Arixtra

Venous thromboembolism (VTE) remains a significant cause of morbidity and mortality in hospitalized patients with acute medical illness. The high prevalence of VTE in this patient population, its clinically silent nature, and associated morbidity and mortality indicate that prophylactic therapy is appropriate in those determined to be at increased risk. Unfractionated heparin (UFH) and low-molecular-weight heparin (LMWH) have been shown to reduce the incidence of VTE and are the primary therapies used for prophylaxis in these patients. Although both UFH and LMWH have received grade 1A recommendations for the prevention of VTE in at-risk medical patients in the 2004 American College of Chest Physicians consensus conference statements, LMWH has advantages over UFH in its once-daily dosing scheme, reduced incidence of major and minor bleeding events, and reduced incidence of heparin-induced thrombocytopenia. Fondaparinux is a novel antithrombotic agent characterized by specificity for factor Xa and a lack of platelet interaction. A recent clinical trial in hospitalized patients with acute medical illness found that fondaparinux significantly reduced the incidence of both VTE and fatal pulmonary embolism compared with placebo, without increased major bleeding. Despite the availability of effective thromboprophylactic therapies, VTE prophylaxis continues to be underutilized in hospitalized medical patients.

Key words: controlled trials; fondaparinux; hospitalized medical patients; low-molecular-weight heparin; randomized, risk assessment model; thromboembolic risk factors; thromboprophylaxis, unfractionated heparin, utilization; venous thromboembolism

Abbreviations: ARTEMIS = arixtra for thromboembolism prevention in a medical indications study; CI = confidence interval; DVT = deep venous thrombosis; HIT = heparin-induced thrombocytopenia; IMPROVE = international medical prevention registry on venous thromboembolism; LMWH = low-molecular-weight heparin; MEDENOX = medical patients with enoxaparin; MI = myocardial infarction; OR = odds ratio; PE = pulmonary embolism; PF4 = platelet factor 4; PREVENT = prospective evaluation of dalteparin efficacy for prevention of VTE in immobilized patients trial; UFH = unfractionated heparin; VTE = venous thromboembolism

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Venous thromboembolism (VTE) remains a significant cause of morbidity and mortality. (1,2) As many as 145 individuals per 100,000 in the general population develop symptomatic deep venous thrombosis (DVT), and [less than or equal to] 69 individuals per 100,000 experience a pulmonary embolism (PE). (3) Untreated DVT may lead to long-term morbidity because of postthrombotic syndrome and recurrent VTE. (4,5) Each year, PE is the primary cause of death in 100,000 individuals and a contributing cause of death in another 100,000. (1)

Although the impact of VTE in the surgical setting has been well-studied, its prevalence among hospitalized medical patients has only recently been investigated in large clinical trials. In the Prophylaxis in Medical Patients with Enoxaparin (MEDENOX) study of 1,102 hospitalized medical patients, approximately 15% of patients who did not receive prophylaxis experienced VTE. (6) In other epidemiologic studies, (7,8) the incidence of DVT has been reported to range from 10 to 26% among the general medical patients. Although the lack of symptoms and low autopsy rates (approximately 45%) make it difficult to determine the exact incidence of fatal PE among general medical patients, mortality that is attributable to PE is thought to be particularly high among hospitalized patients with acute medical illness. Longitudinal studies(9-12) reveal that approximately 75% of fatal PEs occur in nonsurgical patient population groups. Furthermore, a retrospective study (13) of autopsy reports demonstrated that approximately 7.6% of autopsied deaths in nonsurgical hospital patients were caused by PE. A more recent retrospective study (14) reported a 2.5% incidence of autopsy-proven fatal PE. However, because the autopsy rate in this study was only 45%, it was estimated that the total frequency of fatal PE was more than two times higher (5.5%).

