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تعداد آیتم قابل مشاهده باقیمانده : -55 مورد

Prevention of venous thromboembolic disease in acutely ill hospitalized medical adults

Prevention of venous thromboembolic disease in acutely ill hospitalized medical adults
Authors:
James D Douketis, MD, FRCPC, FACP, FCCP
Siraj Mithoowani, MD, MHPE, FRCPC
Section Editors:
Jess Mandel, MD, MACP, ATSF, FRCP
David A Garcia, MD
Deputy Editors:
Han Li, MD
Geraldine Finlay, MD
Literature review current through: Apr 2025. | This topic last updated: Apr 30, 2025.

INTRODUCTION — 

It is estimated that over one-half of hospitalized medical patients are at risk for venous thromboembolism (VTE; ie, deep vein thrombosis and/or pulmonary embolus) [1]. In addition, it is widely believed that PE is the most common preventable cause of hospital death [2-8].

This topic review discusses the prevention of VTE in patients hospitalized for acute medical illnesses [9]. Approaches to the prevention of VTE in surgical patients and patients with cancer and stroke, as well as in pregnancy, are presented separately.

●(See "Prevention of venous thromboembolic disease in adult nonorthopedic surgical patients".)

●(See "Risk and prevention of venous thromboembolism in adults with cancer".)

●(See "Venous thromboembolism in pregnancy: Prevention".)

●(See "Prevention and treatment of venous thromboembolism in patients with acute stroke", section on 'Approach to VTE prevention'.)

EPIDEMIOLOGY — 

While many epidemiologic studies report venous thromboembolism (VTE) rates ranging from 10 to 80 percent among various high-risk patient groups in the absence of prophylaxis, these rates are likely overestimated [2,3,5,10-26].

Accurate estimates of the incidence of clinically meaningful venous thromboembolic disease (ie, pulmonary embolus [PE] and deep vein thrombosis [DVT]) in hospitalized medical patients have been hampered by factors including the derivation of data from mixed surgical and medical populations, the reporting of both symptomatic and asymptomatic events, the increasing use of thromboprophylaxis and early ambulation during hospital admission, and the trend toward reducing length of hospital stay.

Thromboprophylaxis reduces the risk of VTE in hospitalized medical and surgical patients. While thromboprophylaxis has been reported to reduce the risk of death in surgical patients [27,28], most studies and a meta-analysis have not been able to show a consistent beneficial effect of thromboprophylaxis on mortality in hospitalized medical patients [29-38]. The reasons for this difference between medical and surgical patients are unclear but may be related to a greater number of comorbidities in medical patients that contribute to overall deaths. In addition, the baseline risk in medical patients is lower than in surgical patients, and therefore, most studies or meta-analyses may be underpowered to demonstrate an effect of thromboprophylaxis on mortality [39]. Finally, clinicians should be aware that VTE prophylaxis does not eliminate the risk of VTE or VTE-related death in hospitalized patients.

The risk of VTE in specific medical populations is discussed in this section, while the effect of thromboprophylaxis in these groups is described below. (See 'Methods of thromboprophylaxis' below.)

General medical patients — Compared with the community, most patients admitted with an acute medical illness are at increased risk for VTE during and following hospital admission [2,3,5,26,40]. One retrospective medical record review of 911 patients with VTE reported that the age- and sex-adjusted incidence of VTE was more than 130 times greater among hospitalized patients than among community residents with 60 percent of all cases occurring in hospitalized, recently discharged, or nursing home patients [26]. Older age and male sex appeared to be risk factors for the development of in-hospital VTE. Other studies have reported that PE is responsible for death in up to one-third of hospitalized medical patients and 45 percent of VTE events occurs in the three months following discharge, although some of these figures may be an over estimate based upon interpretation of autopsy results [2,3,5,40].

High-risk populations — Compared with other patient groups, the groups of medical patients listed below are at particularly high risk for the development of VTE during hospital admission or after discharge.

Intensive care unit patients — All patients admitted to intensive care units (ICUs) are considered high risk for VTE (both upper and lower extremity venous thrombosis; approximately 10 percent), even after routine prophylactic anticoagulation [21,41-46]. As examples:

●A retrospective study of over 150,000 critically ill adults reported mortality was higher in those who received delayed thromboprophylaxis (ie, after the first 24 hours) compared with those who received prophylaxis from the time of admission (8 versus 6 percent [ICU mortality] and 11 versus 10 percent [hospital mortality]) [47]. The increase in mortality attributed to delayed thromboprophylaxis varied depending upon the population, and was reported as 4 percent (trauma patients), 8 percent (sepsis patients), 9 percent (cancer patients), and 15 percent (patients who survived a cardiac arrest). (See "Overview of inpatient management of the adult trauma patient", section on 'Thromboprophylaxis' and "Venous thromboembolism risk and prevention in the severely injured trauma patient", section on 'Thromboprophylaxis'.)

●In a post-hoc analysis of a randomized trial of 3746 critically ill patients, the incidence of VTE was 8 percent (5 percent DVT, 2 percent PE, 1 percent DVT plus PE) [46]. Predictors of thromboprophylaxis failure included a personal or family history of VTE and obesity).

●In a retrospective analysis of 678 ICU patients, 5 percent had DVT despite being on thromboprophylaxis. A history of DVT was the strongest predictor for the development of proximal DVT [48].

Cancer — VTE is a common complication in patients with active malignancy, defined as cancer in the advanced stages or for which patients are receiving antineoplastic treatment. Detailed discussion of the risk of VTE in patients with active malignancy is provided separately. (See "Risk and prevention of venous thromboembolism in adults with cancer".)

Stroke — VTE is a common complication of stroke, particularly in those with lower limb paralysis. Detailed discussion of the risk of VTE in patients with stroke is provided separately. (See "Prevention and treatment of venous thromboembolism in patients with acute stroke".)

Other — Pregnancy is a risk factor for VTE. Detailed discussion of the overall risk of VTE during pregnancy as well as risk in pregnant patients admitted to hospital are provided separately. (See "Deep vein thrombosis in pregnancy: Clinical presentation and diagnosis" and "Venous thromboembolism in pregnancy: Prevention".)

There are numerous additional risk factors for VTE that may be present in hospitalized medical patients including heart failure, myocardial infarction, and age >60 years, as well as previous VTE, prolonged immobility, kidney failure, obesity, inherited or acquired hypercoagulable states, and coronavirus disease 2019 (COVID-19). These and other causes of VTE are discussed separately. (See "Overview of the causes of venous thrombosis in adults" and "COVID-19: Hypercoagulability".)

Effect of aspirin on risk — Aspirin should not be considered an effective thromboprophylaxis agent in medical patients. A large study and trial have not demonstrated a lower risk of VTE with low-dose aspirin [49,50].

DEFINITION OF VTE PROPHYLAXIS — 

Prevention of venous thromboembolism (VTE) can be defined as primary or secondary. Primary thromboprophylaxis is preferred because its efficacy is well established and it is more cost effective than treatment of complications once they occur [51].

