Division of Public Health Medicine and Epidemiology, Nottingham University,
1 Rheumatology Unit, City Hospital Nottingham and
2 Division of General Practice, Nottingham University, Nottingham, UK
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Abstract |
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Method. A prospective randomized controlled trial with assessment of economic cost/benefits was carried out in five general practices in Nottinghamshire with computerized prescribing systems, representing a mix of rural/urban and fundholding/non-fundholding practices. Patients suffering from non-malignant, non-inflammatory musculoskeletal pain received repeat prescriptions for oral NSAIDs. Two hundred and twenty-two patients were randomized to a control group (simple advice regarding NSAID use) or an intervention group (asked to withdraw their NSAIDs and employ appropriate alternative drug and non-drug therapies). All advice was supported by patient literature and delivered by a nurse practitioner trained in musculoskeletal assessment. The primary outcome measure was change in NSAID use 6 months after the intervention. Secondary outcome measures were changes in health and quality of life (SF-36 and EQ-5D questionnaires) and drug, health service and patient costs.
Results. An extra 28% of patients in the intervention group either stopped taking oral NSAIDs or reduced dosage by 50% at 6 months compared with controls. There was no detrimental effect on health and well-being. Oral NSAID prescription costs were significantly lowered in the intervention group but not in the control group. A non-significant increase in total drug prescription costs occurred in both groups.
Conclusions. Nurse-based intervention can reduce chronic NSAID usage and costs in primary care and would be cost-effective if maintained in the long term. This intervention package would be readily applicable in primary care.
KEY WORDS: Non-steroidal anti-inflammatory drugs, Patient education, Randomized controlled trial, Economic evaluation, Musculoskeletal disease.
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Introduction |
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Quantification of NSAID toxicity is difficult. In the UK in 1994, 2500 episodes of ulcer bleeding and 400 ulcer perforations have been attributed to NSAID use [12]. Other figures suggest 200 NSAID-attributable deaths occur annually in the UK [13]. A quarter of patients with arthritis may experience NSAID-related side-effects [9].
Attempts have been made to educate medical practitioners about appropriate NSAID use [14, 15] and some studies have attempted to replace NSAIDs with other therapeutic approaches [3, 5]. These can be criticized in terms of practicality and general applicability, and this study is an attempt to develop an approach to musculoskeletal NSAID use in primary care that could be widely applicable.
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Methods |
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Subjects and setting
Five general practices representing urban and semirural populations agreed to participate in the study. Patients were eligible for inclusion if all of the following criteria were satisfied: age 18 yr; oral NSAID prescriptions covering 6 or more weeks of the last 12 months; and currently taking oral NSAIDs. Patients were excluded if any of the following criteria applied: presence of terminal disease; inability to give valid informed consent; presence of a defined inflammatory arthropathy; or non-locomotor pain as the reason for NSAID use. Patients were withdrawn from the study for any of the following reasons: patient choice; or development of a defined inflammatory arthropathy or neoplastic disease. Patients electing to withdraw were classified as withdrawn; those developing an inflammatory arthropathy or neoplastic disease were classified as excluded. The handling of these patients with regard to the outcome measures in the study is described in more detail below but in general a pessimistic approach was taken.
Randomization
Patients were randomized, after giving consent and initial assessment, into one of two groups. The control group was given simple advice on safe NSAID use, and patients in the intervention group were asked to stop using NSAIDs and to make appropriate use of alternative drug and non-drug therapies. Randomization was by computer-generated envelopes into permuted blocks (block size, 4) according to the eight permutations of the following three criteria: age (under 65 yr, or 65 yr or older); sex (female, male); NSAID dose as a proportion of defined daily dose (DDD) (patient dose 1 DDD, patient dose of >1 DDD).
The patient's NSAID dose was calculated as a proportion of the standard recognized DDD in order to allow comparison between different NSAIDs and to assess reductions in dose (Table 1) [16]. To mask the intention of the study, patients were asked to consent to take part in a study of the efficacy and side-effects of NSAIDs and were told that this would involve advice on the drugs and their condition from a nurse. They were not informed that the aim of the study was to reduce NSAID usage.
