30-Year Mortality After Venous ThromboembolismCLINICAL PERSPECTIVE
A Population-Based Cohort Study
Background—Studies on long-term mortality after venous thromboembolism (VTE) are sparse.
Methods and Results—Using Danish medical databases, we conducted a 30-year nationwide population-based cohort study of 128 223 patients with first-time VTE (1980–2011) and a comparison cohort of 640 760 people from the general population (without VTE) randomly matched by sex, year of birth, and calendar period. The mortality risks for patients with deep venous thrombosis (DVT) and pulmonary embolism (PE) were markedly higher than for the comparison cohort during the first year, especially within the first 30 days (3.0% and 31% versus 0.4%). Using Cox regression, we assessed mortality rate ratios (MRRs) with 95% confidence intervals (CIs). The overall 30-year MRR was 1.55 (95% CI, 1.53–1.57) for DVT and 2.77 (95% CI, 2.74–2.81) for PE. The 30-day MRR was 5.38 (95% CI, 5.00–5.80) for DVT and 80.87 (95% CI, 76.02–86.02) for PE. Over time, the 30-day MRR was consistently 5- to 6-fold increased for DVT, whereas it improved for PE from 138 (95% CI, 125–153) in 1980 to 1989 to 36.08 (95% CI, 32.65–39.87) in 2000 to 2011. The 1- to 10-year and 11- to 30-year MRRs remained 25% to 40% increased after both DVT and PE but were 3- to 5-fold increased after DVT and 6- to 11-fold increased after PE when VTE was considered the immediate cause of death.
Conclusions—Patients with VTE are at increased risk of dying, especially within the first year after diagnosis, but also during the entire 30 years of follow-up, with VTE as an important cause of death. Although 30-day mortality after DVT remained fairly constant over the last 3 decades, it improved markedly for PE.
Venous thromboembolism (VTE), encompassing deep venous thrombosis (DVT) and pulmonary embolism (PE), is a common condition. In the existing literature, the magnitude of long-term mortality after VTE varies substantially.1–9 A recent study reported an 8-year mortality risk of 12%,1 whereas in an earlier study, mortality risk reached 50% after 8 years of follow-up.5 Previous studies were limited by short follow-up time (maximum, 10 years),1–4,6–11 age restrictions (<70 years of age1 or between 65 and 89 years of age7), lack of adjustment for comorbidity3,12 or calendar period,3,5 and failure to examine mortality for DVT and PE separately.1,8,12 Only a few studies have compared long-term mortality between VTE patients and a comparison cohort from the general population, with inconsistent results.1,3,8,12 The reported risk varied between a null association,3 a 40% higher mortality in VTE patients after 10 years compared with expected mortality in the general population,8 a higher mortality only among patients with cancer,12 and higher mortality for both cancer patients and noncancer patients.1
Clinical Perspective on p 836
Critical unanswered questions remain about long-term VTE mortality in unselected patients. It is not clear if 30-day survivors of VTE remain at increased risk of death compared with the general population and whether recurrent thromboembolic events are frequent causes death among VTE patients. Moreover, it is unclear if mortality differs according to VTE subtypes and underlying comorbidity burden and whether short- and long-term mortality has improved over the last 3 decades.
We therefore undertook this nationwide population-based cohort study to examine 30-year VTE mortality according to VTE subtypes, underlying comorbidity, and calendar periods of diagnosis.