The rationale for the use of prophylactic therapy for VTE in hospitalized medical patients is based on its high prevalence, clinically silent nature, and associated morbidity and mortality. (2) However, emerging data (15,16) suggest that VTE prophylaxis remains underutilized in these patients. The implementation of thromboprophylaxis in the medically ill can be challenging, because these patients tend to be older, suffer from multiple comorbidities, and receive medications that may interact with prophylactic therapies for VTE. (17,18) The identification of patient risk factors for VTE and careful consideration of the risks and the benefits associated with available therapeutic options provide the basis for the appropriate use and selection of prophylactic therapy in this patient population. Unfractionated heparin (UFH) and low-molecular-weight heparin (LMWH) are currently being used for the prevention of VTE in hospitalized medical patients. Novel antithrombotic agents, such as fondaparinux, have also been investigated in hospitalized patients with acute medical illness. This article explores the current status of VTE prophylaxis in hospitalized medical patients and reviews data from recent studies on available and emerging therapies in this patient population.

RISK FACTORS FOR VTE IN HOSPITALIZED MEDICAL PATIENTS

Hospitalized medical patients are often at increased risk for the development of VTE because of several factors. (18-24) Many exposing and predisposing factors have been associated with an increased risk of VTE in hospitalized medical patients, but there are currently no established guidelines that clearly define the risk factor stratification. A group of approximately 15 risk factors, including history of VTE, age [greater than or equal to] 75 years, cancer, and heart disease, are well-established, high-risk factors (Table 1). Another group of probable risk factors (Table 1) are generally shown to be significantly associated with VTE, but this association was found not be significant in some studies. For example, although generally considered to be a risk factor for VTE, estrogen therapy was not significantly associated with VTE in the MEDENOX study (p = 0.71) or the SIRIUS study (p = 0.16). (18,23) In addition, a link between obesity and risk for VTE (odds ratio [OR], 2.39; 95% confidence interval [CI], 1.48 to 3.87]) was found in the SIRIUS study; however, this association has not been reproduced in other clinical trials. (18,22,23,25) A third group of not-as-well-established factors have been reported as possible risk factors in some studies but have not been thoroughly evaluated in epidemiologic studies. (19)

A personal or family history of VTE is a particularly well-established factor that places patients at high risk for VTE (Table 1). (18,19,25) In an epidemiologic study, the OR for the risk of DVT with a history of VTE was 15.6 (95% CI, 6.77 to 35.89), and in a multivariate analysis of the MEDENOX study, the OR was 2.06 (95% CI, 1.10 to 3.69). (18,23) Age is also a well-established risk factor for VTE, with a 200-fold increase seen between ages 20 and 80 years. (1,3,26-28) Age > 75 years was found to be an independent risk factor for VTE in hospitalized medical patients in a multivariate analysis of results from the MEDENOX study (OR, 1.03; 95% CI, 1.00 to 1.06). (18)

Factors that are related to the underlying illness can also increase the risk of VTE in hospitalized medical patients. Cancer, a recent history of myocardial infarction (MI), ischemic stroke, congestive heart failure, COPD, and acute infectious disease have been associated with increased risk. (1,2,18-21,23,26,29,30) Malignancy (OR, 1.62; 95% CI, 0.93 to 2.75) and chronic respiratory disease (OR, 0.60; 95% CI, 0.38 to 0.92) were found to be significantly associated with VTE risk in the MEDENOX study, and chronic heart failure was implicated in the SIRIUS study (OR, 2.93; 95% CI, 1.55 to 5.56). (18,23) Patients with cancer are at an increased risk for the development of VTE because of the hypercoagulable state of malignancy, as well as its therapeutic interventions, including chemotherapy, radiotherapy, surgery, and the use of indwelling central venous catheters. (2,18) Clinically apparent VTE is observed in as many as 15% of all cancer patients. (18,31,32)