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Interventions
Interventions took 3060 min and were delivered by a single study nurse.
Control intervention
This comprised simple verbal advice regarding properties of NSAIDs, the timing of doses in relation to meals and symptoms, and potential benefits and adverse effects of NSAIDs. This advice was reinforced with a simple leaflet.
Active intervention
These patients received advice tailored to the nurse practitioner's assessment of the patients and was reinforced with written information. The types of advice offered included strategies on weight reduction, aerobic exercise, use of local heat and cold, back and neck care, footwear, massage, and relaxation techniques. All intervention group patients were given a strategy for stopping or reducing their NSAID use, reinforced with a flow-chart tailor-made to the patient's current medication. Each leaflet comprised specific sequential instructions regarding the dosage, review and escalation of therapeutic drugs, escalation of simple and compound analgesics, the introduction, if appropriate, of topical NSAIDs, and the introduction of increasing doses of ibuprofen (chosen as a less toxic NSAID [8]). Over-the-counter (OTC) medication was encouraged for those liable for prescription charges; alternatively, prescriptions were available from the patient's general practitioner (GP). All medication was supported by appropriate advice leaflets and further patient-initiated telephone contact was offered.
Nurse training
To enable ready generalization from this study, nurse training was kept basic and easy to implement. After instruction in the use of the specific research instruments, the GALS locomotor screen was taught [17, 18]. This would enable the nurse to identify and localize locomotor symptoms. Reinforcement was provided by examining approximately 20 patients under consultant supervision during two rheumatology outpatient clinics.
Assessments and outcome measures
The primary outcome measure was self-reported reduction in oral NSAID dose at 6 months. Because the nurse was not blind to the aims of the study, we used self-reported data obtained from a self-administered questionnaire and computerized prescription data so as to reduce the possibility of bias. Self-reported rather than prescription data were chosen because they are more likely to represent actual patient drug use [19]. Secondary outcome measures were changes in prescription data, health service, drug and patient costs, and health status and functioning [Short-Form 36 (SF-36) [20] and EuroQoL-5D (EQ-5D) [21] questionnaires].
All patients were examined at their general practice or homes. Basic demographic information, height and weight were obtained and a self-completed questionnaire was completed, incorporating personal details, health service use, medication use (both prescribed and non-prescribed), expenditure on other equipment, incidental costs, the SF-36 and the EQ-5D. Service use and cost data related to the preceding 6 months. Patients were reassessed 6 weeks after the intervention using the same instruments. At 6 months all patients received a postal questionnaire comprising the SF-36, the EQ-5D, a medication use questionnaire and a service use and cost questionnaire.
Economic analysis
Perspectives of the analysis
In the cost-effectiveness study, analysis depended on the perspective for the evaluation. From the GP perspective, the changes in median oral NSAID costs 6 weeks and 6 months after initial assessment were compared for the intervention and control groups [16]. In addition, changes in GP visits for the two groups were assessed. The hypothesis for this perspective was that the reduced costs of NSAID prescribing and reduced visits to the GP due to pain could partly or fully offset the additional costs that would be incurred through implementation of the nurse education package in general practice, with at a minimum no detriment to patient health outcomes.
From the patient perspective, the data collected for the intervention and control groups at baseline and 6 months using the SF-36 and the EQ-5D were used to measure patient health-related quality of life (QoL) benefits compared with the cost of the intervention. Quality-Adjusted Life Years (QALYs) were calculated using the EQ-5D-derived utility values. In addition, patient expenditure on OTC pain relief and equipment and other expenses due to pain were evaluated. The hypothesis was that the intervention would improve or at least maintain the patients' health-related quality of life whilst reducing their use of NSAIDs.
