ORIGINAL INVESTIGATION. Predictors of Recurrence After Deep Vein Thrombosis and Pulmonary Embolism

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1 Predictors of Recurrence After Deep Vein Thrombosis and Pulmonary Embolism A Population-Based Cohort Study ORIGINAL INVESTIGATION John A. Heit, MD; David N. Mohr, MD; Marc D. Silverstein, MD; Tanya M. Petterson, MS; W. Michael O Fallon, PhD; L. Joseph Melton III, MD Background: The appropriate duration of oral anticoagulation after a first episode of venous thromboembolism (VTE) is uncertain and depends upon VTE recurrence rates. Objective: To estimate VTE recurrence rates and determine predictors of recurrence. Methods: Patients in Olmsted County, Minnesota, with a first lifetime deep vein thrombosis or pulmonary embolism diagnosed during the 25-year period from 1966 through 1990 (N = 1719) were followed forward in time through their complete medical records in the community for first VTE recurrence. Results: Four hundred four patients developed recurrent VTE during person-years of follow-up. The overall (probable/definite) cumulative percentages of VTE recurrence at 7, 30, and 180 days and 1 and 10 years were 1.6% (0.2%), 5.2% (1.4%), 10.1% (4.1%), 12.9% (5.6%), and 30.4% (17.6%), respectively. The risk of recurrence was greatest in the first 6 to 12 months after the initial event but never fell to zero. Independent predictors of first overall VTE recurrence included increasing age and body mass index, neurologic disease with paresis, malignant neoplasm, and neurosurgery during the period from 1966 through Independent predictors of first probable/ definite recurrence included diagnostic certainty of the incident event and neurologic disease in patients with hospital-acquired VTE. Recurrence risk was increased by malignant neoplasm but varied with concomitant chemotherapy, patient age and sex, and study year. Conclusions: Venous thromboembolism recurs frequently, especially within the first 6 to 12 months, and continues to recur for at least 10 years after the initial VTE. Patients with VTE with neurologic disease and paresis or with malignant neoplasm are at increased risk for recurrence, while VTE patients with transient or reversible risk factors are at less risk. Arch Intern Med. 2000;160: From the Division of Cardiovascular Diseases and the Section of Hematology Research (Dr Heit) and the Division of Area General Internal Medicine (Drs Mohr and Silverstein), Department of Internal Medicine, and the Sections of Clinical Epidemiology (Drs Silverstein and Melton) and Biostatistics (Ms Petterson and Dr O Fallon), Department of Health Sciences Research, Mayo Clinic and Mayo Foundation, Rochester, Minn. Dr Silverstein is now with the Center for Health Care Research, Medical University of South Carolina, Charleston. RECURRENT VENOUS thromboembolism (VTE) is an important risk factor for death after pulmonary embolism (PE) 1,2 and for venous stasis syndrome after deep vein thrombosis (DVT), 2 and is associated with significantly increased long-term health care costs. 3 While anticoagulation therapy is effective in preventing recurrence, 4,5 the optimal duration of anticoagulation after an initial episode of DVT or PE is uncertain 6 and depends largely on the rate of recurrence. However, the reported rates of recurrent VTE vary widely, ranging from 0.6% to 5% at 90 days and from 13% to 25% at 5 years. 2,7-14 Several factors may account for the variability in reported recurrence rates. For example, studies that identified cases from acute-care hospital discharge data 8,9 or Medicare claims diagnoses 11 are limited by diagnostic uncertainty or misclassification, as well as failure to include autopsy-discovered recurrence or to accurately separate initial from recurrent events. 12 Moreover, studies that identified cases solely from acute-care hospital admissions may have missed recurrent VTE among patients residing in nursing homes or other longterm care facilities 9,11,12 as well as rapidly fatal recurrences occurring out of hospital. 8 Follow-up studies of selected VTE See also page 809 populations, such as elderly patients, 11 patients referred to tertiary care centers for diagnostic evaluation and treatment, 2,15 or patients enrolled in clinical trials 1,7,10,13,14,16 may not estimate the true recurrence rate accurately since these studies did not include the full spectrum of VTE disease. Moreover, information regarding long-term recurrence is limited since follow-up in most studies was restricted 761

2 METHODS STUDY SETTING AND DESIGN Using the data resources of the Rochester Epidemiology Project, 18 we identified the inception cohort of Olmsted County residents with a first lifetime DVT or PE during the 25-year period from 1966 through All subjects were followed forward in time through their linked medical records 19 (retrospective cohort study) until either death or emigration from the community. For each subject, all inpatient and outpatient medical records of any local health care provider were searched for any evidence of recurrence as of the last clinical contact. The study was approved by the Mayo Clinic Institutional Review Board. DEFINITION OF DVT AND PE The initial episode of DVT or PE was categorized into the highest possible of 3 levels of diagnostic certainty (possible, probable, or definite) according to previously defined criteria. 