Claire Bombardier

Vascular and upper gastrointestinal effects of non-steroidal anti-inflammatory drugs: Meta-analyses of individual participant data from randomised trials

Summary Background The vascular and gastrointestinal effects of non-steroidal anti-inflammatory drugs (NSAIDs), including selective COX-2 inhibitors (coxibs) and traditional non-steroidal anti-inflammatory drugs (tNSAIDs), are not well characterised, particularly in patients at increased risk of vascular disease. We aimed to provide such information through meta-analyses of randomised trials. Methods We undertook meta-analyses of 280 trials of NSAIDs versus placebo (124 513 participants, 68 342 person-years) and 474 trials of one NSAID versus another NSAID (229 296 participants, 165 456 person-years). The main outcomes were major vascular events (non-fatal myocardial infarction, non-fatal stroke, or vascular death); major coronary events (non-fatal myocardial infarction or coronary death); stroke; mortality; heart failure; and upper gastrointestinal complications (perforation, obstruction, or bleed). Findings Major vascular events were increased by about a third by a coxib (rate ratio [RR] 1·37, 95% CI 1·14–1·66; p=0·0009) or diclofenac (1·41, 1·12–1·78; p=0·0036), chiefly due to an increase in major coronary events (coxibs 1·76, 1·31–2·37; p=0·0001; diclofenac 1·70, 1·19–2·41; p=0·0032). Ibuprofen also significantly increased major coronary events (2·22, 1·10–4·48; p=0·0253), but not major vascular events (1·44, 0·89–2·33). Compared with placebo, of 1000 patients allocated to a coxib or diclofenac for a year, three more had major vascular events, one of which was fatal. Naproxen did not significantly increase major vascular events (0·93, 0·69–1·27). Vascular death was increased significantly by coxibs (1·58, 99% CI 1·00–2·49; p=0·0103) and diclofenac (1·65, 0·95–2·85, p=0·0187), non-significantly by ibuprofen (1·90, 0·56–6·41; p=0·17), but not by naproxen (1·08, 0·48–2·47, p=0·80). The proportional effects on major vascular events were independent of baseline characteristics, including vascular risk. Heart failure risk was roughly doubled by all NSAIDs. All NSAID regimens increased upper gastrointestinal complications (coxibs 1·81, 1·17–2·81, p=0·0070; diclofenac 1·89, 1·16–3·09, p=0·0106; ibuprofen 3·97, 2·22–7·10, p<0·0001; and naproxen 4·22, 2·71–6·56, p<0·0001). Interpretation The vascular risks of high-dose diclofenac, and possibly ibuprofen, are comparable to coxibs, whereas high-dose naproxen is associated with less vascular risk than other NSAIDs. Although NSAIDs increase vascular and gastrointestinal risks, the size of these risks can be predicted, which could help guide clinical decision making. Funding UK Medical Research Council and British Heart Foundation.

Outcome measures for studying patients with low back pain

There is growing recognition in the treatment of back pain that patient perapectives are essential in judging the results of treatment. Improving the patients “quality of life” is often the main goal of therapy. Thus, although clinical research in the past has focused on physiologic outcomes, such as range of motion, muscle strength, or neurologic deficits, increasing attention is being given to the rigorous measurement of symptoms, functional status, role function, satisfaction with treatment, and health care costs. In many cases, these so called “soft” outcomes can be measured with a level of reproducibility similar to more conventional clinical data such as imaging test results. Because symptoms and functional outcomes are sometimes only loosely associated with physiologic phenomena, the former outcomes should be measured directly. Modern questionnaires for measuring patient quality of life combine the expertise of social scientists and clinicians and have demonstrated validity. Furthermore, they have some important advantages over simple ratings of “excellent, good fair, and poor” outcomes, or work status alone, Several modern instruments for measuring health-related-quality of life in patients with low back pain are reviewed briefly, describing their content and length. Wlder use of these instruments would help to increase clinician familiarity with their meaning and avoid duplication of effort in questionnaire development.

Reporting disease activity in clinical trials of patients with rheumatoid arthritis: EULAR/ACR collaborative recommendations.

