Recurrent Venous Thromboembolism in Men and Women
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《新英格兰医药杂志》
To the Editor: Kyrle et al. (June 17 issue)1 found that the risk of recurrent venous thromboembolism is higher among men than among women. This finding could influence the management of secondary prophylaxis against venous thromboembolism.
We analyzed the effect of sex on recurrent venous thromboembolism among patients who had had a first episode of idiopathic proximal deep-vein thrombosis or pulmonary embolism and who had been included in our previous studies.2,3 The comparison between our results and those presented by Kyrle et al. is shown in Table 1. In our population of patients with proximal idiopathic deep-vein thrombosis or pulmonary embolism, we could not find a difference in the rate of recurrence between men and women. It should be noted that in the study by Kyrle et al., a substantial proportion of the patients had distal thrombosis, which was more common among the women than among the men and which is known to be associated with a lower risk of recurrence than is proximal thrombosis.4,5 Therefore, in the absence of further information, we do not recommend that women be treated differently from men in terms of the prevention of recurrent venous thromboembolism.
Table 1. Sex and the Rate of Recurrence of Venous Thromboembolism.
Giancarlo Agnelli, M.D.
Cecilia Becattini, M.D.
University of Perugia
06126 Perugia, Italy
agnellig@unipg.it
Paolo Prandoni, Ph.D.
University of Padua
35100 Padua, Italy
References
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.
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.
Agnelli G, Prandoni P, Becattini C, et al. Extended oral anticoagulant therapy after a first episode of pulmonary embolism. Ann Intern Med 2003;139:19-25.
Schulman R, Rhedin AS, 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.
Pinede L, Ninet J, Duhaut P, et al. Comparison of 3 and 6 months of oral anticoagulant therapy after a first episode of proximal deep vein thrombosis or pulmonary embolism and comparison of 6 and 12 weeks of therapy after isolated calf deep vein thrombosis. Circulation 2001;103:2453-2460.
To the Editor: Kyrle et al. report an increased risk of recurrent venous thromboembolism among men after the discontinuation of antithrombotic therapy. The Registro Informatizado de Enfermedad Tromboembolica Espa?ola (RIETE) is a multicenter, observational registry of consecutively enrolled patients with symptomatic, objectively confirmed, acute venous thromboembolism.1,2,3,4 We analyzed data from RIETE to compare the rate of recurrence during the first three months of therapy between men and women. Each episode of clinically suspected recurrent venous thromboembolism was documented by objective methods.
As of January 2004, 6361 patients with venous thromboembolism had been enrolled at 94 participating hospitals in Spain. During the study period, 115 of 3169 men (3.6 percent) and 77 of 3192 women (2.4 percent) had a recurrence (odds ratio, 1.50; 95 percent confidence interval, 1.13 to 1.99). Their mean age was 64 and 68 years, respectively. After adjustment for confounding variables (age; the presence or absence of pulmonary embolism, cancer, surgery, immobility, known thrombophilia, and previous venous thromboembolism; the use or nonuse of antithrombotic medication and the dose of any such medication; and the use or nonuse of a vena cava filter), the adjusted odds ratio was 1.43 (95 percent confidence interval, 1.04 to 1.97) (Figure 1). In conclusion, our data support the hypothesis that men are at increased risk for recurrent venous thromboembolism, both during and after antithrombotic treatment.
Figure 1. Kaplan–Meier Estimates of the Probability of the Recurrence of Venous Thromboembolism, According to Sex.
Statistical significance was assessed with use of the log-rank test.
José A. Nieto, Ph.D.
Hospital Virgen de la Luz
16002 Cuenca, Spain
joseanietor@terra.es
Manuel Monreal, Ph.D.
Hospital Universitari German Trias i Pujol
08916 Badalona, Spain
for the RIETE Investigators
The RIETE Investigators report having received financial support from Aventis Pharma.
References
Arcelus JI, Caprini JA, Monreal M, Suárez C, González-Fajardo J. The management and outcome of acute venous thromboembolism: a prospective registry including 4011 patients. J Vasc Surg 2003;38:916-922.
