Conceived and designed the experiments: LEF AvH SCC FRR. Performed the experiments: LEF. Analyzed the data: LEF. Contributed reagents/materials/analysis tools: AvH SCC FRR. Wrote the first draft of the manuscript: LEF. Contributed to the writing of the manuscript: LEF AvH SCC FRR.
The authors have declared that no competing interests exist.
Linda Flinterman and colleagues report on the long-term mortality rate for individuals who have experienced a first venous thrombosis or pulmonary embolism. They describe an ongoing elevated risk of death for individuals who had experienced a venous thrombosis or pulmonary embolism as compared to controls, for up to eight years after the event.
Venous thrombosis is a common disease with a high mortality rate shortly after the event. However, details on long-term mortality in these patients are lacking. The aim of this study was to determine long-term mortality in a large cohort of patients with venous thrombosis.
4,947 patients from the Multiple Environmental and Genetic Assessment study of risk factors for venous thrombosis (MEGA study) with a first nonfatal venous thrombosis or pulmonary embolism and 6,154 control individuals without venous thrombosis, aged 18 to 70 years, were followed up for 8 years. Death and causes of death were retrieved from the Dutch death registration. Standardized mortality ratios (SMRs) were calculated for patients compared with control individuals. Several subgroups were studied as well.
736 participants (601 patients and 135 controls) died over a follow-up of 54,948 person-years. The overall mortality rate was 22.7 per 1,000 person-years (95% CI 21.0–24.6) for patients and 4.7 per 1,000 person-years (95% CI 4.0–5.6) for controls. Patients with venous thrombosis had a 4.0-fold (95% CI 3.7–4.3) increased risk of death compared with controls. The risk remained increased up to 8 years after the thrombotic event, even when no additional comorbidities were present. The highest risk of death was found for patients with additional malignancies (SMR 5.5, 95% CI 5.0–6.1). Main causes of death were diseases of the circulatory system, venous thrombosis, and malignancies. Main limitation was a maximum age of 70 at time of inclusion for the first event. Therefore results can not be generalized to those in the highest age categories.
Patients who experienced a first venous thrombosis had an increased risk of death which lasted up to 8 years after the event, even when no comorbidities were present at time of thrombosis. Future long-term clinical follow-up could be beneficial in these patients.
The term venous thrombosis describes the clinical situation—more common during pregnancy, after surgery, or serious illness—in which a blood clot lodges in a vein. One specific type, which is more serious, involves the clot forming in a major vein in the lower leg and thigh and is termed a deep venous thrombosis. The clot can block blood flow and cause swelling and pain, but more seriously, can break off and move through the bloodstream, causing an embolism. An embolism can get stuck in the brain (and cause a stroke), lungs (and cause a pulmonary embolism), heart (to cause a heart attack), and/or other areas of the body, leading to severe damage.
Venous thrombosis is known to be associated with considerable short-term morbidity and mortality: the mortality rate after venous thrombosis is about 20% within one year and studies to date have suggested that the mortality rate is two to four times higher for patients with pulmonary embolism, of whom 10%–20% die within three months after the event. Many factors are associated with venous thrombosis, and the underlying cause of the thrombosis affects survival; for example, those with thrombotic events provoked by surgery or trauma have a lower mortality risk than patients with thrombosis caused by malignancy. Furthermore, about 10%–20% of patients who have had a venous thrombosis develop a recurrence within five years and up to 50% develop post-thrombotic syndrome—long-term swelling, pain, and changes in skin color.
It is currently unknown whether the poor prognosis associated with venous thrombosis is limited to the months following the thrombotic event, or persists for years afterwards. So in this study, the researchers sought to answer this question by analyzing the long-term survival in a large cohort of patients who had experienced a first venous thrombosis and who were all followed for up to eight years.