Study Design and Setting
This cohort study drew on the entire Danish population, with 7 046 778 residents alive between 1980 and 2011. Data were obtained from the Danish National Registry of Patients, which contains records on >99% of all discharges from Danish hospitals since 197713 and on emergency room and outpatient clinic visits since 1994. Recorded information includes civil registration number (unique personal identifier assigned to all Danish residents), dates of admission and discharge, surgical procedures, and up to 20 discharge diagnoses classified according to the International Classification of Diseases, 8th Revision (ICD-8) until the end of 1993 and 10th revision (ICD-10) thereafter. The main reason for diagnostic workup and treatment during hospitalization is labeled the primary (first-listed) diagnosis, whereas other important acute and chronic diseases or conditions are recorded as secondary diagnoses.13
We used the Danish Register of Causes of Death14 to obtain information on causes of death for VTE patients and the comparison cohort. The register contains information from all Danish death certificates since 1943, coded according to the Danish version of the International Classification of Diseases (ICD-8 from 1972–1993; ICD-10 from 1994–2011).
We also used data from the Danish Civil Registration System, which has monitored changes in vital status and migration on a daily basis for the entire Danish population since 1968.15
Patients With VTE
We identified patients with a first-time hospital discharge diagnosis of DVT or PE from January 1980 through December 2011. Patients with diagnoses of both conditions were considered to have only PE. We included both primary and secondary diagnoses. Patients with only emergency room diagnoses of VTE (7.7%) and patients diagnosed only in the hospital outpatient setting (5.4%) were excluded from the analysis because of the expected low positive predictive value of working diagnoses in these settings.16 Patients with a previous VTE diagnosis during the 3 years before our study period were excluded to avoid inclusion of patients with recurrent thrombosis or complications of previous VTE.
Population Comparison Cohort
We used the Danish Civil Registration System to generate a population-based comparison cohort. For each VTE patient, we randomly matched 5 individuals from the general population on sex, year of birth, and calendar period of VTE diagnosis. To be eligible for the study, persons in the comparison cohort could not have had a hospitalization for VTE before the admission date for the corresponding VTE patient. If a member of the comparison cohort subsequently experienced a VTE, he or she joined the VTE cohort.17 The admission/matching date for VTE patients/comparison cohort members was defined as the index date.
We obtained information on covariates from the Danish National Registry of Patients. First, we defined the classic risk factors for VTE, that is, cancer diagnosed previously or within 90 days after VTE, fracture/trauma, surgery, or pregnancy within 90 days before the VTE diagnosis.18 We also included risk factors and potential prognostic factors for VTE2,4,5,19–21: myocardial infarction, heart failure, intermittent claudication, stroke, chronic pulmonary disease, diabetes mellitus, ulcer disease, chronic kidney disease, severe liver disease, obesity diagnosed any time before the VTE diagnosis, and pneumonia diagnosed simultaneously or within 90 days before the VTE diagnosis. We created a combined covariate covering echocardiography and imaging examinations of the lungs or lower limbs (ultrasonography, computed tomography scan, magnetic resonance venography, angiography, and ventilation-perfusion scan of the lungs).
We followed up all patients until date of death; emigration; December 31, 2011; or 30 years of follow-up, whichever came first. We characterized VTE patients and comparison cohort members in terms of sex, age categories (<55, 55–64, 65–74, and ≥75 years), calendar period of diagnosis (1980–1989, 1990–1999, and 2000–2011), presence of classic VTE risk factors, and other covariates. We computed the median age with the interquartile range (IQR) at inclusion and median follow-up for all patients and for 30-day survivors. Using the Kaplan-Meier estimator, we computed the 30-day, 31- to 364-day, 1- to 10-year, 11- to 30-year, and 30-year mortality risk for VTE patients overall and for subgroups of patients with DVT, PE, cancer, fracture/trauma, and surgery.
We computed standardized mortality rates per 1000 person-years and illustrated graphically standardized mortality risks for DVT and PE patients (standardized to the age distribution of persons diagnosed with VTE in 2000) for the first 30 days, 31 to 364 days, 1 to 10 years, and 11 to 30 years of follow-up. For the same time periods, we used Cox proportional hazards regression to compute mortality rate ratios (MRRs; specifically, hazard ratios) as measures of relative mortality risk, comparing VTE patients with members of the comparison cohort. We used log-log plots to test the proportionality of hazards visually and found that the assumptions were fulfilled for each of the follow-up periods. In the regression analysis, we dissolved the matching and instead included the matching factors as covariates in the model. In addition to sex, age, and calendar period of diagnosis, we adjusted for the established VTE risk factors and the other covariates. We presented adjusted estimates stratified by age, sex, established VTE risk factors, and other covariates in a forest plot. We tested for secular trends using the Wald χ2 test.
