Systematic versus sentinel-lymph-node-driven axillary-lymph-node dissection in clinically node-negative patients with operable breast cancer. Results of the GF-GS01 randomized trial.

PURPOSE: Sentinel-lymph-node (SLN) resection seems to minimize systematic axillary-lymph-node dissection (sALND) side effects in operated breast cancer patients. We explored whether SLN resection achieves similar therapeutic outcomes as sALND but with fewer side effects. METHODS: A randomized, controlled, open-label trial with parallel-group design compared sALND restricted to cases with positive SLN biopsy (test arm, n = 774) versus SLN biopsy followed by sALND (control arm, n = 770). RESULTS: The five-year overall survivals in control and test arms were 96.42 and 95.64% (P = 0.2925). The estimated difference was nearly zero (precisely, - 0.79%, one-tailed 95% confidence interval (CI) limit - 2.44%). In a multivariate Cox model, the adjusted hazard ratio in the test arm was HR 0.81 (upper 95% CI limit 1.17). Advanced age (HR 1.05 per additional year, CI [1.03-1.08]), negative progesterone receptor (HR 2.17 [1.35-3.45]), SLN metastasis (HR 1.69 [1.03-2.79]), and only one SLN identification technique (HR 4.14 [1.21-14.18]) were associated with lower survival. Patients with ≥ 1 severe side effect at 1 month in control and test arms were 173/703 = 24.6% [21.5-28.0%] and 91/693 = 13.1% [10.7-15.9%] (P < 0.001). The estimated sensitivity of SLN biopsy (control arm) was 145/178 = 81.5% [74.8-86.7%]. CONCLUSIONS: Restricting ALND to cases with positive SLN biopsy does not affect the overall survival but reduces by 11.5% [7.5-15.6%] (P < 0.001) the risk of severe short-time side effects of sALND.

Prospective multicentre observational study of lymphedema therapy: POLIT study.

OBJECTIVE: Lymphedema treatment is based on Decongestive Lymphedema Therapy (DLT) with an intensive phase followed by a long-term maintenance phase. This study aimed to observe volume variation over the intensive phase and 6 months later. METHODS: Prospective multicentre observational study of patients with unilateral lymphedema. The primary objective was to assess lymphedema volume variation between baseline, the end of intensive phase and 6 months later. Secondary objectives were to assess the frequency of heaviness limiting limb function and treatments safety predictors for volume reduction. RESULTS: Three hundred and six patients (89.9% women; 59.9±14.3 years old) with upper/lower (n=184/122) limb lymphedema were included. At the end of the intensive phase, median excess lymphedema volume reduction was 31.0% (41.7-19.9) followed by a 16.5% (5.9-42.3) median increase over the 6-month maintenance period phase. Previous intensive treatment was the only significant predictor of this response. As compared to baseline, heaviness limiting limb use was much less frequently reported at the end of the reductive phase (75.5% versus 42.3% respectively), and was more frequent at the end of the maintenance phase (62.6%). The most frequent adverse events reported were skin redness and compression marks (18.4 and 15.7% of patients, respectively). Blisters requiring treatment stoppage were rare (1.4%). CONCLUSIONS: Intensive phase decreases lymphedema volume and heaviness limiting limb function. The benefit is partially abolished after the first 6 months of maintenance. There is a need to consider how to provide optimal patient care for the long-term control of lymphedema.

Annual diagnosis rate of superficial vein thrombosis of the lower limbs: the STEPH community-based study.

BACKGROUND: The incidence of superficial vein thrombosis (SVT) in the general adult population remains unknown. OBJECTIVES: To assess the annual diagnosis rate of symptomatic, objectively confirmed lower limb SVT, associated or not with concomitant deep vein thrombosis and/or symptomatic pulmonary embolism. METHODS/PATIENTS: We conducted, from November 14, 2011, to November 13, 2012, a multicenter, community-based study in the Saint-Etienne urban area, France, representing a population of 265 687 adult residents (according to the 2009 census). All 248 general practitioners located within the area were asked to refer any patient with clinically suspected lower limb acute SVT to a vascular physician for systematic compression ultrasonography. All 28 vascular physicians located within the area participated in the study. The annual diagnosis rate, with the corresponding 95% confidence interval (CI), was calculated as the number of patients with symptomatic, objectively confirmed SVT divided by the number of person-years at risk defined by population data of the area. All venous thromboembolic events were validated by an independent central adjudication committee. RESULTS: Overall, 171 patients with symptomatic, confirmed SVT were reported. The annual diagnosis rate was 0.64& (95% CI, 0.55%-0.74&), was higher in women, and increased with advancing age regardless of gender [corrected]. Concomitant deep vein thrombosis (20 proximal) was observed in 42 patients (24.6% [95% CI, 18.3%-31.7%]), and concomitant symptomatic pulmonary embolism was observed in eight patients (4.7% [95% CI, 2.0%-9.0%]). CONCLUSIONS: This first community-based study showed that symptomatic SVT with confirmed diagnosis is a relatively common disease frequently associated with thromboembolic events in the deep venous system.

