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

Abstract

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.

Abstract

Background

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.

Conclusions

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

Background

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 http://dx.doi.org/10.1371/journal.pmed.1001155.

• Wikipedia provides information about venous thrombosis note that Wikipedia is a free online encyclopedia that anyone can edit; available in several languages)

• Medline has patient-friendly information about deep venous thrombosis and pulmonary embolism