Epidemiology of Venous Thromboembolic Disease

Incidence and clinical relevance of venous thromboembolism

Venous thromboembolism (VTE), consisting of deep vein thrombosis (DVT) and pulmonary embolism (PE), is the third leading cardiovascular disease after coronary heart disease and stroke. The age-standardized incidence rate is 1 to 2 per 1000 people per year. There is no surveillance for VTE, so the precise incidence and prevalence are not clear; three data sources present disparate results as recently reviewed. Estimates from the United States Centers for Disease Control suggest there are 300,000 to 600,000 cases annually in the United States. In contrast, another study suggested 465,715 DVT, 296,000 PE, and 370,000 VTE deaths annually in six European countries with a population size together that is similar to the United States. The American Heart Association estimated that there were 676,000 DVT cases in the United States in 2014.

Estimation of lifetime risk is another way to consider the impact of VTE on the population. A report from an observational cohort of blacks and whites in the United States estimated that the lifetime risk of VTE after age 45 was 8.1% overall and 11.5% in blacks. Reflecting the association of common risk factors for VTE, lifetime risk was 10.9% in those with obesity and 17% to 18% in those with sickle cell anemia/trait or factor V Leiden (the most common genetic thrombophilia). The risk of VTE differs by race-ethnicity, being lower in populations of Asian descent and perhaps higher in those of African descent, compared to Caucasians.

VTE is a chronic disease that is associated with increased short- and long-term complications. In the short term, recurrent VTE and major bleeding predominate, while in the long term post-thrombotic syndrome (PTS), recurrent VTE and chronic thromboembolic pulmonary hypertension (CTEPH) cause morbidity and mortality. The case fatality rate for both recurrent VTE and major bleeding is approximately 11% during the first three months of anticoagulation therapy. PTS is a long-term complication in up to 25% to 50% of patients with DVT, and CTEPH complicates the course of approximately 1% of patients with PE. Hence, VTE is an important cause of disability-adjusted life years lost and poses significant healthcare costs. To reduce incidence and complications of VTE a better understanding of its incidence and associated risk factors is required.

Secular trends in incidence of venous thromboembolism

In North America, the overall incidence of VTE seems to have remained relatively unchanged over time. A large US population-based study reported an age- and sex-adjusted incidence of a first episode of VTE of 10.2 (95% CI: 10.2 to 10.3) per 10,000 person-years and demonstrated that the incidence did not change over a 30-year period (1991 to 2010). A Canadian study also reported a stable age- and sex-adjusted incidence of VTE of 13.8 (95% CI: 13.7 to 14.0) per 10,000 person-years between 2004 and 2012. Finally, a study from the Netherlands reported a stable overall age-adjusted incidence rate of first episode of VTE over a 10-year period from 2003 to 2012. Interestingly, although the incidence rate of overall VTE remained stable over time, a number of studies have reported a decrease in the incidence of DVT but an increase in the incidence of PE. A French study comparing the 2013 incidence rate of VTE to that of 1998 using age- and sex-adjusted standardized incidence ratios (SIRs) reported a lower incidence for isolated DVT (without PE) in 2013 (SIR 0.53 [95 % CI: 0.47 to 0.60]) but an increase in the incidence of isolated PE (without DVT) (SIR 1.29 [95 % CI: 1.10 to 1.52]). Other studies in the United States and the Netherlands also reported a decrease in the incidence of first (distal or proximal) DVT but an increase in the incidence of PE. These observations are consistent with findings from the large population-based Norwegian Tromsø study that reported that the age-adjusted incidence of PE increased from 4.5 (95% CI: 2.3 to 6.7) per 10,000 person-years in 1996 to 11.3 (95% CI: 8.2 to 14.4) in 2010, whereas the incidence of isolated DVT in the same timeframe decreased from 11.2 (95% CI: 7.7 to 14.6) to 8.8 (95% CI: 6.1 to 11.5). In contrast, as shown in Fig. 50.1 , the 2018 statistical update of the American Heart Association reported a tripling of PE hospitalization and an approximate 50% increase in DVT hospitalization over the last two decades in the United States. There are many potential reasons for this reported increase in DVT hospitalization. One explanation could relate to increased detection due to improvements in the sensitivity of imaging tests, such as using full-length leg ultrasonography, which may detect small distal DVTs that would not have been diagnosed with a diagnostic algorithm using proximal ultrasonography alone. However, the differences in findings from these studies with varied designs remain unexplained.

The reason for the increase in the overall incidence rate of PE over time remains unclear. The introduction of computed tomographic pulmonary angiography (CTPA) and its recent increasing availability in hospital emergency rooms is an important factor to consider. Detection of incidental PE, discussed below, might contribute. Advances in technology, more specifically the implementation of multiple-detector CTPA in clinical practice, has led to improvement in the sensitivity of PE diagnosis by allowing better resolution of the 2 to 3 mm diameter subsegmental pulmonary arteries. A large study from the US reported that the increased use of multiple-detector CTPA for the diagnosis of PE seems to have led to a significant increase in the overall incidence of PE diagnosis. Other factors besides improved sensitivity of CTPA may also be contributing, including improvements in effectiveness of PE diagnosis (using diagnostic algorithms including pre-test probability assessment), increased clinical awareness of healthcare providers to the diagnosis, a true increase in the incidence, or overdiagnosis. One study reported a decreasing age-adjusted, in-hospital case fatality rate from 12.1% to 7.8% between 1998 and 2006 without any significant change in overall mortality, suggesting that at least some of the increased PE diagnoses are less severe (or overdiagnosed). Similar findings were reported in an Italian study assessing hospitalization for patients with acute PE. In this study, the incidence of PE increased from 4.0 to 6.2 per 10,000 person-years in women and from 3.5 to 4.6 in men between 2002 and 2012. The case-fatality rate decreased over the same time frame from 15.6% to 10.2% in women and 17.6% to 10.2% in men.

The reported increased incidence of PE diagnosis since the introduction of multiple-detector CTPA may be correlated with an increase in the diagnosis of PE localized in the subsegmental pulmonary arteries without involvement in larger-order vessels (i.e., subsegmental PE, SSPE). A systematic review and meta-analysis of the literature reported that the rate of SSPE diagnosis among patients that underwent single-detector CTPA was 4.7% as compared to 9.4% for those that underwent multiple-detector CTPA. Thus the rate of SSPE diagnosis seems to be increasing with the number of detectors used for PE diagnosis. These rates have been reported to range from 7% to 15% in patients undergoing 4- to 64-detector CTPA, respectively.

In summary, although not all reports agree, the overall incidence of VTE seems to have remained relatively unchanged over time, with lower-limb DVT decreasing and PE increasing in recent years. The rise in PE is likely, in part, a manifestation of the greater sensitivity of diagnostic tests for PE in smaller caliber vessels (e.g., subsegmental pulmonary arteries). The clinical importance of these isolated SSPE is not clear and further studies are required to guide clinical management.

Risk factors for venous thromboembolism