Raffaele Pesavento

Residual Thrombosis on Ultrasonography to Guide the Duration of Anticoagulation in Patients With Deep Venous Thrombosis: A Randomized Trial

BACKGROUND The optimal duration of oral anticoagulant therapy in patients with deep venous thrombosis (DVT) of the lower extremities remains uncertain. OBJECTIVE To assess whether tailoring the duration of anticoagulation on the basis of the persistence of residual thrombi on ultrasonography reduces the rate of recurrent venous thromboembolism (VTE) compared with the administration of conventional fixed-duration treatment in adults with proximal DVT. DESIGN Parallel, randomized trial from 1999 to 2006. Trained physicians who assessed outcomes were blinded to patient assignment status, but patients and providers were not. SETTING 9 university or hospital centers in Italy. PATIENTS 538 consecutive outpatients with a first episode of acute proximal DVT at completion of an uneventful 3-month period of anticoagulation. INTERVENTION Patients were randomly assigned (stratified by center and secondary vs. unprovoked DVT by using a computer-generated list that was accessible only to a trial nurse) to fixed-duration anticoagulation (no further anticoagulation for secondary thrombosis and an extra 3 months for unprovoked thrombosis) or flexible-duration, ultrasonography-guided anticoagulation (no further anticoagulation in patients with recanalized veins and continued anticoagulation in all other patients for up to 9 months for secondary DVT and up to 21 months for unprovoked thrombosis). For the primary outcome assessment, 530 patients completed the trial. MEASUREMENTS The rate of confirmed recurrent VTE during 33 months of follow-up. RESULTS Overall, 46 (17.2%) of 268 patients allocated to fixed-duration anticoagulation and 32 (11.9%) of 270 patients allocated to flexible-duration anticoagulation developed recurrent VTE (adjusted hazard ratio [HR], 0.64 [95% CI, 0.39 to 0.99]). For patients with unprovoked DVT, the adjusted HR was 0.61 (CI, 0.36 to 1.02) and 0.81 (CI, 0.32 to 2.06) for those with secondary DVT. Major bleeding occurred in 2 (0.7%) patients in the fixed-duration group and 4 (1.5%) patients in the flexible-duration group (P = 0.67). LIMITATIONS The trial lacked a double-blind design. The sample size was not powered to detect differences in bleeding between groups and to detect effectiveness of the intervention in the subgroups of patients with unprovoked and secondary DVT. Patients with previous thromboembolism, permanent risk factors for thrombosis, and thrombophilic abnormalities other than factor V Leiden and prothrombin mutation were excluded. CONCLUSION Tailoring the duration of anticoagulation on the basis of ultrasonography findings reduces the rate of recurrent VTE in adults with proximal DVT. PRIMARY FUNDING SOURCE None.

Risk factors and basic mechanisms of chronic thromboembolic pulmonary hypertension: a current understanding

All available evidence today indicates that chronic thromboembolic pulmonary hypertension (CTEPH) is primarily caused by venous thromboembolism, as opposed to primary pulmonary vascular in situ thrombosis. Both the initial magnitude of clot and pulmonary embolism (PE) recurrence may contribute to the development of CTEPH. Only few specific thrombophilic factors, such as phospholipid antibodies, lupus anticoagulant and elevated factor VIII, are statistically associated with CTEPH. A mechanistic view of CTEPH as a disease caused by obliteration of central pulmonary arteries by pulmonary emboli is too simplistic. Based on available data one may speculate that PE may be followed by a pulmonary vascular remodelling process modified by infection, immune phenomena, inflammation, circulating and vascular-resident progenitor cells, thyroid hormone replacement or malignancy. Both plasmatic factors (hypercoagulation, “sticky” red blood cells, high platelet counts and uncleavable fibrinogens) and a misguided vascular remodelling process contribute to major vessel and small vessel obliteration. Endothelial dysfunction and endothelial–mesenchymal transition may be important, but their precise roles remain obscure. There exists no animal model for CTEPH; therefore, experimentation in the future must include human tissues and clinical data in parallel.