DVT is estimated to occur in approximately 24% and 55% of patients, respectively, with a recent history of MI or stroke, with wide variability in rates of DVT associated with these medical conditions reported across clinical trials (Table 2). (2,33,34) Patients with congestive heart failure or chronic respiratory disease are at an increased risk for both the development of VTE and death following PE. Infectious disease is a frequent comorbidity in acutely ill medical patients, particularly those with cardiopulmonary disease, that has recently been revealed as an independent risk factor for VTE in both hospitalized medical patients and medical outpatients. (18,23) Both the MEDENOX and SIRIUS studies found acute infection to be associated with VTE risk, with an OR of 1.74 (95% CI, 1.12 to 2.75) in the MEDENOX study and an OR of 1.95 (95% CI, 1.31 to 2.92) in the SIRIUS study. Other medical conditions thought to be possible risk factors for VTE include paralysis, nephrotic syndrome, inflammatory bowel disorder, systemic lupus erythematosis, and acquired or inherited thrombophilia disorders. (2,18-21)

Although the risk factors listed in Table 1 can help in the assessment of a hospitalized patient's risk of VTE, there is currently no agreed-on risk stratification for these patients. An international consensus group proposed a risk assessment model based on the levels of consensus-based or evidence-based predisposing risk factors or acute medical illnesses that would warrant pharmacologic thromboprophylaxis (Fig 1 and Table 3). (35) The American College of Chest Physicians 2004 guidelines (36) recommend VTE prophylaxis in acutely ill medical patients who have been admitted to the hospital with congestive heart failure or severe respiratory disease or who are confined to the bed and have one or more of the following risk factors: active cancer, previous VTE, sepsis, acute neurologic disease, or inflammatory bowel disease.

[FIGURE 1 OMITTED]

THERAPIES FOR THE PREVENTION OF VTE IN HOSPITALIZED MEDICAL PATIENTS

Two anticoagulants, UFH and LMWH, have grade 1A recommendations in the 2004 American College of Chest Physicians guidelines (36) for VTE prophylaxis in hospitalized medical patients. Mechanical prophylaxis alone is not recommended for this patient population unless there is a contraindication to anticoagulant prophylaxis.

UFH

For > 30 years, UFH has been the primary therapy used for the prevention of VTE in medically ill patients. (37) A number of clinical trials have shown (8,37-42) that UFH reduces the incidence of DVT in patients with MI, stroke, congestive heart failure, and pulmonary disease compared with patients who received no prophylactic therapy. In pooled analyses of trials where DVT was detected by fibrinogen uptake test or contrast venography, UFH prophylaxis reduced the risk for development of DVT by 71% in patients with a recent history of MI (from 24 to 7%) (38,39,43) and by 56% in patients with ischemic stroke (from 55 to 24%). (40,41,44-46) In medically ill patients, UFH prophylaxis (5,000 U administered subcutaneously bid or tid) was shown to reduce the incidence of DVT (measured by fibrinogen uptake test) from 16 to 6%, representing a 61% relative risk reduction. (7,8,47)

There is some evidence that a more frequent dosing of UFH provides patients with better protection against DVT. In a study (8) of 100 immobilized patients with congestive heart failure or chest infection, the incidence of DVT was significantly reduced among patients who received subcutaneous UFH tid, compared with those who did not receive thromboprophylaxis (4% vs 26%, p < 0.01). In contrast, a double-blind study (7) of 131 medical patients who were randomized to receive either subcutaneous UFH bid or placebo did not find a significant reduction in DVT among the patients who received UFH.

Information on the efficacy and safety of different UFH dosing regimens may be ascertained from studies in surgery patients. A pooled analysis (48) of 49 trials in general surgery patients found that, although UFH given every 8 h is associated with a reduced incidence of DVT compared with UFH given every 12 h (7.5% vs 11.8%), the 8-h regimen is also associated with a twofold higher incidence of major bleeding (1.8% vs 0.9%). These findings suggest that, although there appears to be a dosage effect with respect to the efficacy of UFH prophylaxis, more frequent dosing may also increase the risk for bleeding complications. Although the risk of bleeding complications with UFH in hospitalized medical patients is unclear, clinicians should be aware of the possibility of bleeding complications with more frequent dosing. In addition, more frequent dosing adds complexity to the treatment regimens in hospitalized patients who may already be receiving multiple therapies for their underlying medical condition.