Superficial vein thrombosis and recurrent venous thromboembolism: a pooled analysis of two observational studies.

BACKGROUND: The management strategies for symptomatic isolated superficial vein thrombosis (SVT) (without concomitant deep vein thrombosis [DVT] or pulmonary embolism [PE]) have yet to achieve widespread consensus. Concerns have been raised regarding the usefulness of prescribing anticoagulant treatments to all patients with isolated SVT. Determining the isolated SVT subgroups who have the highest risks of venous thromboembolism (VTE) recurrence (composite of DVT, PE, and new SVT) may facilitate the identification of patients who are likely to benefit from anticoagulant treatment. DESIGN AND METHODS: We performed a pooled analysis on individual data from two observational, multicenter, prospective studies, to determine predictors for VTE recurrence and their impact in an unselected population of symptomatic isolated SVT patients. RESULTS: One thousand and seventy-four cases of symptomatic isolated SVT were followed up at 3 months. VTE recurrence was observed in 3.9% of the patients; 16.2% of the patients did not receive anticoagulants, and 0.6% experienced a VTE recurrence. Cancer, personal history of VTE and saphenofemoral/popliteal involvement significantly increased the risk of subsequent VTE or DVT/PE in univariate analyses. Only male sex significantly increased the risk of VTE or DVT/PE recurrence in multivariate analyses. Twelve percent of the patients had cancer or saphenofemoral junction involvement, and were at higher risk of DVT/PE recurrence than patients without those characteristics (4.7% vs. 1.9%, P= 0.06). CONCLUSIONS: In patients with symptomatic SVT, only male sex significantly and independently increased the risk of VTE recurrence. Cancer or saphenofemoral junction involvement defined a population at high risk for deep VTE recurrence. Some SVTs might be safely managed without anticoagulants.

Value of a planned compression ultrasonography after an isolated superficial vein thrombosis: results from a prospective multicentre study.

OBJECTIVES: To assess the efficiency of a systematically planned compression ultrasonography (SP-CUS) to detect venous thrombotic complications (VTCs) in patients with symptomatic isolated superficial vein thrombosis (SVT). DESIGN: Post hoc analysis of a prospective, multicentre, cohort study (POST). PATIENTS: As many as 537 patients with CUS-confirmed isolated SVT undergoing an SP-CUS 8-15 days after the initial CUS. OUTCOMES: Asymptomatic VTC (extension or recurrence of SVT, deep-vein thrombosis (DVT) of the lower limbs) diagnosed by the SP-CUS and symptomatic thromboembolic complications (VTC and pulmonary embolism (PE)) up to 3 months. RESULTS: VTC was suspected before or on the day of the SP-CUS in 18 patients (3.0%). Among the 519 asymptomatic patients (97%) undergoing SP-CUS, this revealed asymptomatic VTC in 12 patients (2.3%; 4 DVT, 4 SVT recurrences, 4 SVT extensions), none of whom subsequently experienced symptomatic thromboembolic events up to 3 months. Among the 507 patients with a normal SP-CUS, 29 (5.7%) presented symptomatic thromboembolic events during follow-up: 2 PE, 7 DVT, 9 SVT recurrences and 11 SVT extensions. CONCLUSIONS: In this study, the SP-CUS detected a few asymptomatic VTC, but failed to identify patients at risk of thromboembolic events during follow-up. Use of an SP-CUS was therefore neither efficient nor cost effective.

No accumulation of the peak anti-factor Xa activity of tinzaparin in elderly patients with moderate-to-severe renal impairment: the IRIS substudy.

