Published online 1 September 2008
Haematologica, Vol 93, Issue 9, 1432-1434 doi:10.3324/haematol.13055
Copyright © 2008 by Ferrata Storti Foundation
Paolo Prandoni1 ,
Javier Trujillo-Santos2 ,
Teresa Surico1 ,
Fabio Dalla Valle1 ,
Andrea Piccioli1 ,
Manuel Monreal3 ,
for the RIETE Investigators*
Our enquiry presents several limitations. Indeed, a relevant number of patients (of whom almost 30% were affected by cancer) had an anticoagulant treatment other than VKA, and, therefore, did not qualify for the study. Data concerning the diagnosis of cancer, disease stage, recurrent VTE, and major bleeding were accepted on assessments made at each participating center, and could not be confirmed by an independent adjudication committee. Finally, information on the quality of anticoagulation achieved during the treatment with VKA was not available. 
we express our gratitude to Sanofi-Aventis Spain for supporting this Registry with an unrestricted educational grant and the Registry Coordinating Center, S & H Medical Science Service, for their logistic and administrative support.
* RIETE Registry. Coordinator: Monreal M. Steering Committee: Decousus H, Prandoni P, Brenner B. National Coordinators: Barba R (Spain), Di Micco P (Italy), Guillot K (France). Coordinating Center: S & H Medical Science Service. Members: Alcalde M, Arcelus JI, Ballaz A, Barba R, Blanco A, Barrón M, Casado I, Cañas I, Cisneros E, Conget F, De Zárraga M, Fernández-Capitán C, Font Ll, Gallego P, García-Bragado F, Gutiérrez J, Gutiérrez MR, Hermosa MJ, Hernández L, Herrera S, Jiménez D, Lecumberri R, León JM, López L, López I, Madridano O, Maestre A, Martín-Villasclaras JJ, Mejias I, Monreal M, Naufall MD, Nieto JA, Oribe M, Orue MT, Otero R, Rabuñal R, Rodríguez C, Rosa V, Ruiz-Giménez N, Ruiz-Ribó MD, Sahuquillo JC, Sampériz AL, Sánchez JF, Sánchez R, Soler S, Soto MJ, Tirado R, Todolí JA, Tolosa C, Trujillo J, Valdés M, Valdés V, Valle R, Vela J (Spain); Mismetti P, Rivron-Guillot K, Boccalon H, Le Corvoisier P, Quere I (France); Di Micco P, Duce R, Enea I, Poggio R, Prandoni P, Schenone A, Tiraferri E (Italy).
Haematologica, Vol 93, Issue 9, 1432-1434 doi:10.3324/haematol.13055
Copyright © 2008 by Ferrata Storti Foundation
Thrombosis |
Recurrent thromboembolism and major bleeding during oral anticoagulant therapy in patients with solid cancer: findings from the RIETE registry
1 Department of Medical and Surgical Sciences, University of Padua, Italy
2 Department of Internal Medicine, Hospital Santa María de Rosell, Cartagena, Murcia, Spain
3 Department of Internal Medicine, Hospital Germans Trias i Pujol, Badalona, Spain
Correspondence: Paolo Prandoni, Dipartimento di Scienze Mediche e Chirurgiche, Clinica Medica II, Università di Padova. E-mail:paoloprandoni{at}tin.it
Following an episode of venous thromboembolism (VTE), the risk of recurrent VTE and major bleeding complications during oral anticoagulant therapy with vitamin K antagonists (VKA) in cancer patients exceeds that observed in patients free from malignancy.1–3 According to the results of several randomized clinical trials,4–7 international guidelines recommend the use of sub-therapeutic doses of low-molecular-weight heparins (LMWH) for the long-term prevention of recurrent VTE in all cancer patients.8–10 However, in clinical practice many clinicians still administer VKA to their cancer patients, especially to those with limited disease and longer life expectancy.
We determined the risk of recurrent VTE and major bleeding in a wide number of patients with and without cancer who were recruited in the international RIETE registry, had an initial treatment with (LMW)heparin overlapped by VKA (targeting an International Normalized Ratio [INR] between 2.0 and 3.0), and then had a 3-month follow-up.