The researchers used the Multiple Environmental and Genetic Assessment of risk factors for venous thrombosis study (MEGA study), which was a case-control study involving 4,965 consecutive patients aged 18 to 70 years who were objectively diagnosed with a deep venous thrombosis or pulmonary embolism and recruited from six anticoagulation clinics in the Netherlands between March 1999 and September 2004. The control group consisted of partners of patients (
Using these methods, the researchers found that the overall mortality rate in patients with thrombosis was substantially greater than in the control group (22.7 per 1,000 person-years compared to 4.7 per 1,000 person-years). Apart from malignancies, the researchers found that the main causes of death were diseases of the circulatory and respiratory system. Patients with venous thrombosis and malignancy had the highest risk of mortality: 55% died during follow-up. Patients with venous thrombosis without malignancy had an overall 2-fold increased risk of mortality compared to the control group and this risk was comparable for patients with different forms of thrombosis (such as deep venous thrombosis and pulmonary embolus). According to the researchers' calculations, the relative risk of death was highest during the first three years after thrombosis, but for those with thrombosis of unknown cause, the risk of death increased by two-fold up to eight years after the thrombosis. Furthermore, the researchers found that the highly increased risk of death for those with pulmonary embolism is mainly only for the first month as long-term survival is similar to that of patients with a deep venous thrombosis.
These findings show that patients who have experienced a venous thrombosis for the first time have an increased risk of death, which may last up to eight years after the event. These findings have important clinical implications and suggest that long-term clinical follow-up could be beneficial in patients who have experienced a venous thrombosis for the first time.
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Venous thrombosis is a multicausal disease that occurs in one to three per 1,000 persons per year
In the present study we determined long-term survival in a large cohort of consecutive patients with a first venous thrombosis compared with age- and sex-matched individuals without venous thrombosis, who were all followed for up to 8 y.
This study was approved by the Ethics Committee of the Leiden University Medical Center and written informed consent was obtained from all the participants. The investigation has been conducted according to the principles expressed in the Declaration of Helsinki.
We used a cohort consisting of all patients and control individuals from the Multiple Environmental and Genetic Assessment of risk factors for venous thrombosis study (MEGA study). Details of the study are described elsewhere
Patients were recruited from six anticoagulation clinics in the Netherlands, which exclusively monitor out-patient treatment with vitamin K antagonists in well-defined geographical regions. Patients were included in the study after a median period of 1 mo (range 13–64 d) after the diagnosis of thrombosis.
The control group consisted of partners of patients (
Vital status was ascertained through community registries, where all inhabitants are registered. Causes of death were obtained from the Central Bureau of Statistics Netherlands, the national repository for death certificates. Both primary and secondary causes of deaths were retrieved. Causes of death were coded according to the ICD-10 classification
In the current study an additional control group was used. We compared cause-specific death rates of the patients to those of the general Dutch population, which, because of the size of the reference group, allowed analyses of cause-specific death rates, for which the control group of the MEGA study was too small.
The observation time was from 30 d after the venous thrombosis, or a similar date in the thrombosis-free cohort, to either death, end of follow-up (between February 2007 and May 2009), emigration (
For 152 individuals (1.4%, nine patients) follow-up was less than 30 d, and they were excluded. Censoring due to emigration concerned 164 individuals (1.5%) and to loss to follow-up 173 individuals (1.5%). This figure implies that follow-up was complete for 97% of the cohort. Vital status was obtained from the community registries and date of retrieving vital status was used as end date of follow-up, if patients were still alive. It was not possible to retrieve all vital statuses at the same date. Therefore, the end date of follow-up lies between February 2007 and May 2009.
The cohort of thrombosis-free individuals has a mortality that was exactly equal to the general population (standardized mortality ratio [SMR] 1.0, 95% CI 0.9–1.2), and there were no differences in mortality within the thrombosis-free cohort, between those who were recruited as partners of thrombosis patients or by random digit dialing.
Cumulative incidences and mortality rates were calculated at 1, 5, and 8 y of follow-up. Survival was estimated and visualized by Kaplan-Meier life-tables and survival curves.
