The Challenge of Preventing Venous Thromboembolism (VTE) in the Hospitalized Medical Patient: Part III
Part III: National Guidelines for DVT Prevention and Their Implications for Emergency Medicine Practice
Authors: Gideon Bosker, MD, FACEP, Assistant Clinical Professor, Section of Emergency Services, Yale University School of Medicine, New Haven, CT; Janet Poponick, MD, Assistant Professor, Department of Emergency Medicine, MetroHealth Medical Center, Cleveland, OH.
Peer Reviewers: Charles L. Emerman, MD, Chairman, Department of Emergency Medicine, MetroHealth Medical Center, Cleveland Clinic Foundation, Cleveland, OH; Kurt Kleinschmidt, MD, FACEP, Associate Professor, University of Texas Southwestern Medical Center, Dallas.
The scope of emergency practice is constantly changing. Although prompt, life-saving interventions in patients with catastrophic medical or surgical events remains the clinical arena of most intense focus, awareness of and therapy directed against predictable complications of serious illness has gained a foothold in the scope of emergency practice. Perhaps nowhere are these landscape changes more visible than in the setting of acute cardiovascular syndromes and thrombotic disorders. For example, physicians should be aware that the risk for acquiring venous thromboembolism (VTE) among seriously ill medical patients ranges from about 5-20%. In particular, patients with congestive heart failure (CHF), acute respiratory failure, infection, malignancy, prolonged immobilization, inflammatory disorders, hypercoagulable conditions, the elderly, and those hospitalized in the intensive care unit (ICU) are among the subgroups of medical patients at highest risk for acquiring VTE during their hospital stays. As might be expected, emergency physicians are playing an increasingly important role in recognizing medically ill patients at risk.
As a result, these patients should be screened and risk-stratified to determine their eligibility for receiving pharmacologic prophylaxis for deep vein thrombosis (DVT). Typically, hospital-based pharmacologic prophylaxis against DVT/pulmonary embolism (PE) in medical patients is achieved with unfractionated heparin (UFH) or low molecular weight heparin (LMWH). Among the LMWHs, the only anticoagulant agent currently approved by the FDA for prophylaxis in medically ill patients is enoxaparin (40 mg subcutaneously [SC] once-daily) for VTE.
Each year approximately 2 million Americans are afflicted with a DVT. Up to 600,000 of these patients subsequently develop a PE; in as many as 200,000 patients, the PE proves fatal.1 In fact, pulmonary thromboembolism is the third most common cause of hospital-related death in the United States, with thromboembolic events accounting for more deaths annually than AIDS, breast cancer, and highway fatalities combined.
In light of this epidemiological data, new guidelines have been developed by a number of national associations—most notably, the American College of Chest Physicians (ACCP)—in an effort to reduce the morbidity and mortality associated with DVT and PE, the most common preventable cause of hospital death. Since death from PE usually occurs within 30 minutes of the embolic event, early identification of patients at risk and initiation of preventive measures are mandatory for optimizing patient outcomes. This is clearly one clinical situation in which an ounce of prevention is worth a pound of cure.
Emergency physicians can and should play a major role in the early recognition of patients at risk for VTE. As such, it is important that emergency medicine physicians become familiar with specific medical conditions and risk factors that are associated with an increased risk of VTE, and also be familiar with current strategies shown to be effective for VTE prophylaxis.