Primary prophylaxis — Primary prophylaxis, the preferred method for VTE prevention, is carried out using either drugs (eg, heparin) or mechanical methods (eg, intermittent pneumatic compression boots) that are effective for preventing deep vein thrombosis (DVT). The characteristics of an ideal primary prophylactic method include ease of administration, effectiveness, safety (particularly with respect to bleeding), and cost-effectiveness or at least cost-neutrality. The prophylactic measures available for hospitalized medical patients include low-dose unfractionated heparin; low molecular weight (LMW) heparins; fondaparinux; oral factor Xa or direct thrombin inhibitors; and intermittent pneumatic compression (IPC) and/or graduated compression stockings (GCS) [52]. (See "Direct oral anticoagulants (DOACs) and parenteral direct-acting anticoagulants: Dosing and adverse effects", section on 'Direct thrombin inhibitors' and "Direct oral anticoagulants (DOACs) and parenteral direct-acting anticoagulants: Dosing and adverse effects", section on 'Direct factor Xa inhibitors' and "Heparin and LMW heparin: Dosing and adverse effects" and "Fondaparinux: Dosing and adverse effects" and "Prevention of venous thromboembolism in adults undergoing hip fracture repair or hip or knee replacement".)

Secondary prophylaxis — Secondary prevention involves the early detection and treatment of subclinical venous thrombosis by screening medical patients with objective tests that are sensitive for the presence of DVT. However, the benefits of available screening methods (eg, venous ultrasound, magnetic resonance imaging venography) on patient important outcomes is not well-established [53,54]. Accordingly, secondary prevention is often reserved for patients in whom primary prophylaxis is either contraindicated or shown to be ineffective. Secondary prophylaxis is also used during pregnancy in patients with a high clinical suspicion for DVT but a negative compressive lower extremity ultrasound, the details of which are discussed separately. (See "Deep vein thrombosis in pregnancy: Clinical presentation and diagnosis", section on 'Calf vein DVT suspected'.)

OUR APPROACH — 

Our approach is, for the most part, consistent with guidelines issued by several societies including the American College of Chest Physicians, the Neurocritical Care Society, the Society of Critical Care Medicine, and the American Society of Hematology [55-58].

Assess risk

Thrombosis risk assessment — The risk of venous thromboembolism (VTE) depends upon the nature of the acute illness and the presence of individual risk factors. A full history and examination should be obtained to assess this risk in all acutely ill hospitalized medical patients. We consider that medical patients admitted to hospital with at least one risk factor for VTE are at risk for the development of deep venous thrombosis and/or pulmonary embolism (PE). Risk factors commonly encountered in hospitalized patients include heart failure, acute respiratory failure (eg, acute exacerbations of chronic pulmonary disease), sepsis, inflammatory bowel disease, known thrombophilia, prolonged immobility ≥3 days, age >60 years, previous VTE, those with multiple risk factors, and possibly patients with an elevated D-dimer [19,29,39-42,52,59-72]. In addition, patients at particularly high risk of VTE include those who are critically ill, patients with lower limb paralysis from stroke, and patients with active cancer. (See "Overview of the causes of venous thrombosis in adults" and 'High-risk populations' above.)

Most clinicians empirically assess risk and administer thromboprophylaxis based upon this assessment (see 'Selection of method of prophylaxis' below). However, a number of empirically generated or data-derived risk models, based upon a number of the above-noted risk factors have been proposed [73]. These prediction scores require further validation from independent, prospective studies before they can be used in routine practice [74] but are described in brief below:

●The Padua Prediction Score was used to determine VTE risk in 1180 consecutive medical patients. Patients were followed for up to 90 days following admission to assess the occurrence of symptomatic VTE [75,76]. The rate of VTE was as follows (calculator 1):

•Low-risk patients (score <4): 0.3 percent

•High-risk patients (score ≥4): 2.2 (receiving adequate in-hospital thromboprophylaxis) and 11 percent (not receiving adequate in-hospital thromboprophylaxis)

●The original IMPROVE risk score was a four-factor risk score (prior VTE, active cancer, age >60 years, thrombophilia) used to determine VTE risk in medical inpatients [40].

It has since been modified (IMPROVE-DD) to incorporate seven risk factors (prior VTE, active cancer, age >60 years, thrombophilia, active lower limb paralysis, immobilized ≥7 days, intensive or coronary care unit admission) plus a D-dimer level measured during hospitalization [77]. A score of 4 or more points, or a score of 2 or 3 plus a high D-dimer indicates high risk of VTE.

●The GENEVA risk score was tested in a multicenter validation study that included 1478 hospitalized medical patients, 43 percent of whom did not receive thromboprophylaxis [19,78]. The risk of symptomatic VTE or VTE-related death at 90 days was the following (calculator 2) [78]:

•Low-risk patients (score <3): 0.6 percent (receiving adequate in-hospital thromboprophylaxis) and 0.8 percent (not receiving adequate in-hospital thromboprophylaxis.

•High-risk patients (score ≥3): 3.2 percent (receiving adequate in-hospital thromboprophylaxis) and 3.5 percent (not receiving adequate in-hospital thromboprophylaxis).

These models were compared in a prospective study of inpatients that found suboptimal accuracy in their ability to predict VTE [79].

Bleeding risk assessment — A full history and examination should be obtained to assess the risk of bleeding in all acutely ill hospitalized medical patients in whom pharmacologic VTE prophylaxis is warranted. Examples of medical patients at high risk of bleeding in whom pharmacologic thromboprophylaxis is typically contraindicated, include those with active bleeding or intracranial hemorrhage, those in whom a surgical procedure is planned in the immediate 6 to 12 hours (eg, spinal neuroaxial anesthesia), patients who have a moderate or severe coagulopathy, and patients with a severe bleeding diathesis or thrombocytopenia (eg, platelet count <50,000/microL or <100,000/microL plus additional risk factors for bleeding). Epistaxis and menstrual bleeding are not contraindications to pharmacologic thromboprophylaxis.

Validated models for evaluating the risk of bleeding in hospitalized medical patients are lacking [80,81]. Retrospective analysis of data from the International Medical Prevention Registry on Venous Thromboembolism (IMPROVE) has been used to assess in-hospital bleeding incidence in 15,156 medical patients and to identify risk factors at the time of admission associated with in-hospital bleeding risk [80]. The cumulative incidence of major and nonmajor in-hospital bleeding within 14 days of admission was 3.2 percent. The strongest independent risk factors for bleeding at the time of admission were the following:

●Active gastroduodenal ulcer (odds ratio [OR] 4.15, 95% CI 2.21-7.77)

●Bleeding within the three months prior to admission (OR 3.64, 95% CI 2.21-5.99)

●Platelet count <50,000/microL (OR 3.37, 95% CI 1.84-6.18)

Other bleeding risk factors included increased age, hepatic and/or kidney failure, intensive care unit stay, presence of a central venous catheter, rheumatic disease, cancer, and male sex (ie, factors that also increase the risk of VTE). Each of the above risk factors, with appropriate weighting, was entered into a risk model (IMPROVE Bleeding risk model) with scores ranging from 0 to 15. Overall rates of bleeding were the following in patients with:

●Risk scores of 1: 0.5 percent

●Risk scores of 4: 1.6 percent

●Risk scores of 7: 4.1 percent

●Risk scores of 15: 14 percent

Further validation of this model is warranted before it can be routinely used to assist clinicians in estimating the risks of bleeding from pharmacologic thromboprophylaxis in patients at risk for VTE.