Costs of the nurse-based educational service
Estimation of the mean cost per patient for the intervention was based on a record of the time spent by the nurse in providing health education advice and checking patient compliance for each patient in the intervention group. These represent costs that would be incurred by the GP. Research-specific costs incurred by the nurse were excluded from the analysis. The unit cost of nurse time used was £16 per hour [22]. Home visit travel was costed at £0.47 per visit [22]. Telephone contact costs, which were negligible, were not included.
Patients costs included the time and expense travelling to the practice for advice sessions and the mean and median travel expenses. For bus and taxi travel, this was the actual fare paid and for other forms of transport this was costed at a rate of 41.52 pence per mile. Costs incurred by patients resulting from the advice given (e.g. additional purchases of drugs and equipment) were not included, although ideally they should be considered when assessing cost-effectiveness.
Statistical analysis
A recruitment target was set of 260 patients. The aim of the intervention was to reduce the oral NSAID dose by at least 50%. If the acceptance rate by patients of this intervention was 50% then the study would have a high power (95%) to detect such differences at the 5% level of significance. [Alternatively, if the expected reduction in NSAID dose was over-optimistic, reducing it to 25% while assuming a modest improvement in acceptance rate to 70% would still provide a good power (>90%) to detect such a difference at the same level of significance.]
Data were entered into SPSS version 6.1.3 (SPSS Ltd, Woking, UK). Normally distributed data were analysed using parametric tests; data that were not normally distributed were analysed using non-parametric tests.
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Results |
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Randomization
The randomization process was successful (Table 2). There was a similar spectrum of symptoms and self-reported physical pain (question 7 of the SF-36 questionnaire: How much bodily pain have you had during the past 4 weeks?,
2=2.27, d.f. 2, P>0.32, with groups none collapsed with very mild and severe collapsed with very severe).
Reduction of oral NSAID use
In calculating the dose reduction for patients with either varying prescriptions and/or missing data, care was taken not to benefit the outcome of the study preferentially, and pessimistic assumptions about changes in dose in the intervention group were made.
At baseline, the median DDD for NSAIDs was 1.00 [interquartile (IQ) range 0.75, 1.33] in the intervention group and 1.00 (IQ range 0.82, 1.50) in the control group (MannWhitney U-test; U=5784.0, P=0.64).
Six months after baseline, 42 (38.5%) intervention group patients had either stopped taking oral NSAIDs altogether or had reduced their dose by 50% or more, compared with 14 (12.7%) control group patients (Table 3,
2=17.82, d.f. 1, P<0.0001). Six months after baseline the median dose in the intervention group was 0.67 (IQ range 0, 1.0) and 1.00 (IQ range 0.67, 1.17) in the control group (MannWhitney U-test; U=4441.0, P=0.0007). Overall, more than half (55.0%) of the patients in the intervention group reduced their dose by at least 50% at 6 weeks after baseline and by 6 months after baseline 38.5% of the patients had remained on a dose of at least 50% less. Comparison with the control group suggests that around one in 10 patients will naturally reduce their oral NSAID dose over time (Table 3
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Predictors of response
We explored post hoc factors associated with patients reducing their NSAID dose by 50% using univariate analysis. These included higher initial NSAID prescribing costs, patients aged 6079 yr, and patients from practices associated with higher NSAID prescribing costs.
Measures of health and well-being
A score [ranging from 0 (worst) to 100 (best state)] was calculated for each of the different dimensions of the SF-36 questionnaire. The two groups had similar pain scores at baseline (median 44.4 in the intervention group and 44.4 in the control group) (MannWhitney U-test; U=5776.0, P=0.41) (Table 2). Six months after baseline, neither group had significantly different scores compared with baseline (Wilcoxon matched pairs signed ranks test: intervention group, Z=-0.8760, P=0.38; control group, Z=-0.5297, P=0.60) (Table 3
).
