Influence of safety warnings on ESA prescribing among dialysis patients using an interrupted time series

BMC Nephrology

Dennis Cotter²  Onkar Kshirsagar²  Dejian Lai¹  Yi Zhang²  Mae Thamer² 

[1] Jiangxi University of Finance and Economics, Nanchang, China;Medical Technology and Practice Patterns Institute, 5272 River Road, Suite 500, Bethesda, MD 20816, USA

关键词: ESRD;    Anemia management;    Interrupted time series;    Black box warnings;    ESA therapy;    Epoetin;   

Others  :  1082867
DOI  :  10.1186/1471-2369-14-172

 received in 2012-12-17, accepted in 2013-08-07,  发布年份 2013

【 摘 要 】

Background

In March, 2007, a black box warning was issued by the Food and Drug Administration (FDA) to use the lowest possible erythropoiesis-stimulating agents (ESA) doses for treatment of anemia associated with renal disease. The goal is to determine if a change in ESA use was observed following the warning among US dialysis patients.

Methods

ESA therapy was examined from September 2004 through August 2009 (thirty months before and after the FDA black box warning) among adult Medicare hemodialysis patients. An interrupted time series model assessed the impact of the warnings.

Results

The FDA black box warning did not appear to influence ESA prescribing among the overall dialysis population. However, significant declines in ESA therapy after the FDA warnings were observed for selected populations. Patients with a hematocrit ≥36% had a declining month-to-month trend before (−164 units/week, p = <0.0001) and after the warnings (−80 units/week, p = .001), and a large drop in ESA level immediately after the black box (−4,744 units/week, p = <.0001). Not-for-profit facilities had a declining month-to-month trend before the warnings (−90 units/week, p = .009) and a large drop in ESA dose immediately afterwards (−2,487 units/week, p = 0.015). In contrast, for-profit facilities did not have a significant change in ESA prescribing.

Conclusions

ESA therapy had been both profitable for providers and controversial regarding benefits for nearly two decades. The extent to which a FDA black box warning highlighting important safety concerns influenced use of ESA therapy among nephrologists and dialysis providers was unknown. Our study found no evidence of changes in ESA prescribing for the overall dialysis population resulting from a FDA black box warning.

【 授权许可】

   
2013 Thamer et al.; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

Figure 2.

Figure 3.

