Meta-analysis of Hyperhomocysteinemia as a Risk Factor for Venous Thromboembolic Disease

Abstract

BACKGROUND: Elevated plasma homocysteine (Hcy) levels are implicated in the development of atherosclerotic and venous thromboembolic disease. A meta-analysis of the risk for venous thromboembolism (VTE) in the presence of hyperhomocysteinemia (hyper-Hcy) was performed. METHODS: Studies were identified through MEDLINE (January 1980 to August 1997) using search terms related to both Hcy and VTE. The bibliographies of all review articles and letters were searched for additional relevant articles. English-language studies were selected if they included 10 or more human subjects; a measurement of the plasma, serum, or whole-blood Hcy level; the presence of VTE; and primary data that were not published elsewhere. Seventy-two articles were retrieved, of which 9 met all inclusion criteria. Data were extracted on the study type, subject demographics, methods for matching control subjects with case patients, whether an objective method was used to diagnose VTE, and whether other causes of thrombophilia and elevated Hcy levels were considered. The mean Hcy levels, both in the fasting state and following methionine loading, if done, were recorded, as were the number of patients and control subjects with Hcy levels greater than 2 SDs or greater than the 95th percentile above the mean value of the control group. RESULTS: Nine case-control studies measured fasting plasma Hcy levels, and 5 also measured Hcy values after methionine loading. All 9 studies showed a similar qualitative trend in fasting levels in the associated risk for hyper-Hcy and VTE. The corresponding pooled odds ratio was 2.95 (95% confidence interval, 2.08-4.17; 2-sided P<.001), with no evidence for heterogeneity across the studies (P = .50). Following methionine loading, the trend was also toward increasing the risk of VTE with hyper-Hcy (odds ratio, 2.15; 95% confidence interval, 1.20-3.85; 2-sided P = .01). Again, no evidence of heterogeneity was found (P = .65). The pooled odds ratio for VTE in the presence of hyper-Hcy rose to 4.37 (95% confidence interval, 1.94-9.84) when studies with patients older than 60 years were excluded. Limitations of the individual studies included a lack of proper matching of patients with control subjects, a limited description of subject recruitment, and a failure to test for other hypercoagulable mechanisms and other causes of elevated Hcy levels, such as renal insufficiency or folate deficiency. CONCLUSIONS: A significant risk for VTE in the presence of hyper-Hcy apparently exists among a spectrum of patients with first or recurrent venous thromboembolic events. This risk appears to be most significant for patients with VTE disease before age 60 years. A well-designed prospective study is needed to confirm these findings.