Similar results were observed for the physical function scores [baseline median score 42.5 in the intervention group and 40.0 in the control group (U=6037.5, P=0.89)]. There was slight, but non-significant, improvement in both groups 6 months after baseline (Wilcoxon matched pairs signed ranks test for improvements in both groups: intervention group; Z=-0.8279, P=0.07; control group, Z=-1.2476, P=0.21).
The intervention and resulting reduction in oral NSAID use had no clear detrimental effect on patients' pain or physical functioning.
An overall utility score was calculated for each patient from the EQ-5D. A maximum score of 1.0 indicates full health whilst a score <0 indicates a state of health considered worse than death. A visual analogue scale (VAS) was used to gauge patients' perceptions of general health and QALYs remaining were calculated for each patient.
Use of the 2 test on utility scores by quartiles showed no difference between groups at baseline or 6 months. Scores improved non-significantly in the control group (Wilcoxon matched pairs signed ranks test; Z=-0.7800, P=0.44) (Table 3
), but deteriorated significantly in the intervention group (Z=-2.2469, P=0.02). Regression analysis demonstrated no relationship between change in NSAID dose and lowered utility scores (P=0.80).
Compared with baseline, the intervention group patients had less QALYs at 6 months (mean-0.8 yr, Z=-2.6440, P=0.008, independent samples t-test), but the control group patients had slightly more (mean 0.6 yr, Z=-0.7747, P=0.44). Regression analysis again failed to demonstrate a relationship change in NSAID dose (P=0.65).
Prescription costs
Baseline prescription costs were significantly higher in the control group (MannWhitney U-test; U=4922.5, P=0.004) (Table 4). After 6 months, oral NSAID costs were significantly reduced in the intervention group compared with baseline (Wilcoxon matched pairs signed ranks test; Z=-2.655, P=0.008), but there was no significant change in the control group (Z=-0.6468, P=-0.52). Total drug costs increased in the intervention group compared with the control group but the difference was not statistically significant (U=5354.0, P=0.25).
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Cost-effectiveness
Table 5 summarizes the main data for interpreting the cost-effectiveness of the intervention. From a GP perspective, there was a small reduction in median NSAID cost over 6 months, achieved at a cost of over £40 per patient for the intervention, but with no apparent detriment to patient health-related QoL. From the patient perspective, a reduction in NSAID cost was obtained with a small additional cost for travel, although other patient-related costs were not included.
Alternative treatments used by patients
The median number of non-drug options tried per patient between the baseline and the 6-week assessments was 6 (range 2, 9). Many patients had never tried acetaminophen or topical NSAIDs for pain relief prior to the study. Of 67 patients switching to paracetamol, 45 reported trying this for the first time and 44 found it gave effective pain relief. Of 81 patients trying a topical NSAID, 68 were doing so for the first time and 52 found it effective (Table 6).
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Discussion |
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This reduction is not associated with a deterioration in the health of patients. This result is encouraging because this study tackles a number of the criticisms which can be made of previous studies. Amongst acute admissions to Health Care of the Elderly wards, reductions in NSAID use both during (86% reduction) and 6 weeks after discharge (76% reduction) were achieved using a similar approach to our current study delivered by a middle-grade doctor [3]. This study can be criticized for its hospital setting, the use of medical staff and short-term follow-up. In a single general practice (list size 12000) 315 patients were identified to be receiving NSAID prescriptions [5]. Thirty-eight of 40 patients who were offered review of their medication and agreed to participate were asked to take alternative non-NSAID analgesia. Twenty-two patients remained off NSAIDs at 1 month, 16 with equivalent pain relief. By 4 months, 24 patients were no longer taking NSAIDs. This study was not controlled and required medical intervention, but did suggest that medium-term reductions in NSAID use are achievable. The use of prescriber education either at a departmental or community level can successfully decrease both NSAID cost and related adverse effects [14, 15]. The maintenance of any benefit may be problematic and the approach is not targeted at at-risk groups.
Our study achieved medium-term reductions in NSAID use by targeting patients receiving chronic NSAID therapy. Similar results might also be obtained by targeting patients in whom a first NSAID prescription is being considered. Whether patient education using the study's leaflets alone would be as effective is unclear, although it would probably be cheaper and more accessible.
