Current and former smoking and risk for venous thromboembolism: a systematic review and meta-analysis

Abstract

Background: Smoking is a well-established risk factor for atherosclerotic disease, but its role as an independent risk factor for venous thromboembolism (VTE) remains controversial. We conducted a meta-analysis to summarize all published prospective studies and case-control studies to update the risk for VTE in smokers and determine whether a dose-response relationship exists.

Methods and findings: We performed a literature search using MEDLINE (source PubMed, January 1, 1966 to June 15, 2013) and EMBASE (January 1, 1980 to June 15, 2013) with no restrictions. Pooled effect estimates were obtained by using random-effects meta-analysis. Thirty-two observational studies involving 3,966,184 participants and 35,151 VTE events were identified. Compared with never smokers, the overall combined relative risks (RRs) for developing VTE were 1.17 (95% CI 1.09-1.25) for ever smokers, 1.23 (95% CI 1.14-1.33) for current smokers, and 1.10 (95% CI 1.03-1.17) for former smokers, respectively. The risk increased by 10.2% (95% CI 8.6%-11.8%) for every additional ten cigarettes per day smoked or by 6.1% (95% CI 3.8%-8.5%) for every additional ten pack-years. Analysis of 13 studies adjusted for body mass index (BMI) yielded a relatively higher RR (1.30; 95% CI 1.24-1.37) for current smokers. The population attributable fractions of VTE were 8.7% (95% CI 4.8%-12.3%) for ever smoking, 5.8% (95% CI 3.6%-8.2%) for current smoking, and 2.7% (95% CI 0.8%-4.5%) for former smoking. Smoking was associated with an absolute risk increase of 24.3 (95% CI 15.4-26.7) cases per 100,000 person-years.

Conclusions: Cigarette smoking is associated with a slightly increased risk for VTE. BMI appears to be a confounding factor in the risk estimates. The relationship between VTE and smoking has clinical relevance with respect to individual screening, risk factor modification, and the primary and secondary prevention of VTE. Please see later in the article for the Editors' Summary.

Figure 1. Flowchart of the selection of studies included in meta-analysis.

Figure 2. Forest plot for VTE incidence: risk estimates for ever versus never smokers.

The size of each square is proportional to the study's weight (inverse of variance).

Figure 3. (A–C) Funnel plots showing associations of smoking with VTE.

Figure 4. Cardiovascular risk factor-adjusted relative risk for VTE.

The size of each square is proportional to the study's weight (inverse of variance). Cardiovascular risk factors (BCDHAP): B, BMI, body weight or waist circumference; C, cholesterol; D, diabetes; H, hypertension; A, alcohol consumption; P, physical activity. For example, Sweetland S 2013 adjusted for body mass index, diabetes, hypertension, alcohol consumption, physical activity, and three other non-cardiovascular risk factors, but not for cholesterol.

Figure 5. Linear dose-response relationship between relative risk of VTE incidence and tobacco consumption with cigarettes per day (A) and pack-years (B) as the explanatory variables.

The solid line represents point estimates of association between tobacco consumption and VTE risk; dashed lines are 95% CIs. Circles present the dose-specific RR estimates reported in each study. The area of each circle is proportional to the inverse variance of the RR. The dotted line represents the null hypothesis of no association. The vertical axis is on a log scale.