Between March 2001 and May 2007, 18,883 consecutive patients with symptomatic, acute DVT or PE, as confirmed by objective tests were enrolled in the RIETE registry, and were, therefore, eligible for our investigation. Of these patients, 6,139 were excluded: 4,999 (of whom 1,496–29.9% - affected by cancer) because of treatment with antithrombotic drugs other than VKA, 838 because of lack of long-term antithrombotic treatment, 223 because of the development of manifest cancer during the 3-month follow-up period, and 79 because of hematologic malignancies. Of the remaining 12,744 patients, 11,365 were free from malignancy, 407 had cancer with distant metastases, and 972 had a more limited cancer disease. The incidence of recurrent VTE and major bleeding was calculated for patients with and without cancer, and then separately for cancer patients with and without distant metastases. The diagnosis of recurrent VTE and major bleeding was carried out according to widely accepted methods and criteria that have been extensively described elsewhere.11,12 Odds ratios (OR) and their 95% confidence intervals (CI) were calculated for the clinical characteristics and the 3-month outcome for patients without malignancy in comparison to the whole group of cancer patients, and separately for those with and without distant metastases. Dichotomous variables were tested with 
2 test and continuous variables with Student’s t-test. In order to measure predictors of 3-month recurrent VTE and major bleeding, a multivariate analysis was carried out using a Cox proportional hazard analysis after adjusting for age, sex, and modality of clinical presentation (symptomatic DVT alone or symptomatic PE with or without DVT). Statistical analyses were conducted with SPSS for Windows Release 13.0 and Epidat 3.1.
Table 1 shows the main demographic and clinical characteristics of the study patients, separately for those without malignancy, cancer patients with distant metastases, and cancer patients with more limited disease. During the study period, 333 patients died: 189 (1.7%) belonging to the first group, 103 (25.3%) to the second group, and 41 (4.2%) to the third. During the first three months of VKA treatment, recurrent VTE developed in 154 patients without malignancy (1.4%, fatal in 16), in 27 cancer patients with distant metastases (6.6%, fatal in 3), and in 31 cancer patients with more limited disease (3.2%, fatal in 4). In comparison to patients without malignancy, the OR of recurrent VTE in the whole group of cancer patients was 3.2 (95% CI, 2.4–4.3), and in cancer patients with and without distant metastases was 5.2 (3.4–7.9) and 2.4 (1.6–3.5) respectively. The corresponding figures for the adjusted hazard ratio (HR) were 3.5 (95% CI, 2.5–4.7), 5.6 (3.7–8.4), and 2.6 (1.8 to 3.8) respectively (Figure 1). During the first three months of VKA treatment, major bleeding developed in 150 patients without malignancy (1.3%, fatal in 19), in 20 cancer patients with distant metastases (4.9%, fatal in 7), and in 16 cancer patients with more limited disease (1.9%, fatal in 4). In comparison to patients without malignancy, the OR of major bleeding in the whole group of cancer patients was 2.0 (95% CI, 1.4–2.9), and in cancer patients with and without metastases was 3.9 (2.4–6.2) and 1.3 (0.7–2.1) respectively. The corresponding figures for the adjusted HR were 1.8 (95% CI, 1.2–2.6) 3.9 (2.4–6.2) and 1.1 (0.6–1.8) respectively.
|
View this table: [in a new window] [Download PPT slide] |
Table 1. Main demographic and clinical characteristics of the study patients.
|
 View larger version (15K): [in a new window] [Download PPT slide] |
Figure 1. Cumulative incidence of recurrent venous thromboembolism in patients without malignancy and in cancer patients with and without distant metastases.
|
In spite of these limitations, the results of our investigation fully confirm that cancer patients with VTE have an overall risk of recurrent VTE and major bleeding complications during VKA that exceeds that expected in patients free from malignancy.1–3 However, in the subgroup of cancer patients with more limited disease the rate of major bleeding does not differ from that expected in cancer free patients. Whether these patients may benefit from more intense regimens of VKA as an alternative to LMWH is worthy of further investigation.
Acknowledgments
we express our gratitude to Sanofi-Aventis Spain for supporting this Registry with an unrestricted educational grant and the Registry Coordinating Center, S & H Medical Science Service, for their logistic and administrative support.
Footnotes
* RIETE Registry. Coordinator: Monreal M. Steering Committee: Decousus H, Prandoni P, Brenner B. National Coordinators: Barba R (Spain), Di Micco P (Italy), Guillot K (France). Coordinating Center: S & H Medical Science Service. Members: Alcalde M, Arcelus JI, Ballaz A, Barba R, Blanco A, Barrón M, Casado I, Cañas I, Cisneros E, Conget F, De Zárraga M, Fernández-Capitán C, Font Ll, Gallego P, García-Bragado F, Gutiérrez J, Gutiérrez MR, Hermosa MJ, Hernández L, Herrera S, Jiménez D, Lecumberri R, León JM, López L, López I, Madridano O, Maestre A, Martín-Villasclaras JJ, Mejias I, Monreal M, Naufall MD, Nieto JA, Oribe M, Orue MT, Otero R, Rabuñal R, Rodríguez C, Rosa V, Ruiz-Giménez N, Ruiz-Ribó MD, Sahuquillo JC, Sampériz AL, Sánchez JF, Sánchez R, Soler S, Soto MJ, Tirado R, Todolí JA, Tolosa C, Trujillo J, Valdés M, Valdés V, Valle R, Vela J (Spain); Mismetti P, Rivron-Guillot K, Boccalon H, Le Corvoisier P, Quere I (France); Di Micco P, Duce R, Enea I, Poggio R, Prandoni P, Schenone A, Tiraferri E (Italy).
