Journal of Thrombosis and Haemostasis, 12: 1–3
LETTER TO THE EDITOR
Meta-analysis of the efficacy and safety of new oral anticoagulants in patients with cancer-associated acute venous thromboembolism: comment M . N . D . D I M I N N O , * † W . A G E N O ‡ and F . D E N T A L I ‡ *Department of Clinical Medicine and Surgery, Federico II University, Naples; †Unit of Cell and Molecular Biology in Cardiovascular Diseases, Centro Cardiologico Monzino, IRCCS, Milan; and ‡Department of Clinical and Experimental Medicine, University of Insubria, Varese, Italy
To cite this article: Di Minno MND, Ageno W, Dentali F. Meta-analysis of the efficacy and safety of new oral anticoagulants in patients with cancer-associated acute venous thromboembolism: comment. J Thromb Haemost 2014; DOI: 10.1111/jth.12746. See also van der Hulle T, den Exter PL, Kooiman J, van der Hoeven JJ, Huisman MV, Klok FA. Meta-analysis of the efficacy and safety of new oral anticoagulants in patients with cancer-associated acute venous thromboembolism. J Thromb Haemost. 2014; 12: 1116–20. and van der Hulle T, Huisman MV, Klok FA. Meta-analysis of the efficacy and safety of new oral anticoagulants in patients with cancer-associated acute venous thromboembolism: reply. J Thromb Haemost 2014; DOI: 10.1111/jth.12758.
We read with great interest the meta-analysis published by van der Hulle et al. [1] on five randomized controlled trials (RCTs) showing similar efficacy and safety of direct oral anticoagulants (DOACs) and vitamin K antagonists (VKAs) in cancer patients with acute venous thromboembolism (VTE) [2–6]. Despite the important message conveyed by this metaanalysis, it is still not clear whether these patients are representative of the real cancer patients with VTE who are usually encountered in clinical practice. Prospective studies have shown that patients with cancer treated with VKAs for acute VTE have an increased risk of VTE recurrence and of major bleeding events in comparison with patients with acute VTE but without cancer treated in the same way [7]. According to the original study protocols, patients at high risk of bleeding and with reduced life-expectancy were excluded. Thus, only a subgroup of ‘healthier’ cancer patients with clinical conditions similar to those of noncancer patients may have been included in these studies. Therefore, to obtain an indirect estimate of the clinical conditions of cancer patients enrolled in the five studies included in this meta-analysis, we compared the risk of Correspondence: Matteo Nicola Dario Di Minno, Department of Clinical Medicine and Surgery, Federico II University, Via S. Pansini 5, 80131 Naples, Italy Tel.: +39 81 7462060; fax: +39 81 7462060 E-mail: [email protected] DOI: 10.1111/jth.12746 Received 23 June 2014 Manuscript handled by: F. R. Rosendaal Final decision: F. R. Rosendaal, 28 September 2014 © 2014 International Society on Thrombosis and Haemostasis
VTE recurrence and of VTE-related death, and the risk of major and clinically relevant non-major bleeding events, in patients with and without cancer treated with VKAs enrolled in these trials. Pooled risk ratios (RRs) and 95% confidence intervals (CIs) were calculated with a random effects model. Heterogeneity among the studies was evaluated with the Cochrane Q v2-test. All five RCTs, with a total of 10 843 patients (404 patients with cancer and 10 439 without cancer) provided data about the efficacy outcome [2–6]. VTE recurrence or VTE-related death occurred in 4.9% of patients with cancer and in 2.6% of patients without cancer, giving a corresponding RR of 2.01 (95% CI 1.29– 3.13, P = 0.002; Cochrane v2 0.26, P = 0.97; Fig. 1A). Three RCTs with a total of 8238 patients (295 patients with cancer and 7943 without cancer) provided data about the safety outcome [4–6]. Major and clinically relevant non-major bleeding events occurred in 16.6% of patients with cancer and in 9.9% of patients without