Journal of Thrombosis and Thrombolysis

, 32:318

Standard or extended-duration prophylaxis in medical patients? A review of the evidence

Authors

    • Department of PharmacyWashington Regional Medical Center
  • W. J. Smith
    • Department of Pharmacy: Clinical and Administrative SciencesUniversity of Oklahoma College of Pharmacy
Article

DOI: 10.1007/s11239-011-0594-5

Cite this article as:
Stark, J.E. & Smith, W.J. J Thromb Thrombolysis (2011) 32: 318. doi:10.1007/s11239-011-0594-5

Abstract

Acutely ill medical patients are at significant risk of venous thromboembolism (VTE). Thromboprophylaxis can substantially reduce the incidence of VTE, but to be optimally effective must consist of the correct choice of agent, at an appropriate dose, and for sufficient duration. Increasing evidence suggests that VTE risk persists beyond the standard period of prophylaxis. Although there is evidence that extended-duration prophylaxis is beneficial in preventing late VTE complications in high-risk surgical patients, few data exist in medical patients. The recent EXCLAIM study demonstrated that, subsequent to a standard prophylaxis regimen of 10 ± 4 days with enoxaparin 40 mg once daily, extended-duration prophylaxis (28 ± 4 days) with enoxaparin reduced total VTE events compared with placebo: 2.5% versus 4.0%; (absolute risk difference −1.53%; 95.8% confidence interval [CI] −2.54 to −0.52), with parallel increases in major bleeding rates (0.8% vs. 0.3%; absolute risk difference 0.51%; 95% CI 0.12–0.89%). The reduction in total VTE was principally driven by a decrease in symptomatic deep-vein thrombosis (absolute risk difference −0.60%; 95.8% CI −1.00 to −0.19%). Favorable benefit-to-risk ratios were observed in certain high-risk patient groups: level 1 immobility, women, and age >75 years. In addition to their underlying medical condition, medical patients often have multiple risk factors, placing them at sustained risk of VTE. Extended-duration prophylaxis might be most relevant in such patients. The development of appropriate risk assessment tools could help identify medical patients at greatest risk of late VTE events who might benefit most from extended-duration prophylaxis.

Keywords

Venous thromboembolismProphylaxisExtended-durationDeep-vein thrombosisPulmonary embolism

Introduction

Many acutely ill medical patients are at risk of venous thromboembolism (VTE), comprising deep-vein thrombosis (DVT) and pulmonary embolism (PE), which is associated with considerable morbidity and mortality [14]. Thromboprophylaxis can substantially reduce the incidence of VTE, and organizations such as the American College of Chest Physicians (ACCP) provide evidence-based recommendations delineating appropriate thromboprophylaxis management [3]. To be effective, prophylaxis must consist of the correct choice of antithrombotic agent or modality, at an appropriate dose, and for a sufficient duration [5].

In addition to the high risk of VTE during hospitalization, there is increasing awareness that risk persists after discharge and for considerably longer than the standard period of prophylaxis [4, 612]. In an observational study of 1,897 patients with confirmed VTE, nearly three-quarters (73.7%) of all VTE occurred in the outpatient setting [12]. For many of these outpatients, the VTE was associated with a recent period of hospitalization as a surgical (23.1%) or medical inpatient (36.8%), and more VTE cases were observed in the 3 months following hospitalization than during hospitalization [12]. Further evidence that the period of VTE risk in medical patients extends beyond the period of hospitalization is provided by a retrospective cohort analysis of 158,325 medical patients using an insurance claim database [4]. This study revealed that VTE events occurred most frequently post-discharge and the median time to VTE occurrence was 74 days [4].

There is strong evidence that an extended period of prophylaxis is beneficial in preventing late VTE complications in high-risk surgical patients, without a significant increase in the risk of major bleeding complications [6, 1316]. Medical patients frequently have multiple thrombotic risk factors, such as immobility, advanced age, obesity, cancer, congestive heart failure, chronic obstructive pulmonary disease, and infection [1, 3, 17]. These risk factors are often present after discharge and place patients at continued and persistent risk of VTE. However, few studies have investigated extended- versus standard-duration prophylaxis in medical patients at high risk of VTE. This review examines the rationale for, and the evidence supporting, extended-duration prophylaxis in medical patients.

