Outpatient treatment of deep venous thrombosis: A clinical care pathway managed by the emergency department☆

Article Outline

• Abstract
• Introduction
• Materials and methods
• Results
• Discussion
• Acknowledgements
• References
• Copyright

Abstract 

Study Objective: We evaluate the effectiveness and safety of an outpatient clinical care pathway for the initial treatment of acute proximal lower-extremity deep venous thrombosis (DVT) with low molecular weight heparin (LMWH) managed by the emergency department of 2 affiliated community hospitals. Methods: This observational, retrospectively defined, population-based study with 39 ½ months of preintervention analysis and 32 ½ months of postintervention analysis was conducted in 2 suburban EDs of a large group model health maintenance organization. Our outpatient DVT clinical care pathway used careful patient selection and multidisciplinary follow-up. Ninety-six patients before the intervention and 178 patients after the intervention met eligibility criteria for the pathway. Adverse events during the first 2 weeks of treatment included symptomatic pulmonary embolism (PE), progressive DVT, minor and major bleeding, and death. Results: Demographic and baseline clinical characteristics of the 2 groups were similar. Five (5.2%) of 96 preintervention subjects (95% confidence interval [CI] 2.4 to 8.1) developed adverse events compared with 5 (2.8%) of 178 postintervention subjects (95% CI 1.5 to 4.1; difference between groups 2.4%; P =.50). In each group, 1 (1.0% versus 0.6%) subject developed a PE, 2 (2.1% versus 1.1%) developed progressive symptoms of progressive DVT, and 2 (2.1% versus 1.1%) developed minor bleeding. Major bleeding occurred in 1 (1.0%) preintervention subject and no postintervention subjects. No patient in either cohort died. Conclusion: Managed by the ED, an outpatient DVT clinical care pathway using careful patient selection and an integrated multidisciplinary approach can provide a similar degree of effectiveness and safety as customary inpatient therapy. [Vinson DR, Berman DA. Outpatient treatment of deep venous thrombosis: a clinical care pathway managed by the emergency department. Ann Emerg Med. March 2001;37:251-258.]

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Introduction 

Proximal lower-extremity deep venous thrombosis (DVT) is often diagnosed in the emergency department. Immediate anticoagulation is necessary to halt progression of the thrombus and to prevent the development of symptomatic pulmonary embolism.¹ The advent of low molecular weight heparins (LMWHs) has greatly simplified the management of DVT. Compared with unfractionated heparin, LMWHs possess a longer serum half-life and better bioavailability when administered subcutaneously, allowing once- or twice-daily administration.², ³ Because LMWHs are as safe and effective as unfractionated heparin in the initial treatment of DVT,⁴, ⁵ the site of care is shifting to the out-of-hospital setting for carefully selected patients.⁶, ⁷, ⁸ Compared with inpatients, those treated for DVT at home have greater levels of physical activity and social functioning, and demonstrate a more rapid return to premorbid levels of activity.⁶, ⁹, ¹⁰ More than 90% of patients are very pleased with outpatient management, and 70% were very satisfied with the self-administration of LMWH.¹¹ Although the initial acquisition costs of LMWH is quite high compared with unfractionated heparin, the savings realized by forgoing hospital admission is far higher.¹², ¹³, ¹⁴

Much of the evidence in favor of the outpatient therapy of DVT was derived in academic settings. The success of this approach in community facilities has not been as well established.¹⁵ Although the ED often is the site of diagnosis, few studies have assessed its role in the management of an outpatient pathway.¹⁶ To translate the experience of clinical trials into community practice, we developed a clinical care pathway for the outpatient treatment of DVT that was orchestrated by emergency physicians. In this retrospective preintervention-postintervention study, we assess the effectiveness and safety of the outpatient DVT clinical care pathway by comparing the 14-day outcomes with control patients meeting the same eligibility criteria who had been treated in the years preceding the implementation of the pathway.

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Materials and methods 

This observational, retrospectively defined, population-based study was performed in 2 neighboring suburban community hospitals that are part of a large group-model health maintenance organization. During the preintervention period (January 1994 through April 14, 1997), only 1 hospital was operational and had a mean annual ED census of 57,000 patient visits. The postintervention period, from April 15, 1997, through December 31, 1999, saw the opening of a second facility, which increased the combined mean annual census to 85,000 patient visits. One group of board-certified emergency physicians staffed both EDs. The clinical care pathway was conducted as a performance improvement project, subject to the regulatory oversight of our quality improvement department. Therefore, the study was granted exemption by the institutional review board.

