Andrea Piccioli

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

Summary.  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.

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.

Cancer and venous thromboembolism

The evidence of the important two-way clinical correlation between cancer and venous thromboembolism (VTE) dates back to Trousseaus time. Over time it has been established that cancer patients not only exhibit a higher risk of developing VTE when compared with noncancer patients, but also that VTE, especially in its idiopathic presentation, sometimes acts as an epiphenomenon of a hidden cancer, offering possible chances for anticipated diagnosis of the pathology. Research has contributed greatly to the progression of this field through the identification of VTE risk factors in this setting, and through the assessment of the most adequate thromboprophylaxis and treatment modalities as well as secondary prophylaxis management. Anticoagulant drugs appear to be an attractive strategy in cancer treatment because there is growing evidence for their possible benefits in terms of cancer prognosis and patient survival.

Predicting recurrences or major bleeding in cancer patients with venous thromboembolism - Findings from the RIETE Registry

Cancer patients with acute venous thromboembolism (VTE) have an increased incidence of recurrences and bleeding complications while on anticoagulant therapy. Methods RIETE is an ongoing registry of consecutive patients with acute VTE. We tried to identify which cancer patients are at a higher risk for recurrent pulmonary embolism (PE), deep vein thrombosis (DVT) or major bleeding. Up to May 2007, 3,805 cancer patients had been enrolled in RIETE. During the first three months of follow-up after the acute, index VTE event, 90 (2.4%) patients developed recurrent PE, 100 (2.6%) recurrent DVT, 156 (4.1%) had major bleeding. Forty patients (44%) died of the recurrent PE,46 (29%) of bleeding. On multivariate analysis, patients aged <65 years (odds ratio [OR]: 3.0; 95% confidence interval [CI]: 1.9-4.9), with PE at entry (OR: 1.9; 95% CI: 1.2-3.1), or with <3 months from cancer diagnosis to VTE (OR: 2.0; 95% CI: 1.2-3.2) had an increased incidence of recurrent PE. Those aged <65 years (OR: 1.6; 95% CI: 1.0-2.4) or with <3 months from cancer diagnosis (OR: 2.4; 95% CI: 1.5-3.6) had an increased incidence of recurrent DVT. Finally, patients with immobility (OR: 1.8; 95% CI: 1.2-2.7), metastases (OR: 1.6; 95% CI: 1.1-2.3), recent bleeding (OR: 2.4; 95% CI: 1.1-5.1), or with creatinine clearance <30 ml/min (OR: 2.2; 95% CI: 1.5-3.4), had an increased incidence of major bleeding. With some variables available at entry we may identify those cancer patients with VTE at a higher risk for recurrences or major bleeding.

Decision analysis for cancer screening in idiopathic venous thromboembolism

Summary.  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.

Epidemiologic characteristics, management, and outcome of deep venous thrombosis in a tertiary-care hospital: The Brigham and Women's Hospital DVT registry

Entry into clinical trials of treatment for deep venous thrombosis (DVT) involves a screening process that excludes many patients with this condition. Therefore, to obtain a profile of patients with DVT that reflects actual day-to-day clinical practice, we initiated a prospective registry of 150 consecutive patients with DVT at Brigham and Womens Hospital, Boston. We reviewed the medical records of all patients who received a diagnosis of DVT from November 1, 1994 through March 31, 1995 and did not exclude any patients. Of the 150 patients, 120 (80%) were symptomatic and 30 (20%) were asymptomatic. Frequent baseline characteristics included surgery within the preceding 6 months (47%), cancer (26%), and previous venous thromboembolism (23%). DVT was diagnosed by ultrasonography(n = 145), contrast venography (n = 3), or clinical evaluation (in 2 patients who had technically unsatisfactory ultrasound results). Overall, 133 (89%) patients received anticoagulation; 5 (3%) received thrombolysis; and 27 (18%) underwent placement of an inferior vena caval filter. In 3 patients major hemorrhage developed from anticoagulation or thrombolysis. The 3-month mortality rate was 19%, including 10 patients who died during the index hospitalization. In no case was pulmonary embolism thought to be the cause of death. Ten patients had recurrent venous thrombosis during the initial 3 months after diagnosis. The most surprising findings in the DVT registry were the high rates of cancer and surgery, the high rate of filter placement, and the high mortality rate. These registry results differ substantially from findings in randomized controlled trials of DVT treatment.

