Journal of Thrombosis and Haemostasis, 13: 323–326
LETTERS TO THE EDITOR
Prevention of venous thromboembolism in cancer outpatients: guidance from the SSC of the ISTH: comment T. H. OO The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA
To cite this article: Oo TH. Prevention of venous thromboembolism in cancer outpatients: guidance from the SSC of the ISTH: comment. J Thromb Haemost 2015; 13: 323–4. See also Khorana AA, Otten HM, Zwicker JI, Connolly GC, Bancel DF, Pabinger I, for the Subcommittee on Haemostasis and Malignancy. Prevention of venous thromboembolism in cancer outpatients: guidance from the SSC of the ISTH. J Thromb Haemost 2014; 12: 1928–31 and Khorana AA, Zwicker JI, Connolly GC, Pabinger I. Prevention of venous thromboembolism in cancer outpatients: guidance from the SSC of the ISTH: reply. This issue, pp 325–6.
I read the article by Khorana et al. with particular interest. The authors stated that ‘clinicians may consider three groups of high-risk patients for outpatient thromboprophylaxis: advanced pancreas cancer based on the results of FRAGEM and CONKO-004; high-risk patients (Khorana Score ≥ 3) based on subgroup analyses of PROTECHT and SAVE-ONCO and myeloma patients receiving imid-based combination regimens based on prophylaxis studies’ [1]. While I agree with outpatient thromboprophylaxis (OTP) with aspirin in myeloma patients who are receiving imid-based combination regimens due to the high incidence of venous thromboembolism (VTE) events in this population, the real efficacy of aspirin in reducing the VTE events, inexpensive nature of long-term aspirin therapy, low major hemorrhagic risks (≤ 0.5%), and the OTP trials being large in nature (total of 909 patients in two trials) [2,3], I have reservations with OTP in two other groups and I believe the authors’ suggestions are premature. In the first category of OTP in advanced pancreas cancer, there are pitfalls with patient enrollment number, and perhaps patient selection in the FRAGEM and CONKO-004 trials. The total number of patients enrolled in the FRAGEM and CONKO-004 trials is only 433. The FRAGEM study is a small phase IIb study and
Correspondence: Thein Hlaing Oo, Section of Thrombosis & Benign Hematology (Unit 1464), The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030, USA. Tel.: +1 713 563 4260; fax: +1 713 563 4443. E-mail: [email protected] DOI: 10.1111/jth.12751 Received 29 September 2014 Manuscript handled by: F. R. Rosendaal Final decision: F. R. Rosendaal, 6 October 2014 © 2014 International Society on Thrombosis and Haemostasis
enrolled only 121 patients (62 in the control group and 59 in the dalteparin group) [4]. Based on this small study, the authors mentioned 6 as the number needed to treat (NNT) to prevent one VTE event. The other quoted CONKO-004 trial has limitations as this study reveals more major hemorrhagic events in the observation arm (9.9%) vs. enoxaparin arm (6.3%) and that this study has not yet been published [5]. How can someone explain the fact that patients in the observation arm develop more major hemorrhagic complications than those in the enoxaparin arm in the CONKO-004 trial? Giving OTP recommendations/suggestions based on small trials can be misleading. For example, Farge et al., published in this journal in 2013, stated, ‘Primary pharmacological prophylaxis of VTE may be indicated in patients with locally advanced or metastatic lung cancer treated with chemotherapy and having a low bleeding risk [Grade 2B]’ [6] based on analysis of pooled data from the PROTECHT and