Two randomized trials (49,50) have investigated the effect of UFH (bid) prophylaxis on mortality in hospitalized medical patients. In an early study (49) of 1,358 general medical patients who were randomized to receive either UFH prophylaxis until discharge (5,000 U subcutaneously every 12 h, n = 669) or no treatment (n = 689), the all-cause mortality rates were significantly reduced among the patients who were treated with UFH (7.8% vs 10.9%, p < 0.0,5). The autopsy rate in this study was only 9.5%, and no detection of VTE was attempted because of the large population; therefore, the difference in VTE incidence between the groups is not known. Based on the difference between the total patients in the UFH group and the total patients in the control group, the decrease in mortality attributable to heparin was estimated to be 31.1% (95% CI, 0.2 to 52.3%). However, more patients allocated to UFH were thought to have contraindications to therapy than those allocated to the control group (31.7% vs 25.1%, p < 0.01), possibly introducing selection bias and making direct comparisons between the groups difficult. The incidence of active or suspected bleeding was similar among the treated and the untreated patients (20.3% vs 22.0%).

In a larger study, > 11,000 patients who were admitted to infectious disease units in six hospitals were randomized to receive UFH (5,000 IU subcutaneously every 12 h, n = 5,776) until discharge or for a maximum of 3 weeks or no prophylaxis (n = 5,917). (50) The primary end point was autopsy-verified PE, and the autopsy rate was similar between the UFH-treated and untreated groups (63.8% and 56.8%, respectively). Mortality rates (5.3% vs 5.6%, p = 0.39) and autopsy-proven PE rates (both 8%) were similar between the UFH-treated patients and those who received no prophylactic therapy. (50) The median time from admission to death was 16 days in both the treated and the untreated patients, but the occurrence of fatal PE was significantly delayed in the UFH-treated group (12.5 vs 28 days, p = 0.007), and this delay corresponded with the duration of heparin prophylaxis. (50) In addition, there was a significant decrease in nonfatal PE in the UFH-treated group (29% vs 58%, p = 0.0026). However, a 57% increase in serious bleeding events was detected at autopsy in the UFH-treated group (14 vs 6 patients, p = 0.076), raising concerns about the risk-benefit ratio of UFH prophylaxis. The compendium of the results of these clinical trials using UFH reveal that there is no large, well-conducted, placebo-controlled trial that supports the efficacy of bid UFH for thromboprophylaxis for hospitalized medical patients.

LMWH

Several studies (6,51,52) have investigated the efficacy and safety of the LMWHs enoxaparin and dalteparin in hospitalized patients with acute medical illness. The MEDENOX study (6) explored the efficacy and safety of thromboprophylaxis with enoxaparin in 1,102 hospitalized medical patients > 40 years of age. In this double-blind study, patients were randomized to receive 40 mg of enoxaparin (n = 367), 20 mg of enoxaparin (n = 364), or placebo (n = 371) subcutaneously once daily for 6 to 14 days. The majority of patients included in the study had either congestive heart failure or acute respiratory failure that did not require ventilatory support. Patients also qualified for inclusion in this study if they had acute infection without septic shock, an acute rheumatic disorder, acute arthritis of the legs, or an episode of inflammatory bowel disease with at least 1 of the following characteristics: age > 75 years, cancer, previous VTE, body mass index [greater than or equal to] 30 for men and [greater than or equal to] 9.8.6 for women, varicose veins, hormone therapy, or chronic heart or respiratory failure.

VTE was defined as DVT detected by bilateral venography (although a minority of patients underwent duplex ultrasonography) or documented PE. By day 14 following the initiation of therapy, the incidence of VTE was significantly lower among patients who received 40 mg of enoxaparin compared with those who received placebo (5.5% vs 14.9%, p < 0.001; Fig 2). This difference was maintained at day 110 (7% vs 17.1%). There was no significant difference in the incidence of VTE between patients who received 20 mg of enoxaparin and those who received the placebo (15.0% vs 14.9%, difference not significant). The reductions in the incidence of VTE among patients treated with 40 mg of enoxaparin remained significant compared with the placebo during the 3-month follow-up period.