17 A DVT was categorized as definite when confirmed by venogram, computed tomographic scan, magnetic resonance image, or pathologic examination of thrombus removed at surgery or autopsy; as probable if either testing for the definite level of diagnostic certainty was not performed or the results were indeterminate and the results of at least one of the following noninvasive tests were positive: impedance plethysmography, continuous-wave Doppler ultrasound examination performed in the Mayo Clinic Vascular Laboratory, compression duplex ultrasonography, radionuclide venography, or radiolabeled fibrinogen leg scan; and as possible if either confirmatory tests were not done or the results were indeterminate and (1) the medical record indicated that a physician had made a diagnosis of DVT (or possible DVT), (2) signs and symptoms consistent with DVT were present, and (3) the patient received a course of anticoagulation therapy with heparin, warfarin, or a similar agent, or a surgical procedure for DVT. A PE was categorized as definite when confirmed by pulmonary angiogram, computed tomographic scan, magnetic resonance image, or pathologic examination of thrombus removed at surgery or autopsy; as probable if either testing for the definite level of diagnostic certainty was not performed or the results were indeterminate and the results of a perfusion or ventilation-perfusion lung scan were interpreted as showing a high probability for PE; and as possible if either confirmatory tests were not done or the results were indeterminate and (1) the medical record indicated that a physician had made a diagnosis of PE, (2) signs and symptoms consistent with PE were present, and (3) the patient received a course of anticoagulation therapy with heparin, warfarin, or a similar agent, or a surgical procedure for PE, such as an inferior vena cava filter. A short period of anticoagulation therapy while awaiting completion of diagnostic evaluation for either suspected DVT or suspected PE was insufficient grounds for inclusion. An episode of VTE consisting of both DVT and PE was categorized into the highest level of diagnostic certainty present for either manifestation. To be categorized as a recurrent DVT or PE, an event had to meet all of the criteria for an incident VTE event. Additionally, recurrent events were categorized as probable/ definite recurrent DVT or PE if the results of confirmatory tests or procedures for a probable or definite VTE were positive and the site of recurrent VTE was previously uninvolved or had documentation of resolution. They were categorized as possible recurrent DVT or PE if confirmatory tests were not done or the results were indeterminate but the other criteria listed above were met and the site of recurrence was previously uninvolved or had documentation of resolution. Extension of a DVT or PE was classified as a recurrence if a substantial change from the incident event was documented by history, physical examination findings, or a diagnostic test result. Classification of autopsy-discovered VTE as a recurrence was adjudicated by a committee of the investigators (J.A.H., D.N.M., and M.D.S.) and based on the likelihood that the initial event had resolved. Pulmonary embolism diagnosed within 24 hours of beginning therapy for a DVT (or vice versa) was considered a single incident event. If more than 24 hours of therapy had elapsed, these events were considered separate and the second event was classified as a recurrence. Because PE is a complication of DVT, results are presented for DVT alone or for PE with or without DVT. POTENTIAL RISK FACTORS More than 25 baseline characteristics were tested as predictors of recurrent VTE. Data on these characteristics were collected by review of all medical records (inpatient and outpatient) in the community for each subject. 18 The characteristics included the following: type of event (PE, DVT, or both); age at incident event; sex; year of incident event; patient location at onset (community, community but hospitalized within the previous 90 days, hospital, or nursing home); body mass index (BMI, calculated as the weight in kilograms divided by the square of the height in meters: weight [kg]/[height (m)] 2 ), categorized as underweight (BMI 20), normal weight (BMI 20 and 24), overweight (BMI 24 and 30), or obese (BMI 30) 20 ; chronic heart disease (congestive heart failure or other heart disease [congenital heart disease, cardiomyopathy, ischemic heart disease, or valvular heart disease]); active malignant neoplasm (excluding nonmelanoma skin cancer) with or without chemotherapy (cytotoxic or immunosuppressive therapy for malignant neoplasm, excluding tamoxifen); serious neurologic disease (stroke or other disease affecting the nervous system with associated extremity paresis, or acute stroke with extremity paresis to 1 to 3 years, 1,9,11 with only 2 studies reporting follow-up to 8 years. 2,12 The duration of anticoagulation therapy also depends upon accurate knowledge of predictors of VTE recurrence. However, all of the 6 studies addressing potential predictors of recurrence had limitations in study design: 1 study had a relatively small sample size, 12 3 were clinical trials with extensive exclusion criteria, 7,10,16 and 4 were limited to patients with DVT only. 2,8,12,16 We have identified the inception cohort of Olmsted County, Minnesota, residents with DVT or PE first diagnosedduringthe25-yearperiodfrom1966through To address the limitations of previous studies, we performed a population-based follow-up study to estimate the rate of recurrent VTE and to determine predictors of recurrence. 762

