Correspondence
Low-Intensity versus Conventional-Intensity Warfarin for Prevention of Recurrent Venous Thromboembolism
N Engl J Med 2003; 349:2164-2167November 27, 2003
- Article
To the Editor:
In the study by Kearon et al. (Aug. 14 issue),1 which compared low-intensity warfarin with conventional-intensity warfarin for long-term prevention of recurrent venous thromboembolism, conventional-intensity therapy (target international normalized ratio [INR], 2.0 to 3.0) resulted in no more major bleeding complications than low-intensity therapy (target INR, 1.5 to 1.9). The rate of major bleeding in the conventional-intensity–therapy group (0.9 percent per person-year) was substantially lower than the rates in previous trials, which ranged from 2.0 to 3.8 percent per person-year.2-4 Selection of patients with an a priori lower risk of bleeding might have been a cause of this lower rate. Indeed, patients with a “high risk of bleeding” were ineligible for participation in the study.
4 ReferencesMenno V. Huisman, M.D., Ph.D.
Felix J.M. van der Meer, M.D., Ph.D.
Cornelis J. van Rooden, M.D.
Leiden University Medical Center, 2333 ZA Leiden, the Netherlands
m.v. huisman@lumc. nl 1
Kearon C ,Ginsberg JS ,Kovacs MJ , et al. Comparison of low-intensity warfarin therapy with conventional-intensity warfarin therapy for long-term prevention of recurrent venous thromboembolism. N Engl J Med 2003;349:631-639
Full Text | Web of Science | Medline2
Schulman S ,Granqvist S ,Holmstrom M , et al. The duration of oral anticoagulant therapy after a second episode of venous thromboembolism. N Engl J Med 1997;336:393-398
Full Text | Web of Science | Medline3
Kearon C ,Gent M ,Hirsh J , et al. A comparison of three months of anticoagulation with extended anticoagulation for a first episode of idiopathic venous thromboembolism. N Engl J Med 1999;340:901-907[Erratum, N Engl J Med 1999;341:298.]
Full Text | Web of Science | Medline4
Agnelli G ,Prandoni P ,Santamaria MG , et al. Three months versus one year of oral anticoagulant therapy for idiopathic deep venous thrombosis. N Engl J Med 2001;345:165-169
Full Text | Web of Science | Medline
To the Editor:
In the study by Kearon et al., patients were eligible for enrollment if they completed three or more months of conventional oral anticoagulant therapy. Two hundred sixty-one patients in the low-intensity–therapy group had had more than one episode of venous thromboembolism. The accepted duration of therapy for such patients is a minimum of 12 months of conventional-intensity therapy.1-4 Table 4 of the article shows that patients in the low-intensity–therapy group in whom the duration of therapy before enrollment was inadequate had an incidence of recurrent venous thromboembolism that was roughly three times as high as the incidence in patients who had had a longer period of therapy. We wonder whether this known danger was pointed out to the patients before enrollment.
A majority of the patients with bleeding had a high INR. The highest INR, 11.3, occurred in the “low-intensity–therapy” group. This study proves that inadequate monitoring of patients during oral anticoagulation will result in bleeding. Bleeding did not occur in the low-intensity–therapy group; it primarily occurred in the super-high-intensity–therapy group. The inadequacy of monitoring is further reflected in the authors' failure to achieve the therapeutic goals more than 30 percent of the time the patients were enrolled.
4 ReferencesVipin Malik, M.D.
Yizhak Kupfer, M.D.
Sidney Tessler, M.D.
