DVT Prophylaxis in Patients with Heart Failure: The Evolving Standard of Care for Hospitalized Patients
The Mandate to Prevent Deep Venous Thrombosis (DVT) and Pulmonary Embolism in Patients with Heart Failure
Author: Gideon Bosker, MD, FACEP, Assistant Clinical Professor, Section of Emergency Services, Yale University School of Medicine, Associate Clinical Professor, Oregon Health Sciences University, Portland.
Peer Reviewers: Charles L. Emerman, MD, Chairman, Department of Emergency Medicine, MetroHealth Medical Center, Cleveland Clinic Foundation, OH; Gregory A. Volturo, MD, FACEP, Vice Chairman and Professor, Department of Emergency Medicine, University of Massachusetts Medical School, Worcester.
There is increasing awareness and evidence that seriously ill, hospitalized medical patients, especially those with heart failure, are at increased risk for sustaining deep venous thrombosis (DVT),1-3 in addition to other complications and sequelae affiliated with left ventricular dysfunction and associated coronary artery disease. Moreover, the potential complications, cost, and morbidity associated with DVT in this patient population can be significant, and may include pulmonary embolism (PE), prolonged hospitalization, and, in some cases, sudden death.4-10 Overall, it is estimated that as many as 10 million patients hospitalized annually for medical conditions merit screening for and prophylaxis against venous thromboembolic disease (VTED).
Although the consequences of acute coronary artery ischemia and/or thrombosis are well-documented and include a spectrum of life-threatening complications ranging from heart failure to cardiac arrhythmias, the venous "thrombosis crisis" rapidly is becoming a clinical focal point for hospital-based practitioners managing medical patients with serious illnesses. In this regard, it should be stressed that immobilized patients with such conditions as congestive heart failure (CHF), chronic respiratory failure, serious pulmonary and systemic infections, and underlying malignancy are at greater risk for sustaining the morbid sequelae and complications associated with DVT. Accordingly, the threshold for empirical prevention of DVT in this patient population must be balanced against the relatively low risk of serious complications associated with antithrombin-mediated prophylaxis.
Along with the acute management of patients with heart failure, the clinical crisis of thrombosis prevention and management presents a daily challenge to physicians practicing in the hospital environment. In this regard, venous and arterial thromboembolic events are responsible for more than 650,000 deaths in the United States each year. Venous thromboembolism (VTE), in particular, is a common disease that affects more than 2 million people each year, and is associated with such comorbid conditions as impaired left ventricular function. 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. Unfortunately, these statistics have not changed in three decades despite aggressive diagnostic evaluation, identification of risk factors (See Table 1), evidence-based treatment protocols, and improved prophylaxis, which remains under-utilized in hospitalized medical patients. Moreover, the prevalence of VTE actually may be on the rise due to the aging population and longer survival of cancer patients.
Table 1. Deep Venous Thrombosis (DVT)
Risk Factors for Hospitalized Medical Patients
|• Congestive Heart Failure|
|• Respiratory Failure|
|• Serious Infection|
|• History of DVT|
|• Intensive Care Unit Setting|
|• Hypercoagulability Syndromes|
|• Inflammatory Rheumatic Disorders|
The burden of VTED in hospitalized patients is especially significant, with certain medical conditions (e.g., CHF, respiratory failure, and systemic infection) being associated with an elevated risk for thromboembolic disease. 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. More than one-third of all deaths from PE occur on the day of presentation. Consequently, emergency practitioners and hospital-based practitioners must recognize patients who are at increased risk of VTE early in their presentations and initiate an appropriate diagnostic evaluation and treatment plan.
From a clinical perspective, perhaps the most important issue is for hospital-based clinicians to recognize those patient subgroups that are at significant risk for acute DVT, including those with CHF. Although numerous trials have identified specific medical disorders which, when they afflict acutely hospitalized, immobilized 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 outweigh the risks. When patients with CHF are selected in a systematic way that accounts for all the risks and benefits, DVT prophylaxis will be outcome-effective.
|Table 2. Patients with Serious Medical Illnesses Who Should Be Considered for DVT Prophylaxis*|
|CLASS III-IV CONGESTIVE HEART FAILURE (CHF)|
• Ischemic cardiomyopathy
• Non-ischemic cardiomyopathy
• CHF secondary to valvular disease
• Chronic idiopathic cardiomyopathy
• CHF secondary to arrhythmias
|SEVERE RESPIRATORY FAILURE|
• Acute exacerbations of chronic obstructive pulmonary
• Adult respiratory distress syndrome
• Community-acquired pneumonia
• Noncardiogenic pulmonary edema
• Pulmonary malignancy
• Interstitial lung disease
• Urinary tract infection
• Abdominal infection
|• All hospitalized elderly patients who are immobilized for three days or more and who have serious underlying medical conditions known to be risk factors for DVT should be considered strongly for prophylaxis with enoxaparin.|
|* Enoxaparin 40 mg subcutaneously QD is indicated providing there are no contraindications and immobilization period of three or more days is anticipated.|
Fortunately, the safety and effectiveness of medical prophylaxis has been analyzed carefully in recent clinical trials. In this regard, a recent landmark study (MEDENOX) has confirmed the effectiveness of at least one low molecular weight heparin (LMWH), enoxaparin in preventing VTED in seriously ill medical patients.1 Risk-stratification strategies that identify those subgroups of patients with CHF who are most suitable for prophylaxis using enoxaparin will expand awareness of the risks of VTED 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.11 Interestingly, studies demonstrate that the majority of patients who suffer a fatal PE have not undergone recent surgery,12 yet PE rarely is suspected as a cause of death in non-surgical patients13 and prophylaxis is used infrequently,14 despite consensus statement recommendations.15 The burden of VTED in non-surgical populations is significant,15 with certain medical conditions (e.g., CHF, respiratory failure, and systemic infection) associated with elevated risk for thromboembolic disease. 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.
