Cecilia Becattini

Cardiovascular Risk Factors and Venous Thromboembolism A Meta-Analysis

Background— The concept that venous thromboembolism (VTE) and atherosclerosis are 2 completely distinct entities has recently been challenged because patients with VTE have more asymptomatic atherosclerosis and more cardiovascular events than control subjects. We performed a meta-analysis to assess the association between cardiovascular risk factors and VTE. Methods and Results— Medline and EMBASE databases were searched to identify studies that evaluated the prevalence of major cardiovascular risk factors in VTE patients and control subjects. Studies were selected using a priori defined criteria, and each study was reviewed by 2 authors who abstracted data on study characteristics, study quality, and outcomes. Odds ratios or weighted means and 95% confidence intervals (CIs) were then calculated and pooled using a random-effects model. Statistical heterogeneity was evaluated through the use of &khgr;2 and I2 statistics. Twenty-one case-control and cohort studies with a total of 63 552 patients met the inclusion criteria. Compared with control subjects, the risk of VTE was 2.33 for obesity (95% CI, 1.68 to 3.24), 1.51 for hypertension (95% CI, 1.23 to 1.85), 1.42 for diabetes mellitus (95% CI, 1.12 to 1.77), 1.18 for smoking (95% CI, 0.95 to 1.46), and 1.16 for hypercholesterolemia (95% CI, 0.67 to 2.02). Weighted mean high-density lipoprotein cholesterol levels were significantly lower in VTE patients, whereas no difference was observed for total and low-density lipoprotein cholesterol levels. Significant heterogeneity among studies was present in all subgroups except for the diabetes mellitus subgroup. Higher-quality studies were more homogeneous, and significant associations remained unchanged. Conclusions— Cardiovascular risk factors are associated with VTE. This association is clinically relevant with respect to individual screening, risk factor modification, and primary and secondary prevention of VTE. Prospective studies should further investigate the underlying mechanisms of this relationship.

Prognostic Value of Troponins in Acute Pulmonary Embolism A Meta-Analysis

Background— Whether elevated serum troponin levels identify patients with acute pulmonary embolism at high risk of short-term mortality or adverse outcome is undefined. Methods and Results— We performed a meta-analysis of studies in patients with acute pulmonary embolism to assess the prognostic value of elevated troponin levels for short-term death and adverse outcome events (composite of death and any of the following: shock, need for thrombolysis, endotracheal intubation, catecholamine infusion, cardiopulmonary resuscitation, or recurrent pulmonary embolism). Unrestricted searches of MEDLINE and EMBASE bibliographic databases from January 1998 to November 2006 were performed using the terms “troponin” and “pulmonary embolism.” Additionally, review articles and bibliographies were manually searched. Cohort studies were included if they had used cardiac-specific troponin assays and had reported on short-term death or adverse outcome events. A random-effects model was used to pool study results; funnel-plot inspection was done to evaluate publication bias; and I2 testing was used to test for heterogeneity. Data from 20 studies (1985 patients) were included in the analysis. Overall, 122 of 618 patients with elevated troponin levels died (19.7%; 95% confidence interval [CI], 16.6 to 22.8) compared with 51 of 1367 with normal troponin levels (3.7%; 95% CI, 2.7 to 4.7). Elevated troponin levels were significantly associated with short-term mortality (odds ratio [OR], 5.24; 95% CI, 3.28 to 8.38), with death resulting from pulmonary embolism (OR, 9.44; 95% CI, 4.14 to 21.49), and with adverse outcome events (OR, 7.03; 95% CI, 2.42 to 20.43). Elevated troponin levels were associated with a high mortality in the subgroup of hemodynamically stable patients (OR, 5.90; 95% CI, 2.68 to 12.95). Results were consistent for troponin I or T and prospective or retrospective studies. Conclusions— Elevated troponin levels identify patients with acute pulmonary embolism at high risk of short-term death and adverse outcome events.