SMRs were calculated to estimate relative rates of all cause mortality, e.g., by type of initial thrombosis. The SMR is the ratio of the observed number of deaths over the number of deaths expected when the mortality rate in the cohort of patients, with its specific age and sex distribution, was the same as that in the reference group. SMRs were calculated for the complete cohort of patients and for several subgroups of venous thrombosis patients: (1) for patients with active malignancy at time of inclusion or diagnosed within 6 mo after thrombosis; (2) for patients with a provoked first thrombosis without malignancy; (3) for patients with an idiopathic first thrombosis; and (4) according to type of first venous thrombosis (PE or DVT). An idiopathic thrombosis was defined as a thrombosis not related to surgery, hospital admission, injury, plaster cast, active malignancy, oral contraceptive use, or pregnancy, all in the year previous to the thrombotic event or during puerperium. SMRs for these categories of patients were calculated with the mortality rates of the complete control group as a reference; and also using only the rates of the controls belonging to the same category (e.g., patients with a provoked event were compared to controls who also had had surgery or plaster cast, etc.). This latter analysis was performed to estimate the effect of venous thrombosis on survival conditional on other risk factors for thrombosis.
Hazard ratios (HRs) of death from all causes per year of follow-up were calculated to estimate the decrease of mortality over time for the different subgroups. To calculate the HRs per year the hazard of dying in year X was calculated with all persons that survived up to year X. If they survived the whole of year X they were censored at the end of that year.
To calculate the reduction in median life expectancy we used the average life table of the birth cohorts of 1935–1965 of the Dutch population to create a population comparable in life expectancy to the MEGA study. To estimate the median life expectancy for the nonmalignant patients we multiplied the death rate per year for the Dutch cohort from the mean age at time of thrombosis by sex. The median life expectancy is the age at which half of a birth cohort of newborns had died. For this calculation we assumed an equal distribution of relative mortality after thrombosis in our population.
The influence of the presence of concurrent disease at the time of thrombosis on mortality was assessed by contrasting the patient cohort with the thrombosis-free cohort by Cox regression in strata of participants with or without concurrent diseases present. In addition, the annual HRs were adjusted for the number of concurrent diseases present at time of thrombosis in the Cox model. Concurrent diseases were diabetes, liver disease, kidney disease, heart failure, rheumatoid arthritis, chronic bronchitis, emphysema, myocardial infarction, stroke or hemorrhage of the brain, surgery 3 mo prior to thrombosis, and multiple sclerosis.
HRs were adjusted for sex and age. The assumption of proportionality was tested both visually from the Kaplan-Meier curve, and statistically, with the proportional hazard test provided by the software package used.
For the analysis of cause-specific mortality SMRs were calculated with the rates from the general population as reference. Analyses were performed using STATA 10.1. (Stata Corporation).
4,947 patients with a first venous thrombosis and 6,154 controls were followed during a total period of 26,515 and 28,433 person-years, respectively. The baseline characteristics of patients and controls are described in
Characteristics | Percent Patients, |
Percent Controls, |
Sex (% men) | 46 (2,271) | 46 (2,854) |
Mean age at index (range) |
49 (18–70) | 47 (18–70) |
Median age at index (range) |
50 (18–70) | 48 (18–70) |
Malignancy |
13 (619) | 4 (233) |
Diabetes | 3.7 (183) | 3.2 (195) |
Liver disease | 0.5 (27) | 0.3 (20) |
Kidney disease | 1.2 (59) | 0.4 (23) |
Myocardial infarction | 2.8 (137) | 1.8 (113) |
Heart failure | 1.2 (76) | 1.0 (60) |
Stroke or hemorrhage of the brain | 3.0 (154) | 1.8 (115) |
Chronic bronchitis | 5.1 (253) | 2.7 (165) |
Emphysema | 1.3 (66) | 0.6 (35) |
Multiple sclerosis | 0.5 (30) | 0.3 (17) |
Rheumatoid arthritis | 3.0 (144) | 2.1 (132) |
Index date was date of thrombosis for patients and date of participation in the study for control individuals.
Malignancy at time of or within 6 mo after the index date types of cancer have been previously reported
The overall mortality rate after thrombosis was 22.7 per 1,000 person-years (95% CI 21.0–24.6), and the overall mortality rate for the control individuals was 4.7 per 1,000 person-years (95% CI 4.0–5.6).