Serial 2-Point Ultrasonography Plus D-Dimer vs Whole-Leg Color-Coded Doppler Ultrasonography for Diagnosing Suspected Symptomatic Deep Vein Thrombosis: A Randomized Controlled Trial

CONTEXT Patients with suspected deep vein thrombosis (DVT) of the lower extremities are usually investigated with ultrasonography either by the proximal veins (2-point ultrasonography) or the entire deep vein system (whole-leg ultrasonography). The latter approach is thought to be better based on its ability to detect isolated calf vein thrombosis; however, it requires skilled operators and is mainly available only during working hours. No randomized comparisons are yet available evaluating the relative values of these 2 strategies. OBJECTIVE To assess if the 2 diagnostic strategies are equivalent for the management of symptomatic outpatients with suspected DVT of the lower extremities. DESIGN, SETTING, AND PATIENTS A prospective, randomized, multicenter study of consecutive symptomatic outpatients (n = 2465) with a first episode of suspected DVT of the lower extremities who were randomized to undergo 2-point or whole-leg ultrasonography. Data were taken from ultrasound laboratories of 14 Italian universities or civic hospitals between January 1, 2003, and December 21, 2006. Patients with normal ultrasound findings were followed up for 3 months, with study completion on March 20, 2007. MAIN OUTCOME MEASURE Objectively confirmed 3-month incidence of symptomatic venous thromboembolism in patients with an initially normal diagnostic workup. RESULTS Of 2465 eligible patients, 345 met 1 or more exclusion criteria and 22 refused to participate; therefore, 2098 patients were randomized to either 2-point (n = 1045) or whole-leg (n = 1053) ultrasonography. Symptomatic venous thromboembolism occurred in 7 of 801 patients (incidence, 0.9%; 95% confidence interval [CI], 0.3%-1.8%) in the 2-point strategy group and in 9 of 763 patients (incidence, 1.2%; 95% CI, 0.5%-2.2%) in the whole-leg strategy group. This met the established equivalence criterion (observed difference, 0.3%;95% CI, -1.4% to 0.8%). CONCLUSION The 2 diagnostic strategies are equivalent when used for the management of symptomatic outpatients with suspected DVT of the lower extremities. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00353093.

The metabolic syndrome and the risk of venous thrombosis: a case–control study

Summary.  Objective: The results of recent studies have suggested that patients with idiopathic venous thromboembolism (VTE) might be at increased risk of asymptomatic atherosclerosis and cardiovascular events. The metabolic syndrome is a cluster of risk factors for atherosclerosis. Its impact on VTE is unknown. Methods: In a case–control study, consecutive patients with objectively confirmed deep vein thrombosis (DVT) and control subjects with objectively excluded DVT underwent clinical assessment for the presence of the metabolic syndrome according to the National Cholesterol Education Program criteria. The presence of known risk factors for DVT was documented. Patients with DVT secondary to cancer were excluded. The prevalence of the metabolic syndrome was compared between patients with idiopathic DVT and controls. Results: We enrolled 93 patients with a first episode of idiopathic DVT and 107 controls. The mean age was 65.1 and 63.7 years, respectively. The metabolic syndrome was diagnosed in 50.5% of patients with idiopathic DVT and in 34.6% of controls [odds ratio (OR) 1.93; 95% confidence interval (CI) 1.05, 3.56]. After adjustment for age, sex, body mass index, and smoke, the metabolic syndrome remained independently associated with idiopathic DVT (OR 1.94; 95% CI 1.04, 3.63). In patients with secondary DVT, the prevalence of the metabolic syndrome was 27%. Conclusions: The metabolic syndrome may play a role in the pathogenesis of idiopathic DVT and may act as link between venous thrombosis and atherosclerosis.

Venous thromboembolism and the risk of subsequent symptomatic atherosclerosis

Summary.  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 1919 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 Coxs 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 1063 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.