We computed standardized mortality rates for the most frequent causes of death and compared cause-specific mortality rates among VTE patients and the comparison cohort. To improve the specificity of the VTE diagnosis, we estimated MRRs comparing VTE patients who were diagnosed after 2000 and had a relevant imaging examination during their hospitalization with matched comparison cohort members.
All statistical analyses were carried out with SAS version 9.2 (SAS Institute Inc, Cary, NC). The study was approved by the Danish Data Protection Agency, record number 1-16-02-1-08. Data in the Danish registries are available to researchers, and their use does not require informed consent or ethics approval.
We identified 128 223 persons with a first-time diagnosis of VTE, among whom 74 157 had DVT and 54 066 had PE (10% registered with simultaneous DVT). The comparison cohort included 640 760 persons from the general population matched by year of birth and sex. There were slightly more women (53%) than men for both DVT and PE. The median age was 69 years (IQR, 55–78 years; Table 1) among all VTE patients, 66 years (IQR, 52–77 years) among DVT patients, and 72 years (IQR, 60–80 years) among PE patients. Median follow-up time was 3.8 years overall (IQR, 0.5–9.9 year): 5.6 years (IQR, 1.8–11.8 years) for DVT patients and 1.2 years (IQR, 0–6.6 years) for PE patients. For 30-day survivors, the median follow-up time for VTE patients was 5.3 years (IQR, 2.0–11.1 years). As expected, obesity and other established VTE risk factors were more common among VTE patients than among members of the comparison cohort. The prevalence of other comorbidities was also higher among VTE patients (Table 1).
Overall 30-Year Mortality
VTE patients had higher mortality risk than members of the comparison cohort, with the most pronounced difference in risk within the first year of follow-up (Table 2). We observed a 2-fold increased MRR for VTE overall throughout the follow-up period (DVT, 1.55 [95% confidence interval (CI), 1.53–1.57]; PE, 2.77 [95% CI, 2.74–2.81]; Table 3).
The 30-day mortality risk for VTE patients was 3% for DVT and 31% for PE versus 0.4% for the comparison cohort. Patients with classic VTE risk factors had markedly elevated mortality risks (Table 2). The adjusted 30-day MRR, comparing VTE patients with the comparison cohort, varied according to VTE type (DVT, 5.38 [95% CI, 5.00–5.80]; PE, 80.87 [95% CI, 76.02–86.02]). The 30-day standardized mortality risk and MRR were fairly consistent across calendar periods for DVT (Table 4 and Figure A) but declined for PE (MRR from 138 [95% CI, 125–153] in 1980 to 1989 to 81.97 [95% CI, 72.27–92.98] in 1990 to 1999 and to 36.08 [95% CI, 32.65–39.87] in 2000 to 2011) (Table 4 and Figure B).
31- to 364-Day Mortality
Risk of death remained high among patients who survived the first 30 days after VTE. The mortality risk during 31 to 364 days of follow-up was 13% for DVT patients, 20% for PE patients, and 4% for comparison cohort members (Table 2). The adjusted MRRs were 2.88 (95% CI, 2.80–2.97) for DVT and 4.20 (95% CI, 4.06–4.35) for PE (Table 3). Although less pronounced than for 30-day mortality, 31- to 364-day mortality after PE declined over time (Table 4 and Figure [B]).
