Men Likelier to Have Recurrent Venous Thromboembolism

ADELAIDE, Australia, July 27 -- Men appear to have a 50% higher risk than women of recurrent venous thromboembolism after stopping anticoagulant treatment, researchers here reported.

However, including sex in decisions about the length of anticoagulant therapy in these patients is not yet ready for prime time, according to the researchers and editorial writers in online reports in the July 29 issue of The Lancet.

The significantly increased risk for men resulted from a meta-analysis of 15 studies including 5,416 individuals, equally divided between men and women. Among these, there were 816 episodes of recurrent venous thromboembolism after stopping treatment, of which 523 (64%) were in men and 293 (36%) in women, said Simon McRae, M.D., at Queen Elizabeth Hospital in nearby Woodville, and colleagues at McMaster in Hamilton, Ontario.

Eligible articles for the study (nine randomized controlled trials and six prospective observational studies) were identified by a search of databases in MEDLINE (1966-2005), EMBase (1980-2005), and in the central Cochrane Library (2005). The methodological quality of the studies was generally good, the researchers said.

The pooled estimate of the relative risk (RR) of recurrent venous thromboembolism in men compared with that for women was 1.6 (95% CI 1.2-2.0; P=0.0004), Dr. McRae reported.

Significant heterogeneity of the relative risk with patient sex was seen among individual study findings, the researchers said. However, they added that the results in all but two small studies favored an increased risk of recurrence in men.

The relative risk for recurrence in men from randomized trials (RR 1.3; CI 1.0-1.8) tended to be lower than that from observational studies (RR 2.1; CI 1.5-2.9). There was significant heterogeneity in the relative risk of recurrence with patient sex in the nine randomized trial, but not in the observational studies, the researchers said, adding that the reasons for this discrepancy are unclear.

In an analysis of provoked and unprovoked thrombi, the researchers reported that the risk for men remained high irrespective of the cause of the thrombotic event.

To determine whether pregnancy or estrogen use protected the women, the researchers analyzed a subgroup of women excluding studies that included women with hormonal risk factors. Even in this subgroup, the risk for women was lower (RR 1.4, CI 1.2-1.7), they said.

Among strengths of the study were the strict inclusion criteria and the large number of patients analyzed, the researchers pointed out.

Study limitations included the heterogeneity among individual study findings, although differences in study design and the inclusion of women with hormonal risk factors could help to explain this finding, the researchers wrote. Also, they noted, the analysis was retrospective, a drawback for all meta-analyses.

In addition, Dr. McRae said, his team was unable to adjust for individual patient characteristics, such as age, body-mass index, subsequent development of malignancy, presence of inherited thrombophilia, and length of follow-up, all differences that could account for the higher risk of recurrence in men.

The difference in risk reported in this study could be sufficient to affect selection of patients for indefinite anticoagulant treatment, especially if, as some studies have suggested, the risk of bleeding is higher in women, Dr. McRae said.

However, he cautioned, "further prospective studies are needed before a firm recommendation can be made to incorporate patient sex into decision making on duration of anticoagulant treatment in individual patients with venous thrombosis."

According to Dr. McRae and co-author Huyen Tran, M.D., both have received an Amgen/HSANZ Scholarship for 2005.

Commenting on the McRae study in the same issue of The Lancet, Vittorio Pengo, M.D., and Paolo Prandoni, M.D., of the University of Padua in Italy, said that although the results were "potentially valuable," they agreed with Dr. McRae and his colleagues that incorporating sex into a decision on the duration of anticoagulant therapy would be premature.

They noted, for example, that the authors were not able to retrieve information about sex distribution in 11 adequate studies and that a multivariate analysis accounting for important individual data, such as age, could not be done.

Increasing evidence suggests that both general and individual characteristics affect the risk, they said. These include, for example, thrombi location, thrombophilia (highly controversial), and clinical presentation. Similarly controversial is the mode of clinical presentation-pulmonary embolism versus deep vein thrombosis.

Individual characteristics, they pointed out, that make certain patients more susceptible to recurrent thrombosis risk include residual venous thrombosis in the leg veins and the D-dimer value assessed one month after stopping anticoagulation. "For both strategies, we are awaiting results of studies to assess the value of tailoring the duration of anticoagulant therapy according to each patient's findings," they said.

"Although we appreciate the contribution of McRae and colleagues, we believe that it is too early to rely on patients' sex when determining the duration of anticoagulation in patients with idiopathic venous thromboembolism," they said. "Further prospective studies are needed before a firm recommendation can be made on this issue."