Consecutive adult outpatients (≥18 years) with acute, symptomatic proximal lower-extremity DVT were eligible for the clinical care pathway. The diagnosis of DVT was documented by compression ultrasonography or contrast venography, as interpreted by the board-certified staff radiologist assigned to ultrasonography that day. Isolated distal DVTs below the popliteal vein were not included in the treatment pathway.

The exclusion criteria were conservative, adopted from the pioneering studies of LMWH in the treatment of DVT,⁶, ⁷ and were provided as a checklist to the emergency physicians during the postintervention period. Patients were excluded from enrollment for any 1 of the following clinical reasons: a previous episode of objective DVT or PE within 2 years of study entry; preexisting thrombophilia (deficiency of antithrombin III, protein C, protein S); family history of bleeding disorder; allergy to heparin; allergy to pork; renal failure (serum creatinine ≥3.0 mg/dL [265 μmol/L]); major hemorrhagic risk (major surgery within 4 weeks; intracranial malignancy or arteriovenous malformation; prior hemorrhagic stroke; ischemic stroke within 6 months); DVT involving the iliac vessels; phlegmasia cerulea dolens and phlegmasia alba dolens; debilitating DVT (refractory pain or inadequate social situation); concurrent symptomatic PE (confirmed or highly suspected); coexisting sepsis; comorbid condition requiring inpatient treatment; pregnancy; active bleeding or active peptic ulcer disease; thrombocytopenia (platelets <100,000/mm³ [100,000×10⁹/L]); anemia (hemoglobin <10 mg/dL [100 g/L]); elevated prothrombin time or partial thromboplastin time. In addition, patients were excluded for any of the following logistical reasons: incapability of administering subcutaneous injections by either the patient or caregiver; the lack of an established primary care provider; residence outside a zip code geographically served by our home health services.

The preintervention control group was composed of ED patients with proximal lower-extremity DVT who met eligibility criteria for the pathway in the years before its implementation. Eligibility was determined by completing the inclusion and exclusion checklist for each preintervention patient on the basis of the comprehensive computerized database and hard copies of both inpatient and outpatient charts. Every record contained the necessary laboratory parameters, medical history, and geographic information. Inadequate social situation, inability of the patient or caregiver to administer subcutaneous injections, and unwillingness to participate in the outpatient pathway were exclusion criteria that could not be determined for the preintervention group.

With the assistance of nursing, pharmacy, home health, internal medicine, hematology, patient education, and quality management services/departments, we designed a clinical care pathway for the ED management of DVT (Figure).

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• Figure. Duties of respective participants in the DVT outpatient clinical care pathway.

Involved personnel were educated in the pathway. All patients with the diagnosis of proximal, lower-extremity DVT were clinically evaluated for enrollment, while exclusion criteria for ineligible patients were documented in the ED record.

Enrolled patients received a packet of educational information on DVT, enoxaparin, and warfarin. The emergency nurse and emergency physician provided additional bedside education which included the reasons for anticoagulation; the importance of compliance; the need for monitoring; the process of warfarin dosage adjustment; potential side effects, complications, and risks of anticoagulation therapy; potential drug-drug and drug-food interactions; the use of over-the-counter medications (particularly those containing aspirin products); the storage and handling of enoxaparin and warfarin; new prescriptions and refill requests. Educational time was not measured. Compression stockings were prescribed to help prevent postphlebitic syndrome. The inpatient pharmacy provided 14 single-dose syringes of weight-based enoxaparin (a 7-day supply), each containing a fixed dose of 1 mg/kg (rounded to the nearest 5 mg). Warfarin was dispensed as thirty 5-mg tablets, one of which was to be taken nightly beginning the day after the ED visit. An initial 7.5-mg dose of warfarin was given in the ED. After a demonstration on subcutaneous administration by videotape, the patient or caregiver administered the first dose of enoxaparin under nursing supervision. Home health services were arranged to provide daily home visits after the second warfarin dose to obtain blood samples for determination of the international normalized ratio (INR). A 12-hour visit (at the time of the second enoxaparin dose) was arranged for the minority of patients who required further assistance with subcutaneous administration. Daily home health visits and subcutaneous enoxaparin therapy were continued until the INR maintained a therapeutic level (2.0 to 3.0) for 2 consecutive days. The serial INR results were monitored by the anticoagulation clinic pharmacy, which then contacted the patient by telephone to adjust the warfarin dose as indicated. A follow-up appointment was made with the patient’s primary care provider within 5 to 7 days of the ED visit. To coordinate this multidisciplinary effort, the patient’s ED record and protocol were faxed to the anticoagulation clinic pharmacy, home health services, and the primary care provider. All patients were insured by Kaiser Foundation Health Plan with coverage of enoxaparin, warfarin, and home health care visits for DVT.

