During the course of anticoagulation, 178 cancer patients developed PE recurrences (5.5 per 100 patient-years; 95% CI: 4.8–6.4). Of these, 51 occurred within the first 10 days of anticoagulation (40 under LMWH, 5 under VKA, 6 other), 105 from Days 11 to 90 (78 on LMWH, 22 VKA, 5 other) and 22 after Day 91 (14 on LMWH, 8 VKA) (Figure 1). PE recurrences most likely occurred in patients initially presenting with PE than in those with DVT alone (6.4 vs. 4.6 per 100 patient-years; P = 0.03) (Table 3). Forty-eight patients (27%) died within less than 24 hours after recurrent PE, with minimal time to change therapy; 62 continued with the same therapy (same drug and doses), 47 received higher doses, 21 moved to LMWH, and VCF was placed in 18. Seventy-three patients (41%) died within the first 2 weeks, of whom 62 (85%) died of the recurrent PE event. Overall, PE recurrences developed more likely in patients receiving long-term LMWH than in those on AVK, but this may be due to the higher proportion of patients with metastatic cancer receiving LMWH than AVK (Table 4).
During the course of anticoagulation, 194 patients presented with recurrent DVT (6.2; 95% CI: 5.3–7.1). Of these, 17 recurrences appeared within the first 10 days of therapy (13 on LMWH, 3 VKA, 1 UFH), 130 during “early maintenance” (76 on LMWH, 54 VKA) and 47 during “long-term” treatment beyond 3 months (28 on LMWH, 19 VKA). DVT recurrences were more likely to appear in cancer patients initially presenting with DVT (8.2 vs. 4.3 per 100 patient-years; P < 0.001) than in those with PE. The type and dose of anticoagulation treatment was not modified in 105 cancer patients treated for VTE recurrence, 38 received higher doses of whom 2 died of bleeding after increasing heparin doses, 49 were moved to LMWH, and a VCF was placed in 8 patients.
During the overall duration of anticoagulation, 367 cancer patients presented major bleeding (11.3 per 100 patient-years; 95% CI: 10.2–12.5). Of these, 249 (68%) were receiving LMWH, 109 (30%) VKA and 9 (2.5%) were on other treatments including UFH. Anticoagulation was discontinued in 237 patients (65%) (for <5 days in 172, ≥5 days in 65), 46 (13%) moved to low-dose LMWH and a VCF was placed in 36 (9.8%). Major bleeding occurred within the first 10 days of therapy in 126 cancer patients (75 under LMWH, 48 VKA, 3 other), in 165 during “early maintenance” (119 on LMWH, 40 VKA, 6 other), and in 76 during “long-term” treatment (55 on LMWH, 21 VKA). The rate of major bleeding was similar in patients initially presenting with initial PE or DVT alone (Table 3). During the first 3 months of anticoagulation, the most common sites of major bleeding were the gastrointestinal (GI) tract (n = 137), urinary (n = 39), brain (n = 29), hematoma (n = 27), menorrhagia (n = 14), and retroperitoneal (n = 11) (Figure 2). After the third month, the most common sites of major bleeding were the GI tract (n = 33), brain (n = 16), urinary (n = 7), and retroperitoneal (n = 5). Sixty-five (18%) of cancer patients with major bleeding died in <24 hours, 130 (35%) within the first 2 weeks. Of these, 104 (80%) died of bleeding and 4 (3.1%) died of recurrent PE (shortly after discontinuing anticoagulation). Overall, major bleeding appeared more likely in patients receiving long-term LMWH than in those on AVK, but this may be due to the higher proportion of patients with metastatic cancer receiving LMWH than AVK (Table 4).