The importance of prophylaxis in medical patients

Several studies have demonstrated that prophylaxis significantly reduces the risk of VTE in acutely ill medical patients [10, 11, 18]. For example, in the landmark Prophylaxis in Medical Patients with Enoxaparin (MEDENOX) trial in acutely ill medical patients (n = 866), the incidence of VTE (including asymptomatic DVT confirmed venographically or by duplex ultrasonography, and symptomatic VTE) was significantly lower in patients who received the low-molecular-weight heparin (LMWH) enoxaparin, 40 mg once daily, compared with placebo (5.5% vs. 14.9%; relative risk [RR] 0.37; 97.6% confidence interval [CI] 0.22–0.63; P < 0.001). During the treatment period six cases of major bleeding were observed in the treatment group compared with four in the placebo group [10]. Similarly, in 3,706 acutely ill medical patients randomized to receive either the LMWH dalteparin (5,000 IU daily) or placebo for 14 days, thromboprophylaxis reduced the incidence of VTE (including symptomatic VTE and asymptomatic DVT confirmed by compression ultrasound) or death up to day 21 from 4.96 to 2.77% (RR 0.55; 95% CI 0.38–0.80; P = 0.0015). Up to day 21, major bleeding occurred in 0.49% of patients treated with dalteparin compared with 0.16% in the placebo group (P = 0.15) [11]. The recent Arixtra for ThromboEmbolism Prevention in a Medical Indications Study (ARTEMIS) conducted in 849 older (≥60 years old), acutely ill medical patients evaluated the efficacy of fondaparinux (2.5 mg) administered subcutaneously once daily for 6–14 days versus placebo. Fondaparinux thromboprophylaxis significantly reduced the incidence of VTE (including DVT detected by routine bilateral venography and symptomatic VTE) compared with placebo up to day 15 (5.6% vs. 10.5%; RR reduction 46.7%; 95% CI 7.7–69.3%; P = 0.029) with no difference in major bleeding; one major bleed (0.2%) occurred in both the fondaparinux and placebo groups [18].

Current evidence-based guidelines from the ACCP recommend that acutely ill medical patients admitted to hospital with congestive heart failure or severe respiratory disease, or who are confined to bed and have one or more additional risk factors, including active cancer, previous VTE, sepsis, acute neurologic disease, or inflammatory bowel disease receive prophylaxis with LMWH, low-dose unfractionated heparin (UFH) or fondaparinux, unless anticoagulants are contraindicated (all Grade 1A) [3]. The International Union of Angiology (IUA) also recommend LMWH, low-dose UFH or fondaparinux as standard and practical options for prophylaxis in medical patients at risk of VTE [19]. However, it is important to note that the optimal duration of prophylaxis with LMWH and other anticoagulants is not well established in medical patients and not specified in the guidelines. The duration of prophylaxis is, however, mentioned in the summary of product characteristics for enoxaparin and dalteparin.

The optimal benefit from prophylaxis can only be gained if it is provided appropriately [5]. A number of studies [2024] illustrate that hospitalized medical patients frequently do not receive “appropriate” prophylaxis (defined as appropriate dose, type, and duration). In addition, many patients do not meet VTE prophylaxis requirements endorsed by organizations in the US such as the Joint Commission [25, 26]. The Joint Commission recently approved a core measure set to reduce and prevent VTE, endorsed by the National Quality Forum and aligned with the Centers for Medicare & Medicaid Services [25, 27]. Rothberg and colleagues retrospectively assessed compliance with one core measure, “patients who received VTE prophylaxis or have documentation why no VTE prophylaxis was given the day of or the day after hospital admission” [26]. Of 351,535 US medical patients at moderate to high risk of VTE, less than half (36%) received prophylaxis within 2 days of hospital admission [26].

Standard-duration prophylaxis

Standard prophylaxis regimens utilized in clinical trials of medical patients are typically 6–14 days in duration [10, 11, 18]. The standard period of prophylaxis in medical patients was related to the standard duration of hospitalization [21]. However, medical patients are more frequently being discharged from hospital after shorter inpatient stays [28], due to availability of oral antibiotics with improved bioavailability, close follow up with clinicians allowing continued diuresis for heart failure, and home health services and infusion clinics providing intravenous medications. These patients represent a subset of patients that would have previously had an extended hospital stay and may have prolonged VTE risk factors present despite discharge from the hospital, such as reduced mobility and active but controlled disease. In this situation, provision of inpatient prophylaxis alone may be insufficient to cover 6–14 days of prophylaxis. This is supported by a real-world study including 62,012 patients hospitalized with a medical condition placing them at risk of VTE [29]. The majority of medical patients in this study (84.7%) were not provided with prophylaxis in compliance with the Sixth ACCP guidelines [30], of which 11.4% (n = 5,994) were noncompliant due to inadequate duration (started late [n = 1,347], started late and ended before discharge [n = 2,961], or ended before discharge [n = 1,686]) [29].

