ASAS recommendations for collecting, analysing and reporting NSAID intake in clinical trials/epidemiological studies in axial spondyloarthritis
- Maxime Dougados1,
- Simon Paternotte1,
- Juergen Braun2,
- Ruben Burgos-Vargas3,
- Walter P Maksymowych4,
- Joachim Sieper5,
- Désirée van der Heijde6
- 1Rheumatology B Department, Paris-Descartes University, Cochin Hospital, Paris, France
- 2Rheumazentrum Ruhrgebeit, Herne, Germany
- 3Rheumatology Unit, Hospital General de Mexico, Mexico City, Mexico
- 4Medicine/Rheumatic Disease Unit, University of Alberta, Edmonton, Alberta, Canada
- 5Medicine/Rheumatology Department, Charite Campus Benjamin Franklin, Berlin, Germany
- 6Rheumatology Department, Leiden University Medical Center, Leiden, The Netherlands
- Correspondence to Professor Maxime Dougados, Rheumatology B Department, Paris-Descartes University, Cochin Hospital, Paris 75014, France;
- Accepted 10 July 2010
- Published Online First 9 September 2010
The amount of NSAID intake could be considered as a clinically relevant outcome measure in ankylosing spondylitis. The information should include at least the following: (1) the type of NSAID; (2) the dose; (3) the number of days taking NSAID during the period of interest. The objectives of this initiative were to propose both an NSAID equivalent score and a way of collecting and analysing this information in longitudinal clinical studies/trials. For the NSAID equivalent scoring system, the recommendations are (1) to refer to a scale in which 0 = no intake, 100 = 150 mg diclofenac, 1000 mg naproxen, 200 mg aceclofenac, 400 mg celecoxib, 600 mg etodolac, 90 mg etoricoxib, 200 mg flurbiprofen, 2400 mg ibuprofen, 150 mg indometacin, 200 mg ketoprofen, 15 mg meloxicam, 400 mg phenylbutazone, 20 mg piroxicam, 20 mg tenoxicam; (2) to present the results as mean daily intake by considering the number of days on which NSAID has been taken during a period of interest. This initiative should facilitate the conduct and analysis of clinical studies/trials.
NSAID treatment has demonstrated its clinically relevant symptomatic effect in the short term5,–,9; some data suggest that NSAID treatment might also have a weak but statistically significant effect on biological markers of inflammation.10 It has been shown that continuous daily chronic (eg, 2 years') intake also had a structural effect in comparison with on-demand use.11 These arguments support chronic daily intake of NSAIDs in patients with SpA and, obviously, in a substantial proportion of patients, continuous treatment with NSAIDs is necessary to reach an optimal treatment effect.12 On the other hand, there is a substantial body of evidence describing both the gastrointestinal and cardiovascular toxicity of this treatment.13,–,23
Consequently, a detailed evaluation of NSAID intake in clinical trials/studies might be important for at least two reasons:
▶ The long-term toxicity of NSAIDs might be related to the amount of NSAIDs taken during a certain period of time.
▶ The ability of a specific treatment (eg, tumour necrosis factor blockers) to decrease the amount of NSAID intake might be considered as clinically relevant.
To calculate NSAID intake, information should be available on (1) the type of NSAID (eg, piroxicam is different from naproxen); (2) the dose; (3) the percentage of days with intake over a certain period of time.
Some preliminary data suggest that either the number of tablets taken during a defined period or a score taking into account the number of tablets taken and also the type and dose of NSAID is the best discriminatory outcome measure.27 28 Currently, the approach to collecting information related to NSAID intake is far from optimal, permitting evaluation of NSAID intake by only a yes or no answer at a specific visit.29
The use of an NSAID scoring system seems to be the most appropriate way forward, but requires that the following data have been collected:
▶ the name and the dose of NSAID;
▶ the percentage of days with NSAID intake during the period of interest.
In addition, information on an inter-NSAID equivalent score is needed. In order to achieve this objective, the Assessment of Spondyloarthritis International Society (ASAS) has promoted an initiative to define both a way to collect the necessary data and to define an NSAID equivalent score, which is reported here.
Collection of details of NSAID intake
Based on the requirements (eg, name and dose of NSAID, percentage of days with intake during a period of interest), and based on examples of recently conducted trials but also of clinical epidemiological studies, one member (MD) of the ASAS steering committee proposed an example of a case report form. This proposal was discussed, modified and finalised during the annual ASAS meeting with 82 participants from more than 10 different countries representing researchers and patients.
NSAID equivalent score
An email was sent to all ASAS members asking them to participate in an online survey. Members were first asked to consider a situation where a dose of 150 mg of diclofenac is being used daily to achieve optimal symptomatic control of a patient with axial SpA. Because of adverse events, it is decided to switch to another NSAID at a daily dose considered equivalent to 150 mg diclofenac daily. Members were asked to indicate whether they had sufficient familiarity with the specific NSAID evaluated. If the answer was ‘yes’ they had to indicate the daily dose that they would use.
