Mars or Venus — Is Sex a Risk Factor for Recurrent Venous Thromboembolism?
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《新英格兰医药杂志》
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In 1856 Rudolph Virchow identified three primary risk factors — commonly called Virchow's triad — for venous thromboembolism: venous stasis, hypercoagulability, and endothelial injury.1 Other risk factors have since been added to the list, and quantitative assessments now allow the classification of these factors as major (e.g., surgery) or minor (e.g., oral-contraceptive use).2 Although the patient's sex has not been implicated as an inherent risk factor for a first episode of venous thromboembolism, pregnancy and the use of estrogen-containing oral contraceptives are recognized sex-specific factors.
The identification of risk factors is pivotal in the management of a first episode of deep-vein thrombosis or pulmonary embolism. Temporary and reversible risk factors, such as recent surgery or trauma, are associated with low rates of recurrent venous thromboembolism. Accordingly, anticoagulant drugs may be safely discontinued three to six months after a thromboembolic event associated with surgery or trauma. In contrast, unprovoked or minimally provoked venous thromboembolism is far more likely to recur after secondary anticoagulant treatment is stopped.3 Approximately 1 of every 10 patients with the latter type of thromboembolism will have a recurrence during the first year after the discontinuation of secondary anticoagulation.
Preventing these recurrences poses a challenge, because prolonged anticoagulation increases the likelihood of serious bleeding complications, a risk that is far from trivial. A recent analysis showed that continuing anticoagulation beyond the first three months of therapy was associated with 2.7 major bleeding events and 0.7 intracranial hemorrhage per 100 patient-years of treatment.4 Similarly, prolonged anticoagulation after a second episode of venous thromboembolism prevents recurrence but sharply increases the risk of major bleeding complications.5 One strategy for dealing with this problem is to identify the patients at greatest risk for recurrent venous thromboembolism, for whom the benefit of prolonged anticoagulation may outweigh the risk.6
Teasing out important risk factors for recurrence is not easy, because recurrent venous thromboembolism is likely to be multifactorial. Clinical features and laboratory tests are often used to identify patients who are at particularly increased risk for recurrence. The risk of recurrence is high among patients whose initial episode of venous thromboembolism is unprovoked by a major risk factor and among those with concomitant cancer.7 Conversely, the risk is low among patients whose venous thrombosis is limited to calf veins or those in whom venous thrombosis is provoked by a major reversible risk factor, such as orthopedic surgery.
Laboratory tests showing a deficiency of antithrombin, homozygosity for factor V Leiden, or the presence of antiphospholipid antibodies also identify patients at increased risk for recurrence, whereas heterozygosity for factor V Leiden or the G20210A prothrombin-gene mutation does not appear to increase the risk of recurrence after the initial treatment of unprovoked venous thromboembolism.8,9 The high cost and low yield of multiple laboratory tests for thrombophilia make the identification of a global test of hemostasis a particularly attractive goal. Recent work suggests that measurement of D-dimer three weeks after the discontinuation of oral anticoagulant therapy can identify patients at low risk for recurrence.10,11
Our current understanding of venous thromboembolism provides a foundation on which to view the finding reported by Kyrle and colleagues in this issue of the Journal that the sex of a patient influences the risk of recurrence.12 Kyrle et al. followed men and women who had stopped taking oral anticoagulant drugs prescribed for a first episode of unprovoked ("spontaneous") venous thromboembolism. All patients received initial treatment with unfractionated heparin or low-molecular-weight heparin. Secondary treatment with oral anticoagulants was maintained for slightly less than one year, and the patients were observed for an average of three years. The authors found that men were more likely than women to have recurrent venous thromboembolic disease. The difference in recurrence rates was substantial: one of every five men had a recurrence, whereas only 6 percent of women had recurrences. At five years, the cumulative probability of recurrence was 30.7 percent among men, as compared with 8.5 percent among women. Interestingly, a recent study of the effects of ximelagatran, a direct inhibitor of thrombin, has also suggested that female sex confers a reduced risk of recurrence.13
The importance of the observation by Kyrle et al. that men were more likely than women to have recurrent venous thromboembolism centers on the authors' ability to control for confounding variables. In this regard, the results of the study are robust and the study has few weaknesses. The investigators excluded patients with major risk factors for recurrence: previous venous thromboembolism; active cancer; pregnancy; a deficiency of antithrombin, protein C, or protein S; or the presence of a lupus anticoagulant. Furthermore, they enlisted an adjudication committee of independent clinicians and radiologists to establish and apply objective tests and clear definitions to confirm that venous thromboembolism had recurred.