cancer, giving a corresponding RR of 1.68 (95% CI 0.86– 3.28, P = 0.13; Cochrane v2 11.68, P = 0.003; Fig. 1B). These data extend the validity for clinical practice of the results reported by van der Hulle et al. [1] showing that patients with cancer included in these studies have a significantly increased risk of VTE recurrence and a nonsignificantly increased risk of bleeding complications. Although our findings should be interpreted with caution, owing to the low number of patients with cancer included in the analysis and to the significant heterogeneity among the trials for the bleeding outcome, our results may have clinical relevance, as VTE is a common complication in cancer patients. Indeed, those with active cancer have a four-fold to seven-fold higher VTE risk than non-cancer patients, and 5–20% of patients diagnosed with cancer will develop VTE [8]. Furthermore, VTE in cancer
2 Letter to the Editor A: Efficacy outcome (recurrent VTE or VTE-related death) Cancer patients Patients without cancer Study or subgroup Events Total Events Total
Risk ratio Weight M-H, Random, 95% CI
EINSTEIN DVT 2012 EINSTEIN PE 2012 HOKUSAY 2013 RECOVER I-II 2014
24.4% 14.7% 36.6% 24.3%
1.99 (0.81–4.88) 1.57 (0.49,–4.99) 2.05 (0.98,–4.26) 2.29 (0.93,–5.62)
10439 100.0% Total (95% CI) 404 20 Total events 276 Heterogeneity: Tau2 = 0.00; Chi2 = 0.26, d.f. = 3 (P = 0.97); I 2 = 0% Test for overall effect: Z = 3.08 (P = 0.002)
2.01 (1.29,–3.13)
5 3 7 5
89 109 99 107
46 41 139 50
1629 2340 4023 2447
Risk ratio M-H, Random, 95% CI
0.2 0.5 1 2 5 Favors cancer patients Favors patients without cancer
B: Safety outcome (major or clinically relevant non-major bleeding) Cancer patients Patients without cancer Study or subgroup Events Total Events Total 124 14 1623 88 EINSTEIN DVT 2012 2297 10 108 264 EINSTEIN PE 2012 99 HOKUSAY 2013 4023 25 398
Risk ratio Weight M-H, Random, 95% CI 2.08 (1.25–3.47) 32.9% 30.6% 0.81 (0.44,–1.47) 2.55 (1.80,–3.63) 36.5%
295 7943 100.0% Total (95% CI) 49 786 Total events Heterogeneity: Tau2 = 0.29; Chi2 = 11.68, d.f. = 2 (P = 0.003); I 2 = 83% Test for overall effect: Z = 1.51 (P = 0.13)
Risk ratio M-H, Random, 95% CI
1.68 (0.86,–3.28) 0.2 0.5 1 2 5 Favors patients with Cancer Favors patients with Cancer
Fig. 1. Forrest plots of the relative risk of efficacy and safety outcomes in patients with and without cancer treated with vitamin K antagonists for an acute episode of VTE. (A) venous thromboembolism (VTE) recurrence and VTE-related death (B) major and clinically relevant nonmajor bleeding events. CI, confidence interval; d.f., degrees of freedom; M-H, Mantel-Haenszel test.
patients is associated with relevant complications, and thromboembolic events constitute the second leading cause of death in cancer patients, accounting for 9% of deaths in this clinical setting [9,10]. Low molecular weight heparin (LMWH) is considered to be the treatment of choice for acute VTE in patients with active cancer [11], as RCTs [12] and a recent Cochrane systematic review [13] have shown a significant reduction in the incidence of VTE recurrence without any difference in the rate of bleeding or survival in patients treated with LMWH in comparison with patients treated with VKAs. Thus, our findings, together with the results of van der Hulle et al. [1], provide a robust rationale to plan a large RCT comparing the safety and efficacy of DOACs and LMWH for the management of acute VTE in cancer patients. Addendum M. N. D. Di Minno conceived and designed the study, performed the analysis, interpreted results, and drafted the manuscript. F. Dentali conceived and designed the study, performed the analysis, interpreted results, and drafted the manuscript. W. Ageno interpreted results and performed critical revision of the manuscript. All authors read and approved the final version of the manuscript. Disclosure of Conflict of Interests The authors state that they have no conflict of interest.