BACKGROUND: In the elderly, concerns have been raised regarding the risk of accumulation of low molecular weight heparins, owing to their renal elimination. Although data exist for tinzaparin, they are observational. OBJECTIVES: To assess whether: (i) there was an accumulation of anti-factor Xa activity; and (ii) there was any relationship between anti-FXa activity and age, weight, creatinine clearance or clinical outcomes in patients with moderate-to-severe renal impairment receiving tinzaparin (175 IU kg(-1) per 24 h) for acute venous thromboembolism. METHODS: In 38 centers participating in the Innohep in Renal Insufficiency Study (IRIS), peak plasma anti-FXa activity was measured on day 2/day 3 and on day 5 or at visit S (VS) (end of tinzaparin treatment). There was considered to be absence of accumulation if the 90% confidence interval (CI) of the (anti-FXa day 5/VS)/(anti-FXa day 2/3) ratio did not exceed the predefined limit of 1.25. RESULTS: Eighty-seven patients, with a mean age of 83 ± 5 years (range: 75-99 years) and a mean creatinine clearance (CrCl) of 40.8 mL min(-1) , 24.1% of whom had severe renal impairment, were included. The mean duration of tinzaparin treatment was 8.4 days. No significant accumulation was detected: the mean accumulation ratio was 1.06 (90% CI 1.01-1.11). There was no correlation between the accumulation ratio and age, weight, or CrCl. The mean anti-FXa activity did not differ significantly between the eight patients who experienced clinically relevant bleeding and those who did not. CONCLUSIONS: No accumulation of anti-FXa activity was observed in elderly patients with renal impairment receiving therapeutic doses of tinzaparin, suggesting that there is no need for systematic anti-FXa monitoring in these patients. The high proportion of high molecular weight moieties in tinzaparin may account for its reduced dependence on renal elimination.

Results of the randomized, placebo-controlled clopidogrel and acetylsalicylic acid in bypass surgery for peripheral arterial disease (CASPAR) trial.

OBJECTIVE: Dual antiplatelet therapy with clopidogrel plus acetylsalicylic acid (ASA) is superior to ASA alone in patients with acute coronary syndromes and in those undergoing percutaneous coronary intervention. We sought to determine whether clopidogrel plus ASA conferred benefit on limb outcomes over ASA alone in patients undergoing below-knee bypass grafting. METHODS: Patients undergoing unilateral, below-knee bypass graft for atherosclerotic peripheral arterial disease (PAD) were enrolled 2 to 4 days after surgery and were randomly assigned to clopidogrel 75 mg/day plus ASA 75 to 100 mg/day or placebo plus ASA 75 to 100 mg/day for 6 to 24 months. The primary efficacy endpoint was a composite of index-graft occlusion or revascularization, above-ankle amputation of the affected limb, or death. The primary safety endpoint was severe bleeding (Global Utilization of Streptokinase and Tissue plasminogen activator for Occluded coronary arteries [GUSTO] classification). RESULTS: In the overall population, the primary endpoint occurred in 149 of 425 patients in the clopidogrel group vs 151 of 426 patients in the placebo (plus ASA) group (hazard ratio [HR], 0.98; 95% confidence interval [CI], 0.78-1.23). In a prespecified subgroup analysis, the primary endpoint was significantly reduced by clopidogrel in prosthetic graft patients (HR, 0.65; 95% CI, 0.45-0.95; P = .025) but not in venous graft patients (HR, 1.25; 95% CI, 0.94-1.67, not significant [NS]). A significant statistical interaction between treatment effect and graft type was observed (P(interaction) = .008). Although total bleeds were more frequent with clopidogrel, there was no significant difference between the rates of severe bleeding in the clopidogrel and placebo (plus ASA) groups (2.1% vs 1.2%). CONCLUSION: The combination of clopidogrel plus ASA did not improve limb or systemic outcomes in the overall population of PAD patients requiring below-knee bypass grafting. Subgroup analysis suggests that clopidogrel plus ASA confers benefit in patients receiving prosthetic grafts without significantly increasing major bleeding risk.

Oral buflomedil in the prevention of cardiovascular events in patients with peripheral arterial obstructive disease: a randomized, placebo-controlled, 4-year study.