Venous Thromboembolism as First Manifestation of Cancer

Since Trousseau’s time numerous studies have addressed the relationship between cancer and venous thromboembolism (VTE) providing firm evidence of the increased risk of subsequent clinically overt malignancy during the follow-up of patients with idiopathic VTE. These malignancies are not limited to certain subtypes, but involve virtually all body systems. This knowledge has led to a long-standing debate on the need to screen for occult malignancies patients with idiopathic VTE with no clinical evidence of cancer at the time of the index thrombotic event. In fact the high incidence of newly discovered cancers does not automatically imply that screening is indicated in these patients since it is unknown whether a substantial proportion of cancers can be diagnosed, whether the diagnosed cancers are treatable and what the impact on cancer-related mortality is. Proper clinical trials are being conducted to find an answer to these questions.

Cancer, thrombosis and heparin-induced thrombocytopenia

Venous thromboembolism (VTE) is a common occurrence in patients with cancer, and can sometimes precede the development of the clinical manifestations of cancer. The pathogenetic mechanisms of thrombosis involve a complex interaction between tumour cells and the host haemostatic system, in addition to cancer-related clinical risk factors. The risk of VTE increases in presence of distant metastases. The development of VTE in patients with cancer is a strong predictor of decreased survival. The most common medical situations that make cancer patients at a higher risk of VTE include immobilization and chemotherapy with or without adjuvant hormone therapy. Recent findings suggest that heparin-induced thrombocytopenia (HIT) and HIT-related thrombotic complications may occur in cancer patients with a higher frequency than in patients free from malignancy. Thromboembolism is a well-recognised complication of malignant disease. Clinical manifestations vary from venous thromboembolism (VTE) to disseminated intravascular coagulation, more commonly observed in patients with haematological malignancies and those with widespread metastatic cancer, to arterial embolism, more commonly observed in patients undergoing chemotherapy and in those with non-bacterial thrombotic endocarditis.

Recurrent thromboembolism and major bleeding during oral anticoagulant therapy in patients with solid cancer: findings from the RIETE registry

Following an episode of venous thromboembolism (VTE), the risk of recurrent VTE and major bleeding complications during oral anticoagulant therapy with vitamin K antagonists (VKA) in cancer patients exceeds that observed in patients free from malignancy.[1][1]–[3][2] According to the results of

The long-term risk of cancer in patients with a first episode of venous thromboembolism

Summary.  Background: In patients with venous thromboembolism (VTE), 15–20% will have prevalent cancer when VTE is diagnosed but little is known about such patients’ long‐term risk, time course and predictors of new cancer. Patients and methods: We studied an inception cohort of patients with a first VTE who were not diagnosed with cancer within 3 months after VTE and who had follow‐up for up to 120 months. We determined the annual risk for a new cancer [number of events and 95% confidence interval (CI)] per 100 person‐years in all patients and in those with unprovoked VTE and identified predictors for new cancer. Results: We studied 1852 patients with VTE who received anticoagulant therapy for 12 months (mean) and were followed for 4.2 years (mean). During follow‐up, there were 105 (5.7%) patients diagnosed with new cancer during the period after the initial 3 months from diagnosis, for an annual risk of 1.32 (CI, 1.09–1.60) per 100 person‐years. The risk for new cancer appeared uniform over time. The annual risk for new cancer was more than 2‐fold higher in patients presenting with unprovoked compared with those with provoked VTE [1.76 (CI, 1.39–2.20) vs. 0.83 (CI, 0.58–1.16) per 100 person‐years; P < 0.001]. Clinical predictors for new cancer were increasing age [hazard ratio (HR), 1.23; CI, 1.05–1.44] and unprovoked VTE (HR, 1.86; CI, 1.21–2.87). Conclusion: In patients with a first VTE and without prevalent cancer, the risk for new cancer is about 1–2% per year, appears to be uniform over time, and is higher in patients with unprovoked VTE and those with advanced age.