Maimonides Medical Center, Brooklyn, NY 11219
stessler@maimonidesmed.org 1
Schulman S ,Rhedin A-S ,Lindmarker P , et al. A comparison of six weeks with six months of oral anticoagulant therapy after a first episode of venous thromboembolism. N Engl J Med 1995;332:1661-1665
Full Text | Web of Science | Medline2
Schulman S ,Granqvist S ,Holmstrom M , et al. The duration of oral anticoagulant therapy after a second episode of venous thromboembolism. N Engl J Med 1997;336:393-398
Full Text | Web of Science | Medline3
Hirsh J . The optimal duration of anticoagulant therapy for venous thrombosis. N Engl J Med 1995;332:1710-1711
Full Text | Web of Science | Medline4
Hyers TM ,Agnelli G ,Hull RD , et al. Antithrombotic therapy for venous thromboembolic disease. Chest 2001;119:Suppl:176S-193S
CrossRef | Web of Science | Medline
To the Editor:
In the study by Kearon et al., conventional-intensity warfarin therapy (target INR, 2.0 to 3.0) was more effective in the prevention of recurrent thrombosis than low-intensity therapy (target INR, 1.5 to 1.9). Furthermore, there was no significant difference between the two groups in the frequency of bleeding. I wonder, however, whether there was a higher incidence of cancer in the low-intensity–therapy group than in the conventional-intensity–therapy group; there were seven deaths due to cancer in the low-intensity–therapy group, as compared with one in the conventional-intensity–therapy group. Studies have shown that patients with cancer have higher rates of both recurrent thromboembolism and major bleeding complications than patients without malignant disease.1,2 Perhaps this is a confounding factor that has not been accounted for, explaining why the low-intensity–therapy group had a higher incidence of recurrent thromboembolism than the conventional-intensity–therapy group and a similar frequency of bleeding.
2 ReferencesHenry A. Tran, M.D.
New York University, New York, NY 10016
tranh01@med.nyu. edu 1
Hutten BA ,Prins MH ,Gent M ,Ginsberg J ,Tijssen JG ,Buller HR . Incidence of recurrent thromboembolic and bleeding complications among patients with venous thromboembolism in relation to both malignancy and achieved international normalized ratio: a retrospective analysis. J Clin Oncol 2000;18:3078-3083
Web of Science | Medline2
Prandoni P ,Lensing AW ,Piccioli A , et al. Recurrent venous thromboembolism and bleeding complications during anticoagulant treatment in patients with cancer and venous thrombosis. Blood 2002;100:3484-3488
CrossRef | Web of Science | Medline
To the Editor:
Kearon et al. report the superiority of conventional-intensity warfarin (target INR, 2.0 to 3.0) over low-intensity therapy (target INR, 1.5 to 1.9) for the prevention of recurrent venous thromboembolism after idiopathic venous thromboembolism. However, the difference in efficacy was apparent solely in patients who had had multiple episodes of venous thromboembolism before enrollment. Among these patients, there were 13 recurrences in the low-intensity–therapy group and 2 in the conventional-intensity–therapy group. Among patients with a single previous episode of venous thromboembolism, there were three recurrences in the low-intensity–therapy group and four in the conventional-intensity–therapy group. This interaction may have been due to chance, but in the recently reported Prevention of Recurrent Venous Thromboembolism (PREVENT) trial1 (in which low-intensity warfarin was compared with placebo in patients with idiopathic venous thromboembolism), patients with recurrent venous thromboembolism who were assigned to low-dose warfarin had a recurrence rate that was four times the rate in the group of patients with a single previous episode. As such, conventional-intensity warfarin may indeed be indicated for secondary prevention in patients with recurrent idiopathic venous thromboembolism, but the jury is still out on the appropriate target INR for secondary prevention after an isolated episode. In this setting, low-dose warfarin may provide sufficient efficacy with less frequent monitoring.1
1 ReferencesDaniel J. Brotman, M.D.
Cleveland Clinic Foundation, Cleveland, OH 44195
brotmad@ccf.org 1
Ridker PM ,Goldhaber SZ ,Danielson E , et al. Long-term, low-intensity warfarin therapy for the prevention of recurrent venous thromboembolism. N Engl J Med 2003;348:1425-1434
Full Text | Web of Science | Medline
To the Editor:
We disagree with Büller and Prins1 and believe that the recommendations in their editorial are inconsistent with the findings of the PREVENT trial2 and of the trial reported by Kearon et al. (the Extended Low-Intensity Anticoagulation for Thrombo-Embolism [ELATE] study).
First, Büller and Prins conclude that therapy after 6 to 12 months “is probably not beneficial for all patients” and suggest that long-term anticoagulation be limited by patients' preferences. However, both the PREVENT and ELATE trials demonstrate that continued long-term therapy with either low-intensity or full-intensity warfarin dramatically reduces the risk of recurrent events. Furthermore, neither trial found subgroups that were more or less likely to benefit from long-term anticoagulation.