In addition, results from studies in medical patients provide evidence that standard prophylaxis regimens may not be of sufficient duration [10, 11, 18, 31]. In the MEDENOX trial, enoxaparin or placebo was administered for 6–14 days to hospitalized acutely ill medical patients; however, between days 15 and 110, eight symptomatic VTE events occurred, including one fatal PE in the placebo group (3 weeks after discontinuation) and three fatal PEs in patients who received enoxaparin (2 months after discontinuation) [10]. In the Prospective Evaluation of Dalteparin Efficacy for Prevention of VTE in Immobilized Patients Trial (PREVENT), acutely ill medical patients were randomly assigned to 2 weeks of dalteparin (5,000 IU) (n = 1,518) or placebo (n = 1,473) [11]. Up to day 21, five symptomatic DVT events were reported in the LMWH group compared with 11 in the no prophylaxis group. Between day 21 and day 90 a further nine cases of symptomatic DVT occurred, five in the dalteparin group and four in the placebo group, representing over a third of all symptomatic DVTs during the study [11].

Other studies have also shown that the risk of VTE persists after standard-duration regimens of anticoagulants [1, 31]. Gärdlund et al. [31] investigated low-dose UFH (n = 5,776), given until hospital discharge or for a maximum of 3 weeks compared with no prophylaxis (n = 5,917) in the prevention of fatal PE in patients with infectious disease. Thromboprophylaxis reduced the total number of non-fatal VTE (70 vs. 116; P = 0.0012) and non-fatal PE events (29 vs. 58; P = 0.0026) without increasing the number of serious bleeding events detected at necropsy (14 vs. 6; P = 0.076). In addition, time to fatal PE was significantly increased in patients who received thromboprophylaxis compared with those who did not (median 28 [range, 24–36] vs. 12.5 [range, 10–20]; P = 0.007) [31]. In addition, in the ARTEMIS trial a further 15 cases of PE were observed after the initial 6–14 day study period, ten of which were fatal (three in the fondaparinux group and seven in the placebo group) [1]. Recent real-world data also illustrate the persistence of VTE risk in medical patients subsequent to discharge from hospital [32]. Discharge data from 15,721 at-risk medical patients in the US illustrated that 1.1% of patients experienced a VTE event after hospitalization [32].

It is clear from these clinical trials and observational studies that the duration of risk extends beyond the period of hospitalization into the outpatient setting. Accordingly, extended-duration prophylaxis may be warranted in certain medical patients.

Benefits of extended-duration prophylaxis

There is clear evidence that extended-duration prophylaxis reduces the risk of late VTE events without increased risk of serious complications in high-risk surgical patients [6, 13, 14, 3335]. In a meta-analysis of eight studies with LMWH and one study with UFH in patients after total hip or knee replacement, extended-duration prophylaxis for 30–42 days significantly reduced the frequency of symptomatic VTE compared with placebo or untreated controls (1.3% vs. 3.3%; odds ratio [OR] 0.38; 95% CI 0.24–0.61; number needed to treat = 50), without increasing the rates of major bleeding (0.1% vs. 0.3%; OR 0.62; 95% CI 0.22–1.75) [35]. Similarly, in a meta-analysis of six studies of out-of-hospital LMWH prophylaxis in patients after elective hip arthroplasty, extended prophylaxis (19–29 days post-discharge) significantly decreased the frequency of symptomatic VTE compared with placebo (1.4% vs. 4.2%; RR 0.36; 95% CI 0.20–0.67; P < 0.001). Major bleeding only occurred in one patient in the placebo group [34].

In addition to orthopedic surgery, patients undergoing major abdominal surgery have also been shown to benefit from extended-duration prophylaxis [15, 16]. In a study of 332 patients undergoing surgery for abdominal or pelvic cancer, enoxaparin 40 mg for 4 weeks significantly reduced the incidence of venographically detected DVT at 3 months compared with enoxaparin 40 mg administered for 1 week followed by placebo (5.5% vs. 13.8%; RR reduction 60%; 95% CI 17–81%; P = 0.01) [15]. No significant increases in the rates of minor (4.7% vs. 3.6%; P = 0.66) or major bleeding (1.2% vs. 0.4%; P = 0.62) were noted with the extended- compared with the standard-duration prophylaxis [15]. Likewise, in a study of patients undergoing major abdominal surgery (n = 427), prophylaxis with dalteparin for 4 weeks significantly reduced the cumulative incidence of VTE compared with a standard 1-week prophylactic regimen (7.3% vs. 16.3%; RR reduction 55%; 95% CI 15–76%; P = 0.012). Bleeding events were not increased with extended- compared with standard-duration prophylaxis (0.5% vs. 1.8%) [16].

