Paul Dieppe

Developing and evaluating complex interventions: the new Medical Research Council guidance

Evaluating complex interventions is complicated. The Medical Research Councils evaluation framework (2000) brought welcome clarity to the task. Now the council has updated its guidance

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BACKGROUND The cyclo-oxygenase 2 inhibitor rofecoxib was recently withdrawn because of cardiovascular adverse effects.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 INTERPRETATION Our findings indicate that rofecoxib should have been withdrawn several years earlier.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.

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 factors for the incidence and progression of radiographic knee osteoarthritis.

OBJECTIVE Preventive strategies against knee osteoarthritis (OA) require a knowledge of risk factors that influence the initiation of the disorder and its subsequent progression. This population-based longitudinal study was performed to address this issue. METHODS Ninety-nine men and 255 women aged > or =55 years had baseline interviews and weight-bearing knee radiographs in 1990-1991. Repeat radiographs were obtained in 1995-1996 (mean followup duration 5.1 years, median age at followup 75.8 years). Risk factors assessed at baseline were tested for their association with incident and progressive radiographic knee OA by logistic regression. RESULTS Rates of incidence and progression were 2.5% and 3.6% per year, respectively. After adjusting for age and sex, the risk of incident radiographic knee OA was significantly increased among subjects with higher baseline body mass index (odds ratio [OR] 18.3, 95% confidence interval [95% CI] 5.1-65.1, highest versus lowest third), previous knee injury (OR 4.8, 95% CI 1.0-24.1), and a history of regular sports participation (OR 3.2, 95% CI 1.1-9.1). Knee pain at baseline (OR 2.4, 95% CI 0.7-8.0) and Heberdens nodes (OR 2.0, 95% CI 0.7-5.7) were weakly associated with progression. Analyses based on individual radiographic features (osteophyte formation and joint space narrowing) supported differences in risk factors for either feature. CONCLUSION Most currently recognized risk factors for prevalent knee OA (obesity, knee injury, and physical activity) influence incidence more than radiographic progression. Furthermore, these factors might selectively influence osteophyte formation more than joint space narrowing. These findings are consistent with knee OA being initiated by joint injury, but with progression being a consequence of impaired intrinsic repair capacity.

EULAR recommendations for the management of knee osteoarthritis: report of a task force of the Standing Committee for International Clinical Studies Including Therapeutic Trials (ESCISIT)

BACKGROUND Osteoarthritis (OA) is the most common joint disease encountered throughout Europe. A task force for the EULAR Standing Committee for Clinical Trials met in 1998 to determine the methodological and logistical approach required for the development of evidence based guidelines for treatment of knee OA. The guidelines were restricted to cover all currently available treatments for knee OA diagnosed either clinically and/or radiographically affecting any compartment of the knee. METHODS The first stage was the selection of treatment modalities to be considered. The second stage comprised a search of the electronic databases Medline and Embase using a combination of subject headings and keywords. All European language publications in the form of systematic reviews, meta-analyses, randomised controlled trials, controlled trials, and observational studies were included. During stage three all the relevant studies were quality scored. The summary statistics for validated outcome measures, when available, were recorded and, where practical, the numbers needed to treat and the effect size for each treatment were calculated. In the fourth stage key clinical propositions were determined by expert consensus employing a Delphi approach. The final stage ranked these propositions according to the available evidence. A second set of propositions relating to a future research agenda was determined by expert consensus using a Delphi approach. RESULTS Over 2400 English language publications and 400 non-English language publications were identified. Seven hundred and forty four studies presented outcome data of the effects of specific treatments on knee OA. Quantitative analysis of treatment effect was possible in only 61 studies. Recommendations for the management of knee OA based on currently available data and expert opinion are presented. Proposals for a future research agenda are highlighted. CONCLUSIONS These are the first clinical guidelines on knee OA to combine an evidence based approach and a consensus approach across a wide range of treatment modalities. It is apparent that certain clinical propositions are supported by substantial research based evidence, while others are not. There is thus an urgent need for future well designed trials to consider key clinical questions.

Determinants of disability in osteoarthritis of the knee.

