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      Long-Term Survival in a Large Cohort of Patients with Venous Thrombosis: Incidence and Predictors

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          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.

          Methods and Findings

          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.

          Please see later in the article for the Editors' Summary

          Editors' Summary


          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.

          Why Was This Study Done?

          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.

          What Did the Researchers Do and Find?

          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 ( n = 3,297) and a random control group matched on age and sex ( n = 3,000). The researchers obtained causes of death from the Central Bureau of Statistics and for the observation period (30 days after the venous thrombosis, to either death or end of follow-up between February 2007 and May 2009) compared cause-specific death rates of the patients to those of the general Dutch population. The researchers devised specialist survival models (called Kaplan-Meier life-tables) and calculated standardized mortality ratios (SMRs—the ratio of the observed number of deaths over the number of deaths expected) to estimate relative rates of all cause mortality by type of the initial thrombosis and the underlying cause.

          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.

          What Do These Findings Mean?

          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.

          Additional Information

          Please access these Web sites via the online version of this summary at

          Related collections

          Most cited references 18

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          Acute pulmonary embolism: clinical outcomes in the International Cooperative Pulmonary Embolism Registry (ICOPER)

          Pulmonary embolism (PE) remains poorly understood. Rates of clinical outcomes such as death and recurrence vary widely among trials. We therefore established the International Cooperative Pulmonary Embolism Registry (ICOPER), with the aim of identifying factors associated with death. 2454 consecutive eligible patients with acute PE were registered from 52 hospitals in seven countries in Europe and North America. The primary outcome measure was all-cause mortality at 3 months. The prognostic effect of baseline factors on survival was assessed with multivariate analyses. 2110 (86.0%) patients had PE proven by necropsy, high-probability lung scan, pulmonary angiography, or venous ultrasonography plus high clinical suspicion; ICOPER accepted without independent review diagnoses and interpretation of imaging provided by participating centres; 3-month follow-up was completed in 98.0% of patients. The overall crude mortality rate at 3 months was 17.4% (426 of 2454 deaths, including 52 patients lost to follow-up): 179 of 397 (45.1%) deaths were ascribed to PE and 70 of 397 (17.6%) to cancer, and no information on the cause of death was available for 29 patients. After exclusion of 61 patients in whom PE was first discovered at necropsy, the mortality rate at 3 months was 15.3% (365 of 2393 deaths). On multiple-regression modelling, age over 70 years (hazard ratio 1.6 [95% CI 1.1-2.3]), cancer (2.3 [1.5-3.5]), congestive heart failure (2.4 [1.5-3.7]), chronic obstructive pulmonary disease (1.8 [1.2-2.7]), systolic arterial hypotension (2.9 [1.7-5.0]), tachypnoea (2.0 [1.2-3.2]), and right-ventricular hypokinesis on echocardiography (2.0 [1.3-2.9]) were identified as significant prognostic factors. PE remains an important clinical problem with a high mortality rate. Data from ICOPER provide rates and highlight adverse prognostic categories that will help in planning of future trials of high-risk PE patients.
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            Prognosis of cancers associated with venous thromboembolism.

            Little is known about the prognosis of cancer discovered during or after an episode of venous thromboembolism. We linked the Danish National Registry of Patients, the Danish Cancer Registry, and the Danish Mortality Files to obtain data on the survival of patients who received a diagnosis of cancer at the same time as or after an episode of venous thromboembolism. Their survival was compared with that of patients with cancer who did not have venous thromboembolism (control patients), who were matched in terms of type of cancer, age, sex, and year of diagnosis. Of 668 patients who had cancer at the time of an episode of deep venous thromboembolism, 44.0 percent of those with data on the spread of disease (563 patients) had distant metastasis, as compared with 35.1 percent of 5371 control patients with data on spread (prevalence ratio, 1.26; 95 percent confidence interval, 1.13 to 1.40). In the group with cancer at the time of venous thromboembolism, the one-year survival rate was 12 percent, as compared with 36 percent in the control group (P<0.001), and the mortality ratio for the entire follow-up period was 2.20 (95 percent confidence interval, 2.05 to 2.40). Patients in whom cancer was diagnosed within one year after an episode of venous thromboembolism had a slightly increased risk of distant metastasis at the time of the diagnosis (prevalence ratio, 1.23 [95 percent confidence interval, 1.08 to 1.40]) and a relatively low rate of survival at one year (38 percent, vs. 47 percent in the control group; P<0.001). Cancer diagnosed at the same time as or within one year after an episode of venous thromboembolism is associated with an advanced stage of cancer and a poor prognosis.
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              Incidence and mortality of venous thrombosis: a population-based study.

              Estimates of the incidence of venous thrombosis (VT) vary, and data on mortality are limited. We estimated the incidence and mortality of a first VT event in a general population. From the residents of Nord-Trøndelag county in Norway aged 20 years and older (n = 94 194), we identified all cases with an objectively verified diagnosis of VT that occurred between 1995 and 2001. Patients and diagnosis characteristics were retrieved from medical records. Seven hundred and forty patients were identified with a first diagnosis of VT during 516,405 person-years of follow-up. The incidence rate for all first VT events was 1.43 per 1000 person-years [95% confidence interval (CI): 1.33-1.54], that for deep-vein thrombosis (DVT) was 0.93 per 1000 person-years (95% CI: 0.85-1.02), and that for pulmonary embolism (PE) was 0.50 per 1000 person-years (95% CI: 0.44-0.56). The incidence rates increased exponentially with age, and were slightly higher in women than in men. The 30-day case-fatality rate was higher in patients with PE than in those with DVT [9.7% vs. 4.6%, risk ratio 2.1 (95% CI: 1.2-3.7)]; it was also higher in patients with cancer than in patients without cancer [19.1% vs. 3.6%, risk ratio 3.8 (95% CI 1.6-9.2)]. The risk of dying was highest in the first months subsequent to the VT, after which it gradually approached the mortality rate in the general population. This study provides estimates of incidence and mortality of a first VT event in the general population.

                Author and article information

                Role: Academic Editor
                PLoS Med
                PLoS Medicine
                Public Library of Science (San Francisco, USA )
                January 2012
                January 2012
                10 January 2012
                : 9
                : 1
                [1 ]Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, The Netherlands
                [2 ]Department of Thrombosis and Haemostasis, Leiden University Medical Center, Leiden, The Netherlands
                University College London, United Kingdom
                Author notes

                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. ICMJE criteria for authorship read and met: LEF AvH SCC FRR. Agree with manuscript results and conclusions: LEF AvH SCC FRR. Final approval of the manuscript to be published: AvH SCC FRR.

                Flinterman et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
                Page count
                Pages: 8
                Research Article



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