Setting
The trial was conducted in two primary care practices (composed of 8–10 GPs each, covering an area with a total of about 34,000 inhabitants) in the province of Reggio Emilia, in northern Italy. The 16 GPs working at the two practices each have 1500 patients, about one-quarter of whom are over age 65. The resident population can choose any GP in the province based on preference, though most residents choose their GP based on geographical convenience. The study was conducted from November 1, 2012 to October 31, 2013 and was subsequently divided in two main seasons: Winter-Spring (from November 1 to April 30) and Summer-Fall (from May 1 to October 31).
Study design
All the GPs in the two practices were asked to participate in the trial. For the Winter-Spring season 2012–2013 (randomization period), those who agreed were randomized to one of the two arms: 1) usual prescribing practice and education about pain control in osteoarthritis; 2) new prescribing modality, i.e. free paracetamol and education about pain control in osteoarthritis. After 6 months, in the Summer-Fall season 2013, (implementation period), the control group also received prescriptions for free paracetamol. Randomization was performed centrally by the Reggio Emilia Epidemiology Unit using a generator of random numbers.
The principal endpoint was the difference in NSAID and PPI consumption in patients with osteoarthritis in the randomization period compared to the pre-intervention period (November 1, 2011 to October 31, 2012). As a secondary endpoint we also monitored the prescription of opioids. Differences in defined daily dose (DDD) per patient in the control and in the experimental arms were compared (Fig. 1).
Outcome definition
The defined dose (DD) is the total sum of grams of paracetamol prescribed to each subject with osteoarthritis. The defined daily dose (DDD) represents the total sum of grams of paracetamol prescribed to each subject with osteoarthritis divided by 180 days (6 months, single period of observation). For the main endpoint the denominator also included patients who did not use that drug at all. We also present data on the proportion of users for each drug in the two periods.
The main comparison is the difference between the control and experimental arms in differences between pre-intervention and randomization period. We also report the comparison within each arm between the pre-intervention period and the randomization period and the comparison within the experimental arm for the pre-intervention and implementation period.
Sample size
It was estimated that there were about 60 patients with osteoarthritis per GP (20% of the over-65-year-olds), 50 of whom are in active treatment. Further, it was assumed that about one-third (16 patients) were taking NSAIDs, with an average of 5 DDD per month and a standard deviation of 2.5. Setting alpha at 0.05, and assuming a design effect of clustering of 2, i.e. we doubled the sample size compared to a simple random sample, we estimated 90% power to detect the relevant difference of halving NSAID consumption randomizing at least 8 GPs per arm; we had the opportunity to randomize 16 GPs.
Participants and randomization procedure
All the 16 GPs working in the two primary care practices were asked to participate in the study. All agreed to participate and signed an informed consent. The randomization unit was the GPs, while the statistical units were osteoarthritic patients. The GPs were randomized centrally by the Epidemiology Unit with a pseudo-random number generator using the first number of most recent extraction of the National Lottery as the seed. The allocation of the arm was also randomly assigned to the two groups.
Description of the intervention
All the participating GPs received a short course on pain control in patients with osteoarthritis.
The GPs in the experimental arm were also briefly informed of the opportunity to prescribe free paracetamol; the patients go to the local hospital or public clinic with the GP’s prescription to receive the paracetamol.
Data sources
The data on drug consumption were taken from the pharmaceutical information system. The information system merges two databases, one recording all the drugs charged to the Italian NHS by pharmacies and one recording all the drugs directly administered by hospitals and outpatient clinics. The system collects information on the patient, the prescriber, the dose, and the drug. It does not include drugs purchased out of pocket at pharmacies.
All the GPs provided a list of their patients with osteoarthritis seen during the study period (November 1, 2012 to October 31, 2013). Patients who did not gave consent for data management and treatment to the GP, would be automatically excluded from the lists. We are not aware of any case of exclusion.
At the end of the study, all the GPs filled in an ad hoc closed-ended questionnaire on the feasibility and acceptability of the new prescription modalities. Questions included GP and patient satisfaction, proportion of patients complying with the proposed protocol at the beginning and at the end of the period, and an open-ended question for comments (see Additional file 1: questionnaire for GP).
Data analyses
The lists of patients provided by the GPs were used to define the population of patients with osteoarthritis.
All data are presented with 95% confidence intervals, built taking into account the cluster randomization using a random effect model to estimate the correct variance. To take into account clustering on GP, all the analyses were conducted with the statistical package for complex survey data of STATA 13.0. Differences within and between arms (Winter-Spring 2011–12 vs. Winter-Spring 2012–13 and Summer-Fall 2012 vs Summer-Fall 2013) were tested using linear regression model adjusting by sex and age. We present the design effect for baseline drug prescription among GPs and for the comparison between experimental and control arm.
In order to prevent seasonal fluctuations and to have the same probability of at least one prescription event, we compared the same time lapse in the pre-intervention period and in the randomization period, i.e. for the main objective analysis, we compared Winter-Spring 2011–12 (pre-intervention period) with the Winter-Spring 2012–13 (randomization period) in the two groups. Differences between pre- and post-intervention periods in the intervention and control arms were compared with a two-tailed t-test; p-value < 0.05 was considered as threshold to reject the null hypothesis.
In order to confirm the trial results, we also compared the changes in the control arm between the pre-intervention period (Summer-Fall 2012) and the last 6 months of the study (Summer-Fall 2013, implementation period) during which the control arm could also receive paracetamol for free with the new prescribing modality.