Second, Büller and Prins conclude that the target INR should be 2.0 to 3.0, since lowering the INR to 1.5 to 2.0 offers “no advantage in terms of the risk of bleeding.” This conclusion is at odds with 50 years of experience with warfarin. The low bleeding rates with full-intensity warfarin in the ELATE trial are inconsistent with all data from prior observational studies and trials, including data reported by the same investigators.3 Furthermore, the observed rate of hemorrhage with full-intensity warfarin differed from the expected rate of 3.0 episodes per 100-person years, the value used for the power calculations. Thus, the study did not have adequate power to detect a difference in the rates of hemorrhage among INR levels.
We believe that the common findings of the PREVENT and ELATE trials should inform patient care. For all patients, after an initial six months of full-intensity warfarin therapy, long-term anticoagulation with an INR based on a balance of the risks and benefits should be considered. For many, that balance clearly will favor low-intensity warfarin.
3 ReferencesPaul M. Ridker, M.D.
Samuel Z. Goldhaber, M.D.
Robert J. Glynn, Sc.D.
Brigham and Women's Hospital, Boston, MA 021151
Buller HR ,Prins MH . Secondary prophylaxis with warfarin for venous thromboembolism. N Engl J Med 2003;349:702-704
Full Text | Web of Science | Medline2
Ridker PM ,Goldhaber SZ ,Danielson E , et al. Long-term, low-intensity warfarin therapy for the prevention of recurrent venous thromboembolism. N Engl J Med 2003;348:1425-1434
Full Text | Web of Science | Medline3
Kearon C ,Gent M ,Hirsh J , et al. A comparison of three months of anticoagulation with extended anticoagulation for a first episode of idiopathic venous thromboembolism. N Engl J Med 1999;340:901-907[Erratum, N Engl J Med 1999;341:298.]
Full Text | Web of Science | Medline
Author/Editor Response
We believe that our study population is representative of patients with venous thromboembolism who are considered candidates for extended anticoagulant therapy, since only 3 percent of the patients were excluded because they had contraindications to long-term warfarin therapy, including a high risk of bleeding. At enrollment, close to half the patients had at least one risk factor for bleeding, and these patients had a higher frequency of major bleeding than did patients without such risk factors (1.8 vs. 0.3 episodes per 100 person-years). However, low-intensity therapy did not reduce the frequency of major bleeding in these high-risk patients (2.1 episodes per 100 person-years, vs. 1.6 episodes per 100 person-years with conventional-intensity therapy). Furthermore, because risk factors for bleeding also conferred a predisposition to thrombosis, half of all episodes of recurrent thrombosis occurred among the 23 percent of patients with risk factors for bleeding who were treated with low-intensity therapy. The previously reported rates of major bleeding of 2.0 to 3.8 episodes per 100 person-years with extended conventional-intensity therapy, cited by Huisman et al., were based on only three episodes of bleeding in one study1 and four episodes in another2 and, in the third study, included bleeding during the first three months of treatment.3
The purpose of our study was to identify the optimal intensity of extended-duration warfarin therapy; all the patients were treated for longer than 12 months and provided informed consent. Although targeting an INR of 1.75 instead of an INR of 2.5 reduces the frequency of high INR values, some high values still occur and confer a predisposition to bleeding.
Patients known to have cancer were ineligible for the study, and it does not appear that the development of new cancers influenced the main findings. No patient who had major bleeding in either group and only three patients who had recurrent thrombosis in the low-intensity group received a diagnosis of cancer during follow-up.
We doubt that low-intensity therapy is truly as effective as conventional-intensity therapy among patients who have had only one episode of venous thromboembolism. First, the overall risk of recurrent thrombosis was not lower in this subgroup of patients than among those with more than one previous episode of thrombosis. Second, the interaction term suggesting a different treatment effect according to the number of previous episodes of thrombosis was of borderline statistical significance (P=0.05) and was not statistically significant after adjustment for covariates. Consequently, we believe that the main results of the study provide the most reliable estimate of the treatment effect for all the subgroups.4
Finally, although Dr. Brotman suggests that “the jury is still out on the appropriate target INR for secondary prevention after an isolated episode” of idiopathic venous thromboembolism, we believe that on the basis of current evidence, the verdict is clear and could only be reversed by the findings of a new trial.
