Room for improvement: a randomised controlled trial with nested qualitative interviews on space, place and treatment delivery.

OBJECTIVE: Healthcare-oriented design in hospitals can promote better clinical outcomes. Creating optimal facilities may increase treatment effects. We investigated the influence of the treatment room on effects of exercise therapy. METHODS: In a mixed-method randomised controlled double-blind trial, middle-aged individuals reporting knee or hip pain performed 8 weeks of exercise therapy in (1) a newly built physically enhanced environment, (2) a standard environment or (3) were waitlisted, receiving no intervention. Participants and therapists were blind to study aim. Primary outcome was participants' Global Perceived Effect (GPE; seven-point Likert scale). Six nested focus group interviews with participants (n=25) and individual interviews with therapists (n=2) explored experiences of the environments. RESULTS: 42 people exercised in the physically enhanced environment, 40 in the standard environment, 21 were waitlisted. Contrary to our hypothesis, the treatment response seemed greater in the standard environment for GPE (0.98, 95% CI0.5 to 1.4) than for the physically enhanced environment (0.37, 95% CI -0.2 to 0.9), between-group difference (0.61, 95% CI -0.1 to 1.3) did not reach statistical significance (p=0.07). Waitlist group reported no improvement (-0.05 95% CI -0.5 to 0.4). In interviews, participants from the standard environment expressed greater social cohesion and feeling at home. Qualitative themes identified; reflection, sense of fellowship and transition. Secondary patient-reported outcomes and qualitative findings supported the primary finding, while improvements in muscle strength and aerobic capacity did not differ between exercise groups. CONCLUSION: Results suggest that the physical environment contributes to treatment response. Matching patients' preferences to treatment rooms may improve patient-reported outcomes. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov identifier: NCT02043613.

The characterisation of unexplained pain after knee replacement.

BACKGROUND: The aims of this study were to characterise the pain experienced by patients with chronic pain after knee replacement (KR), in whom no apparent 'orthopaedic' problem could be identified, and to establish how many have pain sensitisation problems (including neuropathic pain). METHODS: A total of 44 patients were prospectively evaluated at a multidisciplinary tertiary referral clinic by an orthopaedic surgeon, pain specialist, rheumatologist and physiotherapist. These patients had been pre-screened by an orthopaedic surgeon to remove cases where there was an obvious cause of pain that could be treated with revision surgery. They were then followed up to find out whether any subsequent interventions had occurred. RESULTS: The mean time since surgery was 29 months (range: 3-108 months), and 18% were revision KR. Patients were evaluated for symptoms of nociceptive pain, allodynia, pains elsewhere and psychosocial factors. The patients were categorised into nociceptive pain 43% (n = 19), pain sensitisation 25% (n = 11) and mixed pain 32% (n = 14). Mean Visual Analogue Score (VAS) pain scores were 6.7/10 with high scores for both constant (66%) and intermittent (70%) pain elements, and pain caused high levels of interference with life. Fifty percent suffered depression and 25% suffered widespread pains (more than three pains elsewhere in the body). Patients with widespread pains suffered more pain (p = 0.01) and higher rates of both pain sensitisation (p = 0.07) and thermal allodynia (p < 0.04). CONCLUSION: Patients after KR can experience severe pain that interferes with their lives, depression and many have pain sensitisation problems rather than any local, nociceptive cause. We advocate screening patients with unexplained pain after KR for pain sensitisation problems, pains at other sites and depression. Appropriate further treatment and multidisciplinary interventions can then be arranged.

Exploring the effect of space and place on response to exercise therapy for knee and hip pain--a protocol for a double-blind randomised controlled clinical trial: the CONEX trial.

INTRODUCTION: Context effects are described as effects of a given treatment, not directly caused by the treatment itself, but rather caused by the context in which treatment is delivered. Exercise is a recommended core treatment in clinical guidelines for musculoskeletal disorders. Although moderately effective overall, variation is seen in size of response to exercise across randomised controlled trial (RCT) studies. Part of this variation may be related to the fact that exercise interventions are performed in different physical environments, which may affect participants differently. The study aims to investigate the effect of exercising in a contextually enhanced physical environment for 8 weeks in people with knee or hip pain. METHODS AND ANALYSIS: The study is a double-blind RCT. Eligible participants are 35 years or older with persisting knee and/or hip pain for 3 months. Participants are randomised to one of three groups: (1) exercise in a contextually enhanced environment, (2) exercise in a standard environment and (3) waiting list. The contextually enhanced environment is located in a newly built facility, has large windows providing abundant daylight and overlooks a recreational park. The standard environment is in a basement, has artificial lighting and is marked by years of use; that is, resembling many clinical environments. The primary outcome is the participant's global perceived effect rated on a seven-point Likert scale after 8 weeks exercise. Patient-reported and objective secondary outcomes are included. ETHICS AND DISSEMINATION: The Regional Scientific Ethical Committee for Southern Denmark has approved the study. Study findings will be disseminated in peer-reviewed publications and presented at national and international conferences. TRIAL REGISTRATION NUMBER: NCT02043613.