References 1 van der Hulle T, den Exter PL, Kooiman J, van der Hoeven JJ, Huisman MV, Klok FA. Meta-analysis of the efficacy and safety of new oral anticoagulants in patients with cancer-associated acute venous thromboembolism. J Thromb Haemost 2014; 12: 1116–20. 2 Schulman S, Kearon C, Kakkar AK, Mismetti P, Schellong S, Eriksson H, Baanstra D, Schnee J, Goldhaber SZ; RE-COVER Study Group. Dabigatran versus warfarin in the treatment of acute venous thromboembolism. N Engl J Med 2009; 361: 2342–52. 3 Schulman S, Kakkar AK, Goldhaber SZ, Schellong S, Eriksson H, Mismetti P, Christiansen AV, Friedman J, Le Maulf F, Peter N, Kearon C; RE-COVER II Trial Investigators. Treatment of acute venous thromboembolism with dabigatran or warfarin and pooled analysis. Circulation 2014; 129: 764–72. 4 Bauersachs R, Berkowitz SD, Brenner B, Buller HR, Decousus H, Gallus AS, Lensing AW, Misselwitz F, Prins MH, Raskob GE, Segers A, Verhamme P, Wells P, Agnelli G, Bounameaux H, Cohen A, Davidson BL, Piovella F, Schellong S; EINSTEIN Investigators. Oral rivaroxaban for symptomatic venous thromboembolism. N Engl J Med 2010; 363: 2499–510. 5 B€ uller HR, Prins MH, Lensin AW, Decousus H, Jacobson BF, Minar E, Chlumsky J, Verhamme P, Wells P, Agnelli G, Cohen A, Berkowitz SD, Bounameaux H, Davidson BL, Misselwitz F, Gallus AS, Raskob GE, Schellong S, Segers A; EINSTEIN–PE Investigators. Oral rivaroxaban for the treatment of symptomatic pulmonary embolism. N Engl J Med 2012; 366: 1287–97. 6 B€ uller HR, Decousus H, Grosso MA, Mercuri M, Middeldorp S, Prins MH, Raskob GE, Schellong SM, Schwocho L, Segers A, Shi M, Verhamme P, Wells P. Edoxaban versus warfarin for the treatment of symptomatic venous thromboembolism. Hokusai-VTE Investigators. N Engl J Med 2013; 369: 1406–15. 7 Prandoni P, Lensing AW, Piccioli A, Bernardi E, Simioni P, Girolami B, Marchiori A, Sabbion P, Prins MH, Noventa F, © 2014 International Society on Thrombosis and Haemostasis
Letter to the Editor 3
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10
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Girolami A. Recurrent venous thromboembolism and bleeding complications during anticoagulant treatment in patients with cancer and venous thrombosis. Blood 2002; 100: 3484–8. Agnelli G, Verso M. Management of venous thromboembolism in patients with cancer. J Thromb Haemost 2011; 9: 316–24. Sorensen HT, Mellemkjaer L, Olsen JH, Baron JA. Prognosis of cancers associated with venous thromboembolism. N Engl J Med 2000; 343: 1846–50. Chew HK, Wun T, Harvey D, Zhou H, White RH. Incidence of venous thromboembolism and its effect on survival among patients with common cancers. Arch Intern Med 2006; 166: 458–64. Kearon C, Akl EA, Comerota AJ, Prandoni P, Bounameaux H, Goldhaber SZ, Nelson ME, Wells PS, Gould MK, Dentali F, Crowther M, Kahn SR; American College of Chest Physicians. Antithrombotic therapy for VTE disease. Antithrombotic Therapy and Prevention of Thrombosis, 9th ed.: American College of
© 2014 International Society on Thrombosis and Haemostasis
Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012; 141: e419S–94S. 12 Lee AY, Levine MN, Baker RI, Bowden C, Kakkar AK, Prins M, Rickles FR, Julian JA, Haley S, Kovacs MJ, Gent M; Randomized Comparison of Low-Molecular-Weight Heparin versus Oral Anticoagulant Therapy for the Prevention of Recurrent Venous Thromboembolism in Patients with Cancer (CLOT) Investigators. 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. 13 Akl EA, Kahale L, Barba M, Neumann I, Labedi N, Terrenato I, Sperati F, Muti P, Sch€ unemann H. Anticoagulation for the long-term treatment of venous thromboembolism in patients with cancer. Cochrane Database Syst Rev 2014; 7: CD006650.
