Correspondence
The Risk of Recurrent Deep Venous Thrombosis
N Engl J Med 2000; 342:214-215January 20, 2000
- Article
To the Editor:
De Stefano and colleagues (Sept. 9 issue)1 reported the results of their retrospective analysis of the risk of recurrent deep venous thrombosis in patients with deep venous thrombosis who were heterozygous for both factor V Leiden and the G20210A prothrombin mutation. On the basis of this analysis, they recommend lifelong treatment with vitamin K antagonists for all patients with these two defects. We are concerned about this recommendation for two reasons. First, the absolute risk of recurrent deep venous thrombosis observed in this study appears to be spuriously high. Second, depending on the specific characteristics of the patients, extended treatment with vitamin K antagonists may cause more harm than good.
The rate of recurrence of deep venous thrombosis after a median follow-up period of three years in patients without the two mutations appears to be clearly higher in this study (30 percent)1 than that reported previously (15 to 20 percent).2,3 This disparity suggests that selection bias may have occurred (i.e., the inclusion of patients with other, unidentified thrombophilic abnormalities); this would, therefore, also have affected the absolute rate of recurrence among the patients with both defects. Hence, in a less highly selected population, this rate might actually be substantially lower than the 65 percent observed during follow-up in this study.
With regard to our second concern: it is well documented that the risk of recurrent deep venous thrombosis declines over time, whereas the risk of major hemorrhage gradually increases with extended treatment with vitamin K antagonists.2,4 Both of these risks are affected by certain characteristics of the patients (e.g., age, presence or absence of cancer, and presence or absence of bleeding diathesis). Therefore, decisions regarding the duration of treatment should take these factors into account. On the basis of decision analysis, the need to individualize the duration of anticoagulant treatment is apparent.3
We therefore believe that a general recommendation regarding lifelong treatment with vitamin K antagonists for all patients who are heterozygous for both factor V Leiden and the G20210A prothrombin mutation is premature and may even be harmful in older patients and those with an increased risk of bleeding.
4 ReferencesJeroen F. van der Heijden, M.D.
Roderik A. Kraaijenhagen, M.D.
Harry R. Büller, M.D.
Academic Medical Center, 1100 DE Amsterdam, the Netherlands1
De Stefano V ,Martinelli I ,Mannucci PM , et al. The risk of recurrent deep venous thrombosis among heterozygous carriers of both factor V Leiden and the G20210A prothrombin mutation. N Engl J Med 1999;341:801-806
Full Text | Web of Science | Medline2
Prandoni P ,Lensing AW ,Cogo A , et al. The long-term clinical course of acute deep venous thrombosis. Ann Intern Med 1996;125:1-7
Web of Science | Medline3
Prins MH ,Hutten BA ,Koopman MMW ,Buller HR . Long-term treatment of venous thromboembolic disease. Thromb Haemost 1999;82:892-898
Web of Science | Medline4
van der Meer FJ ,Rosendaal FR ,Vandenbroucke JP ,Briet E . Assessment of a bleeding risk index in two cohorts of patients treated with oral anticoagulants. Thromb Haemost 1996;76:12-16
Web of Science | Medline
Author/Editor Response
The authors reply:
To the Editor: Van der Heijden and colleagues claim that the risk of recurrent deep venous thrombosis in our cohort was unusually high. This claim was based on a comparison between the rate of recurrence after three years of follow-up in a prospective cohort (20 percent)1 and the rate of recurrence in the patients in our study who had neither mutation during a median follow-up period of three years (30 percent). The rate in our study was the cumulative prevalence of recurrence at the time of referral to our centers; it is not surprising that this rate was higher than that observed at a given moment in a prospective cohort, since it is likely to have been increased by events that occurred in the patients who were observed for longer than the median period of three years.
We performed a Kaplan–Meier analysis of the time to recurrence for 470 of the 624 patients in our study, excluding those who had a deficiency of naturally occurring coagulation inhibitors, cancer, or myeloproliferative or autoimmune diseases. Data on the patients with factor V Leiden, the prothrombin-gene mutation, or neither mutation were analyzed together in order to obtain a data set similar to that of the other cohorts. We found a probability of recurrence of 12.2 percent at two years (95 percent confidence interval, 9.2 to 15.3 percent) and 18.8 percent at four years (95 percent confidence interval, 14.8 to 22.8 percent), which is in agreement with the data obtained from two prospective cohorts.2,3 At eight years, the probability of recurrence (estimated on the basis of 126 patients with follow-up of eight years or longer after the first event) was 32.4 percent (95 percent confidence interval, 26.6 to 38.2 percent), similar to the rate of recurrence of 30.3 percent at eight years in a prospective cohort of consecutive patients.1
A comparison of these results with ours demonstrates that the rate of recurrence was not overestimated in our patients and that our results can be generalized. In addition, we estimated the likelihood of recurrence as the relative risk between groups, assuming that the possibility of referral bias was similarly distributed among the patients. Carriers of both factor V Leiden and the prothrombin-gene mutation had a risk of spontaneous recurrence after a spontaneous first episode of thrombosis that was five times as high as that of patients with only factor V Leiden or those with no mutation. On the basis of these results and in the absence of results of prospective studies, we conclude that carriers of both mutations are candidates for lifelong treatment with oral anticoagulants.
3 ReferencesValerio De Stefano, M.D.
Catholic University, 00168 Rome, ItalyIda Martinelli, M.D., Ph.D.
Istituto di Ricovero e Cura a Carattere Scientifico,, Ospedale Maggiore, 20122 Milan, ItalyGiuseppe Leone, M.D.
Catholic University, 00168 Rome, ItalyPier Mannuccio Mannucci, M.D.
Istituto di Ricovero e Cura a Carattere Scientifico,, Ospedale Maggiore, 20122 Milan, Italy1
Prandoni P ,Lensing AW ,Cogo A , et al. The long-term clinical course of acute deep venous thrombosis. Ann Intern Med 1996;125:1-7
Web of Science | Medline2
Eichinger S ,Pabinger I ,Stumpflen A , et al. The risk of recurrent venous thromboembolism in patients with and without factor V Leiden. Thromb Haemost 1997;77:624-628
Web of Science | Medline3
Lindmarker P ,Schulman S ,Sten-Linder M ,Wiman B ,Egberg N ,Johnsson H . The risk of recurrent venous thromboembolism in carriers and non-carriers of the G1691A allele in the coagulation factor V gene and the G20210A allele in the prothrombin gene. Thromb Haemost 1999;81:684-689
Web of Science | Medline