With these issues in focus, the purpose of this, the final installment of a three-part series on VTE, is to highlight strategies for identifying medical patients who should be screened and considered for DVT prevention upon admission to the hospital.—The Editor
VTE in Medical Patients—Screening and Pharmacologic Strategies in the Emergency Department Setting
There is increasing awareness and trial-based evidence that hospitalized medical patients—in particular those with restricted mobility and one or more risk factors for VTE—are at increased risk for developing DVT during their hospitalization.2-4 The most important and common risk factors for VTE include advancing age, previous history of DVT or PE, thrombophilia, heart failure, serious infection, malignancy, acute respiratory failure, and related medical conditions. Because medical patients ill enough to require admission through the emergency department (ED) frequently have severe underlying conditions, the potential complications, cost, and morbidity associated with DVT in this patient population can be significant, and may include PE, prolonged hospitalization, and, in some cases, sudden death.5-11
The role of the emergency medicine physician in screening and initiating prophylaxis for DVT is evolving rapidly. A recent Consensus Panel consisting of emergency physicians, and organized by the Centers of Excellence in Venous and Arterial Thrombosis (CEVAT) Leadership Council, generated evidence-based recommendations for emergency practitioners and the role they should play in prevention of VTE in medical patients admitted through the ED. In the current health care environment, in which the failure to adequately prevent VTE in medical patients has become a problem of significant proportions, it was the council’s recommendation that emergency physicians strongly should consider initiating VTE prophylaxis with enoxaparin 40 mg subcutaneously in the ED in the following patient subgroups: 1) eligible patients (restricted mobility and VTE risk factors) expected to undergo long observation periods in the ED; 2) individuals with restricted mobility expected to have prolonged delays prior to admission; and 3) all medical patients admitted to the hospital who meet risk-stratification criteria for VTE prophylaxis (see below). To maintain continuity of pharmacologic prevention in hospitalized patients, and to ensure the admitting physician is informed of and in agreement with prophylactic anticoagulation, it was advised that emergency physicians consult with the admitting physician to discuss the need, indications, and strategies for VTE prophylaxis.12
Epidemiology. Clinical decisions related to thrombosis prevention and management present a daily challenge to physicians practicing in the hospital environment. Overall, venous and arterial thromboembolic events are responsible for more than 650,000 deaths in the United States each year. VTE, in particular, is a common disease that affects more than 2 million people each year. With an incidence in the United States of 1 in 1000, VTE may present as DVT or as PE. Approximately 600,000 patients each year develop PE, and 60,000 deaths due to this disease are reported annually. Some authorities estimate that PE may be responsible for up to 200,000 deaths annually.8-11
Unfortunately, these statistics have not changed in three decades despite aggressive diagnostic evaluation, identification of DVT risk factors (See Table 1), evidence-based treatment protocols, and improved prophylaxis, which remains under-utilized in hospitalized medical patients. In fact, the prevalence of VTE actually may be on the rise due to the aging population and longer survival of cancer patients. DVT and PE are two manifestations of the same disease process, VTE. Of patients diagnosed with DVT, approximately 30% develop symptomatic PE. The survival rates for those with a diagnosis of VTE are poor. Moreover, the detection of PE frequently is elusive, with the diagnosis being made at autopsy in a large percentage of cases.13 More than one-third of all deaths from PE occur on the day of presentation.9-11 Consequently, emergency physicians as well as other hospital-based practitioners must recognize patients who are at increased risk of VTE during the early stages of their hospitalization and initiate an appropriate diagnostic evaluation and management plan.
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From a clinical perspective, perhaps the most important issue is for hospital-based clinicians to screen all patients entering the hospital through the ED and identify, on a case by case basis, all those individuals who are at significant risk for developing acute DVT. Although numerous trials, both retrospective and prospective, have identified specific medical disorders which, when present in acutely ill hospitalized patients, increase the risk of acquiring acute DVT (See Table 2), there is no single patient profile that mandates medical prophylaxis against DVT. Rather, the clinician must weigh all of the relevant risk factors (e.g., respiratory status, cardiovascular function, patient age, etc.) and determine, based on clinical judgment, whether the risks of prophylaxis (minor or major hemorrhage) outweigh the risks of thrombosis (DVT and/or PE). When patients at risk are selected in a systematic way that accounts for all the risks and benefits, DVT prophylaxis will be outcome-effective.
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SOS (Sick, Old, Surgery) DVT QuickSCREEN®
Multiple trials, meta-analyses, and editorials in peer-reviewed journals stress the fact that patients are being under-prophylaxed against VTE in both the community hospital and academic settings, and that measures aimed at augmenting the rate of risk stratification-supported VTE prevention will reduce mortality rates linked to the current thrombosis crisis in hospital medicine.6-10 One recently developed, evidence-based tool that will help increase awareness among emergency physicians of patients who require VTE evaluation upon admission to the hospital is the SOS (Sick, Old, Surgery) DVT QuickSCREEN® assessment tool (See Figures 1-2, and Figure 3.)
Encompassing a broad range of patients who, on the basis of three rudimentary criteria—the clinical appearance of looking "sick, being old, or requiring surgery"—the SOS DVT QuickScreen® guides physicians down bifurcated pathways as follows: 1) a risk factor assessment and pharmacologic prophylaxis algorithm for hospitalized medical patients who, because they are either "sick" or "old" also meet risk-stratification criteria for VTE prevention; and 2) a risk factor scheme for general surgery or orthopedic patients who, depending on their risk factor assessment and type of surgery (hip or knee replacement, general surgery, etc.), should have VTE prophylaxis upon admission to the hospital.
