Frequency Of Recurrent Venous Thromboembolism Research Articles

Comparative analysis of COVID-19-associated venous thromboembolism outcomes: evolution from 2020 to 2021-2022.

Patients with COVID-19 are at an increased risk for venous thromboembolism (VTE). With the advent of vaccinations and novel treatments from 2020 through 2022, the landscape of COVID-19 has evolved. Notably, the effects of such interventions on the outcomes of COVID-19-associated VTE have not been thoroughly examined. Data from the RIETE registry were analyzed to evaluate 90-day VTE-related outcomes (all-cause mortality, major bleeding, and VTE recurrences) in patients with COVID-19-associated VTE. We compared the periods before and after the widespread introduction of COVID-19 vaccines: March to December 2020 (pre-vaccine period) and March 2021 to December 2022 (post-vaccine period). Statistical analysis included mixed-effects parametric survival-time models. Among 1,620 patients with COVID-19-associated VTE, most (74.1%) were identified during 2020 period. The analysis revealed a more than two-fold increase in the risk of death within 90days (adjusted hazard ratio [HR]: 2.27; 95% confidence interval, CI: 1.18-4.38) and major bleeding (adjusted HR: 2.91; 95%CI: 1.08-7.84) for patients from the 2020 period compared to those from the 2021-2022 period. Inpatient subgroup analysis confirmed the observed mortality differences. The frequency of recurrent VTE was low (1.1 vs. 0.7%, respectively), and did not show significant variation between the two periods. Our research provides a comparative perspective on the clinical outcomes of COVID-19-associated VTE before and after the introduction of vaccines. Our findings reveal a significant decrease in the incidence of 90-day mortality and major bleeding in patients with COVID-19-associated VTE in the 2021-2022 period.

Low Dose Apixaban As Secondary Prophylaxis for Venous Thromboembolism in Cancer Patients, 30 Months Follow-up

Background: Apixaban is a treatment option for venous thromboembolism (VTE) in cancer patients. There are no data on the effect of low dose apixaban after 6 months treatment. We wanted to assess the efficacy and safety of apixaban 2.5 mg twice daily as prophylaxis for recurrent VTE after 6 months initial treatment with full-dose apixaban.Patients and methods: We included 298 patients with cancer and any type of VTE. All patients were treated with full dose apixaban for the first 6 months. After 6 months, all patients with active cancer continued with apixaban 2.5 mg twice daily and were followed for the next 30 months. The primary endpoint of efficacy was recurrent VTE, the primary safety endpoint was major bleedings. Clinically relevant non-major bleedings was a secondary endpoint. The endpoints are reported as incidence rates or fractions with 95% confidence intervals, and as Kaplan-Meier plots.Results: During the first 6 months of full-dose anticoagulation 12 of 298 patients had recurrent VTE (4.0%, 95% confidence interval 2.1-6.9), 16 experienced major bleeding (5.4%, 95% CI 2.8-7.9%), and 26 patients experienced one or more episodes of CRNMB (8.9%, 95% CI 5.5-12) as previously reported. 1 Of the 298 patients included, 196 continued with apixaban 2.5 mg twice daily after 6 months. During treatment from 6 to 36 months with low-dose apixaban 15 of 196 (7.6%, 95% CI: 4.4-12) patients had recurrent VTE, 7 (3.6%, CI: 1.5-7.2) patients experienced major bleeding and 16 (8.2%, 95% CI: 4.7-13) patients experienced CRNMB. The highest incidence rate of both recurrent VTE and major bleedings were seen during the first month of full-dose apixaban (Table 1). After the dose reduction of apixaban, the incidence rate of recurrent VTE increased slightly during 6 to 12 months while the incidence rate of major bleeding decreased during the same time-period. After 12 months the incidence rate of both recurrent VTE and major bleeding was low and remained low during the entire 30 months follow-up (Table 1 and Figure 1). The Kaplan-Meier plot of the composite endpoint of recurrent VTE or major bleeding did not change after dose-reduction. After about 9 months treatment (i.e. 3 months on low dose apixaban) the Kaplan-Meier curve of the composite endpoint flattened out.Conclusion: Dose reduction of apixaban to 2.5 mg twice daily after 6 months of full dose anticoagulation resulted in a small increase in recurrent VTE, but a marked decrease in major bleedings during the 6-12 months period. After approximately 9 months the frequency of recurrent VTE and major bleedings remained low compared with the first 6 months of full-dose treatment. Reducing the dose of apixaban to 2.5 mg twice daily after 6 months of full-dose treatment appears safe and effective.

