M. Monreal

Fatal bleeding in patients receiving anticoagulant therapy for venous thromboembolism: findings from the RIETE registry

Summary.u2002 Background:u2002Fatal bleeding is a serious consequence of anticoagulant therapy, but factors associated with fatal bleeding during the first 3u2003months of treatment of venous thromboembolism (VTE) are uncertain. Methods:u2002Using data from RIETE, an ongoing registry of consecutive patients with acute VTE, we assessed risk factors for fatal bleeding among all patients. We then used this information to derive a clinical model that would stratify a patient’s risk of fatal bleeding during the first 3u2003months of treatment. Results:u2002Of 24u2003395 patients, 546 (2.24%) had a major bleed and 135 (0.55%) had a fatal bleed. The gastrointestinal tract was the most common site (40% of fatal bleeds), followed by intracranial bleeding (25%). Fatal bleeding was independently associated with the following factors at the time of VTE diagnosis: age >75u2003years (OR, 2.16), metastatic cancer (OR, 3.80), immobility ≥u20034u2003days (OR, 1.99), a major bleed within the past 30u2003days (OR, 2.64), an abnormal prothrombin time (OR, 2.09), a platelet count <u2003100u2003×u2003109u2003L−1 (OR, 2.23), creatinine clearance <u200330u2003mLu2003min−1 (OR, 2.27), anemia (OR, 1.54), and distal deep vein thrombosis (OR, 0.39). INR at the time of bleeding is not known. A clinical prediction rule for risk of fatal bleeding that included nine baseline factors was derived. Fatal bleeding occurred in 0.16% (95% CI, 0.11–0.23) of the low‐risk, 1.06% (95% CI, 0.85–1.30) of the moderate‐risk, and 4.24% (95% CI, 2.76–6.27) of the high‐risk category. Conclusions:u2002Patient characteristics and laboratory variables can identify patients at high risk for fatal bleeding during treatment of VTE.

Treatment of venous thromboembolism in cancer patients with dalteparin for up to 12 months: the DALTECAN Study

Treatment of venous thromboembolism (VTE) in patients with cancer has a high rate of recurrence and bleeding complications. Guidelines recommend low‐molecular‐weight heparin (LMWH) for at least 3–6 months and possibly indefinitely for patients with active malignancy. There are, however, few data supporting treatment with LMWH beyond 6 months. The primary aim of the DALTECAN study (NCT00942968) was to determine the safety of dalteparin between 6 and 12 months in cancer‐associated VTE.

The influence of extreme body weight on clinical outcome of patients with venous thromboembolism: findings from a prospective registry (RIETE).

Summary.u2002 Background:u2002Data evaluating the safety of using weight‐based dosing of low‐molecular‐weight heparin (LMWH) in either underweight or obese patients with venous thromboembolism (VTE) are limited. Thus, recommendations based on evidence from clinical trials might not be suitable for patients with extreme body weight. Patients and Methods:u2002Patients with objectively confirmed, symptomatic acute VTE are consecutively enrolled into the Registro Informatizado de la Enfermedad TromboEmbólica (RIETE) registry. For this analysis, data from patients in the following ranges of body weight were examined: <50, 50–100, and >100u2003kg. Patient characteristics, underlying conditions, treatment schedules and clinical outcomes during the first 15u2003days of treatment were compared. Results:u2002As of August 2004, 8845 patients with acute VTE were enrolled from 94 participating centers. Of these, 169 (1.9%) weighed <50u2003kg, 8382 (95%) weighed 50–100u2003kg and 294 (3.3%) weighed >100u2003kg. Patients weighing <50u2003kg were more commonly females, were taking non‐steriodal antiinflammatory drugs (NSAIDs), and had severe underlying diseases more often than patients weighing 50–100u2003kg. Their incidence of overall bleeding complications was significantly higher than in patients weighing 50–100u2003kg (odds ratio 2.2; 95% CI: 1.2–4.0). Patients weighing >100u2003kg were younger, most commonly males, and had cancer less often than those weighing 50–100u2003kg. Incidences of recurrent VTE, fatal pulmonary embolism or major bleeding complications were similar in both groups. Conclusions:u2002Patients with VTE weighing <50u2003kg have a significantly higher rate of bleeding complications. The clinical outcome of patients weighing over 100u2003kg was not significantly different from that in patients weighing 50–100u2003kg.