However, the study has potential weaknesses. The risk of venous thromboembolism increases exponentially with increasing age,14 and the men in this study were older than the women at the time of the index episode of venous thromboembolism, making the investigators' method of adjusting for this difference critical to their analysis. In addition, the adjudication committee was not blinded to the sex of the patients, although there is no reason to suppose that bias in the adjudication of events would account for the findings. More important, the investigators do not provide data with respect to the use of oral contraceptives or estrogens for hormone replacement after the index episode of venous thromboembolism. Accordingly, the discontinuation of these medications may have lowered the risk of recurrent thromboembolism in some of the women but not the men. This factor does not appear to explain the results, however, since the risk of recurrent thromboembolism was still greater for men than for women who were not taking hormone replacements. Another possible weakness is that the study depended on the patients' reporting of symptoms to one of the thrombosis centers — were women simply less likely to be evaluated for symptoms suggestive of recurrent venous thromboembolism?
Decisions regarding the duration of anticoagulant treatment remain in the domain of the treating physician and the patient. They must weigh the relative risks of continued anticoagulation, the discomfort and costs associated with the use of oral anticoagulants, and the risks of withdrawing anticoagulants. Physicians should ensure the adequacy of initial and secondary anticoagulant treatment, because this measure lowers the risk of recurrence. In general, secondary anticoagulation should maintain the international normalized ratio between 2.0 and 3.0.6 Finally, at least six months of secondary anticoagulation should be provided for those at increased risk for recurrent venous thromboembolism (those with an unprovoked first episode of deep-vein thrombosis), and anticoagulants should be discontinued after three to six months in patients with a low risk of recurrent venous thromboembolism (those with provoked venous thromboembolism).
Can we conclude from the findings of Kyrle et al. that the risk of recurrent venous thromboembolism is higher among men than women? As the authors themselves point out, "Independent confirmation of our findings is required before they can be translated into routine clinical practice." We agree. Nevertheless, their finding that male sex may be a major risk for recurrent thrombosis provides a new focus for future studies that seek to clarify the risks and benefits of prolonged anticoagulation in specific subgroups of patients with venous thromboembolic disease.
Source Information
From the Pulmonary/Critical Care Division, Departments of Internal Medicine, LDS Hospital and University of Utah School of Medicine, Salt Lake City (C.G.E.); and the Division of Pulmonary and Critical Care Medicine, University of California, San Diego, La Jolla (L.J.R.).
References
Phlogose und thrombose in Gef?sssystem. In: Virchow R. Gesammelte Abhandlungen zur Wissenschaftlichen Medicin. Berlin: Verlag von Max Hirsch, 1862:458.
British Thoracic Society Standards of Care Committee Pulmonary Embolism Guideline Development Group. British Thoracic Society guidelines for the management of suspected acute pulmonary embolism. Thorax 2003;58:470-483.
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.
Linkins LA, Choi PT, Douketis JD. Clinical impact of bleeding in patients taking oral anticoagulant therapy for venous thromboembolism: a meta-analysis. Ann Intern Med 2003;139:893-900.
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.
Büller HR, Prins MH. Secondary prophylaxis with warfarin for venous thromboembolism. N Engl J Med 2003;349:702-704.
Hansson PO, Sorbo J, Eriksson H. Recurrent venous thromboembolism after deep vein thrombosis: incidence and risk factors. Arch Intern Med 2000;160:769-774.
Ridker PM, Goldhaber SZ, Danielson E, et al. Long-term, low-intensity warfarin therapy for prevention of recurrent venous thromboembolism. N Engl J Med 2003;348:1425-1434.
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.
Eichinger S, Minar E, Bialonczyk C, et al. D-dimer levels and risk of recurrent venous thromboembolism. JAMA 2003;290:1071-1074.
Palareti G, Legnani C, Cosmi B, et al. Risk of venous thromboembolism recurrence: high negative predictive value of D-dimer performed after oral anticoagulation is stopped. Thromb Haemost 2002;87:7-12.
Kyrle PA, Minar E, Bialonczyk C, Hirschl M, Weltermann A, Eichinger S. The risk of recurrent venous thromboembolism in men and women. N Engl J Med 2004;350:2558-2563.
Schulman S, W?hlander K, Lundstr?m T, Clason SB, Eriksson H. Secondary prevention of venous thromboembolism with the oral direct thrombin inhibitor ximelagatran. N Engl J Med 2003;349:1713-1721.