OBJECTIVE To make recommendations on how to report disease activity in clinical trials of rheumatoid arthritis (RA) endorsed by the European League Against Rheumatism (EULAR) and the American College of Rheumatology (ACR). METHODS The project followed the EULAR standardized operating procedures, which use a three-step approach: 1) expert-based definition of relevant research questions (November 2006); 2) systematic literature search (November 2006 to May 2007); and 3) expert consensus on recommendations based on the literature search results (May 2007). In addition, since this is the first joint EULAR/ACR publication on recommendations, an extra step included a meeting with an ACR panel to approve the recommendations elaborated by the expert group (August 2007). RESULTS Eleven relevant questions were identified for the literature search. Based on the evidence from the literature, the expert panel recommended that each trial should report the following items: 1) disease activity response and disease activity states; 2) appropriate descriptive statistics of the baseline, the endpoints and change of the single variables included in the core set; 3) baseline disease activity levels (in general); 4) the percentage of patients achieving a low disease activity state and remission; 5) time to onset of the primary outcome; 6) sustainability of the primary outcome; 7) fatigue. CONCLUSION These recommendations endorsed by EULAR and ACR will help harmonize the presentations of results from clinical trials. Adherence to these recommendations will provide the readership of clinical trials with more details of important outcomes, while the higher level of homogeneity may facilitate the comparison of outcomes across different trials and pooling of trial results, such as in meta-analyses.

Minimum clinically important improvement and patient acceptable symptom state in pain and function in rheumatoid arthritis, ankylosing spondylitis, chronic back pain, hand osteoarthritis, and hip and knee osteoarthritis: Results from a prospective multinational study

To estimate the minimum clinically important improvement (MCII) and patient acceptable symptom state (PASS) values for 4 generic outcomes in 5 rheumatic diseases and 7 countries.

Reliability, validity, and responsiveness of five at‐work productivity measures in patients with rheumatoid arthritis or osteoarthritis

Arthritis often impacts a workers ability to be productive while at work. However, the ideal approach to measuring arthritis‐attributable at‐work productivity loss remains unclear. Our objective was to evaluate the relative strengths and weaknesses of 5 measures aimed at quantifying health‐related at‐work productivity loss and to determine the best available instrument for this population.

Identifying phases of investigation helps planning, appraising, and applying the results of explanatory prognosis studies

OBJECTIVE To present an explanatory framework for understanding prognosis and illustrate it using data from a systematic review. STUDY DESIGN AND SETTING A framework including three phases of explanatory prognosis investigation was adapted from earlier work and a discussion of causal understanding was integrated. For illustration, prognosis studies were identified from electronic and supplemental searches of literature between 1966 and December 2006. We extracted characteristics of the populations, exposures, and outcomes and identified three phases of explanatory prognosis investigation: Phase 1, identifying associations; Phase 2, testing independent associations; and Phase 3, understanding prognostic pathways. The purpose of each phase is exploration, confirmation, and development of understanding, respectively. RESULTS It is important to consider a framework of explanatory prognosis studies for: (1) defining the study objectives, (2) presenting the study methods and data, and (3) interpreting and applying the results of the study. CONCLUSION When conducting and reporting prognosis studies, researchers should consider the approach to prognosis (explanatory or outcome prediction) and phase of investigation, use best methods to limit biases, report completely, and cautiously interpret results. Readers of health care research will then be better able to evaluate the goals and interpret and appropriately use the results of prognosis studies.

RECORD LINKAGE TO CONDUCT AN EPIDEMIOLOGIC STUDY ON THE ASSOCIATION OF RHEUMATOID ARTHRITIS AND LYMPHOMA IN THE PROVINCE OF SASKATCHEWAN, CANADA