Edoxaban for treatment of venous thromboembolism in patients with cancer: Rationale and design of the hokusai VTE-cancer study

Direct oral anticoagulants may be effective and safe for treatment of venous thromboembolism (VTE) in cancer patients, but they have not been compared with low-molecular-weight heparin (LMWH), the current recommended treatment for these patients. The Hokusai VTE-cancer study is a randomised, open-label, clinical trial to evaluate whether edoxaban, an oral factor Xa inhibitor, is non-inferior to LMWH for treatment of VTE in patients with cancer. We present the rationale and some design features of the study. One such feature is the composite primary outcome of recurrent VTE and major bleeding during a 12-month study period. These two complications occur frequently in cancer patients receiving anticoagulant treatment and have a significant impact. The evaluation beyond six months will fill the current gap in the evidence base for the long-term treatment of these patients. Based on the observation that the risk of recurrent VTE in patients with active cancer is similar to that in those with a history of cancer, the Hokusai VTE-cancer study will enrol patients if whose cancer was diagnosed within the past two years. In addition, patients with incidental VTE are eligible because their risk of recurrent VTE is similar to that in patients with symptomatic disease. The unique design features of the Hokusai VTE-cancer study should lead to enrolment of a broad spectrum of cancer patients with VTE who could benefit from oral anticoagulant treatment.

Comparison of the clinical history of symptomatic isolated distal deep‐vein thrombosis vs. proximal deep vein thrombosis in 11 086 patients

Background:u2002The clinical significance of symptomatic isolated distal deep vein thrombosis (DVT) is uncertain. Consequently, this leads to important disparities in its management. Objective:u2002To examine the clinical history of isolated distal DVT and to compare it with that of proximal DVT. Methods:u2002Using data from the international, prospective, RIETE registry on patients with confirmed symptomatic venous thromboembolism (VTE), we compared the risk factors and 3‐month outcome in patients with isolated distal DVT vs. proximal DVT. Results:u2002Eleven thousand and eighty‐six patients with symptomatic DVT, but without pulmonary embolism, were included between 2001 and 2008; 1921 (17.3%) exhibited isolated distal DVT. Anticoagulant treatment was received by 89.1% (1680/1885) of isolated distal DVT and 91.8% (7911/8613) of proximal DVT patients for the entire follow‐up period. Isolated distal DVTs were more associated with transient risk factors (i.e. recent travel, hospitalization, recent surgery), whereas proximal DVTs were more associated with chronic states (i.e. ≥75u2003years or with active cancer). At 3u2003months, major bleeding rate was lower in patients with isolated distal DVT (1.0% vs. 2.2%, Pu2003<u20030.01), whereas VTE recurrence rate was equivalent (2.0% vs. 2.7%, Pu2003=u20030.07). The mortality rate was lower in patients with isolated distal DVT (2.7% vs. 7.5%; Pu2003<u20030.001); this was mainly due to a lower rate of non‐VTE‐related deaths (2.2% vs. 6.3%; Pu2003<u20030.001). Active cancer was the main predictive factor of death in patients with isolated distal DVT. Conclusions:u2002Proximal and isolated distal DVT patients differ in terms of risk factors and clinical outcomes, suggesting different populations. In the short term, the life expectancy of patients with isolated distal DVT depended chiefly on their cancer status.

Adverse effects of three different forms of heparin therapy: thrombocytopenia, increased transaminases, and hyperkalaemia

SummaryA prospective study has been made of the incidence of changes in transaminase levels, hyperkalaemia and thrombocytopenia in three groups of patients: 89 consecutive patients with venous thrombosis receiving therapeutic heparinization, 49 patients admitted because of hip fracture and receiving prophylactic low-dose conventional heparin, and 43 patients admitted because of hip fracture and randomly allocated to receive low molecular weight heparin.Laboratory measurements were made on admission and 8 days after commencing heparin. Only two patients on high-dose heparin developed thrombocytopenia. Increased transaminases were frequent with conventional heparin (18% and 32% of patients on high-dose heparin developed abnormal AsT and AlT values, respectively compared with 14% and 17% patients on low dose therapy). In contrast, only one patient on low molecular weight heparin developed abnormal AlT activity. Hyperkalaemia was uncommon in patients on any form of heparin therapy, and severe hyperkalaemia occurred in only one patient.

Real-Time Ultrasound for Diagnosis of Symptomatic Venous Thrombosis and for Screening of Patients at Risk: Correlation with Ascending Conventional Venography

This is a prospective study of 108 patients in two distinct groups undergoing real-time ultrasonography (US) and ascending conventional venography within the same day. The two patient groups consisted of the following: Those patients evaluated because of suspicion of deep venous thrombosis of lower limbs (69 patients) and those at high risk for venous thrombosis (19 patients with a recent hip fracture, 20 with a suspected pulmonary embolism). In the diagnosis group 48 patients had venographic evidence of thrombosis. The predictive value of abnormal findings from real-time US was 97%, and that of a negative study was 75%. Thus, real-time US may have a role as a diagnostic procedure, to be fol lowed by x-ray venography in patients with negative US results. By contrast, real-time US is far less sensitive as a screening test in patients without clinical evidence of thrombosis. Only 3 of 9 patients with thrombosis were detected, with a 50% sensitivity for proximal vein thrombosis. Therefore, the use of real-time US for screening high-risk patients must be limited to very high risk patients in whom other tests are ineffective (as in hip surgery).

