Factors Associated With Adverse Outcomes in Outpatients Presenting With Pulmonary Embolism
The Worcester Venous Thromboembolism Study
Background— Data from clinical trials suggest that short-term mortality in outpatients presenting with pulmonary embolism (PE) is low and that outpatient therapy may be appropriate. However, subjects enrolled in these studies may not be representative of patients seen in the community setting.
Methods and Results— The medical records of residents from Worcester, Mass, with International Classification of Disease, Ninth Edition, codes consistent with potential venous thromboembolism during 1999, 2001, and 2003 were independently validated and reviewed by trained abstractors. A total of 305 patients presented with PE from the outpatient setting. The rates of recurrent PE, major bleeding, mortality, or occurrence of any 1 of these end points at 90 days were 1.4%, 9.5%, 11.1%, and 20.1%, respectively. Patients with a history of congestive heart failure, recent intensive care unit discharge, cancer, severe infection, systolic blood pressure <100 mm Hg, and male sex were at increased risk for the composite end point.
Conclusions— In the present population-based study, morbidity and mortality after outpatient PE were much higher than what was observed in clinical studies. Our findings raise questions about broad-based outpatient treatment of PE in the community setting. In our study, comorbid conditions and recent illness were important determinants of adverse outcomes, suggesting that these variables should be carefully considered before embarking on outpatient therapy of PE.
A significant proportion of patients with pulmonary embolism (PE) present to an emergency department and ambulatory clinic from home.1 Data from clinical trials and observational studies that have included patients with PE suggest that short-term mortality in such patients is quite low and that outpatient antithrombotic therapy is appropriate.2,–,6 However, 17% to 59% of screened subjects in these studies were excluded due to comorbidities, contraindications to treatment, poor expected survival, refusal to participate, and so forth. As such, patients enrolled in these studies may not be representative of patients typically seen in the community setting.
Using data from the population-based Worcester Venous Thromboembolism Study, we characterized residents of the Worcester, Mass, metropolitan area presenting with PE to all area hospitals in 1999, 2001, and 2003, including their sociodemographic and clinical characteristics, their management, and their outcomes. In addition, we identified patient and treatment variables associated with an increased risk of recurrent PE, major bleeding, or total mortality. We evaluated our patient population with a previously developed prognostic model for PE.7
Computerized printouts of all greater Worcester residents with healthcare system encounters in which any of 34 International Classification of Disease, Ninth Edition, diagnosis codes consistent with venous thromboembolism (VTE) had been listed in 1999, 2001, or 2003 were obtained from each of the 12 hospitals serving the residents of Worcester metropolitan area (2000 census, 478 000).8,9 These data queries were not limited to hospital discharge diagnoses but encompassed all outpatient, emergency department, radiology, and laboratory encounters.
Trained data abstractors reviewed the medical records of all patients meeting our geographic inclusion criteria. Validation and characterization of each case of VTE as being definite, probable, possible, or absent was performed by trained abstractors using prespecified criteria.8,10 For purposes of this study, only definite and probable cases of PE (PE documented by high-probability lung scans or positive-CT pulmonary angiograms or by pulmonary angiograms) were used. Potential cases of recurrent PE were classified using similar criteria as those used for incident cases and were reviewed and validated by the principal investigator (F.A.S.). Definite or probable cases of recurrent VTE required the presence of thrombus in a previously uninvolved pulmonary segment.
Short-term mortality in clinical treatment trials of outpatients presenting with pulmonary embolism (PE) is low.
Outpatient therapy with low-molecular weight heparins has been shown to be safe and effective in these trials.
Subjects enrolled in clinical treatment trials are not necessarily representative of patients typically encountered in the community setting.
WHAT IS KNOWN
Morbidity and mortality following in outpatients presenting with PE in the community setting is significantly higher than that observed in randomized clinical trials.
Concomitant comorbidities (eg, cancer, severe infection, congestive heart failure) are strongly associated with subsequent poor outcomes in the community setting and should be considered (in addition to markers of PE severity) when making management decisions.
WHAT THE STUDY ADDS
Information about demographic and clinical characteristics, diagnostic test results, management practices, and short- and long-term outcomes was collected by reviewing hospital and ambulatory medical records. Only medical history variables documented by a physician in the medical record were abstracted. Medical history variables defined as recent were those occurring within 3 months of the diagnosis of VTE. Severe infection was defined as any infection requiring IV antibiotics or hospital admission. Major bleeding was defined as any bleeding episode requiring transfusion, resulting in hospitalization, stroke, or myocardial infarction or causing death.
Short- and long-term rates of recurrent PE and first episodes of major bleeding were determined by complete review of subsequent medical records at the hospital site where the diagnosis of the index event was established as well as by screening medical records from the other participating hospital sites. Mortality data were obtained by hospital record review and review of death certificates at the Massachusetts Division of Vital Statistics.