Burden of Thromboembolic Disease
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,16,17 according to the risk categories (low, moderate, high) defined for surgical patients.18 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.16,17,19-23 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.24 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.
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)25 and the International Consensus Conference.20 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 UK-based second Thromboembolic Risk Factors (THRIFT II) Consensus Group are based on the individual level of thromboembolic risk assessed for each patient.26
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 are 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.27 In particular, stroke, MI, malignant disease, and critical care patients are strongly linked to thromboembolic events.
A number of clinical trials have demonstrated a reduction in the frequency of asymptomatic DVT in CHF patients through the use of pharmacological prophylaxis. 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.25 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.28 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 (PRIME) that also assessed the efficacy and safety profile of enoxaparin. 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.
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.1
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.26 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.
Inclusionary 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.25
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,26 and would be expected to increase the likelihood of a VTE event. The ACCP guidelines25 and International Consensus Statement20 also cite these risk factors and emphasize their importance when assessing prophylaxis requirements for medical patients.
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.1
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).2
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 occurr-ed 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%.1 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.
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).29 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,30 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.31 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 (Prophylaxis in Internal Medicine with Enoxaparin) 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.31 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 Analysis: Selecting the Optimal, Outcome-Effective Agent for Prevention of DVT in the Hospitalized Patient with Heart Failure
The clinical benefits3 and cost-effectiveness32-34 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.11,35-37 There are estimates that up to one in 20 patients who present with multiple problems and severe immobility are suffering a fatal PE.4,5,38
A meta-analysis of medical patients who are at moderate risk for VTE has confirmed the benefits of prophylaxis with heparinoids.6 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).6
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.7
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.39 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 LWMH at doses recommended for prophylaxis in medical patients.6
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.6 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,1 it was used in this analysis, as evidence exists that UFH is used for thromboprophylaxis in hospitalized medical patients.8,9
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)].39
The results of this cost-analytical model indicate that thromboprophylaxis with enoxaparin (enoxaparin 40 mg SC QD) 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.39
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 (40 mg SC QD) should be considered the preferred strategy of VTE prevention in appropriately selected and screened hospitalized patients with heart failure.
Prevention of VTE in Patients with Heart Failure: Clinical Implications and Adoption of LMWH Prophylaxis Strategies into Clinical Pathways
Based on recent studies, in immobilized patients—or those with significant restrictions in ambulation that place them at risk for DVT—who present to the hospital with CHF (NYHA Classes III-IV), prophylaxis should be considered mandatory if there are no significant contraindications.25 (See Table 3.) It should be added that the ACCP guidelines26 and International Consensus Statement20 also cite CHF as a risk factor for VTED and emphasize the importance of this risk factor when assessing prophylaxis requirements for hospitalized medical patients.
Table 3. Exclusionary Criteria for Prophylaxis
in Seriously Ill Medical Patients
• Pregnancy or possible pregnancy
• Major surgery in the past three months
• Breast feeding
• Bleeding disorder
• Uncontrolled hypertension
• Conditions conferring risk for hemorrhage
• Abnormal clotting tests
• Hypersensitivity to heparin, LMWHs, or heparin products
• Severe renal failure
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 Stages III-IV NYHA functional class CHF 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. In addition, the study strongly suggests that a wide range of hospitalized medical patients, in particular those who have heart failure and are elderly, should, if there are no contraindications to the use of anticoagulants, be prophylaxed with enoxaparin 40 mg SC QD upon admission to the hospital to prevent DVT and its associated life-threatening complications. (See Insert.)
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To help physicians:
• quickly recognize or increase index of suspicion for specific conditions;
• understand the epidemiology, etiology, pathophysiology, and clinical features of the entity discussed;
• be educated about how to correctly perform necessary diagnostic tests;
• take a meaningful patient history that will reveal the most important details about the particular medical problem discussed;
• apply state-of-the-art therapeutic techniques (including the implications of pharmaceutical therapy discussed) to patients with the particular medical problems discussed;
• understand the differential diagnosis of the entity discussed;
• understand both likely and rare complications that may occur;
• and provide patients with any necessary discharge instructions.
Physician CME Questions
1. Which of the following is a possible, relative contraindication for DVT prophylaxis in seriously ill medical patients?
A. Stage III-IV NYHA heart failure
B. Lack of hypersensitivity to heparin or LMWHs
C. Uncontrolled hypertension
D. Minor surgery in the past two months
2. Which of the following risk factors is linked to an increased risk for thromboembolic events?
B. Critical care patients
C. Myocardial infarction
D. Malignant disease
E. All of the above
3. In the MEDENOX trial, the relative risk reduction of proximal DVT at three months follow-up was:
4. The primary conclusions of the MEDENOX trial include which of the following?
A. Acutely ill medical patients with cardiopulmonary or infectious disease are at significant risk of VTE.
B. Enoxaparin, given once daily at a dose of 40 mg for 6-14 days, reduces the risk of VTE by 63%.
C. The reduction in thromboembolic risk is achieved without increasing the frequency of hemorrhage, thrombocytopenia, or any other adverse event compared with placebo.
D. All of the above