In line with these findings, clinical guidelines from the ACCP and IUA advocate extended-duration prophylaxis in several groups of high-risk surgical patients [3, 19]. The ACCP guidelines recommend prophylaxis beyond 10 days and up to 35 days after hip replacement or hip fracture surgery [3]. ACCP guidelines also suggest that for selected high-risk patients undergoing major general surgery or gynecologic surgery, including those who had major cancer surgery or previous VTE, prophylaxis with a LMWH for up to 28 days post-discharge should be considered. In acutely ill medical patients, current guidelines from the ACCP and IUA do not provide any specific recommendations regarding the duration of prophylaxis [3, 19].

Since the ACCP issued the 2008 guidelines [3], the EXtended CLinical prophylaxis in Acutely Ill Medical patients (EXCLAIM) study has been published [36]. A total of 6,085 acutely ill medical patients, >40 years of age, with recent reduced mobility were randomized, in a double-blind manner, to receive subcutaneous enoxaparin 40 mg once daily (n = 3,034) or placebo (n = 3,051) for 28 ± 4 days, subsequent to receiving open-label enoxaparin 40 mg once daily for 10 ± 4 days. Of these patients, 5,963 received at least one dose of the study drug and comprised the safety population. The efficacy population (excluding those patients with ultrasonography problems and withdrawals) consisted of 4,995 patients; 2,485 and 2,510 patients received enoxaparin and placebo, respectively. The primary efficacy endpoint was the incidence of symptomatic or asymptomatic proximal DVT, symptomatic PE or fatal PE during the 28 ± 4 days after randomization, and the primary safety endpoint was the incidence of major hemorrhagic complications during and up to 48 h after the double-blind treatment period.

In the efficacy population, extended-duration enoxaparin significantly reduced the primary endpoint compared with placebo (2.5% vs. 4.0%; absolute risk difference −1.53%; 95.8% CI −2.54 to −0.52) (Table 1) [36]. However, the rate of major bleeding complications at 30 days was also significantly greater in the extended-duration group than the placebo group: 0.8 and 0.3%, respectively (absolute risk difference 0.51%; 95% CI 0.12–0.89) (Table 1). Subgroup analysis revealed a favorable benefit-to-risk ratio of extended-duration enoxaparin was limited to acutely ill medical patients with level 1 immobility (i.e. total bed rest or sedentary without bathroom privileges), women, and in particular, those patients aged >75 years (Table 1). The study was limited by a change in eligibility criteria during the trial period, which resulted in an amendment focusing on enrollment of patients at increased risk of VTE. Thus, the overall findings cannot be generalized to the patient population as a whole. They do, however, identify certain high-risk medical patient subgroups that could benefit most from extended-duration prophylaxis regimens, further highlighting the need for individual patient VTE risk assessment to determine which patients fit into such subgroups.
Table 1

Incidence of primary efficacy and safety outcomes in the EXtended CLinical prophylaxis in Acutely Ill Medical patients (EXCLAIM) study [36]

 

Venous thromboembolism

Major bleeding events

Extended-duration enoxaparin n/N (%)

Placebo n/N (%)

Absolute risk difference % (95.8% CI)

Extended-duration enoxaparin n/N (%)

Placebo n/N (%)

Absolute risk difference % (95% CI)

Total population

61/2485 (2.5)

100/2510 (4.0)

−1.53 (−2.54 to −0.52)

25/2975 (0.8)

10/2988 (0.3)

0.51 (0.12–0.89)

Subgroup analyses

 Level 1 immobilitya

25/1070 (2.3)

47/1040 (4.5)

−2.18 (−3.80 to −0.57)

9/1292 (0.7)

2/1281 (0.2)

0.54 (0.04–1.04)

 Women

23/1237 (1.9)

57/1247 (4.6)

−2.71 (−4.15 to −1.28)

14/1508 (0.9)

4/1511 (0.3)

0.66 (0.11–1.21)

 Age >75 years

18/725 (2.5)

50/743 (6.7)

−4.25 (−6.45 to −2.04)

6/878 (0.7)

4/903 (0.4)

0.24 (−0.46 to 0.94)