Silverstein MD, Heit JA, Mohr DN, et al. Trends in the incidence of deep vein thrombosis and pulmonary embolism. Arch Intern Med 1998;158:585-593.(C. Gregory Elliott, M.D.,)
In 1856 Rudolph Virchow identified three primary risk factors — commonly called Virchow's triad — for venous thromboembolism: venous stasis, hypercoagulability, and endothelial injury.1 Other risk factors have since been added to the list, and quantitative assessments now allow the classification of these factors as major (e.g., surgery) or minor (e.g., oral-contraceptive use).2 Although the patient's sex has not been implicated as an inherent risk factor for a first episode of venous thromboembolism, pregnancy and the use of estrogen-containing oral contraceptives are recognized sex-specific factors.
The identification of risk factors is pivotal in the management of a first episode of deep-vein thrombosis or pulmonary embolism. Temporary and reversible risk factors, such as recent surgery or trauma, are associated with low rates of recurrent venous thromboembolism. Accordingly, anticoagulant drugs may be safely discontinued three to six months after a thromboembolic event associated with surgery or trauma. In contrast, unprovoked or minimally provoked venous thromboembolism is far more likely to recur after secondary anticoagulant treatment is stopped.3 Approximately 1 of every 10 patients with the latter type of thromboembolism will have a recurrence during the first year after the discontinuation of secondary anticoagulation.
Preventing these recurrences poses a challenge, because prolonged anticoagulation increases the likelihood of serious bleeding complications, a risk that is far from trivial. A recent analysis showed that continuing anticoagulation beyond the first three months of therapy was associated with 2.7 major bleeding events and 0.7 intracranial hemorrhage per 100 patient-years of treatment.4 Similarly, prolonged anticoagulation after a second episode of venous thromboembolism prevents recurrence but sharply increases the risk of major bleeding complications.5 One strategy for dealing with this problem is to identify the patients at greatest risk for recurrent venous thromboembolism, for whom the benefit of prolonged anticoagulation may outweigh the risk.6
Teasing out important risk factors for recurrence is not easy, because recurrent venous thromboembolism is likely to be multifactorial. Clinical features and laboratory tests are often used to identify patients who are at particularly increased risk for recurrence. The risk of recurrence is high among patients whose initial episode of venous thromboembolism is unprovoked by a major risk factor and among those with concomitant cancer.7 Conversely, the risk is low among patients whose venous thrombosis is limited to calf veins or those in whom venous thrombosis is provoked by a major reversible risk factor, such as orthopedic surgery.
Laboratory tests showing a deficiency of antithrombin, homozygosity for factor V Leiden, or the presence of antiphospholipid antibodies also identify patients at increased risk for recurrence, whereas heterozygosity for factor V Leiden or the G20210A prothrombin-gene mutation does not appear to increase the risk of recurrence after the initial treatment of unprovoked venous thromboembolism.8,9 The high cost and low yield of multiple laboratory tests for thrombophilia make the identification of a global test of hemostasis a particularly attractive goal. Recent work suggests that measurement of D-dimer three weeks after the discontinuation of oral anticoagulant therapy can identify patients at low risk for recurrence.10,11
Our current understanding of venous thromboembolism provides a foundation on which to view the finding reported by Kyrle and colleagues in this issue of the Journal that the sex of a patient influences the risk of recurrence.12 Kyrle et al. followed men and women who had stopped taking oral anticoagulant drugs prescribed for a first episode of unprovoked ("spontaneous") venous thromboembolism. All patients received initial treatment with unfractionated heparin or low-molecular-weight heparin. Secondary treatment with oral anticoagulants was maintained for slightly less than one year, and the patients were observed for an average of three years. The authors found that men were more likely than women to have recurrent venous thromboembolic disease. The difference in recurrence rates was substantial: one of every five men had a recurrence, whereas only 6 percent of women had recurrences. At five years, the cumulative probability of recurrence was 30.7 percent among men, as compared with 8.5 percent among women. Interestingly, a recent study of the effects of ximelagatran, a direct inhibitor of thrombin, has also suggested that female sex confers a reduced risk of recurrence.13
The importance of the observation by Kyrle et al. that men were more likely than women to have recurrent venous thromboembolism centers on the authors' ability to control for confounding variables. In this regard, the results of the study are robust and the study has few weaknesses. The investigators excluded patients with major risk factors for recurrence: previous venous thromboembolism; active cancer; pregnancy; a deficiency of antithrombin, protein C, or protein S; or the presence of a lupus anticoagulant. Furthermore, they enlisted an adjudication committee of independent clinicians and radiologists to establish and apply objective tests and clear definitions to confirm that venous thromboembolism had recurred.