During anticoagulation for VTE, 2351 cancer patients died (71.5 per 100 patient-years; 95% CI: 68.6–74.5). The most common causes of death were: disseminated malignancy (n = 1277), PE (n = 191), respiratory insufficiency (n = 138, of whom 48 had lung cancer, 32 chronic lung disease, and 17 chronic heart failure), and bleeding (n = 100). Of 191 cancer patients with fatal PE, 129 died of the initial PE and 62 of recurrent PE. Among 100 cancer patients with fatal bleeding, the most common sites of bleeding were the GI tract (n = 51), and the brain (n = 19). During the first 3 months of anticoagulation, 59 fatal PE recurrences and 77 fatal bleeds occurred (Figure 3). Beyond the third month, there were 3 fatal PE recurrences and 23 fatal bleeds. During the first 3 months of anticoagulation, the CFR of recurrent PE was 37.8% (95% CI, 30.2–45.9), compared to 13.6% (95% CI, 3.0–44.9) beyond the third month. The CFR of major bleeding was 26.3% (95% CI, 21.4–31.7) during the first 3 months, and 31.1% (95% CI, 20.8–42.9) beyond this period.
One in every 4 cancer patients dying of recurrent PE (26%) or bleeding (27%) had no metastases, 1 in every 2 (61% and 34%, respectively) were aged <65 years, and 1 in every 10 patients dying of bleeding had a history of recent bleeding before the index VTE (Table 5). Moreover, patients with prostate, bladder, stomach, or uterine cancers less likely died of PE than of bleeding, while those with breast cancer more likely died of PE than of bleeding. Finally, 21 patients had a sudden, unexpected death. Unfortunately, no necropsy studies were performed, and there is no way to know how many of them (if any) died of PE or bleeding.
This prospective multicenter RIETE cohort analysis of cancer patients treated for acute VTE, obtained from a large number of consecutive cancer patients treated for VTE, allowed to analyze a large cohort of cancer patients treated by anticoagulation at best according to these guidelines or according to local practice. In this specific cancer population treated for VTE, the overall rate of VTE recurrences during anticoagulation was close to the rate of major bleeding (372 events vs. 367 events), but mortality due to recurrent PE was lower than the mortality due to bleeding (62 vs. 100 deaths, respectively), particularly after the third month of anticoagulation (3 vs. 23 deaths, respectively).
These results confirm 2 recent studies showing that the CFR of recurrent VTE and major bleeding were similar during initial treatment of VTE in cancer patients, but that the CFR of recurrent VTE decreased after the third month of anticoagulation.15,20 The higher risk of dying from bleeding than from PE after the first 3 months of anticoagulation suggests that a less aggressive anticoagulant strategy (or a shorter duration) might reduce fatal bleeding, but could also in turn increase the incidence of PE.
We also found that, irrespective of the type of anticoagulant drugs, the risk of dying from recurrence of PE during anticoagulation treatment, varied according to VTE presentation at baseline. In patients initially presenting with PE, the risk of fatal recurrent PE during anticoagulation and the risk of fatal bleeding were similar. The lower risk of dying from recurrent PE in patients initially presenting with DVT can be attributed to the fact that DVT patients most likely recurred as DVT, and no patient with recurrent DVT died of PE. The dose of anticoagulation treatment did not appear to account for difference in outcomes between cancer patients presenting with VTE alone or with PE, and the rate of fatal bleeding was similar over time. The much lower risk of dying from PE than from bleeding in patients with DVT has been previously reported also in the elderly (with or without cancer),21 and in patients with renal insufficiency.22 Patients with prostate, bladder, stomach, or uterine cancers were less likely to die from PE than from bleeding and patients with breast cancer died more of PE than of bleeding, underlying the need for tailored anticoagulation regimen according to the cancer type in the future.
The incidence of 11 VTE recurrences per 100 patient-years observed in our study is similar to results from the control arms of randomized clinical trials using VKA after 10 days as compared to long-term LMWH for 36,8 or 6 months,7 but the incidence of 11 major bleeding events per 100 patient-years was over 2-fold higher than reported in these trials.6–8 The higher incidence of major bleeding in the current analysis reflects enrollment of consecutive unselected patients, including more patients with metastatic cancer and patients with multiple risk factors for bleeding who are often excluded from randomized trials. The RIETE registry provides data on the treatment and outcome of VTE in a real-world situation with an unselected patient population, in contrast to the rigorously controlled conditions of randomized clinical studies. There was a relatively low rate of VCF insertion, although 10% of the patients dying of bleeding had a history of recent bleeding before the index VTE. A recent RIETE study in 371 patients (of whom 60 with cancer) has shown that inferior VCF insertion, as compared with anticoagulant therapy, in patients with acute symptomatic VTE and a significant risk of bleeding was associated with a lower risk of PE-related death, but did not decrease the rate of major bleeding at 30 days.23
In the literature, no studies have yet assessed the efficacy and safety of anticoagulant therapy beyond the first 6 months, but in a recent survey containing 49 questions on different aspects of the treatment of cancer patients with VTE, almost half of the respondents chose to continue LMWH treatment after the initial 3 to 12 months, most often for life-long.24 According to our findings, indefinite anticoagulation should probably be reconsidered for some of these patients.