Selection of method of prophylaxis — Selecting a method of thromboprophylaxis is dependent upon many factors including the nature of the acute medical illness, the risk of hemorrhage and thrombosis, preferences and values of the patient, institutional policy, and cost. Although thromboprophylaxis is typically individualized, our approach in hospitalized medical patients is outlined in the sections below. These suggestions apply to hospitalized medical patients regardless of whether they are receiving aspirin on admission. (See 'Effect of aspirin on risk' above.)

Low-risk patients — For most patients hospitalized with an acute medical illness and who are without obvious risk factors for VTE (eg, young patients admitted for a 12 hour observation following an episode of syncope from hypoglycemia), pharmacologic thromboprophylaxis is not warranted. Options for this low-risk group include early ambulation with or without mechanical methods of thromboprophylaxis. (See 'Mechanical methods of thromboprophylaxis' below.)

Moderate-risk patients — For most patients hospitalized with an acute medical illness, who have at least one risk factor for VTE and do not have an increased risk of bleeding, we recommend the use of pharmacologic thromboprophylaxis rather than mechanical methods or no prophylaxis. Low molecular weight (LMW) heparin is generally the preferred anticoagulant based upon randomized trials that suggest it is superior for preventing deep vein thrombosis (DVT). For those with kidney failure (creatinine clearance <30 mL/min) or for those in whom cost is an issue, unfractionated heparin (UFH) is a reasonable alternative to LMW heparin. (See 'Pharmacologic thromboprophylaxis' below.)

High-risk patients — For most patients hospitalized with an acute medical illness who are considered to be at high risk for VTE (eg, critically ill, cancer, stroke) and at low risk of bleeding, we recommend the use of pharmacologic thromboprophylaxis rather than mechanical methods or no prophylaxis. In general, we prefer LMW heparin rather than other anticoagulants but UFH is an alternative in those with kidney failure or in whom cost is an issue. (See 'Pharmacologic thromboprophylaxis' below.)

Special populations

Heparin-induced thrombocytopenia — Fondaparinux may be used as an alternative to heparin in patients with a history of heparin-induced thrombocytopenia. (See 'Pharmacologic thromboprophylaxis' below and "Management of heparin-induced thrombocytopenia".)

At risk of bleeding — For most patients hospitalized with an acute medical illness who have risk factors for VTE and who are at high risk of bleeding or in whom anticoagulation is contraindicated (eg, gastrointestinal or intracranial hemorrhage), mechanical methods of VTE prevention (eg, intermittent pneumatic compression, graduated compression stockings, venous foot pump) are suggested over no prophylaxis [55]. Among these methods, pneumatic compression devices and graduated compression stockings are the most common forms of mechanical prophylaxis used. When mechanical forms of prophylaxis are used, transition to a pharmacologic agent should occur as soon as the bleeding risk becomes acceptably low (eg, often within 24 to 48 hours) or has been reversed [55]. (See 'Mechanical methods of thromboprophylaxis' below.)

Other — Special populations of medical patients require an individualized approach to thromboprophylaxis during an acute hospitalization. Detailed discussion of those populations is provided separately:

●Patients undergoing neuraxial anesthesia or analgesia (see "Neuraxial anesthesia/analgesia techniques in the patient receiving anticoagulant or antiplatelet medication")

●Patients with stroke (see "Prevention and treatment of venous thromboembolism in patients with acute stroke")

●Patients who are pregnant (see "Venous thromboembolism in pregnancy: Prevention")

●Patients with cancer (see "Risk and prevention of venous thromboembolism in adults with cancer")

●Patients traveling for extended periods (see "Pathogenesis, risk factors, and prevention of venous thromboembolism in adult travelers")

●Patients with spinal cord injury (see "Respiratory complications in the adult patient with chronic spinal cord injury")

●Patients with hemophilia (See "Acute treatment of bleeding and surgery in hemophilia A and B".)

Duration of prophylaxis — Ideally, VTE prophylaxis should continue until the patient is discharged from the hospital or fully ambulatory. We do not routinely extend the duration of thromboprophylaxis beyond the acute hospital stay, except in select high-risk populations (eg, immobile patients transferred from an acute stroke unit to a rehabilitation unit within one week of presentation, elderly patients with active cancer, mechanically ventilated patients in a long-term acute care facility). However, we do not provide extended thromboprophylaxis to chronically immobilized patients residing at home or in a nursing home [55]. The optimal degree of ambulation that provides protection or reduced risk for DVT is unknown. In the absence of data to support a specific agent, choosing a medication is generally left to the individual discretion of the clinician or institutional policy.

In general, studies of extended duration thromboprophylaxis in acutely ill medical patients demonstrate some reduction in VTE risk but at the expense of an increased risk of major bleeding [82-86]. This contrasts with extended duration prophylaxis in some high-risk orthopedic patients (eg, post total hip replacement), in which data indicate a decreased risk of VTE without an increase in major bleeding. (See "Prevention of venous thromboembolism in adults undergoing hip fracture repair or hip or knee replacement", section on 'Duration'.)

The best evidence on the benefits and risks of extended duration thromboprophylaxis in medical patients is described below:

●In a meta-analysis of randomized trials comparing extended versus standard duration thromboprophylaxis in medical patients (including EXCLAIM [30,87], ADOPT [88], MAGELLAN [89], APEX [83], MARINER [90], and MICHELLE [91]), extended duration thromboprophylaxis [86]:

•Reduced the short-term risk of symptomatic VTE (7 versus 12 per 1000 participants, RR 0.60, 95% CI 0.46-0.78, number needed to treat [NNT] to prevent 1 VTE event = 204)

•But increased the short-term risk of major bleeding (6 versus 3 per 1000 participants, RR 2.05, 95% CI 1.51-2.79, number needed to treat for an additional harmful outcome [NNTH] = 314)

Extended duration thromboprophylaxis did not significantly affect short-term all-cause mortality (RR 0.97, 95% CI 0.87-1.08) or VTE-related mortality (RR 0.78, 95% CI 0.58-1.05).

There was significant heterogeneity between trials in strategies employed to enroll patients at higher risk for VTE (for example, use of D-dimer and older age in some trials versus elevated IMPROVE scores in others), duration of extended duration thromboprophylaxis (ranging from 10 to 45 days post discharge), and choice of anticoagulant agents. However, a sensitivity analysis taking heterogeneity into account still showed a similar reduced risk of symptomatic VTE with extended duration thromboprophylaxis. When omitting COVID-19 patients from analysis, reduced symptomatic VTE was also observed, but at the expense of an increase in risk of major bleeding.