Patients with venous thrombosis and malignancy had, as expected, the highest risk of mortality. Overall, 55% of the patients' with malignancy and thrombosis died during follow-up, half of whom during the first year after thrombosis (
Groups | 1 y | 5 y | Overall (8 y) | ||||
Percent Cumulative Incidence (95% CI) | Percent Cumulative Incidence (95% CI) | Percent Cumulative Incidence (95% CI) | |||||
Patients | 4,947 | 197 | 4.0 (3.4–4.5) | 500 | 10.1 (9.3–10.9) | 601 | 12.1 (11.6–13.4) |
Malignancy+ | 650 | 165 | 25.4 (22.0–28.7) | 332 | 51.1 (47.2–54.9) | 358 | 55.1 (51.3–58.9) |
Malignancy− | 4,297 | 32 | 0.7 (0.5–1.0) | 168 | 3.9 (3.3–4.5) | 243 | 5.7 (5.0–6.3) |
Provoked |
2,949 | 21 | 0.7 (0.4–1.0) | 94 | 3.2 (2.6–3.8) | 122 | 4.1 (3.4–4.9) |
Idiopathic |
1,348 | 11 | 0.8 (0.3–1.3) | 74 | 5.5 (4.3–6.7) | 121 | 9.0 (7.5–10.5) |
Controls | 6,154 | 19 | 0.3 (0.2–0.4) | 112 | 1.8 (1.5–2.2) | 135 | 2.2 (1.8–2.6) |
Individuals with malignancy excluded.
Idiopathic venous thrombosis were those without malignancy, surgery, hospital admission, injuries, plaster, oral contraceptive use, and pregnancy or puerperium.
Groups | SMR Overall (95% CI) |
SMR Specific (95% CI) |
|
Overall | 4,947 (601) | 4.0 (3.7–4.3) | 4.0 (3.7–4.3) |
Malignancy+ | 650 (358) | 17.2 (15.5–19.1) | 5.5 (5.0–6.1) |
Malignancy− | 4,297 (243) | 1.9 (1.7–2.1) | 2.2 (1.9–2.5) |
DVT | 2,505 (144) | 1.9 (1.7–2.3) | 2.3 (1.9–2.7) |
PE | 1,257 (72) | 1.9 (1.5–2.4) | 2.2 (1.7–2.8) |
DVT+PE | 535 (27) | 1.6 (1.1–2.3) | 1.8 (1.2–2.6) |
Provoked |
2,949 (122) | 1.9 (1.6–2.2) | 2.1 (1.8–2.5) |
Idiopathic |
1,348 (121) | 1.9 (1.6–2.3) | 2.2 (1.8–2.6) |
SMRs are calculated with the nonthrombosis cohort as a reference.
SMRs are calculated with the controls with the same selection criteria as the patients as a reference.
Individuals with malignancy excluded.
Idiopathic venous thrombosis were those without malignancy, surgery, hospital admission, injuries, plaster, oral contraceptive use, and pregnancy or puerperium.
DVT, patients with a first venous thrombosis of the leg without malignancies; DVT+PE, patients diagnosed with both PE and DVT without malignancies; PE, patients with a first PE without a diagnosis of a DVT without malignancies.