TOPIC-2 trials [7]. The assumption that OTP with low-molecular-weight heparin (LWMH) may be substantially beneficial in patients with advanced lung cancer receiving chemotherapy has recently been refuted by the large FRAGMATIC trial (which enrolled 1100 patients in each arm) that demonstrated the VTE reduction by OTP in lung cancer population is just marginal (7.1% in observation vs. 4.1% in the dalteparin group) [8]. Are the authors convinced that they would get the same NNT if the same FRAGEM study enrolled hundreds of patients (e.g. 300–400 patients in each arm)? I am also concerned with the suggested dalteparin dosage of 200 IU kg 1 per day for 4 weeks and 150 IU kg 1 per day thereafter, or enoxaparin dose of 1 mg kg 1 per day in pancreatic cancer patients for OTP because of the following reasons: (i) a very small number of patients enrolled in the FRAGEM trial from which really reliable efficacy cannot be calculated and (ii) probable underestimation of dalteparin-associated major hemorrhagic risk in the FRA-
324 Letters to the Editor
GEM trial. In the larger CLOT trial, the dalteparin-associated major hemorrhagic risk was 6%, while in the FRAGEM trial, it was 3%, although both trials use the same dalteparin dosing regimen [4,9]. The discrepancy in the rate of dalteparin-associated major hemorrhagic complications could have been due to the small number of patients enrolled in the FRAGEM trial. In addition, consider the (iii) high major hemorrhagic complication rate in the enoxaparin arm (6.3%) in the CONKO-004 trial [5] and that (iv) many pancreatic cancer patients who will never develop VTE events will be receiving therapeutic doses of LMWH unnecessarily. In conclusion, both the FRAGEM and CONKO-004 trials had problems with study designs and patient selection. In the second category of OTP in solid cancer patients with a Khorana score ≥ 3, the authors made this suggestion based on post-hoc subgroup analysis. There are always potential problems with subset analysis such as multiple comparison problems, overinterpretation of noted differences, apparent interaction effects, provision of indirect evidence, and being subject to substantial bias [10]. Conclusions should not be drawn from subset analyses. We have to keep in mind that OTP with LMWH is very different from other supportive care modalities such as antiemetics, zoledronic acid, or growth factors. Those supportive care modalities are mostly given intermittently and do not carry the risk of substantial major hemorrhagic complications. I would also like to point out that OTP in solid cancer patients is a novel idea and that I am not antagonizing the authors from the SSC of the ISTH. However, the authors should be very cautious in issuing guidance on this highly controversial topic. Certain things are clear, such as the high cost of LMWH, patient discomfort, anticoagulant-associated major hemorrhagic risks of up to 6%, risk of heparin-induced thrombocytopenia, a large NNT to prevent one VTE, and no survival benefits. In my opinion, OTP should not be recommended or suggested at present in solid cancer patients receiving chemotherapy. Larger well-designed randomized controlled trials are needed to address those questions. Disclosure of Conflict of Interests The author states that he has no conflict of interest.