Mortality Beyond 1 Year
MRRs for VTE patients surviving >1 year remained elevated for both DVT and PE, but the differences between the 2 groups were reduced. Compared with the population comparison cohort, the MRRs within 1 to 10 years and 11 to 30 years after diagnosis were 36% and 31% higher for DVT and 41% and 24% higher for PE. The 1- to 10-year and 11- to 30-year DVT- and PE-specific MRRs were similar during all calendar periods of diagnosis (Table 4).
Cause of Death
Compared with the general population, patients with VTE had markedly higher death rates for VTE and other cardiovascular diseases, cancer, and respiratory system diseases (Table 5). The adjusted MRR was overall 25-fold increased for VTE. The MRRs for death from PE and DVT were, as expected, substantially increased within the first 30 days but remained 3- to 5-fold increased after DVT and 6- to 10-fold increased after PE within both 1 to 10 years and 11 to 30 years of follow-up (Table 6).
Thirty-year mortality remained consistently elevated among all subgroups of VTE patients, regardless of demographics and underlying comorbidity (Figures I and II in the online-only Data Supplement). Of note, patients with cancer had even higher MRRs after DVT and PE than patients without cancer, and patients with diabetes mellitus and liver disease had higher MRRs after PE than patients without these conditions (Figures I and II in the online-only Data Supplement). MRRs were higher for younger than older patients (Figures I and II in the online-only Data Supplement), independently of length of follow-up (Table I in the online-only Data Supplement).
For patients diagnosed between 2000 and 2011, 69% were registered as having had a relevant imaging procedure performed during their hospitalization. The 30-day adjusted MRR for PE was markedly lower for this group compared with all PE patients diagnosed in the same period (20.73; 95% CI, 18.16–23.65) versus 36.08 (95% CI, 32.65–39.87). For patients with DVT who had imaging examinations, the 30-day adjusted MRR was 5.83 (95% CI, 5.09–6.68) compared with 6.36 (95% CI, 5.68–7.13) for all DVT patients. MRRs for other follow-up periods were similar to those for the overall analysis.
In this population-based 30-year cohort study, we found that patients with a first-time hospitalization for VTE compared with members of a population comparison cohort had a markedly increased risk of dying within the first year after the event, driven mainly by mortality associated with PE. However, an excess mortality risk persisted throughout the 30-year follow-up period, with similar risks for DVT and PE patients after the first year. We demonstrated a consistently increased mortality regardless of underlying comorbidities. Although DVT and PE were likely to be the cause of death in the short term, this finding persisted even 11 to 30 years after diagnosis. We observed no mortality improvement for patients with DVT, whereas 1-year mortality among patients with PE was markedly reduced over the last 3 decades.
The reported long-term mortality after VTE varies widely (between 12% and 50%) in the existing literature,1–7,9 with advanced age,7 cardiovascular disease,2 underlying cancer,2–4,12 recurrent VTE, or other medical conditions4,5 representing important predictors of mortality. Only a few previous studies compared mortality among VTE patients and a population comparison cohort.1,3,12,22 A recent cohort study from the Netherlands including 5000 adults (age, 18–70 years) diagnosed with a first-time VTE between 1999 and 2004 and with median follow-up of 5.5 years (maximum, 8 years) reported an almost 5-fold overall increased relative risk of mortality among 30-day survivors compared with the general population.1 Mortality was markedly higher among patients with underlying cancer but was still twice as high in noncancer patients compared with control subjects after adjustment for several comorbidities.1 Our study confirmed this finding by showing consistently increased relative mortality estimates for all comorbidities, with only a slight decline in the relative mortality rate after comprehensive adjustment. The Dutch study1 found similar standardized mortality rates for cancer-free patients with DVT versus PE for the complete follow-up period. We found a substantial difference in standardized mortality rates for DVT versus PE within the first year after diagnosis. Thereafter, the difference in standardized mortality rates leveled out and remained consistently increased in subsequent years.