A total of 13.9% of patients who received placebo, 14.7% of patients who received 20 mg of enoxaparin, and 11.4% of patients who received 40 mg of enoxaparin died by day 110. Death that was attributable to PE was reported in 0.4% of patients who received placebo, 0.4% of patients who received 20 mg of enoxaparin, and 0.7% of patients who received 40 mg of enoxaparin. The risk of death was lower in the 40-mg group than in the placebo group, but this difference was not significant (risk ratio, 0.83; 95% CI, 0.56 to 1.21; p = 0.31). The frequency of adverse events, including bleeding, was 'also similar across the treatment groups. These findings provide additional support that prophylaxis with 40 mg of enoxaparin significantly reduces the risk of VTE in hospitalized medical patients without increasing bleeding complications.

The efficacy and safety of dalteparin for the prevention of VTE in hospitalized medical patients was explored in the Prospective Evaluation of Dalteparin Efficacy for Prevention of VTE in Immobilized Patients Trial (PREVENT). (52) In this double-blind, placebo-controlled study, 3,706 hospitalized medical patients who were at moderate risk for VTE (congestive heart failure, acute respiratory failure, or infection without septic shock; acute rheumatologic disorders; or inflammatory bowel disease with one or more of the following characteristics: age [greater than or equal to] 75 years, cancer, previous VTE, obesity, varicose veins, hormone replacement therapy, history of chronic heart failure, chronic respiratory failure, or myeloproliferative syndrome) were randomized to receive either dalteparin (5,000 IU) or placebo once daily by subcutaneous injection for 14 days. Most of the patients enrolled in this study had acute congestive heart failure, acute respiratory failure, or infectious disease. VTE was defined as objectively verified (by objective imaging or autopsy) symptomatic DVT, PE, sudden death, or asymptomatic proximal DVT detected by compression ultrasound. Compression ultrasonography was performed in all of the patients who had not had symptomatic VTE diagnosed between days 21 and 24 following the initiation of therapy.

By day 21, VTE was observed in 2.77% of patients who received dalteparin and 4.96% of patients who received the placebo, representing a 45% relative risk reduction in favor of dalteparin (95% CI, 20 to 62%, p = 0.0015). Two patients who received the placebo (0.11%) and none who received dalteparin experienced a fatal PE. (52) Major bleeding occurred in 0.49% of patients who received dalteparin and 0.16% of patients who received placebo (p = 0.15). Dalteparin appears to reduce the incidence of VTE in hospitalized medical patients, including those with respiratory failure, without increasing the risk for major bleeding.

A number of direct comparison, randomized studies (17,47,53-55) have shown that LMWHs are at least as effective as UFH (tid) for the prevention of VTE in acutely ill medical patients. Clinical trials (44,56) comparing enoxaparin (40 mg subcutaneously once daily) with UFH (5,000 U subcutaneously tid) in patients with ischemic stroke found that enoxaparin provided equivalent or superior protection against DVT. A metaanalysis of eight studies (17,47,53-55,57) comparing the two therapies found that LMWH was associated with a 52% lower incidence of major hemorrhage (p = 0.049). A primary analysis of study data also reveals that enoxaparin once daily provides a superior safety profile over tid UFH. (17,55)

A larger study, (17) the Thromboembolism-Prevention in Cardiac or Respiratory Disease With Enoxaparin study, compared the efficacy of enoxaparin (40 mg subcutaneously once daily) and UFH (5,000 IU subcutaneously tid) for the prevention of VTE in 665 patients (332 treated with enoxaparin and 333 treated with UFH) with heart failure (New York Heart Association class III or IV) or severe respiratory disease who were confined to the bed for more than two thirds of each day. The primary efficacy parameter in this study was a VTE event up to 1 day after the treatment period (10 [+ or -] 2 days).

