J Thromb Thrombolysis DOI 10.1007/s11239-014-1152-8
REPLY TO THE LETTER
Primary venous thromboembolism prophylaxis in patients with solid tumors A. Casanegra • A. Mansfield • A. Tafur
Ó Springer Science+Business Media New York 2014
Dear Editor, Our meta-analysis: ‘‘Primary venous thromboembolism prophylaxis in patients with solid tumors’’, was published on line in November 2013 [1]. We are writing to respond to comments made in a letter to the editor referencing our work. The abstracted and analyzed information in our metaanalysis was obtained independently by 2 reviewers. In the year since our initial abstraction and analysis, similar studies have found equivalent results to the question of primary thrombosis prevention in outpatients with cancer. Most recently, in a meta-analysis by DiNisio et al., including patients with all types of cancer the use of preventive low molecular weight heparin (LMWH) was associated with a reduction in venous thromboembolism (VTE) (RR 0.53, 95 % CI 0.38–0.75) [2]. This estimate is concordant with ours (OR 0.53; 95 %CI 0.41–0.70) despite small differences in methodology [1]. Note the risk ratio and odd ratio pooled point estimate were the same. Indeed, odd ratio is known to be an adequate estimate of risk ratio when the events are not very common [3]. In meta-analyses, due to mathematical advantages odds ratio are often This is a response to Letter to the Editor (doi: 10.1007/s11239-0141138-6). Original Article to this reply can be found at doi: 10.1007/ s11239-013-1014-9. A. Casanegra A. Tafur (&) Cardiovascular Medicine Section, Health Sciences Center, University of Oklahoma, 920 Stanton L Young Blvd., WP3010, Oklahoma, OK 73104, USA e-mail: [email protected] A. Mansfield Department of Medical Oncology, Mayo Clinic, Rochester, MN, USA
used over risk ratios to standardize results of different trials [4], as we elected to do in ours. Although we acknowledge that there are important differences in the interpretation of risk ratios and odds ratios, and that the appropriateness of which to use depends on study design, our use of odd ratios was adequate. Tun adequately noted that 2 studies included arterial events in the definition of vascular thromboembolic events. Arterial events represented the minority of outcomes [5, 6]. However, if we exclude from our pooled analysis FRAGMEN and PROTECHT, the overall interpretation still translates into a significant reduction of VTE among patients with cancer who receive LMWH (OR 0.6; 95 %CI 0.42–0.9). Tun also argues that it was not appropriate to include a trial including upper extremity catheter associated thrombosis. Most clinicians will agree that an upper extremity deep vein thrombosis (DVT) is a concerning event regardless of the triggering event, as they convey a risk of pulmonary embolism, recurrent DVT and postthrombotic syndrome. Indeed, in the study by Young et al. two of the catheter related events were pulmonary embolisms, and four involved the superior vena cava [7]. In addition, we did provide estimates excluding catheter associated thrombosis. Although the trial by Young et al. was designed to evaluate a prophylactic regime to prevent catheter associated thrombosis (CAT) in cancer patients, they report all thrombotic events CAT and non-CAT, and those were the events included in our meta-analysis. Other studies included in our meta-analysis did not exclude CAT in the definition of their outcomes, for this reason and considering that CAT are prevalent in cancer patients we did not exclude them either. Finally, in patients with cancer it is recommended to treat catheter associated thrombosis with the same agents, intensity and duration as any other thrombosis [8].
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A. Casanegra et al.
Accordingly, we maintain our conclusion as previously stated: ‘‘thromboprophylaxis reduced the episodes of VTE in patients with solid tumors’’. We agree however with current guidelines, which recommend against routine thromboprophylaxis among outpatients with cancer [9]. Improved risk stratification techniques will allow us to better interpret who will benefit from primary prevention.
