Antibiotic prophylaxis for Lyme disease: how the way of reporting a clinical trial can alter the perception of effectiveness.

Question: Is a single 200-mg dose of doxycycline effective for preventing Lyme disease after an Ixodes scapularis tick bite? Design: Nadelman et al conducted a randomized, doubleblind (patients and study personnel), placebo-controlled clinical trial over a period of 9.5 years (May 1987 to December 1996) to determine the effect of a single dose of doxycycline on prevention of Lyme disease after a tick bite. Some patients were included twice during this time. At baseline and at 3 weeks’ and 6 weeks’ follow-up, patients were interviewed and examined, and serum antibody tests were performed and blood cultures done for Borrelia burgdorferi. A randomization list was used to maintain a 1:1 ratio. Patients swallowed the pills under direct observation of study personnel. Sample size calculations were clearly defined. The trial included 506 patients with 482 meeting the inclusion parameters (235 doxycycline, 247 placebo) and who had removed identifiable I scapularis ticks from their bodies. Twenty-eight had removed multiple ticks at the time of the enrollment bite. Species, sex, and stage of ticks were determined by a medical entomologist. Ticks were initially classified as unfed (flat) or partly fed (partially engorged) on the basis of a visual inspection. When possible, the tick’s attachment time to the subject was estimated on the basis of a measurement of the tick body. Specific questions regarding the adverse effects of doxycycline use were added to a questionnaire. Additional subjects were enrolled after it was discovered that the risk of erythema migrans was limited to subjects who had been bitten by nymphal ticks (to obtain a sample size with enough statistical power). Setting: The evaluations occurred at Westchester Medical Center (461 patients [91%]) or at a nearby community hospital (45 patients [8.9%]) in Westchester County, New York. Patients: Patients were older than 12 years. Inclusion and exclusion criteria were clearly defined. All patients recruited had removed an attached I scapularis tick from their bodies within the preceding 72 hours and had been bitten in Westchester County where Lyme disease is hyperendemic. Excluded patients had clinical signs of Lyme disease (eg, erythema migrans) at the time of enrollment, were taking or had just completed a course of antibiotics effective against B burgdorferi, were pregnant or lactating, had been vaccinated against Lyme disease, or did not submit the tick that bit them. The demographic characteristics were similar in both the doxycycline and placebo groups. In 482 patients (median age, 41 years; 53% men), the ticks were confirmed to be I scapularis ticks. Patients who had tick bites identified as something other than scapularis were included only in the analysis of safety. Interventions: A single 200-mg dose of doxycycline (2 capsules, 100 mg each) or matched placebo (lactose). Main Outcome Measures: The primary outcome was the development of erythema migrans at the site of the tick bite. Secondary outcomes were erythema migrans occurring at a different site from that of the identified tick bite and laboratory evidence of B burgdorferi infection (positive skin culture or seroconversion) in the absence of erythema migrans. Results: End points and follow-up data were available for 431 subjects (89.4%), 235 in the doxycycline group and 247 in the placebo group. One patient (1/235, 0.4%) in the doxycycline group and 8 patients (8/247, 3.2%) in the placebo group developed erythema migrans at the site of the tick bite. The authors reported the efficacy of prophylaxis as the relative risk reduction (using an indirect formula: 1−relative risk, where relative risk is the ratio of the risk in the experimental group in relation to the risk in the control group) that for the primary outcome was 87% (95% confidence interval [CI], 14%-160%). The risk difference was 2.8% (95% CI, 0.5%-5.2%) and the number needed to treat was 36 (95% CI, 19-220). One patient in the doxycycline group and one in the placebo group developed erythema migrans at a different site from that of the identified tick bite. One patient in the doxycycline group and 2 patients in the placebo group had laboratory evidence of B burgdorferi infection. The relaEVIDENCE-BASED DERMATOLOGY: RESEARCH COMMENTARY