LETTER TO THE EDITOR
Meta-analysis of the efficacy and safety of new oral anticoagulants in patients with cancer-associated acute venous thromboembolism: comment M . N . D . D I M I N N O , * † W . A G E N O ‡ and F . D E N T A L I ‡ *Department of Clinical Medicine and Surgery, Federico II University, Naples; †Unit of Cell and Molecular Biology in Cardiovascular Diseases, Centro Cardiologico Monzino, IRCCS, Milan; and ‡Department of Clinical and Experimental Medicine, University of Insubria, Varese, Italy
To cite this article: Di Minno MND, Ageno W, Dentali F. Meta-analysis of the efficacy and safety of new oral anticoagulants in patients with cancer-associated acute venous thromboembolism: comment. J Thromb Haemost 2014; DOI: 10.1111/jth.12746. See also van der Hulle T, den Exter PL, Kooiman J, van der Hoeven JJ, Huisman MV, Klok FA. Meta-analysis of the efficacy and safety of new oral anticoagulants in patients with cancer-associated acute venous thromboembolism. J Thromb Haemost. 2014; 12: 1116–20. and van der Hulle T, Huisman MV, Klok FA. Meta-analysis of the efficacy and safety of new oral anticoagulants in patients with cancer-associated acute venous thromboembolism: reply. J Thromb Haemost 2014; DOI: 10.1111/jth.12758.
We read with great interest the meta-analysis published by van der Hulle et al. [1] on five randomized controlled trials (RCTs) showing similar efficacy and safety of direct oral anticoagulants (DOACs) and vitamin K antagonists (VKAs) in cancer patients with acute venous thromboembolism (VTE) [2–6]. Despite the important message conveyed by this metaanalysis, it is still not clear whether these patients are representative of the real cancer patients with VTE who are usually encountered in clinical practice. Prospective studies have shown that patients with cancer treated with VKAs for acute VTE have an increased risk of VTE recurrence and of major bleeding events in comparison with patients with acute VTE but without cancer treated in the same way [7]. According to the original study protocols, patients at high risk of bleeding and with reduced life-expectancy were excluded. Thus, only a subgroup of ‘healthier’ cancer patients with clinical conditions similar to those of noncancer patients may have been included in these studies. Therefore, to obtain an indirect estimate of the clinical conditions of cancer patients enrolled in the five studies included in this meta-analysis, we compared the risk of Correspondence: Matteo Nicola Dario Di Minno, Department of Clinical Medicine and Surgery, Federico II University, Via S. Pansini 5, 80131 Naples, Italy Tel.: +39 81 7462060; fax: +39 81 7462060 E-mail: [email protected] DOI: 10.1111/jth.12746 Received 23 June 2014 Manuscript handled by: F. R. Rosendaal Final decision: F. R. Rosendaal, 28 September 2014 © 2014 International Society on Thrombosis and Haemostasis
VTE recurrence and of VTE-related death, and the risk of major and clinically relevant non-major bleeding events, in patients with and without cancer treated with VKAs enrolled in these trials. Pooled risk ratios (RRs) and 95% confidence intervals (CIs) were calculated with a random effects model. Heterogeneity among the studies was evaluated with the Cochrane Q v2-test. All five RCTs, with a total of 10 843 patients (404 patients with cancer and 10 439 without cancer) provided data about the efficacy outcome [2–6]. VTE recurrence or VTE-related death occurred in 4.9% of patients with cancer and in 2.6% of patients without cancer, giving a corresponding RR of 2.01 (95% CI 1.29– 3.13, P = 0.002; Cochrane v2 0.26, P = 0.97; Fig. 1A). Three RCTs with a total of 8238 patients (295 patients with cancer and 7943 without cancer) provided data about the safety outcome [4–6]. Major and clinically relevant non-major bleeding events occurred in 16.6% of patients with cancer and in 9.9% of patients without cancer, giving a corresponding