Fibrinolysis for patients with intermediate-risk pulmonary embolism

BACKGROUND The role of fibrinolytic therapy in patients with intermediate-risk pulmonary embolism is controversial. METHODS In a randomized, double-blind trial, we compared tenecteplase plus heparin with placebo plus heparin in normotensive patients with intermediate-risk pulmonary embolism. Eligible patients had right ventricular dysfunction on echocardiography or computed tomography, as well as myocardial injury as indicated by a positive test for cardiac troponin I or troponin T. The primary outcome was death or hemodynamic decompensation (or collapse) within 7 days after randomization. The main safety outcomes were major extracranial bleeding and ischemic or hemorrhagic stroke within 7 days after randomization. RESULTS Of 1006 patients who underwent randomization, 1005 were included in the intention-to-treat analysis. Death or hemodynamic decompensation occurred in 13 of 506 patients (2.6%) in the tenecteplase group as compared with 28 of 499 (5.6%) in the placebo group (odds ratio, 0.44; 95% confidence interval, 0.23 to 0.87; P=0.02). Between randomization and day 7, a total of 6 patients (1.2%) in the tenecteplase group and 9 (1.8%) in the placebo group died (P=0.42). Extracranial bleeding occurred in 32 patients (6.3%) in the tenecteplase group and 6 patients (1.2%) in the placebo group (P<0.001). Stroke occurred in 12 patients (2.4%) in the tenecteplase group and was hemorrhagic in 10 patients; 1 patient (0.2%) in the placebo group had a stroke, which was hemorrhagic (P=0.003). By day 30, a total of 12 patients (2.4%) in the tenecteplase group and 16 patients (3.2%) in the placebo group had died (P=0.42). CONCLUSIONS In patients with intermediate-risk pulmonary embolism, fibrinolytic therapy prevented hemodynamic decompensation but increased the risk of major hemorrhage and stroke. (Funded by the Programme Hospitalier de Recherche Clinique in France and others; PEITHO EudraCT number, 2006-005328-18; ClinicalTrials.gov number, NCT00639743.).

Aspirin for Preventing the Recurrence of Venous Thromboembolism

BACKGROUND About 20% of patients with unprovoked venous thromboembolism have a recurrence within 2 years after the withdrawal of oral anticoagulant therapy. Extending anticoagulation prevents recurrences but is associated with increased bleeding. The benefit of aspirin for the prevention of recurrent venous thromboembolism is unknown. METHODS In this multicenter, investigator-initiated, double-blind study, patients with first-ever unprovoked venous thromboembolism who had completed 6 to 18 months of oral anticoagulant treatment were randomly assigned to aspirin, 100 mg daily, or placebo for 2 years, with the option of extending the study treatment. The primary efficacy outcome was recurrence of venous thromboembolism, and major bleeding was the primary safety outcome. RESULTS Venous thromboembolism recurred in 28 of the 205 patients who received aspirin and in 43 of the 197 patients who received placebo (6.6% vs. 11.2% per year; hazard ratio, 0.58; 95% confidence interval [CI], 0.36 to 0.93) (median study period, 24.6 months). During a median treatment period of 23.9 months, 23 patients taking aspirin and 39 taking placebo had a recurrence (5.9% vs. 11.0% per year; hazard ratio, 0.55; 95% CI, 0.33 to 0.92). One patient in each treatment group had a major bleeding episode. Adverse events were similar in the two groups. CONCLUSIONS Aspirin reduced the risk of recurrence when given to patients with unprovoked venous thromboembolism who had discontinued anticoagulant treatment, with no apparent increase in the risk of major bleeding. (Funded by the University of Perugia and others; WARFASA ClinicalTrials.gov number, NCT00222677.).

