Department of Rheumatology, King's College Hospital (Dulwich), East Dulwich Grove, London SE22 8PT,
1 Centre for Rheumatic Diseases, Royal Infirmary, Glasgow G4 0SF,
2 Department of Rheumatology, Coventry and Warwickshire Hospital, Stoney Stanton Road, Coventry CV1 4FH,
3 Department of Rheumatology, District General, Chester Road, Sunderland SR4 7TP,
4 Whipps Cross Hospital, Leytonstone, London E11 1NR,
5 Department of Rheumatology, Royal Sussex County Hospital, Eastern Road, Brighton BN2 5BE,
6 Department of Rheumatology, Addenbrooke's Hospital, Cambridge CB2 2QQ,
7 Gartnavel General Hospital, Great Western Road, Glasgow G12 0YN,
8 14a Milford House, 7 Queen Anne Street, London W1M 9FD,
9 Musculoskeletal Directorate, The Royal London Hospital (Mile End), 275 Bancroft Road, London E1 4DG,
10Department of Rheumatology, Selly Oak Hospital, Birmingham B29 6JB,
11Wirral Hospital NHS Trust, Upton, Wirral L49 5PE,
12Stobhill General Hospital, Balornock Road, Glasgow G21 3UW,
13Department of Rheumatology, Leicester Royal Infirmary, Leicester,
14Department of Rheumatology, Basildon Hospital, Nether Mayne, Basildon, Essex SS16 5NL,
15Stoke Mandeville Hospital, Aylesbury, Bucks HP21 8AL,
16Department of Rheumatology, Royal Cornwall Hospital, Truro, Cornwall TR1 2HZ and
17District General Hospital, Eastbourne, East Sussex BN21 2UD, UK
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Abstract |
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Methods. A parallel-group, randomized, single-blind trial of patients with knee OA recruited 812 patients from 20 centres; 307 patients received tiaprofenic acid (300 mg b.d.), 202 indomethacin (25 mg t.d.s.) and 303 matching placebo for up to 5 yr. At the end of the parallel-group study, patients receiving tiaprofenic acid or placebo entered a 4-week blinded cross-over study of tiaprofenic acid or placebo, both given for 2 weeks. Assessments were at baseline, 4 weeks, then at 6-month intervals for up to 5 yr in the parallel group study and at 2-week intervals in the cross-over study. They comprised pain scores, duration of morning stiffness, patients' global assessments, paracetamol consumption, adverse reactions, withdrawals and functional outcomes.
Results. There were significant falls in overall pain scores in patients receiving NSAIDs compared with placebo at 4 weeks in the parallel-group phase. Thereafter there were no advantages favouring active therapy. In the cross-over phase, pain scores were significantly lower in patients receiving tiaprofenic acid than placebo. Patients who had been receiving long-term tiaprofenic acid showed significant rises in their pain scores when receiving placebo therapy and vice versa. Adverse events were reported by 61% of patients receiving tiaprofenic acid, 63% on indomethacin and 51% on placebo. Potentially severe side-effects were rare; for example, there were only three cases of gastrointestinal bleeding on NSAIDs. The pattern of withdrawal was similar in patients taking NSAIDs and placebo in the parallel-group study; at 48 weeks 53% of the patients remained on tiaprofenic acid, 50% on indomethacin and 54% on placebo.
Conclusions. NSAIDs significantly reduce overall pain over 4 weeks. This short-term responsiveness is retained, and even after several years of therapy with tiaprofenic acid pain scores increased over 2 weeks when it was changed to placebo. Our results do not show long-term benefits from the use of NSAIDs in OA and the majority of patients had persisting pain and disability despite therapy.
KEY WORDS: NSAIDs, Osteoarthritis, Knee, Randomized controlled trial.
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Introduction |
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We report the results of a long-term randomized placebo-controlled trial in 812 patients with knee OA treated for a mean of 20 months. This trial evaluated the efficacy and adverse effects of NSAIDs against the background of the functional outcome of OA. Our aim in reporting these results is to help define the value of long-term NSAIDs in treating knee OA.
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Patients and methods |
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The indomethacin arm was discontinued when interim analysis showed significantly more X-ray progression in patients taking indomethacin. The tiaprofenic acid and placebo arms continued until the study achieved its predefined sample size based on the radiological end-point. At this point all remaining patients were asked to participate in a 4-week cross-over study. Due to the early withdrawal of indomethacin, only patients initially randomized to tiaprofenic acid or placebo could enter the cross-over phase: 161 patients took part.