Unprovoked Versus Provoked Venous Thromboembolism in Pediatric Patients: Comparison of Characteristics and Outcomes

Background: The incidence of Venous thromboembolism (VTE) is increasing in the pediatric population which has led to a significant impact on morbidity, mortality and health care costs. The majority of VTE episodes diagnosed in children are considered provoked events secondary to an identifiable risk factor. In contrast, truly unprovoked VTE events are rare in children and there is limited data describing clinical course and outcomes in this population. The aim of this study is to highlight important differences in characteristics and outcomes of unprovoked VTE compared to provoked VTE in pediatric patients.Method: We performed a retrospective analysis of a prospectively maintained institutional thrombosis database. We identified all patients with an objectively confirmed VTE at our institution over a 5-year period from 2011 to 2016. Patients were managed according to standardized institutional protocols based on published guidelines. We compared patients with unprovoked VTE to those with provoked VTE with regards to demographics, prevalence of high risk thrombophilia (defined as inherited deficiency of antithrombin, protein C, or protein S, or antiphospholipid antibody syndrome), frequency of extensive VTE (defined as completely occlusive thrombosis involving >1 venous segment), frequency of pulmonary embolism (PE), frequency of recurrent VTE and frequency of post-thrombotic syndrome (PTS) assessed using the Manco-Johnson instrument in evaluable patients with history of VTE involving extremity veins, inferior vena cava, and/or superior vena cava. Data was compared using the Mann-Whitney U test or Fisher exact test as appropriate. Two-tailed p value less than 0.05 was considered statistically significant.Results: See Table 1 for a summary of the results. A total of 313 patients developed 336 VTE events at our institution during the study period. Of 336 VTE events, 24 (7%) were unprovoked events affecting 19 patients. Patients with unprovoked VTE were significantly older compared to patients with provoked VTE while gender distribution was similar between the 2 groups. The prevalence of high risk thrombophilia was significantly higher in patients with unprovoked VTE. Similarly, the frequencies of extensive VTE, PE and recurrent VTE were significantly higher in patients with unprovoked VTE. The frequency of physically and functionally significant PTS was not significantly different between the two groups. However, the frequency of PTS of any severity was significantly higher in patients with unprovoked VTE.Conclusion: Our study indicates that pediatric patients with unprovoked VTE represent a distinct patient population that appears to be at high risk for poor outcomes. Multicenter, prospective studies are needed to confirm our results and for developing optimal evidence-based risk stratified treatment approaches. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

O-109 Risk Factors and Frequency of Recurrent Venous Thrombo-Embolism After Superficial Vein Thrombosis: Venous Diseases (including Malformations)

O-109 Risk Factors and Frequency of Recurrent Venous Thrombo-Embolism After Superficial Vein Thrombosis: Venous Diseases (including Malformations)

Safety and effectiveness of oral rivaroxaban versus standard anticoagulation for the treatment of symptomatic deep-vein thrombosis (XALIA): an international, prospective, non-interventional study