Patients with venous thrombosis without malignancy had an overall 2-fold increased risk of mortality compared to the control group (
Group | Controls | Year of Follow-up | Overall | |||||||
1 | 2 | 3 | 4 | 5 | 6 | 7 | 8 | |||
HR |
HR (95% CI) | HR (95% CI) | HR (95% CI) | HR (95% CI) | HR (95% CI) | HR (95% CI) | HR (95% CI) | |||
Overall | All |
14.4 (7.1–29.2) | 7.1 (3.7–13.6) | 4.2 (2.3–7.5) | 1.7 (1.0–3.1) | 2.5 (1.4–4.8) | 1.8 (0.9–3.6) | 2.1 (1.0–4.6) | 3.8 (0.5–30.8) | 4.3 (3.4–5.5) |
Malignancy | All | 116.6 (56.5–240.9) | 45.6 (22.9–90.7) | 28.5 (14.8–54.9) | 3.5 (1.6–7.9) | 11.7 (5.1–27.1) | 5.2 (2.0–13.6) | 2.4 (0.6–9.0) | 2.6 (0.1–77.7) | 26.0 (20.1–33.7) |
Malignancy | Malignancy |
18.4 (4.6–74.4) | 11.3 (2.8–45.9) | 5.5 (1.7–18.9) | 2.2 (0.5–9.9) | 2.2 (0.5–9.8) | — |
0.4 (0.1–1.7) | — |
6.6 (3.9–11.3) |
Provoked |
All | 3.7 (1.6–8.3) | 3.2 (1.5–6.9) | 1.8 (0.9–3.7) | 1.2 (0.6–2.4) | 2.7 (1.3–5.4) | 1.0 (0.4–2.6) | 1.8 (0.7–4.8) | 3.2 (0.3–34.8) | 2.1 (1.7–2.9) |
Provoked |
Risk factors | 5.7 (1.3–24.6) | 3.3 (1.0–11.3) | 1.6 (0.6–4.4) | 1.4 (0.4–4.7) | 1.7 (0.6–4.4) | 1.0 (0.3–4.0) | — |
0.3 (0.0–4.1) | 2.3 (1.5–3.6) |
Idiopathic |
All | 2.9 (1.1–7.9) | 2.4 (1.0–5.7) | 2.5 (1.2–5.4) | 1.7 (0.8–3.6) | 1.2 (0.5–2.9) | 1.7 (0.7–3.8) | 3.4 (1.4–8.2) | 3.6 (0.4–31.7) | 2.2 (1.6–3.0) |
Idiopathic |
No risk factors | 3.1 (1.0–10.2) | 2.5 (0.9–7.1) | 4.1 (1.5–11.3) | 1.5 (0.7–3.3) | 1.9 (0.6–5.8) | 1.7 (0.7–4.0) | 2.9 (1.1–7.6) | — |
2.5 (1.8–3.6) |
All HRs were adjusted for age and sex and number of comorbidities.
All, all controls were taken into account.
Selected, controls with the same characteristics as the patient subgroup were taken into account, e.g., selected malignancy are only controls with malignant disease.
HR could not be calculated, because there were no events.
Individuals with malignancy excluded.
Idiopathic venous thrombosis were those without malignancy, surgery, hospital admission, injuries, plaster, oral contraceptive use and pregnancy and were not during puerperium.
The reduction of median life expectancy for those without malignancy was 5 y for men and women. The estimated median life expectancy was 76 for men and 79 for women compared to 81 and 84 y respectively for the Dutch population.
Patients with thrombosis and without malignancy have an increased risk of death, which could be explained by concurrent other major disorders (
The main primary cause of death was malignancy (
Cause of Death (Primary) | SMR Overall (95% CI) | SMR Patients without Malignancy (95% CI) | ||
I00–I99 Diseases of the circulatory system | 80 (13) | 2.0 (1.6–2.5) | 72 (30) | 2.2 (1.7–2.7) |
I21 Acute myocardial infarction | 26 (4) | 2.4 (1.6–3.5) | 23 (10) | 2.5 (1.7–3.8) |
I61 Cerebral Hemorrhage | 4 (0.6) | 1.9 (0.7–5.0) | 2 (1) | 1.1 (0.3–4.5) |
I63 Cerebral infarction | 1 (0.1) | 0.7 (0.1–5.0) | 1 (0.5) | 0.8 (0.1–5.9) |
I64 Stroke | 2 (0.3) | 0.8 (0.2–3.3) | 2 (1) | 1.0 (0.2–4.0) |
I26 and I80 Venous thromboembolism | 7 (1) | 5.5 (2.6–11.4) | 7 (3) | 6.5 (3.1–13.7) |
C00–C99 Neoplasms | 392 (65) | 5.5 (5.0–6.0) | 69 (29) | 1.1 (0.9–1.4) |
J00–J99 Diseases of the respiratory system | 34 (6) | 3.3 (2.3–4.6) | 29 (12) | 3.3 (2.3–4.8) |
J44 Chronic obstructive pulmonary disease | 19 (3) | 3.7 (2.4–5.8) | 16 (7) | 3.7 (2.3–6.1) |
J18 Pneumonia | 5 (0.8) | 2.1 (0.9–4.9) | 5 (2) | 2.4 (1.0–5.9) |
Cause-specific mortality was compared with data from the general population. Patients had two times higher rates of deaths from diseases of the circulatory system (
For patients without malignancy the main causes of death were diseases of the respiratory system and diseases of the circulatory system (SMR 3.3, 95% CI 2.3–4.8 and 2.2, 95% CI 1.7–2.7, respectively). Compared with the general population they did not have an increased risk of death due to malignancies (