4 ReferencesClive Kearon, M.B., Ph.D.
Jim A. Julian, M.Math.
Jeffrey S. Ginsberg, M.D.
McMaster University, Hamilton, ON L8V 1C3, Canada1
Kearon C ,Gent M ,Hirsh J , et al. A comparison of three months of anticoagulation with extended anticoagulation for a first episode of idiopathic venous thromboembolism. N Engl J Med 1999;340:901-907[Erratum, N Engl J Med 1999;341:298.]
Full Text | Web of Science | Medline2
Agnelli G ,Prandoni P ,Santamaria MG , et al. Three months versus one year of oral anticoagulant therapy for idiopathic deep venous thrombosis. N Engl J Med 2001;345:165-169
Full Text | Web of Science | Medline3
Schulman S ,Svenungsson E ,Granqvist S . Anticardiolipin antibodies predict early recurrence of thromboembolism and death among patients with venous thromboembolism following anticoagulant therapy. Am J Med 1998;104:332-338
CrossRef | Web of Science | Medline4
Yusuf S ,Wittes J ,Probstfield J ,Tyroler HA . Analysis and interpretation of treatment effects in subgroups of patients in randomized clinical trials. JAMA 1991;266:93-98
CrossRef | Web of Science | Medline
Author/Editor Response
There are two fundamental differences between the interpretation of existing data offered by Ridker et al. and our interpretation. First, their belief is that low-intensity anticoagulation must be safer than full-intensity anticoagulation — a position that is not, however, supported by the findings of Kearon et al., in the only randomized study that was explicitly powered to detect differences in bleeding. A comparison with historical controls is not only inappropriate but also risky. Much has changed in the past 50 years, most notably the introduction of INR monitoring and quality control. Furthermore, one should realize that the observed bleeding rates were obtained in patients who had completed a three-to-six-month course of vitamin K antagonists. It is well known that a large proportion of hemorrhages occur during the first months of exposure. Finally, Ridker and colleagues believe that there is inconsistency between this and a previous study by Kearon et al.1 This is not true. In the previous study, only 79 patients who had three bleeding events were included, resulting in a 95 percent confidence interval of 0.8 to 10.7 percent for the risk of major bleeding.
The second difference concerns the duration of treatment. We argued, on the basis of published data, that the decision to continue anticoagulation therapy requires the consideration of several factors, in addition to the risk of recurrence. These factors include not only the risk of bleeding but also patients' preferences and the now well-established “catch-up phenomenon” in recurrences after discontinuation.
Careful decision analyses clearly suggest, as we stated in our editorial, that continuation of therapy is probably not beneficial for all patients. Therefore, the advice to continue it in all patients may cause harm.
1 ReferencesHarry R. Büller, M.D., Ph.D.
Academic Medical Center, 1105 AZ Amsterdam, the NetherlandsMartin H. Prins, M.D., Ph.D.
University of Maastricht, 6229 ER Maastricht, the Netherlands1
Kearon C ,Gent M ,Hirsh J , et al. A comparison of three months of anticoagulation with extended anticoagulation for a first episode of idiopathic venous thromboembolism. N Engl J Med 1999;340:901-907[Erratum, N Engl J Med 1999;341:298.]
Full Text | Web of Science | Medline
- Citing Articles (4)
Citing Articles
1
S. C. CHRISTIANSEN, W. M. LIJFERING, F. M. HELMERHORST, F. R. ROSENDAAL, S. C. CANNEGIETER. (2010) Sex difference in risk of recurrent venous thrombosis and the risk profile for a second event. Journal of Thrombosis and Haemostasis 8:10, 2159-2168
CrossRef2
Christina M. Scifres, George A. Macones. (2008) The utility of thrombophilia testing in pregnant women with thrombosis: fact or fiction?. American Journal of Obstetrics and Gynecology 199:4, 344.e1-344.e7
CrossRef3
Tracy Minichiello, Patrick F. Fogarty. (2008) Diagnosis and Management of Venous Thromboembolism. Medical Clinics of North America 92:2, 443-465
CrossRef4
M. J. Kovacs. (2004) Long-term low-dose warfarin use is effective in the prevention of recurrent venous thromboembolism: no. Journal of Thrombosis and Haemostasis 2:7, 1041-1043
CrossRef
