Traditional CVD risk factors should not be used to assess risk of VTE
Association of Traditional Cardiovascular Risk Factors with Venous Thromboembolism: An Individual Participant Data Meta-analysis of Prospective StudiesMahmoodi BK, Cushman M, Næss IA, et al. - Circulation 2017; 135: 7-13
Venous thromboembolism (VTE), consisting of deep vein thrombosis (DVT) or pulmonary embolism (PE), is clinically defined as either provoked or unprovoked. Provoked events are triggered by risk factors such as immobilization, surgery, major trauma, or cancer, and are more frequent in people with older age, a family history of VTE, certain genetic variants, oral contraceptive use and obesity . Unprovoked events occur in the absence of any risk factors and account for approximately 50% of VTEs . On the other hand, arterial thromboembolism is due to atherosclerosis and CVD risk factors include hypertension, hyperlipidaemia, diabetes, and smoking .
Traditional CVD and VTE risk factors are viewed as being different, although they share common risk factors such physical inactivity and obesity . To validate whether traditional CVD risk factors also apply to VTE risk factors, this individual-level data meta-analysis of prospective studies validated traditional CVD risk factors and VTE events.
- 244,865 participants were included in nine studies, with a mean follow-up of 4.7 to 19.7 years per study.
- Overall, 44% of the VTE events were unprovoked and 44% were provoked.
- Except for current smoking, all variables (hypertension, hyperlipidaemia, diabetes, current- and former smoking) showed clear positive associations with VTE in the unadjusted models.
- Adjustment for age, gender and BMI resulted in elimination of VTE risk associations for hypertension (HR: 0.98; 95% CI: 0.89-1.07), hyperlipidaemia (HR: 0.97; 95% CI: 0.88-1.08), diabetes (HR: 1.01; 95% CI: 0.89-1.15) and former smoking (HR: 0.99; 95% CI: 0.93-1.06).
- Current smoking (HR: 1.19; 95% CI: 1.08-1.32) was positively associated with VTE in the age, gender and BMI adjusted model.
- Results were generally similar for unprovoked versus provoked VTE, and PE versus DVT. However, in the fully adjusted models current smoking was only associated with provoked (HR: 1.36; 95% CI: 1.22-1.52; I2=0%) and not with unprovoked VTE (HR: 1.08; 95% CI: 0.90-1.29; I2=42%). Similarly, former smoking was only associated with provoked (HR: 1.11; 95% CI: 1.00-1.23; I2=0%) but not unprovoked (HR: 1.01; 95% CI: 0.89-1.16; I2=21%) VTE.
- Compared to the reference value of 110 mmHg, the HR for VTE was 0.79 (95% CI: 0.68-0.92) at SBP of 160 mmHg. The HR was 1.02 (95% CI: 0.85-1.22) at DBP of 100 mmHg as compared to the reference value of 75 mmHg. The inverse association of SBP was somewhat more prominent for unprovoked as compared to provoked VTE.
- No clinically significant associations with VTE were observed for lipid measures.
- For glucose levels, there was a weak inverse relation in the normal glucose range but not at elevated glucose levels.
In an individual-level data meta-analysis of prospective studies, the modifiable traditional CVD risk factors were not associated with increased risk of VTE, with the exception of the association of cigarette smoking with provoked VTE. This association may be mediated through comorbid conditions such as cancer. These findings support the different pathogenesis between venous and arterial thrombotic events.
In her editorial article, S. Anand  comments on cigarette smoking as a common risk factor for both VTEs and CVD, and on the strengths of the Mahmoodi et al publication, which include the individual-level meta-analysis methodology, the statistical power, the harmonised risk factor definitions across studies, as well as the careful measurement of the outcomes of interest. She also notes that there was no adjustment for some co-variables, such as estrogen/progesterone use in the Women’s Health Initiative study, and she concludes: ‘To summarize, we learn a great deal from the meta-analysis by Mahmoodi and colleagues, for example, that smokers have a higher risk of VTE, whereas there are no strong signals for hypertension, diabetes mellitus, and elevated cholesterol. Although the effect size is low, it is likely that many cases of VTE are caused by the presence of multiple risk factors, all with small effects (i.e. risk ratios <2.0) that increase risk above a certain threshold and clinical thrombosis develops. It also demonstrates that caution must be given to small studies and meta-analyses of small studies in which errors can be multiplied and not obviated. The best way forward to characterize risk factors for relatively uncommon conditions is to design and conduct large studies or to conduct individual-level patient meta-analyses with careful consideration of and adjustment for potential confounders.’