High vs. low doses of low-molecular-weight heparin for the treatment of superficial vein thrombosis of the legs: a double-blind, randomized trial.

Summary.  In contrast with extensive information on the management of deep vein thrombosis of the lower extremities, little is known on the most appropriate treatment of the superficial vein thrombosis (SVT). In a multicenter, prospective, controlled, double‐blind, double‐dummy clinical trial, 164 consecutive patients with acute SVT of the great saphenous vein were randomized to receive the s.c. administration of either fixed prophylactic doses (2850 a‐Xa IU) or body‐weight adjusted therapeutic doses of nadroparin once daily for 1 month. The main study outcome was to compare the rate of asymptomatic and symptomatic extension of SVT and/or venous thromboembolic (VTE) complications during a 3‐month follow‐up period. Of the 81 patients randomized to the prophylactic doses, seven [8.6%; 95% confidence interval (CI), 3.5–17.0] developed SVT progression or VTE complications as compared with six of the 83 (7.2%; 95% CI, 2.8–15.1) allocated to the treatment group (absolute difference, 1.4; 96% CI, −6.9 to 9.7; P = 0.74). No patient in either group developed major bleeding. Our findings suggest that therapeutic doses of low‐molecular‐weight heparin, administered for 1 month in patients with SVT of the greater saphenous vein do not improve results obtained by prophylactic doses, administered for the same period, over a 3‐month follow‐up period.

Risk stratification and outcomes in hemodynamically stable patients with acute pulmonary embolism: a prospective, multicentre, cohort study with three months of follow-up

Summary.  Background: The role of risk stratification in normotensive patients with acute pulmonary embolism (PE) is still unclear. Objectives: We evaluated, in these patients, the usefulness of six prognostic markers for predicting in‐hospital adverse events related to PE and 3‐month mortality. Patients/Methods: Two hundred and one consecutive patients with confirmed acute PE and normal blood pressure, who were administered conventional anticoagulation, were recruited in a multicentre prospective cohort study with 3 months of follow‐up. At baseline, they received a comprehensive risk‐evaluation including echocardiographic assessment of right ventricular dysfunction, determination of troponin I, brain natriuretic peptide and D‐dimer, arterial blood gas analysis and a clinical score. Primary outcome of the study was PE‐related in‐hospital death or clinical deterioration. Secondary outcomes were in‐hospital and 3‐month all‐cause mortality. Results: The primary outcome occurred in one patient (0.5%), who died from PE during hospitalization. The in‐hospital and 3‐month all‐cause mortality were 2% and 9%, respectively. None of the prognostic markers was predictive of the primary outcome. Clinical score, troponin I and hypoxemia predicted in‐hospital all‐cause mortality (P = 0.02, 0.01 and < 0.01, respectively). Clinical score (HR, 4.7; 95% CI, 1.9–12.0), D‐dimer (4.8; 1.4–16.3), hypoxemia (5.7; 2.1–15.1) and troponin I (7.5; 2.5–22.7) were predictors of 3‐month all‐cause mortality on univariate analysis. On multivariate analysis clinical score and troponin I remained independently predictive. Conclusions: We did not find prognostic markers useful as predictors of in‐hospital PE‐related adverse events. Clinical score, troponin I and hypoxemia predicted in‐hospital all‐cause mortality. Clinical score and troponin I independently predicted 3‐month all‐cause mortality.

