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Spencer FA, Gore JM, Lessard D, Douketis JD, Emery C, Goldberg RJ. Patient Outcomes After Deep Vein Thrombosis and Pulmonary EmbolismThe Worcester Venous Thromboembolism Study. Arch Intern Med. 2008;168(4):425–430. doi:10.1001/archinternmed.2007.69
Copyright 2008 American Medical Association. All Rights Reserved. Applicable FARS/DFARS Restrictions Apply to Government Use.2008
Despite advances in the management of deep vein thrombosis (DVT) and pulmonary embolism (PE), relatively few contemporary data describe and compare outcomes in patients with these common conditions from a more generalizable community-based perspective. The purpose of this study was to measure and compare clinical characteristics and outcomes of patients with validated symptomatic PE and isolated DVT in a New England community.
The medical records of residents from the Worcester area with International Classification of Diseases, Ninth Revision (ICD-9) codes consistent with possible venous thromboembolism (VTE) during 1999, 2001, and 2003 were independently validated and reviewed by trained abstractors.
Patients who presented with PE or isolated DVT experienced similar rates of subsequent PE, overall VTE, and major bleeding during 3-year follow-up (5.9% vs 5.1%, 15.0% vs 17.9%, and 15.6% vs 12.4%, respectively). Mortality was significantly increased at 1-month follow-up in patients who initially presented with PE (13.0% vs 5.4%); this difference persisted at 3 years (35.3% vs 29.6%). Patients whose course was complicated by major bleeding were more likely to experience recurrent VTE or to die at 3 years than those without these complications.
Patients who presented with PE had similar rates of subsequent PE or recurrent VTE compared with patients with isolated DVT. However, rates of recurrent VTE and major bleeding after DVT and PE remain unacceptably high in the community setting. Efforts are needed to identify patients most at risk for VTE-associated complications and to develop better anticoagulation strategies conducive to long-term use in the community setting.
Despite advances in the medical management of deep vein thrombosis (DVT) and pulmonary embolism (PE) during the last decade, relatively few contemporary data describe and compare outcomes in patients with these common conditions from a more generalizable community-based perspective. The objectives of the Worcester Venous Thromboembolism Study are to provide contemporary population-based data about the clinical epidemiologic features of DVT and PE, their management, and associated outcomes.1 The primary objective of this report is to provide data on venous thromboembolism (VTE) recurrence, major bleeding, and mortality rates in patients with validated DVT and PE in the real-world setting.
Both DVT and PE are generally considered to be manifestations of the same disease process. Several studies2-4 have suggested that a substantial proportion of patients with clinically recognized DVT, but without symptoms suggestive of PE, will have radiologic evidence of PE. Nevertheless, other studies5-9 have suggested that patients with symptomatic PE have a higher risk of subsequent PE or fatal PE and/or a worse long-term survival than patients with isolated DVT. Unfortunately, most prior studies that examined the natural history of PE and DVT had small sample sizes, were conducted more than a decade ago, or relied on administrative databases for case ascertainment. We hypothesized that although patients who presented with symptomatic PE in the community setting would be older, have more comorbidities, and have higher mortality rates than their counterparts with isolated DVT, recurrent rates of PE and overall VTE would not significantly differ between these 2 patient subsets. Therefore, a secondary objective of this investigation was to compare patient characteristics, management practices, and short- and long-term outcomes in residents of the Worcester, Massachusetts, metropolitan area with independently validated DVT and PE.
Computerized printouts of all greater Worcester residents with health care system encounters in which any of 34 International Classification of Diseases, Ninth Revision (ICD-9)10 diagnosis codes possibly consistent with VTE had been listed in 1999, 2001, or 2003 were obtained from each of the 12 hospitals that served the Worcester metropolitan area (population of 478 000 based on 2000 US Census).1 These data queries were not limited to hospital discharge diagnoses but encompassed all outpatient, emergency department, radiologic, and laboratory encounters.
Trained data abstractors reviewed the medical records of all identified patients who met our geographic inclusion criteria. Validation and characterization of each case of VTE as being definite, probable, possible, or absent were performed by trained abstractors using prespecified criteria.1,11 For purposes of this study, all possible, probable, and definite cases of VTE were used. Potential cases of VTE recurrence were classified using criteria similar to those used for incident cases and were reviewed and validated by the principal investigator (F.A.S.). Definite or probable recurrence of VTE required the new occurrence of thrombosis in a previously uninvolved venous or pulmonary segment.
Information was collected about patients' demographic and clinical characteristics, diagnostic test results and treatment practices, and short- and long-term outcomes through the review of hospital and ambulatory medical records. Medical history variables defined as “recent” were those that occurred in the 3 months before the diagnosis of VTE. Major bleeding was defined as any bleeding episode that required transfusion; resulted in hospitalization, stroke, or myocardial infarction; or caused death.