2 Larocca A, Cavallo F, Bringhen S, Di Raimondo F, Falanga A, Evangelista A, Cavalli M, Stanevsky A, Corradini P, Pezzatti S, Patriarca F, Cavo M, Peccatori J, Catalano L, Carella AM, Cafro AM, Siniscalchi A, Crippa C, Petrucci MT, Yehuda DB, et al. Aspirin or enoxaparin thromboprophylaxis for patients with newly diagnosed multiple myeloma treated with lenalidomide. Blood 2012; 119: 933–9. 3 Palumbo A, Cavo M, Bringhen S, Zamagni E, Romano A, Patriarca F, Rossi D, Gentilini F, Crippa C, Galli M, Nozzoli C, Ria R, Marasca R, Montefusco V, Baldini L, Elice F, Callea V, Pulini S, Carella AM, Zambello R, et al. Aspirin, warfarin, or enoxaparin thromboprophylaxis in patients with multiple myeloma treated with thalidomide: a phase III, open-label, randomized trial. J Clin Oncol 2011; 29: 986–93. 4 Maraveyas A, Waters J, Roy R, Fyfe D, Propper D, Lofts F, Sgouros J, Gardiner E, Wedgwood K, Ettelaie C, Bozas G. Gemcitabine versus gemcitabine plus dalteparin thromboprophylaxis in pancreatic cancer. Eur J Cancer 2012; 48: 1283–92. 5 Riess H, Pelzer U, Deutschinoff G, Opitz B, Stauch M, Reitzig P, Hahnfeld S, Hilbig A, Stieler J, Oettle H. A prospective, randomized trial of chemotherapy with or without the low molecular weight heparin (LMWH) enoxaparin in patients (pts) with advanced pancreatic cancer (APC): results of the CONKO 004 trial. J Clin Oncol 2009; 27 (Suppl): 203s, abstr LBA450. 6 Farge D, Debourdeau P, Beckers M, Baglin C, Bauersachs RM, Brenner B, Brilhante D, Falanga A, Gerotzafias GT, Haim N, Kakkar AK, Khorana AA, Lecumberri R, Mandala M, Marty M, Monreal M, Mousa SA, Noble S, Pabinger I, Prandoni P, et al. International clinical practice guidelines for the treatment and prophylaxis of venous thromboembolism in patients with cancer. J Thromb Haemost 2013; 11: 56–70. 7 Verso M, Gussoni G, Agnelli G. Prevention of venous thromboembolism in patients with advanced lung cancer receiving chemotherapy: a combined analysis of the PROTECHT and TOPIC-2 studies. J Thromb Haemost 2010; 8: 1649–51. 8 Macbeth F, Noble S, Griffiths G, Chowdhury R, Rolfe C, Hood K, Linnane S, Moore B, Cohen D, Cowles R, Longo M, Knoyle D. Preliminary results from the FRAGMAIC trial: a randomized phase III clinical investigating the effect of FRAGMinâ added to standard therapy in patients with lung cancer [conference abstract MO27.02]. J Thorac Oncol 2013; 8 (Suppl 2): Abstract O27.02. 9 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. 10 Gelber RD, Goldhirsch A. Interpretation of results from subset analyses within overviews of randomized clinical trials. Stat Med 1987; 6: 371–88.
References 1 Khorana AA, Otten HM, Zwicker JI, Connolly GC, FargeBancel D, Pabinger I. Prevention of VTE in cancer outpatients: guidance from the SSC of the ISTH. J Thromb Haemost 2014; 12: 1928–31.
© 2014 International Society on Thrombosis and Haemostasis
Copyright of Journal of Thrombosis & Haemostasis is the property of Wiley-Blackwell and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.
LETTERS TO THE EDITOR
Prevention of venous thromboembolism in cancer outpatients: guidance from the SSC of the ISTH: comment T. H. OO The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA
To cite this article: Oo TH. Prevention of venous thromboembolism in cancer outpatients: guidance from the SSC of the ISTH: comment. J Thromb Haemost 2015; 13: 323–4. See also Khorana AA, Otten HM, Zwicker JI, Connolly GC, Bancel DF, Pabinger I, for the Subcommittee on Haemostasis and Malignancy. Prevention of venous thromboembolism in cancer outpatients: guidance from the SSC of the ISTH. J Thromb Haemost 2014; 12: 1928–31 and Khorana AA, Zwicker JI, Connolly GC, Pabinger I. Prevention of venous thromboembolism in cancer outpatients: guidance from the SSC of the ISTH: reply. This issue, pp 325–6.