Patients
There were 572 females and 240 males, median age 61 yr (range 2787), median disease duration 5 yr (range 0.150), median weight 74 kg (range 38126) and median number of affected joints 6 (range 128). All had symptomatic and radiological evidence of OA of one or both knee joints; their clinical features were in accordance with the description of OA in UK and North American clinical guidelines. Patients were excluded who had previous dyspeptic problems with NSAIDs or end-stage radiological joint destruction. The groups had similar age, sex, weight, duration and distribution of involved joints. There were no significant differences in initial pain, morning stiffness or global assessments. All patients gave written informed consent to participation. Patients were asked to continue in the study until their treatment arm was stopped unless they desired or were advised to withdraw.
Treatments
The patients were randomized to receive tiaprofenic acid (300 mg b.d.), indomethacin (25 mg t.d.s.) or matching placebo. Paracetamol tablets were available to all patients throughout the study as escape analgesics, and patients were allowed to take up to 8 tablets per day. Other drugs were used as required and their use and any change of use recorded. There was a 3-day wash-out period to eliminate previous anti-inflammatory and analgesic therapy; this period was longer for patients receiving drugs with a long half-life, such as piroxicam. Compliance with therapy and paracetamol use was determined by return tablet counts. Patients returned the study medication at each visit and the majority were at least 80% compliant.
Assessments
These were at the beginning (baseline), after 4 weeks, and then every 6 months for up to 5 yr. Additional visits were at 3-month intervals to ensure compliance and to check for adverse events. Visual analogue scales (VAS), using 100 mm horizontal scales (0 = no pain; 100 mm = maximum pain) were used to record overall pain, pain at rest and pain on movement. Four-point Lickert scales were also used for these three types of pain (none, mild, moderate, severe). The duration of morning stiffness was recorded in minutes. Patients global assessments of their condition were recorded on a 4-point Lickert scale (poor, fair, good, excellent). Patients were also asked about any possible adverse events due to the treatment. Any concomitant illness was recorded.
Cross-over study
Patients received their study treatment for 2 weeks and the alternative treatment for 2 weeks. There was no washout period between these two periods. The order of assignment to treatment combinations was randomized, creating four groups of patients: (Group 1) placebo in main study; tiaprofenic acid in weeks 12; placebo in weeks 34; (Group 2) placebo in main study; placebo in weeks 12; tiaprofenic acid in weeks 34; (Group 3) tiaprofenic acid in main study; placebo in weeks 12; tiaprofenic acid in weeks 34; (Group 4) tiaprofenic acid in main study; tiaprofenic acid in weeks 12; placebo in weeks 34. There were 3443 patients in each group. They were of similar age, sex and disease durations. There were no significant differences in pain, morning stiffness or global assessments between groups at the beginning of the cross-over trial.
Statistical analysis
Summary statistics comprised group means, standard deviations and 95% confidence intervals (CI). Initial descriptions of the patients used medians and ranges. VAS pain levels (overall, rest and movement pain) were evaluated using analysis of covariance. In the parallel-group study, the following treatment effects were determined: greatest pain between the two knees at the first on-treatment visit; greatest pain between the two knees at the last on-treatment visit; greatest pain between the two knees at the last on-treatment visit; and change from baseline of the greatest pain between the two knees at each annual assessment. In the cross-over study, treatment, period and carry-over effects were determined using the greatest pain level between the two knees at the start of the cross-over study, after 2 and 4 weeks of treatment. Covariates comprised: baseline pain (in the parallel-group study), baseline age, baseline weight, sex, duration of OA, number of joints involved, pattern of OA, previous therapy, concomitant medication, centre, physiotherapy, morning stiffness, analgesic use, and number of completed years. Differences between groups in categorical data (e.g. for adverse events) were analysed by 2 testing. Differences between groups in the time of withdrawal were analysed by the log-rank test.
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Results |
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Altogether, NSAIDs reduced overall VAS pain scores during the first 4 weeks of treatment by 8%, while with placebo the reduction was less than 1% (Fig. 1). Analysis of covariance confirmed that this was a significant treatment effect (P = 0.02). Significant covariates (baseline pain, centre, morning stiffness, duration of OA, weight and completed years in study) accounted for 40% of the variation in overall pain.
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After 4 weeks there were no further significant differences in overall pain between patients receiving active treatment and placebo. There were no significant effects of active treatment on rest pain, movement pain, morning stiffness, patients' global assessments and analgesic consumption at any time during the parallel-group phase.