CI confidence interval

aLevel 1 immobility defined as total bed rest or sedentary without bathroom privileges

The ANCIANOS study, a prospective observational trial conducted at 49 centers in Spain, evaluated the use of bemiparin, a LMWH, for VTE prophylaxis in elderly medical (non-surgical) patients [37]. Patients aged ≥65 years who were bedridden for at least 4 days due to acute medical illness and who resided in geriatric centers (GCs) or hospital-at-home units (HHUs) were eligible for inclusion. Prophylaxis consisted of subcutaneous bemiparin 2,500 international units (IU) daily if at moderate VTE risk (age ≥65 and minor medical illness) or 3,500 IU daily if at high risk (pulmonary or cardiac disease, cancer, inflammatory bowel disease, rheumatologic disorder, serious infection, stroke, etc.). Prophylaxis was continued during the period of risk or until full mobilization. The primary outcome measure was symptomatic and objectively confirmed VTE, including DVT, PE, or both. A total of 507 patients were enrolled in the study with a mean age of 82 years (range 65–102 years). The most common VTE risk factors among patients included age ≥70, chronic venous insufficiency, and obesity; approximately 64% of patients had two or more VTE risk factors. Sixty-three percent of patients were considered high risk and received the higher daily dose of bemiparin. The mean duration of prophylaxis was 33 days. Documented symptomatic VTE occurred in 3 (0.6%) of patients, and all 3 cases were distal DVTs in high risk patients. No cases of proximal DVT or PE were detected. Bleeding events occurred in 10 (2.0%) patients—2 were considered major and 8 minor. There were no differences in bleeding rates when the two doses of bemiparin were compared and no cases of heparin-induced thrombocytopenia (HIT) were observed. There were 21 (4.1%) deaths during the study, none of which were considered related to study treatment.

Most recently, the extended-duration rivaroxaban thromboprophylaxis in acutely ill medical patients: MAGELLAN study was completed. [38, 39] This multicenter, double-blind controlled trial compared a new oral anticoagulant rivaroxaban 10 mg once daily (n = 4,050) administered for 35 ± 4 days to subcutaneous enoxaparin 40 mg once daily (n = 4,051) administered for 10 ± 4 days in patients ≥40 years of age hospitalized for acute medical illness. The median age was 71 years and the average length of stay was 11 days. The most frequently reported acute medical conditions were acute infectious disease, heart failure, acute respiratory insufficiency, and acute ischemic stroke.

The primary efficacy outcome was the composite of asymptomatic proximal DVT, symptomatic DVT, pulmonary embolism, and VTE-related death at 10 and 35 days. The composite efficacy outcome occurred at a rate of 2.7% in both study arms at 10 days and was significantly lower at 35 days in the rivaroxaban group compared to the enoxaparin group (4.4% vs. 5.7%; P < 0.05 for superiority). The primary safety outcome was a composite of major bleeding and clinically relevant nonmajor bleeding, which was significantly increased in the rivaroxaban group compared to the enoxaparin group at both 10 and 35 days (2.8% vs. 1.2% at 10 days and 1.4% vs. 0.5% at 35 days). A post hoc analysis is underway to identify which patient groups in the heterogeneous MAGELLAN study population may derive benefit from extended prophylaxis with rivaroxaban.

In addition, a study evaluating extended-duration regimens of the oral anticoagulant apixaban in acutely ill medical patients is also underway (Table 2) [40]. The ADOPT study assessing apixaban 2.5 mg twice-daily administered for 30 days is expected to end in May 2011 [40]. It is important to note that no anticoagulants currently have an indication for extended duration prophylaxis in medical patients.
Table 2

Ongoing study evaluating extended VTE prophylaxis in hospitalized medical patients [40]

Study name

Status

Study design

Population

Experimental arm

Active comparator

Primary outcome measure

ADOPT

Recruiting participants

R, DB

Adults age 40 years and older and hospitalized for an acute medical illness

Apixaban 2.5 mg PO twice daily for 30 days

Enoxaparin 40 mg SQ once daily for 6–14 days

Composite of VTE and VTE-related death

R randomized, DB double-blind, PO by mouth, SQ subcutaneously, VTE venous thromboembolism, DVT deep vein thrombosis, PE pulmonary embolism

Identifying medical patients at risk of late VTE complications

The risk of VTE in medical patients depends upon the presence of predisposing risk factors (e.g. advanced age and previous history of VTE), triggering risk factors (e.g. immobilization and pregnancy) and the effect of the presenting medical condition (e.g. cancer and acute infection) (Table 3) [41].
Table 3