I read the article by Khorana et al. with particular interest. The authors stated that ‘clinicians may consider three groups of high-risk patients for outpatient thromboprophylaxis: advanced pancreas cancer based on the results of FRAGEM and CONKO-004; high-risk patients (Khorana Score ≥ 3) based on subgroup analyses of PROTECHT and SAVE-ONCO and myeloma patients receiving imid-based combination regimens based on prophylaxis studies’ [1]. While I agree with outpatient thromboprophylaxis (OTP) with aspirin in myeloma patients who are receiving imid-based combination regimens due to the high incidence of venous thromboembolism (VTE) events in this population, the real efficacy of aspirin in reducing the VTE events, inexpensive nature of long-term aspirin therapy, low major hemorrhagic risks (≤ 0.5%), and the OTP trials being large in nature (total of 909 patients in two trials) [2,3], I have reservations with OTP in two other groups and I believe the authors’ suggestions are premature. In the first category of OTP in advanced pancreas cancer, there are pitfalls with patient enrollment number, and perhaps patient selection in the FRAGEM and CONKO-004 trials. The total number of patients enrolled in the FRAGEM and CONKO-004 trials is only 433. The FRAGEM study is a small phase IIb study and
Correspondence: Thein Hlaing Oo, Section of Thrombosis & Benign Hematology (Unit 1464), The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030, USA. Tel.: +1 713 563 4260; fax: +1 713 563 4443. E-mail: [email protected] DOI: 10.1111/jth.12751 Received 29 September 2014 Manuscript handled by: F. R. Rosendaal Final decision: F. R. Rosendaal, 6 October 2014 © 2014 International Society on Thrombosis and Haemostasis
enrolled only 121 patients (62 in the control group and 59 in the dalteparin group) [4]. Based on this small study, the authors mentioned 6 as the number needed to treat (NNT) to prevent one VTE event. The other quoted CONKO-004 trial has limitations as this study reveals more major hemorrhagic events in the observation arm (9.9%) vs. enoxaparin arm (6.3%) and that this study has not yet been published [5]. How can someone explain the fact that patients in the observation arm develop more major hemorrhagic complications than those in the enoxaparin arm in the CONKO-004 trial? Giving OTP recommendations/suggestions based on small trials can be misleading. For example, Farge et al., published in this journal in 2013, stated, ‘Primary pharmacological prophylaxis of VTE may be indicated in patients with locally advanced or metastatic lung cancer treated with chemotherapy and having a low bleeding risk [Grade 2B]’ [6] based on analysis of pooled data from the PROTECHT and TOPIC-2 trials [7]. The assumption that OTP with low-molecular-weight heparin (LWMH) may be substantially beneficial in patients with advanced lung cancer receiving chemotherapy has recently been refuted by the large FRAGMATIC trial (which enrolled 1100 patients in each arm) that demonstrated the VTE reduction by OTP in lung cancer population is just marginal (7.1% in observation vs. 4.1% in the dalteparin group) [8]. Are the authors convinced that they would get the same NNT if the same FRAGEM study enrolled hundreds of patients (e.g. 300–400 patients in each arm)? I am also concerned with the suggested dalteparin dosage of 200 IU kg 1 per day for 4 weeks and 150 IU kg 1 per day thereafter, or enoxaparin dose of 1 mg kg 1 per day in pancreatic cancer patients for OTP because of the following reasons: (i) a very small number of patients enrolled in the FRAGEM trial from which really reliable efficacy cannot be calculated and (ii) probable underestimation of dalteparin-associated major hemorrhagic risk in the FRA-
324 Letters to the Editor
GEM trial. In the larger CLOT trial, the dalteparin-associated major hemorrhagic risk was 6%, while in the FRAGEM trial, it was 3%, although both trials use the same dalteparin dosing regimen [4,9]. The discrepancy in the rate of dalteparin-associated major hemorrhagic complications could have been due to the small number of patients enrolled in the FRAGEM trial. In addition, consider the (iii) high major hemorrhagic complication rate in the enoxaparin arm (6.3%) in the CONKO-004 trial [5] and that (iv) many pancreatic cancer patients who will never develop VTE events will be receiving therapeutic doses of LMWH unnecessarily. In conclusion, both the FRAGEM and CONKO-004 trials had problems with study designs and patient selection. In the second category of OTP in solid cancer patients with a Khorana score ≥ 3, the authors made this suggestion based on post-hoc subgroup analysis. There are always potential problems with subset analysis such as multiple comparison problems, overinterpretation of noted differences, apparent interaction effects, provision of indirect evidence, and being subject to substantial bias [10]. Conclusions should not be drawn from subset analyses. We have to keep in mind that OTP with LMWH is very different from other supportive care modalities such as antiemetics, zoledronic acid, or growth factors. Those supportive care modalities are mostly given intermittently and do not carry the risk of substantial major hemorrhagic complications. I would also like to point out that OTP in solid cancer patients is a novel idea and that I am not antagonizing the authors from the SSC of the ISTH. However, the authors should be very cautious in issuing guidance on this highly controversial topic. Certain things are clear, such as the high cost of LMWH, patient discomfort, anticoagulant-associated major hemorrhagic risks of up to 6%, risk of heparin-induced thrombocytopenia, a large NNT to prevent one VTE, and no survival benefits. In my opinion, OTP should not be recommended or suggested at present in solid cancer patients receiving chemotherapy. Larger well-designed randomized controlled trials are needed to address those questions. Disclosure of Conflict of Interests The author states that he has no conflict of interest.