Association of radiographic osteoarthritis, pain on passive movement and knee range of motion: a cross-sectional study.

BACKGROUND: Knee pain is associated with radiographic knee osteoarthritis, but the relationships between physical examination, pain and radiographic features are unclear. OBJECTIVE: To examine whether deficits in knee extension or flexion were associated with radiographic severity and pain during clinical examination in persons with knee pain or radiographic features of osteoarthritis. DESIGN: Cross-sectional data of the Somerset and Avon Survey of Health (SASH) cohort study. METHODS: Participants with knee pain or radiographic features of osteoarthritis were included. We assessed the range of passive knee flexion and extension, pain on movement and Kellgren and Lawrence (K/L) grades. Odds ratios were calculated for the association between range of motion and pain as well as radiographic severity. RESULTS/FINDINGS: Of 1117 participants with a clinical assessment, 805 participants and 1530 knees had complete data and were used for this analysis. Pain and radiographic changes were associated with limited range of motion. In knees with pain on passive movement, extension and flexion were reduced per one grade of K/L by -1.4° (95% CI -2.2 to -0.5) and -1.6° (95% CI -2.8 to -0.4), while in knees without pain the reduction was -0.3° (95% CI -0.6 to -0.1) (extension) and -1.1° (-1.8 to -0.3) (flexion). The interaction of pain with K/L was significant (p = 0.021) for extension but not for flexion (p = 0.333). CONCLUSIONS: Pain during passive movement, which may be an indicator of reversible soft-tissue changes, e.g., reversible through physical therapy, is independently associated with reduced flexion and extension of the knee.

Predictors of outcomes of total knee replacement surgery.

OBJECTIVE: To identify pre-operative predictors of patient-reported outcomes of primary total knee replacement (TKR) surgery. METHODS: The Elective Orthopaedic Centre database is a large prospective cohort of 1991 patients receiving primary TKR in south-west London from 2005 to 2008. The primary outcome is the 6-month post-operative Oxford Knee Score (OKS). To classify whether patients had a clinically important outcome, we calculated a patient acceptable symptom state (PASS) for the 6-month OKS related to satisfaction with surgery. Potential predictor variables were pre-operative OKS, age, sex, BMI, deprivation, surgical side, diagnosis, operation type, American Society of Anesthesiologists grade and EQ5D anxiety/depression. Regression modelling was used to identify predictors of outcome. RESULTS: The strongest determinants of outcome include pre-operative pain/function-those with less severe pre-operative disease obtain the best outcomes; diagnosis in relation to pain outcome-patients with RA did better than those with OA; deprivation-those living in poorer areas had worse outcomes; and anxiety/depression-worse pre-operative anxiety/depression led to worse pain. Differences were observed between predictors of pain and functional outcomes. Diagnosis of RA and anxiety/depression were associated with pain, whereas age and gender were specifically associated with function. BMI was not a clinically important predictor of outcome. CONCLUSION: This study identified clinically important predictors of attained pain/function post-TKR. Predictors of pain were not necessarily the same as functional outcomes, which may be important in the context of a patient's expectations of surgery. Other predictive factors need to be identified to improve our ability to recognize patients at risk of poor TKR outcomes.

Clinical tool to identify patients who are most likely to achieve long-term improvement in physical function after total hip arthroplasty.

