Treatment Trends for Prostate Cancer—Reply

Letters Conflict of Interest Disclosures: The authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported. 1. Couturaud F, Sanchez O, Pernod G, et al; PADIS-PE Investigators. Six months vs extended oral anticoagulation after a first episode of pulmonary embolism: the PADIS-PE randomized clinical trial. JAMA. 2015;314(1):31-40. 2. Roldan V, Lecumberri R, Munoz-Torrero JF, et al; RIETE Investigators. Thrombophilia testing in patients with venous thromboembolism: findings from the RIETE registry. Thromb Res. 2009;124(2):174-177. 3. Keeling D, Mackie I, Moore GW, Greer IA, Greaves M; British Committee for Standards in Haematology. Guidelines on the investigation and management of antiphospholipid syndrome. Br J Haematol. 2012;157(1):47-58. In Reply Dr Rhinehart and colleagues raise an important and controversial issue concerning the effect of thrombophilia on the risk of recurrent venous thromboembolism. They were con- cerned that the results of the PADIS-PE trial may be biased due to the inclusion of patients with identified and unidentified thrombophilia. First, misclassification bias was avoided because throm- bophilia testing was performed at the end of the study on stored frozen blood samples taken on the day of randomization using the same standardized laboratory techniques for all included patients by technicians blinded to the study treatment allo- cation. Second, the frequency of thrombophilias was equally dis- tributed between the 2 randomized groups and, as reported in the article supplement, we found no heterogeneity of the study treatment effect in subgroups of patients with and with- out thrombophilia at 18 months (relative risk reduction of the primary outcome, 90% in the 94 patients with thrombo- philia, 70% in 255 patients without thrombophilia, and 77% in all 371 patients). Therefore, our observation that an addi- tional 18 months of warfarin therapy produced a major ben- efit during the study treatment period is unlikely to be driven by patients with thrombophilia. We agree that thrombophilia screening in our study was not exhaustive. Because blood samples were collected at inclusion of patients while taking warfarin, we could not measure protein C and protein S levels and lupus anticoagu- lant. However, the prevalence of such abnormalities is expected to be low (1% to 3% for each) 1 and equally distrib- uted between the 2 groups so that the treatment effect observed at 18 months and at 42 months is unlikely to be substantially affected. We did not require systematic thrombophilia screening before inclusion in the study. Systematic screening for thrombophilias in patients with unprovoked venous throm- boembolism is questionable because most thrombophilias are not associated with a demonstrated independent increased risk of recurrent venous thromboembolism in ran- domized trials. 2,3 This is particularly true for common throm- bophilias (eg, heterozygous factor V Leiden or prothrombin gene variant). 2,3 The available relative risk estimates of recur- rence associated with major thrombophilias appear to be weak (relative risks of about 2). 4 Clinical guidelines 5,6 do not recommend systematic ex- tensive thrombophilia screening for all patients with unpro- voked venous thromboembolism, and, consistent with these guidelines, some patients in the PADIS-PE trial did not have previous extensive thrombophilia testing. Francis Couturaud, MD, PhD Guy Meyer, MD Dominique Mottier, MD Author Affiliations: Departement de Medecine Interne et Pneumologie, Centre Hospitalo-Universitaire de Brest, Brest, France (Couturaud); Service de Pneumologie, Hopital Europeen Georges Pompidou, AP-HP, Paris, France (Meyer); Centre Hospitalo-Universitaire de Brest, Brest, France (Mottier). Corresponding Author: Francis Couturaud, MD, PhD, Departement de Medecine Interne et Pneumologie, Hopital de la Cavale Blanche, CHRU de Brest, 29609 Brest cedex, France (francis.couturaud@chu-brest.fr). Conflict of Interest Disclosures: The authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Couturaud reported receiving a grant from Pfizer; personal fees from AstraZeneca and Bayer; and travel expenses from Bayer, Daiichi Sankyo, Leo Pharma, Intermune, and Actelion. Dr Meyer reported receiving a grant and travel support from Bayer; receiving grants and serving on boards (uncompensated) for Boehringer Ingelheim, Leo Pharma, and Sanofi; serving as a consultant for Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Leo Pharma, and Pfizer; serving on boards (uncompensated) for Bayer, Bristol-Myers Squibb and Pfizer; and receiving travel support from Bayer, Boehringer Ingelheim, Daiichi Sankyo, Leo Pharma, and Sanofi. No other disclosures were reported. 1. Christiansen SC, Cannegieter SC, Koster T, Vandenbroucke JP, Rosendaal FR. Thrombophilia, clinical factors, and recurrent venous thrombotic events. JAMA. 2. Ridker PM, Goldhaber SZ, Danielson E, et al; PREVENT Investigators. Long-term, low-intensity warfarin therapy for the prevention of recurrent venous thromboembolism. N Engl J Med. 2003;348(15):1425-1434. 3. Kearon C, Julian JA, Kovacs MJ, et al; ELATE Investigators. Influence of thrombophilia on risk of recurrent venous thromboembolism while on warfarin: results from a randomized trial. Blood. 2008;112(12):4432-4436. 4. Di Minno MND, Ambrosino P, Ageno W, Rosendaal F, Di Minno G, Dentali F. Natural anticoagulants deficiency and the risk of venous thromboembolism: a meta-analysis of observational studies. Thromb Res. 2015;135(5):923-932. 5. Kearon C, Akl EA, Comerota AJ, et al; American College of Chest Physicians. Antithrombotic therapy for VTE disease: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest. 2012;141(2 suppl):e419S-e494S. 6. Baglin T, Gray E, Greaves M, et al; British Committee for Standards in Haematology. Clinical guidelines for testing for heritable thrombophilia. Br J Haematol. 2010;149(2):209-220. Treatment Trends for Prostate Cancer To the Editor Drs Cooperberg and Carroll highlighted a recent increase in active surveillance for patients with low-risk pros- tate cancer enrolled in the Cancer of the Prostate Strategic Uro- logic Research Endeavor (CaPSURE) registry. 1 However, the study also demonstrated that radical prostatectomy contin- ues to be the primary management strategy in patients with low-, intermediate-, and high-risk disease during 2010-2013 and that the use of radical prostatectomy increased between 2005-2009 and 2010-2013 (with a concomitant decline in ra- diation therapy) in patients with intermediate- and high-risk disease. These changes in management may be consistent with the concept of treatment migration, in which the increase in radi- cal prostatectomies in patients with higher-risk disease cor- responds to the lower use of radical prostatectomy in pa- tients with low-risk disease due to the increase in surveillance. This raises the question whether the net number of prostatec- tomies has declined. JAMA November 10, 2015 Volume 314, Number 18 (Reprinted) Copyright 2015 American Medical Association. All rights reserved. Downloaded From: http://jama.jamanetwork.com/ by a UCSF LIBRARY User on 07/11/2016 jama.com