BACKGROUND: Cardiovascular-related morbidity and mortality in patients with peripheral arterial obstructive disease remain high. We performed an international, multicenter, randomized, double-blind, placebo-controlled trial to investigate whether long-term administration of oral buflomedil could reduce the rate of cardiovascular events in patients with intermittent claudication. METHODS AND RESULTS: Patients >40 years of age with documented peripheral arterial obstructive disease, intermittent claudication, and an ankle-brachial index between 0.30 and 0.80 were eligible for inclusion and were randomized to receive orally either buflomedil or placebo for 2 to 4 years. Aspirin was recommended for all patients (unless they were receiving other antithrombotic treatments at inclusion). The primary efficacy outcome was critical cardiovascular events, defined as the composite of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, symptomatic deterioration of peripheral arterial obstructive disease, or leg amputation. A total of 2078 patients were recruited. Mean treatment duration was 33 months. The rate of critical cardiovascular events was significantly lower in buflomedil-randomized patients than in placebo-randomized patients (9.1% versus 12.4%; hazard ratio, 0.742; 95% confidence interval, 0.603 to 0.915; P=0.0163). Ankle-brachial index increased by 9.2% in buflomedil-randomized patients and decreased by 3.6% in placebo-randomized patients (P<0.001). Tolerance of buflomedil and placebo was comparable. CONCLUSIONS: Compared with placebo, buflomedil administered for 3 years reduced the occurrence of symptomatic cardiovascular events by 26%. The main contributor to the difference in the composite outcome was the reduction in symptomatic deterioration of peripheral arterial disease. The use of buflomedil should be considered in addition to an antiplatelet agent in patients with peripheral arterial obstructive disease and intermittent claudication.

Influence of age on the prescription of vitamin K antagonists in outpatients with permanent atrial fibrillation in France.

PURPOSE: The aim of the study was to describe the current rate and determinants of the prescription of antithrombotics in outpatients with permanent atrial fibrillation, with a pre-specified emphasis on the influence of age on the prescription of vitamin K antagonists. METHODS: This was a prospective observational survey in France among 5893 consecutive outpatients with documented permanent atrial fibrillation being seen by 770 physicians from August to December 2002. We recruited physicians from two random lists of general practitioners and cardiologists, respectively, stratified according to their administrative region, from the list of all French private general practitioners and cardiologists. RESULTS: The mean age of patients was 75.8 years. Mean duration since diagnosis of atrial fibrillation was 5.0 years; 31.7% of patients had valvular heart disease and 60.3% hypertension. An antithrombotic was prescribed to 95.5% of patients at the time of consultation. The percentage of patients treated with vitamin K antagonists was 76.4%; it decreased from 86.0% in patients aged 60-70 years to 63.5% in patients aged 80 years or above. On multivariate analysis, high age was a significant predictor (p = 0.001) for the non-prescription of vitamin K antagonists. In patients above 70 years currently receiving an antithrombotic, the probability of prescription of vitamin K antagonists decreased on average by 9.6% per year. CONCLUSIONS: Vitamin K antagonists are administered to most outpatients with permanent atrial fibrillation at high thromboembolic risk seen by French physicians in private practice. However, their use decreases with age.

Prevention of cardiovascular events in end-stage renal disease: results of a randomized trial of fosinopril and implications for future studies.

Cardiovascular events (CVEs) are the leading cause of death in chronic hemodialysis patients. Results of trials in non-end-stage renal disease (ESRD) patients cannot be extrapolated to patients with ESRD. It is critical to test cardiovascular therapies in these high-risk patients who are usually excluded from major cardiovascular trials. The study objective was to evaluate the effect of fosinopril on CVEs in patients with ESRD. Eligible patients were randomized to fosinopril 5 mg titrated to 20 mg daily (n=196) or placebo (n=201) plus conventional therapy for 24 months. The primary end point was combined fatal and nonfatal first major CVEs (cardiovascular death, resuscitated death, nonfatal stroke, heart failure, myocardial infarction, or revascularization). No significant benefit for fosinopril was observed in the intent to treat analysis (n=397) after adjusting for independent predictors of CVEs (RR=0.93, 95% confidence interval (CI) 0.68-1.26, P=0.35). The per protocol secondary supportive analysis (n=380) found a trend towards benefit for fosinopril (adjusted RR=0.79 (95% CI 0.59-1.1, P=0.099)). In the patients who were hypertensive at baseline, systolic and diastolic blood pressures were significantly decreased in the fosinopril as compared to the placebo group. After adjustment for risk factors, trends were observed suggesting fosinopril may be associated with a lower risk of CVEs. These trends may have become statistically significant had the sample size been larger, and these findings warrant further study.

Epidemiology of venous thromboembolism in Asian patients undergoing major orthopedic surgery without thromboprophylaxis. The SMART study.