2 Larocca A, Cavallo F, Bringhen S, Di Raimondo F, Falanga A, Evangelista A, Cavalli M, Stanevsky A, Corradini P, Pezzatti S, Patriarca F, Cavo M, Peccatori J, Catalano L, Carella AM, Cafro AM, Siniscalchi A, Crippa C, Petrucci MT, Yehuda DB, et al. Aspirin or enoxaparin thromboprophylaxis for patients with newly diagnosed multiple myeloma treated with lenalidomide. Blood 2012; 119: 933–9. 3 Palumbo A, Cavo M, Bringhen S, Zamagni E, Romano A, Patriarca F, Rossi D, Gentilini F, Crippa C, Galli M, Nozzoli C, Ria R, Marasca R, Montefusco V, Baldini L, Elice F, Callea V, Pulini S, Carella AM, Zambello R, et al. Aspirin, warfarin, or enoxaparin thromboprophylaxis in patients with multiple myeloma treated with thalidomide: a phase III, open-label, randomized trial. J Clin Oncol 2011; 29: 986–93. 4 Maraveyas A, Waters J, Roy R, Fyfe D, Propper D, Lofts F, Sgouros J, Gardiner E, Wedgwood K, Ettelaie C, Bozas G. Gemcitabine versus gemcitabine plus dalteparin thromboprophylaxis in pancreatic cancer. Eur J Cancer 2012; 48: 1283–92. 5 Riess H, Pelzer U, Deutschinoff G, Opitz B, Stauch M, Reitzig P, Hahnfeld S, Hilbig A, Stieler J, Oettle H. A prospective, randomized trial of chemotherapy with or without the low molecular weight heparin (LMWH) enoxaparin in patients (pts) with advanced pancreatic cancer (APC): results of the CONKO 004 trial. J Clin Oncol 2009; 27 (Suppl): 203s, abstr LBA450. 6 Farge D, Debourdeau P, Beckers M, Baglin C, Bauersachs RM, Brenner B, Brilhante D, Falanga A, Gerotzafias GT, Haim N, Kakkar AK, Khorana AA, Lecumberri R, Mandala M, Marty M, Monreal M, Mousa SA, Noble S, Pabinger I, Prandoni P, et al. International clinical practice guidelines for the treatment and prophylaxis of venous thromboembolism in patients with cancer. J Thromb Haemost 2013; 11: 56–70. 7 Verso M, Gussoni G, Agnelli G. Prevention of venous thromboembolism in patients with advanced lung cancer receiving chemotherapy: a combined analysis of the PROTECHT and TOPIC-2 studies. J Thromb Haemost 2010; 8: 1649–51. 8 Macbeth F, Noble S, Griffiths G, Chowdhury R, Rolfe C, Hood K, Linnane S, Moore B, Cohen D, Cowles R, Longo M, Knoyle D. Preliminary results from the FRAGMAIC trial: a randomized phase III clinical investigating the effect of FRAGMinâ added to standard therapy in patients with lung cancer [conference abstract MO27.02]. J Thorac Oncol 2013; 8 (Suppl 2): Abstract O27.02. 9 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. 10 Gelber RD, Goldhirsch A. Interpretation of results from subset analyses within overviews of randomized clinical trials. Stat Med 1987; 6: 371–88.
References 1 Khorana AA, Otten HM, Zwicker JI, Connolly GC, FargeBancel D, Pabinger I. Prevention of VTE in cancer outpatients: guidance from the SSC of the ISTH. J Thromb Haemost 2014; 12: 1928–31.
© 2014 International Society on Thrombosis and Haemostasis
Copyright of Journal of Thrombosis & Haemostasis is the property of Wiley-Blackwell and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.