Monreal M, Suárez C, González-Fajardo JA, et al. Management of patients with acute venous thromboembolism: findings from the RIETE Registry. Pathophysiol Haemost Thromb (in press).
Monreal M, López L, Montero M, González-Fajardo JA, Arcelus JI, Caprini JA. Venous thromboembolism treatment in the elderly: findings from the RIETE Registry. Blood 2003;102:166a-166a. abstract.
Monreal M, Kakkar AK, Caprini JA, et al. Is the natural history of venous thromboembolism different in surgical and non-surgical patients? Findings from the RIETE Registry. Blood 2003;102:112a-112a. abstract.
To the Editor: In their prospective study of patients with an initial episode of spontaneous venous thromboembolism, Kyrle et al. found that men, as compared with women, had 3.6 times the risk of recurrent venous thromboembolism, and they concluded that sex is a major determinant of recurrence. However, the authors provide no details regarding the clinical context of the recurrences. Since about 50 percent of cases of venous thromboembolism occur as a result of acquired clinical risk factors,1 the apparent association between male sex and recurrence may reflect confounding by clinical risk factors that are potent precipitants of venous thromboembolism. For example, men are more likely than women to have a fracture or trauma or to undergo knee surgery, and each of these factors confers at least a 10-fold risk of venous thromboembolism.2 Even a small imbalance between the sexes in terms of exposure to clinical risk factors could be manifested as an apparently increased risk of venous thromboembolism among men. Can Kyrle et al. provide sex-stratified data on the prevalence of clinical risk factors among patients who did and did not have recurrences and a relative risk for men after adjustment for such risk factors?
Susan R. Kahn, M.D.
Sir Mortimer B. Davis Jewish General Hospital
Montreal, QC H3T 1E2, Canada
References
Cogo A, Bernardi E, Prandoni P, et al. Acquired risk factors for deep-vein thrombosis in symptomatic outpatients. Arch Intern Med 1994;154:164-168.
Anderson FA Jr, Spencer FA. Risk factors for venous thromboembolism. Circulation 2003;107:Suppl 1:I-9.
To the Editor: Kyrle et al. make no mention of a temporal variation in recurrent venous thromboembolism. Both deep-vein thrombosis and pulmonary embolism increased in prevalence during the winter.1,2 When we analyzed subgroups according to sex, the prevalence of deep-vein thrombosis, but not pulmonary embolism, had a significant peak during the winter among women.1,2 It would be interesting to determine whether a seasonal variation exists for recurrences as well.
Benedetta Boari, M.D.
University of Ferrara
I-44100 Ferrara, Italy
Raffaella Salmi, M.D.
St. Anna General Hospital of Ferrara
I-44100 Ferrara, Italy
Roberto Manfredini, M.D.
University of Ferrara
I-44100 Ferrara, Italy
References
Gallerani M, Boari B, de Toma D, Salmi R, Manfredini R. Seasonal variation in the occurrence of deep vein thrombosis. Med Sci Monit 2004;10:191-196.
Manfredini R, Gallerani B, Boari B, Salmi R, Mehta RH. Seasonal variation in onset of pulmonary embolism is independent of patients' underlying risk comorbid conditions. Clin Appl Thromb Hemost 2004;10:39-43.
To the Editor: Kyrle et al. do not mention plasma homocysteine levels, increases in which are well known to be a risk factor for venous thromboembolism and its recurrence.1,2,3 Plasma homocysteine levels are higher in men than in women and increase with age, especially in women after menopause. We believe that homocysteine levels should be regarded as one of the variables that account for the findings presented in the article by Kyrle et al.
Hiroyuki Morita, M.D., Ph.D.
Ryozo Nagai, M.D., Ph.D.
University of Tokyo
Tokyo 113-8655, Japan
hmrt-tky@umin.ac.jp
References
den Heijer M, Koster T, Blom HJ, et al. Hyperhomocysteinemia as a risk factor for deep-vein thrombosis. N Engl J Med 1996;334:759-762.
