Generalizability in two clinical trials of Lyme disease
Tóm tắt
To examine the generalizability of two National Institutes of Health (NIH)-funded double-blind randomized placebo-controlled clinical trials in patients with chronic Lyme disease and to determine whether selection factors resulted in the unfavorable outcomes. Epidemiologic review of the generalizability of two trials conducted by Klempner et al. This paper considers whether the study group was representative of the general chronic Lyme disease population. In their article in The New England Journal of Medicine, Klempner et al. failed to discuss the limitations of their clinical trials. This epidemiologic review argues that their results are not generalizable to the overall Lyme disease population. The treatment failure reported by the authors may be the result of enrolling patients who remained ill after an average of 4.7 years and an average of 3 previous courses of treatment. The poor outcome cited in these trials may be explained by having selected patients who had undergone delayed treatment or multiple treatments unsuccessfully. These selection factors were not addressed by the studies' authors, nor have they been discussed by reviewers. The trials have been over-interpreted by the NIH and widely publicized in a press release. The results have been extrapolated to other groups of Lyme disease patients by commentators, by a case discussant in an influential medical journal, and by health insurance companies to deny antibiotic treatment. The Klempner et al. trials are assumed to be internally valid based on a Randomized Control Trial (RCT) design. However, this review argues that the trials have limited generalizability beyond the select group of patients with characteristics like those in the trial. Applying the findings to target populations with characteristics that differ from those included in these trials is inappropriate and may limit options for chronic Lyme disease patients who might benefit from antibiotic treatment.
Tài liệu tham khảo
Lyme disease--United States, 2001–2002MMWR Morb Mortal Wkly Rep 2004,53(17):365–369.
Barbour AG: Fall and rise of Lyme disease and other Ixodes tick-borne infections in North America and Europe. Br Med Bull 1998,54(3):647–658.
Smith R, O'Connell S, Palmer S: Lyme disease surveillance in England and Wales, 1986 1998. Emerg Infect Dis 2000,6(4):404–407.
Orloski KA, Hayes EB, Campbell GL, Dennis DT: Surveillance for Lyme disease--United States, 1992–1998. MMWR CDC Surveill Summ 2000,49(3):1–11.
http://www.cdc.gov/ncidod/dvbid/lyme/ld_UpClimbLymeDis.htm: .
Chen H, White DJ, Caraco TB, Stratton HH: Epidemic and spatial dynamics of Lyme disease in New york State, 1990–2000. J Med Entomol 2005,42(5):899–908.
Shadick NA, Phillips CB, Logigian EL, Steere AC, Kaplan RF, Berardi VP, Duray PH, Larson MG, Wright EA, Ginsburg KS, et al.: The long-term clinical outcomes of Lyme disease. A population-based retrospective cohort study. Ann Intern Med 1994,121(8):560–567.
Asch ES, Bujak DI, Weiss M, Peterson MG, Weinstein A: Lyme disease: an infectious and postinfectious syndrome. J Rheumatol 1994,21(3):454–461.
Lightfoot RW Jr., Luft BJ, Rahn DW, Steere AC, Sigal LH, Zoschke DC, Gardner P, Britton MC, Kaufman RL: Empiric parenteral antibiotic treatment of patients with fibromyalgia and fatigue and a positive serologic result for Lyme disease. A cost-effectiveness analysis. Ann Intern Med 1993,119(6):503–509.
Gerber MA, Shapiro ED, Burke GS, Parcells VJ, Bell GL: Lyme disease in children in southeastern Connecticut. Pediatric Lyme Disease Study Group. N Engl J Med 1996,335(17):1270–1274.
Dattwyler RJ, Luft BJ, Kunkel MJ, Finkel MF, Wormser GP, Rush TJ, Grunwaldt E, Agger WA, Franklin M, Oswald D, Cockey L, Maladorno D: Ceftriaxone compared with doxycycline for the treatment of acute disseminated Lyme disease. N Engl J Med 1997,337(5):289–294.
Wormser GP, Ramanathan R, Nowakowski J, McKenna D, Holmgren D, Visintainer P, Dornbush R, Singh B, Nadelman RB: Duration of antibiotic therapy for early Lyme disease. A randomized, double-blind, placebo-controlled trial. Ann Intern Med 2003,138(9):697–704.
Nowakowski J, Nadelman RB, Sell R, McKenna D, Cavaliere LF, Holmgren D, Gaidici A, Wormser GP: Long-term follow-up of patients with culture-confirmed Lyme disease. Am J Med 2003,115(2):91–96.
Klempner MS, Hu LT, Evans J, Schmid CH, Johnson GM, Trevino RP, Norton D, Levy L, Wall D, McCall J, Kosinski M, Weinstein A: Two controlled trials of antibiotic treatment in patients with persistent symptoms and a history of Lyme disease. N Engl J Med 2001,345(2):85–92.
Logigian EL, Kaplan RF, Steere AC: Chronic neurologic manifestations of Lyme disease. N Engl J Med 1990,323(21):1438–1444.
Logigian EL, Kaplan RF, Steere AC: Successful treatment of Lyme encephalopathy with intravenous ceftriaxone. J Infect Dis 1999,180(2):377–383.