Short- and long-term rates of an initial recurrence of VTE and first episodes of major bleeding were determined through the complete review of subsequent medical records at the same hospital site as the index event and through the screening of medical records from the other participating hospital sites. Mortality data were obtained through hospital record reviews and review of death certificates at the Massachusetts Division of Vital Statistics. Follow-up data were available for our 3 patient cohorts for a minimum of 1 year and a maximum of 3 years.
Differences in the distribution of demographic and clinical characteristics, as well as short- and long-term outcomes, between patients with PE vs isolated DVT were examined using χ2 tests of statistical significance for categorical variables and t tests for continuous variables. Cumulative incidence rates of VTE recurrence, PE recurrence, and major bleeding (censoring patients at the time of death) and all-cause mortality were estimated using the life-table method.
Cox proportional hazards regression model analyses were constructed to evaluate whether type of VTE at presentation (PE with or without DVT or isolated DVT) was associated with specific outcomes, including occurrence of new PE, recurrent VTE, major bleeding, and all-cause mortality. All variables listed in Table 1, with the exception of body mass index (BMI), were considered potential covariates. Since BMI data were missing for approximately a third of patients, this variable was not included in our final regression analyses. Repeated analyses performed, including BMI, did not significantly alter our study findings (data not shown). Recurrent VTE and major bleeding occurrences were included in these analyses as time-dependent variables to assess the impact of these complications on our principal study outcomes. Candidate variables possibly associated with the outcomes of interest (P < .25 after univariate analysis) were included in each multivariate regression model. Variables with P > .05 were eliminated in a stepwise fashion so that only variables with a statistically significant association with the outcome of interest were included in the final regression models.
The study sample consisted of 1691 men and women from the Worcester metropolitan area with a validated episode of acute VTE (both hospitalized and nonhospitalized cases) during the 3 study years of 1999, 2001, and 2003. Of these, 549 patients were diagnosed as having PE (with or without DVT) (32.5%), whereas the remainder (n = 1142) were diagnosed as having isolated DVT. The mean age of the study sample was 65 years; 54.0% were women and 91.0% were white.
Patients with PE were more likely to be obese than patients with isolated DVT (Table 1). Patients with PE were more likely to have been recently hospitalized (within <3 months), to have undergone surgery, to have been admitted to an intensive care unit or intubated, to have had an infection, or to have experienced congestive heart failure than patients with isolated DVT. They were also more likely to have developed their episode of VTE during hospitalization for a non–VTE-related condition (Table 1).
Patients with PE were more likely to be initially treated with unfractionated heparin alone or in combination with low-molecular-weight heparin, to have an inferior vena cava filter placed during hospitalization, or to be given warfarin sodium therapy during the initial hospital encounter. Patients with PE were less likely to already have an inferior vena cava filter in place at the time of presentation (Table 2).
Among the 549 patients who presented with PE, 31 (5.7%) had recurrent PE, 75 (13.7%) had recurrent VTE, 82 (14.9%) experienced a major bleeding episode, and 226 (41.7%) died during the follow-up period. Among 1142 patients who presented with isolated DVT, 64 (5.6%) had subsequent PE, 217 (19%) had recurrent VTE, 146 (12.8%) experienced a major bleeding episode, and 411 (36.0%) died during the follow-up period.
Cumulative incidence rates of recurrent VTE (DVT or PE) were similar between patients who presented with PE vs isolated DVT at 30 days (3.8% vs 4.8%), 1 year (10.7% vs 12.0%), and 3 years (15.0% vs 17.9%) (Table 3). After Cox proportional hazards regression model analysis, presentation with PE (compared with isolated DVT) was not significantly associated with an increased risk of recurrent VTE at 30 days, 1 year, or 3 years (Table 4). However, occurrence of a bleeding complication after initial VTE (hazard ratio [HR], 2.94; 95% confidence interval [CI], 2.00-4.33) was associated with a significantly increased risk of a recurrent episode of VTE at 3-year follow-up.
Patients who presented with PE initially had essentially similar cumulative incidence rates of new PE at 30 days (1.1% vs 1.5%), 1 year (3.6% vs 3.6%), and 3 years (5.9% vs 5.1%) compared with patients with isolated DVT (Table 3). After Cox proportional hazards regression model analysis, presentation with PE (compared with isolated DVT) was not significantly associated with increased risk of subsequent PE at 30 days, 1 year, or 3 years. Occurrence of major bleeding during follow-up was not associated with an increased risk of subsequent PE in the overall cohort.