OBJECTIVES: To evaluate the influences of radiographic severity, quadriceps strength, knee pain, age, and gender on functional ability in patients with osteoarthritis of the knee. METHODS: Equal numbers of knee pain positive and negative respondents to a survey of registrants aged more than 55 years at a general practice were invited to attend for knee radiographs and quadriceps femoris isometric strength estimations. Disability was measured using the Stanford Health Assessment Questionnaire. RESULTS: Complete data were available on 70 men (mean age 72.7 years) and 89 women (mean age 68.1 years); 44% reported knee pain, 48% had radiographic features of osteoarthritis, and 32% reported some degree of disability. Significant correlations were observed between disability and radiographic score, quadriceps strength, and knee pain. Logistic regression analysis, however, showed significant independent contributions from quadriceps strength (odds ratio 0.84 kgF), knee pain (odds ratio 1.67), and age (odds ratio 1.06 per year) only; the radiographic score had no influence on the model. These results were not influenced by confining the analysis to the group with radiographic features of osteoarthritis. CONCLUSIONS: Quadriceps strength, knee pain, and age are more important determinants of functional impairment in elderly subjects than the severity of knee osteoarthritis as assessed radiographically. Strategies designed to optimise muscle strength may have the potential to reduce a vast burden of disability, dependency, and cost.

Radiographic patterns of osteoarthritis of the knee joint in the community: the importance of the patellofemoral joint.

The intimate relation which the patella has with the knee joint and quadriceps muscle suggests that patellofemoral joint osteoarthritis is likely to be an important cause of knee pain and disability. Two hundred and seventy three subjects who reported knee pain in a postal questionnaire survey and 240 control subjects consented to have anteroposterior weightbearing and lateral knee radiographs. Each subject completed a Stanford Health Assessment Questionnaire (HAQ). Radiographic knee osteoarthritis was found in 53% of symptomatic and 17% of asymptomatic subjects. Three patterns predominated patellofemoral, medial, and medial/patellofemoral joint disease in 11, 21, and 7% of the men and in 24, 12, 6% of the women respectively. The occurrence of isolated symptomatic patellofemoral joint osteoarthritis in this sample aged more than 55 years was estimated as 8% in women and 2% in men. All patterns of symptomatic knee joint osteoarthritis increased with age in women but peaked at 70 years in men. Medial joint and patellofemoral joint osteoarthritis were significantly associated with disability (46 v 17% in controls and 64 v 25% in controls respectively) but higher HAQ scores were more common in subjects with patellofemoral joint osteoarthritis. Patellofemoral joint osteoarthritis is common, associated with disability, occurs in the absence of tibiofemoral disease, and can no longer be omitted from future studies of osteoarthritis of the knee joint.