Patients who remained on treatment for 12 months or longer not only showed no measurable benefit from active treatment but also had a static clinical picture with unchanging pain levels and durations of morning stiffness (Fig. 2). The clinical features after 12 months, expressed as mean values (95% CI), were: overall pain 48 mm (4750); rest pain 31 mm (2932); movement pain 50 mm (4852); duration of morning stiffness 30 min (2633). There was constant analgesic use, with mean daily paracetamol consumption of 1.9 tablets/day (1.42.2); 12% of patients took additional analgesics (predominantly co-proxamol).
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Cross-over study.
All pain scores were 1719% lower with tiaprofenic acid than with placebo (Fig. 3); analysis of covariance showed that these differences were significant (P > 0.005 in all cases) without carry-over or period effects. An example of these changes is shown by the 43 patients who received long-term placebo then received 2 weeks of tiaprofenic acid treatment followed by 2 weeks on placebo: their mean overall pain scores at 0, 2 and 4 weeks were 48, 39 and 48 mm respectively. A summary of the mean changes in overall pain in each group of patients is shown in Fig. 4
. The duration of morning stiffness was less with tiaprofenic acid (mean 28 min, 95% CI 1838) than with placebo (mean 54 min, 95% CI 4464); analysis of covariance after log transformation showed a significant treatment effect (P < 0.01).
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Adverse reactions
Parallel-group study.
Sixty-one per cent of patients receiving tiaprofenic acid, 63% of those receiving indomethacin and 50% of those receiving placebo reported adverse events (Table 1); the number of adverse reactions was significantly greater with active treatment (
2 = 11.0; DF = 2; P < 0.01). Adverse reactions in the digestive system, including dyspepsia and nausea, were the commonest side effects, occurring in 46% of patients receiving tiaprofenic acid, 47% receiving indomethacin and 32% on placebo (
2 = 14.6; DF = 2; P < 0.001). Potentially serious gastrointestinal events were uncommon, with only three reports of gastrointestinal bleeding (haematemesis on indomethacin, gastrointestinal haemorrhage on tiaprofenic acid and melaena on tiaprofenic acid). Adverse effects were also often seen in the nervous system, and these involved 16% of patients receiving tiaprofenic acid, 25% receiving indomethacin and 17% on placebo; the frequency was significantly higher with indomethacin than in the other two groups (
2 = 7.6; DF = 1; P < 0.01). We evaluated withdrawals due to urogenital problems in some detail: there were three withdrawals for polyuria in the tiaprofenic acid group and none with indomethacin or placebo. However, the overall numbers reporting urogenital problems were similar in the groups treated with tiaprofenic acid (seven cases) and placebo (six cases).
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Cross-over study.
Thirty-three (21%) patients receiving tiaprofenic acid and 28 (17%) on placebo reported adverse events; this difference is not significant. Gastrointestinal reactions were commonest, affecting 22 (14%) patients on tiaprofenic acid and 13 (8%) on placebo.
Withdrawals
Parallel group.
Mean treatment durations were similar with tiaprofenic acid (mean 20 months; 95% CI 1823), indomethacin (18 months; 1520) and placebo (21 months; 1823). The pattern of withdrawals was similar (Fig. 5) and the log-rank test showed no significant differences between treatments from study start to time of withdrawal. At 48 weeks, 53% of patients receiving tiaprofenic acid, 50% receiving indomethacin and 54% on placebo remained on therapy.
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Cross-over study.
Seven patients withdrew: four failed to return for a visit, two reported inefficacy and one had an adverse effect (drowsiness with tiaprofenic acid).
Outcomes
Parallel group.
Global outcomes at 4 weeks showed that significantly more patients who received active treatment had improved compared with patients on placebo therapy (2 = 18.4; DF = 2; P < 0.001). There were no further differences between active treatment and placebo; patients final assessments of their overall condition showed that about 30% of each group had improved or deteriorated (Table 2
). The number of patients who could not undertake simple everyday tasks was similar in all treatment groups and increased with time. Initially, 49% of patients had some difficulty walking upstairs, 51% walking downstairs and 66% walking on uneven ground; over the duration of the study 5% had more difficulty walking upstairs, 6% walking downstairs and 6% walking on uneven ground (all differences significant at the 5% level on
2 tests). Although there were no increases in the number of patients who had difficulty kneeling to put something on a low shelf, only 18% could do this without difficulty at the onset of the study. There was a modest increase in the number of patients requiring an aid (such as a walking stick or frame): in the early months of the study 14% of patients needed an aid compared with 21% at the end-point; there were no differences between treatment groups. Thirty-four patients required knee surgery, including 11 who had replacement arthroplasty and four who were waiting for knee replacement; again there were no consistent differences between treatment groups.