【 参考文献 】

• [1]Collins AJ, Li S, St Peter W, Ebben J, Roberts T, Ma JZ, Manning W: Death, hospitalization, and economic associations among incident hemodialysis patients with hematocrit values of 36 to 39%. J Am Soc Nephrol 2001, 12:2465-2473.
• [2]Lowrie EG, Huang WH, Lew NL, Liu Y: The relative contribution of measured variables to death risk among hemodialysis patients. In Death on hemodialysis. Edited by Friedman EA. New York: Dordrecht Kluwer Academic Publishers; 1994:121-141.
• [3]Ma JZ, Ebben J, Xia H, Collins AJ: Hematocrit level and associated mortality in hemodialysis patients. J Am Soc Nephrol 1999, 10:610-619.
• [4]U.S. Renal Data System: USRDS 2006 Annual Data Report, Atlas of End-stage Renal Disease in the United States. http://www.usrds.org/adr.htm webcite
• [5]US Government Accountability Office: End-Stage Renal Disease: CMS Should Monitor Access to and Quality of Dialysis Care Promptly after Implementation of New Bundled Payment System. Washington DC: GAO-10-295; 2010.
• [6]Besarab A, Bolton WK, Browne JK, Egrie JC, Nissenson AR, Okamoto DM, Schwab SJ, Goodkin DA: The effects of normal as compared with low hematocrit values in patients with cardiac disease who are receiving hemodialysis and epoetin. N Engl J Med 1998, 339:584-590.
• [7]Singh AK, Szczech L, Tang KL, Barnhart H, Sapp S, Wolfson M, Reddan D, CHOIR Investigators: Correction of anemia with epoetin alfa in chronic kidney disease. N Engl J Med 2006, 355:2085-2098.
• [8]Drüeke TB, Locatelli F, Clyne N, Eckardt KU, Macdougall IC, Tsakiris D, Burger HU, Scherhag A: CREATE investigators: normalization of hemoglobin level in patients with chronic kidney disease and anemia. N Engl J Med 2006, 355:2071-2084.
• [9]United States Renal Data System: USRDS 2009 Researcher’s Guide to the USRDS Database. Bethesda, MD: National Institutes of Health, National Institute of Diabetes and Digestive Diseases; 2010.
• [10]Garey KW, Lai D, Dao-Tran TK, Gentry LO, Hwang LY, Davis BR: Vancomycin compared to cefuroxime for surgical prophylaxis in patients undergoing cardiac surgery: an interrupted time series analysis. Antimicrob Agents Chemother 2008, 52:446-451.
• [11]Gillings D, Makuc D, Siegel E: Analysis of interrupted time series mortality trends: an example to evaluate regionalized perinatal care. Am J Pub Health 1981, 71:38-46.
• [12]SAS Institute Inc: SAS/STAT 9.2 User’s Guide. Cary, NC: SAS Institute Inc; 2008.
• [13]Lai D: White noise. International Encyclopedia of Social Sciences. 2nd edition 2008, 9:82-83.
• [14]MEDICATION GUIDE Epogen® (Ee-po-jen) (epoetin alfa) Amgen Manufacturing Limited, a subsidiary of Amgen Inc: One Amgen Center Drive Thousand Oaks, CA 91320–1799, Revised: 06/2011 ©1989-2011 Amgen Inc. http://www.fda.gov/downloads/Drugs/DrugSafety/ucm088591.pdf webcite
• [15]Parfrey PS, Foley RN, Wittreich BH, Sullivan DJ, Zagari MJ, Frei D: Double-blind comparison of full and partial anemia correction in incident hemodialysis patients without symptomatic heart disease. J Am Soc Nephrol 2005, 16:2180-2189.
• [16]Foley RN, Parfrey PS, Morgan J, Barré PE, Campbell P, Cartier P, Coyle D, Fine A, Handa P, Kingma I, Lau CY, Levin A, Mendelssohn D, Muirhead N, Murphy B, Plante RK, Posen G, Wells GA: Effect of hemoglobin levels in hemodialysis patients with asymptomatic cardiomyopathy. Kidney Int 2000, 58:325-335.
• [17]Laupacis A: A randomized double-blind study of recombinant human erythropoietin in anaemic hemodialysis patients. Canadian erythropoietin study group. Transplant Proc 1991, 23:1825-1826.
• [18]Furuland H, Linde T, Ahlmen J, Christensson A, Strombom U, Danielson BG: A randomized controlled trial of haemoglobin normalization with epoetin alfa in pre-dialysis and dialysis patients. Nephrol Dial Transplant 2003, 18:353-361.
• [19]Foley RN, Collins AJ: End-stage renal disease in the United States: an update from the United States renal data system. J Am Soc Nephrol 2007, 18:2644-2648.
• [20]Thamer M, Zhang Y, Kaufman J, Cotter D, Dong F, Hernán MA: Dialysis facility ownership and epoetin dosing in patients receiving hemodialysis. JAMA 2007, 297:1667-1674.
• [21]Goozner M: The making and selling of a star drug. Chicago: Tribune News; 1999.
• [22]Office of Inspector General: Medicare Reimbursement for Existing End-stage Renal Disease Drugs. Washington DC: OIC Publication #OEI-03-04-00120; 2004.
• [23]U.S. Renal Data System: USRDS 2007 Annual Data Report. Bethesda, MD: Atlas of Chronic Kidney Disease and End-Stage Renal Disease in the United States, National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases; 2007. Figure 5.9
• [24]US Government Accountability Office: End Stage Renal Disease: Bundling Medicare’s Payment for Drugs with Payment for All ESRD Services Would Promote Efficiency and Clinical Flexibility. Washington DC: GAO-07-77; 2006. Nov 13
• [25]Carless PA, Henry DA, Carson JL, Hebert PP, McClelland B, Ker K: Transfusion thresholds and other strategies for guiding allogeneic red blood cell transfusion (Review). Cochrane Database Syst Rev 2010., 10CD002042
• [26]Fink JC, Blahut SA, Briglia AE, Gardner JF, Light PD: Effect of center- versus patient-specific factors on variations in dialysis adequacy. J Am Soc Nephrol 2001, 12:164-169.
• [27]Hirth RAM, Turenne N, Wheeler JR, Ma Y, Messana JM: Do resource utilization and clinical measures still vary across dialysis chains after controlling for the local practices of facilities and physicians? Med Care 2010, 48:726-732.
• [28]Tangri N, Moorthi R, Tighiouhart H, Meyer KB, Miskulin DC: Variation in fistula use across dialysis facilities: is it explained by case-mix? Clin J Am Soc Nephrol 2010, 5:307-313.
• [29]Garg PP, Frick KD, Diener-West M, Powe NR: Effect of the ownership of dialysis facilities on patients’ survival and referral for transplantation. N Engl J Med 1999, 341:1653-1660.
• [30]Zhang Y, Thamer M, Cotter DJ, Kshirsagar O: Does higher injectable medication use mediate increased mortality? Health Serv Res 2013, 48:949-971.
• [31]Zhang Y, Thamer M, Cotter D: The effect of dialysis chains on mortality among patients receiving hemodialysis. Health Serv Res 2011, 46:747-767.
• [32]Lasser KE, Allen PD, Woolhandler SJ, Himmelstein DU, Wolfe SM, Bor DH: Timing of new black box warnings and withdrawals for prescription medications. JAMA 2002, 287:2215-2220.
• [33]Green L, Kreuter M, Deeds S, Partridge K: Health Education Planning: A diagnostic approach. Palo Alto, CA: Mayfield Press; 1980.
• [34]Amgen Media News Release. http://www.amgen.com/media/media_pr_detail.jsp?year=2007&-++releaseID=1067247 webcite
• [35]Bennett CL, McKoy JM, Henke M, Silver SM, MacDougall IC, Birgegård G, Luminari S, Casadevall N, Schellekens H, Sartor O, Lai SY, Armitage JO: Reassessments of ESAs for cancer treatment in the US and Europe. Oncology (Williston Park) 2010, 24:260-268.
• [36]US Goverment Accountability Office: End-Stage Renal Disease: Medicare Should Pay A Bundled Rate For All ESRD Items and Services. Washington DC: GAO-07-1050T; 2007.
• [37]EPOGEN® (Epoetin alfa) sales decreased 27 percent to $476 million in the third quarter of 2011 reflecting a decrease in dose utilization due to implementation of the bundled payment system. http://www.amgen.com/media/media_pr_detail.jsp?year=2011&releaseID=1620695 webcite
• [38]DOPPS Practice Monitor. http://www.dopps.org/DPM/Default.aspx webcite
• [39]U.S. Renal Data System: USRDS 2010 Annual Data Report, Atlas of End-Stage Renal Disease in the United States. http://www.usrds.org/adr.htm webcite