BACKGROUND: In Asian patients undergoing surgery, the incidence of venous thromboembolism (VTE) is thought to be low relative to Western patients, and the routine use of thromboprophylaxis is controversial. OBJECTIVES: The aim of this work was to study the epidemiology of VTE in Asian patients undergoing orthopedic surgery without thromboprophylaxis. PATIENTS AND METHODS: We performed a prospective observational study of a cohort of consecutive Asian patients hospitalized for total hip or knee replacement or hip fracture surgery without thromboprophylaxis. The primary study outcome was the incidence of the composite of symptomatic VTE or sudden death at hospital discharge. This outcome was also assessed at 1 month's follow-up. RESULTS: Between April 2001 and July 2002, 2420 patients were enrolled. Median age was 68 years and the median duration of hospital stay was 13 days. The rate of symptomatic VTE or sudden death as notified by investigators was 2.3%[55 patients, 99% confidence interval (CI) 1.6, 3.2] and 1.2% (28 patients, 99% CI 0.7, 1.8) after adjudication by an independent committee. Chronic heart failure, varicose veins and a history of VTE were independent risk factors (P < 0.05) for the occurrence of the primary endpoint. At 1 month's follow-up, the incidence of adjudicated symptomatic VTE or sudden death was 1.5% (35/2264 patients). CONCLUSION: In Asian patients, the incidence of symptomatic VTE after major orthopedic surgery is not low, consistent with the rates observed in Western countries. The use of thromboprophylaxis should be considered in Asian patients undergoing such high-risk surgical procedures.

[Risk factors management in 5708 ambulatory patients suffering from peripheral vascular disease followed in urban practices]. / Contrôle des facteurs de risque dans une population de 5 708 artériopathes des membres inférieurs vus en médecine de ville.

STUDY OBJECTIVE: we examined the management of risk factors in patients suffering from obliterating peripheral arterial disease (OPAD), in urban medical practice. METHODS: PRISMA, ECLAT1 and APRES are surveys based on urban medicine in France. These 3 studies have allowed a compilation of data pertaining to the control of risk factors in patients suffering from one or more clinical manifestations of atherothrombosis, including cerebral vascular accident, coronary insufficiency or OPAD. The study population was divided among patients with isolated OPAD, versus OPAD associated with coronary artery disease (CAD), versus OPAD associated with cerebral vascular disease. RESULTS: a total of 5 708 patients with stable OPAD were included among the 3 studies. Risk factors were not managed in the majority of patients, including 62.6% of hypercholesterolemic patients, 71.1% of diabetics, and 77.4% of hypertensive patients. Overall, the control of risk factors was less satisfactory in patients with OPAD than in patients with CAD. Smoking (70.6% current or past smokers) remains a major risk factor in OPAD. The proportion of current smokers was significantly higher is the group with isolated OPAD than in the other 2 groups of patients (p < 0.0001). CONCLUSIONS: The control of risk factors in patients with OPAD is suboptimal, mainly because of failure to reach the therapeutic goals, rather than because of poor medical management. It is important that recent recommendations be implemented in medical practice. Awareness of the primary physicians will be key in the optimisation of treatment prescriptions and, above all, in the achievement of a higher level of clinical performance.

[Management of the cardiology patient with polyvascular disease: PRISMA study]. / Prise en charge du patient polyvasculaire en cardiologie de ville. Résultats de l'étude PRISMA.

INTRODUCTION: Myocardial infarction (MI), peripheral vascular disease and ischaemic cerebral vascular accident (CVA) are three manifestations of the same disease, atherothrombosis, and they share the same pathophysiology and prognosis. OBJECTIVE: The aim of this work was to describe the clinical characteristics and the medical management of polyvascular patients in cardiology. METHOD: Cardiologists from all over the country participated in a consultation register for 3 weeks. The clinical characteristics and medical management for the first 3 patients on the register for each cardiologist were studied in a national multicentre study and then compared according to whether the atherothrombotic disease was isolated or polyvascular. RESULTS: In total, 100,429 patients were examined during the period of the register and 2,780 were included in the study. Polyvascular patients represented 7% of the register and 22% of the vascular patients. These patients with multiple manifestations were frequently diabetics. A lipid profile was available less often in the cardiac patients when they had another disorder (72.4%) than in the case of an isolated disorder (78.9%). Whatever the initial disorder, dyslipidaemia was less often controlled in the case of polyvascular disease (63% of LDL-C > or = 1.3g/l in polyvascular cardiac patients vs 52% in cardiac patients with isolated disease). In cardiac patients, the presence of peripheral vascular disease was associated with less prescription of beta blockers (OR=0.4 [0.3-0.6]), the presence of CVA was associated with less prescription of statins (OR=0.7 [0.5-0.9]). Eight out of 10 polyvascular patients received anti-platelet aggregation treatment. The presence of multiple atherothrombotic manifestations was associated with greater prescription of ACEI, except in cardiac patients. CONCLUSION: These results improve our understanding of the specific management of polyvascular patients, for whom secondary prevention is paramount due to the higher risk of recurrence. They should prompt the reinforcement of measures which have been shown to be effective, such as managing major risk factors, and in particular the dislipidaemias.