The efficacy and safety of the anticoagulant rivaroxaban for the treatment and secondary prevention of deep-vein thrombosis and pulmonary embolism has been shown in phase 3 trials. However, data about rivaroxaban use in routine clinical practice are needed. XA inhibition with rivaroxaban for Long-term and Initial Anticoagulation in venous thromboembolism (XALIA) was a multicentre, international, prospective, non-interventional study of patients with deep-vein thrombosis, done in hospitals and community care centres in 21 countries. The study investigated the safety and effectiveness of rivaroxaban compared with standard anticoagulation therapy (initial treatment with unfractionated heparin, low-molecular-weight heparin, or fondaparinux, usually overlapping with and followed by a vitamin K antagonist) for at least 3 months. Eligible patients were adults (aged ≥18 years) with an objectively confirmed diagnosis of deep-vein thrombosis, and an indication to receive anticoagulation treatment for at least 3 months. Following approval of rivaroxaban for the pulmonary embolism indication, patients with deep-vein thrombosis and concomitant pulmonary embolism were also eligible; however, those with isolated pulmonary embolism were not included. Type, dose, and duration of therapy for each patient were at the physician's discretion. The primary effectiveness and safety outcomes were major bleeding, recurrent venous thromboembolism, and all-cause mortality. Propensity score-adjusted analyses were done to account for potential imbalances between groups. This study is registered with ClinicalTrials.gov, number NCT01619007. Between June 26, 2012, and March 31, 2014, 5142 patients were enrolled. The safety population (all patients who received at least one dose of the anticoagulant of interest) comprised 2619 patients in the rivaroxaban group and 2149 in the standard anticoagulant therapy group. Patients in the rivaroxaban group were younger and fewer had active cancer or concomitant pulmonary embolism than those in the standard anticoagulation group. In the propensity score-adjusted population, the frequency of major bleeding was 0·8% (19/2505) in the rivaroxaban group and 2·1% (43/2010) in the standard anticoagulation group, with a propensity score-adjusted hazard ratio (HR) of 0·77 (95% CI 0·40-1·50); p=0·44. The frequency of recurrent venous thromboembolism was 1·4% (36/2505) in the rivaroxaban group and 2·3% (47/2010) in the standard anticoagulation group (propensity score-adjusted HR 0·91 [95% CI 0·54-1·54], p=0·72). The all-cause mortality frequency was 0·4% (11/2505) in the rivaroxaban group and 3·4% (69/2010) in the standard anticoagulation group (propensity score-adjusted HR 0·51 [95% CI 0·24-1·07], p=0·074). The incidence of treatment-emergent adverse events in the safety population was similar between the two groups (944 [36·0%] of 2619 in the rivaroxaban group vs 805 [37·5%] of 2149 in the standard anticoagulation group). In routine clinical practice, rivaroxaban-treated patients had a lower risk profile at baseline than those treated with standard anticoagulation. Propensity score-adjusted results confirm that rivaroxaban is a safe and effective alternative to standard anticoagulation therapy in a broad range of patients. Rates of major bleeding and recurrent venous thromboembolism were low in rivaroxaban-treated patients and consistent with phase 3 findings. Bayer HealthCare Pharmaceuticals and Janssen Research & Development, LLC.

Index clinical manifestation of venous thromboembolism predicts early recurrence type and frequency: a meta-analysis of randomized controlled trials

Observational studies suggest index clinical manifestation of venous thromboembolism (VTE) predicts recurrence type. Data regarding the association between index manifestation and recurrence rates are conflicting. To perform a meta-analysis of randomized controlled trials (RCTs) to determine the type and frequency of recurrent VTE (rVTE) in persons after an index deep vein thrombosis (DVT) or pulmonary embolism (PE). We searched bibliographic databases for RCTs of acute (early) treatment of rVTE in persons with an index DVT or PE (±DVT), enrolling ≥ 50 subjects anticoagulated ≥ 3-months and reporting types of rVTE. We pooled (random-effects) the proportion of rVTEs that were DVTs, PEs, and fatal PEs, the proportion of recurrent PEs that were fatal, and absolute rVTE rates. In nine RCTs (N = 13 640; 413 rVTEs) evaluating persons with an index PE; 66% (95% CI, 60-72%) of rVTEs were PE and 27% (95% CI, 22-33%) were fatal PE. Among 25 RCTs (N = 17 340; 692 rVTEs) evaluating persons with an index DVT, 36% (95% CI, 29-44%) experienced a recurrent PE and 10% (95% CI, 7-13%) a fatal PE. Recurrent PEs following an index PE had a higher fatality rate than after an index DVT (41%; 95% CI, 33-48% vs. 25%; 95% CI, 18-33%; P = 0.007). The rVTE rate was higher following an index DVT compared with a PE (2.6%; 95% CI, 1.6-3.8% vs. 4.9%; 95% CI, 4.0-6.0%; P = 0.002). Our meta-analysis suggests most rVTEs will be the same type as the index event. While index DVTs are associated with a higher rVTE rate than index PEs; recurrent PEs are associated with high fatality.