Venous thromboembolism during pregnancy, postpartum or during contraceptive use Findings from the RIETE Registry

Venous thromboembolism (VTE) is a leading cause of maternal death during pregnancy or postpartum, and in women using hormonal contraceptives. However, important issues concerning its natural history and therapy remain unsolved, and most of the protocols for treatment of VTE in this patient population are based on data extrapolated from other populations. RIETE is an ongoing registry of consecutive patients with objectively confirmed, symptomatic, acute VTE. We examined the clinical characteristics and three-month outcome of all enrolled women with pregnancy, postpartum or using hormonal contraceptives. As of December 2008, 173 pregnant women, 135 postpartum, and 798 contraceptive users were enrolled. Of these, 438 (40%) presented with pulmonary embolism (PE) and 668 with deep-vein thrombosis (DVT). Most women with acute PE had dyspnea (72%) or chest pain (75%), but only 2.0% had hypoxaemia. During the three-month study period, five women (0.45%; 95% CI: 0.17-1.00) died (3 had fatal PE), 13 (1.18%; 95% CI: 0.66-1.95) had VTE recurrences, and seven (0.63%; 95% CI: 0.28-1.25) major bleeding. Two of the three women with fatal PE died during the first few hours after arriving at the emergency ward, with no time to start any therapy. The outcome of pregnant or postpartum women with VTE is similar to that in contraceptive users, even though the treatment is different. The non-specific nature of PE signs may have caused some delay in PE diagnosis.

Body mass index and mortality in patients with acute venous thromboembolism: findings from the RIETE registry

Summary.u2002 Background:u2002There is little information on the influence of body mass index (BMI) on mortality in patients with acute venous thromboembolism (VTE). Patients and methods:u2002RIETE is an ongoing registry of consecutive patients with symptomatic, objectively confirmed, acute VTE. We examined the association between BMI and mortality during the first 3u2003months of therapy. Results:u2002Of the 10u2003114 patients enrolled as of March 2007: 153 (1.5%) were underweight (BMIu2003<u200318.5); 2882 (28%) had a normal weight (BMI 18.5–24.9); 4327 (43%) were overweight (BMI 25.0–30); and 2752 (27%) were obese (BMIu2003>u200330). The overweight and obese patients were significantly older, and were less likely to have had cancer, recent immobility or renal insufficiency. After 3u2003months of therapy their death rates were 28%, 12%, 6.2% and 4.2%, respectively. In multivariate analysis, the relative risks for death after adjusting for confounding variables including age, cancer, renal insufficiency or idiopathic VTE were: 2.1 (95% CI, 1.5–2.7); 1.0 (reference); 0.6 (95% CI, 0.5–0.7); and 0.5 (95% CI, 0.4–0.6), respectively. The rates of fatal pulmonary embolism (2.0%, 2.1%, 1.2% and 0.8%, respectively) also decreased with BMI. There were no differences in the rate of fatal bleeding, but patients who were underweight had an increased incidence of major bleeding complications (7.2% vs. 2.7%; odds ratio, 2.7; 95% CI, 1.4–5.1). Conclusions:u2002Obese patients with acute VTE have less than half the mortality rate when compared with normal BMI patients. This reduction in mortality rates was consistent among all subgroups and persisted after multivariate adjustment.

Acute venous thromboembolism in patients with recent major bleeding. The influence of the site of bleeding and the time elapsed on outcome

Summary.u2002 Background: Patients with major bleeding who subsequently develop clinically apparent venous thromboembolism (VTE) present a particularly difficult therapeutic dilemma. Methods: RIETE is a prospective registry of consecutive patients with symptomatic, objectively confirmed, acute VTE. We retrospectively studied those who had experienced recent major bleeding (<u200330u2003days prior to VTE) to assess the influence of the site of bleeding and the time elapsed to VTE on their 3u2003month outcome. Results: Of 12 294 patients enrolled up to July 2005, 306 (2.5%) had recent major bleeding: gastrointestinal (GI) tract, 116 (38%); intracranial, 94 (31%); other, 96 (31%). During the study period, 19 patients [6.2%; 95% confidence interval (CI) 3.5–8.9] with recent bleeding rebled (eight died): 13 of them (68%) during the first 2u2003weeks. Multivariate analysis confirmed that patients with recent GI bleeding had an increased risk for both major rebleeding (hazard ratio 2.8; 95% CI 1.4–5.3) and death (hazard ratio 1.9; 95% CI 1.2–3.1) compared to those with no recent bleeding. Those who bled in other sites had an increased risk only for death (hazard ratio 2.0; 95% CI 1.2–3.3). An elapsed time of <u20032u2003weeks from bleeding to the index VTE event was also associated with an increased risk for major rebleeding (hazard ratio 2.4; 95% CI 1.2–5.0) and death (hazard ratio 2.8; 95% CI 1.8–4.5). Conclusion: The incidence of new bleeding or death depends on the site of prior bleeding and the time elapsed until VTE. This information may help to identify the best therapeutic approach for these high‐risk patients.