Risk factors for venous thromboembolism (VTE) in medical patients

Predisposing risk factors

 Age

 History of VTE

 Venous insufficiency

 Obesity

 Standing >6 h/day

 >3 pregnancies

 Antiphospholipid syndrome

Triggering risk factors

 Immobilization

 Pregnancy

 Trauma

 Institutionalization

 Violent effort or muscular trauma

 Long-distance travel

 Central venous catheterization

 Recent surgery

 Hormone replacement therapy

Presenting medical conditions

 Cancer

 Infectious disease

 Chronic heart failure

 Myocardial infarction

 Chronic respiratory disease

 Neurological disease with extremity paresis

Adapted with permission from [41] ©Springer Science + Business Media, LLC 2006

Predisposing risk factors

In a multivariate analysis of data from the MEDENOX study to identify predisposing risk factors, a history of VTE was associated with the highest increase in the risk of VTE (OR 2.06; 95% CI 1.10–3.69) [42]. Previous history of VTE was also the strongest risk factor in the SIRIUS study, a case–control investigation of risk factors for DVT in medical patients (n = 1,272) [43]; the odds of developing a DVT were increased by more than 15 times in patients with prior VTE (OR 15.6; 95% CI 6.77–35.89; P < 0.001).

Age is also a key predisposing factor for VTE. Studies suggest that patients aged >40 years are at higher risk of VTE compared with younger patients and that risk approximately doubles with each subsequent decade [17]. The elderly population is at particularly high risk [4446]. One study utilizing data from the National Hospital Discharge Survey illustrates that, throughout the 21-year period studied, rates of DVT and PE were consistently higher in elderly patients (≥70 years) compared with younger patients (21–69 years); DVT rate ratio 4.72 (95% CI 4.30–5.14; P < 0.001), PE rate ratio 6.20 (95% CI 5.74–6.65; P < 0.001) [41]. A multivariate analysis of the MEDENOX trial has shown that age >75 years is independently related to the risk of VTE (OR 1.03; 95% CI 1.00–1.06) [44]. Likewise, in a case–control study by Heit et al. [48] advancing age positively correlated with the odds of developing a VTE (OR 1.38; 95% CI 1.09–1.74). These results are supported by clinical practice data [46, 47]. In 234 consecutive outpatients, venous compression ultrasonography within 48 h of hospital admission revealed a higher prevalence of asymptomatic DVT in patients >80 years than in those <55 years (17.8 and 0%, respectively) [49]. More recently, a Canadian study of 524 consecutive patients with VTE illustrated that almost a third (31%) were >75 years [50]. Notably, data from a retrospective cohort of 2,218 patients with a confirmed VTE demonstrate that the odds of survival are also seen to be lower with increasing age [51]. Taken together, these results emphasize the considerable need for thromboprophylaxis in the elderly patient population, which must be balanced against the known risk of increased bleeding associated with anticoagulation in elderly patients, particularly those with impaired renal function [45, 46, 52, 53].

Triggering factors

In the SIRIUS study, the triggering factor most strongly associated with DVT was pregnancy (OR 11.41; 95% CI 1.40–93.29; P = 0.02) [43]. Immobilization is also an important and prevalent triggering risk factor among medical patients [17, 43]. A prolonged period of immobility can lead to venous stasis, which is a key contributor to the development of thrombosis. Hospitalization is associated with lengthy periods of immobility; in a case–control study of 625 patients, a period of institutionalization without recent surgery was associated with almost an eightfold increase in the odds of developing VTE (OR 7.98; 95% CI 4.49–14.18) [48]. The risk of DVT was increased more than five-fold in immobilized patients in the SIRIUS study (OR 5.61; 95% CI 2.30–13.67; P < 0.001) [43]. Importantly, risk is also dependent on the degree of immobility. Severe limitations on mobility, such as the inability to walk for 10 m unaided or total bed rest, are associated with increased VTE risk [36, 42, 54].