In the Thromboembolism-Prevention in Cardiac or Respiratory Disease With Enoxaparin Study, the incidence of VTE in patients treated with 40 mg of enoxaparin was similar to that observed in patients who received UFH (8.4% vs 10.4%, difference not significant; Fig 3). Significantly fewer patients who received enoxaparin experienced adverse events compared with patients who received UFH (45.8% vs 53.8%, p = 0.044). Although enoxaparin appeared to be associated with fewer deaths (2.7% vs 4.5%) and less bleeding (1.5% vs 3.6%), differences between the treatment groups were not significant. These data provide additional support that 40 mg of enoxaparin is at least as effective as, and may be safer than, UFH in bedridden patients with heart failure or severe respiratory disease. An unexpected finding was the high rate of VTE observed among patients treated with UFH (10.4%), which is higher than that previously reported in UFH-treated heart or respiratory failure patients.

The efficacy and safety of extended prophylaxis with LMWH in acutely ill medical patients is currently being investigated in the Extended Thromboprophylaxis With Enoxaparin in Acutely Ill Medical Patients With Restricted Mobility trial. (58) In this multicenter study, 5,800 acutely ill medical patients with restricted mobility at high risk for developing VTE were given 40 mg of enoxaparin once daily for an open-label treatment period of approximately 10 days and were then randomized in a double-blind manner to receive either 40 mg of enoxaparin once daily or placebo for an additional 28 days. Patients who were enrolled in this study suffered from a variety of acute medical illnesses, including 37% who had an acute infection and 35% who had acute respiratory insufficiency. Preliminary results show that only 3.16% of the 601 patients that have been examined for DVT to date, using a standardized ultrasound protocol, have developed DVT. (58) The final results for this study are not yet available.

The potential for development of heparin-induced thrombocytopenia (HIT) is a concern among patients treated with either UFH or LMWH, although the incidence of HIT-associated thrombocytopenia in orthopedic patients treated with UFH is greater than that observed in medical patients. (59,60) HIT can occur in patients treated with UFH or LMWH who develop antibodies against platelet factor 4 (PF4)/ heparin complexes. LMWH is associated with a substantially lower incidence of HIT-associated thrombosis and thrombocytopenia in medical patients than that seen with UFH; (59) however, it should not be used in medical patients at risk for HIT. (61,62)

Additionally, applied pharmacoeconomic analyses reveal that once-daily LMWH therapy is the dominant strategy when compared with bid UFH therapy for VTE prevention in the hospitalized medical patient. (63,64) In these studies, thromboprophylaxis with the LMWH enoxaparin resulted in lower total estimated costs with fewer adverse events than UFH therapy.

Fondaparinux

Fondaparinux is a novel synthetic pentasaccharide antithrombotic agent with pure antifactor Xa activity that is currently under investigation for VTE prophylaxis in hospitalized patients with acute medical illness. (65,66) It acts by selectively binding to antithrombin III, resulting in the neutralization of factor Xa. (65) Fondaparinux is characterized by a lack of protein binding and predictable pharmacokinetics, even in patients with an increased body weight ([less than or equal to] 169 kg in orthopedic surgery trials). (65,67) It is 2currently approved for VTE prophylaxis in patients undergoing hip fracture surgery, hip replacement surgery, or knee replacement surgery; for extended prophylaxis in patients who have undergone hip fracture surgery; and for the treatment of VTE and acute PE. (68)

The efficacy and safety of fondaparinux for the prevention of VTE in hospitalized medical patients was investigated in the Arixtra for Thromboembolism Prevention in a Medical Indications Study (ARTEMIS). (66) In this multinational, double-blind trial, 849 acutely ill medical patients > 60 years of age who were expected to remain bedridden for [greater than or equal to] 4 days with congestive heart failure, acute or chronic lung disease, or acute infectious or inflammatory disease with no other risk factor analysis were randomized to receive either 2.5 mg of fondaparinux once daily (n = 429) or placebo (n = 420) for a treatment period of 6 to 14 days. VTE was defined as any combination of venographic DVT or confirmed symptomatic DVT, nonfatal PE, or fatal PE. A mandatory bilateral venography was performed between days 6 and 15 following the initiation of therapy and within 1 day of the last dose. By day 15 following the initiation of therapy, the incidence of VTE was significantly lower among patients who received fondaparinux compared with those who received the placebo (5.6% vs 10.5%, p = 0.029; Fig 4), representing an odds reduction of 49.5% (95% CI, 72.1 to 8.6%). No cases of fatal PE were observed among the patients who received fondaparinux compared with a 1.2% incidence of fatal PE among those who received the placebo (p = 0.029). By day 32, 3.3% of all patients who received fondaparinux had died compared with 6.0% of patients who received the placebo (p = 0.06).