Heart Disease May Be a Risk Factor for Pulmonary Embolism Without Peripheral Deep Venous Thrombosis

Background— Heart diseases increase the risk of arterial embolism; whether they increase the risk of pulmonary embolism without peripheral venous thrombosis is less certain. Methods and Results— We conducted a nationwide, population-based case-control study in Denmark using patients diagnosed with pulmonary embolism and/or deep venous thrombosis between 1980 and 2007. We computed odds ratios to estimate relative risks associating preceding heart disease with pulmonary embolism, pulmonary embolism and deep venous thrombosis, or deep venous thrombosis alone. In this study, 45 282 patients had pulmonary embolism alone, 4680 had pulmonary embolism and deep venous thrombosis, and 59 790 had deep venous thrombosis alone; 541 561 were population controls. Myocardial infarction and heart failure in the preceding 3 months conferred high risks of apparently isolated pulmonary embolism (odds ratio, 43.5 [95% confidence interval (CI), 39.6–47.8] and 32.4 [95% CI, 29.8–35.2], respectively), whereas the risks of combined pulmonary embolism and deep venous thrombosis (19.7 [95% CI, 16.0–24.2] and 22.1 [95% CI, 18.7–26.0], respectively) and deep venous thrombosis alone (9.6 [95% CI, 8.6–10.7] and 12.7 [95% CI, 11.6–13.9], respectively) were lower. Left-sided valvular disease was associated with an odds ratio of 13.5 (95% CI, 11.3–16.1), whereas the odds ratio was 74.6 (95% CI, 28.4–195.8) for right-sided valvular disease. Restricting the analysis to cases diagnosed after 2000 led to lower risk estimates but the same overall pattern. Conclusion— Heart diseases increase the near-term risk for pulmonary embolism not associated with diagnosed peripheral vein thrombosis.

Prevalence, Clinical Features, and Acute Course of Atypical Myocardial Infarction:

Ninety-four consecutive patients (60 men and 34 women; mean age 68.5 ± 11.5 years) with acute myocardial infarction (MI) were investigated ret rospectively, in order to evaluate the prevalence, clinical features, and short- term course of the atypical forms (symptoms other than chest pain). An atypical MI was found in 30 patients, with a prevalence of 32% (95% confidence limits 27-36%). It was most prevalent in women above sixty-five years old (P < 0.05). Abdominal pain, paroxysmal dyspnea, and pulmonary edema were the most frequent symptoms (33%, 17%, 13%, respectively). No differences were ob served between typical and atypical MI in regard to risk factors (hypercholes terolemia, arterial hypertension, diabetes mellitus, cigarette smoking) and history of MI, cerebrovascular disease, peripheral vascular disease, or chronic lung disease. Significantly fewer patients with atypical MI had a history of an gina pectoris (P < 0.05). No differences were observed in regard to previous medication, except for antiarrhythmic drugs, more often used by atypical pa tients (P < 0.05). Location and severity of MI (as judged by ECG and peak levels of creatine kinase in the serum) were similar in both subgroups, as were the complications (34% typical and 50% atypical) and death rate (12.5% and 16.7%, respectively). In conclusion, atypical MI is not less severe than typical. This emphasizes the need for a high suspicion index in many different clinical settings, but particu larly (although not exclusively) in elderly females, in the presence of abdominal pain or otherwise unexplained paroxysmal dyspnea.

Intimal medial thickening of common carotid artery as indicator of coronary artery disease

The authors investigated the relation between coronary atherosclerosis, angiographically detected, and intimal-medial (I-M) thickening of the common carotid artery (CCA), as measured by high-resolution B-mode ultrasound system. They studied 31 patients with coronary artery disease (CAD) and 23 healthy control subjects. I-M thickening of CCAs and atheromatous plaques at the carotid bifurcation were evaluated. A score system was defined (range 0-20) based on the absence or presence of atherosclerotic lesions at common and internal carotid arteries. A coronary angiography score was defined based on the presence of atherosclerotic lesions at nine coronary arterial segments (range 0-36) . The thickness of CCAs (M ±SD) in CAD patients was significantly higher (1.45 ±0.95 mm) than in controls (0.87 ±0.10 mm, P < 0.005), and an I-M thickening of 1.1 mm or more was specific and positively predictive of CAD. A significant positive correlation between coronary and carotid score was observed (P < 0.028, r=0.373). The study suggests that I-M thickening could be helpful for the identification of patients at risk for CAD.