The SOS DVT QuickSCREEN represents a clinically useful response to the "failure to prevent" syndrome which, historically, has compromised disease management in the arena of arterial and venous thrombosis, including coronary artery disease.14 In an environment characterized by under-prevention, this tool can be used by physicians, nurses, case managers, or pharmacists to improve quality of care, reduce medico-legal risk, and ensure that patients who are eligible for VTE prophylaxis benefit from low-risk, high-benefit drug-based intervention.
Burden of Thromboembolic Disease
Fortunately, the safety and effectiveness of medical prophylaxis for VTE has been analyzed carefully in recent clinical trials.2-7,15,16 In this regard, a recent landmark study (MEDENOX) has confirmed the effectiveness of at least one LMWH, enoxaparin, in preventing VTE in seriously ill medical patients.2 Risk-stratification strategies that identify those subgroups of patients who are most suitable for prophylaxis using enoxaparin will expand awareness of the risks of VTE in this patient population, and make medical prophylaxis against DVT a mandated clinical strategy in a broad range of hospitalized patients.
VTE remains a major cause of mortality and morbidity in hospitalized patients, despite the availability of effective prophylactic agents.17 Interestingly, studies demonstrate that the majority of patients who suffer a fatal PE have not undergone recent surgery, yet PE rarely is suspected as a cause of death in non-surgical patients, and prophylaxis is used infrequently, despite consensus statement recommendations.18-21 The burden of VTE disease in non-surgical populations is significant, with certain medical conditions (e.g., CHF, respiratory failure, and systemic infection) associated with elevated risk for thromboembolic disease.21 A review of recent studies evaluating risk factors in individual patients will help clarify the need for and value of thromboprophylaxis in clearly defined groups of medical patients.
Compared with surgical populations, far fewer studies have reported the frequency of VTE in medical patients. However, those figures that are available suggest a moderate risk of DVT in general medical patients in the absence of prophylaxis, according to the risk categories (low, moderate, high) defined for surgical patients.22-24 It should be noted that much higher rates of VTE have been observed in specific groups which, accordingly, should be risk-stratified to receive thromboembolic prophylaxis when indicated.1,22,23,25-28 In this regard, a recent study reported that up to one in 20 hospitalized medical patients with multiple problems and severe immobility may suffer a fatal PE.29 It should be noted, however, that current management practices emphasizing extensive use of thrombolytics, unfractionated heparin (UFH), GP IIb/IIIa inhibitors, LMWH, and antiplatelet agents may contribute to a reduction in the incidence of VTE, including PE.
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In light of the substantial burden of VTE in medical populations, current consensus statements on the prevention of VTE recommend assessment of all hospitalized patients, both medical and surgical, for thromboembolic risk and the use of appropriate prophylaxis. Specific prophylaxis recommendations have been made for patients with stroke and myocardial infarction (MI) by the American College of Chest Physicians (ACCP) and the International Consensus Conference.26,30 Prophylaxis also is recommended for other groups of medical patients with clinical risk factors for VTE. However, recommendations are for poorly defined patient groups and vary among consensus documents. For example, recommendations by the United Kingdom-based second Thromboembolic Risk Factors (THRIFT II) Consensus Group are based on the individual level of thromboembolic risk assessed for each patient.31
Patient Risk Stratification and Prophylaxis. Despite current consensus statement recommendations, surveys show that prophylaxis still is underused in medical settings.14 Several reasons explain these practice patterns. First, despite epidemiological data demonstrating the prevalence of VTE, many clinicians remain unaware of the level of thromboembolic risk in medical settings. The diversity of medical patients, lack of reliable evidence demonstrating risk levels, and perceived difficulty in assessing individual thromboembolic risk in the presence of multiple risk factors may contribute to the problem.
The paucity of data from well-designed trials demonstrating the efficacy of prophylaxis in medical patients provides a further barrier to widespread use. Finally, even those studies that have been published to date are mostly small, involve poorly defined populations, and vary in their end points, undermining confidence in their findings and preventing cross-trial comparisons.
From a clinical, need-to-prophylax perspective, a broad range of medical conditions is associated with an increased risk of VTE. Some of these have been stratified according to the level of risk they confer, although classifications may vary depending on concomitant risk factors.32 In particular, patients with stroke, MI, malignant disease, and CHF, along with critical care patients, have been identified as being at risk for thromboembolic events. But as the SOS DVT QuickSCREEN makes clear, the total patient population eligible for prophylaxis is far greater than simply these high-risk patient subgroups that consistently have been highlighted in the medical literature.