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Cross-over study.
Global outcomes showed that 66 (41%) of patients improved with tiaprofenic acid compared with 31 (19%) with placebo, and 46 (25%) of patients deteriorated with tiaprofenic acid compared with 76 (47%) with placebo; both differences were significant (P > 0.001, 2 test).
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Discussion |
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The 812 patients we studied were followed for a period equivalent to 1336 patient-yr, and we were able to evaluate their long-term outcome. Each year 35% of patients developed difficulty walking up or down stairs or started using aids such as walking sticks, and approximately 1% needed knee replacement surgery. These outcomes must be treated with some caution as patients withdrawing from the study may have had outcomes markedly different from those of patients remaining on treatment, and we are reporting only the latter group. Despite this progression, their overall clinical state was relatively static, with mean overall pain scores of 48 mm, mean morning stiffness lasting 30 min and average paracetamol consumptions of 2 tablets daily. It is uncertain whether improving pain control and reducing morning stiffness would improve functional outcomes. It is interesting that the doses of analgesics taken were substantially below maximal; increasing the amount of analgesics taken could be very beneficial to OA patients and this needs testing in a randomized controlled trial. The previously reported radiological data [13] clearly show that indomethacin increases the risk of progression damage (assessed radiologically) compared with tiaprofenic acid and placebo. Although this was not translated into an obvious functional difference, we suspect this was because the sample size was insufficient to detect a relationship.
Our study was planned in 1984 and started in 1986, the clinical observations ended in 1993, a preliminary statistical overall report was issued in 1995, a revised statistical report delivered in 1996, and this paper was prepared between 1996 and 1998. During these years, diagnostic criteria changed [14], clinical trial methods altered [15], new functional and outcome assessments were introduced, and clinical priorities changed. Although none of this detracts from our findings, it means that some of our clinical and analytical methods seem dated; it also partly explains the rarity of long-term randomized trials in OA, as this study has lasted for one-third of the average medical career. We recognize other weaknesses of this trial: the number of observations was limited, the dose of the NSAIDs was fixed and the severity of disease was mild. Despite these limitations, we believe that the large numbers of patients involved and the duration of follow-up make the results robust and relevant.
A systematic review of randomized trials of pharmacological therapy in OA of the knee by Towheed and Hochberg [16] evaluated 80 trials reported between 1996 and 1994. Nine short-term trials comparing NSAIDs with placebo [1725] showed that active drugs (ketoprofen, aspirin, naproxen, zomepirac, fenbufen, diclofenac, etodolac and nimesulide) were more effective. These short-term trials lasted 28 weeks. Other short-term placebo-controlled trials of NSAIDs not reviewed by Towheed and Hochberg also show short-term benefits of lornoxicam [26] and etodolac and nabumetone [27]. Two longer-term trials, lasting 96 and 104 weeks respectively, showed no difference between naproxen, diclofenac and placebo [28] and between diclofenac and placebo [12]. Three studies compared NSAIDs with paracetamol, evaluating diclofenac over 2 weeks [11], ibuprofen over 4 weeks [10] and naproxen over 104 weeks [29]; all studies showed equivalence, with no evidence that the NSAIDs were more effective.
We conclude that NSAIDs are effective in the control of pain due to OA over 24 weeks and that mean scores improve by up to 20%. But there is less evidence supporting their longer-term effectiveness. Although our failure to demonstrate long-term efficacy with NSAIDs may be an accurate representation of the situation, we consider it is more likely to be the combined result of using assessments of joint pain that were designed to show short-term efficacy and the general inadequacy of therapy in OA. It is also likely that OA patients are a heterogeneous collection of responders and non-responders [30, 31]. In clinical practice, discontinuation rates with NSAIDs are high in OA patients and this probably accurately reflects their limited clinical value [32]. We suggest that there is a need to undertake long-term trials to identify management strategies that give a prolonged improvement in the symptoms of OA. In the meantime, the balance of evidence suggests that we should continue to use NSAIDs in OA patients but try to restrict the long-term use of individual NSAIDs to the minority of patients who start therapy and have a good and persisting clinical response.
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Notes |
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References |
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