[Factors influencing secondary prevention of atherothrombotic disease in the private outpatient cardiology setting: results of the Prisma survey]. / Etude sur les facteurs influençant les prescriptions en prévention secondaire de la maladie athérothrombotique en pratique de ville: résultats de l'étude Prisma.

From March to July 1999, 940 private cardiologists in France recruited 100,429 patients of whom 30,430 (30%) had a previous history of atherothrombotic disease. The prevalence of patients with a previous history of Myocardial Infarction (MI), Ischemic Stroke (IS) or Peripheral Arterial Disease (PAD) was 19.7%, 7.2% and 10.7% respectively. Among patients with a history of atherothrombotic disease, myocardial infarction was the most frequent diagnosis responsible for 65% of all consultations. Each cardiologist described the secondary prevention treatment for 3 consecutive patients among whom 1 corresponded to each of the 3 atherothrombotic territories. The most frequent cardiovascular risk factors were hypercholesterolemia for myocardial infarction (77.9%), smoking for PAD (32.5%) and hypertension for IS (73.2%). Diabetes mellitus (1/4 patients), obesity (1/3) and sedentary way of life (1/3) were equally prevalent for each of the atherothrombotic territories. More than 90% of the patients received an antithrombotic drug. Antiplatelet agents were largely prescribed, anticoagulants being more frequently used for patients with atrial fibrillation, symptomatic cardiac heart failure or stroke of embolic origin. Thienopyridines represent 17.9% of the prescriptions. The prescription rate of statins after MI (58.9%) is lower than in published studies in secondary prevention. The lack of lipid measurement and the delay since last measurement are non-prescription factors. The rates of prescription are even lower in case of PAD (44.6%) or IS history (33.3%). More than half of the patients (56.6%) are treated with beta-blockers and 40.1% with ACE inhibitors. These rates are similar to what has been published. Atherothrombotic disease represents a large part of the daily activity of private cardiologists and is not limited to coronary heart disease. Despite their proven efficacy, drugs for secondary prevention for MI, except antithrombotic drugs, are insufficiently prescribed. This under-prescription is even higher in patients with PAD or IS history and may be related to the lack of clinical trials in these specific territories.

Rationale and design of a clinical trial of a low-molecular-weight heparin in preventing clinically important venous thromboembolism in medical patients: the prospective evaluation of dalteparin efficacy for prevention of venous thromboembolism in immobilized patients trial (the PREVENT study).

The utility of low-molecular-weight heparin (LMWH) in the prophylaxis of venous thromboembolic disease has been examined using the surrogate endpoint of venographically identified thrombi. The largest portion of these thrombi were asymptomatic calf-vein thrombi. The clinical relevance of this observation is a matter of debate. The present study is designed to evaluate the impact of an LMWH on clinically important endpoints. The current study is a randomized, prospective, double-blinded, multicenter, multinational, controlled clinical trial comparing dalteparin with placebo in moderately high-risk hospitalized medical patients. A total of 3300 patients will be randomized to receive either 5,000 IU per day of dalteparin or placebo for 14 days. Patients will undergo appropriate evaluation for any symptomatic episodes and all patients will undergo a bilateral compression ultrasound (CUS) on day 21 to search for asymptomatic proximal thrombi. The primary endpoint is the combination of objectively confirmed symptomatic deep vein thrombi (DVT), fatal or non-fatal pulmonary emboli, all proximal DVT, and sudden death. This study will be the first study to examine clinically important endpoints in evaluating the effect of a LMWH in hospitalized medical patients. This study also is the first study to use CUS rather than venography in concordance with contemporary medical practice. This trial is thus designed to address this important question in a clinically relevant manner.