A number of clinical trials have demonstrated a reduction in the frequency of asymptomatic DVT in medical patients through the use of pharmacological prophylaxis.33 Some of these studies, illustrate a substantial reduction in the rate of DVT in medical patients as detected by the fibrinogen uptake test, suggesting that prophylaxis with either UFH or LMWH may be of value in these groups.30 The validity of these findings is questionable, however, because the fibrinogen uptake test has been shown to be a weak predictor of clinically important VTE.34 Furthermore, while the benefit in high-risk stroke and MI patients appears significant, the evidence in general medical patients is less conclusive. Given the diversity of general medical patients, there is an urgent need for further investigation to assess the potential benefit of anticoagulant treatment in more clearly defined medical populations.
The venous thrombosis risk in non-surgical patients was evaluated in an epidemiological study (Prophylaxis in Internal Medicine with Enoxaparin [PRIME]) that also assessed the efficacy and safety profile of enoxaparin.35 This was a multicenter, randomized, double-blinded comparison of enoxaparin (40 mg) vs. heparin (5000 U TID) in DVT prophylaxis. The 959 patients were expected to be immobilized for more than half of the daytime for the study period of seven days and have at least one additional risk factor (older than age 60, malignancy, obesity, previous VTE event, CHF, paresis, hemiplegia, or severe infection). New VTE disease occurred in 0.2% of the enoxaparin group and in 1.4% of the heparin groups (P = NS). Bleeding complications were comparable. The investigators concluded that enoxaparin is at least as efficacious as standard heparin in the prophylaxis of venous thrombosis.
MEDENOX Trial. In response to the need for evidence to clarify the role of prophylaxis in specific non-surgical patient subgroups, the MEDENOX (prophylaxis in MEDical patients with ENOXaparin) trial was conducted using the LMWH enoxaparin in clearly identified risk groups. In contrast to previous investigations, the MEDENOX trial included a clearly defined patient population (patients immobilized with severe chest [cardiopulmonary] disease), and was designed to answer questions about the need for prophylaxis in this group of medical patients and to determine the optimal dose of LMWH.2
Study Design. The design of the MEDENOX trial included a placebo arm, allowing determination of the thromboembolic risk and the need for prophylaxis in the clearly defined patient group. According to the THRIFT II classification, the population would be expected to be at moderate risk of VTE, since low-risk patients and those with high-risk conditions (e.g., stroke or MI) were excluded.31 However, the actual risk level for the defined population has not been confirmed in any previous trial. The use of systematic venography to detect DVT provided a reliable and accurate means of assessing prophylactic efficacy.
Inclusion criteria for MEDENOX were intended to define clearly the risk groups within the general medical population. Patients were considered eligible if they were 40 years of age or older; had been immobilized for fewer than three days; and were hospitalized due to a specific, acute medical condition (i.e., heart failure, respiratory failure, infectious disease, or rheumatic disorder). In this regard, it should be stressed that patients with CHF and/or pulmonary infections have been highlighted in the most recent ACCP consensus statement as a specific target group requiring thromboprophylaxis.30
Patients randomized in the MEDENOX trial had a projected hospital stay of at least six days. Patients with respiratory failure were considered eligible provided they did not require respiratory support. The primary exclusion criteria were: pregnancy or possible pregnancy, breastfeeding, stroke, major surgery in the previous three months, contraindications to iodinated contrast media, thrombophilia, serum creatinine greater than 150 mmol/L, intubation, HIV infection, uncontrolled hypertension, conditions conferring risk of hemorrhage, abnormal clotting tests, or hypersensitivity to heparin.
Patients with an acute infectious condition without septic shock, an acute rheumatic disorder, or an active episode of inflammatory bowel disease were considered eligible only if the acute illness was accompanied by at least one additional predefined risk factor for VTE. The risk factors for VTE (age, malignancy, obesity, varicose veins, etc.) closely mirror the clinical risk factors defined by the THRIFT II consensus document, and would be expected to increase the likelihood of a VTE event.31 The ACCP guidelines and International Consensus Statement also cite these risk factors and emphasize their importance when assessing prophylaxis requirements for medical patients.26,30
Patients in the MEDENOX trial were randomized to receive enoxaparin, 20 or 40 mg subcutaneously, or placebo once daily, beginning within 24 hours of randomization. They were treated for 10 ± 4 days in the hospital and followed up in person or by telephone contact on day 90 (days 83-110). During follow-up, patients were instructed to report any symptoms or signs of VTE or any other clinical event. The primary and secondary efficacy end points for MEDENOX were chosen to allow an objective assessment of the risk of VTE in the study population and the extent of any benefit of prophylaxis. The primary end point was any VTE event between day 1 and day 14. All patients underwent systematic bilateral venography at day 10 ± 4, or earlier if clinical signs of DVT were observed. Venous ultrasonography was performed if venography was not possible. Suspected PE was confirmed by high-probability lung scan, pulmonary angiography, helical computerized tomography, or at autopsy.