The primary study outcomes were all-cause mortality and the composite end point of recurrent PE, major bleeding, or death at 90 days after the index PE. We evaluated these outcomes in the overall patient cohort and in subjects further stratified as low and high risk based on a previously validated risk model. This model was derived from a prospective cohort study of 296 consecutive patients with PE admitted through a single-center emergency ward in Geneva, Switzerland, from 1992–1997.7
Differences in the distribution of demographic and clinical characteristics between patients with recurrent PE or death and those without these end points were examined using χ2 tests for categorical variables and t tests for continuous variables. Cumulative incidence rates of PE recurrence, major bleeding (censoring subjects at the time of death), and all-cause mortality were estimated using Kaplan–Meier method.
Multivariable logistic regression models were estimated using data from 294 patients (those with nonmissing data on all relevant variables) in order to identify variables associated with our primary composite end point at 90 days after the index PE event. All variables listed in Table 1 were considered as potential covariates. Candidate variables possibly associated with the outcomes of interest (an unadjusted association with P<0.25) were considered initially in each multivariable regression model. Both forward and backward regressions were examined and in all cases resulted in a consistent model. Variables that were not included in the original analyses were then examined for inclusion in the adjusted models.
The study sample consisted of 305 men and women from the Worcester metropolitan area who presented from outside the hospital setting to either an emergency department or an outpatient clinic and were determined to have a validated episode of acute PE. The mean age of this population was 62 years, 48% were women, and 91% were white. The majority (98%) were admitted to hospital for treatment. The median length of hospital stay was 5 days, and 17% were discharged within 3 days.
The rates of recurrent PE, major bleeding, and mortality at 90 days were 1.4%, 9.5%, and 11.1%, respectively. The incidence rate of the composite end point of recurrent PE, major bleeding, or death at 90 days was 20.1%. Rates of recurrent PE, major bleeding, or death or the composite end point in the first 30 days after the incident PE were 0.3%, 8.5%, 5.9%, and 13.8%, respectively.
Characteristics of Patients Who Died at 90 Days
Compared with survivors, patients who died within 90 days of the incident PE were older and were more likely to have a history of congestive heart failure, active malignancy, hospitalization within the past 3 months, recent ICU discharge, or severe infection (Table 1). Patients who died within 90 days also were more likely to present with a systolic blood pressure (BP) <100 mm Hg. Characteristics of patients with the 90-day composite end point were relatively similar to those who died but also included a history of chronic lung disease.
Predictors of 90-Day Mortality of the Composite End Point
Based on the multivariable logistic regression model, a history of congestive heart failure, active cancer, recent severe infection, heart rate >100 bpm, and male sex were significantly associated with mortality at 90 days (Table 2). Area under the receiver operating characteristic curve for this model was 0.82. Congestive heart failure, recent ICU discharge, active cancer, recent severe infection, systolic BP <100 mm Hg, and male sex were associated with an increased risk of the composite end point (recurrent PE, major bleeding, and death) at 90 days (Table 2). Area under the curve for this model was 0.76.
Swiss Risk Score
Using the Swiss risk score,7 75% of our patients were classified as low risk (≤2 points) and 25% as being at high risk (>2 points) for subsequent events. Mortality at 90 days was 7.0% for patients with low-risk scores and 23.4% for those with high-risk scores. The composite end point at 90 days was 15.8% for those with low-risk scores and 32.5% for those with high-risk scores.
The results of several prior studies suggest that a significant proportion of outpatients who present with newly diagnosed PE have a sufficiently low risk of subsequent morbidity and mortality to warrant outpatient management.4,5 However, because these data have been generated from randomized clinical trials as well as from prospective studies in which patients were carefully selected and outcome rates were low, the findings may not be generalizable to those patients with PE in the broader community setting.
In our population-based surveillance study, approximately 1 out of every 10 outpatients presenting with PE died by 90 days after their index event, and 1 in every 5 experienced recurrent PE, major bleeding, or death during this period. These event rates are considerably higher than those observed in randomized treatment trials of patients with PE3,12 or in observational studies evaluating outpatient treatment for PE.4,5 The 90-day mortality rate of 11.1% observed in the present study is also higher than the 8.4% mortality rate observed in a prospective cohort study of 296 PE patients presenting to a tertiary-care center in Geneva, Switzerland.7
Predictors of Poor Outcomes
Data from a number of randomized clinical trials and observational studies have shown that selected patients presenting with PE can be safely managed at home.3,–,6 Our findings raise questions about this approach. Our observed mortality rate was high even though almost all of our patients were admitted to the hospital for treatment. To better identify patients at increased risk for adverse outcomes, we compared the demographic and clinical characteristics of patients with a poor outcome with those with a favorable outcome in the community setting.
After regression analysis, male sex, active cancer, a history of recent severe infection, a history of recent ICU stay, or a history of congestive heart failure, and systolic BP <100 mm Hg at presentation predicted increased risk of developing adverse outcomes. Interestingly, a number of variables previously noted to be of prognostic importance in other risk models were not predictive in our community-based sample.