The present study has a number of potential limitations. First, patients were not treated with a standardized anticoagulant regimen and treatment varied with local practice, which was influenced by a physician's assessment of a patient's risk of bleeding. Second, data from registries are susceptible to selection bias if a nonrepresentative sample of patients is selected for analysis. However, the RIETE registry captured a broad range of cancer patients with acute symptomatic VTE from multiple medical centers, countries, and treatment settings, and the study cohort was less likely a skewed population. Third, to fulfill the definition of fatal PE in RIETE patients must first experience an objectively confirmed recurrent PE followed by death within 10 days. Thus, all sudden unexplained deaths, usually considered as “likely” fatal recurrent PE, and many patients dying of respiratory insufficiency are not considered in this analysis. Therefore, the rate of fatal PE may have been underestimated, especially after hospital discharge. However, over 50% of these patients had chronic lung or heart disease, or lung cancer, and objective tests ruled out PE in some of them. Moreover, some deaths occurring at home without diagnosis may also have been due to cerebral bleeding. Finally, the study did not use a central committee to assign cause of death, but the number of deaths in the registry renders this task virtually impossible. On the other hand, strengths of the current analysis include that a large number of consecutive unselected patients were enrolled, and that fatal PE and fatal bleeding are by far the most important outcomes during the treatment of acute DVT. When considering the trade-off between increases in bleeding and decreases in recurrent VTE with different approaches to management, fatal PE and fatal bleeding are of equal importance, whereas that is not the case when nonfatal episodes of recurrent VTE and bleeding are included (eg, a recurrent DVT and a nonfatal intracranial bleed).
In conclusion, this large prospective RIETE study showed that the risk of dying from recurrent PE, varied according to VTE presentation at baseline, irrespective of the type of anticoagulation, and also according to cancer characteristics. In patients initially presenting with DVT, the risk of dying from recurrent PE was lower than in those initially presenting with PE. The overall rate of fatal recurrent PE was close to the rate of fatal bleeding, but was much higher within the first 3 months of anticoagulation therapy, suggesting that a less aggressive anticoagulant strategy (or a shorter duration) might reduce fatal bleeding over time. Implementation of current guidelines in cancer patients with VTE would benefit from randomized trials, which are needed to establish whether any different strategy is superior to standard anticoagulation after 3 months in cancer patients with VTE.
We thank the Registry Coordinating Center, S & H Medical Science Service, for their quality control, logistic, and administrative support.
Addendum: D. Farge-Bancel contributed to the design, analysis and interpretation of data, collected patients, and wrote the article.
J. Trujillo-Santos contributed to the design, analysis and interpretation of data, collected patients, and approved the final version of the article.
P. Debourdeau contributed to the design, collected patients, and approved the final version of the article.
A. Bura-Riviere contributed to the interpretation of data, collected patients, and approved the final version of the article.
E. Rodriguez-Beltran contributed to the interpretation of data and approved the final version of the article.
J.A. Nieto contributed to the design, interpretation of data, revised the intellectual content, collected patients, and approved the final version of the article.
L. Peris contributed to the interpretation of data, collected patients, and approved the final version of the article.
D. Zeltser contributed to the interpretation of data, collected patients, and approved the final version of the article.
L. Mazzolai contributed to the interpretation of data, collected patients, and approved the final version of the article.
A. Hij contributed to the interpretation of data, collected patients, and approved the final version of the article.
M. Monreal contributed to the design, analysis and interpretation of data, collected patients, wrote the article, and obtained funding.