The primary safety end points were hemorrhagic events, death, thrombocytopenia, or other adverse event or laboratory abnormalities. As the principal adverse event associated with anticoagulant therapy, hemorrhage was a key safety outcome. Major and minor hemorrhagic events occurring during treatment were recorded. Major hemorrhage was defined as overt hemorrhage associated with a need for transfusion of two or more units of packed red blood cells or whole blood; a decrease in hemoglobin concentration of 20 g/L or more compared with baseline; or retroperitoneal, intracranial, or fatal bleeding. Overt hemorrhage that did not meet the criteria for major hemorrhage was defined as minor. Injection sites were checked daily for hematomas larger than 5 cm in diameter. Full blood counts were performed prior to treatment, and then at three-day intervals.
A total of 1102 patients from 60 centers and nine countries were included in the MEDENOX trial. Overall, the mean age was 73.4 ± 10.5 years, the gender distribution was 50:50, and the mean body mass index was 25.0 ± 6.2 kg/m2. The mean patient ages, gender distribution, and body mass index were similar in all three treatment groups; there were slightly more males than females in the placebo and enoxaparin 20 mg groups, and more females than males in the enoxaparin 40 mg group, but this difference was not significant. The reasons for hospitalization of randomized patients varied. The majority of patients were hospitalized for acute cardiac failure, respiratory failure, or infectious disease. The frequency of different reasons for hospitalization was similar across all treatment groups. The number of patients in each hospitalization group suggests that a high proportion of acutely ill medical patients have two or more concomitant conditions, each contributing to the overall thromboembolic risk.2
For the study population as a whole, the most prevalent risk factor in addition to the underlying illness was advanced age (50.4%), followed by varicose veins (25.4%) and obesity (20.2%). A similar number and proportion of patients in the three treatment groups exhibited each of the separate risk factors. Just more than one-third of patients in each group had chronic cardiac failure, and about one-half suffered from chronic respiratory insufficiency.
A large percentage of the patients in all three treatment groups had multiple risk factors. Overall, 96.9% of the study population (1068 patients) had at least one additional risk factor for VTE, in addition to their qualifying medical condition (heart failure or acute respiratory failure). Only 31 patients (2.8%) had no additional risk factors, 335 (30.2%) had one risk factor, and 733 (66.7%) had two or more risk factors. This pattern was similar in all treatment groups. The mean number of risk factors per patient was 2.1 ± 1.1, 2.0 ± 1.1, and 2.1 ± 1.1 in the placebo, enoxaparin 20 mg, and enoxaparin 40 mg groups, respectively. Multiple risk factors, therefore, appear to affect a high proportion of patients with acute cardiopulmonary or infectious disease. Risk factors for VTE have a cumulative effect on total risk.
The mean duration of treatment in MEDENOX was approximately seven days, with a standard deviation of three days. Duration of treatment did not differ significantly among the groups. Overall, 16% of patients had fewer than six days’ treatment (i.e., less than the planned minimum period), and 26% had more than eight days. No patients were treated for longer than 14 days as per protocol specifications. The continuation of any anticoagulant therapy after the end of the treatment period was left to the individual investigator’s judgment. Of the 1102 patients included in the study, 1073 received at least one dose of the study drug and were included in the safety analysis.
Results. Of the 1102 patients enrolled, a total of 866 patients were assessed for primary efficacy at day 14. The incidence of total, proximal, and distal DVT was significantly reduced with enoxaparin 40 mg compared with placebo. By day 14, the incidence of VTE was 14.9% in the placebo group and 5.5% in the enoxaparin 40 mg group, representing a significant 63% relative risk reduction (97% CI: 37-78%; P = 0.0002). A subgroup analysis of enoxaparin-mediated benefits demonstrated a VTE relative risk reduction of 72% in patients with acute heart failure (95% CI, 19-91, P = 0.01); 74% in patients with chronic heart failure (95% CI, 9-93, P = 0.022); and 78% for all patients older than age 75 (95% CI, 49-91, P = 0.0001).3
Outcomes in the enoxaparin 20 mg group were not significantly different from placebo. A total of four symptomatic non-fatal PEs occurred, three in the placebo group and one in the enoxaparin 20 mg group. Finally, there was a trend toward mortality reduction with enoxaparin. By day 110, death had occurred in 50 (13.9%), 51 (14.7%), and 41 (11.4%) patients in the placebo, enoxaparin 20 mg, and enoxaparin 40 mg groups, respectively. The 2.5% reduction in overall mortality in the enoxaparin 40 mg group was clinically meaningful but did not reach statistical significance.