In this study, major bleeding was defined as fatal bleeding, nonfatal critical organ bleeding, bleeding requiring surgical intervention, bleeding associated with a [greater than or equal to] 2 g/dL fall in hemoglobin, and/or transfusion of [greater than or equal to] 2 U. The rates of confirmed major bleeding among patients who received fondaparinux were similar to those seen among patients who received the placebo (0.2% in both treatment groups) and were derived solely from bleeding associated with a decreased hemoglobin level and/or the need for transfusion. The results of this study demonstrate that fondaparinux significantly reduces the incidence of both VTE and fatal PE, without increasing major bleeding, in hospitalized patients with acute medical illness.

Fondaparinux has not been associated with HIT. (69,70) The lack of association between fondaparinux and HIT is most likely because the molecule is too small to bind to PF4 and cannot form the complex that is recognized by pathogen HIT antibodies. (70,71) It has been demonstrated (69,70,72,73) that fondaparinux in the presence of PF4 does not exhibit cross-reactivity with HIT antibodies from patients with confirmed HIT and failed to produce platelet activation in the presence of sera from patients with HIT. These results suggest that clinical HIT is unlikely to occur with fondaparinux.

CURRENT USE OF VTE PROPHYLAXIS IN HOSPITALIZED MEDICAL PATIENTS

Despite evidence (15,16,74,75) that prophylaxis can reduce the incidence of VTE in hospitalized medical patients, emerging data from large registry studies suggest that thromboprophylactic therapies remain underutilized in this patient population. The International Medical Prevention Registry on Venous Thromboembolism (IMPROVE) (15,16,74) examined the current clinical practices for the prevention of VTE in acutely ill medical patients hospitalized for at least 3 days. In this prospective cohort study, a total of 1,595 patients from 21 hospitals in eight countries was evaluated with respect to whether the patients would have met eligibility requirements for inclusion in medical VTE prophylaxis trials, as well as whether they had been given thromboprophylactic therapy. The VTE prophylaxis trials considered in this study included the MEDENOX, PREVENT, and ARTEMIS studies.

Three-month follow-up data revealed that only 37% of all of the IMPROVE patients had received VTE prophylaxis. Of the 13 to 19% of IMPROVE patients who would have been eligible for inclusion in MEDENOX, PREVENT, or ARTEMIS, only 47 to 52% had received VTE prophylaxis. The results were similar across geographic regions, where only 38% of European patients and 44% of United States patients were given thromboprophylactic therapy. (74) VTE was suspected in 10% of the IMPROVE patients during hospitalization and in an additional 4% during the 3 months after discharge. (16) A total of 7% of patients died during hospitalization, and an additional 11% died within 3 months after discharge. (16) Data from this study highlight the underutilization of thromboprophylactic therapies in hospitalized medical patients and high rates of suspected VTE in this patient population.

The results from another registry study reveal the underutilization of VTE prophylaxis in hospitalized patients, particularly nonsurgical hospitalized medical patients. In DVT FREE, a prospective registry of patients with ultrasound-confirmed DVT, more than half of the hospitalized patients did not receive VTE prophylaxis. (76) Of the 5,451 patients enrolled, 2,726 were inpatients at the time of diagnosis, and approximately 50% (n = 1,364) were nonsurgical patients. The most common admission diagnoses for hospitalized medical patients who subsequently had their DVT diagnosed were infection, cardiovascular disease, neurologic disease, and cancer. Of the 2,726 hospitalized patients with DVT diagnosed, 58% received no prophylaxis within 30 days of diagnosis of DVT. Furthermore, nonsurgical patients were much less likely to receive prophylaxis compared with surgical patients.