RR of 1.68 (95% CI 0.86– 3.28, P = 0.13; Cochrane v2 11.68, P = 0.003; Fig. 1B). These data extend the validity for clinical practice of the results reported by van der Hulle et al. [1] showing that patients with cancer included in these studies have a significantly increased risk of VTE recurrence and a nonsignificantly increased risk of bleeding complications. Although our findings should be interpreted with caution, owing to the low number of patients with cancer included in the analysis and to the significant heterogeneity among the trials for the bleeding outcome, our results may have clinical relevance, as VTE is a common complication in cancer patients. Indeed, those with active cancer have a four-fold to seven-fold higher VTE risk than non-cancer patients, and 5–20% of patients diagnosed with cancer will develop VTE [8]. Furthermore, VTE in cancer
2 Letter to the Editor A: Efficacy outcome (recurrent VTE or VTE-related death) Cancer patients Patients without cancer Study or subgroup Events Total Events Total
Risk ratio Weight M-H, Random, 95% CI
EINSTEIN DVT 2012 EINSTEIN PE 2012 HOKUSAY 2013 RECOVER I-II 2014
24.4% 14.7% 36.6% 24.3%
1.99 (0.81–4.88) 1.57 (0.49,–4.99) 2.05 (0.98,–4.26) 2.29 (0.93,–5.62)
10439 100.0% Total (95% CI) 404 20 Total events 276 Heterogeneity: Tau2 = 0.00; Chi2 = 0.26, d.f. = 3 (P = 0.97); I 2 = 0% Test for overall effect: Z = 3.08 (P = 0.002)
2.01 (1.29,–3.13)
5 3 7 5
89 109 99 107
46 41 139 50
1629 2340 4023 2447
Risk ratio M-H, Random, 95% CI
0.2 0.5 1 2 5 Favors cancer patients Favors patients without cancer
B: Safety outcome (major or clinically relevant non-major bleeding) Cancer patients Patients without cancer Study or subgroup Events Total Events Total 124 14 1623 88 EINSTEIN DVT 2012 2297 10 108 264 EINSTEIN PE 2012 99 HOKUSAY 2013 4023 25 398
Risk ratio Weight M-H, Random, 95% CI 2.08 (1.25–3.47) 32.9% 30.6% 0.81 (0.44,–1.47) 2.55 (1.80,–3.63) 36.5%
295 7943 100.0% Total (95% CI) 49 786 Total events Heterogeneity: Tau2 = 0.29; Chi2 = 11.68, d.f. = 2 (P = 0.003); I 2 = 83% Test for overall effect: Z = 1.51 (P = 0.13)
Risk ratio M-H, Random, 95% CI
1.68 (0.86,–3.28) 0.2 0.5 1 2 5 Favors patients with Cancer Favors patients with Cancer
Fig. 1. Forrest plots of the relative risk of efficacy and safety outcomes in patients with and without cancer treated with vitamin K antagonists for an acute episode of VTE. (A) venous thromboembolism (VTE) recurrence and VTE-related death (B) major and clinically relevant nonmajor bleeding events. CI, confidence interval; d.f., degrees of freedom; M-H, Mantel-Haenszel test.
patients is associated with relevant complications, and thromboembolic events constitute the second leading cause of death in cancer patients, accounting for 9% of deaths in this clinical setting [9,10]. Low molecular weight heparin (LMWH) is considered to be the treatment of choice for acute VTE in patients with active cancer [11], as RCTs [12] and a recent Cochrane systematic review [13] have shown a significant reduction in the incidence of VTE recurrence without any difference in the rate of bleeding or survival in patients treated with LMWH in comparison with patients treated with VKAs. Thus, our findings, together with the results of van der Hulle et al. [1], provide a robust rationale to plan a large RCT comparing the safety and efficacy of DOACs and LMWH for the management of acute VTE in cancer patients. Addendum M. N. D. Di Minno conceived and designed the study, performed the analysis, interpreted results, and drafted the manuscript. F. Dentali conceived and designed the study, performed the analysis, interpreted results, and drafted the manuscript. W. Ageno interpreted results and performed critical revision of the manuscript. All authors read and approved the final version of the manuscript. Disclosure of Conflict of Interests The authors state that they have no conflict of interest.
