety of the synthetic antithrombotic agent fondaparinux with those of unfractionated heparin and to document noninferiority in terms of efficacy. Patients received either fondaparinux (5.0, 7.5, or 10.0 mg in patients weighing less than 50, 50 to 100, or more than 100 kg, respectively) subcutaneously once daily or a continuous intravenous infusion of unfractionated heparin (ratio of the activated partial-thromboplastin time to a control value, 1.5 to 2.5), both given for at least five days and until the use of vitamin K antagonists resulted in an international normalized ratio above 2.0. The primary efficacy outcome was the three-month incidence of the composite end point of symptomatic, recurrent pulmonary embolism (nonfatal or fatal) and new or recurrent deep-vein thrombosis. RESULTS: Forty-two of the 1103 patients randomly assigned to receive fondaparinux (3.8 percent) had recurrent thromboembolic events, as compared with 56 of the 1110 patients randomly assigned to receive unfractionated heparin (5.0 percent), for an absolute difference of -1.2 percent in favor of fondaparinux (95 percent confidence interval, -3.0 to 0.5). Major bleeding occurred in 1.3 percent of the patients treated with fondaparinux and 1.1 percent of those treated with unfractionated heparin. Mortality rates at three months were similar in the two groups. Of the patients in the fondaparinux group, 14.5 percent received the drug in part on an outpatient basis. CONCLUSIONS: Once-daily, subcutaneous administration of fondaparinux without monitoring is at least as effective and is as safe as adjusted-dose, intravenous administration of unfractionated heparin in the initial treatment of hemodynamically stable patients with pulmonary embolism.

The use of specific antidotes as a response to bleeding complications during anticoagulant therapy for venous thromboembolism.

When a bleeding complication occurs during therapy with heparin or vitamin K antagonists, there is an option to give a specific antidote. Several new anticoagulants have been developed that are likely to have some risk of bleeding complications, for which no specific antidotes are available. Interestingly, it is unknown how often the use of an antidote is necessary in clinical practice. We investigated 1877 patients treated for venous thromboembolism included in three large clinical trials, of which 181 (9.6%) had a total of 225 adjudicated bleeding episodes; 46 hemorrhages being designated as major. Some form of antidote was given to 26 (14.4%) patients with a hemorrhage. Of the patients with at least one major hemorrhage, 19 (41.3%) received an antidote. Vitamin K was given to 23 (1.2%) patients, one (0.05%) patient received protamin sulfate and seven (0.4%) patients received fresh frozen plasma. The use of antidotes was comparable for initial and long-term treatment. Antidotes were statistically significantly more frequently given in Canada as compared to other participating countries. Vitamin K was more frequently given in case of a higher international normalized ratio value. Although antidotes against anticoagulant treatment are widely available, our analysis shows that in only a very small number of patients a direct, or slow-acting antidote to reverse the anticoagulant effect was used.