3 requiring hospitalization within the previous 3 months); surgery requiring anesthesia (general, orthopedic, neurologic, or gynecologic surgery); anesthesia (general, epidural/ spinal, other); trauma requiring hospital admission (major fracture or severe soft-tissue injury); chronic lung disease (chronic obstructive pulmonary disease, emphysema, chronic bronchitis, bronchiectasis, interstitial lung disease, or pulmonary hypertension [asthma was included only if there was documented evidence of fixed airflow obstruction]); chronic liver disease (including active hepatitis within the previous 3 months); chronic renal disease (physician s diagnosis and creatinine level 175 µmol/l [2 mg/ dl] for at least 3 months, or nephrotic syndrome); inflammatory bowel disease; previous superficial vein thrombosis; varicose veins (varicose veins or treated varicose veins [injection sclerotherapy or stripping]); central venous catheter or transvenous pacemaker; anticoagulation therapy or prophylaxis immediately preceding or at the time of the incident event; smoking status (none, former, or current [cigarettes only]); hormone therapy (estrogen or progesterone); and (for women only) pregnancy or postpartum (within 3 months of delivery) at the time of the incident event, oral contraceptive use, gynecologic surgery, and tamoxifen therapy. The characteristics related to active malignant neoplasm, chemotherapy, surgery, anesthesia, trauma, hormone therapy, oral contraceptive use, and tamoxifen therapy were recorded as present only if documented within the 3 months prior to the VTE event. All other characteristics were recorded as present if documented any time prior to the incident VTE event. Body mass index calculations were based on the most recent height and weight measurements prior to the incident event. The BMI could not be calculated for 82 cases, mainly because of missing height measurements. For these cases, BMI values were imputed by assigning to each case the average height and/or weight of those incident cases of the same sex and age group. For the one child younger than 15 years with a missing measurement for height, we used the 50th height percentile from the published 1976 National Center for Health Statistics growth chart. Smoking status was based on tobacco use in the 3 months prior to the incident event. Smoking status was missing for 92 patients and was evaluated only after determination of the otherwise final model (including interactions). In the subset of cases with complete smoking information, we verified that the final multivariate model variables did not have hazard ratios differing from those computed using all cases. We then categorized those patients with missing smoking status as nonsmokers, reasoning that this would be the most conservative approach. Because pregnancy and the postpartum period, oral contraceptive use, gynecologic surgery, and tamoxifen therapy could only be evaluated in women, these variables were assessed after determining the otherwise final model, including interactions. ANALYSIS Survival free of VTE recurrence was estimated using the Kaplan-Meier product-limit method. Hazard rates for recurrence were computed using the life table method for analyzing survival. Follow-up began on the date of the incident VTE event. Data were censored at the earliest of death, last clinical contact, or December 31, Because our criteria for a possible VTE recurrence did not require objective diagnostic testing, some of these events may not have been true recurrences. On the other hand, some patients with a true recurrence may not have undergone objective testing and therefore could not meet our criteria for a definite or probable event. For example, many noninvasive diagnostic tests (eg, venous duplex ultrasonography, lung scan, computed tomography, magnetic resonance imaging) were unavailable early in our study. Moreover, many patients were too ill to tolerate invasive procedures (eg, pulmonary angiography), or exposure to radiation was contraindicated (eg, pregnancy). Since the true rate of clinically recognized recurrence is bounded by these 2 rates, we performed 2 analyses for first VTE recurrence: (1) first overall VTE recurrence, defined as the first possible, probable, or definite recurrent event, and (2) first probable/definite VTE recurrence. The relationship of the independent variables to time to recurrent VTE was assessed using the Cox proportional hazards model. We used stepwise and backwards conditional logistic regression to identify a final model. Initially, P.10 was required to enter the model. The resulting model was validated using a bootstrap method, 21 in which random samples of the same size as the incidence cohort were drawn with replacement from these cases; a stepwise proportional hazards model was run on the sample, with P.05 required for a variable to enter the model. This was repeated 500 times, and the percentage of times a variable came into the 500 models was used to validate its presence in the final model. Variables were considered validated and were retained in the final model if they entered more than 70% of the models. 