Extended Oral Anticoagulant Therapy after a First Episode of Pulmonary Embolism

Context Optimal duration of anticoagulation after pulmonary embolism is uncertain, but physicians commonly prescribe 3 months of therapy for patients with transient risk factors for thrombosis and 6 months for patients with continuing or no known risk factors. Contribution After 3 months of successful anticoagulation, 326 patients were randomly assigned to stop therapy immediately or extend therapy to 6 months or 1 year. Regardless of duration of anticoagulation, 33 patients had recurrent thromboembolic events but only one event occurred in a patient still receiving therapy. Implications Extending the duration of anticoagulation does not seem to protect against recurrence once therapy has been discontinued. Patients at high risk for recurrence may require indefinite anticoagulation. The Editors Recent studies have shown that patients with a first episode of venous thromboembolism are protected from a recurrence while they are receiving anticoagulant treatment (1, 2). On the basis of differences in the risk for recurrence when anticoagulant treatment is discontinued, different durations of oral anticoagulation are currently recommended in different patient categories. A shorter period of anticoagulation is recommended for patients with venous thromboembolism associated with transient risk factors than for patients with idiopathic venous thromboembolism or venous thromboembolism associated with continuing risk factors (3-5). Current recommendations on the duration of oral anticoagulant treatment for venous thromboembolism are based on studies that mostly included patients presenting with deep venous thrombosis (1, 2, 5-7). Only a limited proportion of patients included in these studies presented with pulmonary embolism. Deep venous thrombosis and pulmonary embolism are generally considered to be two clinical manifestations of the same disease. However, patients presenting with pulmonary embolism are reported to have a higher incidence of fatal recurrent venous thromboembolism than patients presenting with deep venous thrombosis (8, 9). We performed a multicenter randomized trial to evaluate the long-term clinical benefit of extending a 3-month course of oral anticoagulant therapy to 6 months (pulmonary embolism associated with temporary risk factors) or to 1 year (idiopathic pulmonary embolism) in patients with a first episode of pulmonary embolism. The primary outcome of the study was symptomatic, objectively confirmed recurrence of venous thromboembolism. Methods Study Patients Consecutive patients ranging from 15 to 85 years of age with a first episode of symptomatic, objectively confirmed pulmonary embolism were included in the study if they had completed 3 uninterrupted months of oral anticoagulant therapy without having a recurrence or bleeding. The diagnosis of pulmonary embolism was confirmed by pulmonary angiography or spiral computed tomography or by a lung scan indicating a high probability of pulmonary embolism or a lung scan indicating an intermediate probability of pulmonary embolism in a patient with objectively diagnosed deep venous thrombosis. Study patients were categorized as having idiopathic pulmonary embolism or pulmonary embolism associated with transient risk factors. Idiopathic pulmonary embolism was defined as pulmonary embolism occurring in the absence of known cancer, known thrombophilia, or any transient risk factor for venous thromboembolism. Pulmonary embolism associated with transient risk factors was pulmonary embolism occurring after recent trauma with or without bone fracture, recent surgery or childbirth, or prolonged immobilization (that is, lasting >7 days), or occurring during the use of oral contraceptives or pregnancy. Patients with pulmonary embolism associated with permanent risk factors (known cancer or known thrombophilia) were excluded from the study. Systematic screening for occult cancer or thrombophilia was not performed before enrollment. Patients who required prolonged anticoagulant therapy for reasons other than venous thromboembolism were excluded from the study, as were patients with major psychiatric disorders, patients with a life expectancy shorter than 2 years, those who could not return for the follow-up visits, and those who declined to participate. The institutional review boards of the participating hospitals approved the study; all patients gave informed consent. Study Design and Interventions The Warfarin Optimal Duration Italian Trial in patients with pulmonary embolism (WODIT-PE) was a multicenter randomized, open trial with independent, blinded assessment of the outcome events. The study was designed to evaluate the clinical benefit of extending the 3-month course of oral anticoagulant therapy after a first episode of pulmonary embolism. Patients who had completed 3 months of warfarin or acenocumarol therapy were randomly assigned to discontinue anticoagulation or to continue it for 3 additional months (pulmonary embolism associated with transient risk factors) or 9 additional months (idiopathic pulmonary embolism). Randomization was performed centrally in permuted blocks of six. The dose of warfarin or acenocumarol was adjusted to achieve a target international normalized ratio (INR) between 2.0 and 3.0. The therapy was monitored in anticoagulant clinics associated with the study centers, all in Italy. Outcome Measures The primary outcome of the study was the recurrence of symptomatic, objectively confirmed venous thromboembolism after the initial 3 months of anticoagulation. The secondary outcome was the cumulative incidence of adverse outcome events (recurrence of venous thromboembolism, death, or major bleeding). The criteria for the diagnosis of recurrence of pulmonary embolism were a new filling defect revealed by pulmonary angiography or spiral computed tomography or a new high-probability perfusion defect revealed by ventilation-perfusion lung scan. Sudden, otherwise unexplained death was also considered a recurrence of pulmonary embolism. The criteria for the diagnosis of deep venous thrombosis as an outcome for recurrence of venous thromboembolism in patients without deep venous thrombosis at baseline were the presence of a noncompressible proximal vein on ultrasonography or an intraluminal filling defect on venography. In patients with deep venous thrombosis at baseline, the criteria for the diagnosis of recurrent deep venous thrombosis were abnormal results on compression ultrasonography (proximal veins) or venography in the contralateral leg or, in the ipsilateral leg, an extension of an intraluminal filling defect on venography; a newly noncompressible venous segment; or an increase of 4 mm or more in the diameter of the thrombus (proximal veins) on ultrasonography (10). Bleeding was defined as major if it was clinically overt and associated with either a decrease in the hemoglobin level of at least 20 g/L or the need to transfuse two or more units of red blood cells, if it was retroperitoneal or intracranial, if it warranted the permanent discontinuation of therapy with the study drug, or if it required rehospitalization. Deaths were classified as the result of pulmonary embolism, bleeding, or another identifiable cause or as unexplained. All suspected outcome events (recurrent thromboembolism and bleeding episodes) and all deaths were reviewed centrally by an independent, external adjudication committee whose members were unaware of the treatment group assignments. Follow-up Patients were instructed to return for follow-up visits at 3, 6, and 12 months after randomization and every 6 months thereafter until the completion of the study. Patients were asked to return to the study center immediately if symptoms suggestive of recurrent venous thromboembolism or bleeding developed. For all patients who died during the follow-up period, the date and cause of death were documented. We attempted to gain permission for autopsies of all patients in whom pulmonary embolism could not be excluded as the cause of death. Statistical Analysis The primary analysis of efficacy was a comparison of the rates of symptomatic, objectively confirmed recurrence of venous thromboembolism in the two treatment groups. The analysis was performed on an intention-to-treat basis. It was assumed that the rate of recurrence of venous thromboembolism would be 12% in patients assigned to the discontinue oral anticoagulant therapy in the 2 years after discontinuation. We also assumed that the prolongation of oral anticoagulant therapy would produce a 50% reduction in the risk for recurrence. Given these assumptions, we needed 312 patients in each group to detect a difference of this magnitude between groups with a power of 80% and a type I error rate of 5%. To avoid the exposure of the study patients to an ineffective or dangerous therapeutic regimen, one prespecified interim analysis of efficacy and safety was planned after we randomly assigned 50% of planned patients. The following criteria for stopping the trial were defined a priori: an overall rate of recurrence of thromboembolic events lower than 7.5%, an unequivocal reduction in the rate of recurrent venous thromboembolism in the patients assigned to continue therapy (P < 0.001 by a one-sided test), a risk for recurrence in the continued therapy group that was less than 25% lower than that in the group assigned to discontinue therapy, or a rate of major bleeding higher than 5% in the continued therapy group. The cumulative hazard of recurrent venous thromboembolism was calculated according to the Kaplan-Meier life-table method (11). Rates of recurrence in the two groups were compared with the use of the log-rank test (12). Results Patients Patients were recruited between January 1997 and December 2000 when, after 326 patients were included, the results of the interim analysis showed a difference of less than 25% in the risk for recurrent venous thromboembolism between the two treatment groups. At the time of