References 1 van der Hulle T, den Exter PL, Kooiman J, van der Hoeven JJ, Huisman MV, Klok FA. Meta-analysis of the efficacy and safety of new oral anticoagulants in patients with cancer-associated acute venous thromboembolism. J Thromb Haemost 2014; 12: 1116–20. 2 Schulman S, Kearon C, Kakkar AK, Mismetti P, Schellong S, Eriksson H, Baanstra D, Schnee J, Goldhaber SZ; RE-COVER Study Group. Dabigatran versus warfarin in the treatment of acute venous thromboembolism. N Engl J Med 2009; 361: 2342–52. 3 Schulman S, Kakkar AK, Goldhaber SZ, Schellong S, Eriksson H, Mismetti P, Christiansen AV, Friedman J, Le Maulf F, Peter N, Kearon C; RE-COVER II Trial Investigators. Treatment of acute venous thromboembolism with dabigatran or warfarin and pooled analysis. Circulation 2014; 129: 764–72. 4 Bauersachs R, Berkowitz SD, Brenner B, Buller HR, Decousus H, Gallus AS, Lensing AW, Misselwitz F, Prins MH, Raskob GE, Segers A, Verhamme P, Wells P, Agnelli G, Bounameaux H, Cohen A, Davidson BL, Piovella F, Schellong S; EINSTEIN Investigators. Oral rivaroxaban for symptomatic venous thromboembolism. N Engl J Med 2010; 363: 2499–510. 5 B€ uller HR, Prins MH, Lensin AW, Decousus H, Jacobson BF, Minar E, Chlumsky J, Verhamme P, Wells P, Agnelli G, Cohen A, Berkowitz SD, Bounameaux H, Davidson BL, Misselwitz F, Gallus AS, Raskob GE, Schellong S, Segers A; EINSTEIN–PE Investigators. Oral rivaroxaban for the treatment of symptomatic pulmonary embolism. N Engl J Med 2012; 366: 1287–97. 6 B€ uller HR, Decousus H, Grosso MA, Mercuri M, Middeldorp S, Prins MH, Raskob GE, Schellong SM, Schwocho L, Segers A, Shi M, Verhamme P, Wells P. Edoxaban versus warfarin for the treatment of symptomatic venous thromboembolism. Hokusai-VTE Investigators. N Engl J Med 2013; 369: 1406–15. 7 Prandoni P, Lensing AW, Piccioli A, Bernardi E, Simioni P, Girolami B, Marchiori A, Sabbion P, Prins MH, Noventa F, © 2014 International Society on Thrombosis and Haemostasis
Letter to the Editor 3
8 9
10
11
Girolami A. Recurrent venous thromboembolism and bleeding complications during anticoagulant treatment in patients with cancer and venous thrombosis. Blood 2002; 100: 3484–8. Agnelli G, Verso M. Management of venous thromboembolism in patients with cancer. J Thromb Haemost 2011; 9: 316–24. Sorensen HT, Mellemkjaer L, Olsen JH, Baron JA. Prognosis of cancers associated with venous thromboembolism. N Engl J Med 2000; 343: 1846–50. Chew HK, Wun T, Harvey D, Zhou H, White RH. Incidence of venous thromboembolism and its effect on survival among patients with common cancers. Arch Intern Med 2006; 166: 458–64. Kearon C, Akl EA, Comerota AJ, Prandoni P, Bounameaux H, Goldhaber SZ, Nelson ME, Wells PS, Gould MK, Dentali F, Crowther M, Kahn SR; American College of Chest Physicians. Antithrombotic therapy for VTE disease. Antithrombotic Therapy and Prevention of Thrombosis, 9th ed.: American College of
© 2014 International Society on Thrombosis and Haemostasis
Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012; 141: e419S–94S. 12 Lee AY, Levine MN, Baker RI, Bowden C, Kakkar AK, Prins M, Rickles FR, Julian JA, Haley S, Kovacs MJ, Gent M; Randomized Comparison of Low-Molecular-Weight Heparin versus Oral Anticoagulant Therapy for the Prevention of Recurrent Venous Thromboembolism in Patients with Cancer (CLOT) Investigators. 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. 13 Akl EA, Kahale L, Barba M, Neumann I, Labedi N, Terrenato I, Sperati F, Muti P, Sch€ unemann H. Anticoagulation for the long-term treatment of venous thromboembolism in patients with cancer. Cochrane Database Syst Rev 2014; 7: CD006650.