Langman LJ, Ray JG, Evrovski J, Yeo E, Cole DE. Hyperhomocyst(e)inemia and the increased risk of venous thromboembolism: more evidence from a case-control study. Arch Intern Med 2000;160:961-964.
Eichinger S, Stumpflen A, Hirschl M, et al. Hyperhomocysteinemia is a risk factor of recurrent venous thromboembolism. Thromb Haemost 1998;80:566-569.
To the Editor: Of the 826 patients in the study by Kyrle et al., 102 (74 men and 28 women) were judged to have recurrent venous thromboembolism, but 451 patients (sex unspecified) had been excluded before the start of the trial because of previous episodes of venous thromboembolism. A small bias in such a large excluded group can have a large effect on the rates among those included. Moreover, the population studied was much younger than those described in other reports1,2: the mean age of the women fell close to or within childbearing age, an age group in which a greater proportion of women than men will have had previous venous thromboembolism.
It is credible that a disproportionate number of women with a high risk of recurrence were excluded.
David J. Ross, M.Sc., M.A.
St. Richard's Hospital
Chichester PO19 4SE, United Kingdom
david.ross@rws-tr.nhs.uk
References
Silverstein MD, Heit JA, Mohr DN, Petterson TM, O'Fallon MW, Melton LJ III. Trends in the incidence of deep vein thrombosis and pulmonary embolism: a 25-year population-based study. Arch Intern Med 1998;158:585-593.
Nordstrom M, Lindblad B, Bergqvist D, Kjellstrom T. A prospective study of the incidence of deep-vein thrombosis within a defined urban population. J Intern Med 1992;232:155-160.
The authors reply: Agnelli et al. speculate that the higher risk of recurrent venous thromboembolism among men than among women in our study may have resulted from the inclusion of a relatively large number of women with distal thrombosis. We therefore recalculated the risk of recurrence among men and women after excluding patients with distal thrombosis or thrombosis in the axillary veins. In the remaining 633 patients with proximal thrombosis, pulmonary embolism, or both, the relative risk of recurrence was 3.6 among men as compared with women (95 percent confidence interval, 2.2 to 6.0; P<0.001). We also adjusted for the site of thrombosis and found a relative risk of recurrent venous thrombosis of 3.6 among men (95 percent confidence interval, 2.2 to 5.7; P<0.001). Therefore, the discrepancy between our study and the Italian study cannot be explained by the inclusion of patients with thrombosis in the distal veins of the leg.
Our patients received rigorous thromboprophylaxis with low-dose heparin to prevent recurrent venous thrombosis related to exposure to circumstantial risk factors. Consequently, the majority of recurrences (94 of 108 ) occurred spontaneously, and only eight patients had recurrent venous thrombosis related to surgery (in three patients), trauma (in three patients), or prolonged bed rest (in two patients). The number of recurrences was not large enough for us to investigate reliably whether the risk of recurrent venous thromboembolism varies seasonally. According to a preliminary analysis, the risk of recurrence did not increase during winter in either men or women.
We agree with Drs. Morita and Nagai that hyperhomocysteinemia is an important risk factor for recurrent venous thromboembolism. We therefore recalculated the risk of recurrence among men and women after adjustment for elevated homocysteine levels and found that the risk of recurrence among men remained unchanged (relative risk, 3.9 ; P<0.001).
Patients who have had more than one episode of venous thrombosis are at risk for recurrence.1 Thus, a large proportion of them received indefinite oral anticoagulation. Considering the high risk of recurrence among men, the inclusion of patients who have had more than one event would probably further increase the difference between men and women in the rates of recurrent thrombosis. We agree with Mr. Ross that the mean age of our study population was relatively low. However, when we excluded patients younger than 50 years of age from the analysis, the risk of recurrent venous thrombosis was still substantially higher among men than among women (relative risk, 2.8 ; P<0.002).
Paul A. Kyrle, M.D.
Sabine Eichinger, M.D.
Ansgar Weltermann, M.D.
Medical University of Vienna
A-1090 Vienna, Austria
paul.kyrle@meduniwien.ac.at
References
Schulman S, Granqvist S, Holmstr?m M, et al. The duration of oral anticoagulant therapy after a second episode of venous thromboembolism. N Engl J Med 1997;336:393-398.