METHODS OF THROMBOPROPHYLAXIS

Pharmacologic thromboprophylaxis — In randomized trials, pharmacologic prophylaxis with low molecular weight (LMW) heparin, unfractionated heparin (UFH), or fondaparinux have all been shown to be superior to placebo or mechanical devices in preventing VTE [39,64,65,92-100]. Among these, we prefer LMW heparin because meta-analyses suggest it is superior to UFH (twice daily or three times daily dosing regimens), particularly in high-risk populations (see 'High-risk populations' above). Most data from randomized studies suggest that there is no appreciable effect of heparin prophylaxis on mortality and limited effect on bleeding. The quality of data are limited by the heterogeneity of included study populations (low risk and high risk) and the failure to distinguish symptomatic from asymptomatic VTE. Aspirin and warfarin should not be used as primary agents for VTE prevention.

Low molecular weight heparin

Efficacy — Trials comparing LMW heparin with UFH and/or placebo in specific populations are discussed below:

●General medical populations – Examples of randomized studies and meta-analyses that illustrate the value of pharmacologic prophylaxis in general medical populations include the following:

•One meta-analysis of 36 randomized trials of a mixed population of hospitalized medical patients that included those at low and high risk for VTE, compared heparin with placebo for the prevention of deep vein thrombosis (DVT) and pulmonary embolism (PE) [64]. Both UFH and LMW heparin reduced the risk of DVT (risk ratio [RR] 0.33, 95% CI 0.26-0.42; RR 0.56, 95% CI 0.45-0.7, respectively) and PE (RR 0.64, 95% CI 0.50-0.82; RR 0.37, 95% CI 0.21-0.64, respectively) without any effect on mortality. When compared with UFH, use of LMW heparin was associated with a lower risk of DVT (RR 0.68, 95% CI 0.52-0.88) but no difference was reported between the two agents in the risk of bleeding or thrombocytopenia.

•Another meta-analysis of 16 randomized studies reported similar results in a population of over 34,000 medical patients that excluded those at high risk for VTE (myocardial infarction, stroke, intensive care unit patients) [99]. In that population, compared with placebo, both UFH and LMW heparin reduced the risk of DVT (odds ratio [OR] 0.38, 95% CI 0.29-0.51) as well as symptomatic and fatal PE (OR 0.65, 95% CI 0.42-1) with no effect on mortality and thrombocytopenia. However, an increase in major hemorrhage was reported with use of heparin (OR 1.81, 95% CI 1.1-2.98). Compared with UFH, LMW heparin was associated with a reduced risk of DVT (OR 0.77, 95% CI 0.62-0.96) and lower rates of major bleeding (OR 0.43, 95% CI 0.22-0.83).

•Another meta-analysis of 44 randomized trials (over 90,000 mostly medical patients) reported that all pharmacologic anticoagulants reduced symptomatic VTE compared with placebo and that none offered a mortality benefit [101]. Among the agents, those that offered superior efficacy for preventing VTE included intermediate dose LMW heparin (OR 0.66, 95% CI 0.46-0.93), direct oral anticoagulants (DOACs; 0.68, 95% CI 0.33-1.34), and intermediate dose unfractionated heparin (0.71, 95% CI 0.43-1.19) (very low to low quality evidence). However, bleeding rates were higher with intermediate dose unfractionated heparin (2.63, 95% CI 1.00 to 6.21) and DOACs (2.31, 95% CI 0.82-6.47) (low to moderate quality evidence).

●High-risk populations – Studies have also investigated the use of prophylaxis in select populations considered to be at high risk for VTE:

•Stroke – In patients with leg paralysis from ischemic stroke, data derived from randomized studies reported that, compared with UFH, LMW heparin was associated with a greater risk reduction for VTE with no significant increase in clinically relevant bleeding [69,102-104]. (See "Prevention and treatment of venous thromboembolism in patients with acute stroke", section on 'Approach to VTE prevention'.)

•Critically ill – Randomized trials and meta-analyses have examined the importance of prophylaxis in the critically ill [105-109]. As examples:

-One network meta-analysis of 13 randomized trials that enrolled a total of 9619 critically ill patients reported that LMW heparin reduced the incidence of all DVT (OR 0.59, 95% CI 0.33-0.90; high certainty) when compared with control treatment (a composite of no prophylaxis, placebo, or compression stockings only) [109]. LMW heparin appeared to be more effective than UFH (OR 0.72, 95% CI 0.46-0.98; moderate certainty), and mechanical methods of thromboprophylaxis (eg, intermittent compressive devices) were least effective (OR 0.85, 95% CI 0.50-1.50; low certainty). The effect of combination therapy was unclear.

-Another randomized trial (PROTECT) of 3764 critically ill patients directly compared UFH with the LMW heparin, dalteparin [106]. Dalteparin was associated with a rate reduction in PE (1 versus 2 percent; hazard ratio 0.5) but had no effect on DVT, bleeding, mortality, or cost [106,108].

•Older patients – A meta-analysis of 5657 patients ≥75 years of age showed that, compared with placebo, prophylaxis reduced the incidence of VTE (4 versus 11 percent) without affecting bleeding events, or all-cause mortality [98]. However, among all the VTE events seen in the placebo group (symptomatic and asymptomatic DVT, PE and fatal PE), two-thirds were asymptomatic or ultrasound-detected DVT. Although major bleeding events were rare (1.1 versus 0.7 percent; OR 1.77, 95% CI 0.52-6.08), the wide confidence limits suggest that some patients are more at risk for bleeding than others. Further randomized studies are required to assess the safety and efficacy of VTE prophylaxis in the older population. (See 'Assess risk' above.)

•Patients hospitalized with COVID-19 – Such patients represent a special population at markedly increased risk for VTE, especially if critically ill in an intensive care unit setting. The use of anticoagulants as prophylaxis against COVID-19-associated VTE is covered elsewhere. (See "COVID-19: Hypercoagulability".)

Dosing — A number of LMW heparin preparations are available (enoxaparin, dalteparin, tinzaparin, nadroparin), none of which have proven superiority over the other when administered as agents to prevent VTE. Suggested prophylactic doses for medical patients with a creatinine clearance >30 mL/minute and assuming no extremes in body weight are the following:

●Enoxaparin 40 mg subcutaneously once daily

●Dalteparin 5000 units subcutaneously once daily

Less commonly used are:

●Tinzaparin 4500 anti-Xa subcutaneously once daily

●Nadroparin 3800 anti-Xa units/day in patients ≤70 kg and 5700 units per day in patients >70 kg once daily

The platelet count may be monitored regularly (eg, day 5 and 9) in all patients receiving LMW heparin to detect the development of heparin-induced thrombocytopenia (HIT). All LMW heparin agents are contraindicated in patients with HIT. Management of heparin anticoagulants in patients with HIT is discussed separately. (See "Management of heparin-induced thrombocytopenia".)

The ideal dose for patients with obesity, including those with a body weight greater than 100 kg or body mass index >35 kg/m2, is unknown. Dosing is based on expert opinion, individualized on a case-by-case basis and varies amongst medical institutions. One approach used with LMW heparin prophylaxis is to increase the dose by 50 percent (eg, enoxaparin 60 mg once daily or dalteparin 7500 units once daily). Alternate dosing options are provided in the table (table 1).