OBJECTIVE: To develop a clinical risk prediction tool to identify patients most likely to experience long-term clinically meaningful functional improvement following total hip arthroplasty (THA). METHODS: We studied 282 patients from 2 health districts in England (Portsmouth and North Staffordshire) who were ≥45 years of age and undergoing THA for primary osteoarthritis. Baseline data on age, sex, comorbidity, body mass index (BMI), functional status (Short Form 36 [SF-36]), and preoperative radiographic severity were collected by interview and examination. The outcome was a clinically significant (30-point) improvement in SF-36 physical function score assessed ~8 years after THA. Logistic regression modeling was used to identify predictors of functional improvement. RESULTS: Improvement in physical function was less likely in patients with better preoperative functioning (odds ratio [OR] 0.73 [95% confidence interval (95% CI) 0.60, 0.89]), older people (OR 0.94 [95% CI 0.90, 0.98]), women (OR 0.37 [95% CI 0.19, 0.72]), those with a previous hip injury (OR 0.14 [95% CI 0.03, 0.74]), and those with a greater number of painful joint sites (OR 0.61 [95% CI 0.46, 0.80]). Patients with worse radiographic grades were most likely to improve (OR 2.15 [95% CI 1.17, 3.93]). We found no influence of BMI or patient comorbidity on functional outcome. Predictors of good outcomes were the same as those of bad outcomes, acting in the opposite direction. A clinical risk prediction tool was developed to identify patients who are most likely to receive functional improvement following THA. CONCLUSION: This prediction tool has the potential to inform health care professionals and patients about functional improvement following THA (as distinct from driving rationing or commissioning decisions regarding who should have surgery); it requires introduction into clinical practice under research conditions to investigate its impact on decisions made by patients and clinicians.

Association of bone attrition with knee pain, stiffness and disability: a cross-sectional study.

OBJECTIVES: Bone pathologies as detected on MRI are associated with the presence of pain in knee osteoarthritis (OA). The authors examined whether bone attrition assessed on x-rays was associated with pain, stiffness and disability. METHODS: The authors analysed x-rays of 1326 knees with OA from 783 individuals participating in the cross-sectional population-based Somerset and Avon Survey of Health. The diagnosis of OA was defined by the presence of osteophytes in anteroposterior (AP) or lateral views. Bone attrition was graded from 0 (no attrition) to 3 (severe attrition >10 mm) and Kellgren and Lawrence (K/L) scores were assigned on AP views. Logistic regression models adjusted for gender, age, body mass index, effusion and K/L scores were used to determine whether bone attrition was associated with pain, stiffness and disability. RESULTS: Pain was reported in 84 knees (74%) with radiographic bone attrition compared with 505 (42%) without bone attrition (adjusted OR 2.22, 95% CI 1.29 to 3.80). The adjusted OR was increased for day pain but not for night pain (p for interaction <0.001). Stiffness was reported for 85 knees with bone attrition (75%) and 437 knees without (36%) (adjusted OR 3.23, 95% CI 1.85 to 5.64). Disability was reported by 40 individuals with bone attrition (50%) and 140 individuals without (24%) (adjusted OR 2.09, 95% CI 1.19 to 3.68). CONCLUSIONS: Bone attrition detected on conventional x-rays using a simple cheap technique is strongly associated with the presence of day pain, stiffness and disability in knee OA.

Unstated factors in orthopaedic decision-making: a qualitative study.

BACKGROUND: Total joint replacement (TJR) of the hip or knee for osteoarthritis is among the most common elective surgical procedures. There is some inequity in provision of TJR. How decisions are made about who will have surgery may contribute to disparities in provision. The model of shared decision-making between patients and clinicians is advocated as an ideal by national bodies and guidelines. However, we do not know what happens within orthopaedic practice and whether this reflects the shared model. Our study examined how decisions are made about TJR in orthopaedic consultations. METHODS: The study used a qualitative research design comprising semi-structured interviews and observations. Participants were recruited from three hospital sites and provided their time free of charge. Seven clinicians involved in decision-making about TJR were approached to take part in the study, and six agreed to do so. Seventy-seven patients due to see these clinicians about TJR were approached to take part and 26 agreed to do so. The patients' outpatient appointments ('consultations') were observed and audio-recorded. Subsequent interviews with patients and clinicians examined decisions that were made at the appointments. Data were analysed using thematic analysis. RESULTS: Clinical and lifestyle factors were central components of the decision-making process. In addition, the roles that patients assigned to clinicians were key, as were communication styles. Patients saw clinicians as occupying expert roles and they deferred to clinicians' expertise. There was evidence that patients modified their behaviour within consultations to complement that of clinicians. Clinicians acknowledged the complexity of decision-making and provided descriptions of their own decision-making and communication styles. Patients and clinicians were aware of the use of clinical and lifestyle factors in decision-making and agreed in their description of clinicians' styles. Decisions were usually reached during consultations, but patients and clinicians sometimes said that treatment decisions had been made beforehand. Some patients expressed surprise about the decisions made in their consultations, but this did not necessarily imply dissatisfaction. CONCLUSIONS: The way in which roles and communication are played out in decision-making for TJR may affect the opportunity for shared decisions. This may contribute to variation in the provision of TJR. Making the importance of these factors explicit and highlighting the existence of patients' 'surprise' about consultation outcomes could empower patients within the decision-making process and enhance communication in orthopaedic consultations.