21 When the list of main effect variables was finalized, all 2-way interactions of the main variables in the model were explored using the bootstrap technique. Discrete variables with multiple components could not be assessed using the usual stepwise technique. Such variables were checked separately, as were all their interactions. We used a modification of the bootstrap technique described above to validate interactions with P.05. We also checked all 2-way interactions of those variables that were no longer in the model with those that were in the final list of main effect variables. The proportional hazards assumption was checked for all variables in the final model by testing whether the interaction of time since the incident VTE event and the variable was significant. RESULTS Altogether, 2218 Olmsted County residents had a confirmed first lifetime diagnosis of DVT or PE between January 1, 1966, and December 31, Their mean ± SD age at onset was 61.7 ± 20.4 years, and 1244 patients (56%) were female. Of the total, 938 patients (42%) had DVT, while 969 (44%) had PE and 308 (14%) had evidence of both DVT and PE; 3 patients (0.1%) had chronic thromboembolic pulmonary hypertension. Of the 2218 incident cases, 494 either died on the event date or were first discovered to have VTE at autopsy. Three additional patients had no follow-up available (all 3 died within a few days). One patient s last medical contact occurred 201 days before her autopsyconfirmed PE following an out-of-state motor vehicle 763

4 accident. One additional patient was excluded from most analyses because of missing values, leaving 1719 patients available for multivariate analysis. Of the patients diagnosed prior to death, 96% received standard treatment; 86% received anticoagulation therapy, with mean ± SD durations of intravenous heparin and oral anticoagulation therapy of 5.9 ± 4.2 days (median, 5) and ± 559 days (median, 88), respectively. Other standard treatments included subcutaneous heparin (n = 48) in the early years of the study; inferior vena cava ligation, interruption, or filter (n = 33) or other treatment (eg, vein ligation or thrombectomy; n = 13) for patients in whom anticoagulation therapy was contraindicated; and thrombolytic therapy (n = 14) or pulmonary embolectomy (n = 3) for patients with phlegmasia or hypotension. Patients not treated were often terminally ill with cancer. CUMULATIVE INCIDENCE OF FIRST OVERALL VTE RECURRENCE The 1719 patients were followed up for a total of person-years. The median duration of follow-up was 7.4 Table 1. Kaplan-Meier Estimates of the Cumulative Incidence of First Overall or First Probable/Definite Venous Thromboembolism Recurrence Among Olmsted County, Minnesota, Residents With a First Lifetime Venous Thromboembolism Diagnosed From 1966 Through 1990 Time to Recurrence Overall Recurrence No. at Risk Cumulative Incidence, % Probable/Definite Recurrence No. at Risk Cumulative Incidence, % 0 d d d d d y y y y years for patients with DVT and 6.1 years for patients with PE. During the follow-up period, 404 patients had a total of 588 recurrences. The first such recurrence was a possible recurrence in 205 of the 404 patients, probable recurrence in 50, and definite recurrence in 149. The estimated cumulative incidence of first overall VTE recurrence was 1.6% at 7 days, 5.2% at 30 days, 8.3% at 90 days, 10.1% at 180 days, 12.9% at 1 year, 16.6% at 2 years, 22.8% at 5 years, and 30.4% at 10 years (Table 1 and Figure 1). The hazard rate per 1000 person-days (±SD) for the first overall recurrence was highest in the first 6 to 12 months after the initial event, ranging from 170 ± 30 recurrent VTE events at 7 days to 130 ± 20 events at 30 days, 30 ± 5 events at 90 days, 20 ± 4 events at 180 days, and 20 ± 2 events at 1 year. However, the recurrence hazard rate never fell to zero, continuing at 10 ± 1 events at 2 years, 6 ± 1 events at 5 years, and 5 ± 1 events at 10 years. CUMULATIVE INCIDENCE OF FIRST PROBABLE/DEFINITE VTE RECURRENCE Of the 404 patients with a VTE recurrence, 240 had at least one probable/definite recurrence (probable in 59 patients and definite in 181 patients). The numbers of first probable and first definite recurrences described herein are higher than the numbers described above, since if a possible recurrence preceded a probable/definite recurrence in the analysis of time to first overall recurrence, the subsequent probable/definite recurrence was not counted. The estimated cumulative incidence of first definite or probable recurrence was 0.2% at 7 days, 1.4% at 30 days, 3.1% at 90 days, 4.1% at 180 days, 5.6% at 1 year, 7.6% at 2 years, 12.4% at 5 years, and 17.6% at 10 years (Table 1 and Figure 2). The hazard rate per 1000 person-days (±SD) for first probable/definite recurrence also was highest in the first 6 to 12 months after the initial event, ranging from 30 ± 10 recurrent VTE events at 7 days to 50 ± 10 events at 30 days, 20 ± 4 events at 90 days, 10 ± 3 events at 180 days, and 10 ± 1 events at 1 year. Similar to first overall recurrence, the hazard rate for the first probable/definite recurrence also never fell to zero, continuing at 6 ± 1 events at 2 years and 4 ± 1 events at 5 and 10 years. Cumulative Recurrence, % ( ) Overall Time Since Incident VTE Event, y Figure 1. Kaplan-Meier estimates of cumulative incidence of first overall venous thromboembolism (VTE) recurrence and hazard of first overall recurrence per 1000 person-days among Olmsted County, Minnesota, residents with a first life-time VTE diagnosed from 1966 through Hazard Rate, per 1000 Person-Days ( ) Cumulative Recurrence, % ( ) Probable/Definite Time Since Incident VTE Event, y Figure 2. Kaplan-Meier estimates of cumulative incidence of first probable/definite venous thromboembolism (VTE) recurrence and hazard of first probable/definite recurrence per 1000 person-days among Olmsted County, Minnesota, residents with a first life-time VTE diagnosed from 1966 through Hazard Rate, per 1000 Person-Days ( ) 764