Based upon data extrapolated from patients receiving therapeutic doses of LMW heparin, some experts prefer the avoidance of these agents in patients with severe kidney function impairment (eg, creatinine clearance <30 mL/min). However, we and other experts continue to use selected LMW heparins in patients with kidney function impairment (eg, tinzaparin and dalteparin), but a dose reduction of enoxaparin is needed for those with severe kidney function impairment (table 2). For those who develop severe kidney injury during hospitalization, it is prudent that selected LMW heparins be discontinued and replaced with UFH. (See "Heparin and LMW heparin: Dosing and adverse effects".)

Low-dose unfractionated heparin

Efficacy — Thromboprophylactic doses of UFH are effective at preventing VTE when compared with placebo or mechanical devices. However, when compared with UFH, LMW heparin appears to be marginally superior for the prevention of VTE, the details of which are discussed separately. (See 'Low molecular weight heparin' above.)

Dosing — Typical prophylactic dosing for UFH is 5000 units subcutaneously twice or three times daily. The frequency of UFH dosing is controversial. While one meta-analysis of 12 randomized studies, reported a nonsignificant reduction in the overall rate of VTE with three times daily compared with twice daily UFH heparin dosing (3.5 versus 5.4 events/1000 patient-days), the risk for major bleeding was significantly greater (0.96/1000 patient-days versus 0.35/1000 patient-days) [110]. In a second meta-analysis, when compared with placebo, UFH injected three times daily was more effective in preventing DVT than a twice daily dosing regimen (RR 0.27; versus RR 0.52; 95% CI 0.28-0.96) [64]. However, a third meta-analysis found no difference between twice and three times daily UFH dosing in the rates of VTE, VTE-related death, or major bleeding [111]. Our preference is for twice daily UFH dosing since the evidence to support three times daily is inconclusive. Factors including cost, institutional policy, body weight, and risk of bleeding may also be used to help the clinician make the decision to choose the frequency of dosing.

The ideal dose for patients with obesity is unknown, such that dosing should be individualized on a case-by-case basis. We generally prefer to empirically treat with UFH 5000 to 7500 units three times daily; alterations in the dosing and frequency should be tailored to individual patients.

Compared with LMW heparin, the dose of UFH does not need to be adjusted for patients with kidney failure. In addition, in some countries, low-dose UFH has the advantage of being inexpensive. However, similar to LMW heparin, UFH is contraindicated in patients with heparin-induced thrombocytopenia (HIT) and the platelet count should be monitored regularly (eg, days 5 and 9) in all patients receiving low-dose UFH to detect the development of HIT [112,113]. (See "Heparin and LMW heparin: Dosing and adverse effects", section on 'Platelet count monitoring'.)

Fondaparinux

Efficacy — Fondaparinux is superior to placebo and probably as effective as LMW heparin for patients who are not critically ill, although compared with LMW heparin, very little data are available to support its routine use.

Fondaparinux (2.5 mg subcutaneously once daily) was compared with placebo in 849 medical patients ≥60 years of age, hospitalized due to acute cardiac, respiratory, infectious, or inflammatory disease, who were expected to remain in bed for at least four days, and considered to be at moderate risk for VTE (ARTEMIS) [61]. There was a significant reduction in the rate of symptomatic and asymptomatic VTE (11 versus 6 percent). Major bleeding occurred in one patient (0.2 percent) in each group. This study is discussed in greater detail separately. (See "Fondaparinux: Dosing and adverse effects".)

Dosing — Fondaparinux is typically administered as 2.5 mg subcutaneously once daily. Fondaparinux should be avoided in those with a creatinine clearance <30 mL/min. If necessary, a dose reduction to 1.5 mg subcutaneously daily can be used in those with a creatinine clearance in the range of 30 to 50 mL/min [114]. The safety and efficacy of reduced dosing was tested in a multicenter prospective cohort study in 206 acutely ill older (mean age 82 years) medical patients (mean creatinine clearance 33 mL/minute [range 20 to 50 mL/min]) at high risk for both bleeding and thrombosis [115]. Symptomatic VTE developed in three patients (1.5 percent) and major bleeding occurred in only one patient (0.5 percent).

Aspirin — We agree with others that aspirin not be used, either alone or in combination, as prophylaxis against VTE in any medical patient group [55]. Although aspirin, is highly effective in reducing major arterial thrombotic events, there is little evidence that aspirin and/or other antiplatelet agents (eg, clopidogrel) can prevent venous thromboembolic events in hospitalized medical patients. Although a 1994 meta-analysis suggested that aspirin reduced the incidence of VTE by approximately 20 percent compared with placebo or no treatment [116,117], studies since then have shown either no significant benefit or inferiority when compared with other modalities such as LMW heparin [117].

In the community setting, aspirin does not appear to reduce the overall risk of VTE prior to admission, the details of which are discussed separately. (See 'Effect of aspirin on risk' above.)

In contrast, aspirin has been shown to decrease the recurrence rate in patients with a first episode of VTE, the details of which are also discussed separately. (See "Selecting adult patients with lower extremity deep venous thrombosis and pulmonary embolism for indefinite anticoagulation".)

Warfarin — Initiating warfarin in patients who are not already anticoagulated is not appropriate for immediate and short-term (ie, one month or less) prevention of VTE; the anticoagulant effect is delayed and does not occur until 36 to 72 hours after drug administration. In addition, hospitalized medical patients often have comorbidities (eg, impaired liver function) and/or are on medications that interfere with consistent prediction of the anticoagulant effect. (See "Warfarin and other VKAs: Dosing and adverse effects" and "Biology of warfarin and modulators of INR control", section on 'Mechanism of action'.)

Direct oral anticoagulants — Though not commonly utilized for VTE thromboprophylaxis during hospitalization, rivaroxaban is approved for this indication in acutely ill medical patients during hospitalization and following discharge [118]. In a study of over 7000 hospitalized medically ill patients, compared with enoxaparin, the composite outcome of asymptomatic and symptomatic VTE plus VTE-related death was reduced in patients taking betrixaban (which is no longer available) compared with subcutaneous enoxaparin (4.4 versus 6 percent) without any increase in the bleeding rate [119]. Rivaroxaban has been studied in the extended duration setting [89,120]. These studies are discussed above. (See 'Duration of prophylaxis' above.)

Dosing in patients with obesity is unclear. The International Society on Thrombosis and Hemostasis suggest that for patients with a body mass index (BMI) >40 kg/m2 or weight >120 kg, that standard dosing for rivaroxaban and apixaban rather than other DOACs can be used in this population [121].

Mechanical methods of thromboprophylaxis — We agree with others that mechanical methods for the prevention of VTE are primarily indicated in patients at high risk of bleeding or in whom anticoagulation is contraindicated (eg, gastrointestinal or intracranial hemorrhage) [55]. When used in these circumstances, transition to a pharmacologic agent should be considered as soon as the bleeding risk becomes acceptably low or has been reversed [55]. Data that supports this approach are derived mostly from surgical patients and limited data performed in acutely ill hospitalized medical patients.