However, the study has potential weaknesses. The risk of venous thromboembolism increases exponentially with increasing age,14 and the men in this study were older than the women at the time of the index episode of venous thromboembolism, making the investigators' method of adjusting for this difference critical to their analysis. In addition, the adjudication committee was not blinded to the sex of the patients, although there is no reason to suppose that bias in the adjudication of events would account for the findings. More important, the investigators do not provide data with respect to the use of oral contraceptives or estrogens for hormone replacement after the index episode of venous thromboembolism. Accordingly, the discontinuation of these medications may have lowered the risk of recurrent thromboembolism in some of the women but not the men. This factor does not appear to explain the results, however, since the risk of recurrent thromboembolism was still greater for men than for women who were not taking hormone replacements. Another possible weakness is that the study depended on the patients' reporting of symptoms to one of the thrombosis centers — were women simply less likely to be evaluated for symptoms suggestive of recurrent venous thromboembolism?
Decisions regarding the duration of anticoagulant treatment remain in the domain of the treating physician and the patient. They must weigh the relative risks of continued anticoagulation, the discomfort and costs associated with the use of oral anticoagulants, and the risks of withdrawing anticoagulants. Physicians should ensure the adequacy of initial and secondary anticoagulant treatment, because this measure lowers the risk of recurrence. In general, secondary anticoagulation should maintain the international normalized ratio between 2.0 and 3.0.6 Finally, at least six months of secondary anticoagulation should be provided for those at increased risk for recurrent venous thromboembolism (those with an unprovoked first episode of deep-vein thrombosis), and anticoagulants should be discontinued after three to six months in patients with a low risk of recurrent venous thromboembolism (those with provoked venous thromboembolism).
Can we conclude from the findings of Kyrle et al. that the risk of recurrent venous thromboembolism is higher among men than women? As the authors themselves point out, "Independent confirmation of our findings is required before they can be translated into routine clinical practice." We agree. Nevertheless, their finding that male sex may be a major risk for recurrent thrombosis provides a new focus for future studies that seek to clarify the risks and benefits of prolonged anticoagulation in specific subgroups of patients with venous thromboembolic disease.
Source Information
From the Pulmonary/Critical Care Division, Departments of Internal Medicine, LDS Hospital and University of Utah School of Medicine, Salt Lake City (C.G.E.); and the Division of Pulmonary and Critical Care Medicine, University of California, San Diego, La Jolla (L.J.R.).
References
Phlogose und thrombose in Gef?sssystem. In: Virchow R. Gesammelte Abhandlungen zur Wissenschaftlichen Medicin. Berlin: Verlag von Max Hirsch, 1862:458.
British Thoracic Society Standards of Care Committee Pulmonary Embolism Guideline Development Group. British Thoracic Society guidelines for the management of suspected acute pulmonary embolism. Thorax 2003;58:470-483.
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.
Linkins LA, Choi PT, Douketis JD. Clinical impact of bleeding in patients taking oral anticoagulant therapy for venous thromboembolism: a meta-analysis. Ann Intern Med 2003;139:893-900.
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.
Büller HR, Prins MH. Secondary prophylaxis with warfarin for venous thromboembolism. N Engl J Med 2003;349:702-704.
Hansson PO, Sorbo J, Eriksson H. Recurrent venous thromboembolism after deep vein thrombosis: incidence and risk factors. Arch Intern Med 2000;160:769-774.
Ridker PM, Goldhaber SZ, Danielson E, et al. Long-term, low-intensity warfarin therapy for prevention of recurrent venous thromboembolism. N Engl J Med 2003;348:1425-1434.
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.
Eichinger S, Minar E, Bialonczyk C, et al. D-dimer levels and risk of recurrent venous thromboembolism. JAMA 2003;290:1071-1074.
Palareti G, Legnani C, Cosmi B, et al. Risk of venous thromboembolism recurrence: high negative predictive value of D-dimer performed after oral anticoagulation is stopped. Thromb Haemost 2002;87:7-12.
Kyrle PA, Minar E, Bialonczyk C, Hirschl M, Weltermann A, Eichinger S. The risk of recurrent venous thromboembolism in men and women. N Engl J Med 2004;350:2558-2563.
Schulman S, W?hlander K, Lundstr?m T, Clason SB, Eriksson H. Secondary prevention of venous thromboembolism with the oral direct thrombin inhibitor ximelagatran. N Engl J Med 2003;349:1713-1721.
Silverstein MD, Heit JA, Mohr DN, et al. Trends in the incidence of deep vein thrombosis and pulmonary embolism. Arch Intern Med 1998;158:585-593.(C. Gregory Elliott, M.D.,)