Progressive DVT, symptomatic PE, major bleeding, minor bleeding, and death were considered adverse events. Progressive DVT was diagnosed clinically in the presence of increasing pain or swelling in the index leg. A second imaging study was not required but was left to the discretion of the clinician. DVT progression was present also if a previously unsuspected DVT in the contralateral proximal lower extremity was detected by compression ultrasonography or venogram. Ventilation/perfusion imaging, with pulmonary arteriography if indicated, was used to establish the diagnosis of symptomatic PE. Bleeding was detected only if clinically overt. Major bleeding was diagnosed in the following circumstances: a decrease in the hemoglobin level of at least 2.0 g/dL or a need for the transfusion of packed RBCs, retroperitoneal or intracranial bleeding, or bleeding that warranted the permanent discontinuation of treatment.¹⁷ All bleeding that did not meet the aforementioned criteria was considered minor.

Adverse events among the postintervention group were determined by explicit review of each patient’s medical records including the comprehensive computerized database and hard copies of both inpatient and outpatient charts.

Active surveillance of the postintervention group was multidisciplinary. At each daily home health visit, a checklist was used to elicit information on signs and symptoms of bleeding and of progressive venous thromboembolism. Blood samples were obtained and sent to the anticoagulation laboratory. Nurses also provided continued assistance with subcutaneous injections if needed. Compliance was not explicitly measured. The anticoagulation clinic pharmacists explicitly inquired about adverse events when contacting patients by telephone to adjust warfarin doses. Primary care providers also checked for complications at the follow-up examination.

The chart of every patient with a diagnosis of DVT (International Classification of Diseases, 9th revision code 453.8) in both EDs from 1994 through 1999 was explicitly reviewed in a systematic fashion by one of the authors. Demographic, historical, and clinical data addressing baseline characteristics, eligibility criteria, and adverse events were collected from each patient’s record and transcribed onto a structured data sheet. We used both the organization’s comprehensive computerized database as well as hard copies of both outpatient and inpatient records. No records were irretrievable.

To evaluate the differences between the groups, t test was used for the continuous variables and χ² test for the categorical data. A 2-tailed P value less than .05 was considered to indicate statistical significance. The normal approximation to the binomial distribution was used to calculate the confidence intervals (CIs). Analyses were performed using statistical software (StatView, version 4.57; SAS Institute, Inc, Cary, NC).

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Results 

During the preintervention period, 132 ED patients had a diagnosis of proximal lower-extremity DVT and were admitted for standard inpatient therapy with intravenous unfractionated heparin. Of these, 96 (72.7%) met eligibility criteria for the outpatient pathway and constitute the control group. The study group was composed of 178 ED patients who were enrolled in the clinical care pathway during the postintervention period. This group represented 81.3% of the 219 patients with an ED diagnosis of proximal lower-extremity DVT during the postintervention period. Demographic and baseline clinical characteristics of the 2 groups were similar (Table 1). Reasons for patient exclusion from both groups are listed in Table 2.

Table 1. Baseline characteristics of ED patients with proximal lower-extremity DVT who met eligibility criteria for outpatient therapy treated before and after implementation of outpatient clinical care pathway.

Table 2. ED patients with proximal lower-extremity DVT who met exclusion criteria for DVT outpatient clinical care pathway both before and after implementation.

NA, Not applicable, as these criteria could not be determined for the preintervention group.

Over the 14-day surveillance, 5 (5.2% [95% CI 2.4 to 8.1]) of 96 preintervention patients developed adverse events compared with 5 (2.8% [95% CI 1.5 to 4.1]) of 178 postintervention patients (difference between groups 2.4%; P =.50; Table 3). The 4 patients who appeared eligible for the pathway, but were admitted to the hospital without an exclusion criterion documented on the chart (see Table 2), were treated with LMWH without adverse events.

Table 3. Adverse events within 2 weeks of initiating treatment among ED patients with proximal lower-extremity DVT before and after implementation of outpatient clinical care pathway.

Of the postintervention cohort, 2 (1.1%) patients developed progressive symptoms of DVT and both were admitted for 2 days of inpatient treatment. They had returned complaining of increasing pain and swelling in their index legs; 1 patient returned after 4 hours and the other 4 days after enrollment. Neither patient underwent a second ultrasound scan nor developed further sequelae. One (0.6%) patient developed a symptomatic PE. She was a 40-year-old nonsmoker who returned to the ED after 3 days with complaints of cough, hemoptysis, and dyspnea. The INR was 3.4. Negative chest radiographic findings and a high-probability ventilation-perfusion scan supported the diagnosis of PE. She was admitted to the hospital for 2 days for the placement of an inferior vena cava filter. Her symptoms improved before discharge. Two (1.1%) patients developed minor bleeding. One had more bruising on day 3 at the injection sites than anticipated. The other sustained mild trauma to the contralateral thigh on day 9 and developed ecchymosis. Both were provided with reassurance and followed up as outpatients. No sequelae developed.