5 PREDICTORS OF VTE RECURRENCE Hazard ratios and 95% confidence intervals for more than 25 baseline characteristics tested as predictors of VTE recurrence are presented in Table 2 (univariate analyses). In general, persistent or irreversible characteristics present at the initial VTE were associated with an increased risk of recurrence, both overall and for probable/ definite recurrence. These characteristics included increasing age, being male, institutionalization, inflammatory bowel disease, neurologic disease associated with extremity paresis, previous central venous catheter or transvenous pacemaker placement, and malignant neoplasm (with and without chemotherapy). Several additional persistent characteristics were variably associated with an increased risk of either overall or probable/ definite recurrence, including the incident event year, smoking history, congestive heart failure, other heart disease, chronic lung disease, and chronic renal disease. Body mass index, previous superficial vein thrombosis, varicose veins, serious liver disease, and nephrotic syndrome were not predictors of recurrence. Of equal importance, most transient or reversible baseline characteristics either were associated with a reduced risk of recurrence or were not predictive of recurrence. For women, pregnancy or the postpartum state and oral contraceptive use were associated with a reduced risk of recurrence, both overall and for probable/ definite recurrence. Similarly, gynecologic surgery was associated with a reduced risk of overall recurrence. Additional transient baseline characteristics that had no significant effect on recurrence risk included the incident event type (DVT vs PE), anticoagulation prophylaxis immediately preceding or at the time of the incident event, immobilization, general surgery, orthopedic surgery, trauma, fracture, hormone therapy, and tamoxifen therapy. Neurosurgery within the 3 months preceding the incident VTE event was the only transient characteristic that was associated with an increased risk, both for overall and probable/definite recurrence. In the multivariate analyses of first overall VTE recurrence (Table 3) or first probable/definite VTE recurrence (Table 4), many persistent baseline characteristics remained significant independent predictors of increased recurrence risk. For example, the risk of overall VTE recurrence was increased by 17% per decade increase in age at incident VTE and by 24% per 10-point 2 increase in BMI. The level of diagnostic certainty was an independent predictor of probable/definite recurrence; patients with a probable or definite initial DVT or PE had a 56% increased risk of recurrence compared with patients with a possible incident event. Neurologic disease with extremity paresis was an independent predictor of overall recurrence; however, the risk of probable/ definite recurrence among patients with neurologic disease varied by patient location at incident event onset; patients with neurologic disease requiring hospital confinement at the time of the initial event had a more than 3.5-fold increased risk of recurrence. Compared with female patients with VTE without malignant neoplasm, male patients with VTE without malignant neoplasm had a higher risk of recurrence for all ages and incident event Table 2. Univariate Cox Proportional Hazards Analyses of Potential Predictors of First Overall or First Probable/Definite Venous Thromboembolism Recurrence Among Olmsted County, Minnesota, Residents With a First Lifetime Venous Thromboembolism Diagnosed From 1966 Through 1990* Hazard Ratio (95% CI) Baseline Characteristic Overall Definite/Probable Event year 0.99 ( ) 1.06 ( ) Age 1.18 ( ) 1.36 ( ) Male 1.29 ( ) 2.07 ( ) Weight (BMI, kg/m 2 ) Underweight ( 20) 0.72 ( ) 0.67 ( ) Normal (20 to 24) Overweight ( 24 to 30) 1.12 ( ) 1.24 ( ) Obese ( 30) 1.21 ( ) 1.15 ( ) Smoking history None Current 0.96 ( ) 0.84 ( ) Former 1.06 ( ) 1.40 ( ) Incident PE with or without DVT 1.07 ( ) 1.15 ( ) vs incident DVT only Probable/definite vs possible 1.09 ( ) 2.11 ( ) incident event Previous superficial vein 1.08 ( ) 1.00 ( ) thrombosis Varicose veins 0.88 ( ) 0.85 ( ) Anticoagulation 1.19 ( ) 1.36 ( ) Location at onset Community Community, recent 1.01 ( ) 0.98 ( ) hospitalization Hospital 1.29 ( ) 1.46 ( ) Nursing home 1.38 ( ) 1.68 ( ) Heart disease No CHF or other heart disease CHF 1.43 ( ) 1.54 ( ) Other heart disease 1.08 ( ) 1.53 ( ) Chronic lung disease 1.25 ( ) 1.88 ( ) Serious liver disease 0.99 ( ) 1.09 ( ) Inflammatory bowel disease 2.37 ( ) 2.57 ( ) Chronic renal disease 1.61 ( ) 2.83 ( ) Nephrotic syndrome 0.54 ( ) 0.95 ( ) Neurologic disease with 1.92 ( ) 2.02 ( ) extremity paresis Prior central venous catheter or 1.62 ( ) 2.14 ( ) pacemaker Malignant neoplasm None Malignant neoplasm with 3.57 ( ) 7.53 ( ) chemotherapy Malignant neoplasm without 2.56 ( ) 3.16 ( ) chemotherapy General surgery 1.14 ( ) 1.22 ( ) Orthopedic surgery 0.85 ( ) 0.66 ( ) Neurologic surgery 2.25 ( ) 2.59 ( ) Trauma 1.03 ( ) 0.92 ( ) Fracture 0.97 ( ) 0.96 ( ) Women only Pregnancy or postpartum 0.44 ( ) 0.20 ( ) Postpartum 0.44 ( ) 0.20 ( ) Oral contraceptive use 0.58 ( ) 0.30 ( ) Estrogen or progesterone 0.90 ( ) 0.63 ( ) replacement therapy Estrogen replacement therapy 1.02 ( ) 0.70 ( ) Gynecologic surgery 0.48 ( ) 0.49 ( ) Tamoxifen therapy 1.05 ( ) 3.08 ( ) *CI indicates confidence interval; BMI, body mass index; PE, pulmonary embolism; DVT, deep vein thrombosis; and CHF, congestive heart failure. Unless otherwise specified, the comparison group consists of incident cases without the indicated disease or condition. Per 1 calendar year increase. Per decade increase in age. 765