Options include intermittent pneumatic compression, graduated compression stockings, and venous foot pumps. Neuromuscular electrical stimulation remains investigational [122].

Intermittent pneumatic compression — Intermittent pneumatic compression (IPC) (picture 1) prevents DVT by enhancing blood flow in the deep veins of the legs, thereby preventing venous stasis [123]. IPC also reduces plasminogen activator inhibitor-1 (PAI-1), thereby increasing endogenous fibrinolytic activity [124]. (See "Thrombotic and hemorrhagic disorders due to abnormal fibrinolysis", section on 'PAI-1'.)

IPC devices are an alternative for VTE prevention in medical patients with a high risk of bleeding or in whom anticoagulant drugs are contraindicated (eg, GI bleeding, intracranial hemorrhage) [55]. Although there are no data available on skin complications of IPC use, skin breakdown is a known complication, especially in the frail older adult population. IPC devices are also contraindicated in patients with evidence of leg ischemia due to peripheral vascular disease. Attention must be paid to optimal compliance, as well as proper fit of the IPC device.

Data on the efficacy and safety of IPCs are limited. However, one large randomized trial in patients with stroke suggested that IPCs reduce the incidence of VTE [125]. A multicenter, randomized trial of 2876 immobile patients with acute stroke (CLOTS 3) reported that, compared with no device, IPC use was associated with a lower rate of VTE at 30 days (12 versus 8.5 percent) without altering mortality (13 versus 11 percent). However, the use of LMW heparin was similar in both groups (32 versus 30 percent). Further results of this trial and clot prevention in patients with stroke are discussed separately. (See "Prevention and treatment of venous thromboembolism in patients with acute stroke", section on 'Intermittent pneumatic compression'.)

Contraindications to anticoagulant prophylaxis are discussed above. (See 'Bleeding risk assessment' above.)

Graduated compression stockings and venous foot pump — There is even less convincing evidence regarding the efficacy of graduated compression stockings (GCS) and venous foot pumps (VFP) in medical patients (picture 2).

In a meta-analysis, GCS was found to be ineffective in the prevention of VTE in patients with ischemic stroke [126]. One randomized trial of stroke patients showed that thigh-length GCS was associated with no benefit with respect to reduction of VTE, along with a fourfold increase in skin ulcers and necrosis [127]. The use of GCS to prevent VTE following stroke is discussed separately. (See "Prevention and treatment of venous thromboembolism in patients with acute stroke", section on 'Ineffective or unproven treatments'.)

Similarly, randomized studies showing efficacy of VFP devices in medical patients are lacking and most data to support their use are derived from the surgical population [128]. In theory, they prevent thrombosis by stimulating lower limb venous flow at the level of the foot [129].

Combined methods — Despite the widespread practice of combining mechanical and pharmacologic methods of thromboprophylaxis, few studies have systematically examined the efficacy of this approach on the rates of VTE or VTE-related death in acutely ill hospitalized medical patients. One large randomized trial assessing the use of GCS in medical patients, with or without low-dose LMW heparin, found no added mortality benefit with the use of LMW heparin. However, this trial may have been underpowered to detect a significant difference in mortality [34]. A second randomized trial (PREVENT) of 2003 critically ill patients, 80 percent of whom were medical intensive care unit patients, reported that the addition of intermittent pneumatic compression (IPC) for at least 18 hours a day to unfractionated or LMW heparin did not reduce the rate of ultrasound-detected deep venous thrombosis (3.9 versus 4.2 percent) or symptomatic pulmonary embolism (0.8 versus 1.0 percent) or death from any cause (26 percent each) [130]. However the incidence of VTE was lower than expected in the control group, thereby reducing the power of the trial to detect a difference between the groups. The value of combined prophylaxis in surgical patients is discussed separately. (See "Prevention of venous thromboembolic disease in adult nonorthopedic surgical patients", section on 'With low bleeding risk: Combined prophylaxis'.)

ANTICOAGULANTS IN DEVELOPMENT — 

Anticoagulants in development for thrombosis prophylaxis are discussed separately. (See "Investigational anticoagulants".)

QUALITY IMPROVEMENT INITIATIVES

●National programs – The prevention of venous thromboembolism (VTE) is a major patient safety issue in hospitals according to the Agency for Health Care Research and Quality [131]. As an example, the Center for Medicare and Medicaid Services (CMS) considers appropriate VTE prophylaxis to be a pay-for-performance quality measure for specific surgical procedures [132].

Thus, in the United States there have been a number of initiatives aimed at calling attention to the prevalence of VTE and advocating for increased use of VTE prophylaxis in hospitalized patients. These initiatives have come from The National Quality Forum [133], The Surgical Care Improvement Project [102], the Centres for Medicine and Medicinal Services, the Joint Commission on Accreditation of Health Care Organizations [134], and the Office of the Surgeon General of the United States [135]. Similar initiatives have been developed in Canada [136], the United Kingdom [59,137], and Europe.

However, despite these efforts, numerous audits and reviews have demonstrated that appropriate thromboprophylaxis is not being offered to large numbers of patients, particularly those hospitalized with medical conditions [92,138-147]. Reasons for this may include contraindications to anticoagulants or altered risk as the patient progresses throughout their admission as well as clinician reluctance to change practice.

●Hospital decision support programs – Various strategies designed to improve the appropriate use of thromboprophylaxis have shown inconsistent or unproven effects on reducing VTE incidence [148-153]. Such strategies include clinician alerts, computerized order sets with electronic alerts or pre-printed orders, risk assessment models, and quality improvement in the form of audit and feedback. Despite the existence of such programs, formal educational programs for involved health care professionals may still be needed to significantly improve the appropriate use of thromboprophylaxis [154,155]. Further efforts are required at improving the translation of data from clinical trials into clinical practice [75,156-165].

●Predictive models – Predictive models that identify those at greatest risk and in need of thromboprophylaxis have been reported. As an example, one database analysis identified factors independently associated with VTE as previous VTE, known thrombophilia, cancer, age >60 years, lower-limb paralysis, immobilization for seven days or longer, and admission to an ICU or coronary care unit [40]. Points were assigned to each factor identified to give a total risk score for each patient. During hospitalization, a score ≥2 was associated with higher overall and VTE-related mortality. Predictive models such as these need validation before they can be routinely used at the time of admission or during hospitalization to identify those at greatest risk in whom thromboprophylaxis should be administered.

SOCIETY GUIDELINE LINKS — 

Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Superficial vein thrombosis, deep vein thrombosis, and pulmonary embolism".)

INFORMATION FOR PATIENTS — 

UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Beyond the Basics topics (see "Patient education: Deep vein thrombosis (DVT) (Beyond the Basics)" and "Patient education: Warfarin (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

●Epidemiology and thrombosis risk – While many studies report venous thromboembolism (VTE) rates ranging from 10 to 80 percent among various high-risk patient groups in the absence of prophylaxis, these rates are likely overestimated.

•General medical patients – While thromboprophylaxis reduces the risk of VTE in hospitalized medical patients, mortality benefits are unclear in this population. Importantly, clinicians should be aware that VTE prophylaxis does not eliminate the risk of VTE or VTE-related death. (See 'Epidemiology' above.)