Rates of major bleeding after 30 days (9.4% vs 6.5%), 1 year (11.6% vs 10.3%), and 3 years (15.6% vs 12.4%) were similar between patients who presented with PE vs isolated DVT. After Cox proportional hazards regression model analysis, presentation with PE was not significantly associated with major bleeding at 30-day, 1-year, or 3-year follow-up. In the overall cohort, patients who experienced a recurrent VTE event were more likely to experience bleeding by the time of our 3-year follow-up (HR, 2.80; 95% CI, 1.63-4.83).
The observed all-cause mortality was higher at 30 days (13.0% vs 5.4%), 1 year (26.0% vs 20.3%), and 3 years (35.3% vs 29.6%) for patients with PE compared with those with isolated DVT (Table 3). Most of this increase in mortality occurred in the first 30 days. After Cox proportional hazards regression model analysis, presentation with PE was significantly associated with increased 30-day (HR, 3.22; 95% CI, 2.18-4.79), 1-year (HR, 1.52; 95% CI, 1.20-1.93), and 3-year mortality (HR, 1.43; 95% CI, 1.16-1.76) (Table 4). Patients who experienced a recurrent episode of VTE were not at significantly increased risk of 3-year mortality (HR, 1.18; 95% CI, 0.93-1.50). Occurrence of a major bleeding complication was associated with an increase in 3-year death rates (HR, 1.36; 95% CI, 1.07-1.73).
The results of our population-based study in residents of an entire New England metropolitan area provide contemporary insights into the clinical profile and outcomes of patients with symptomatic PE and isolated DVT.
Rates of recurrent VTE in our community-based study did not differ between our 2 comparison cohorts but were relatively high; approximately 4% and 11% of all patients had developed a recurrent episode of VTE at 1 month and 1 year, respectively. Not surprisingly, these rates are higher than those reported in recent clinical trials of anticoagulant treatment in patients with VTE in whom study inclusion criteria are narrowly defined and therapy is carefully specified and monitored.12,13 Disappointingly, the rates of recurrent VTE observed in our study do not differ significantly from those reported by Prandoni et al14 in their landmark study of the natural history of VTE more than a decade ago. In their study of 355 consecutive patients referred to a tertiary care center with a first symptomatic VTE, approximately 10% of their study sample had experienced a recurrent episode of VTE at 1 year. Similarly, in a population-based cohort study of 1719 residents of the Rochester, Minnesota, area with a first episode of VTE between 1966 and 1990, the cumulative incidence of recurrent VTE at 30 days and 1 year was 5.2% and 12.9%, respectively.15 Although one must be cautious in comparing outcome data from different observational studies, the present findings suggest that VTE recurrence rates in the community have not improved appreciably during the last decade.
Several studies7,9,16 have suggested that patients who present with PE are at increased risk for recurrent PE compared with patients with isolated DVT. In an analysis of the California Patient Data Set,7 which included information from more than 70 000 adult patients hospitalized with VTE from 1991 to 1996, initial presentation with PE was the strongest predictor of recurrent VTE manifesting as subsequent hospitalization for PE. In a prospective study9 of 436 patients with unprovoked VTE from 1992 to 2002, patients who presented with PE had an approximately 4-fold increased risk of recurrent PE compared with those who presented with isolated DVT during a 30-month follow-up. These findings have led some to suggest that DVT and PE are distinct clinical entities with different natural histories.
These findings are at odds with our observations that suggest that patients with PE and isolated DVT may have a similar VTE-specific prognosis. Our findings are consistent with prior studies2-4 that have suggested that up to half of patients with DVT who are asymptomatic for PE will have radiologic evidence of PE. In the community setting, patients with DVT who are asymptomatic for PE rarely undergo further diagnostic testing for PE. Only 6.8% of patients with isolated lower extremity symptoms in our study also underwent diagnostic testing for possible PE (data not shown). As a result, there may have been a potential for misclassification bias in our study in that patients with symptomatic DVT may also have had undiagnosed PE. Although we cannot account for this bias, this misclassification is what occurs in the real-world clinical setting.
We also acknowledge that physicians in the community may be prescribing anticoagulation for patients with PE for longer durations than they do for patients with isolated DVT. This may have decreased the recurrence rates of VTE, and possibly of PE, in patients with an initial episode of PE. This, in turn, would mask any difference in recurrence rates in these 2 patient cohorts.
Finally, we cannot exclude the possibility that some of the excess mortality observed in patients who presented with PE in our study was secondary to fatal (undiagnosed) PE recurrences. In a literature review8 of 25 studies of VTE treatment, patients who presented with PE had higher rates of fatal PE during anticoagulant therapy than those with isolated DVT (1.5% vs 0.4%). Interestingly, no significant difference was found in the occurrence rates of fatal PE between these cohorts after anticoagulant therapy.
