Adherence-adjusted estimates of benefits and harms from treatment with amoxicillin for LRTI: secondary analysis of a 12-country randomised placebo-controlled trial using randomisation-based efficacy estimators.
OBJECTIVE
Estimate the efficacy of amoxicillin for acute uncomplicated lower-respiratory-tract infection (LRTI) in primary care and demonstrate the use of randomisation-based efficacy estimators.


METHODS
Secondary analysis of a two-arm individually-randomised placebo-controlled trial.


METHODS
Primary care practices in 12 European countries.


METHODS
Patients aged 18 or older consulting with an acute LRTI in whom pneumonia was not suspected by the clinician.


METHODS
Amoxicillin (two 500 mg tablets three times a day for 7 days) or matched placebo.


METHODS
Clinician-rated symptom severity between days 2-4; new/worsening symptoms and presence of side effects at 4-weeks. Adherence was captured using self-report and tablet counts.


RESULTS
2061 participants were randomised to the amoxicillin or placebo group. On average, 88% of the prescribed amoxicillin was taken. The original analysis demonstrated small increases in both benefits and harms from amoxicillin. Minor improvements in the benefits of amoxicillin were observed when an adjustments for adherence were made (mean difference in symptom severity -0.08, 95% CI -0.17 to 0.01, OR for new/worsening symptoms 0.81, 95% CI 0.66 to 0.98) as well as minor increases in harms (OR for side effects 1.32, 95% CI 1.12 to 1.57).


CONCLUSIONS
Adherence to amoxicillin was high, and the findings from the original analysis were robust to non-adherence. Participants consulting to primary care with an acute uncomplicated LRTI can on average expect minor improvements in outcome from taking amoxicillin. However, they are also at an increased risk of experiencing side effects.


BACKGROUND
Eudract-CT 2007-001586-15 and ISRCTN52261229. The trial was registered at EudraCT in 2007 due to an administrative misunderstanding that EudraCT was a suitable registry--which it was not in 2007, but has become since. On discovery of this error, the trial was also registered at ISRCTN (January 2009). Trial procedures did not change between the two registrations.
South East Wales Trials Unit (SEWTU), Institute of Primary Care & Public Health, Cardiff University School of Medicine, Cardiff, UK.
David
D
Gillespie
South East Wales Trials Unit (SEWTU), Institute of Primary Care & Public Health, Cardiff University School of Medicine, Cardiff, UK.
Kerenza
K
Hood
Institute of Primary Care & Public Health, Cardiff University School of Medicine, Cardiff, UK.
Daniel
D
Farewell
Institute of Primary Care & Public Health, Cardiff University School of Medicine, Cardiff, UK Department of Primary Care Health Sciences, Oxford University, Oxford, UK.
Christopher C
CC
Butler
University Medical Center Utrecht, Julius Center for Health, Sciences and Primary Care, Utrecht, The Netherlands.
Theo
T
Verheij
Laboratory of Medical Microbiology, Vaccine & Infectious Disease Institute (VAXINFECTIO), University of Antwerp, Antwerp, Belgium.
Herman
H
Goossens
Primary Care and Population Sciences Division, University of Southampton, Southampton, UK.
Beth
B
Stuart
Primary Care and Population Sciences Division, University of Southampton, Southampton, UK.
Mark
M
Mullee
Department of Primary Medical Care, Aldermoor Health Centre, Southampton, UK.
Paul
P
Little
D000208:Acute Disease; D000328:Adult; D000368:Aged; D000658:Amoxicillin / Q000009:adverse effects / Q000627:therapeutic use; D000900:Anti-Bacterial Agents / Q000009:adverse effects / Q000627:therapeutic use; D064420:Drug-Related Side Effects and Adverse Reactions; D005060:Europe; D005260:Female; D006801:Humans; D008297:Male; D055118:Medication Adherence; D011014:Pneumonia / Q000188:drug therapy*; D011320:Primary Health Care; D012141:Respiratory Tract Infections / Q000188:drug therapy*; D012307:Risk Factors
D000900:Anti-Bacterial Agents; D000658:Amoxicillin
PRIMARY CARE; RESPIRATORY MEDICINE (see Thoracic Medicine); STATISTICS & RESEARCH METHODS