By day 110, 798 patients had been assessed for secondary efficacy. The significant reduction in total VTE and proximal and distal DVT observed in the enoxaparin 40 mg group was maintained at the three-month follow-up. Relative risk reduction at three-month follow-up was: all VTE, 59%; and proximal DVT, 66%.2 Four additional fatal PEs occurred during follow-up, one in the placebo group (three weeks after the treatment period ended), and one and two in the enoxaparin 20 mg and 40 mg groups, respectively (two months after the treatment period ended).
From a clinical safety perspective, there were no significant differences among the groups in the frequency of major or minor hemorrhage, thrombocytopenia, or any other adverse events. Major hemorrhage occurred in 11 patients during the treatment period; the fatal hemorrhage in the enoxaparin 40 mg group was considered unrelated to the study treatment by the investigators. Two additional fatal hemorrhages occurred during follow-up, one in the enoxaparin 20 mg group and one in the enoxaparin 40 mg group, eight and three weeks after discontinuation of the study medication, respectively.
A total of 31 cases of thrombocytopenia occurred during the treatment period (13 cases in the placebo group, 10 in the enoxaparin 20 mg group, and eight in the enoxaparin 40 mg group). Fourteen of them were judged to be probably related to study medication, eight in the placebo group, four in the enoxaparin 20 mg group, and two in the enoxaparin 40 mg group. Remarkably, the three patients who experienced severe thrombocytopenia were in the placebo group.
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The PRINCE Study. Other investigations have focused more specifically on patients with heart failure. The PRINCE (Prevention in Cardiopulmonary Disease with Enoxaparin) study group conducted a randomized, multicenter trial in 665 hospitalized patients with severe cardiopulmonary diseases (332 with respiratory disorders, 333 with New York Heart Association [NYHA] Grade III/IV heart failure).36 Patients were treated with enoxaparin 40 mg subcutaneously (SC) daily or 5000 IU UFH SC TID for 8-12 days in an open-label study. Efficacy rates were evaluated in 454 patients using an intention-to-treat analysis.
Although the rate of VTE was similar in both groups (8.4% in the enoxaparin group vs 10.4% in the UFH group), a subgroup analysis indicated that the incidence of VTE was greater in patients with heart failure than those with respiratory diseases. All patients were included in an adverse event analysis, which indicated that the incidence of adverse events, including bleeding events (1.5% vs 3.6%) and injection site hematomas (7.2% vs 12.6%), occurred more frequently in the UFH group. The authors concluded that enoxaparin 40 mg SC QD was at least as effective and safe as UFH for the prophylaxis of VTE in acutely ill medical patients.
In a further subset analysis,37 the PRINCE II study group revealed that administration of enoxaparin 40 mg SC QD was at least as effective as UFH 5000 IU SC TID for the prevention of DVT and/or PE in the 333 patients with NYHA Class III/IV heart failure.38 The incidence of DVT and/or PE was 11/113 (9.7%) in the enoxaparin group and 15/93 (16.1%) in the UFH group (P = 0.014), respectively. Moreover, significantly fewer adverse events occurred in the group prophylaxed with enoxaparin (51.8% vs. 59.7%, P = 0.02).
The PRIME Study Group. The PRIME study group conducted a randomized, double-blind, multi-center trial to compare the efficacy and safety of enoxaparin 40 mg SC QD with UFH 5000 IU SC TID for the prevention of VTE in hospitalized medical patients.35 A total of 959 patients initiated enoxaparin (n = 477) or UFH (n = 482) therapy 24 hours after hospital admission and continued prophylactic therapy for seven days. Demographic characteristics were comparable between the two groups; the mean age of the participants was 74 years (82.7% > 60 years of age). Based on the intent-to-treat analysis, 0.25% of patients in the enoxaparin group and 1.4% of patients in the UFH group developed VTE during the seven-day period (P = 0.1235). The safety analysis found fewer adverse events and fewer major hemorrhagic complications in the enoxaparin group. The results indicated that enoxaparin 40 mg SC QD was at least as effective as 5000 IU UFH SC TID for prophylaxis of immobilized medical patients. Furthermore, the enoxaparin group experienced fewer adverse events than the UFH-treated group.