Management and adherence to VTE treatment guidelines in a national prospective cohort study in the Canadian outpatient setting

Documenting patterns and outcomes of venous thromboembolism (VTE) management and degree of adherence by clinicians to treatment guidelines could help identify remediable gaps in patient care. Prospective, clinical practice-based data from Canadian outpatient settings on management of VTE, degree of adherence with treatment guidelines and frequency of recurrent VTE and bleeding during follow-up was obtained in a multicentre, prospective observational study. From 12 Canadian centres, we assessed 868 outpatients with acute symptomatic VTE who received the low-molecular-weight heparin (LMWH) enoxaparin alone or with vitamin K antagonists (VKA), at baseline and at six months (or at the end of treatment, whichever came first). Index VTE was limb deep venous thrombosis (DVT) in 583 (67.2%) patients, pulmonary embolism (PE) with or without DVT in 262 (30.2%) patients, and unusual site DVT in 23 (2.6%) patients. VTE was unprovoked in 399 (46.0%) patients, associated with cancer in 74 (8.5%) patients, transient risk factors in 327 (37.7%) patients and hormonal factors in 68 (7.8%) patients.With regard to guideline adherence, 58 (7.3%) patients received <5 days LMWH and 114 (14.5%) had overlap <1 day. Among patients with cancer-related VTE, 59.5% were prescribed LMWH monotherapy and 43.2% received such treatment for >3 months. Only 38.1% of patients with transient VTE risk factors had received thromboprophylaxis. Our study provides useful information on clinical presentation, management and related outcomes in Canadian outpatients with VTE. Our results suggest there may be important gaps in use of thromboprophylaxis to prevent VTE and use of LMWH monotherapy to treat cancer-related VTE.

Prolongation d’un traitement par antivitamine K pendant dix-huit mois versus placebo au décours d’un premier épisode d’embolie pulmonaire idiopathique traité six mois : un essai randomisé multicentrique en double aveugle. Essai « PADIS-EP »

After stopping a 3 to 6 months course of oral anticoagulation for a first episode of idiopathic venous thromboembolism (VTE), the risk of recurrent VTE is high (10% per year). In this setting, international guidelines recommend at least 6 months treatment. However, this recommendation is not satisfactory for the following reasons: (1) no randomized trial has compared 6 months to extended duration (2 years) anticoagulation; and (2), even though the frequency of recurrent VTE is similar after pulmonary embolism (PE) and deep vein thrombosis (DVT), the fatality rate of recurrent VTE after PE is higher than that after DVT. A French multicentre double blind randomized trial. The main objective is to demonstrate, after a first episode of symptomatic idiopathic PE treated for 6 months using a vitamin K antagonist, that extended anticoagulation for 18 months (INR between 2 and 3) is associated with an increased benefit / risk ratio (recurrent VTE and severe anticoagulant-related bleeding) compared to placebo. The double blind evaluation is ensured using by active warfarin and placebo, and blinded INR. The protocol was approved by the ethics board of the Brest Hospital on the 7th of March 2006. For an alpha risk of 5% and a beta risk of 20%, the estimated sample size is 374 patients. This study has the potential to: (1) demonstrate that the benefit / risk ratio of extended anticoagulation for 18 months is higher than that observed with placebo in patients with a first episode of idiopathic PE initially treated for 6 months, during and after the treatment period; and (2) to validate or invalidate the contribution of isotope lung scans, lower limb Doppler ultrasound and D-Dimer at 6 months of treatment as predictors of recurrent VTE (medico-economic analysis included).

Long-term outcomes of venous thrombosis in children

Venous thromboembolism has become an increasingly recognized clinical entity in children over the past decade. Recently, important efforts have been made to track post thrombotic outcomes. The present review discusses the knowledge gained from seminal studies in the field over the past decade, with particular emphasis on the findings of numerous published reports on outcomes of various types of venous thromboembolism in the pediatric literature from January 2003 to January 2005. Large cohort studies involving acute venous thromboembolism of all types in children have recently confirmed a rather low frequency of recurrent venous thromboembolism, but have shown a lack of thrombus resolution following standard-duration anticoagulant therapy in as many as 50% of patients. In addition, the development of the post thrombotic syndrome has been demonstrated in greater than one third of children with venous thromboembolism involving the extremities. Persistent thrombosis despite adequate anticoagulation has been independently associated with complete vaso-occlusion at diagnosis. Furthermore, the presence of elevated levels of factor VIII and D-dimer either at diagnosis or following three to six months anticoagulation has now been defined as a predictor of adverse long-term outcomes of pediatric thrombosis. This body of work indicates that the various forms of venous thromboembolism in children are in general associated with a considerable degree of adverse outcomes, particularly in the form of venous thromboembolism-related mortality, recurrent thromboembolism, and development of post thrombotic syndrome. Advances in the prediction of post thrombotic outcomes have begun, and must continue to facilitate a risk-stratified approach to antithrombotic management in children, and to ultimately achieve meaningful improvements in long-term outcomes.