Acute Pulmonary Embolism

Pulmonary embolism should be suspected in all patients who present with new or worsening dyspnea, chest pain, or sustained hypotension without a clear alternative cause. This review focuses on the optimal diagnostic strategy and management, according to the clinical presentation.

Direct Oral Anticoagulants in Patients With VTE and Cancer

BACKGROUND Direct oral anticoagulants (DOAs) have been shown to be as effective and at least as safe as conventional anticoagulation for the prevention of recurrences in patients with VTE. Whether this is the case in patients with cancer-associated VTE remains undefined. METHODS We performed a meta-analysis of randomized controlled trials with the aim of assessing the efficacy and safety of DOAs in patients with VTE and cancer. MEDLINE, EMBASE, and CENTRAL were searched up to December 2013 with no language restriction. The primary outcome of the analysis was recurrent VTE. Data on major bleeding (MB) and clinically relevant nonmajor bleeding were analyzed. Data were pooled and compared by ORs and 95% CIs. RESULTS Overall, 10 studies comparing DOAs with conventional anticoagulation for treatment of VTE including patients with cancer were included in the review. Six studies were included in the meta-analysis (two with dabigatran, two with rivaroxaban, one with edoxaban, and one with apixaban), accounting for a total of 1,132 patients. VTE recurred in 23 of 595 (3.9%) and in 32 of 537 (6.0%) patients with cancer treated with DOAs and conventional treatment, respectively (OR, 0.63; 95% CI, 0.37-1.10; I2, 0%). MB occurred in 3.2% and 4.2% of patients receiving DOAs and conventional treatment, respectively (OR, 0.77; 95% CI, 0.41-1.44; I2, 0%). CONCLUSIONS DOAs seem to be as effective and safe as conventional treatment for the prevention of VTE in patients with cancer. Further clinical trials in patients with cancer-associated VTE should be performed to confirm these results.