We analyzed the effect of sex on recurrent venous thromboembolism among patients who had had a first episode of idiopathic proximal deep-vein thrombosis or pulmonary embolism and who had been included in our previous studies.2,3 The comparison between our results and those presented by Kyrle et al. is shown in Table 1. In our population of patients with proximal idiopathic deep-vein thrombosis or pulmonary embolism, we could not find a difference in the rate of recurrence between men and women. It should be noted that in the study by Kyrle et al., a substantial proportion of the patients had distal thrombosis, which was more common among the women than among the men and which is known to be associated with a lower risk of recurrence than is proximal thrombosis.4,5 Therefore, in the absence of further information, we do not recommend that women be treated differently from men in terms of the prevention of recurrent venous thromboembolism.
Table 1. Sex and the Rate of Recurrence of Venous Thromboembolism.
Giancarlo Agnelli, M.D.
Cecilia Becattini, M.D.
University of Perugia
06126 Perugia, Italy
agnellig@unipg.it
Paolo Prandoni, Ph.D.
University of Padua
35100 Padua, Italy
References
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.
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.
Agnelli G, Prandoni P, Becattini C, et al. Extended oral anticoagulant therapy after a first episode of pulmonary embolism. Ann Intern Med 2003;139:19-25.
Schulman R, Rhedin AS, 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.
Pinede L, Ninet J, Duhaut P, et al. Comparison of 3 and 6 months of oral anticoagulant therapy after a first episode of proximal deep vein thrombosis or pulmonary embolism and comparison of 6 and 12 weeks of therapy after isolated calf deep vein thrombosis. Circulation 2001;103:2453-2460.
To the Editor: Kyrle et al. report an increased risk of recurrent venous thromboembolism among men after the discontinuation of antithrombotic therapy. The Registro Informatizado de Enfermedad Tromboembolica Espa?ola (RIETE) is a multicenter, observational registry of consecutively enrolled patients with symptomatic, objectively confirmed, acute venous thromboembolism.1,2,3,4 We analyzed data from RIETE to compare the rate of recurrence during the first three months of therapy between men and women. Each episode of clinically suspected recurrent venous thromboembolism was documented by objective methods.
As of January 2004, 6361 patients with venous thromboembolism had been enrolled at 94 participating hospitals in Spain. During the study period, 115 of 3169 men (3.6 percent) and 77 of 3192 women (2.4 percent) had a recurrence (odds ratio, 1.50; 95 percent confidence interval, 1.13 to 1.99). Their mean age was 64 and 68 years, respectively. After adjustment for confounding variables (age; the presence or absence of pulmonary embolism, cancer, surgery, immobility, known thrombophilia, and previous venous thromboembolism; the use or nonuse of antithrombotic medication and the dose of any such medication; and the use or nonuse of a vena cava filter), the adjusted odds ratio was 1.43 (95 percent confidence interval, 1.04 to 1.97) (Figure 1). In conclusion, our data support the hypothesis that men are at increased risk for recurrent venous thromboembolism, both during and after antithrombotic treatment.
Figure 1. Kaplan–Meier Estimates of the Probability of the Recurrence of Venous Thromboembolism, According to Sex.
Statistical significance was assessed with use of the log-rank test.
José A. Nieto, Ph.D.
Hospital Virgen de la Luz
16002 Cuenca, Spain
joseanietor@terra.es
Manuel Monreal, Ph.D.
Hospital Universitari German Trias i Pujol
08916 Badalona, Spain
for the RIETE Investigators
The RIETE Investigators report having received financial support from Aventis Pharma.
References
Arcelus JI, Caprini JA, Monreal M, Suárez C, González-Fajardo J. The management and outcome of acute venous thromboembolism: a prospective registry including 4011 patients. J Vasc Surg 2003;38:916-922.
Monreal M, Suárez C, González-Fajardo JA, et al. Management of patients with acute venous thromboembolism: findings from the RIETE Registry. Pathophysiol Haemost Thromb (in press).
Monreal M, López L, Montero M, González-Fajardo JA, Arcelus JI, Caprini JA. Venous thromboembolism treatment in the elderly: findings from the RIETE Registry. Blood 2003;102:166a-166a. abstract.
Monreal M, Kakkar AK, Caprini JA, et al. Is the natural history of venous thromboembolism different in surgical and non-surgical patients? Findings from the RIETE Registry. Blood 2003;102:112a-112a. abstract.
To the Editor: In their prospective study of patients with an initial episode of spontaneous venous thromboembolism, Kyrle et al. found that men, as compared with women, had 3.6 times the risk of recurrent venous thromboembolism, and they concluded that sex is a major determinant of recurrence. However, the authors provide no details regarding the clinical context of the recurrences. Since about 50 percent of cases of venous thromboembolism occur as a result of acquired clinical risk factors,1 the apparent association between male sex and recurrence may reflect confounding by clinical risk factors that are potent precipitants of venous thromboembolism. For example, men are more likely than women to have a fracture or trauma or to undergo knee surgery, and each of these factors confers at least a 10-fold risk of venous thromboembolism.2 Even a small imbalance between the sexes in terms of exposure to clinical risk factors could be manifested as an apparently increased risk of venous thromboembolism among men. Can Kyrle et al. provide sex-stratified data on the prevalence of clinical risk factors among patients who did and did not have recurrences and a relative risk for men after adjustment for such risk factors?
Susan R. Kahn, M.D.
Sir Mortimer B. Davis Jewish General Hospital
Montreal, QC H3T 1E2, Canada
References
Cogo A, Bernardi E, Prandoni P, et al. Acquired risk factors for deep-vein thrombosis in symptomatic outpatients. Arch Intern Med 1994;154:164-168.
Anderson FA Jr, Spencer FA. Risk factors for venous thromboembolism. Circulation 2003;107:Suppl 1:I-9.
To the Editor: Kyrle et al. make no mention of a temporal variation in recurrent venous thromboembolism. Both deep-vein thrombosis and pulmonary embolism increased in prevalence during the winter.1,2 When we analyzed subgroups according to sex, the prevalence of deep-vein thrombosis, but not pulmonary embolism, had a significant peak during the winter among women.1,2 It would be interesting to determine whether a seasonal variation exists for recurrences as well.
Benedetta Boari, M.D.
University of Ferrara
I-44100 Ferrara, Italy
Raffaella Salmi, M.D.
St. Anna General Hospital of Ferrara
I-44100 Ferrara, Italy
Roberto Manfredini, M.D.
University of Ferrara
I-44100 Ferrara, Italy
References
Gallerani M, Boari B, de Toma D, Salmi R, Manfredini R. Seasonal variation in the occurrence of deep vein thrombosis. Med Sci Monit 2004;10:191-196.
Manfredini R, Gallerani B, Boari B, Salmi R, Mehta RH. Seasonal variation in onset of pulmonary embolism is independent of patients' underlying risk comorbid conditions. Clin Appl Thromb Hemost 2004;10:39-43.
To the Editor: Kyrle et al. do not mention plasma homocysteine levels, increases in which are well known to be a risk factor for venous thromboembolism and its recurrence.1,2,3 Plasma homocysteine levels are higher in men than in women and increase with age, especially in women after menopause. We believe that homocysteine levels should be regarded as one of the variables that account for the findings presented in the article by Kyrle et al.
Hiroyuki Morita, M.D., Ph.D.
Ryozo Nagai, M.D., Ph.D.
University of Tokyo
Tokyo 113-8655, Japan
hmrt-tky@umin.ac.jp
References
den Heijer M, Koster T, Blom HJ, et al. Hyperhomocysteinemia as a risk factor for deep-vein thrombosis. N Engl J Med 1996;334:759-762.
Langman LJ, Ray JG, Evrovski J, Yeo E, Cole DE. Hyperhomocyst(e)inemia and the increased risk of venous thromboembolism: more evidence from a case-control study. Arch Intern Med 2000;160:961-964.
Eichinger S, Stumpflen A, Hirschl M, et al. Hyperhomocysteinemia is a risk factor of recurrent venous thromboembolism. Thromb Haemost 1998;80:566-569.
To the Editor: Of the 826 patients in the study by Kyrle et al., 102 (74 men and 28 women) were judged to have recurrent venous thromboembolism, but 451 patients (sex unspecified) had been excluded before the start of the trial because of previous episodes of venous thromboembolism. A small bias in such a large excluded group can have a large effect on the rates among those included. Moreover, the population studied was much younger than those described in other reports1,2: the mean age of the women fell close to or within childbearing age, an age group in which a greater proportion of women than men will have had previous venous thromboembolism.
It is credible that a disproportionate number of women with a high risk of recurrence were excluded.
David J. Ross, M.Sc., M.A.
St. Richard's Hospital
Chichester PO19 4SE, United Kingdom
david.ross@rws-tr.nhs.uk
References
Silverstein MD, Heit JA, Mohr DN, Petterson TM, O'Fallon MW, Melton LJ III. Trends in the incidence of deep vein thrombosis and pulmonary embolism: a 25-year population-based study. Arch Intern Med 1998;158:585-593.
Nordstrom M, Lindblad B, Bergqvist D, Kjellstrom T. A prospective study of the incidence of deep-vein thrombosis within a defined urban population. J Intern Med 1992;232:155-160.
The authors reply: Agnelli et al. speculate that the higher risk of recurrent venous thromboembolism among men than among women in our study may have resulted from the inclusion of a relatively large number of women with distal thrombosis. We therefore recalculated the risk of recurrence among men and women after excluding patients with distal thrombosis or thrombosis in the axillary veins. In the remaining 633 patients with proximal thrombosis, pulmonary embolism, or both, the relative risk of recurrence was 3.6 among men as compared with women (95 percent confidence interval, 2.2 to 6.0; P<0.001). We also adjusted for the site of thrombosis and found a relative risk of recurrent venous thrombosis of 3.6 among men (95 percent confidence interval, 2.2 to 5.7; P<0.001). Therefore, the discrepancy between our study and the Italian study cannot be explained by the inclusion of patients with thrombosis in the distal veins of the leg.
Our patients received rigorous thromboprophylaxis with low-dose heparin to prevent recurrent venous thrombosis related to exposure to circumstantial risk factors. Consequently, the majority of recurrences (94 of 108 ) occurred spontaneously, and only eight patients had recurrent venous thrombosis related to surgery (in three patients), trauma (in three patients), or prolonged bed rest (in two patients). The number of recurrences was not large enough for us to investigate reliably whether the risk of recurrent venous thromboembolism varies seasonally. According to a preliminary analysis, the risk of recurrence did not increase during winter in either men or women.
We agree with Drs. Morita and Nagai that hyperhomocysteinemia is an important risk factor for recurrent venous thromboembolism. We therefore recalculated the risk of recurrence among men and women after adjustment for elevated homocysteine levels and found that the risk of recurrence among men remained unchanged (relative risk, 3.9 ; P<0.001).
Patients who have had more than one episode of venous thrombosis are at risk for recurrence.1 Thus, a large proportion of them received indefinite oral anticoagulation. Considering the high risk of recurrence among men, the inclusion of patients who have had more than one event would probably further increase the difference between men and women in the rates of recurrent thrombosis. We agree with Mr. Ross that the mean age of our study population was relatively low. However, when we excluded patients younger than 50 years of age from the analysis, the risk of recurrent venous thrombosis was still substantially higher among men than among women (relative risk, 2.8 ; P<0.002).
Paul A. Kyrle, M.D.
Sabine Eichinger, M.D.
Ansgar Weltermann, M.D.
Medical University of Vienna
A-1090 Vienna, Austria
paul.kyrle@meduniwien.ac.at
References
Schulman S, Granqvist S, Holmstr?m M, et al. The duration of oral anticoagulant therapy after a second episode of venous thromboembolism. N Engl J Med 1997;336:393-398.