Recurrent thromboembolism and major bleeding during oral anticoagulant therapy in patients with solid cancer: findings from the RIETE registry

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 χ 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.Main demographic and clinical characteristics of the study patients.

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.

Figure 1.Cumulative incidence of recurrent venous thromboembolism in patients without malignancy and in cancer patients with and without distant metastases.

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.

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).