Coordinator of the RIETE Registry: Dr. Manuel Monreal (Spain)
RIETE Steering Committee Members:
Dr. Hervé Decousus (France); Dr. Paolo Prandoni (Italy); Dr. Benjamin Brenner (Israel)
RIETE National Coordinators: Dr. Raquel Barba (Spain); Dr. Pierpaolo Di Micco (Italy); Dr. Laurent Bertoletti (France)
Dr. Manolis Papadakis (Greece); Dr. Marijan Bosevski (R. Macedonia); Dr. Henri Bounameaux (Switzerland); Dr. Radovan Maly[Combining Acute Accent] (Czech Republic)
RIETE Registry Coordinating Center: S & H Medical Science Service
Members of the RIETE Group: SPAIN: Alcalde M, Arcelus JI, Ballaz A, Barba R, Barrón M, Barrón-Andrés B, Bascuñana J, Bedate P, Blanco-Molina A, Bueso T, Casado I, Conget F, del Molino F, del Toro J, Falgá C, Fernández-Capitán C, Fuentes MI, Gallego P, García J, García-Bragado F, Gavín O, Gómez V, González J, González-Bachs E, Grau E, Guil M, Guijarro R, Gutiérrez J, Hernández L, Jara-Palomares L, Jaras MJ, Jiménez D, Jiménez S, Lobo JL, López-Jiménez L, López-Sáez JB, Lorente MA, Lorenzo A, Luque JM, Madridano O, Macià M, Maestre A, Marchena PJ, Martín M, Monreal M, Mora JM, Muñoz FJ, Nauffal MD, Nieto JA, Núñez MJ, Ogea JL, Otero R, Pedrajas JM, Peris ML, Riera-Mestre A, Rivas A, Rodríguez-Dávila MA, Román P, Rosa V, Ruiz J, Ruiz-Ribó MD, Ruiz-Gamietea A, Ruiz-Giménez N, Sahuquillo JC, Samperiz A, Sánchez Muñoz-Torrero JF, Soler S, Tiberio G, Tilvan RM, Tolosa C, Trujillo J, Uresandi F, Valdés M, Valero B, Valle R, Vela J, Vidal G, Villalobos A, Villalta J, BRAZIL: Gadelha T, CZECH REPUBLIC: Malý R, Hirmerova J, Tomko T. FRANCE: Bertoletti L, Bura-Riviere A, Farge-Bancel D, Grange C, Hij A, Mahe I, Merah A, Quere I. GERMANY: Schellong S, GREECE: Babalis D, Papadakis M, Tzinieris I, IRELAND: Faul J, ISRAEL: Braester A, Brenner B, Tzoran I, Zeltser D, ITALY: Barillari G, Ciammaichella M, Dalla Valle F, Di Micco P, Duce R, Maida R, Pasca S, Piovella C, Poggio R, Prandoni P, Quintavalla R, Rocci A, Rota L, Schenone A, Tiraferri E, Tonello D, Tufano A, Visonà A, Zalunardo B, PORTUGAL: Brinquinho M, Gomes D, Gonçalves F, Santos M, Saraiva M, REPUBLIC OF MACEDONIA: Bosevski M, Kovacevic D, SWITZERLAND: Alatri A, Aujeski D, Bounameaux H, Calanca L, Mazzolai L, UNITED STATES: Caprini J.