Variation in age and physical status prior to total knee and hip replacement surgery: a comparison of centers in Australia and Europe.

OBJECTIVE: To investigate whether variation exists in the preoperative age, pain, stiffness, and physical function of people undergoing total knee replacement (TKR) and total hip replacement (THR) at several centers in Australia and Europe. METHODS: Individual Western Ontario and McMaster Universities Osteoarthritis Index data (range 0-100, where 0 = best and 100 = worst) collected within 6 weeks prior to primary TKR and THR were extracted from 16 centers (n = 2,835) according to specified eligibility criteria. Analysis of covariance was used to evaluate differences in pain, stiffness, and physical function between centers, with adjustment for age and sex. RESULTS: There was marked variation in the age of people undergoing surgery between the centers (TKR mean age 67-73 years; F[6,1004] = 4.21, P < 0.01, and THR mean age 63-72 years; F[14,1807] = 7.27, P < 0.01). Large differences in preoperative status were observed between centers, most notably for pain (TKR adjusted mean pain 52.5-61.1; F[6,1002] = 4.26, P < 0.01, and THR adjusted mean pain 49.2-65.7; F[14,1802] = 8.44, P < 0.01) and physical function (TKR adjusted mean function 52.7-61.4; F[6,1002] = 5.27, P < 0.01, and THR adjusted mean function 53.3-71.0; F[14,1802] = 6.71, P < 0.01). Large effect sizes (up to 0.98) reflect the magnitude of variation between centers and highlight the clinical relevance of these findings. CONCLUSION: The large variations in age and preoperative status indicate substantial differences in the timing of joint replacement across the centers studied, with potential for compromised surgical outcomes due to premature or delayed surgery. Possible contributing factors include patient preferences, the absence of concrete indications for surgery, and the capacity of the health care systems.

Hylan versus hyaluronic acid for osteoarthritis of the knee: a systematic review and meta-analysis.

OBJECTIVE: To compare the effectiveness and safety of intraarticular high-molecular hylan with standard preparations of hyaluronic acids in osteoarthritis of the knee. METHODS: We performed a systematic review and meta-analysis of randomized controlled trials comparing hylan with a hyaluronic acid in patients with knee osteoarthritis. Trials were identified by systematic searches of Central, Medline, EMBase, Cinahl, the Food and Drug Administration, and Science Citation Index supplemented by hand searches of conference proceedings and reference lists (last update November 2006). Literature screening and data extraction were performed in duplicate. Effect sizes were calculated from differences in means of pain-related outcomes between treatment and control groups at the end of the trial, divided by the pooled standard deviation. Trials were combined using random-effects meta-analysis. RESULTS: Thirteen trials with a pooled total of 2,085 patients contributed to the meta-analysis. The pooled effect size was -0.27 (95% confidence interval [95% CI] -0.55, 0.01), favoring hylan, but between-trial heterogeneity was high (I(2) = 88%). Trials with blinded patients, adequate concealment of allocation, and an intent-to-treat analysis had pooled effect sizes near null. The meta-analyses on safety revealed an increased risk associated with hylan for any local adverse events (relative risk [RR] 1.91; 95% CI 1.04, 3.49; I(2) = 28%) and for flares (RR 2.04; 95% CI 1.18, 3.53; I(2) = 0%). CONCLUSION: Given the likely lack of a superior effectiveness of hylan over hyaluronic acids and the increased risk of local adverse events associated with hylan, we discourage the use of intraarticular hylan in patients with knee osteoarthritis in clinical research or practice.

Efficacy and safety of intraarticular hylan or hyaluronic acids for osteoarthritis of the knee: a randomized controlled trial.