References 1. Phan M, John S, Casanegra AI, Rathbun S, Mansfield A, Stoner JA, Tafur AJ (2013) Primary venous thromboembolism prophylaxis in patients with solid tumors: a meta-analysis. J Thromb Thrombolysis. doi:10.1007/s11239-013-1014-9 2. Di Nisio M, Porreca E, Otten HM, Rutjes AW (2014) Primary prophylaxis for venous thromboembolism in ambulatory cancer patients receiving chemotherapy. Cochrane Database Syst Rev 8:CD008500. doi:10.1002/14651858.CD008500.pub3 3. Altman DG, Deeks JJ, Sackett DL (1998) Odds ratios should be avoided when events are common. BMJ 317:1318 4. Deeks JJ, Altman DG (2007) Effect measures for Meta-Analysis of trials with binary outcomes. In: Egger M (ed) Systematic reviews in health care. BMJ, London, pp 313–335
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5. Maraveyas A, Waters J, Roy R, Fyfe D, Propper D, Lofts F, Sgouros J, Gardiner E, Wedgwood K, Ettelaie C, Bozas G (2012) Gemcitabine versus gemcitabine plus dalteparin thromboprophylaxis in pancreatic cancer. Eur J Cancer 48:1283–1292. doi:10. 1016/j.ejca.2011.10.017 6. Agnelli G, Gussoni G, Bianchini C, Verso M, Mandala M, Cavanna L, Barni S, Labianca R, Buzzi F, Scambia G, Passalacqua R, Ricci S, Gasparini G, Lorusso V, Bonizzoni E, Tonato M (2009) Nadroparin for the prevention of thromboembolic events in ambulatory patients with metastatic or locally advanced solid cancer receiving chemotherapy: a randomised, placebo-controlled, double-blind study. Lancet Oncol 10:943–949. doi:10.1016/ S1470-2045(09)70232-3 7. Young AM, Billingham LJ, Begum G, Kerr DJ, Hughes AI, Rea DW, Shepherd S, Stanley A, Sweeney A, Wilde J, Wheatley K (2009) Warfarin thromboprophylaxis in cancer patients with central venous catheters (WARP): an open-label randomised trial. Lancet 373:567–574. doi:10.1016/S0140-6736(09)60205-1 8. Zwicker JI, Connolly G, Carrier M, Kamphuisen PW, Lee AY (2014) Catheter-associated deep vein thrombosis of the upper extremity in cancer patients: guidance from the SSC of the ISTH. J Thromb Haemost 12:796–800. doi:10.1111/jth.12527 9. Khorana AA, Otten HM, Zwicker JI, Connolly GC, Bancel DF, Pabinger I (2014) Prevention of venous thromboembolism in cancer outpatients: guidance from the SSC of the ISTH. J Thromb Haemost. doi:10.1111/jth.12725
REPLY TO THE LETTER
Primary venous thromboembolism prophylaxis in patients with solid tumors A. Casanegra • A. Mansfield • A. Tafur
Ó Springer Science+Business Media New York 2014
Dear Editor, Our meta-analysis: ‘‘Primary venous thromboembolism prophylaxis in patients with solid tumors’’, was published on line in November 2013 [1]. We are writing to respond to comments made in a letter to the editor referencing our work. The abstracted and analyzed information in our metaanalysis was obtained independently by 2 reviewers. In the year since our initial abstraction and analysis, similar studies have found equivalent results to the question of primary thrombosis prevention in outpatients with cancer. Most recently, in a meta-analysis by DiNisio et al., including patients with all types of cancer the use of preventive low molecular weight heparin (LMWH) was associated with a reduction in venous thromboembolism (VTE) (RR 0.53, 95 % CI 0.38–0.75) [2]. This estimate is concordant with ours (OR 0.53; 95 %CI 0.41–0.70) despite small differences in methodology [1]. Note the risk ratio and odd ratio pooled point estimate were the same. Indeed, odd ratio is known to be an adequate estimate of risk ratio when the events are not very common [3]. In meta-analyses, due to mathematical advantages odds ratio are often This is a response to Letter to the Editor (doi: 10.1007/s11239-0141138-6). Original Article to this reply can be found at doi: 10.1007/ s11239-013-1014-9. A. Casanegra A. Tafur (&) Cardiovascular Medicine Section, Health Sciences Center, University of Oklahoma, 920 Stanton L Young Blvd., WP3010, Oklahoma, OK 73104, USA e-mail: [email protected] A. Mansfield Department of Medical Oncology, Mayo Clinic, Rochester, MN, USA
used over risk ratios to standardize results of different trials [4], as we elected to do in ours. Although we acknowledge that there are important differences in the interpretation of risk ratios and odds ratios, and that the appropriateness of which to use depends on study design, our use of odd ratios was adequate. Tun adequately noted that 2 studies included arterial events in the definition of vascular thromboembolic events. Arterial events represented the minority of outcomes [5, 6]. However, if we exclude from our pooled analysis FRAGMEN and PROTECHT, the overall interpretation still translates into a significant reduction of VTE among patients with cancer who receive LMWH (OR 0.6; 95 %CI 0.42–0.9). Tun also argues that it was not appropriate to include a trial including upper extremity catheter associated thrombosis. Most clinicians will agree that an upper extremity deep vein thrombosis (DVT) is a concerning event regardless of the triggering event, as they convey a risk of pulmonary embolism, recurrent DVT and postthrombotic syndrome. Indeed, in the study by Young et al. two of the catheter related events were pulmonary embolisms, and four involved the superior vena cava [7]. In addition, we did provide estimates excluding catheter associated thrombosis. Although the trial by Young et al. was designed to evaluate a prophylactic regime to prevent catheter associated thrombosis (CAT) in cancer patients, they report all thrombotic events CAT and non-CAT, and those were the events included in our meta-analysis. Other studies included in our meta-analysis did not exclude CAT in the definition of their outcomes, for this reason and considering that CAT are prevalent in cancer patients we did not exclude them either. Finally, in patients with cancer it is recommended to treat catheter associated thrombosis with the same agents, intensity and duration as any other thrombosis [8].