There are caveats to the current study. (i) Those who took part were volunteers and perhaps more likely to adopt alternative behaviours. The lack of change in NSAID use in the control group appeared to make this less likely. (ii) The number of eligible patients was smaller than expected, perhaps because educational messages regarding NSAIDs have already been heeded [2]. The prevalence of NSAID use will clearly affect the intervention's cost-effectiveness. (iii) A heterogeneous group of patients was studied and whether the intervention is more effectively targeted at certain disorders or age groups is unanswered. (iv) The effect of discordance between prescription data and self-reported use is unclear. The use of 6-month time windows should have reduced any such effect, but it is possible that the collection and use of prescriptions may have been differentially affected in the two groups. (v) This study period was only 6 months. The intervention is only likely to become truly cost-effective if long-term NSAID reductions are maintained, particularly if secondary savings due to reduction in NSAID-related adverse effects accrue. (vi) The nurse was not blind to the intention of the study and thus some bias may have been introduced. This was minimized by the duration of the study and the use of self-completed questionnaires and computer records of prescribing data for the primary outcome variables. In addition, the patients were masked as to the hypothesis under examination.
The cost-effectiveness of the intervention requires a number of considerations. For the health service, the cost of employing nurse time to give educational advice has to be partly offset by cost savings from a reduction in use of NSAIDs. From a GP/health-care purchaser perspective, the lower the intervention cost then the greater the cost-effectiveness. The cost of £40.70 includes the time taken to complete the study questionnaire and is therefore an overestimate of the true cost to primary care. In addition, if this advice were to be given during a patient's attendance at the surgery for other reasons, there would be a reduction in opportunity costs associated with travel and attendance.
Cost-effectiveness could be increased further if NSAID reductions could be maintained beyond the 6-month period of the present study, or produced long-term reductions in health service costs, so long as health-related QoL does not decrease. Any need, however, for reinforcement of the advice to the same patients to maintain the reductions in NSAID use would be likely to reduce cost-effectiveness. To keep the cost of the intervention low to the health service may result in greater costs being incurred by patients, and whether this is acceptable is a matter of debate.
From the patient perspective, reduction in NSAID costs could represent a personal financial benefit if they normally pay prescription charges or purchase OTC medication. Only 17.3% (n=19) of the intervention group and 15.2% of the control group stated they were liable for prescription charges. For patients, therefore, the cost-effectiveness of the intervention would be reduced if they incurred significant additional personal costs. Only a few patients incurred such expense from purchasing OTC medication, footwear, local heat or cold appliances, other equipment or services. At 6 months, there was no evidence of any reduction in patient expenditure in either group and in fact costs increased for both. From the patient perspective, cost-effectiveness is difficult to substantiate.
There was no statistically significant difference between the groups in the SF-36 and QALY outcomes at 6 months. This suggests that any reduction in NSAID reliance was not associated with any deterioration in health-related QoL. For the EQ-5D results this finding must be treated with caution because of the insensitivity of the instrument to small changes in well-being. The EQ-5D is easy and quick to complete and has been validated in the UK amongst other countries. The SF-36 is more sensitive to change and the results for this support the reliability of the EQ-5D utility and QALY results.
In economic evaluations, QALYs allow health-care purchasers to compare the cost-effectiveness of different interventions. It was not possible to determine an incremental cost per QALY gained for this nurse educational package. There is thus a small additional net cost in using this package in primary care, there are potential economic benefits to the health service, and patients do not experience any loss in health status or quality of life. The intervention thus demonstrates overall affordability and reasonably good cost-effectiveness. A greater level of cost-effectiveness from GP and patient perspectives could be achieved if benefits were maintained over the long term, with no or little need for further intervention. The longer-term perspective can be modelled in an extension of the economic evaluation, which is planned for further research.
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Acknowledgments |
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Notes |
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References |
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