In addition, members were asked to indicate the highest dose they would use to treat an SpA flare. For each of the 15 different NSAIDs that were evaluated, the ASAS members had the opportunity to tick the box “I am not familiar with this NSAID” instead of providing a particular dose. During the ASAS annual meeting, these results were presented and discussed, and an equivalent score was finalised based on voting with key pads.
Analysis of NSAID intake
Based on the data available in the literature and the available information in clinical trials/studies, several approaches to the analysis were discussed during the ASAS annual meeting.
Collection of details of NSAID intake in clinical studies/trials
Table 1 proposes an example of a case report form for collecting the information related to NSAID intake over a period of time, the latter is defined by the time between visits. When visits are too infrequent, or this is applied in a cross-sectional study, a period can also be defined, such as the past 4 or 12 weeks. Moreover, if patients have changed the way they used NSAIDs during the visits, several rows should be completed.
NSAID equivalent score
Table 2 summarises the results obtained during the survey aimed at evaluating the 150 mg diclofenac daily dose with regard to (1) comparable efficacy (first column); (2) maximum daily dose used in axial SpA for different NSAIDs (second column); (3) the proposed equivalent dose based on voting during the ASAS annual meeting (in parentheses).
Analysis and report of NSAID intake during clinical trials/studies
As soon as the information contained in table 1 is available (eg, name, mean dose, number of days of intake during a period of time, the recommendation is to analyse/report the data in terms of NSAID equivalent dose in mg/day on a 0–100 scale. The 150 mg equivalent diclofenac is set to 100. When the exact number of days with NSAID intake is not known (usually when the interval of time between two visits exceeds 2 weeks), it is recommended to refer to the semiquantitative estimation summarised in table 1. In this case, a score of 7/7 is proposed for the answer ‘every day’, 6/7 for >5 days/week, 4/7 for >3 to ≤5 days/week, 2 for >1 to ≤3 days/week, 0.5 for ≤1 day/week and 0 if the patient did not take any NSAID during the study period.
The general formula for the calculation is:
(equivalent NSAID score) × (days of intake during period of interest) × (days per week)/(period of interest in days)
For example, if during a period of interest (between two visits) of 6 months, the patient has taken piroxicam 20 mg during 4 months and if during this 4-month period he has taken piroxicam 3–5 days per week the calculation is as follows:
100 (20 mg piroxicam score) × 120 (4 months) × 4/7 (3–5 days/week)/180 (6 months) = 38.1
If the patient has used 10 mg piroxicam during the remaining 2 months on 2 days a week, the NSAID score for this period is:
50 (10 mg piroxicam score) ×60 (2 months) × 2/7 (1–3 days/week)/180 (6 months) = 4.8
In this example the total score for the 6 month period is 42.9 (38.1 plus 4.8).
When the name and the dose of the NSAID intake are not available but the number of days with NSAID intake is available, the recommendation is to present the results as the percentage days with at least NSAID intake during a period of time.
When the only available data are the NSAID intake at a specific visit, the recommendation is to present the results as the percentage patients taking an NSAID at a specific visit.
The current ASAS recommendations for collecting/analysing and reporting NSAID intake have many strengths. This uniform recording, analysis and reporting of NSAID intake will facilitate and allow comparison between different studies particularly for its two main objectives—that is, to compare the potential NSAID sparing effect of a particular treatment such as tumour necrosis factor blockers and to evaluate the relationship between NSAID intake and comorbidities such as cardiovascular events and/or renal failure. These recommendations have been based on both the expertise of the ASAS members and the evaluation of available information in the literature, which can be seen as a strength. However, this can also been seen as a weakness since this was not a data-driven approach as has been used previously in osteoarthritis.20 In contrast, the way in which the information was collected on NSAID intake in recently conducted therapeutical trials evaluating disease-modifying antirheumatic drugs or biological agents does not permit this detailed evaluation, which is a missed opportunity.21
Other potential weaknesses of these recommendations can be pointed out: (1) the lack of data evaluating the validity with regard to its relationship to the potential long-term toxicity of NSAIDs (eg, cardiovascular events); (2) these recommendations, and particularly the NSAID equivalent score, will need to be regularly updated as soon as a novel NSAID is made available for use in SpA; the number of experts familiar with the issue of evaluated NSAIDs was quite small; (3) such a scoring system does not take into account the timing intake (eg, morning versus evening), the potential slow release preparation and also the question of drug compliance. The optimal way of using this scoring system is to check carefully the exact daily dose of NSAID intake—for example, by using a diary. Otherwise, such a scoring system has to rely on a patient's memory, which is not optimally accurate.
In conclusion, we think that these recommendations are a major step forward in the collection and reporting of NSAID intake in a more informative and standardised manner. Application of these recommendations should be the first step by researchers in charge of designing clinical trials and/or epidemiological studies and might thereby allow as yet unresolved methodological issues to be examined.
Competing interests None.
Provenance and peer review Not commissioned; externally peer reviewed.