As noted, one such model was derived from 296 consecutive outpatients presenting with PE to a tertiary-care hospital in Switzerland.7 In this risk model, predictors of adverse outcomes at 3 months included history of cancer, heart failure, systolic BP <100 mm Hg, Pao2 <8 kPa, history of prior deep venous thrombosis, and presence of new deep venous thrombosis by ultrasound. Application of the Swiss score to our patients identified approximately 75% of our population as being at low risk, but these patients had a 90-day mortality rate of 7.0% and composite end point rate of 15.8%. Similarly, application of the Swiss score to 599 patients presenting to an emergency department in Spain suggested that 84% of patients were at low risk, but their 30-day mortality rate was 5.6%.13 Therefore, although this score successfully stratified patients according to risk, event rates in the low-risk group were unacceptably high.
Some of the differences in the variables identified to be predictive of adverse outcome between the two studies may reflect differences in the characteristics of the respective study populations. Most notably, our community-based population included patients with greater acuity of illness and a higher prevalence of comorbidities. Overall, 90-day mortality was only 8.4% in the Swiss population validation cohort compared with 11.1% in our community-based sample. Approximately 20% of our patients had a recent infection, 30% had cancer (compared with 18% in the Swiss study), and 40% had a history of recent hospitalization.
Indeed, in our model only a systolic BP <100 mm Hg at the time of hospital presentation could be considered reflective of the severity of the PE. In contrast to prior studies,7,11 a history of VTE, concomitant deep venous thrombosis, a heart rate >100 bpm, or Pao2 <60% were not associated with an increased risk of adverse outcomes. Furthermore, 4 of the 6 variables included in our prediction model reflect comorbid conditions, suggesting that in many patients, the outcome of PE may be as dependent on accompanying comorbidities as it is on the extent of the PE itself. This finding is similar to those of a recent prospective study of 201 patients with hemodynamically stable patients with PE in whom only the clinical score (and troponin) was predictive of 3-month mortality.14
Our data suggests that the high morbidity and mortality associated with “outpatient” PE stems from recent illnesses and/or comorbidities (that likely predisposed to the incident PE itself). Prior randomized clinical trials have clearly shown that outpatient antithrombotic therapy using low-molecular-weight heparins overlapping with warfarin can be as effective as inpatient therapy for the prevention of recurrent and/or fatal PE. Nevertheless, approximately 1 in 5 outpatients with PE in the community will experience either a major bleeding episode or death over the ensuing 3 months (and 1 in 7 in the first 30 days). For many of these patients, a brief hospitalization to ensure safe initiation of antithrombotic therapy and adequate management of coexisting illnesses may be more appropriate.
Study Strengths and Limitations
A strength of this study is that all patients with pulmonary embolism within a geographically defined community were included thereby greatly increasing the generalizability of our study. Like any observational study, the present investigation also has several limitations. Although we conducted a broad screening for all possible cases of VTE in the greater Worcester population, we cannot claim complete case ascertainment of index VTE events, episodes of VTE recurrence, or episodes of major bleeding. Most notably, we will not have captured events occurring in greater Worcester residents who sought care at hospitals outside of this metropolitan area. As in any retrospective study based on medical record review, the quality of data abstracted with respect to other medical conditions is limited by the quality of the medical documentation itself. We also do not routinely collect data on anticoagulation management practices after hospital discharge. Consequently, we cannot comment on the impact of quality of anticoagulation management on our observed study outcomes. Because of the low autopsy rates (<2%) in the period under study, we are unable to estimate the rates of fatal PE. Therefore, we can only comment on complication rates and overall mortality associated with clinically recognized VTE. Finally, the overall number of events in our study was small relative to the number of factors entertained and retained in our final regression models. Therefore it is likely that only risk factors with large effects (or moderate effects and balanced distribution) emerged from our analysis.
Our study provides insights into the clinical outcomes of outpatients presenting with PE in the community setting. Not surprisingly, the observed death rate in these persons was higher than those reported from previous randomized clinical trials or from observational studies of patients who were treated for PE at tertiary care centers. This finding raises questions about a broad based outpatient treatment of PE patients in the community setting. In contrast to other studies, we identified several clinical variables reflective of concomitant illness as being most predictive of short-term morbidity and mortality. This finding raises the possibility that comorbid conditions are at least as important or more important determinants, of pertinent clinical outcomes than the extent of the PE in most patients. If this concept is correct, only PE patients with minimal comorbidities may be considered appropriate candidates for out-of-hospital treatment.
This study was made possible by the cooperation of administrators, physicians, and medical records personnel in 12 central Massachusetts hospitals.
Sources of Funding
This study was supported by a grant from the National Heart, Lung, and Blood Institute (R01-HL70283). Dr Spencer also has a Career Investigator Award from the Heart and Stroke Foundation of Canada. The sponsors had no role in the design and conduct of this study; collection, management, analysis, and interpretation of the data; or preparation, review, or approval of the manuscript.
- Received January 8, 2010.
- Accepted May 11, 2010.
- © 2010 American Heart Association, Inc.
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