Pharmacoeconomic Issues and CLOT (Cost-Lowering Options for Optimizing Outcomes in Thrombosis) Analysis.
The clinical benefits4 and cost-effectiveness39-41 of thromboprophylaxis in most moderate- and high-risk surgical patients already has been established firmly, and attention among hospital-based practitioners has turned to the hospitalized medical patient, especially since the majority of inpatients who suffer a fatal PE have not undergone recent surgery.17,42-44 There are estimates that up to one in 20 patients who present with multiple problems and severe immobility are suffering a fatal PE.45-47
A meta-analysis of medical patients who are at moderate risk for VTE has confirmed the benefits of prophylaxis with heparinoids.7 In this analysis, seven studies combining data from 15,095 patients and comparing heparin (LMWH or UFH) with placebo showed significant reductions of 56% and 58% in the incidence of DVT and clinical PE, respectively. Nine studies comparing LMWH and UFH (4699 patients) revealed no significant difference between LMWH and UFH on the incidence of DVT, clinical PE, or mortality, although LMWH significantly reduced the risk of major hemorrhage compared to UFH (52% risk reduction).7
Identifying a cost-effective strategy for preventing DVT and/or PE in patients with heart failure has been an area of intense interest, inasmuch as the most recent ACCP Consensus Conference introduced thromboprophylaxis recommendations (LMWH or UFH) for general medical patients admitted to the hospital with risk factors for VTE, of which heart failure is cited as one of the principal indications.8
Enoxaparin vs. UFH. To assess the cost-effectiveness of enoxaparin prophylaxis (40 mg SC QD) compared with UFH (5000 units SC BID) for patients bedridden due to medical illness, a British group performed a pharmacoeconomic evaluation to assess the cost-effectiveness of these two therapeutic options.48 Because no head-to-head studies comparing enoxaparin vs. UFH prophylaxis in medical patients are available for analysis, this group’s comparison was based on the aforementioned meta-analysis that included randomized studies of UFH and LMWH at doses recommended for prophylaxis in medical patients.7
The primary end point considered was DVT detected by systematic objective screening, while secondary end points included PE confirmed by lung scan or necropsy and major bleeding.7 Secondary effectiveness measures included estimated mortality. The authors identified nine trials in 4660 patients that compared LMWH to UFH, and calculated the relative risk of DVT to be 83% (95%, CI 0.56-1.24, P = 0.37) and major bleeding to be 0.48 (95%, CI 0.23-1.00, P = 0.049). Although UFH was not included as a comparator in the MEDENOX trial,2 it was used in this analysis, as evidence exists that UFH is used for thromboprophylaxis in hospitalized medical patients.9,10
To estimate the overall costs of managing VTE, an economic model was used to extrapolate beyond the timescale of the studies, and the best available evidence was used to estimate the clinical manifestations and progression of DVT. Long-term complications up to 15 years also were included. In addition to the drug acquisition costs associated with prophylaxis, other costs of managing VTE also were accounted for, including the costs of radiology and other investigations for suspected DVT and PE, treatment of confirmed cases, management of major bleeding, and management of long-term sequelae of VTE. Results were estimated for a hypothetical cohort of 100 patients.
To evaluate the effect of using enoxaparin vs. no prophylaxis for VTE, both incremental costs and effectiveness were considered, thereby permitting the authors to evaluate whether enoxaparin prophylaxis represented a cost-effective approach to DVT prevention in a medical population. Cost-effectiveness ratios were calculated by dividing the increase in costs estimated in the model [(cost of VTE if patients are given prophylaxis with enoxaparin 40 mg QD) - (cost of VTE if no prophylaxis is given)] by the decrease in the number of events [(number of events related to VTE if no prophylaxis given) - (number of events related to VTE if patients are given prophylaxis with enoxaparin)].48
The results of this cost-analytical model indicate that thromboprophylaxis with enoxaparin is cost-effective in acutely ill medical patients compared to no prophylaxis. The authors also emphasize that the effectiveness analysis in their model is consistent with the large body of clinical evidence that there is a better risk-to-benefit ratio when using LMWH, rather than UFH, for DVT prevention.10 Moreover, compared to thromboprophylaxis with UFH, enoxaparin prophylaxis was found to be cost-neutral.48
This landmark pharmacoeconomic evaluation has important clinical implications for the hospital-based practitioner, especially those managing medical patients with serious medical conditions such as heart failure. Inasmuch as: 1) enoxaparin is the only LMWH that carries a formal indication for prophylaxis of DVT that may lead to PE in medical patients who are at risk for thromboembolic complications due to severely restricted mobility during acute illness; 2) the most recent ACCP Consensus Conference statement mandates either LMWH or UFH for thromboprophylaxis in hospitalized, acutely ill medical patients; and 3) the risk of major hemorrhage appears to be lower with LMWH as compared to UFH, enoxaparin prophylaxis should be considered the preferred strategy of VTE prevention in appropriately selected and screened hospitalized patients with heart failure.