We studied long-term mortality after a first venous thrombosis in 4,947 patients followed for a median period of 5.5 y, compared with a thrombosis-free cohort of 6,154 individuals. The overall mortality rates were 22.7 per 1,000 person-years for all patients. Overall, the death rate in patients was 4.0-fold increased and in those without a malignancy over two-fold increased. In all patients except those with a transient provoking risk factor underlying the initial event, death rates remained elevated up to 8 y after the thrombotic event.
Few studies have studied the long-term risk of mortality after venous thrombosis. In a previous study from Norway, the cumulative incidences at 1 y were much higher than those we found. In the Norwegian study a cumulative incidence at 1 y of 14.5% was found for cases with an idiopathic venous thrombosis, of 9.7% for provoked cases, and of 63.4% for cancer patients, while we found cumulative incidences of 0.8%, 0.7%, and 25.4%, respectively
We confirmed previous observations that patients with malignancy and venous thrombosis have a very poor prognosis, substantially worse than patients with cancer without thrombosis, with a 5.5-fold difference in our study
Main causes of death, apart from malignancies, were diseases of the circulatory and respiratory system. These results are in line with previous studies that described associations between risk factors for venous and arterial thrombosis as well as an increased risk of arterial thrombosis for those who experienced venous thrombosis
Our study may have suffered from some limitations: as discussed above causes of death were not objectively verified. However misclassification by the physician determining the cause of death is most likely to have been equal in this population and in the general population, which would have led to an underestimation of the risks we have found. Furthermore, we only recruited patients after discharge from hospital, and therefore overall mortality is underestimated. Moreover, our results cannot be extrapolated to patients older than 70 y at the time of thrombosis, or to children.
Among the major strengths of this study are the large size of the cohort, and the long follow-up period. Mortality data were retrieved from the national registry where 98.5% of participants were found. Therefore, loss to follow-up was minimal and dates of death were accurate. To our knowledge, this has been the first study to calculate mortality rates compared with the general population and compared to specific control groups. Therefore, we were able to define overall risks of death up to 8 y after thrombosis as well as the risk for several subgroups. Our results underline the major consequences of venous thrombosis, not only with regard to morbidity but also to mortality.
We acknowledge the directors of the Anticoagulation Clinics of Amersfoort (M.H.H. Kramer), Amsterdam (M. Remkes), Leiden (F.J.M. van der Meer), The Hague (E. van Meegen), Rotterdam (A.A.H. Kasbergen), and Utrecht (J. de Vries-Goldschmeding) who made the recruitment of patients possible; and the interviewers J.C.M. van den Berg, B. Berbee, S. van der Leden, M. Roosen, and E.C. Willems of Brilman. We thank I. de Jonge, R. Roelofsen, M. Streevelaar, L.M.J. Timmers, and J.J. Schreijer for their secretarial, administrative support, and data management, and I. de Jonge and I.A. Noordermeer for collecting vital status from the community registries. We express our gratitude to all individuals who participated in the MEGA study.
deep vein thrombosis
hazard ratio
Multiple Environmental and Genetic Assessment
pulmonary embolism
standardized mortality ratio