Osteoarthritis: New Insights. Part 2: Treatment Approaches

There is no known cure for osteoarthritis, and the goal of contemporary management of the patient with osteoarthritis remains control of pain and improvement in function and health-related quality of life with avoidance, if possible, of therapeutic toxicity. Recent studies have demonstrated the potential of treatments ranging from newly approved oral medications to nutriceuticals, patient education interventions, and surgery. Increasingly, appropriate treatment of osteoarthritis combines one or more oral agents with exercise and other biomechanical techniques. This article is part 2 of a two-part summary of a National Institutes of Health (NIH) conference, Stepping Away from OA: Prevention of Onset, Progression, and Disability of Osteoarthritis. The conference brought together experts from diverse backgrounds and provided a multidisciplinary and comprehensive summary of recent advances in the prevention of osteoarthritis onset, progression, and disability. For research questions and opportunities identified at the conference, see www.nih.gov/niams/reports/oa/oareport.htm(accessed on 25 May 2000). Systemic and Topical Treatments Dr. Marc C. Hochberg (University of Maryland School of Medicine, Baltimore, Maryland), Dr. Timothy McAlindon (Boston University School of Medicine, Boston, Massachusetts), and Dr. David T. Felson (Boston University School of Medicine): Drug therapy for pain management is most effective when combined with nonpharmacologic strategies (1, 2). In 1995, the American College of Rheumatology issued guidelines for the medical management of osteoarthritis of the hip and knee (2, 3). Since then, several systematic reviews of drug therapy for osteoarthritis have been published (4-6). The following recommendations for systemic and topical treatments (except for glucosamine and chondroitin, which were not evaluated) are derived from updated recommendations of the American College of Rheumatology for the treatment of osteoarthritis. Systemic Treatments Nonopioid Analgesics For many patients with osteoarthritis, the relief of mild to moderate joint pain afforded by the simple analgesic acetaminophen is comparable to that achieved with a nonsteroidal anti-inflammatory drug (NSAID) (7, 8). Accordingly, although acetaminophen fails to adequately relieve pain in many patients, it merits a trial as initial therapy on the basis of its overall cost, efficacy, and toxicity profile (9, 10). The daily dose of acetaminophen should not exceed 4 g. Although it is one of the safest analgesics, acetaminophen can be associated with clinically important adverse events, such as prolongation of the half-life of warfarin (11). At therapeutic doses acetaminophen rarely causes hepatic toxicity, but it should be used cautiously in patients with existing liver disease and avoided in patients with chronic alcohol abuse because of known increased risk in these patients (12-14). Even though acetaminophen was reported to be weakly associated with end-stage renal disease, the Scientific Advisory Committee of the National Kidney Foundation recommended it as the drug of choice for analgesia in patients with impaired renal function (15). Tramadol, a centrally acting oral analgesic, is a synthetic opioid agonist that inhibits reuptake of norepinephrine and serotonin. It has been approved by the U.S. Food and Drug Administration for treatment of moderate to severe pain and can be considered for use in patients in whom acetaminophen therapy has failed and who have contraindications to NSAIDs, including the cyclooxygenase-2 (COX-2)specific inhibitors. Although numerous studies have examined use of tramadol to treat general pain, few controlled studies have examined its use in osteoarthritis. The efficacy of tramadol has been found to be comparable to that of ibuprofen in patients with hip and knee osteoarthritis (16), and it is useful as adjunctive therapy in patients with osteoarthritis whose symptoms were inadequately controlled with NSAIDs (17). Daily doses of tramadol have generally been in the range of 200 to 300 mg given in four divided doses. Side effects are common and include nausea, constipation, and drowsiness. Despite the opioid pharmacology of tramadol, a comprehensive surveillance program has failed to demonstrate significant abuse, and tramadol remains an unscheduled agent. Seizures have been reported as a rare side effect, either at doses above the recommended range or at doses within the recommended range in patients with a history of epilepsy and those taking concomitant medications that lower the seizure threshold. NSAIDs For patients who do not obtain adequate symptom relief with nonopioid analgesics, use of NSAIDs should be considered. The choice between a nonselective NSAID and a COX-2specific inhibitor should be made after evaluation of risk factors, particularly for upper gastrointestinal and renal toxicity. Data from epidemiologic studies show that among persons 65 years of age or older, 20% to 30% of all hospitalizations and deaths due to peptic ulcer disease were attributable to therapy with NSAIDs (18-20). Furthermore, the risk for a catastrophic gastrointestinal event in elderly patients taking NSAIDs is dose dependent (18). Risk factors for upper gastrointestinal bleeding in patients treated with NSAIDs include age 65 years or older, history of peptic ulcer disease or previous upper gastrointestinal bleeding, concomitant use of oral corticosteroids or anticoagulants, and possibly smoking and alcohol consumption (21-23). Risk factors for reversible renal failure in patients with intrinsic renal disease who are treated with NSAIDs include age 65 years or older, hypertension or congestive heart failure, and concomitant use of diuretics and angiotensin-converting enzyme inhibitors (24). Additional considerations involved in a practitioners decision to treat an individual patient with osteoarthritis include existing comorbid conditions and concomitant therapy, as well as the side effects and costs of specific treatments. The options for medical management of the patient with osteoarthritis who is at increased risk for a serious adverse upper gastrointestinal event, such as bleeding, perforation, or obstruction, are use of a COX-2specific inhibitor or a nonselective NSAID with gastroprotective therapy. Two COX-2specific inhibitors, celecoxib and rofecoxib, have been approved by the U.S. Food and Drug Administration for use in patients with osteoarthritis (25, 26). Celecoxib has been found to be more effective than placebo and as effective as naproxen for symptoms in patients with hip or knee osteoarthritis (27-29). Rofecoxib has also been found to be more effective than placebo and is comparable in efficacy to both ibuprofen and diclofenac in patients with hip or knee osteoarthritis (30, 31). Endoscopic studies have shown that celecoxib and rofecoxib are associated with an incidence of gastroduodenal ulcers lower than that of comparator NSAIDs and similar to that of placebo (25). These data suggest an advantageous safety profile compared with nonselective NSAIDs, especially for treatment of high-risk patients (21-23). However, no large long-term studies have been published that were designed to demonstrate differences between COX-2specific inhibitors and nonselective NSAIDs with respect to major gastrointestinal clinical outcomes; such studies are in progress. A further advantage of COX-2specific inhibitors with respect to upper gastrointestinal bleeding is that celecoxib and rofecoxib do not have a clinically significant effect on platelet aggregation or bleeding time. In addition, at doses recommended for treatment of osteoarthritis, these drugs appear to be better tolerated than comparator nonselective NSAIDs, with a lower incidence of dyspepsia and other gastrointestinal side effects. As with nonselective NSAIDs, however, COX-2specific inhibitors can cause renal toxicity. Caution must be exercised, therefore, if these drugs are used in patients with mild to moderate renal insufficiency, and they should not be used in patients with severe renal insufficiency. In addition, celecoxib is contraindicated in patients with a history of allergic reaction to a sulfonamide. The alternative to use of a COX-2specific inhibitor is use of a nonselective NSAID with a gastroprotective agent, an approach endorsed by the American College of Gastroenterology (23). As noted earlier, serious adverse upper gastrointestinal events attributed to NSAIDs in the elderly are dose dependent. Therefore, if nonselective NSAIDs are used, therapy should be begun at low, analgesic doses and increased to full anti-inflammatory doses only if lower doses do not provide adequate relief of symptoms. In a study of 8843 patients with rheumatoid arthritis, misoprostol at a dosage of 200 g four times daily reduced the incidence of serious ulcer complications, including perforation, bleeding, and obstruction, by 51% (32). In a 12-week randomized, double-blind, placebo-controlled endoscopy study, misoprostol at a dosage of 200 g three times per day had comparable efficacy in prevention of both gastric and duodenal ulcers; however, 200 g twice daily conferred significantly less protection against gastric ulcers (33). Side effects, particularly diarrhea and flatulence, may occur with this agent in a dose-dependent manner (33). Alternative approaches to prophylaxis with misoprostol include use of omeprazole or high-dose famotidine, both of which have been shown in carefully conducted endoscopy studies to be effective in treating and preventing NSAID-induced gastropathy (34-37). Histamine-2 blockers in usual doses, however, have not been found to be as effective as misoprostol (36), whereas omeprazole (20 mg/d or 40 mg/d) was as effective as misoprostol (200 g twice daily) in treatment of existing ulcers and was better tolerated and associated with a lower rate of relapse (37). Of note, proton-pump inhibitors have not been approved by the U.S. Food and Dr