The risk of VTE has recently been reported to be significant even in patients who have reached ambulatory status [55]. A post-hoc subgroup analysis of the MEDENOX trial reports that medical patients who ambulate early are at significant risk of VTE and that thromboprophylaxis with enoxaparin (40 mg once daily for 6–14 days) can reduce this risk with a favorable benefit-to-risk profile [55]. In this analysis, the rate of VTE (including asymptomatic DVT confirmed venographically and symptomatic VTE) in patients not receiving thromboprophylaxis was lower in ambulatory patients than in non-ambulatory patients (10.6% [n = 607] vs. 19.7% [n = 477]; P = 0.03). Despite this, a reduction in VTE incidence was observed in ambulatory patients receiving enoxaparin compared with placebo (3.3% vs. 10.6%; RR 0.31; 95% CI 0.13 − 0.78; P = 0.008) as well as in non-ambulatory patients (9.0% vs. 19.7%; RR 0.46; 95% CI 0.23 − 0.91; P = 0.02). Multivariate regression analysis revealed that VTE risk was lower in ambulatory patients receiving enoxaparin compared with placebo (OR 0.28; 95% CI 0.11 − 0.74; P = 0.01). There was no difference in the incidence of major bleeding events in patients receiving enoxaparin or placebo in both ambulatory (0.5% vs. 0.5%) and non-ambulatory patient groups (1.8% vs. 3.4%). In real-world clinical practice, the ambulatory status of hospitalized medical patients is often a criterion for patient discharge and discontinuation of thromboprophylaxis. This study highlights that such practices may not be appropriate, as patients who become ambulatory are at VTE risk and should receive recommended thromboprophylaxis [55].

Presenting medical conditions

Among the medical conditions that have been reported to be associated with VTE, cancer, moderate or severe congestive heart failure, respiratory disease and infectious diseases appear to have the strongest effects on VTE risk [41, 47, 56] (Table 3).

Cancer

In the MEDENOX study, cancer was independently associated with the highest risk of VTE (OR 1.62; 95% CI 0.93–2.75) compared with other medical conditions [47]. The increased risk of VTE in patients with cancer is directly related to a hypercoagulable state induced by the disease itself [57]. In addition, adjuvant therapies, such as chemotherapy or hormonal therapy and interventions including central venous catheterization further increase and sustain the risk of VTE in patients with active cancer [48, 57, 58]. Indeed, in a case–control study by Heit et al. [48], a four-fold risk of VTE was observed among patients with malignant neoplasm (OR 4.1; 95% CI 1.9–8.5) and more than a six-fold increase in risk was found in patients with malignant neoplasm who received chemotherapy (OR 6.5; 95% 2.1–20.2). Moreover, VTE in cancer patients is associated with significantly poorer patient outcomes. In a recent study in patients with cancer receiving chemotherapy, 2.1% of patients had VTE and its occurrence was a significant independent predictor of early mortality (hazard ratio 6.98; 95% CI 2.83–17.21; P < 0.0001) [59].

Other medical conditions

A number of other medical conditions are also associated with increased VTE risk. Infectious disease was an independent risk factor in the MEDENOX study (OR 1.74; 95% CI 1.12–2.75) [47] and was also identified as a risk factor for the development of DVT in the SIRIUS study (OR 1.95; 95% CI 1.31–2.92; P = 0.001) [43]. In addition, patients with congestive heart failure or respiratory failure are known to be at increased risk of VTE events [17, 60]. In the SIRIUS study, an almost three-fold increase in DVT risk was observed in patients with chronic heart failure (OR 2.93; 95% CI 1.55–5.56; P = 0.001) [43]. The risk of VTE in patients with heart failure or severe respiratory disease has been shown to be effectively reduced by thromboprophylaxis [56]. In Thromboembolism-Prevention in Cardiac or Respiratory Disease with Enoxaparin (THE-PRINCE) study (n = 665), enoxaparin 40 mg once daily was at least as effective at reducing the incidence of VTE events as UFH 5,000 IU three-times-daily in patients with heart failure or severe respiratory disease (8.4% vs. 10.4%; one-sided shifted test P = 0.015) [56]. Major bleeding was comparable between groups (0.3% vs. 0.3%), but enoxaparin was associated with significantly fewer death, bleeding and adverse events, as a composite endpoint (45.8% vs. 53.8%; P = 0.44) [56].

Many hospitalized medical patients have multiple thrombotic risk factors [3, 17]. In a US population-based study, 80% of patients with a first diagnosis of DVT had three or more risk factors, including cancer, congestive heart failure, respiratory disease, obesity, stroke or myocardial infection [61]. These multiple risk factors are known to cumulatively increase the risk of VTE [17, 43, 62]. In the SIRIUS study, 60% of patients had a predisposing risk factor compared with only 18% of controls, and the risk of DVT was higher in patients presenting with ≥2 risk factors compared with those with ≤1 risk factor [43]. Given the benefits of extended-duration prophylaxis in other patient groups at high risk of VTE, extended prophylaxis may also prove beneficial for improving outcomes in medical patients with multiple and prolonged risk factors.