The objective of this effort was to assess the utility of the large automated database in Saskatchewan as a resource for pharmacoepidemiologic studies. To this end a study was undertaken to test the hypothesis that rheumatoid arthritis (RA) increases the risk of cancer, especially lymphoma. This was done by performing a retrospective cohort study based on record linkage data from Saskatchewan Health. From hospital discharge diagnoses in the hospital file an exposed group (RA) and two comparison groups matched to the RA group by age and sex were identified: (1) the RA group consisted of people with a discharge diagnosis of rheumatoid arthritis; (2) the osteoarthritis (OA) group consisted of people with OA discharge diagnoses; and (3) a comparison (CN) group consisted of hospitalized people with no discharge diagnoses of arthritis. Drug exposures were determined by linkage with the Prescription Drug File, cancer outcomes were determined by linkage with the Cancer Foundation file, and length of eligibility in the health plan and demographics information were determined by linkage with the registration file. The data were checked for quality of linkages across files and consistency with study definitions. Of 13,333 identified subjects, 2.8% were excluded because of apparent incorrect assignment to study group or age group or because of ineligibility in health plan during the study period. In order to decrease the possibility of misclassification of exposure (rheumatoid arthritis), hospital discharge diagnoses were used to exclude subjects with any inflammatory rheumatic diseases (IRD) from the CN (7.8%) and OA (8.3%) groups and subjects with IRD other than rheumatoid arthritis (4.6%) from the RA group. To decrease selection bias, those who had cancer within 1 year of enrollment (to exclude those in hospital because of symptoms of undiagnosed cancer) were excluded. Because RA subjects hospitalized by a rheumatologist were most likely to have valid rheumatoid arthritis diagnoses, each analysis was run twice: once with the entire RA group (N = 1210) and once with those in the RA group who were rheumatologist-hospitalized (N = 646). Logistic regression of incidence was used to control for age, sex, and use of individual disease-modifying anti-rheumatoid drugs (DMARDs). For the rheumatologist-hospitalized RA group compared to the CN group, a significant 4-fold greater risk for lymphoma/myeloma was detected when DMARD use was not controlled for, and a 3.4-fold increase in risk was detected even when use of individual DMARDs was controlled for.(ABSTRACT TRUNCATED AT 400 WORDS)

A BRIEF INTRODUCTION TO THE CRITICAL READING OF THE CLINICAL LITERATURE

Clinicians are bombarded by reports of new diagnostic tests or treatments for patients with spine problems. To provide the best possible patient care, clinicians need to be able to critically appraise the results of such studies for validity and relevance to patient care. Important questions to be asked of any description of diagnostic or treatment studies are the following questions: 1) Are the patients described in detail so that you can decide whether they are comparable to those that you see in your practice? 2) Are the treatments or assessments described well enough so that you could provide the same for your patients? 3) Was a clinically relevant endpoint measured? 4) Is there an appropriate comaparison group? 5) Are potential sources of bias appropriately attended to? 6) Are the results clinically significant?

VALIDITY OF RHEUMATOID ARTHRITIS DIAGNOSES LISTED IN THE SASKATCHEWAN HOSPITAL SEPARATIONS DATABASE

A Saskatchewan hospital separations database was compared to abstracted hospital records to determine the reliability of the database (i.e. accuracy with which the computer data reflect the charts from which they were coded) and the validity of classifying rheumatoid arthritis status with the database (i.e. the extent to which rheumatoid arthritis mentioned in the database reflected the condition of the patient). A sample of hospitalized subjects fell into three categories: 144 who never had a database diagnosis of any arthritis, 146 who had a database diagnosis of osteoarthritis, and 142 who had a database diagnosis of rheumatoid arthritis. These 432 people experienced 1717 hospitalizations eligible to match a hospital database listing by date, and 1618 matched. Of the remaining 99, 35 were relatively recent and probably had not yet been entered into the database, 39 were possibly entered incorrectly, and 25 could not be matched in any way. Of 150 hospitalizations with a database diagnosis of rheumatoid arthritis, this diagnosis was in the hospital record for 125. Chart documentation of rheumatoid arthritis status was greatest for subjects who, according to the database, were hospitalized by a rheumatologist: of 73 subjects in this category, abstractions showed 69.9% met > or = 5 American Rheumatism Association criteria, 15.1% met < 5 criteria but had a rheumatologists diagnosis of rheumatoid arthritis, 1.3% met < 5 criteria and had a rheumatoid arthritis diagnosis by a non-rheumatologist, and 13.7% had no mention of rheumatoid arthritis or its symptoms in any medical record abstracted. In summary, reliability of the database was excellent, but validity depended on the source of diagnosis.