Further study of the subsequent risk of clinically significant PE in patients who present with symptomatic PE vs isolated DVT remains warranted. Currently, the American College of Chest Physicians treatment guidelines for VTE still consider DVT and PE as manifestations of the same disease process and recommend similar durations of anticoagulation for both.17
As opposed to data derived from recent randomized clinical trials of VTE treatment in which the occurrence of major bleeding episodes was shown to be 4% or less at 3 to 6 months,12,13 the cumulative incidence of major bleeding in our population at 1 month was approximately twice this rate. In addition, the occurrence of major bleeding after VTE was associated with a 3-fold increased risk of recurrent VTE and a 30% increased risk of mortality at 3 years.
These data suggest a parallel to research currently being conducted in patients with acute coronary syndromes. There is growing recognition that the occurrence of major bleeding after treatment of patients with acute coronary syndromes is associated with significantly worse outcomes.18,19 Accordingly, a considerable amount of contemporary research has been aimed at improving our ability to identify patients with acute coronary syndromes who are at increased risk for major bleeding, clarifying the impact of selected antithrombotic therapies on serious bleeding and minimizing the impact of bleeding on mortality when it occurs.20,21 Further study of patient, clinical, and treatment characteristics associated with VTE-related bleeding is needed if we are to improve the short- and long-term outcomes associated with this prevalent condition.
Patients who presented with PE had significantly higher death rates from all causes than those who presented with isolated DVT, particularly during the first 30 days of follow-up. Although much of this increase in mortality may be due to the increased prevalence of severe concomitant illnesses in patients with PE, some of this increased risk may be attributable to fatal (but undiagnosed) recurrent PE. The short-term mortality associated with clinically recognized PE in our study is similar to that observed in the International Cooperative Pulmonary Embolism Registry in which 13% of 2048 patients with PE diagnosed in the mid-1990s (and not treated with thrombolysis) had died at 3 months.22 These observations suggest that substantial room for improvement remains in the short-term detection and management of PE in the community setting.
Approximately 1 in 4 patients with clinically recognized VTE died within the first year after their initial diagnosis in our population-based study. This finding represents only a slight improvement in total VTE-associated mortality compared with the original Worcester DVT Study conducted in the 1980s, in which nearly one-third of patients with validated VTE had died at 1 year.23 Much of this substantial mortality likely stems from the advanced age and serious comorbidities typically seen in patients with VTE in the community setting. These data highlight the poor prognosis of this group as a whole and remind us of the difficulties inherent in treating this condition in the real-world setting.
Similar to the design and conduct of any observational study, the present investigation has several limitations. Although we conducted 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. Notably, we will not have captured events that occurred in residents of greater Worcester who sought care at hospitals outside this metropolitan area. We do not collect data on anticoagulation management practices that occurred after hospital discharge, so we cannot comment on the impact of use (or nonuse) of anticoagulation on our observed study outcomes. Finally, because of the low autopsy rates during the period under study, we are unable to estimate the rates of fatal PE. Therefore, we can comment only on complication rates and mortality associated with clinically recognized VTE.
Our study provides insights into the clinical profiles of patients with PE or isolated DVT and their short- and long-term outcomes within this well-defined New England community. Patients who presented with PE had similar rates of VTE recurrence or subsequent PE compared with patients with DVT. Nevertheless, short-term case fatality rates associated with PE, as well as rates of recurrent VTE and major bleeding after an initial episode of DVT or PE, remain unacceptably high. Although recent randomized clinical trials have resulted in important advances in the management of VTE, our data suggest that, at least in the community setting, considerable room for improvement remains in the treatment of these high-risk patients.
Correspondence: Frederick A. Spencer, MD, Department of Medicine, McMaster University, Faculty of Health Sciences and Blood Institute, 1200 Main St W, Hamilton, ON L8N 3Z5, Canada (email@example.com).
Accepted for Publication: September 20, 2007.
Author Contributions: Dr Spencer had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Spencer, Gore, and Goldberg. Acquisition of data: Spencer and Emery. Analysis and interpretation of data: Spencer, Lessard, and Goldberg. Drafting of the manuscript: Spencer, Gore, Douketis, and Goldberg. Critical revision of the manuscript for important intellectual content: Spencer, Gore, Douketis, Lessard, Emery, and Goldberg. Statistical expertise: Spencer, Lessard, and Goldberg. Administrative, technical, or material support: Spencer and Goldberg. Obtained funding: Spencer and Goldberg. Study supervision: Spencer, Emery, and Goldberg.
Financial Disclosure: None reported.
Funding/Support: This study was supported by grant R01-HL70283 from the National Heart, Lung, and Blood Institute. Dr Spencer has also received a Career Investigator Award from the Heart and Stroke Foundation of Canada.
Role of the Sponsor: 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.
Additional Contributions: This study was made possible by the cooperation of administrators, physicians, and medical records personnel in 12 central Massachusetts hospitals.