OBJECTIVE: To compare the efficacy and safety of intraarticular hylan and 2 hyaluronic acids (HAs) in osteoarthritis (OA) of the knee. METHODS: This was a multicenter, patient-blind, randomized controlled trial in 660 patients with symptomatic knee OA. Patients were randomly assigned to receive 1 cycle of 3 intraarticular injections per knee of 1 of 3 preparations: a high molecular weight cross-linked hylan, a non-cross-linked medium molecular weight HA of avian origin, or a non-cross-linked low molecular weight HA of bacterial origin. The primary outcome measure was the change in the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain score at 6 months. Secondary outcome measures included local adverse events (effusions or flares) in injected knees. During months 7-12, patients were offered a second cycle of viscosupplementation. RESULTS: Pain relief was similar in all 3 groups. The difference in changes between baseline and 6 months between hylan and the combined HAs was 0.1 on the WOMAC pain score (95% confidence interval [95% CI] -0.2, 0.3). No relevant differences were observed in any of the secondary efficacy outcomes, and stratified analyses provided no evidence for differences in effects across different patient groups. There was a trend toward more local adverse events in the hylan group than in the HA groups during the first cycle (difference 2.2% [95% CI -2.4, 6.7]), and this trend became more pronounced during the second cycle (difference 6.4% [95% CI 0.6, 12.2]). CONCLUSION: We found no evidence for a difference in efficacy between hylan and HAs. In view of its higher costs and potential for more local adverse events, we see no rationale for the continued use of hylan in patients with knee OA.

Meta-analysis: chondroitin for osteoarthritis of the knee or hip.

BACKGROUND: Previous meta-analyses described moderate to large benefits of chondroitin in patients with osteoarthritis. However, recent large-scale trials did not find evidence of an effect. PURPOSE: To determine the effects of chondroitin on pain in patients with osteoarthritis. DATA SOURCES: The authors searched the Cochrane Central Register of Controlled Trials (1970 to 2006), MEDLINE (1966 to 2006), EMBASE (1980 to 2006), CINAHL (1970 to 2006), and conference proceedings; checked reference lists; and contacted authors. The last update of searches was performed on 30 November 2006. STUDY SELECTION: Studies were included if they were randomized or quasi-randomized, controlled trials that compared chondroitin with placebo or with no treatment in patients with osteoarthritis of the knee or hip. There were no language restrictions. DATA EXTRACTION: The authors extracted data in duplicate. Effect sizes were calculated from the differences in means of pain-related outcomes between treatment and control groups at the end of the trial, divided by the pooled SD. Trials were combined by using random-effects meta-analysis. DATA SYNTHESIS: 20 trials (3846 patients) contributed to the meta-analysis, which revealed a high degree of heterogeneity among the trials (I2 = 92%). Small trials, trials with unclear concealment of allocation, and trials that were not analyzed according to the intention-to-treat principle showed larger effects in favor of chondroitin than did the remaining trials. When the authors restricted the analysis to the 3 trials with large sample sizes and an intention-to-treat analysis, 40% of patients were included. This resulted in an effect size of -0.03 (95% CI, -0.13 to 0.07; I2 = 0%) and corresponded to a difference of 0.6 mm on a 10-cm visual analogue scale. A meta-analysis of 12 trials showed a pooled relative risk of 0.99 (CI, 0.76 to 1.31) for any adverse event. LIMITATIONS: For 9 trials, the authors had to use approximations to calculate effect sizes. Trial quality was generally low, heterogeneity among the trials made initial interpretation of results difficult, and exploring sources of heterogeneity in meta-regression and stratified analyses may be unreliable. CONCLUSIONS: Large-scale, methodologically sound trials indicate that the symptomatic benefit of chondroitin is minimal or nonexistent. Use of chondroitin in routine clinical practice should therefore be discouraged.

Concomitant therapy: an outcome variable for musculoskeletal disorders? Part 2: total joint replacement in osteoarthritis trials.

Interest has grown in using the requirement of total joint replacement (TJR) as a "hard" outcome measure. Limitations exist, however, in the use of such an outcome, in particular the variability in the decision to perform surgery, length of surgical waiting lists, and sensitivity to change. This special interest group is exploring ways of retaining the clinical relevance of TJR but overcoming the problems--2 alternative outcomes are being considered: "time to physician's decision to recommend surgery" and "time to fulfilling criteria for total joint replacement."

Assessing bone loss on radiographs of the knee in osteoarthritis: a cross-sectional study.