•High-risk patient groups – Patients at highest risk of VTE include patients who are critically ill, patients with cancer or stroke, and patients with multiple risk factors for VTE including pregnancy, heart failure, myocardial infarction, old age (>75 years), previous VTE, prolonged immobility, kidney failure, obesity, and inherited or acquired hypercoagulable states. (See 'Epidemiology' above and "Overview of the causes of venous thrombosis in adults".)

•Risk assessment – For patients admitted to the hospital with an acute medical illness, a full history and examination should be performed to assess both the risk of VTE and bleeding. Validated models for evaluating this risk in hospitalized medical patients are lacking. (See 'Assess risk' above.)

●Low-risk patients – For hospitalized medical patients without obvious risk factors for VTE, we recommend that pharmacologic thromboprophylaxis not be employed. Options for this low-risk group include early ambulation with or without mechanical methods of thromboprophylaxis. (See 'Selection of method of prophylaxis' above and 'Mechanical methods of thromboprophylaxis' above.)

●Moderate- or high-risk patients – For most patients hospitalized with an acute medical illness who have at least one risk factor for VTE (moderate or high risk) and do not have an increased risk of bleeding, we recommend the use of pharmacologic thromboprophylaxis rather than mechanical methods or no prophylaxis (Grade 1B).

•Agent of choice – Among the available agents, we prefer low molecular weight heparin rather than other anticoagulants (table 2) (Grade 2C), particularly in high-risk populations (eg, critically ill, cancer, stroke).

•Alternatives – For those with kidney failure (creatinine clearance <30 mL/min) or for those in whom cost is an issue, unfractionated heparin is a reasonable alternative. For patients with heparin-induced thrombocytopenia, fondaparinux may be used as an alternative to heparin. (See 'Selection of method of prophylaxis' above and 'Pharmacologic thromboprophylaxis' above.)

•Combined prophylaxis – While some experts administer more aggressive prophylaxis in the form of increased intensity of a pharmacologic agent or the addition of a mechanical device, data do not support this approach in medical patients. (See 'Combined methods' above.)

●Patients at risk of bleeding – For most patients hospitalized with an acute medical illness who have risk factors for VTE and who are at high risk of bleeding or in whom anticoagulation is contraindicated (eg, gastrointestinal or intracranial hemorrhage), we suggest mechanical methods of VTE prevention (eg, intermittent pneumatic compression, graduated compression stockings, venous foot pump (picture 1)) over no prophylaxis (Grade 2C). Transition to a pharmacologic agent should occur as soon as the bleeding risk becomes acceptably low or has been reversed. (See 'Mechanical methods of thromboprophylaxis' above and 'At risk of bleeding' above.)

●Special populations – Special populations of medical patients require an individualized approach to thromboprophylaxis during an acute hospitalization. These include patients with heparin-induced thrombocytopenia, patients undergoing neuraxial anaesthesia or analgesia, patients with stroke or cancer, patients who are traveling for extended periods, and patients who are pregnant. (See "Neuraxial anesthesia/analgesia techniques in the patient receiving anticoagulant or antiplatelet medication" and "Risk and prevention of venous thromboembolism in adults with cancer" and "Venous thromboembolism in pregnancy: Prevention" and "Prevention and treatment of venous thromboembolism in patients with acute stroke".)

●Duration – VTE prophylaxis should typically continue until the patient is ambulatory or discharged from the hospital. We suggest not routinely extending the duration of thromboprophylaxis beyond the period of the acute hospital stay (Grade 2B). However, select populations may benefit from extended duration prophylaxis, including immobile patients transferred from an acute stroke unit to a rehabilitation unit within one week of presentation, elderly patients with active cancer, and mechanically ventilated patients in a long-term acute care facility. (See 'Duration of prophylaxis' above.)

ACKNOWLEDGMENT — 

The UpToDate editorial staff acknowledges Menaka Pai, MD, FRCPC, who contributed to earlier versions of this topic review.

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Topic 1346 Version 114.0

References

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61 : Efficacy and safety of fondaparinux for the prevention of venous thromboembolism in older acute medical patients: randomised placebo controlled trial.

62 : A safety analysis of thromboprophylaxis in acute medical illness.

63 : Venous thromboembolism prophylaxis in hospitalized heart failure patients.

64 : Pharmacological venous thromboembolism prophylaxis in hospitalized medical patients: a meta-analysis of randomized controlled trials.

65 : Efficacy and safety of anticoagulant prophylaxis to prevent venous thromboembolism in acutely ill medical inpatients: a meta-analysis.

66 : Variability in the use of thromboprophylaxis and outcomes in critically ill medical patients.

67 : Meta-analysis of venous thromboembolism prophylaxis in medically Ill patients.

68 : The magnitude of an iatrogenic disorder: a systematic review of the incidence of venous thromboembolism for general medical inpatients.

69 : The efficacy and safety of enoxaparin versus unfractionated heparin for the prevention of venous thromboembolism after acute ischaemic stroke (PREVAIL Study): an open-label randomised comparison.

70 : A multicenter randomized double-blind study of enoxaparin compared with unfractionated heparin in the prevention of venous thromboembolic disease in elderly in-patients bedridden for an acute medical illness. The Enoxaparin in Medicine Study Group.

71 : Thromboprophylaxis is associated with reduced post-hospitalization venous thromboembolic events in patients with inflammatory bowel diseases.

72 : D-dimer as a predictor of venous thromboembolism in acutely ill, hospitalized patients: a subanalysis of the randomized controlled MAGELLAN trial.

73 : The use of weighted and scored risk assessment models for venous thromboembolism.

74 : Validation of Risk Assessment Models of Venous Thromboembolism in Hospitalized Medical Patients.

75 : Electronic alerts to prevent venous thromboembolism among hospitalized patients.

76 : A risk assessment model for the identification of hospitalized medical patients at risk for venous thromboembolism: the Padua Prediction Score.

77 : The IMPROVEDD VTE Risk Score: Incorporation of D-Dimer into the IMPROVE Score to Improve Venous Thromboembolism Risk Stratification.

78 : Multicentre validation of the Geneva Risk Score for hospitalised medical patients at risk of venous thromboembolism. Explicit ASsessment of Thromboembolic RIsk and Prophylaxis for Medical PATients in SwitzErland (ESTIMATE).

79 : Risk Assessment Models for Venous Thromboembolism in Medical Inpatients.

80 : Factors at admission associated with bleeding risk in medical patients: findings from the IMPROVE investigators.

81 : Risk factors and impact of major bleeding in critically ill patients receiving heparin thromboprophylaxis.

82 : Extended thromboprophylaxis for medically ill patients with decreased mobility: does it improve outcomes?

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87 : Impact of age on the efficacy and safety of extended-duration thromboprophylaxis in medical patients. Subgroup analysis from the EXCLAIM randomised trial.

88 : Apixaban versus enoxaparin for thromboprophylaxis in medically ill patients.

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90 : Rivaroxaban for Thromboprophylaxis after Hospitalization for Medical Illness.