Risk assessment

Risk assessment is essential to facilitate provision of appropriate prophylaxis in patients at risk of VTE and exclusion of patients without a favorable risk-to-benefit ratio. Patients that merit specific consideration include pregnant women, geriatric patients, and patients with renal impairment. A good risk assessment model (RAM) should be evidence-based, validated, transparent in terms of methodology, and simple to use in clinical practice [63]. Accurate assessment of VTE risk is often difficult due to multiple risk factors present in medical patients, which may have a cumulative weight that should be considered when assessing overall VTE risk [3, 17, 43]. Two approaches to risk assessment can be taken: group-specific, as applied to hospitalized medical patients in the most recent ACCP guidelines [3], or individual risk assessment, as applied and validated in a number of studies in surgical and non-surgical patient populations [1, 2, 6468].

Based on clinical evidence regarding the most important risk factors for VTE, several RAMs in medical patients have been developed [1, 2, 4, 65, 69, 70]. A simple RAM was specifically designed by Cohen et al. [1] for use in medical patients to assist physicians in determining whether prophylaxis is needed and provide recommendations for the prescription of appropriate agents along with possible contraindications for pharmacological prophylaxis. In this model, physicians progress through simple steps providing yes and no answers to each question in order to move forward to the next step. Risk assessment is individualized in this model and encouraged for all medical patients. VTE risk factors and recommended pharmacologic prophylaxis options included in the model are evidence-based. The model also incorporates contraindications to VTE prophylaxis as well as mechanical alternatives to pharmacologic prophylaxis.

As part of a study assessing the use of a computer-based electronic alert system to encourage VTE prophylaxis, Kucher et al. [65] devised a system where risk factors were weighted according to a point scale (major—3 points, intermediate—2 points, and minor—1 point) to identify hospitalized medical and surgical patients at increased risk of VTE. Cancer was the most common coexisting condition, occurring in approximately 80% of the patient population. An increased risk of VTE was defined as a cumulative risk score of at least four (i.e. at least two risk factors). In the intervention cohort (n = 1,255), where an electronic alert informed the physician of the patient’s increased VTE risk, the risk of developing a VTE at 90 days was reduced by 41% (hazard ratio 0.59; 95% CI 0.43–0.81; P = 0.001). VTE prophylaxis was ordered for 33.5% of patients in the intervention cohort, compared with 14.5% of patients in the control group (P < 0.001).

The authors practice in two different healthcare facilities. One is a university health center in which individual risk assessment is utilized. The individual risk factors used in screening are based on clinical trials and those risk factors listed in the most recent ACCP guidelines. The other healthcare facility is a community hospital, which has been using a group-specific method; however the facility is in the midst of transitioning to an individual risk assessment model. Neither facility has a process to consistently identify high-risk patients to receive prophylaxis following discharge. Prescribing VTE prophylaxis after discharge from the hospital is prescriber dependent and is primarily utilized in surgical populations at this time. It may take time for dissemination and adoption of the newest evidence. One process that should be explored is a reassessment of patients prior to discharge to identify potential candidates for extended outpatient VTE prophylaxis, because most hospitals are currently focusing efforts on consistent VTE risk assessment upon hospital admission.

Conclusions

Many patients have acute medical conditions, and also comorbidities, predisposing and triggering risk factors associated with VTE. A number of studies have shown that the risk of VTE in medical patients persists beyond hospital discharge and for considerably longer than the standard duration of thromboprophylaxis. Although extended-duration prophylaxis has been shown to reduce the risk of late VTE events in high-risk surgical patients with a good safety profile, until recently there has been no direct evidence in medical patients. Data from the large-scale EXCLAIM study now demonstrate that extended-duration prophylaxis with LMWH reduces the incidence of VTE in subgroups of high-risk medical patients with a favorable risk-to-benefit ratio. Use of prolonged prophylaxis in high-risk medical patients may help to improve long-term outcomes and reduce the considerable clinical burden of VTE. The development of appropriate risk assessment tools may help in the identification of those medical patients at greatest risk of late VTE complications who might benefit most from extended-duration prophylaxis.

Acknowledgment

The authors received editorial/writing support in the preparation of this manuscript from Katherine Roberts, PhD of Excerpta Medica, funded by Sanofi-Aventis U.S., Inc. The authors were fully responsible for all content and editorial decisions and received no financial support or other form of compensation related to the development of the manuscript.

Conflict of interest

Authors have no conflicts to disclose.

Copyright information

© Springer Science+Business Media, LLC 2011