Prediction of the progression of joint space narrowing in osteoarthritis of the knee by bone scintigraphy.

OBJECTIVES--To test the hypothesis that bone scintigraphy will predict the outcome of osteoarthritis (OA) of the knee joint. METHODS--Ninety four patients (65 women, 29 men; mean age 64.2 years) with established OA of one or both knee joints were examined in 1986, when radiographs and bone scan images (early and late phase) were also obtained. The patients were recalled, re-examined, and had further radiographs taken in 1991. Paired entry and outcome radiographs were read by a single observer, blinded to date order and other data. Scan findings and other entry variables were related to outcome. Progression of OA of the knee was defined as an operation on the knee or a decrease in the tibiofemoral joint space of 2 mm or more. RESULTS--Over the five year study period 10 patients died and nine were lost to follow up. Fifteen had an operation on one or both knees (22 knees). Of the remaining 120 knees (60 patients) analysed radiographically, 14 (12%) had progressed in the manner defined. Of 32 knees with severe scan abnormalities, 28 (88%) showed progression, whereas none of the 55 knees with no scan abnormality at entry progressed. The strong negative predictive power of scintigraphy could not be accounted for by disease severity or any combination of entry variables. Pain severity predicted a subsequent operation, but age, sex, symptom duration, and obesity had no predictive value. CONCLUSIONS--Scintigraphy predicts subsequent loss of joint space in patients with established OA of the knee joint. This is the first description of a powerful predictor of change in this disease. The finding suggests that the activity of the subchondral bone may determine loss of cartilage.

What proportion of patients report long-term pain after total hip or knee replacement for osteoarthritis? A systematic review of prospective studies in unselected patients.

Background Total hip or knee replacement is highly successful when judged by prosthesis-related outcomes. However, some people experience long-term pain. Objectives To review published studies in representative populations with total hip or knee replacement for the treatment of osteoarthritis reporting proportions of people by pain intensity. Data sources MEDLINE and EMBASE databases searched to January 2011 with no language restrictions. Citations of key articles in ISI Web of Science and reference lists were checked. Study eligibility criteria, participants and interventions Prospective studies of consecutive, unselected osteoarthritis patients representative of the primary total hip or knee replacement population, with intensities of patient-centred pain measured after 3 months to 5-year follow-up. Study appraisal and synthesis methods Two authors screened titles and abstracts. Data extracted by one author were checked independently against original articles by a second. For each study, the authors summarised the proportions of people with different severities of pain in the operated joint. Results Searches identified 1308 articles of which 115 reported patient-centred pain outcomes. Fourteen articles describing 17 cohorts (6 with hip and 11 with knee replacement) presented appropriate data on pain intensity. The proportion of people with an unfavourable long-term pain outcome in studies ranged from about 7% to 23% after hip and 10% to 34% after knee replacement. In the best quality studies, an unfavourable pain outcome was reported in 9% or more of patients after hip and about 20% of patients after knee replacement. Limitations Other studies reported mean values of pain outcomes. These and routine clinical studies are potential sources of relevant data. Conclusions and implications of key findings After hip and knee replacement, a significant proportion of people have painful joints. There is an urgent need to improve general awareness of this possibility and to address determinants of good and bad outcomes.