Using a 7.5-mg loading dose of warfarin in the ED, followed by 5 mg daily, an INR of 2.0 or greater was reached within 7 days by 141 (79%) patients, between days 8 and 14 by 29 (16%) patients, and between days 15 and 19 by 8 (5%) patients. The mean time was 5.8 days.

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Discussion 

We demonstrate that a community ED can successfully direct the initial outpatient care for the majority of ambulatory patients with proximal lower-extremity DVT using a clinical care pathway. Short-term outcomes after the implementation of the outpatient pathway were comparable with those of a similar cohort of inpatients in the years preceding the pathway. This DVT management strategy offers the advantages of home care (eg, increased convenience, quality of life, and satisfaction) with the same degree of effectiveness and safety as customary inpatient treatment.

Results generated in carefully controlled trials conducted in academic research settings (efficacy) need to be shown to be reproducible in nonacademic community practice (effectiveness). Demonstrating comparable outcomes when new interventions are translated from the research setting to the usual site of care is a critical step in testing pioneering health care interventions.¹⁸ Several studies have shown that LMWH can work in the treatment of outpatient DVT; we demonstrate that it does work in a community emergency medicine practice.¹⁹

In our outpatient DVT pathway, the incidence of progressive DVT at 14 days was low, as was the development of symptomatic PE (Table 3). The infrequency of progressive thromboembolic disease confirms the effectiveness of this management approach. Even during inpatient treatment with LMWH, life-threatening PE has been exceedingly rare. When deaths have occurred from PE in the early management of DVT, it is not clear whether the patients’ presence in the hospital would have prevented them.²⁰ The bleeding rate during our outpatient LMWH therapy was very low (minor bleeding <1%, with no instances of major bleeding), affirming the safety of this approach. These short-term outcomes compare favorably with those of large efficacy trials of LMWH among combined inpatients and outpatients, as well as smaller series of patients treated exclusively at home (Table 4).

Table 4. Characteristics and 2-week event rates for patients with DVT treated with LMWHs.

NR, Not reported; TE, thromboembolic.

However, disparate inclusion criteria of these studies and the variously reported clinical characteristics of their subjects temper the comparability between these heterogeneous studies.

The safety of outpatient DVT management requires careful patient selection. Despite our strict criteria, between 73% and 81% of ED DVT patients qualified for home therapy. Although higher than earlier studies,⁶, ⁷, ⁸ these figures are consistent with more recent series of ambulatory patients with DVT (79%¹¹ and 83%²¹). Eligibility criteria for initial outpatient treatment of DVT are expanding,¹⁵, ²¹ allowing safe application to a greater number of patients. For example, more recent studies have not excluded patients with a history of prior thromboembolic disease.¹⁵, ²¹ An exaggerated risk of bleeding appears to be the most important factor precluding initial outpatient therapy. Because major life-threatening hemorrhage, although rare, is potentially treatable while the patient is under observation, it would seem prudent to begin heparin therapy in the hospital in patients with coexisting risk factors for hemorrhage.²⁰ Another traditional reason to hospitalize patients with DVT for intravenous unfractionated heparin therapy is the presence of concomitant symptomatic PE. That approach, however, is undergoing reevaluation. LMWH has been shown to be safe and effective in the treatment of submassive PE in the inpatient setting.²³ Limited data suggest equal safety for selected patients with PE treated exclusively as outpatients.²⁴ Although many patients with symptomatic DVT are believed to have concomitant silent pulmonary emboli,²⁵ outpatient treatment of symptomatic PE is still undergoing investigation.