123
A. Casanegra et al.
Accordingly, we maintain our conclusion as previously stated: ‘‘thromboprophylaxis reduced the episodes of VTE in patients with solid tumors’’. We agree however with current guidelines, which recommend against routine thromboprophylaxis among outpatients with cancer [9]. Improved risk stratification techniques will allow us to better interpret who will benefit from primary prevention.
References 1. Phan M, John S, Casanegra AI, Rathbun S, Mansfield A, Stoner JA, Tafur AJ (2013) Primary venous thromboembolism prophylaxis in patients with solid tumors: a meta-analysis. J Thromb Thrombolysis. doi:10.1007/s11239-013-1014-9 2. Di Nisio M, Porreca E, Otten HM, Rutjes AW (2014) Primary prophylaxis for venous thromboembolism in ambulatory cancer patients receiving chemotherapy. Cochrane Database Syst Rev 8:CD008500. doi:10.1002/14651858.CD008500.pub3 3. Altman DG, Deeks JJ, Sackett DL (1998) Odds ratios should be avoided when events are common. BMJ 317:1318 4. Deeks JJ, Altman DG (2007) Effect measures for Meta-Analysis of trials with binary outcomes. In: Egger M (ed) Systematic reviews in health care. BMJ, London, pp 313–335
123
5. Maraveyas A, Waters J, Roy R, Fyfe D, Propper D, Lofts F, Sgouros J, Gardiner E, Wedgwood K, Ettelaie C, Bozas G (2012) Gemcitabine versus gemcitabine plus dalteparin thromboprophylaxis in pancreatic cancer. Eur J Cancer 48:1283–1292. doi:10. 1016/j.ejca.2011.10.017 6. Agnelli G, Gussoni G, Bianchini C, Verso M, Mandala M, Cavanna L, Barni S, Labianca R, Buzzi F, Scambia G, Passalacqua R, Ricci S, Gasparini G, Lorusso V, Bonizzoni E, Tonato M (2009) Nadroparin for the prevention of thromboembolic events in ambulatory patients with metastatic or locally advanced solid cancer receiving chemotherapy: a randomised, placebo-controlled, double-blind study. Lancet Oncol 10:943–949. doi:10.1016/ S1470-2045(09)70232-3 7. Young AM, Billingham LJ, Begum G, Kerr DJ, Hughes AI, Rea DW, Shepherd S, Stanley A, Sweeney A, Wilde J, Wheatley K (2009) Warfarin thromboprophylaxis in cancer patients with central venous catheters (WARP): an open-label randomised trial. Lancet 373:567–574. doi:10.1016/S0140-6736(09)60205-1 8. Zwicker JI, Connolly G, Carrier M, Kamphuisen PW, Lee AY (2014) Catheter-associated deep vein thrombosis of the upper extremity in cancer patients: guidance from the SSC of the ISTH. J Thromb Haemost 12:796–800. doi:10.1111/jth.12527 9. Khorana AA, Otten HM, Zwicker JI, Connolly GC, Bancel DF, Pabinger I (2014) Prevention of venous thromboembolism in cancer outpatients: guidance from the SSC of the ISTH. J Thromb Haemost. doi:10.1111/jth.12725