A Norwegian population-based study of 740 patients with a first-time VTE diagnosed between 1995 and 2001 compared mortality risk after 8 years of follow-up with that in a population comparison cohort.12 Patients with underlying cancer had 13-fold age- and sex-adjusted increased mortality risk compared with the comparison cohort. This risk remained 2.5-fold increased for cancer patients who survived 3 years. For idiopathic VTE, the MRR was 2.6-fold higher than in the comparison cohort, but among 3-year survivors, the relative risk after 8 years was near unity.12 The latter finding of unaltered long-term survival was supported by a recent cohort study comparing mortality among patients with VTE and population control subjects.3 The follow-up period started 3 months after a first or subsequent VTE, and cancer patients were excluded from the study.3 Similarly, a cohort study of VTE patients did not find an elevated standardized mortality rate among patients surviving cessation of oral anticoagulant treatment.22 Finally, a population-based cohort study of 1567 patients with first-time VTE indicated a 10% decline in 3-year mortality in patients diagnosed in 2003 compared with 1999 (mortality risk, 0.90; 95% CI, 0.74–1.10).23
The mechanism behind the increased long-term mortality risk remains to be further investigated, but it likely reflects both the severity of underlying disease and a VTE-associated excess mortality rate. The high 30-day mortality risk for PE patients is likely directly caused by the thromboembolic event and subsequent complications. In addition to recurrent episodes of thrombosis, patients with VTE are at higher risk of subsequent cancer and cardiovascular disease.8,24–27 We confirmed that cancer and cardiovascular diseases were frequent causes of death,2,3,8 but more important, we also found that VTE and pneumonia were important causes of death among the patients in the VTE cohort. This long-term increased VTE-related death rate among patients diagnosed with VTE has not been reported before. This is highly relevant clinically, pointing to the need for individual patient counseling with a focus on optimizing treatment of VTE and reducing risk factors for VTE recurrence to prevent VTE-related death.
Our study was conducted in a setting with a national health service providing unfettered access to health care, thereby allowing us to avoid referral and selection biases. We included the entire Danish population and achieved complete patient-level follow-up with access to patients’ full hospital registry histories (since 1977) and outpatient clinic histories (since 1994).
The validity of our absolute mortality risk estimates depends on the accuracy of VTE diagnoses, whereas that of the relative estimates depends on the ability to adjust for comorbid conditions and other confounders. A validation study comparing VTE diagnoses in the Danish National Registry of Patients and chart review demonstrated that the positive predictive value of inpatient diagnoses of DVT and PE was ≈70% and 80%, respectively.16 However, these data are >10 years old. With the current use of improved diagnostic imaging, less serious embolisms may be detected, improving the positive predictive value of VTE diagnoses. As a consequence of this enhanced diagnostic procedure (together with a possible improvement in the treatment of VTE), our 30-year risk estimates may not be applicable to VTE diagnosed in more recent years. Although the proportion of patients diagnosed only in the outpatient clinics was very low, exclusion of these patients could potentially have increased our mortality estimates for DVT slightly.
Our finding of increased long-term mortality risk after VTE is likely generalizable to most industrial Western societies with comparable lifestyle, risk factor prevalence, and treatment regimens, but it may not apply to all races, ethnic subgroups, or socioeconomic classes of patients. Importantly, the Danish population is homogeneous in respect to ethnicities, with a majority of Scandinavian and European citizens. The relative mortality estimates are likely generalizable to most industrial Western societies and may apply to other more diverse populations assuming no effect modification by ethnicity or environmental factors.28
The cancer and procedure data that we used for defining classic VTE risk factors have high validity.29 We adjusted for comorbidity-related confounding using a comprehensive list of comorbidities. Overall, the positive predictive values of the diagnoses included in the study have been shown to be consistently high (overall 98%),30 whereas the completeness of coding is probably lower. Any misclassification of covariates as a result of incomplete registration would most likely be independent of a subsequent diagnosis of VTE. Therefore, if misclassification had any effect on our estimates, it biased them toward the null.31 Nevertheless, in case of misclassification occurring not at random, the impact on our effect estimates would be less predictable. The registration of all-cause death is accurate.14 However, the specific cause of death is based on a subjective judgment and therefore is not always correct. Unfortunately, we had no information on the extent of differential misclassification of VTE as the cause of death among our patients.