In addition to careful patient selection, another attribute of our ED-managed DVT pathway is its 24-hour availability and multispecialty integration. The presence of the ED staff around the clock to initiate and direct the program was supported at all hours by both inpatient pharmacy and on-call radiology staff. Additionally, home health services and the anticoagulation pharmacy laboratory were available all days of the week to continue care in the community.²⁶

Our study has several limitations. Because this was a retrospective analysis, there was potential for more disparity between groups than if they had been randomly allocated to inpatient versus outpatient care. The similarities, however, are increased because both groups were drawn from the same socioeconomic population and demonstrate comparable demographic and clinical characteristics (Table 1). Also inherent in the retrospective study design are shortcomings of data collection. However, we had the advantage of gathering data on the postintervention study group from a well-conducted quality improvement program that had instituted active and well-documented multidisciplinary prospective surveillance. To minimize the possibility of missed events because of incomplete charting or inadequate follow-up, the clinical care pathway was designed with a number of safeguards. Patients were contacted multiple times during the 2-week surveillance by personnel from various services, all of whom inquired about adverse events: home health nurses made daily visits; pharmacists were in contact by telephone with each patient for the adjustment of warfarin doses; and primary care providers evaluated 86% of the cohort within 14 days. Moreover, our retrospective review was thorough; both electronic and paper records were reviewed on every subject. No records of either cohort were irretrievable or incomplete. In addition, all patients in both groups were enrolled in a closed-panel health maintenance organization and received care exclusively within the system. No patient in the postintervention group received care outside the organization, nor did any chart of the preintervention group note such care. By nature of the eligibility criteria for the pathway, all postintervention subjects were required to live close to the facilities and had been instructed to report any new or progressive symptoms.

Another weakness of the study was the lack of objective testing performed on patients who returned with increasing symptoms of their index DVT. The diagnosis of progressive DVT in the index leg was made on clinical grounds alone. A second compression ultrasound scan was not a mandatory component of the pathway and, in the case of the 2 patients admitted for this adverse event, was not undertaken. This practice differs from earlier trials⁶, ⁷, ⁸ that excluded from their catalogue of adverse events symptomatic progression without ultrasonographic extension. On the other hand, Pearson et al²² included all patients with worsening symptoms and found that only 1 of 3 had objective ultrasonographic extension. We do not know whether our 2 patients with progressive DVT had true extension of their thrombi.

Ours is one of the larger reported cohorts of patients with DVT treated outside the hospital; nevertheless, our absolute numbers are small. Although the occurrence of adverse events was uncommon, the degree of uncertainty, depicted by the upper limits of the 95% CIs (Table 3), deserves attention. Although no patients in our series experienced major bleeding or died, we cannot claim that the risk of these adversities is absent. Because our denominator of the postintervention group is small (178), the 95% CI for the incidence of major bleeding and death extends as high as 1.7%. Statistically, the question remains: “If nothing goes wrong, is everything all right?”²⁷

Our cohort is broadly representative of persons insured by a health maintenance organization and their dependents, whereas the indigent population is underrepresented compared with the general population of the region. This may limit the external validity of our results. In addition, we restricted our period of surveillance to 14 days because we were evaluating only the initial management of DVT. This limited duration of follow-up contrasts with several comparative trials that followed patients for several months,⁶, ⁷, ⁸ but is not discrepant with smaller case series.²² Our focus was the transfer of care from the traditional 5- to 7-day inpatient stay to the outpatient setting. Hemorrhagic complications of enoxaparin would be evident within 24 hours after the final injection.², ³ Progression of thromboembolic disease not evident within the first 2 weeks of therapy was outside our window of surveillance.

Our results were obtained by integrating resources readily available to a large, multispecialty health maintenance organization. The organizational structure used in this pathway may not be possible in smaller, less-integrated systems of health care. This may limit the study’s applicability. However, different non-Kaiser facilities have demonstrated the success of integrated services in the outpatient treatment of DVT.¹¹, ¹⁵, ²¹, ²² Their follow-up strategies vary widely: twice-daily home health care visits,²² once-daily visits,¹⁵ daily telephone calls,²¹ or routine warfarin monitoring through the outpatient coagulation service.¹¹ The latter 2 options require the patient to visit a clinic or a laboratory⁹ for serial phlebotomy to monitor the INR and adjust warfarin dosing as needed.

In summary, we describe an outpatient clinical care pathway for the treatment of proximal lower-extremity DVT that is managed by a community ED and uses careful patient selection and an integrated multidisciplinary approach. Comparing preintervention with postintervention cohorts, we demonstrate that outpatient DVT therapy with LMWH is similar in effectiveness and safety to customary inpatient therapy with intravenous unfractionated heparin.

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Acknowledgements 

We thank the members of the DVT Committee for their help in the creation of the clinical care pathway and the careful monitoring of its safety and impact. We also thank Liz Lewis and Kennie Stevenson-Baker from Performance Improvement for their conscientious assistance with data acquisition. We are grateful to Drs. Carin Olson, Pankaj Patel, and Daniel McIlmail for their constructive critique of an earlier version of this manuscript. Bennett Bradley, Jr., PhD, served as statistical consultant.

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