6 Table 3. Multivariate Cox Proportional Hazards Analysis of Predictors of First Overall Venous Thromboembolism Recurrence Among Olmsted County, Minnesota, Residents With a First Lifetime Venous Thromboembolism Diagnosed From 1966 Through 1990* Hazard Ratio Baseline Characteristic (95% CI) Age 1.17 ( ) Body mass index 1.24 ( ) Neurologic disease with extremity paresis 1.87 ( ) Malignant neoplasm None 1.00 Malignant neoplasm with chemotherapy 4.24 ( ) Malignant neoplasm without chemotherapy 2.21 ( ) Neurologic surgery and event 5-year interval 1965 Surgery 7.95 ( ) 1970 Surgery 5.12 ( ) 1975 Surgery 3.30 ( ) 1980 Surgery 2.13 ( ) 1985 Surgery 1.37 ( ) 1990 Surgery 0.88 ( ) *CI indicates confidence interval. Per decade increase in age. Per 10-point increase in body mass index. years. Older patients without malignant neoplasm had a higher risk of probable/definite recurrence than younger patients for both sexes. Patients with malignant neoplasm had a more than 2-fold increased risk of overall recurrence, and patients with malignant neoplasm receiving concurrent chemotherapy had a more than 4-fold increased risk of overall recurrence (Table 3). While the risk of probable/definite recurrence also was increased among patients with malignant neoplasm, the risk varied by concurrent chemotherapy, age, sex, and incident event year (Table 4). Concurrent chemotherapy interacted with sex and also with age; age also interacted with event year. Among patients with malignant neoplasm who were receiving chemotherapy, male patients and older patients had a higher recurrence risk. In contrast, female patients with malignant neoplasm who were not receiving chemotherapy had a higher risk for probable/ definite recurrence compared with similar male patients, for all ages and incident event years. Neurosurgery within the 3 months preceding the incident event was the only transient risk factor that remained an independent predictor of VTE recurrence (Table 3). However, neurosurgery was an independent predictor only for overall recurrence, and the risk varied by incident event year such that by 1985, neurosurgery no longer was an independent predictor of recurrence. COMMENT We determined VTE recurrence in an inception cohort of patients from a well-defined geographic population 18 that included the full spectrum of disease in all clinical settings (the community, nursing home, and hospital) where VTE may occur. In addition to our access to both outpatient and inpatient medical records, we used information from autopsy findings and death certificates to ensure essentially complete ascertainment of all recognized disease. Moreover, we stratified our analysis by either first overall recurrence or first probable/definite recurrence alone to provide estimates of the respective maximum and minimum true recurrence rates. Finally, we systematically evaluated a large number of baseline characteristics as potential predictors of recurrence. Our results demonstrate two important findings. First, VTE recurs frequently and continues to recur for at least 10 years after the incident event and possibly longer. The hazard of recurrence was particularly high in the first 6 to 12 months after the initial event but never fell to zero. Second, patients can be stratified into higher- and lowerrisk categories for recurrence according to several persistent or irreversible baseline characteristics. In general, our observed VTE recurrence rates are higher than most previously reported rates. We believe our higher rates are best explained by more complete case ascertainment and the inclusion of patients with the full spectrum of disease. Other cohort studies and clinical trials included only patients with DVT alone 2,8,14,16 or patients with PE alone (with or without DVT), 1,13,22 failed to separate incident from recurrent events, 1,10,12,13,16,22,23 or only reported PE recurrence rather than all VTE recurrence. 1,11 Since DVT or PE tends to recur in the same form as the initial clinical manifestation, 6,15,23 studies that did not include the full spectrum of disease may not estimate recurrence rates accurately. Moreover, many clinical trials excluded patients with the highest risk of recurrence (eg, patients with familial thrombophilia, cancer, paresis, or prolonged immobility). 6,10,24 Our higher rates cannot be explained by inadequate therapy. Over the course of our study, the standard of care for both DVT and PE was intravenous unfractionated heparin therapy overlapping with oral anticoagulation (eg, warfarin sodium) therapy for 5 to 7 days, followed by at least 3 months of warfarin anticoagulation therapy. The target intensity of anticoagulation was a 1.5- to 2.5-fold increase in the activated partial thromboplastin time and a 2- to 3-fold increase in the prothrombin time ratio (the international normalized ratio [INR] system was unavailable during the period of this study). Nearly all patients received standard heparin and warfarin anticoagulation therapy for mean durations of 6 days and 6 months, respectively, which is consistent with the current standard of care. 7 Moreover, the level of diagnostic certainty of the initial VTE event did not interact with other predictors of either first overall or first probable/definite recurrence, suggesting that no bias was incurred by including possible cases. We believe our observed rates may still underestimate the true recurrence rate because patients with unsuspected recurrent fatal VTE (eg, PE) who did not undergo an autopsy were missed. 766