OBJECTIVE: The only established system to grade subchondral bone attrition in knee osteoarthritis (OA) has low interobserver reliability. In this study, our aim was to convert this system into a reliable tool for the assessment of subchondral bone loss in knee OA. METHODS: Templates that were designed to outline the normal contours of the knee were overlaid onto conventional radiographs of a random sample of 100 knees of OA patients who were awaiting total knee replacement (TKR). Seventy-five films from individuals with chronic knee pain who were not awaiting TKR and 75 films from asymptomatic control subjects were also assessed. Bone loss was graded from 0 (no attrition) to 3 (severe attrition of >10 mm); other established radiologic features were also graded. Spearman's rho was used to determine the correlation of attrition scores with other features, and logistic regression was used to explore whether definite bone attrition was associated with night pain. RESULTS: The inter- and intraobserver reliability values were high for attrition scores and for the presence of definite attrition (score > or =2). Bone attrition was evident in 62% of films from patients awaiting TKR, in 9% of films from individuals with chronic knee pain who were not awaiting TKR, and in 1% of films from controls. In all groups, the correlation between attrition and other features was weak to moderate. There was a nonsignificant association between definite bone attrition and night pain. CONCLUSION: Bone attrition is an additional dimension of knee OA that can be measured reliably. Definite attrition may be associated with night pain.

Using expert patients' narratives as an educational resource.

In this article, we examine the topic of patient participation in health care and report on how we have drawn on the concept of patient expertise to produce a new kind of information booklet for chronic arthritis patients. The booklet is patient-generated and contains the illness narratives of patients with three kinds of arthritis. The booklet draws upon the knowledge of patients who feel they are flourishing despite their condition. By communicating information through the powerful medium of narrative it is hoped the booklet will be a useful educational and supportive resource for other patients with a similar condition. We would encourage health professionals to acknowledge patient expertise and to consider the expertise of certain patients as a valuable educational resource both for themselves and for other patients.

Pathogenesis and management of pain in osteoarthritis.

The term osteoarthritis describes a common, age-related, heterogeneous group of disorders characterised pathologically by focal areas of loss of articular cartilage in synovial joints, associated with varying degrees of osteophyte formation, subchondral bone change, and synovitis. Joint damage is caused by a mixture of systemic factors that predispose to the disease, and local mechanical factors that dictate its distribution and severity. Various genetic abnormalities have been described, but most sporadic osteoarthritis probably depends on minor contributions from several genetic loci. Osteoarthritic joint damage may be associated with clinical problems, but the severity of joint disease is only weakly related to that of the clinical problem. For this reason the associations and pathogenesis of pain are in as much need of investigation as joint damage. Subchondral bone and synovium may be responsible for nociceptive stimuli, and peripheral neuronal sensitisation is an important feature, and can result in normal activities (such as walking) causing pain. Central pain sensitisation can also occur, and psychosocial factors are important determinants of pain severity. We present a stepwise approach to the management of osteoarthritis.

Risk of cardiovascular events and rofecoxib: cumulative meta-analysis.

BACKGROUND: The cyclo-oxygenase 2 inhibitor rofecoxib was recently withdrawn because of cardiovascular adverse effects. An increased risk of myocardial infarction had been observed in 2000 in the Vioxx Gastrointestinal Outcomes Research study (VIGOR), but was attributed to cardioprotection of naproxen rather than a cardiotoxic effect of rofecoxib. We used standard and cumulative random-effects meta-analyses of randomised controlled trials and observational studies to establish whether robust evidence on the adverse effects of rofecoxib was available before September, 2004. METHODS: We searched bibliographic databases and relevant files of the US Food and Drug Administration. We included all randomised controlled trials in patients with chronic musculoskeletal disorders that compared rofecoxib with other non-steroidal anti-inflammatory drugs (NSAIDs) or placebo, and cohort and case-control studies of cardiovascular risk and naproxen. Myocardial infarction was the primary endpoint. FINDINGS: We identified 18 randomised controlled trials and 11 observational studies. By the end of 2000 (52 myocardial infarctions, 20742 patients) the relative risk from randomised controlled trials was 2.30 (95% CI 1.22-4.33, p=0.010), and 1 year later (64 events, 21432 patients) it was 2.24 (1.24-4.02, p=0.007). There was little evidence that the relative risk differed depending on the control group (placebo, non-naproxen NSAID, or naproxen; p=0.41) or trial duration (p=0.82). In observational studies, the cardioprotective effect of naproxen was small (combined estimate 0.86 [95% CI 0.75-0.99]) and could not have explained the findings of the VIGOR trial. INTERPRETATION: Our findings indicate that rofecoxib should have been withdrawn several years earlier. The reasons why manufacturer and drug licensing authorities did not continuously monitor and summarise the accumulating evidence need to be clarified.