We found that patients with VTE have a long-term increased risk of dying. The risk is substantially elevated in the first year after diagnosis but remained increased during the entire 30 years of follow-up with VTE as an important cause of death. Over the past 3 decades, 30-day mortality has remained fairly constant after DVT but has improved markedly for PE.
Sources of Funding
The study was supported by the Clinical Epidemiological Research Foundation, Denmark, and a grant from Aarhus University Research Foundation. The sponsor had no role in the study design, collection of data, analysis, interpretation, or writing of the manuscript or in the decision to submit the paper for publication. The authors had full access to all the data in the study and had final responsibility for the decision to submit for publication.
The online-only Data Supplement is available with this article at http://circ.ahajournals.org/lookup/suppl/doi:10.1161/CIRCULATIONAHA.114.009107/-/DC1.
- Received January 27, 2014.
- Accepted June 20, 2014.
- © 2014 American Heart Association, Inc.
- Ng AC,
- Chung T,
- Yong AS,
- Wong HS,
- Chow V,
- Celermajer DS,
- Kritharides L
- Prandoni P,
- Villalta S,
- Bagatella P,
- Rossi L,
- Marchiori A,
- Piccioli A,
- Bernardi E,
- Girolami B,
- Simioni P,
- Girolami A
- Schulman S,
- Lindmarker P,
- Holmström M,
- Lärfars G,
- Carlsson A,
- Nicol P,
- Svensson E,
- Ljungberg B,
- Viering S,
- Nordlander S,
- Leijd B,
- Jahed K,
- Hjorth M,
- Linder O,
- Beckman M
- Tagalakis V,
- Patenaude V,
- Kahn SR,
- Suissa S
- Helweg-Larsen K
- Schmidt M,
- Pedersen L,
- Sørensen HT
- Rothman KJ,
- Greenland S,
- Lash TL
- Glynn RJ,
- Rosner B
- Spencer FA,
- Goldberg RJ,
- Lessard D,
- Reed G,
- Emery C,
- Gore JM,
- Pacifico L,
- Weitz JI
- Copeland KT,
- Checkoway H,
- McMichael AJ,
- Holbrook RH
Venous thromboembolism (VTE), encompassing deep venous thrombosis and pulmonary embolism (PE), is a common condition. The existing literature has focused mainly on short-term outcomes after VTE, but critical unanswered questions remain about long-term mortality. What is the absolute long-term mortality risk after deep venous thrombosis and PE, and is recurrent VTE an important cause of death? How does underlying comorbidity affect mortality? Has mortality associated with VTE improved over the last 3 decades? We examined 30-year VTE mortality and compared it with that of the general population. We estimated mortality according to VTE subtypes, underlying comorbidity, and calendar periods of diagnosis. We demonstrated high 30-day mortality for patients with PE, caused directly by the thromboembolic event or immediate complications. Mortality risk remained increased up to 30 years after the initial diagnosis for both deep venous thrombosis and PE, with VTE an important cause of death. We confirmed an increased overall mortality among patients with underlying cancer, congestive heart failure, and several other chronic and acute conditions. We observed no mortality improvement for patients with deep venous thrombosis, whereas 1-year mortality among patients with PE was markedly reduced over the last 3 decades. Our finding of increased short-term and long-term mortality after VTE may apply to most industrial Western societies in which changes in lifestyle, risk factor modification, and treatment regimens followed international recommendations. The clinical implications of our study point to the need for individual patient counseling with a focus on optimizing treatment of VTE and reducing risk factors for VTE recurrence to prevent VTE-related death.