Funding: the project has been partially supported by Red Respira from the Instituto Carlos III (RedRespira-ISCiii-RTIC-03/11).
References
 TOP References |
|---|
- Prandoni P, Lensing AWA, Piccioli A, Bernardi E, Simioni P, Girolami B, et al. Recurrent venous thromboembolism and bleeding complications during anticoagulant treatment in patients with cancer and venous thrombosis. Blood 2002;100:3484-8.
[Abstract/Free Full Text] - Hutten B, Prins M, Gent M, Ginsberg J, Tijsen JGP, Buller HR. Incidence of recurrent thromboembolic and bleeding complications among patients with venous thromboembolism in relation to both malignancy and achieved international normalized ratio: a retrospective analysis. J Clin Oncol 2000;18:3078-83.
[Abstract/Free Full Text] - Palareti G, Legnani C, Agnes L, Manotti C, Hirsh J, D'Angelo A, et al. A comparison of the safety and efficacy of oral anticoagulation for the treatment of venous thromboembolic disease in patients with or without malignancy. Thromb Haemost 2000;84:805-10.[Web of Science][Medline]
- Lee AY, Levine MN, Baker RI, Bowden C, Kakkar AK, Prins M, et al. Low-molecular-weight heparin versus a coumarin for the prevention of recurrent venous thromboembolism in patients with cancer. N Engl J Med 2003;349:146-53.
[Abstract/Free Full Text] - Meyer G, Marjanovic Z, Valcke J, Lorcerie B, Gruel Y, Solal-Celigny P, et al. Comparison of low-molecular-weight heparin and warfarin for the secondary prevention of venous thromboembolism in patients with cancer. Arch Intern Med 2002;162:1729-35.
[Abstract/Free Full Text] - Hull RD, Pineo GF, Brant RF, Mah AF, Burke N, Dear R, et al. Long-term low-molecular-weight heparin versus usual care in proximal-vein thrombosis patients with cancer. Am J Med 2006;119:1062-72.[CrossRef][Web of Science][Medline]
- Deitcher SR, Kessler CM, Merli G, Rigas JR, Lyons RM, Fareed J. Secondary prevention of venous thromboembolic events in patients with active cancer: enoxaparin alone versus initial enoxaparin followed by warfarin for a 180-day period. Clin Appl Thromb Hemost 2006;12:389-96.
[Abstract/Free Full Text] - Büller HR, Agnelli G, Hull RD, Hyers TM, Prins MH, Raskob GE. Antithrombotic therapy for venous thromboembolic disease: the seventh ACCP conference on anti-thrombotic and thrombolytic therapy. Chest 2004;126:401-28S.[CrossRef]
- Nicolaides AN, Fareed J, Kakkar AK, Breddin HK, Goldhaber SZ, Hull R, et al. Prevention and treatment of venous thromboembolism. International Consensus Statement. Guidelines according to scientific evidence. Int Angiol 2006;25:101-61.[Web of Science][Medline]
- Lyman GH, Khorana AA, Falanga A, Clarke-Pearson D, Flowers C, Jahanzeb M, et al. American Society of Clinical Oncology Guideline: recommendations for venous thromboembolism prophylaxis and treatment in patients with cancer. J Clin Oncol 2007;25:5490-505.
[Abstract/Free Full Text] - Arcelus JI, Monreal M, Caprini JA, Suárez C, González-Fajardo JA. The management and outcome of acute venous thromboembolism: a prospective registry including 4011 patients. J Vasc Surg 2003;38:916-22.[CrossRef][Web of Science][Medline]
- Monreal M, Falgá C, Valdés M, Suárez C, Gabriel F, Tolosa C, Montes J. Fatal pulmonary embolism and fatal bleeding in cancer patients with venous thromboembolism: findings from the RIETE registry. J Thromb Haemost 2006;4:1950-6.[CrossRef][Web of Science][Medline]
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||