The outcomes in medical and surgical patients with objectively confirmed acute VTE were analyzed in the Registry of Patients With Venous Thromboembolism study. (75) Of the 4,526 patients enrolled and followed up for 3 months, 1,286 patients (28%) were medical (nonsurgical) patients with immobility lasting [greater than or equal to] 4 days, and 671 patients (15%) were surgical patients who developed a VTE within 2 months following surgery. Although 68% of surgical patients in this registry had been given thromboprophylaxis, only 24% of the immobilized medical patients had received therapy for protection against VTE. Both overall mortality (OR, 2.8, 95% CI, 2.0 to 3.9) and rates of PE (OR, 4.6, 95% CI, 1.7 to 13.3) were significantly higher among immobilized medical patients compared with surgical patients. Major bleeding complications (OR, 2.8; 95% CI, 1.4 to 5.9) and fatal bleeding (OR, 9.0; 95% CI, 1.3 to 18.1) also occurred more frequently among immobilized medical patients. In addition, the rates of major bleeding complications were found to increase with age. (77) Major bleeding was observed in 1.6% of all patients < 65 years of age, 3.4% of patients between 66 and 80 years of age, and 4.0% of patients > 80 years of age. These findings indicate that although acute VTE appears to be associated with a more aggressive natural history in medical patients, medical patients are less likely than surgical patients to receive thromboprophylaxis. In addition, the risk of major bleeding appears to increase with advanced age.

CONCLUSIONS

VTE remains a significant cause of morbidity and mortality despite the availability of effective therapies for thromboprophylaxis. This may be attributable, in part, to the underutilization of prophylactic therapies in patients at increased risk for the development of VTE, particularly hospitalized medical patients. Hospitalized medical patients are at an increased risk for DVT, as well as fatal PE, because a number of medical conditions, including congestive heart failure, respiratory illness, acute infectious disease, certain inflammatory diseases, and cancer, increase the risk for VTE. In addition, patient factors, such as advanced age, immobility, and obesity, can contribute to VTE risk. Thromboprophylaxis should be considered for all hospitalized medical patients with risk factors for VTE following careful consideration of the risks and the benefits associated with available therapies.

UFH and LMWH are the primary therapies used for thromboprophylaxis in hospitalized medical patients. Numerous studies have shown that these agents are effective for the prevention of VTE in medical patients, although advantages of LMWH include once-daily dosing, an improved safety profile (including reduced major bleeding), and a reduced incidence of HIT. A novel agent, fondaparinux, is under investigation for the prevention of VTE in hospitalized medical patients characterized by specificity for factor Xa and a lack of association with HIT.

Randomized, controlled studies conducted with UFH, LMWH, and fondaparinux have shown that the proximal DVT rates of approximately 5% and overall DVT rates of 10.5 to 15% in hospitalized medical patients who did not receive prophylaxis (Table 4) place this patient population into the moderate-to-high-risk categories if surgical risk schemes are used, necessitating pharmacologic means of thromboprophylaxis. Additional research is needed to determine the optimal management of VTE risk stratification in hospitalized medical patients. However, given the availability of safe and effective thromboprophylactic therapies for hospitalized medical patients, preventative therapy against VTE should now be considered the standard of care.

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* From the Clinical Thrombosis Center, Lovelace Sandia Health Systems, Albuquerque, NM.

Dr. Spyropoulos is on the speaker's bureau and is a consultant for Sanofi-Aventis Pharmaceuticals and Astra-Zeneca.

Manuscript received December 13, 2004; revision accepted January 18, 2005.

Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (www.chestjournal. org/misc/reprints.shtml).

Correspondence to: Alex C Spyropoulos, MD, FCCP, Clinical Thrombosis Center, Lovelace Sandia Health Systems, 5400 Gibson Blvd SE, Albuquerque, NM 87108; e-mail: alex.spyropoulos@ lovelacesandia.com

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