7 Table 4. Multivariate Cox Proportional Hazards Analysis of Predictors of First Probable/Definite Venous Thromboembolism Recurrence Among Olmsted County, Minnesota, Residents With a First Lifetime Venous Thromboembolism Diagnosed From 1966 Through 1990* Baseline Characteristic Hazard Ratio (95% CI) Probable/definite vs possible incident event 1.56 ( ) Patient location at event onset and neurologic disease Community No neurologic disease 1.00 Neurologic disease 0.57 ( ) Nursing home No neurologic disease 1.00 Neurologic disease 2.01 ( ) Hospital No neurologic disease 1.00 Neurologic disease 3.60 ( ) Hazard Ratio (95% CI) Characteristic Age, y Study Year Female Male No malignant neoplasm ( ) ( ) 2.43 ( ) ( ) 3.96 ( ) ( ) 6.45 ( ) ( ) 4.88 ( ) ( ) 6.15 ( ) ( ) 7.76 ( ) ( ) 9.77 ( ) ( ) 9.55 ( ) ( ) 9.34 ( ) Malignant neoplasm with chemotherapy ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) Malignant neoplasm without chemotherapy ( ) 8.14 ( ) ( ) ( ) ( ) ( ) ( ) 8.72 ( ) ( ) ( ) ( ) ( ) ( ) 9.34 ( ) ( ) 9.13 ( ) ( ) 8.92 ( ) *CI indicates confidence interval. We have confirmed and extended the observation of others suggesting that patients with VTE can be stratified into high- and low-risk categories for recurrence according to persistent or transient baseline patient characteristics. 2,7,8,10,12,16 For example, we confirmed that active cancer is a predictor of recurrence. 2,8,23 However, among cancer patients with VTE, the risk of recurrence can be further refined based on age, sex, and the presence of concurrent cytotoxic or immunosuppresive chemotherapy. In general, recurrence risk was increased for male cancer patients receiving chemotherapy, for female cancer patients not receiving chemotherapy, and for older cancer patients regardless of sex or therapy. While data regarding cancer type, histologic characteristics, and stage were not collected, most male cancer patients receiving chemotherapy have cancers unresponsive to hormonal therapy, while most female cancer patients not receiving chemotherapy have breast cancer. Consequently, we speculate that the risk of recurrence is greatest among male cancer patients receiving chemotherapy for nonprostate cancer and among female patients with breast cancer. This hypothesis should be confirmed in studies of patients affected with these particular malignant neoplasms. Increasing age has been reported as an independent predictor of reduced risk of recurrence among patients with DVT alone. 8 In contrast, we found increasing age to be an independent predictor of increased overall recurrence risk. Aside from the difference in study populations and our more complete case ascertainment, we cannot explain this discrepancy. 767

8 Of equal importance, many transient or reversible baseline characteristics suggested as risk factors for incident VTE were not predictors of recurrence. In particular, an incident PE (eg, the most serious initial presentation of VTE) was not an independent predictor of recurrence, nor was other evidence of venous disease, such as previous superficial vein thrombosis or varicose veins. Moreover, failure of anticoagulation prophylaxis did not predict recurrence, nor did other reversible baseline characteristics, such as smoking history, immobilization, surgery, trauma, fracture, hormone therapy, and, among women, pregnancy or the postpartum period, oral contraceptive use, tamoxifen therapy, and gynecologic surgery. Our findings have several important implications. First, among a subset of patients, VTE is a chronic disease with acute exacerbations. For these patients, longterm anticoagulation therapy after an initial VTE episode may offer significant benefit. Because the hazard of recurrence is especially high during the first 6 to 12 months after an incident event, we speculate that a standard intensity of anticoagulation therapy (eg, target INR, 2.5; INR range, ) may provide optimal benefit during this period despite the associated increase in bleeding risk. After 12 months, the hazard of recurrence decreases such that a lower intensity of anticoagulation therapy (eg, target INR, 1.85) 7 may be equally effective with less risk of anticoagulant-related bleeding. Second, among a different subset of patients, VTE is a selflimited disease precipitated by a transient exposure. For these patients, a shortened course of anticoagulation therapy may offer similar benefit with less risk of bleeding. Additional clinical trials are warranted to address these hypotheses, and we have identified predictors of recurrence that will be useful in the design of such trials. Finally, additional studies addressing familial or acquired 28 procoagulant disorders (thrombophilia) as predictors of recurrence are needed. We believe such studies will allow physicians to better stratify recurrence risk and target long-term anticoagulation therapy to those at highest risk for recurrence. Accepted for publication July 14, This study was funded in part by grants HL46974 