Wahlberg P, Granlund H, Nyman D, Panelius J, Seppala I: Treatment of late Lyme borreliosis. J Infect 1994,29(3):255–261.
Donta ST: Tetracycline therapy for chronic Lyme disease. Clin Infect Dis 1997, 25 Suppl 1:S52–6.
Hassler D, Zoller L, Haude M, Hufnagel HD, Heinrich F, Sonntag HG: Cefotaxime versus penicillin in the late stage of Lyme disease--prospective, randomized therapeutic study. Infection 1990,18(1):16–20.
Dattwyler RJ, Halperin JJ, Volkman DJ, Luft BJ: Treatment of late Lyme borreliosis--randomised comparison of ceftriaxone and penicillin. Lancet 1988,1(8596):1191–1194.
Siderowf AD: Evidence from clinical trials: can we do better? NeuroRx 2004,1(3):363–371.
Juni P, Altman DG, Egger M: Systematic reviews in health care: Assessing the quality of controlled clinical trials. Bmj 2001,323(7303):42–46.
Forrest CB, Shipman SA, Dougherty D, Miller MR: Outcomes research in pediatric settings: recent trends and future directions. Pediatrics 2003,111(1):171–178.
Steere AC: Clinical definitions and differential diagnosis of Lyme arthritis. Scand J Infect Dis Suppl 1991, 77:51–54.
Donta ST: Macrolide therapy of chronic Lyme Disease. Med Sci Monit 2003,9(11):PI136–42.
Borg R, Dotevall L, Hagberg L, Maraspin V, Lotric-Furlan S, Cimperman J, Strle F: Intravenous ceftriaxone compared with oral doxycycline for the treatment of Lyme neuroborreliosis. Scand J Infect Dis 2005,37(6–7):449–454.
Dattwyler RJ, Wormser GP, Rush TJ, Finkel MF, Schoen RT, Grunwaldt E, Franklin M, Hilton E, Bryant GL, Agger WA, Maladorno D: A comparison of two treatment regimens of ceftriaxone in late Lyme disease. Wien Klin Wochenschr 2005,117(11–12):393–397.
Bloch AB, Cauthen GM, Simone PM, Kelly GD, Dansbury KG, Castro KG: Completion of tuberculosis therapy for patients reported in the United States in 1993. Int J Tuberc Lung Dis 1999,3(4):273–280.
Fischbach LA, Goodman KJ, Feldman M, Aragaki C: Sources of variation of Helicobacter pylori treatment success in adults worldwide: a meta-analysis. Int J Epidemiol 2002,31(1):128–139.
Wells KB: Treatment research at the crossroads: the scientific interface of clinical trials and effectiveness research. Am J Psychiatry 1999,156(1):5–10.
Kamradt T: Lyme disease and current aspects of immunization. Arthritis Res 2002,4(1):20–29.
Wormser GP, Nadelman RB, Dattwyler RJ, Dennis DT, Shapiro ED, Steere AC, Rush TJ, Rahn DW, Coyle PK, Persing DH, Fish D, Luft BJ: Practice guidelines for the treatment of Lyme disease. The Infectious Diseases Society of America. Clin Infect Dis 2000, 31 Suppl 1:1–14.
Wormser GP, Nowakowski J, Nadelman RB: Treatment of Early Lyme Disease . Ann Intern Med 2004,140(7):577–578.
Weinstein A, Britchkov M: Lyme arthritis and post-Lyme disease syndrome. Curr Opin Rheumatol 2002,14(4):383–387.
Radolf J: Posttreatment chronic Lyme disease--what it is not. J Infect Dis 2005,192(6):948–949.
Klempner MS, Wormser GH, Wade K, Trevino RP, Tang J, Kaslow RA, Schmid C: A case-control study to examine HLA haplotype associations in patients with posttreatment chronic Lyme disease. J Infect Dis 2005,192(6):1010–1013.
Coulter P, Lema C, Flayhart D, Linhardt AS, Aucott JN, Auwaerter PG, Dumler JS: Two-year evaluation of Borrelia burgdorferi culture and supplemental tests for definitive diagnosis of Lyme disease. J Clin Microbiol 2005,43(10):5080–5084.
Cameron D, Gaito A, Harris N, Bach G, Bellovin S, Bock K, Bock S, Burrascano J, Dickey C, Horowitz R, Phillips S, Meer-Scherrer L, Raxlen B, Sherr V, Smith H, Smith P, Stricker R: Evidence-based guidelines for the management of Lyme disease. Expert Rev Anti Infect Ther 2004,2(1 Suppl):S1–13.
Steere AC: A 58-year-old man with a diagnosis of chronic lyme disease. Jama 2002,288(8):1002–1010.
Dinerman H, Steere AC: Lyme disease associated with fibromyalgia. Ann Intern Med 1992,117(4):281–285.
Marshall E: Lyme disease. Patients scarce in test of long-term therapy. Science 1999,283(5407):1431.
Krupp LB, Hyman LG, Grimson R, Coyle PK, Melville P, Ahnn S, Dattwyler R, Chandler B: Study and treatment of post Lyme disease (STOP-LD): a randomized double masked clinical trial. Neurology 2003,60(12):1923–1930.