Pathophysiology and diagnosis of deep venous thrombosis

Lower-limb deep venous thrombosis (DVT) affects between 1% to 2% of hospitalized patients. These thrombi disrupt the vascular integrity of the lower limbs and are the source of emboli that kill approximately 200,000 patients each year in the United States. The causes of thrombosis include vessel wall damage, stasis or low flow, and hypercoagulability. These factors favor clot formation by disrupting the balance of the opposing coagulative and fibrinolytic systems. The symptoms and signs of venous thrombosis are caused by obstruction to venous outflow, vascular inflammation, or pulmonary embolization. About 70% of patients referred for clinically suspected venous thrombosis, however, do not have the diagnosis confirmed by objective testing. Among the 30% who have venous thrombosis, about 85% have proximal vein thrombosis, and the remainder have thrombosis confined to the calf. Physicians cannot rely on signs and symptoms to make the diagnosis of DVT and must depend on imaging studies to guide treatment. Patients with proximal vein thrombosis who are inadequately treated have a 47% frequency of recurrent venous thromboembolism over 3 months. In contrast, clinically detectable recurrence occurs in less than 2% of patients with proximal vein thrombosis if an adequate anticoagulant response is achieved. Of the diagnostic procedures for DVT, venography is the only invasive test of proven value, and ultrasonographic (US) studies are the most commonly used noninvasive modaity. Other procedures are occasionally used to diagnose DVT, including impedance plethysmography, computed tomography, and magnetic resonance imaging. US examinations are noninvasive, they are rapidly obtained, and they can be performed serially. In symptomatic patients, venous US is sensitive and specific for proximal DVT; however, US is insensitive to calf vein thrombosis and to asymptomatic DVT occurring after surgery. Patients with symptoms of recurrent DVT also can present a difficult diagnostic problem. Only about 20% to 30% of these individuals actually have the disease; the rest have symptoms arising from chronic venous insufficiency or from any of the causes of lower extremity pain. After an acute episode, up to 50% of patients have compression ultrasound abnormalities for 6 months that are indistinguishable from the original findings of DVT. Hence, there are a significant number of patients and clinical circumstances in which the diagnosis of DVT is difficult. 99mTc-radiolabeled peptides that target the molecular biology of thrombosis should aid in the management of the disease, particularly in asymptomatic patients at high risk, in patients with recurrent symptoms, in patients with active DVT in the calf and/or pelvis, and in patients with intermediate- or low-probability lung scans.

Long-term Clinical Follow-up in 265 Patients with Deep Venous Thrombosis Initially Treated with either Unfractionated Heparin or Dalteparin: A Retrospective Analysis

The primary objective of this retrospective study was to describe the frequency of a post-thrombotic syndrome in 265 patients previously treated for deep venous thrombosis (DVT). The secondary objectives were to document the frequency of recurrent venous thromboembolism (VTE) and mortality, especially from malignant disease. The patients were evaluated 5-14 years after inclusion in three randomized trials comparing continuous intravenous (i.v.) infusion of unfractionated heparin (UFH) (n = 85) with a low molecular weight heparin (LMWH), dalteparin (n = 180). The median post-thrombotic score at follow-up was 2 (range 0-8). In a multiple step-wise regression analysis the postthrombotic score was significantly higher among patients with initial proximal DVT (p = 0.0001) as compared with those who had distal DVT. A recurrent venous thromboembolic event was diagnosed in 29.4% of the patients treated with dalteparin and in 23.5% of the patients treated with UFH (ns). A secondary risk factor for venous thromboembolism and a longer duration of treatment with oral anticoagulants (OAC) were significantly associated with a lower risk for recurrent VTE, whereas malignant disease diagnosed during follow-up was associated with a higher risk. During follow-up a total of 40.7% of patients had died. No difference in total mortality or mortality from malignant disease was demonstrated between the two drugs. In conclusion, a severe post-thrombotic syndrome occured relatively infrequent. considering the long observation period. Proximal DVT was significantly associated with a more severe post-thrombotic syndrome. After 14 years follow-up, no significant differences were observed in overall mortality, mortality from malignant disease or recurrent VTE between UFH- and dalteparin-treated patients. Malignant disease was a risk factor for recurrent VTE, the presence of a secondary risk factor and a longer duration of treatment with OAC decreased the risk for recurrent VTE.