and AR30582 from the National Institutes of Health, Bethesda Md; by a grant from the US Public Health Service, Washington, DC; and by a grant from the Mayo Foundation, Rochester, Minn. The authors thank C. Mary Beard, RN, for assistance in managing the study; Janet Ebersold, RN, Kay Traverse, RN, Mary Lou Notermann, RN, and Susan Stotz, RN, for untiring medical record review; Randall Stick, BS, for programming; Diana Rademacher, BS, and Christine Lohse, BS, for assistance with data analysis; and Stephanie Wellik for secretarial support. Reprints: John A. Heit, MD, Hematology Research, Plummer 549, Mayo Clinic, 200 First St SW, Rochester, MN ( heit.john@mayo.edu). REFERENCES 1. Carson JL, Kelley MA, Duff A, et al. The clinical course of pulmonary embolism. N Engl J Med. 1992;326: Prandoni P, Lensing AWA, Cogo A, et al. The long-term clinical course of acute deep venous thrombosis. Ann Intern Med. 1996;125: Bergqvist D, Jendteg S, Johansen L, Persson U, Ödegaard K. Cost of long-term complications of deep venous thrombosis of the lower extremities: an analysis of a defined patient population in Sweden. Ann Intern Med. 1997;126: Hull R, Delmore T, Genton E, et al. Warfarin sodium versus low-dose heparin in the long-term treatment of venous thromboembolism. N Engl J Med. 1979;301: Brandjes DP, Heijboer H, Büller H, derijk M, Jagt H, ten Cate JW. Acenocoumarol and heparin compared with acenocoumarol alone in the initial treatment of proximal vein thrombosis. N Engl J Med. 1992;327: Hirsh J. Duration of anticoagulant therapy after first episode of venous thrombosis in patients with inherited thrombophilia. Arch Intern Med. 1997;157: Schulman S, Rhedin A-S, Lindmarker P, et al. A comparison of six weeks with six months of oral anticoagulant therapy after a first episode of venous thromboembolism. N Engl J Med. 1995;332: White RH, Zhou H, Romano PS. Length of hospital stay for treatment of deep venous thrombosis and the incidence of recurrent thromboembolism. Arch Intern Med. 1998;158: Anderson FA Jr, Wheeler HB, Goldberg RJ, et al. A population-based perspective of the hospital incidence and case-fatality rates of deep vein thrombosis and pulmonary embolism: the Worchester DVT Study. Arch Intern Med. 1991;151: Research Committee of the British Thoracic Society. Optimum duration of anticoagulation for deep-vein thrombosis and pulmonary embolism. Lancet. 1992; 340: Kniffin WD JR, Baron JA, Barrett J, Birkmeyer JD, Anderson FA Jr. The epidemiology of diagnosed pulmonary embolism and deep venous thrombosis in the elderly. Arch Intern Med. 1994;154: Beyth RJ, Cohen AM, Landefeld CS. Long-term outcomes of deep-vein thrombosis. Arch Intern Med. 1995;155: van Beek EJR, Kuijer PMM, Büller HR, Brandjes DPM, Bossuyt PMM, ten Cate JW. The clinical course of patients with suspected pulmonary embolism. Arch Intern Med. 1997;157: Hull RD, Raskob GE, Brant RF, Pineo GF, Valentine KA. The importance of initial heparin treatment on long-term clinical outcomes of antithrombotic therapy: the emerging theme of delayed recurrence. Arch Intern Med. 1997;157: Douketis JD, Kearon C, Bates S, Duku EK, Ginsberg JS. Risk of fatal pulmonary embolism in patients with treated venous thromboembolism. JAMA. 1998;279: Levine MN, Hirsh J, Gent M, et al. Optimal duration of oral anticoagulant therapy: a randomized trial comparing four weeks with three months of warfarin in patients with proximal deep vein thrombosis. Thromb Haemost. 1995;74: Silverstein MD, Heit JA, Mohr DN, Petterson TM, O Fallon WM, Melton LJ III. Trends in the incidence of deep vein thrombosis and pulmonary embolism: a 25-year population-based study. Arch Intern Med. 1998;158: Melton LJ. History of the Rochester Epidemiology Project. Mayo Clinic Proc. 1996; 71: Kurland LT, Molgaard DA. The patient record in epidemiology. Sci Am. October 1981;245: National Institutes of Health. Clinical guidelines on the identification, evaluation, and treatment of overweight and obesity in adults: the evidence report [published correction appears in Obes Res. 1998;6:464]. Obes Res. 1998;6(suppl 2): 51S-209S. 21. Saerbrei W, Schumacher M. A bootstrap resampling procedure for model building: application to the Cox regression model. Stat Med. 1992;11: Simonneau G, Sors H, Charbonnier B, et al. A comparison of low-molecularweight heparin with unfractionated heparin for acute pulmonary embolism. N Engl J Med. 1997;337: The Columbus Investigators. Low-molecular-weight heparin in the treatment of patients with venous thromboembolism. N Engl J Med. 1997;337: Schulman S, Granqvist S, Holmström M, et al. The duration of oral anticoagulation therapy after a second episode of venous thromboembolism. N Engl J Med. 1997;336: Ridker PM, Miletich JP, Stampfer MJ, Goldhaber SZ, Lindpaintner K, Hennekens CH. Factor V Leiden and risks of recurrent idiopathic venous thromboembolism. Circulation. 1995;92: Simioni P, Prandoni P, Lensing AWA, et al. The risk of recurrent venous thromboembolism in patients with an Arg506-Gln mutation in the gene for Factor V (Factor V Leiden). N Engl J Med. 1997;336: van den Belt AGM, Sanson B-J, Simioni P, et al. Recurrence of venous thromboembolism in patients with familial thrombophilia. Arch Intern Med. 1997;157: Schulman S, Svenungsson E, Granqvist S, and the Duration of Anticoagulation Study Group. Anticardiolipin antibodies predict early recurrence of thromboembolism and death among patients with venous thromboembolism following anticoagulant therapy. Am J Med. 1998;104: