- Email: [email protected]
Recurrent Venous Thromboembolism in a Spanish Population
Thrombosis Research 96 (1999) 335–341
REGULAR ARTICLE
Recurrent Venous Thromboembolism in a Spanish Population: Incidence, Risk Factors, and Management in a Hospital Setting Enric Grau1, Esperanza Real1, Jose Medrano2, Emilio Pastor1 and Salvador Selfa3 Departments of 1Hematology, 2Surgery, and 3Radiology, Hospital Lluis Alcanyis, Xativa, Spain. (Received 26 January 1999 by Editor C.W. Francis; revised/accepted 9 June 1999)
Abstract The major concern in the management of venous thromboembolism is the propagation of thrombus and rethrombosis. The incidence of recurrences and the duration of oral anticoagulant therapy in these patients are still controversial. The aim of this study was to determine the incidence, timing, and outcome of further thrombotic events after an initial episode of venous thromboembolism in a hospital setting. In addition, we evaluated potential risk factors for all these outcomes. This was designed as a retrospective analysis of all patients admitted to our Center with an episode of deep vein thrombosis and/or pulmonary embolism between 1986 and 1996. The patients included in the study had to be treated with unfractionated heparin or low molecular weight heparin, followed by at least 3 months of oral anticoagulants. Natural and acquired hemostasis inhibitors were assayed in patients aged less than 50 years. A total of 290 patients with a first episode of venous thromboembolism were included in the study. A total of 33 patients (11.9%, 95% confidence interval, 7.4–14.6) had reAbbreviations: VTE, venous thromboembolism; UFH, unfractionated heparin; LMWH, low molecular weight heparin; PE, pulmonary embolism; DVT, deep vein thrombosis; APTT, activated partial prothrombin time; APC, resistance to activated protein C; CI, confidence interval. Corresponding author: Dr. Enric Grau. Department of Hematology, Hospital Lluis Alcanyis, Ctra. Xativa-Silla, km 2, 46800 Xativa, Spain. Tel. 134 (96) 228 9595; Fax: 134 (96) 228 9572; E-mail: ,[email protected]..
current episodes. The cumulative incidence of recurrent venous thromboembolism after 2, 5, and 10 years was 7.68, 10, and 12.4%, respectively. The incidence of rethrombosis was significantly higher in patients with idiopathic venous thromboembolism than in patients with secondary thrombosis. Abnormalities of hemostasis were found in 54.5% (95% confidence interval, 37.6–71.4) of the patients with recurrences and under the age of 50 years. Three of seven patients who stopped anticoagulant therapy after the second episode presented a third thrombotic event. In our study population, those patients with idiopathic venous thromboembolism seem to have an increased risk of recurrence. The second thrombotic episode occurs more frequently during the following 2 years after cessation of anticoagulation therapy. Our findings strongly support the use of long-term anticoagulant therapy in patients with recurrent venous thromboembolism. 1999 Elsevier Science Ltd. All rights reserved. Key Words: Venous thromboembolism; Rethrombosis; Incidence; Treatment; Risk factors
V
enous thromboembolism (VTE) constitutes a major health problem in developed countries. It has been estimated that VTE is responsible for more than 300,000 hospital admissions and 50,000 deaths each year in the United States [1]. The pathogenesis of VTE is multifactorial, involving acquired risk factors such as surgery, trauma, malignant disease, and genetic factors [2,3]. The standard treatment of patients with DVT
0049-3848/99 $–see front matter 1999 Elsevier Science Ltd. All rights reserved. PII S0049-3848(99)00121-8
336
E. Grau et al./Thrombosis Research 96 (1999) 335–341
and/or PE is usually an initial course (5–10 days) of unfractionated heparin (UFH) or low molecular weight heparin (LMWH), followed by oral anticoagulant therapy for 3 to 6 months [4,5]. The major concern in the management of VTE is propagation of thrombus to uninvolved segments and rethrombosis of partially occluded or recanalized venous segments. Both propagation and rethrombosis have been associated with an increased risk of PE and post-thrombotic syndrome [6,7]. The information available about the short-term and long-term incidences of recurrent VTE is still controversial [8–10]. Furthermore, the optimal duration of oral anticoagulant therapy for patients who have a first episode of thrombosis and for those who have recurrent disease leaves some degree of uncertainty [11–13]. The purpose of this study was to determine the hospital incidence, timing, and outcome of further thrombotic events after an initial episode of pulmonary embolism (PE) and/or deep vein thrombosis (DVT).
tion was obtained on possible risk factors for VTE. These included previous DVT/PE, bedrest, surgery, trauma, concurrent medical conditions such as pregnancy or infection, and malignancy. Idiopathic VTE was considered when DVT and/or PE occurred without any of these risk factors within the preceding 6 months. Secondary VTE was considered when thromboembolism occurred within 6 months of at least one of these risk factors. The definition of recurrent VTE included four distinct entities: (1) the development of new thrombi in initially involved limbs or/and PE within the 3 months of anticoagulant treatment (thrombus progression); (2) propagation of thrombus to uninvolved segments in the ipsilateral limb after completion of anticoagulant treatment; (3) the development of a contralateral DVT; and (4) PE suspected in a patient on the basis of clinical symptoms or signs and confirmed by lung scanning (showing a new perfusion defect, segmental or larger, with ventilation mismatch) after completion of anticoagulant treatment.
1. Patients and Methods
1.2. Coagulation Tests
1.1. Patients
At the end of anticoagulant treatment (at least 15 days after its completion), natural and acquired inhibitors of hemostasis were studied in all patients under the age of 50 years. Blood samples were subject to a thrombophilia screen that included prothrombin time, activated partial thromboplastin time, thrombin time, antithrombin III and protein C activity, free and total protein S, lupus anticoagulant screen [activated partial thromboplastin time (APTT) performed on a mix of four parts patient platelet-poor plasma to one part normal platelet-poor plasma, and dilute Russells’ viper venom test with platelet neutralization step], plasminogen activity, and immunoglobulin G and immunoglobulin M anticardiolipin antibody assays. Testing for resistance to activated protein C (APC resistance) was not performed in our laboratory until 1995. All patients diagnosed with recurrent VTE, even those with the first thrombotic episode before 1995, have been subsequently invited to attend for a new blood sampling and have been screened for APC resistance and hyperhomocysteinemia. Antithrombin III, protein C, and plasminogen activities were determined by automated, amidolytic techniques. Protein S antigens and
This was a retrospective analysis of all patients admitted to the Hospital Lluis Alcanyis with an episode of symptomatic PE and/or DVT between the inclusive years 1986–1996. The Hospital Lluis Alcanyis serves as a primary care referral center for patients with VTE for a community of approximately 200,000 people (1996 Census). Patients were eligible for the study if duplex ultrasonography or venography showed DVT and perfusionventilation pulmonary scintigraphy confirmed diagnosis of PE. Moreover, the patients included in the study had to be treated with UFH or LMWH for a week and oral anticoagulants for a period of at least 3 months. All patients included in the study were assessed monthly for 3 to 6 months from discharge from the first VTE until cessation of oral anticoagulant therapy. In addition, the hospital medical record of each patient was reviewed, searching all significant clinical data until 31 December 1996. All patients with recurrent VTE were reassessed in our clinical center on an outpatient basis. Each visit included history taking and physical examination. Informa-
337
E. Grau et al./Thrombosis Research 96 (1999) 335–341
Table 1. Demographic and clinical characteristics of the study population (n5290) Age (years) (median6SD) Sex (M/F) Localization DVT (without clinical PE) PE (6confirmed DVT) Known risk factors Idiopathic Secondary Bedrest Surgery Trauma Concurrent medical process Previous VTE Malignancy
61.5615.7 166/124 193 (66.6%) 97 (33.4%) 161 129 21 56 24 17 5 6
(55.5%) (44.5%) (7.2%) (19.3%) (8.3%) (5.9%) (1.7%) (2.0%)
anticardiolipin antibodies were measured by an ELISA method. APC resistance was assessed by measuring the anticoagulant response in plasma on the addition of APC (Coatest, Chromogenix, Mo¨lndal, Sweden). The results were expressed as the APC sensitivity ratio, obtained by dividing APTT plus APC by APTT minus APC. When APC sensitivity ratio was lower than 1.8, it was considered to be positive. The total homocysteine concentration was measured by high performance liquid chromatography.
1.3. Statistical Analysis Differences were investigated by means of standard x2 tests. Incidences are shown as percentage and 95% confidence intervals (CI) on the assumption that the number of events followed a Poisson distribution. The probability of recurrent VTE was estimated following the method of Kaplan-Meier.
2. Results Between 1 January 1986 and 31 December 1996, 290 patients met our criteria for VTE. The demographic and clinical characteristics of the study population are presented in Table 1. Twelve patients were excluded for the analysis of recurrent VTE because they did not receive complete anticoagulant treatment: older than 85 years (four patients) and concomitant processes (eight patients). Of the remaining 278 patients, 10 (3.6%) had bleeding
Table 2. Demographic and clinical characteristics of patients with recurrent VTE (n533) Age (years) (median6SD) (first episode) Sex (M/F) Localization First episode DVT (without clinical PE) PE (6confirmed DVT) Second episode DVT (without clinical PE) Ipsilateral Contralateral PE (6confirmed DVT) Known risk factors First episode Idiopathic Secondary Second episode Idiopathic Secondary Interval between episodes 0–2 years 2–5 years 5–10 years
57.1615.6 22/11
32 (97%) 1 (3%)
24 15 9 9
(72.7%) (45.4%) (27.3%) (27.3%)
29 (87.9%) 4 (12.1%) 28 (84.8%) 5 (15.2%) 21 (63.6%) 6 (18.2%) 6 (18.2%)
complications during anticoagulant therapy; five patients had minor hemorrhages and five patients had major bleeding episodes (two had hemarthrosis, two had gastrointestinal bleeding, and one had retroperitoneal hematoma). The thrombophilia screen was performed in all patients younger than 50 years (55 patients, 19%). Of these 55 patients, 44 did not developed recurrent VTE. None of these patients with a single VTE showed any abnormality in the thrombophilia screen. Of the 278 patients, a total of 33 (11.9%) (95% CI, 7.4–14.6) experienced one or more documented recurrent VTE. Demographic and clinical characteristics of these population of patients with recurrent VTE are presented in Table 2. None of these patients died due to the recurrent thrombotic events. Two patients were diagnosed with malignancy and both died after the second thrombotic event. Age at the time of the first VTE was similar between patients with or without recurrent VTE. In our series there were twice as many men with recurrent VTE as women (Table 2).
338
E. Grau et al./Thrombosis Research 96 (1999) 335–341
The first episode of VTE was DVT in almost all patients, and only one patient had PE. Ipsilateral DVT was the most frequent localization of rethrombosis. The incidence of PE was higher in the second episode than in the first episode. In our series none of the patients presented fatal PE (Table 2). The incidence of idiopathic thrombotic episodes was 87.9% (95% CI, 76.8–99) for first episodes and 84.8% (95% CI, 72.6–97) for second episodes in our series of patients with recurrent VTE. This incidence was statistically higher than that observed in our the study population (55.5%, 95% CI, 49.8–61.2) (p,0.001). Eight patients (24.2%) had moderate to severe post-thrombotic syndrome at the time of the second thrombotic event. Six (54.5%, 95% CI, 37.6–71.4) of the 11 patients with recurrent VTE and aged under 50 years at the time of the first episode of VTE were found to have hemostasis abnormalities: APC resistance (three), deficiency of protein C (one), deficiency of protein S (one), and lupus anticoagulant (one). Another patient, aged over 50 years, was found to have APC resistance. The majority of patients (21 patients, 63.6%, 95% CI, 47.2–80) had the second thrombotic event within the following 2 years of the first episode. The interval between episodes was longer than 2 years in 12 patients (36.4%, 95% CI, 20–52.8). Recurrent VTE was observed 10 years after the first episode in 2 patients (Table 2). Considering the study population alive during the 10 years of follow-up, the cumulative incidence of recurrent VTE after 1, 2, and 3 years was 4.67, 7.68, and 9.23%, respectively. This incidence increased to 10% after 5 years, and 12.4% after 10 years of follow-up (Figure 1). Thrombus progression was observed in three patients (1% of the study population and 9% of the patients with recurrent VTE) (two with ipsilateral thrombus progression and one with PE). All three cases showed anticoagulant levels under the therapeutic range at the time of thrombus progression. Ipsilateral DVT was the most common localization (14 patients) when rethrombosis occurred before 5 years of follow-up. In contrast PE was the most common localization (four patients) after 5 years. Of these 33 patients with a second episode of VTE, seven patients without a known hemostatic disorder stopped anticoagulant treatment for dif-
Fig. 1. Cumulative incidence of recurrent venous thromboembolism in the study population.
ferent reasons. Three of these patients presented a third thrombotic episode. The remaining 26 patients with two episodes of VTE received permanent anticoagulant treatment and only one had a third thrombotic event.
3. Discussion Our study assessed the hospital incidence of recurrent VTE in a large cohort of Spanish patients during long-term follow-up. Demographic and clinical characteristics of our patients are comparable to those in other large series of patients with VTE [14–16]. Our findings are similar to previous studies in which recurrent VTE was reported in 4 to 6% of patients treated with heparin and warfarin for 3 to 9 months, and in 6 to 7% of patients monitored for 2 years after a 3-month course of warfarin [17– 19]. Although the risk for recurrent VTE seems to persist for many years, the incidence decreases after 2 years of the first thrombotic episode. Thus, our data do not provide evidence that the risk for recurrent VTE remains high for many years as has been reported for other investigators [20,21]. Several issues complicate the interpretation of such differences between those studies. Diagnosis of recurrent VTE can be difficult, and the predefined criteria applied to its diagnosis may be different. Although patients were treated according to standard practice, there may be differences in dose intensity and duration of anticoagulant treatment. Finally, we performed a retrospective review of the inpatient medical records and cases not oc-
E. Grau et al./Thrombosis Research 96 (1999) 335–341
curring in our hospital could be missed. These limitations prevent us from suggesting guidelines for the long-term clinical care of patients with a single episode of VTE. Further prospective studies are needed to clarify the exact long-term incidence of recurrent VTE because of its implication about the duration of the anticoagulant treatment in patients with a single episode of VTE. Thrombus progression was observed in only three patients and it was clearly correlated to inadequate heparinization early in the course of therapy. Our data reaffirm the clinical importance of rapidly achieving therapeutic levels of heparin [22,23]. Therapy with LMWH has been introduced in the last 3 years in the routine clinical practice and the body of evidence indicates that LMWH has a longer half-life and a more predictable anticoagulant response to a fixed dose than does UFH [24]. Therefore, LMWH therapy might reduce the incidence of thrombus progression. The fact that almost all patients with recurrent VTE suffered DVT but not PE in the first thrombotic episode and the high incidence of ipsilateral DVT in the second and even the third thrombotic event confirms the important role of moderate to severe post-thrombotic syndrome in the development of recurrent VTE. Our data suggest that the incidence of second ipsilateral thrombosis is high in the first 2 years after cessation of the anticoagulant treatment. These findings are supported by the results of other studies showing post-thrombotic syndrome manifestations within the 2 years following the acute thrombosis in more than 80% of patients [21]. We believe that prolongation of anticoagulant treatment for at least 2 years could be considered in some patients with a single VTE and severe post-thrombotic syndrome. Our series of patients with recurrent VTE had a high incidence of idiopathic VTE episodes. In contrast, our study population showed a low incidence of idiopathic VTE. Therefore, our data indicate that idiopathic VTE is a risk factor for recurrent VTE in this Spanish population. The low incidence of idiopathic VTE in our study population is fully consistent with the results of a recent study performed among different ethnic groups in California (USA) [25]. Compared with white persons, Hispanic persons had a much lower incidence of idiopathic DVT. These differences between ethnic groups could be explained at least in part by
339
differences in the prevalence of the factor V Leiden mutation and possibly other genetic disorders [26,27]. We found hemostasis abnormalities in about 55% of patients under age 50 years with recurrent VTE at the time of the first thrombotic episode. On the other hand, we did not find any inherited or acquired inhibitor of hemostasis in those patients younger than 50 years with a single VTE. These results may be explained by the fact that in our study population only 55 patients (19%) were aged under 50 years, and of these patients only 14 had idiopathic VTE. In contrast, patients with recurrent VTE and under the age of 50 years have a high prevalence of thrombophilic abnormalities. Therefore, thrombophilia screen is highly recommended in patients with recurrent VTE, especially in those with idiopathic VTE and under the age of 50 years. Our data strongly support the use of long-term anticoagulant therapy in patients with recurrent VTE. From our point of view, cessation of anticoagulant therapy in recurrent VTE should be considered only in those patients with a high hemorrhagic risk or other major contraindications to oral anticoagulants.
References 1. Anderson FA Jr, Wheeler HB, Goldberg RJ, Hosmer DW, Patwardhan NA, Jovanovic B, Forcier A, Dalen JE. A population-based perspective of the hospital incidence and casefatality rates of deep vein thrombosis and pulmonary embolism: The Worcester DVT Study. Arch Intern Med 1991;151:933–8. 2. Kniffin WD, Baron JA, Barret J, Birkmeyer JD, Anderson FA Jr. The epidemiology of diagnosed pulmonary embolism and deep venous thrombosis in the elderly. Arch Intern Med 1994;154:861–6. 3. De Stefano V, Finazzi G, Mannucci PM. Inherited thrombophilia. Pathogenesis, clinical syndromes and management. Blood 1996;87: 3531–44. 4. Clark S. Current issues in management of thrombosis. Lancet 1995;346:113–4. 5. Ginsberg JS. Management of venous thromboembolism. N Engl J Med 1996;335:1816–28.
340
E. Grau et al./Thrombosis Research 96 (1999) 335–341
6. Meissner MH, Caps MT, Bergelin RO, Manzo RA, Strandness DE. Propagation, rethrombosis and new thrombus formation after acute deep venous thrombosis. J Vasc Surg 1995; 22:558–67. 7. Kakkar VV, Lawrence D. Hemodynamic and clinical assessment after therapy for acute deep vein thrombosis: A prospective study. Am J Surg 1985;150:54–63. 8. Hull RD, Raskob GE, Pineo GF. Subcutaneous low-molecular-weight heparin compared with continuous intravenous heparin in the treatment of proximal-vein thrombosis. N Engl J Med 1992;326:975–82. 9. Holm HA, Finnanger B, Hartmann A. Heparin treatment of deep venous thrombosis in 280 patients: Symptoms related to dosage. Acta Med Scand 1984;215:47–53. 10. Koopman MM, Buller HR, ten Cate JW. Diagnosis of recurrent deep vein thrombosis. Haemostasis 1995;25:49–57. 11. Hirsh J, Fuster V. AHA Medical/Scientific Statement. Special Report. Guide to anticoagulant therapy. Pt. 2: Oral anticoagulants. Circulation 1994;89:1469–80. 12. Schulman S, Rhedin AS, Lindmarker P, Carlsson A, Larfars G, Nicol P, Loogna E, Svensson E, Ljungberg B, Walter H. A comparison of six weeks with six months of oral anticoagulant therapy after a first episode of venous thromboembolism. Duration of Anticoagulation Trial Study Group. N Engl J Med 1995;332: 1661–5. 13. Levine MN, Hirsh J, Gent M, Turpie AG, Weitz J, Ginsberg J, Geerts W, Leclerc J, Neemeh J, Powers P, Piovella F. Optimal duration of oral anticoagulant therapy: A randomized trial comparing four weeks with three months of warfarin in patients with proximal deep vein thrombosis. Thromb Haemost 1995; 74:606–11. 14. Hull RD, Carter CJ, Jay RM, Ockelford PA, Hirsh J, Turpie AG, Zielinsky A, Gent M, Powers PJ. The diagnosis of acute, recurrent, deep-vein thrombosis: A diagnostic challenge. Circulation 1983;67:901–6. 15. Eichinger S, Stumpflen A, Hirschl M, Bialonczyk C, Herkner K, Stain M, Schneider B, Pab-
inger I, Lechner K, Kyrle PA. Hyperhomocysteinemia is a risk factor of recurrent venous thromboembolism. Thromb Haemost 1998; 80:566–9. 16. Brandjes DP, Bu¨ller HR, Heijboer H, Huisman MV, de Rijk M, Jagt H, ten Cate JW. Randomised trial of effect of compression stocking in patients with symptomatic proximal-vein thrombosis. Lancet 1997;349:759–62. 17. Hull RD, Raskob GE, Hirsh J, Jay RM, Leclerc JR, Geerts WH, Rosenbloom D, Sackett DL, Anderson C, Harrison L, Gent M. Continuous intravenous heparin compared with intermittent subcutaneous heparin in the initial treatment of proximal-vein thrombosis. N Engl J Med 1986;315:1109–14. 18. Hull RD, Delmore T, Genton E, Hirsh J, Gent M, Sackett D, Mcloughlin D, Armstrong P. Warfarin sodium versus low-dose heparin in the treatment of venous thrombosis. N Engl J Med 1979;301:855–8. 19. Huisman MV, Buller HR, ten Cate JW. Utility of impedance plethysmography in the diagnosis of recurrent deep-vein thrombosis. Arch Intern Med 1988;148:681–3. 20. Prandoni P, Lensing AW, Cogo A, Cuppini S, Villalta S, Carta M, Cattelan AM, Polistena P, Bernardi E, Prins MH. The long-term clinical course of acute deep venous thrombosis. Ann Intern Med 1996;125:1–7. 21. Prandoni P, Villalta S, Bagatella P, Rossi L, Marchiori A, Piccioli A, Bernardi E, Girolami B, Simioni P, Girolami A. The clinical course of deep-vein thrombosis. Prospective long-term follow-up of 528 symptomatic patients. Haematologica 1997;82:423–8. 22. Hull RD, Raskob GE, Brant RF, Pineo GF, Valentine KA. Relation between the time to achieve the lower limit of the APTT therapeutic range and recurrent venous thromboembolism during heparin treatment for deep vein thrombosis. Arch Intern Med 1997;157:2562–8. 23. Hirsh J, Fuster V. AHA Medical/Scientific Statement. Special Report. Guide to anticoagulant therapy. Part 1: Heparin. Circulation 1994;89:1449–68. 24. Hirsh J, Levine MN. Low molecular weight heparin. Blood 1992;79:1–17. 25. White RH, Zhou H, Romano PS. Incidence of
E. Grau et al./Thrombosis Research 96 (1999) 335–341
idiopathic deep venous thrombosis and secondary thromboembolism among ethnic groups in California. Ann Intern Med 1998;128:737–40. 26. Ridker PM, Miletich JP, Hennekens CH, Buring JE. Ethnic distribution of factor V Leiden
341
in 4047 men and women. Implications for venous thromboembolism screening. JAMA 1997; 277:1305–7. 27. Rees DC, Cox M, Clegg JB. World distribution of factor V Leiden. Lancet 1995;346:1133–4.
REGULAR ARTICLE
Recurrent Venous Thromboembolism in a Spanish Population: Incidence, Risk Factors, and Management in a Hospital Setting Enric Grau1, Esperanza Real1, Jose Medrano2, Emilio Pastor1 and Salvador Selfa3 Departments of 1Hematology, 2Surgery, and 3Radiology, Hospital Lluis Alcanyis, Xativa, Spain. (Received 26 January 1999 by Editor C.W. Francis; revised/accepted 9 June 1999)
Abstract The major concern in the management of venous thromboembolism is the propagation of thrombus and rethrombosis. The incidence of recurrences and the duration of oral anticoagulant therapy in these patients are still controversial. The aim of this study was to determine the incidence, timing, and outcome of further thrombotic events after an initial episode of venous thromboembolism in a hospital setting. In addition, we evaluated potential risk factors for all these outcomes. This was designed as a retrospective analysis of all patients admitted to our Center with an episode of deep vein thrombosis and/or pulmonary embolism between 1986 and 1996. The patients included in the study had to be treated with unfractionated heparin or low molecular weight heparin, followed by at least 3 months of oral anticoagulants. Natural and acquired hemostasis inhibitors were assayed in patients aged less than 50 years. A total of 290 patients with a first episode of venous thromboembolism were included in the study. A total of 33 patients (11.9%, 95% confidence interval, 7.4–14.6) had reAbbreviations: VTE, venous thromboembolism; UFH, unfractionated heparin; LMWH, low molecular weight heparin; PE, pulmonary embolism; DVT, deep vein thrombosis; APTT, activated partial prothrombin time; APC, resistance to activated protein C; CI, confidence interval. Corresponding author: Dr. Enric Grau. Department of Hematology, Hospital Lluis Alcanyis, Ctra. Xativa-Silla, km 2, 46800 Xativa, Spain. Tel. 134 (96) 228 9595; Fax: 134 (96) 228 9572; E-mail: ,[email protected]..
current episodes. The cumulative incidence of recurrent venous thromboembolism after 2, 5, and 10 years was 7.68, 10, and 12.4%, respectively. The incidence of rethrombosis was significantly higher in patients with idiopathic venous thromboembolism than in patients with secondary thrombosis. Abnormalities of hemostasis were found in 54.5% (95% confidence interval, 37.6–71.4) of the patients with recurrences and under the age of 50 years. Three of seven patients who stopped anticoagulant therapy after the second episode presented a third thrombotic event. In our study population, those patients with idiopathic venous thromboembolism seem to have an increased risk of recurrence. The second thrombotic episode occurs more frequently during the following 2 years after cessation of anticoagulation therapy. Our findings strongly support the use of long-term anticoagulant therapy in patients with recurrent venous thromboembolism. 1999 Elsevier Science Ltd. All rights reserved. Key Words: Venous thromboembolism; Rethrombosis; Incidence; Treatment; Risk factors
V
enous thromboembolism (VTE) constitutes a major health problem in developed countries. It has been estimated that VTE is responsible for more than 300,000 hospital admissions and 50,000 deaths each year in the United States [1]. The pathogenesis of VTE is multifactorial, involving acquired risk factors such as surgery, trauma, malignant disease, and genetic factors [2,3]. The standard treatment of patients with DVT
0049-3848/99 $–see front matter 1999 Elsevier Science Ltd. All rights reserved. PII S0049-3848(99)00121-8
336
E. Grau et al./Thrombosis Research 96 (1999) 335–341
and/or PE is usually an initial course (5–10 days) of unfractionated heparin (UFH) or low molecular weight heparin (LMWH), followed by oral anticoagulant therapy for 3 to 6 months [4,5]. The major concern in the management of VTE is propagation of thrombus to uninvolved segments and rethrombosis of partially occluded or recanalized venous segments. Both propagation and rethrombosis have been associated with an increased risk of PE and post-thrombotic syndrome [6,7]. The information available about the short-term and long-term incidences of recurrent VTE is still controversial [8–10]. Furthermore, the optimal duration of oral anticoagulant therapy for patients who have a first episode of thrombosis and for those who have recurrent disease leaves some degree of uncertainty [11–13]. The purpose of this study was to determine the hospital incidence, timing, and outcome of further thrombotic events after an initial episode of pulmonary embolism (PE) and/or deep vein thrombosis (DVT).
tion was obtained on possible risk factors for VTE. These included previous DVT/PE, bedrest, surgery, trauma, concurrent medical conditions such as pregnancy or infection, and malignancy. Idiopathic VTE was considered when DVT and/or PE occurred without any of these risk factors within the preceding 6 months. Secondary VTE was considered when thromboembolism occurred within 6 months of at least one of these risk factors. The definition of recurrent VTE included four distinct entities: (1) the development of new thrombi in initially involved limbs or/and PE within the 3 months of anticoagulant treatment (thrombus progression); (2) propagation of thrombus to uninvolved segments in the ipsilateral limb after completion of anticoagulant treatment; (3) the development of a contralateral DVT; and (4) PE suspected in a patient on the basis of clinical symptoms or signs and confirmed by lung scanning (showing a new perfusion defect, segmental or larger, with ventilation mismatch) after completion of anticoagulant treatment.
1. Patients and Methods
1.2. Coagulation Tests
1.1. Patients
At the end of anticoagulant treatment (at least 15 days after its completion), natural and acquired inhibitors of hemostasis were studied in all patients under the age of 50 years. Blood samples were subject to a thrombophilia screen that included prothrombin time, activated partial thromboplastin time, thrombin time, antithrombin III and protein C activity, free and total protein S, lupus anticoagulant screen [activated partial thromboplastin time (APTT) performed on a mix of four parts patient platelet-poor plasma to one part normal platelet-poor plasma, and dilute Russells’ viper venom test with platelet neutralization step], plasminogen activity, and immunoglobulin G and immunoglobulin M anticardiolipin antibody assays. Testing for resistance to activated protein C (APC resistance) was not performed in our laboratory until 1995. All patients diagnosed with recurrent VTE, even those with the first thrombotic episode before 1995, have been subsequently invited to attend for a new blood sampling and have been screened for APC resistance and hyperhomocysteinemia. Antithrombin III, protein C, and plasminogen activities were determined by automated, amidolytic techniques. Protein S antigens and
This was a retrospective analysis of all patients admitted to the Hospital Lluis Alcanyis with an episode of symptomatic PE and/or DVT between the inclusive years 1986–1996. The Hospital Lluis Alcanyis serves as a primary care referral center for patients with VTE for a community of approximately 200,000 people (1996 Census). Patients were eligible for the study if duplex ultrasonography or venography showed DVT and perfusionventilation pulmonary scintigraphy confirmed diagnosis of PE. Moreover, the patients included in the study had to be treated with UFH or LMWH for a week and oral anticoagulants for a period of at least 3 months. All patients included in the study were assessed monthly for 3 to 6 months from discharge from the first VTE until cessation of oral anticoagulant therapy. In addition, the hospital medical record of each patient was reviewed, searching all significant clinical data until 31 December 1996. All patients with recurrent VTE were reassessed in our clinical center on an outpatient basis. Each visit included history taking and physical examination. Informa-
337
E. Grau et al./Thrombosis Research 96 (1999) 335–341
Table 1. Demographic and clinical characteristics of the study population (n5290) Age (years) (median6SD) Sex (M/F) Localization DVT (without clinical PE) PE (6confirmed DVT) Known risk factors Idiopathic Secondary Bedrest Surgery Trauma Concurrent medical process Previous VTE Malignancy
61.5615.7 166/124 193 (66.6%) 97 (33.4%) 161 129 21 56 24 17 5 6
(55.5%) (44.5%) (7.2%) (19.3%) (8.3%) (5.9%) (1.7%) (2.0%)
anticardiolipin antibodies were measured by an ELISA method. APC resistance was assessed by measuring the anticoagulant response in plasma on the addition of APC (Coatest, Chromogenix, Mo¨lndal, Sweden). The results were expressed as the APC sensitivity ratio, obtained by dividing APTT plus APC by APTT minus APC. When APC sensitivity ratio was lower than 1.8, it was considered to be positive. The total homocysteine concentration was measured by high performance liquid chromatography.
1.3. Statistical Analysis Differences were investigated by means of standard x2 tests. Incidences are shown as percentage and 95% confidence intervals (CI) on the assumption that the number of events followed a Poisson distribution. The probability of recurrent VTE was estimated following the method of Kaplan-Meier.
2. Results Between 1 January 1986 and 31 December 1996, 290 patients met our criteria for VTE. The demographic and clinical characteristics of the study population are presented in Table 1. Twelve patients were excluded for the analysis of recurrent VTE because they did not receive complete anticoagulant treatment: older than 85 years (four patients) and concomitant processes (eight patients). Of the remaining 278 patients, 10 (3.6%) had bleeding
Table 2. Demographic and clinical characteristics of patients with recurrent VTE (n533) Age (years) (median6SD) (first episode) Sex (M/F) Localization First episode DVT (without clinical PE) PE (6confirmed DVT) Second episode DVT (without clinical PE) Ipsilateral Contralateral PE (6confirmed DVT) Known risk factors First episode Idiopathic Secondary Second episode Idiopathic Secondary Interval between episodes 0–2 years 2–5 years 5–10 years
57.1615.6 22/11
32 (97%) 1 (3%)
24 15 9 9
(72.7%) (45.4%) (27.3%) (27.3%)
29 (87.9%) 4 (12.1%) 28 (84.8%) 5 (15.2%) 21 (63.6%) 6 (18.2%) 6 (18.2%)
complications during anticoagulant therapy; five patients had minor hemorrhages and five patients had major bleeding episodes (two had hemarthrosis, two had gastrointestinal bleeding, and one had retroperitoneal hematoma). The thrombophilia screen was performed in all patients younger than 50 years (55 patients, 19%). Of these 55 patients, 44 did not developed recurrent VTE. None of these patients with a single VTE showed any abnormality in the thrombophilia screen. Of the 278 patients, a total of 33 (11.9%) (95% CI, 7.4–14.6) experienced one or more documented recurrent VTE. Demographic and clinical characteristics of these population of patients with recurrent VTE are presented in Table 2. None of these patients died due to the recurrent thrombotic events. Two patients were diagnosed with malignancy and both died after the second thrombotic event. Age at the time of the first VTE was similar between patients with or without recurrent VTE. In our series there were twice as many men with recurrent VTE as women (Table 2).
338
E. Grau et al./Thrombosis Research 96 (1999) 335–341
The first episode of VTE was DVT in almost all patients, and only one patient had PE. Ipsilateral DVT was the most frequent localization of rethrombosis. The incidence of PE was higher in the second episode than in the first episode. In our series none of the patients presented fatal PE (Table 2). The incidence of idiopathic thrombotic episodes was 87.9% (95% CI, 76.8–99) for first episodes and 84.8% (95% CI, 72.6–97) for second episodes in our series of patients with recurrent VTE. This incidence was statistically higher than that observed in our the study population (55.5%, 95% CI, 49.8–61.2) (p,0.001). Eight patients (24.2%) had moderate to severe post-thrombotic syndrome at the time of the second thrombotic event. Six (54.5%, 95% CI, 37.6–71.4) of the 11 patients with recurrent VTE and aged under 50 years at the time of the first episode of VTE were found to have hemostasis abnormalities: APC resistance (three), deficiency of protein C (one), deficiency of protein S (one), and lupus anticoagulant (one). Another patient, aged over 50 years, was found to have APC resistance. The majority of patients (21 patients, 63.6%, 95% CI, 47.2–80) had the second thrombotic event within the following 2 years of the first episode. The interval between episodes was longer than 2 years in 12 patients (36.4%, 95% CI, 20–52.8). Recurrent VTE was observed 10 years after the first episode in 2 patients (Table 2). Considering the study population alive during the 10 years of follow-up, the cumulative incidence of recurrent VTE after 1, 2, and 3 years was 4.67, 7.68, and 9.23%, respectively. This incidence increased to 10% after 5 years, and 12.4% after 10 years of follow-up (Figure 1). Thrombus progression was observed in three patients (1% of the study population and 9% of the patients with recurrent VTE) (two with ipsilateral thrombus progression and one with PE). All three cases showed anticoagulant levels under the therapeutic range at the time of thrombus progression. Ipsilateral DVT was the most common localization (14 patients) when rethrombosis occurred before 5 years of follow-up. In contrast PE was the most common localization (four patients) after 5 years. Of these 33 patients with a second episode of VTE, seven patients without a known hemostatic disorder stopped anticoagulant treatment for dif-
Fig. 1. Cumulative incidence of recurrent venous thromboembolism in the study population.
ferent reasons. Three of these patients presented a third thrombotic episode. The remaining 26 patients with two episodes of VTE received permanent anticoagulant treatment and only one had a third thrombotic event.
3. Discussion Our study assessed the hospital incidence of recurrent VTE in a large cohort of Spanish patients during long-term follow-up. Demographic and clinical characteristics of our patients are comparable to those in other large series of patients with VTE [14–16]. Our findings are similar to previous studies in which recurrent VTE was reported in 4 to 6% of patients treated with heparin and warfarin for 3 to 9 months, and in 6 to 7% of patients monitored for 2 years after a 3-month course of warfarin [17– 19]. Although the risk for recurrent VTE seems to persist for many years, the incidence decreases after 2 years of the first thrombotic episode. Thus, our data do not provide evidence that the risk for recurrent VTE remains high for many years as has been reported for other investigators [20,21]. Several issues complicate the interpretation of such differences between those studies. Diagnosis of recurrent VTE can be difficult, and the predefined criteria applied to its diagnosis may be different. Although patients were treated according to standard practice, there may be differences in dose intensity and duration of anticoagulant treatment. Finally, we performed a retrospective review of the inpatient medical records and cases not oc-
E. Grau et al./Thrombosis Research 96 (1999) 335–341
curring in our hospital could be missed. These limitations prevent us from suggesting guidelines for the long-term clinical care of patients with a single episode of VTE. Further prospective studies are needed to clarify the exact long-term incidence of recurrent VTE because of its implication about the duration of the anticoagulant treatment in patients with a single episode of VTE. Thrombus progression was observed in only three patients and it was clearly correlated to inadequate heparinization early in the course of therapy. Our data reaffirm the clinical importance of rapidly achieving therapeutic levels of heparin [22,23]. Therapy with LMWH has been introduced in the last 3 years in the routine clinical practice and the body of evidence indicates that LMWH has a longer half-life and a more predictable anticoagulant response to a fixed dose than does UFH [24]. Therefore, LMWH therapy might reduce the incidence of thrombus progression. The fact that almost all patients with recurrent VTE suffered DVT but not PE in the first thrombotic episode and the high incidence of ipsilateral DVT in the second and even the third thrombotic event confirms the important role of moderate to severe post-thrombotic syndrome in the development of recurrent VTE. Our data suggest that the incidence of second ipsilateral thrombosis is high in the first 2 years after cessation of the anticoagulant treatment. These findings are supported by the results of other studies showing post-thrombotic syndrome manifestations within the 2 years following the acute thrombosis in more than 80% of patients [21]. We believe that prolongation of anticoagulant treatment for at least 2 years could be considered in some patients with a single VTE and severe post-thrombotic syndrome. Our series of patients with recurrent VTE had a high incidence of idiopathic VTE episodes. In contrast, our study population showed a low incidence of idiopathic VTE. Therefore, our data indicate that idiopathic VTE is a risk factor for recurrent VTE in this Spanish population. The low incidence of idiopathic VTE in our study population is fully consistent with the results of a recent study performed among different ethnic groups in California (USA) [25]. Compared with white persons, Hispanic persons had a much lower incidence of idiopathic DVT. These differences between ethnic groups could be explained at least in part by
339
differences in the prevalence of the factor V Leiden mutation and possibly other genetic disorders [26,27]. We found hemostasis abnormalities in about 55% of patients under age 50 years with recurrent VTE at the time of the first thrombotic episode. On the other hand, we did not find any inherited or acquired inhibitor of hemostasis in those patients younger than 50 years with a single VTE. These results may be explained by the fact that in our study population only 55 patients (19%) were aged under 50 years, and of these patients only 14 had idiopathic VTE. In contrast, patients with recurrent VTE and under the age of 50 years have a high prevalence of thrombophilic abnormalities. Therefore, thrombophilia screen is highly recommended in patients with recurrent VTE, especially in those with idiopathic VTE and under the age of 50 years. Our data strongly support the use of long-term anticoagulant therapy in patients with recurrent VTE. From our point of view, cessation of anticoagulant therapy in recurrent VTE should be considered only in those patients with a high hemorrhagic risk or other major contraindications to oral anticoagulants.
References 1. Anderson FA Jr, Wheeler HB, Goldberg RJ, Hosmer DW, Patwardhan NA, Jovanovic B, Forcier A, Dalen JE. A population-based perspective of the hospital incidence and casefatality rates of deep vein thrombosis and pulmonary embolism: The Worcester DVT Study. Arch Intern Med 1991;151:933–8. 2. Kniffin WD, Baron JA, Barret J, Birkmeyer JD, Anderson FA Jr. The epidemiology of diagnosed pulmonary embolism and deep venous thrombosis in the elderly. Arch Intern Med 1994;154:861–6. 3. De Stefano V, Finazzi G, Mannucci PM. Inherited thrombophilia. Pathogenesis, clinical syndromes and management. Blood 1996;87: 3531–44. 4. Clark S. Current issues in management of thrombosis. Lancet 1995;346:113–4. 5. Ginsberg JS. Management of venous thromboembolism. N Engl J Med 1996;335:1816–28.
340
E. Grau et al./Thrombosis Research 96 (1999) 335–341
6. Meissner MH, Caps MT, Bergelin RO, Manzo RA, Strandness DE. Propagation, rethrombosis and new thrombus formation after acute deep venous thrombosis. J Vasc Surg 1995; 22:558–67. 7. Kakkar VV, Lawrence D. Hemodynamic and clinical assessment after therapy for acute deep vein thrombosis: A prospective study. Am J Surg 1985;150:54–63. 8. Hull RD, Raskob GE, Pineo GF. Subcutaneous low-molecular-weight heparin compared with continuous intravenous heparin in the treatment of proximal-vein thrombosis. N Engl J Med 1992;326:975–82. 9. Holm HA, Finnanger B, Hartmann A. Heparin treatment of deep venous thrombosis in 280 patients: Symptoms related to dosage. Acta Med Scand 1984;215:47–53. 10. Koopman MM, Buller HR, ten Cate JW. Diagnosis of recurrent deep vein thrombosis. Haemostasis 1995;25:49–57. 11. Hirsh J, Fuster V. AHA Medical/Scientific Statement. Special Report. Guide to anticoagulant therapy. Pt. 2: Oral anticoagulants. Circulation 1994;89:1469–80. 12. Schulman S, Rhedin AS, Lindmarker P, Carlsson A, Larfars G, Nicol P, Loogna E, Svensson E, Ljungberg B, Walter H. A comparison of six weeks with six months of oral anticoagulant therapy after a first episode of venous thromboembolism. Duration of Anticoagulation Trial Study Group. N Engl J Med 1995;332: 1661–5. 13. Levine MN, Hirsh J, Gent M, Turpie AG, Weitz J, Ginsberg J, Geerts W, Leclerc J, Neemeh J, Powers P, Piovella F. Optimal duration of oral anticoagulant therapy: A randomized trial comparing four weeks with three months of warfarin in patients with proximal deep vein thrombosis. Thromb Haemost 1995; 74:606–11. 14. Hull RD, Carter CJ, Jay RM, Ockelford PA, Hirsh J, Turpie AG, Zielinsky A, Gent M, Powers PJ. The diagnosis of acute, recurrent, deep-vein thrombosis: A diagnostic challenge. Circulation 1983;67:901–6. 15. Eichinger S, Stumpflen A, Hirschl M, Bialonczyk C, Herkner K, Stain M, Schneider B, Pab-
inger I, Lechner K, Kyrle PA. Hyperhomocysteinemia is a risk factor of recurrent venous thromboembolism. Thromb Haemost 1998; 80:566–9. 16. Brandjes DP, Bu¨ller HR, Heijboer H, Huisman MV, de Rijk M, Jagt H, ten Cate JW. Randomised trial of effect of compression stocking in patients with symptomatic proximal-vein thrombosis. Lancet 1997;349:759–62. 17. Hull RD, Raskob GE, Hirsh J, Jay RM, Leclerc JR, Geerts WH, Rosenbloom D, Sackett DL, Anderson C, Harrison L, Gent M. Continuous intravenous heparin compared with intermittent subcutaneous heparin in the initial treatment of proximal-vein thrombosis. N Engl J Med 1986;315:1109–14. 18. Hull RD, Delmore T, Genton E, Hirsh J, Gent M, Sackett D, Mcloughlin D, Armstrong P. Warfarin sodium versus low-dose heparin in the treatment of venous thrombosis. N Engl J Med 1979;301:855–8. 19. Huisman MV, Buller HR, ten Cate JW. Utility of impedance plethysmography in the diagnosis of recurrent deep-vein thrombosis. Arch Intern Med 1988;148:681–3. 20. Prandoni P, Lensing AW, Cogo A, Cuppini S, Villalta S, Carta M, Cattelan AM, Polistena P, Bernardi E, Prins MH. The long-term clinical course of acute deep venous thrombosis. Ann Intern Med 1996;125:1–7. 21. Prandoni P, Villalta S, Bagatella P, Rossi L, Marchiori A, Piccioli A, Bernardi E, Girolami B, Simioni P, Girolami A. The clinical course of deep-vein thrombosis. Prospective long-term follow-up of 528 symptomatic patients. Haematologica 1997;82:423–8. 22. Hull RD, Raskob GE, Brant RF, Pineo GF, Valentine KA. Relation between the time to achieve the lower limit of the APTT therapeutic range and recurrent venous thromboembolism during heparin treatment for deep vein thrombosis. Arch Intern Med 1997;157:2562–8. 23. Hirsh J, Fuster V. AHA Medical/Scientific Statement. Special Report. Guide to anticoagulant therapy. Part 1: Heparin. Circulation 1994;89:1449–68. 24. Hirsh J, Levine MN. Low molecular weight heparin. Blood 1992;79:1–17. 25. White RH, Zhou H, Romano PS. Incidence of
E. Grau et al./Thrombosis Research 96 (1999) 335–341
idiopathic deep venous thrombosis and secondary thromboembolism among ethnic groups in California. Ann Intern Med 1998;128:737–40. 26. Ridker PM, Miletich JP, Hennekens CH, Buring JE. Ethnic distribution of factor V Leiden
341
in 4047 men and women. Implications for venous thromboembolism screening. JAMA 1997; 277:1305–7. 27. Rees DC, Cox M, Clegg JB. World distribution of factor V Leiden. Lancet 1995;346:1133–4.