Multidetector computed tomography for acute pulmonary embolism: diagnosis and risk stratification in a single test

AIMS In patients with acute pulmonary embolism (PE), right ventricular dysfunction at echocardiography is associated with increased in-hospital mortality. The aims of this study in patients with acute PE were to identify a sensitive and simple criterion for right ventricular dysfunction at multidetector computed tomography (MDCT) using echocardiography as the reference standard and to evaluate the predictive value of the identified MDCT criterion for in-hospital death or clinical deterioration. METHODS AND RESULTS Right ventricular dysfunction at MDCT was defined as the right-to-left ventricular dimensional ratio and was centrally assessed by a panel unaware of clinical and echocardiographic data. A right-to-left ventricular dimensional ratio ≥0.9 at MDCT had a 92% sensitivity for right ventricular dysfunction [95% confidence interval (CI) 88-96]. Overall, 457 patients were included in the outcome study: 303 had right ventricular dysfunction at MDCT. In-hospital death or clinical deterioration occurred in 44 patients with and in 8 patients without right ventricular dysfunction at MDCT (14.5 vs. 5.2%; P< 0.004). The negative predictive value of right ventricular dysfunction for death due to PE was 100% (95% CI 98-100). Right ventricular dysfunction at MDCT was an independent predictor for in-hospital death or clinical deterioration in the overall population [hazard ratio (HR) 3.5, 95% CI 1.6-7.7; P= 0.002] and in haemodynamically stable patients (HR 3.8, 95% CI 1.3-10.9; P= 0.007). CONCLUSION In patients with acute PE, MDCT might be used as a single procedure for diagnosis and risk stratification. Patients without right ventricular dysfunction at MDCT have a low risk of in-hospital adverse outcome.

Prevalence and Clinical History of Incidental, Asymptomatic Pulmonary Embolism: A Meta-Analysis

CONTEXT Recently, there has been an increasing number of reports of incidental pulmonary embolism (PE) in patients undergoing chest computer tomography (CT) for reasons other than the research of suspected PE. Natural history of incidental PE remains unclear. OBJECTIVES To estimate the prevalence of incidental PE, to assess potential factors associated with incidental PE, and to evaluated its clinical history. DATA SOURCES MEDLINE, EMBASE databases (up to January 2009). STUDY SELECTION Studies were included if the prevalence of incidental PE was assessed using CT scanning. DATA EXTRACTION The prevalence of incidental PE in these patients was documented. Separate data for inpatients and outpatients and according to the reason for CT scanning were collected. Weighted mean proportion of the prevalence of incidental PE was calculated. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated to test the association with potential predictors of incidental PE. RESULTS Twelve studies for a total of more than 10 thousand patients were included. The weighted mean prevalence of incidental PE was 2.6% (95% CI 1.9, 3.4). Hospitalization at the time of CT scanning and the presence of cancer were associated with a significantly increased risk of incidental PE (OR 4.27 and OR 1.80 respectively). CONCLUSIONS The prevalence of incidental PE is clinically relevant. Future studies are necessary to properly evaluate the clinical history of these patients.

Aspirin for the Prevention of Recurrent Venous Thromboembolism: The INSPIRE Collaboration

Background— In patients with a first unprovoked venous thromboembolism (VTE) the risk of recurrent VTE remains high after anticoagulant treatment is discontinued. The Aspirin for the Prevention of Recurrent Venous Thromboembolism (the Warfarin and Aspirin [WARFASA]) and the Aspirin to Prevent Recurrent Venous Thromboembolism (ASPIRE) trials showed that aspirin reduces this risk, but they were not individually powered to detect treatment effects for particular outcomes or subgroups. Methods and Results— An individual patient data analysis of these trials was planned, before their results were known, to assess the effect of aspirin versus placebo on recurrent VTE, major vascular events (recurrent VTE, myocardial infarction, stroke, and cardiovascular disease death) and bleeding, overall and within predefined subgroups. The primary analysis, for VTE, was by intention to treat using time-to-event data. Of 1224 patients, 193 had recurrent VTE over 30.4 months’ median follow-up. Aspirin reduced recurrent VTE (7.5%/yr versus 5.1%/yr; hazard ratio [HR], 0.68; 95% confidence interval [CI], 0.51–0.90; P=0.008), including both deep-vein thrombosis (HR, 0.66; 95% CI, 0.47–0.92; P=0.01) and pulmonary embolism (HR, 0.66; 95% CI, 0.41–1.06; P=0.08). Aspirin reduced major vascular events (8.7%/yr versus 5.7%/yr; HR, 0.66; 95% CI, 0.50–0.86; P=0.002). The major bleeding rate was low (0.4%/yr for placebo and 0.5%/yr for aspirin). After adjustment for treatment adherence, recurrent VTE was reduced by 42% (HR, 0.58; 95% CI, 0.40–0.85; P=0.005). Prespecified subgroup analyses indicate similar relative, but larger absolute, risk reductions in men and older patients. Conclusions— Aspirin after anticoagulant treatment reduces the overall risk of recurrence by more than a third in a broad cross-section of patients with a first unprovoked VTE, without significantly increasing the risk of bleeding. Clinical Trial Registration— URL: www.anzctr.org.au. Unique identifier: ACTRN12611000684921.