Utility of intravascular stents for ostial renal artery stenoses

In view of the potential of low-molecular-weight heparins (LMWH) to simplify initial therapy and allow outpatient treatment of proximal deep-vein thrombosis, we undertook a randomised comparison of fixed-dose subcutaneous LMWH with adjusted-dose intravenous standard heparin in the initial treatment of this disorder. Our main objectives were to compare the efficacy of these regimens for 6 months of follow-up and to assess the risk of clinically important bleeding. Of 170 consecutive symptomatic patients with venographically proven proximal deep-venous thrombosis, 85 received standard heparin (to achieve an activated partial thromboplastin time of 1·5 to 2·0 times the pretreatment value) and 85 LMWH (adjusted only for body weight) for 10 days. Oral coumarin was started on day 7 and continued for at least 3 months. The frequency of recurrent venous thromboembolism diagnosed objectively did not differ significantly between the standard-heparin and LMWH groups (12 [14%] vs 6 [7%]; difference 7% [95% confidence interval -3% to 15%]; p=0·13). Clinically important bleeding was infrequent in both groups (3·5% for standard heparin vs 1·1% for LMWH; p>0·2). We conclude that fixed-dose subcutaneous LMWH is at least as effective and safe as intravenous adjusted-dose heparin in the initial treatment of symptomatic proximal-vein thrombosis. Since there is no need for laboratory monitoring with the LMWH regimen, patients with venous thrombosis can be treated at home.

Comparison of subcutaneous low-molecular-weight heparin with intravenous standard heparin in proximal deep-vein thrombosis

In view of the potential of low-molecular-weight heparins (LMWH) to simplify initial therapy and allow outpatient treatment of proximal deep-vein thrombosis, we undertook a randomised comparison of fixed-dose subcutaneous LMWH with adjusted-dose intravenous standard heparin in the initial treatment of this disorder. Our main objectives were to compare the efficacy of these regimens for 6 months of follow-up and to assess the risk of clinically important bleeding. Of 170 consecutive symptomatic patients with venographically proven proximal deep-venous thrombosis, 85 received standard heparin (to achieve an activated partial thromboplastin time of 1·5 to 2·0 times the pretreatment value) and 85 LMWH (adjusted only for body weight) for 10 days. Oral coumarin was started on day 7 and continued for at least 3 months. The frequency of recurrent venous thromboembolism diagnosed objectively did not differ significantly between the standard-heparin and LMWH groups (12 [14%] vs 6 [7%]; difference 7% [95% confidence interval -3% to 15%]; p=0·13). Clinically important bleeding was infrequent in both groups (3·5% for standard heparin vs 1·1% for LMWH; p>0·2). We conclude that fixed-dose subcutaneous LMWH is at least as effective and safe as intravenous adjusted-dose heparin in the initial treatment of symptomatic proximal-vein thrombosis. Since there is no need for laboratory monitoring with the LMWH regimen, patients with venous thrombosis can be treated at home.

Prophylaxis and Therapy of Venous Thromboembolism

Heparin is an anticoagulant drug which is used for the prophylaxis and treatment of venous thromboembolism and for the treatment of some cases of arterial thromboembolism. Venous thromboembolism is the commonest preventable cause of death in hospitalized patients, and the best approach to reduce its morbidity and mortality is the use of safe, effective, prophylaxis in patients at high risk. The use of low doses of heparin given s.c. (5000 units, 8 hourly)) has been shown in prospective clinical trials to be effective prophylaxis against venous thrombosis and nonfatal and fatal pulmonary embolism in patients undergoing general abdominothoracic surgery, without producing dangerous bleeding. Low-dose heparin, however, is not totally effective in patients undergoing hip surgery and suprapubic prostatectomy. The lack of benefit in these patients may be related to the intensity of the provocation to thrombosis. The use of heparin in large doses to treat thrombosis is associated with hemorrhagic complications in up to 30% of patients. There is evidence that continuous i.v. heparin is associated with fewer hemorrhagic complications than intermittent i.v. heparin, but the frequency is not related to the dose or to the use of laboratory monitoring. Hemorrhagic complications occur more frequently in elderly patients and in females and is more common following surgical operations. The frequency of recurrent venous thromboembolism is low in patients on therapeutic doses of heparin, and there is no difference in the frequency of recurrence in patients receiving heparin by continuous i.v. or intermittent i.v. administration.