1. Prandoni P, Lensing AW, Cogo A, et al. The long-term clinical course of acute deep venous thrombosis. Ann Intern Med
2. Levitan N, Dowlati A, Remick SC, et al. Rates of initial and recurrent thromboembolic disease among patients with malignancy versus those without malignancy. Risk analysis using Medicare claims data. Medicine (Baltimore)
3. Monreal M, Falgá C, Valdés M, et al. Fatal pulmonary embolism and fatal bleeding in cancer patients with venous thromboembolism: findings from the RIETE Registry. J Thromb Haemost
4. Lee AY, Peterson EA. Treatment of cancer-associated thrombosis. Blood
5. Wagman LD, Baird MF, Bennett CL, et al. Venous thromboembolic disease. NCCN clinical practice guidelines in oncology. J Natl Compr Canc Netw
6. Meyer G, Marjanovic Z, Valcke J, et al. Comparison of low-molecular-weight heparin and warfarin for the secondary prevention of venous thromboembolism in patients with cancer. Arch Intern Med
7. Lee AYY, Levine MN, Baker RI, et al. Low-molecular-weight heparin versus a coumarin for the prevention of recurrent venous thromboembolism in patients with cancer. N Engl J Med
8. Hull RD, Pineo GF, Brant RF, et al. Long-term low-molecular-weight heparin versus usual care in proximal-vein thrombosis patients with cancer. Am J Med
9. Akl EA, Vasireddi SR, Gunukula S, et al. Anticoagulation for the initial treatment of venous thromboembolism in patients with cancer (Review). Cochrane Database Syst Rev
10. Mandala M, Falanga A, Roila F. Management of venous thromboembolism (VTE) in cancer patients: ESMO Clinical Practice Guidelines. Ann Oncol
11. Kearon C, Akl EA, Comerota AJ, et al. Antithrombotic therapy for VTE disease. Antithrombotic therapy and prevention of thrombosis. American College of Chest Physicians evidence-based clinical practice guidelines (9th Edition). Chest
2012; 141 (2 Suppl):e419S–e494S.doi: 10.1378/chest.11-2301.
12. Farge D, Debourdeau P, Beckers M, et al. International clinical practice guidelines for the treatment and prophylaxis of venous thromboembolism in patients with cancer. J Thromb Haemost
13. Debourdeau P, Farge D, Beckers M, et al. International clinical practice guidelines for the treatment and prophylaxis of thrombosis associated with central venous catheters in patients with cancer. J Thromb Haemost
14. Lyman GH, Khorana AA, Kuderer NM, et al. Venous thromboembolism prophylaxis and treatment in patients with cancer. American Society of Clinical Oncology Clinical Practice Guideline Update. J Clin Oncol
15. Carrier M, Le Gal G, Wells PS, et al. Systematic review: case-fatality rates of recurrent venous thromboembolism and major bleeding events among patients treated for venous thromboembolism. Ann Intern Med
16. Laporte S, Mismetti P, Décousus H, et al. Clinical predictors for fatal pulmonary embolism in 15,520 patients with venous thromboembolism; Findings from the Registro Informatizado de la Enfermedad TromboEmbólica venosa (RIETE) Registry. Circulation
17. Trujillo-Santos, Nieto JA, Tiberio G, et al. Predicting recurrences or major bleeding in cancer patients with venous thromboembolism. Findings from the RIETE Registry. J Thromb Haemost
18. Gussoni G, Frasson S, La Regina M, et al. Three-month mortality rate and clinical predictors in patients with venous thromboembolism and cancer. Findings from the RIETE registry. Thromb Res
19. Montreal M, Falga C, Valdes M, et al. Fatal pulmonary embolism and fatal bleeding in cancer patients with venous thromboembolism; findings from the RIETE registry. J Thromb Hemost
20. Lecumberri R, Alfonso A, Jiménez D, et al. Dynamics of case-fatalilty rates of recurrent thromboembolism and major bleeding in patients treated for venous thromboembolism. J Thromb Haemost
21. Sánchez Muñoz-Torrero JF, Bounameaux H, Pedrajas JM, et al. Effects of age on the risk of dying from pulmonary embolism or bleeding during treatment of deep vein thrombosis. J Vasc Surg
22. Monreal M, Falgá C, Valle R, et al. Venous thromboembolism in patients with renal insufficiency: findings from the RIETE Registry. Am J Med
23. Muriel A, Jiménez D, Aujesky D, et al. Survival effects of inferior vena cava filter in patients with acute symptomatic venous thromboembolism and a significant bleeding risk. J Am Coll Cardiol
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
24. Kleinjan A, Aggarwal A, Van de Geer A, et al. A worldwide survey to assess the current approach to the treatment of patients with cancer and venous thromboembolism. J Thromb Haemost