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96 : Outcomes of thromboprophylaxis with enoxaparin vs. unfractionated heparin in medical inpatients.

97 : Individual patient data meta-analysis of enoxaparin vs. unfractionated heparin for venous thromboembolism prevention in medical patients.

98 : Routine pharmacological venous thromboembolism prophylaxis in frail older hospitalised patients: where is the evidence?

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100 : Thrombosis prophylaxis and mortality risk among critically ill adults.

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104 : Differences between low-molecular-weight and unfractionated heparin for venous thromboembolism prevention following ischemic stroke: a metaanalysis.

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106 : Dalteparin versus unfractionated heparin in critically ill patients.

107 : Thromboprophylaxis with low molecular weight heparin versus unfractionated heparin in intensive care patients: a systematic review with meta-analysis and trial sequential analysis.

108 : Cost-effectiveness of dalteparin vs unfractionated heparin for the prevention of venous thromboembolism in critically ill patients.

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110 : Twice vs three times daily heparin dosing for thromboembolism prophylaxis in the general medical population: A metaanalysis.

111 : Dosing frequency of unfractionated heparin thromboprophylaxis: a meta-analysis.

112 : Heparin-induced thrombocytopenia in patients treated with low-molecular-weight heparin or unfractionated heparin.

113 : Risk for heparin-induced thrombocytopenia with unfractionated and low-molecular-weight heparin thromboprophylaxis: a meta-analysis.

114 : Parenteral anticoagulants: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines.

115 : Safety and efficacy of low-dose fondaparinux (1.5 mg) for the prevention of venous thromboembolism in acutely ill medical patients with renal impairment: the FONDAIR study.

116 : Antiplatelet therapy for thromboprophylaxis: the need for careful consideration of the evidence from randomised trials. Antiplatelet Trialists' Collaboration.

117 : Does acetyl salicylic acid (ASA) have a role in the prevention of venous thromboembolism?

118 : Does acetyl salicylic acid (ASA) have a role in the prevention of venous thromboembolism?

119 : The safety and efficacy of full- versus reduced-dose betrixaban in the Acute Medically Ill VTE (Venous Thromboembolism) Prevention With Extended-Duration Betrixaban (APEX) trial.

120 : Edoxaban for the Treatment of Cancer-Associated Venous Thromboembolism.

121 : Use of direct oral anticoagulants in patients with obesity for treatment and prevention of venous thromboembolism: Updated communication from the ISTH SSC Subcommittee on Control of Anticoagulation.

122 : Neuromuscular electrical stimulation for the prevention of venous thromboembolism.

123 : The effect of intermittently applied external pressure on the haemodynamics of the lower limb in man.

124 : The fibrinolytic effects of intermittent pneumatic compression: mechanism of enhanced fibrinolysis.

125 : Effectiveness of intermittent pneumatic compression in reduction of risk of deep vein thrombosis in patients who have had a stroke (CLOTS 3): a multicentre randomised controlled trial.

126 : Prevention of deep venous thrombosis and pulmonary embolism following stroke: a systematic review of published articles.

127 : Effectiveness of thigh-length graduated compression stockings to reduce the risk of deep vein thrombosis after stroke (CLOTS trial 1): a multicentre, randomised controlled trial.

128 : Is venous foot pump effective in prevention of thromboembolic disease after joint arthroplasty: a meta-analysis.

129 : The anatomy and physiology of the venous foot pump.

130 : Adjunctive Intermittent Pneumatic Compression for Venous Thromboprophylaxis.

131 : Adjunctive Intermittent Pneumatic Compression for Venous Thromboprophylaxis.

132 : Adjunctive Intermittent Pneumatic Compression for Venous Thromboprophylaxis.

133 : Adjunctive Intermittent Pneumatic Compression for Venous Thromboprophylaxis.

134 : Adjunctive Intermittent Pneumatic Compression for Venous Thromboprophylaxis.

135 : Cardiology patient pages. The Surgeon General's call to action to prevent deep vein thrombosis and pulmonary embolism.

136 : Cardiology patient pages. The Surgeon General's call to action to prevent deep vein thrombosis and pulmonary embolism.

137 : Cardiology patient pages. The Surgeon General's call to action to prevent deep vein thrombosis and pulmonary embolism.

138 : Risk factors associated with symptomatic pulmonary embolism in a large cohort of deep vein thrombosis patients.

139 : Venous thromboembolism risk and prophylaxis in the acute hospital care setting (ENDORSE study): a multinational cross-sectional study.

140 : Efficacy and safety of fixed low-dose dalteparin in preventing venous thromboembolism among obese or elderly hospitalized patients: a subgroup analysis of the PREVENT trial.

141 : Postdischarge thromboprophylaxis and mortality risk after hip-or knee-replacement surgery.

142 : Multicenter evaluation of the use of venous thromboembolism prophylaxis in acutely ill medical patients in Canada.

143 : Antithrombotic therapy practices in US hospitals in an era of practice guidelines.

144 : Prophylaxis of venous thromboembolism in the US: improving hospital performance.

145 : Venous thromboembolism risk and prophylaxis in hospitalised medically ill patients. The ENDORSE Global Survey.

146 : The AVAIL ME Extension: a multinational Middle Eastern survey of venous thromboembolism risk and prophylaxis.

147 : Prophylaxis against venous thromboembolism in hospitalized medically ill patients.

148 : Venous thromboembolism prevention: a systematic review of methods to improve prophylaxis and decrease events in the hospitalized patient.

149 : Comprehensive VTE prevention program incorporating mandatory risk assessment reduces the incidence of hospital-associated thrombosis.

150 : Interventions for implementation of thromboprophylaxis in hospitalized medical and surgical patients at risk for venous thromboembolism.

151 : Randomized trial of physician alerts for thromboprophylaxis after discharge.

152 : External validation of a risk assessment model for venous thromboembolism in the hospitalised acutely-ill medical patient (VTE-VALOURR).

153 : Universal EHRs Clinical Decision Support for Thromboprophylaxis in Medical Inpatients

154 : The use of an exclusion-based risk-assessment model for venous thrombosis improves uptake of appropriate thromboprophylaxis in hospitalized medical patients.

155 : Venous thromboembolism in medical outpatients - a cross-sectional survey of risk assessment and prophylaxis.

156 : A systematic review of strategies to improve prophylaxis for venous thromboembolism in hospitals.

157 : Venous thromboembolism prophylaxis in medically ill patients and the development of strategies to improve prophylaxis rates.

158 : Antithrombotic and thrombolytic therapy: from evidence to application: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy.

159 : Hospitals' compliance with prophylaxis guidelines for venous thromboembolism.

160 : Physician alerts to prevent symptomatic venous thromboembolism in hospitalized patients.

161 : Computerized decision support for the cardiovascular clinician: applications for venous thromboembolism prevention and beyond.

162 : Physician compliance with advanced electronic alerts for preventing venous thromboembolism among hospitalized medical patients.

163 : Venous thromboembolic events in hospitalised medical patients.

164 : Long-term complications of medical patients with hospital-acquired venous thromboembolism.

165 : Defining the population in need of thromboprophylaxis - making hospitals safer.