Adoption of LMWH Prophylaxis Strategies in Emergency Medicine
Based on recent studies in immobilized medical patients—and in all individuals with significant restrictions in ambulation that place them at risk for DVT—prophylaxis against VTE should be considered mandatory if there are no significant contraindications.30 (See Figure 4.) It should be added that the ACCP guidelines and International Consensus Statement also cite CHF as a risk factor for VTE and emphasize the importance of this risk factor when assessing prophylaxis requirements for hospitalized medical patients.26,49
The primary efficacy and safety results, as well as the conclusions of the MEDENOX trial can and should be applied directly to clinical practice. First, acutely ill medical patients with a number of conditions commonly encountered in emergency practice are at significant risk of VTE. Second, based on the MEDENOX trial, enoxaparin, given once daily subcutaneously at a dose of 40 mg for 6-14 days, reduces the risk of VTE by 63%; and third, the reduction in thromboembolic risk is achieved without increasing the frequency of hemorrhage, thrombocytopenia, or any other adverse event compared with placebo.
Emergency Nursing Issues. The cost and practical advantages of enoxaparin must be considered when designing a nursing strategy for VTE prevention in the hospitalized medical patient. It should be emphasized that overall costs of preventing VTE in hospitalized patients is linked less to drug acquisition cost than to the aggregate total cost and expenditure of laboratory and human resources, including: monitoring costs, costs and risk management implications of patient convenience (multiple hematomas and pain associated with frequent administration of UFH), daily dose frequency, nursing administration costs, and servicing costs associated with drug-related adverse events (heparin-induced thrombocytopenia and increased risk of major hemorrhage with UFH). Unlike UFH, which when used in treatment doses requires vigilant monitoring and laboratory surveillance, in typical patient populations, the LMWH enoxaparin does not require monitoring of coagulation parameters.
This decreases overall costs of enoxaparin prophylaxis and therapy by reducing both laboratory monitoring costs and phlebotomy resources required to draw blood samples and measure clotting parameters. In addition, patient care is enhanced and patient comfort is promoted by using a once-daily administration of enoxaparin as compared to multiple (BID or TID) subcutaneous injections of UFH. Finally, drug-related adverse events, in particular major hemorrhage and thrombocytopenia, more commonly are encountered with UFH, features that increase not only the risk of producing poor outcomes, but overall cost of patient care. When these practical and safety advantages of enoxaparin are considered, it becomes clear that the overall cost, human resource, and laboratory resource costs associated with UFH are greater than those for LMWH.
In summary, based on recent data and a growing body of evidence, there is a mandate from a number of national organizations and consensus panels for hospital-based nurses and physicians to screen and identify medical patients who may be at risk for VTE. The SOS DVT QuickSCREEN patient assessment and risk stratification tool is a useful adjunct to clinical evaluation. To reduce the risk of adverse outcomes and death associated with DVT and PE, a wide range of hospitalized medical patients—in particular, those with restricted mobility and at least one or more medical illnesses requiring hospitalization—should, if there are no contraindications to the use of anticoagulants, be prophylaxed with enoxaparin 40 mg SC QD upon admission to the hospital, and this therapy generally should be continued for a period of 6-14 days to prevent DVT and its associated life-threatening complications.
Summary
VTE, which includes the entities of DVT and PE, continues to be recognized as a potentially serious complication for patients undergoing general and orthopedic surgery. Recently, however, based on well-designed clinical trials and epidemiological studies, health care professionals have begun to recognize that DVT—sometimes accompanied by life-threatening PE—predictably affects a significant percentage of hospitalized medical patients, as well as individuals undergoing major surgery.
Based on these observations, it now is generally accepted that hospitalized medical patients entering the hospital through the emergency department—in particular, those patients with restricted mobility and underlying risk factors for VTE—require a systematic evaluation to determine their risk for developing not only DVT, but associated acute complications. Moreover, it has become clear that the majority of those patients at risk for VTE will benefit from pharmacological approaches to DVT prevention, especially strategies that emphasize use of once-daily LMWHs such as enoxaparin.
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