An evidence‐informed, integrated framework for rheumatoid arthritis care

Introduction Providing adequate care for persons with rheumatoid arthritis (RA) is an ongoing challenge. Although the current evidence supports the use of disease-modifying antirheumatic drugs (DMARDs) within the first 3 months of symptoms appearing (1–3), delay in DMARD use and other gaps in care have been reported across communities (4–9). The situation has worsened due to the shortage of specialists (10). The process of seeking medical treatment begins with the person’s recognition of the symptoms and the action of visiting a family physician (FP) (Figure 1, levels A and B). The FP then performs the appropriate investigations, and if RA is suspected, the FP refers the person to a rheumatologist (levels B and C) who then conducts further tests, provides a diagnosis, and prescribes DMARDs and other appropriate medications (level D). Next, the person may be referred to the available community resources and/or rehabilitation programs that enable self-management (levels E1–E4), and will be periodically assessed by a rheumatologist (level F). Successful delivery of these interventions is largely dependent on the availability of local programs and the coordination among the rheumatologist, the FP, and other health professionals. In the case of severe joint damage, the person is referred for an orthopedic consultation and surgery may be considered (levels G1–G4). Moving from one level to the next involves a potential wait period, which may be caused by, for example, delays in patients’ and health professionals’ recognition of RA symptoms, delays in referral to rheumatologists, lack of access to specialist care or community resources, or patients’ own choices. Delays may occur at any of the following periods (Figure 1): Wait 1: the time between a person’s development and awareness of the seriousness of the symptoms and the first visit with an FP; Wait 2: the time between the first visit with an FP and the first visit with a rheumatologist; Wait 3: from the first rheumatology visit to the date the patient starts the appropriate therapy; Wait 4: from a patient starting medication to the date when he or she has access to adequate resources that enable self-management; andWait 5: from the decision date for an orthopedic consultation to the date of the patient’s first visit with a surgeon and, subsequently, the date of surgery. The delay between symptom onset and DMARD prescription for individuals with RA is a problem across countries (Waits 1–3), with a median lag time ranging from 6.5 to 19 months (5–9). A few studies have attempted to estimate the length of Wait 1, but the findings are inconsistent. Two studies, a retrospective cohort from the US (11) and a prospective study from Norway (12), estimated a median delay of 4 weeks for the first FP visit. However, more recent research from the UK estimated 12 weeks (13), with 38% of people waiting more than 3 months before seeing an FP (14). The lag time from FP visit to rheumatologist consultation is believed to be a major source of the delay (Wait 2). In a UK study, 44% waited more than 3 months for a specialist referral (14). Recent research from Canada also found a median lag time of 79 days between the FP visit and the first rheumatologist visit (15). In contrast, the Linda C. Li, PT, PhD: University of British Columbia and Arthritis Research Centre of Canada, Vancouver, British Columbia, Canada; Elizabeth M. Badley, DPhil: Arthritis Community Research and Evaluation Unit, Toronto Western Research Institute and University of Toronto, Toronto, Ontario, Canada; Crystal MacKay, PT, MHSc: Arthritis Community Research and Evaluation Unit, Toronto Western Research Institute, Toronto, Ontario, Canada; Dianne Mosher, MD, FRCP(C): Queen Elizabeth II Health Sciences Centre, Halifax, Nova Scotia, Canada; Shahin (Walji) Jamal, MD, FRCP(C): St. Michael’s Hospital and University of Toronto, Toronto, Ontario, Canada; Anamaria Jones, PT, PhD(Candidate): Arthritis Research Centre of Canada, Vancouver, British Columbia, Canada, and Federal University of Sao Paulo, Sao Paulo, Brazil; Claire Bombardier, MD, FRCP(C): University Health Network, University of Toronto, Institute for Work & Health, and Mount Sinai Hospital, Toronto, Ontario, Canada. Dr. Mosher has received honoraria (less than