Stories of Trials That Matter

Following a stroke around two-thirds of patients suffer long-term disability. Many preclinical and clinical studies have suggested that selective serotonin reuptake inhibitors (SSRIs) might improve functional outcomes after stroke, including a number of small randomised trials.

The present trial was a pragmatic, multicentre, parallel group, double-blind, randomised, placebo-controlled trial done at 103 hospitals in the UK. Patients were eligible if they were 18 or older, had a clinical diagnosis of acute stroke with brain imaging compatible with intracerebral haemorrhage or ischaemic stroke. Further, eligible patients were randomised between 2 and 15 days from stroke onset and had a persisting focal neurological deficit at the time of randomisation to warrant 6 months treatment. Patients were excluded if they had subarachnoid haemorrhage except where secondary to a primary intracerebral haemorrhage.

Patients were randomly assigned in a 1:1 ratio to either receive fluoxetine or placebo for 6 months. The primary outcome measure was functional status assessed using the simplified modified Rankin scale. Secondary outcomes were survival at 6 and 12 months, functional status at 12 months measured with the simplified modified Rankin scale and health status assessed using the Stroke Impact Scale.

A total of 3,127 patients were enrolled comprising 1,564 allocated to fluoxetine and 1,563 allocated to placebo. Baseline characteristics were well balanced between the two groups and were similar to unselected stroke patients admitted to UK hospitals. The primary outcome, an ordinal comparison of the distribution of patients across the modified Rankin Scale categories at 6 months, adjusted for variables included in the minimisation algorithm, was similar in the two groups (common OR 0·951 [95% CI 0·839–1·079]; p=0·439). The unadjusted analysis showed a similar result (common OR 0·961 [95% CI 0·848–1·089]; p=0·531). Analysis of the modified Rankin Scale dichotomised into 0-2 versus 3-6 was also similar between the two groups (adjusted OR 0·955 [95% CI 0·812–1·123], p=0·576).

Secondary outcomes and adverse events at 6 months were generally similar between the groups, with the exception of new onset depression at 6 months which was significantly lower in the fluoxetine group (210 [13·4%] patients vs 269 [17·2%]; difference in proportions 3·78% [95% CI 1·26–6·30]; p=0·0033). Mood as assessed using the Mental Health Inventory (MHI-5) was significantly higher in the fluoxetine group (median 76 [IQR 60–88] vs 72 [56–88]; p=0·0100). Further, bone fractures were significantly higher in the fluoxetine group (45 [2·88%] patients vs 23 [1·47%]; difference in proportions 1·41% [95% CI 0·38–2·43]; p=0·0070)

In summary, the results of the FOCUS trial show that fluoxetine 20 mg given daily for 6 months after an acute stroke did not influence patients’ functional outcomes but did decrease the occurrence of depression and increase the occurrence of bone fractures.

The full report is available here.

Gout is the most common inflammatory arthritis worldwide with a prevalence in the UK of around 2.5%. Gout results from sodium urate crystals that form when sodium urate persistently exceeds saturation. Deposition of sodium urate crystals causes extremely painful gout flares, joint damage and subcutaneous nodules, known as tophi.

Despite a good understanding of the disease and the availability of effective treatment, gout care remains suboptimum. In the UK, gout is managed predominantly in primary care by general practitioners (GPs), but less than half of patients receive urate-lowering therapy. Further, in those who do receive urate-lowering therapy the dose is usually fixed without titration to achieve a target serum urate concentration.

The present trial was conducted at 56 general practices. Potential participants were identified from practice databases and screened by postal questionnaire. Patient eligibility was confirmed by a research nurse. All eligible participants were greater than 21 years old, had a confirmed diagnosis of gout and had at least one gout flare in the previous 12 months. Randomisation was undertaken by the research nurse telephoning a central co-ordinating centre and the allocation was 1:1 to either nurse-led care or usual GP-led care. The trial duration was 2 years.

Nurses delivering the nurse-led arm received full training in gout and its management according to national and international guidelines and recommendations. Follow up patient assessments, including sodium urate concentrations, were done as often as the nurse required. Urate-lowering therapy was prescribed according to a guideline. First line treatment was oral allopurinol, started at 100mg once per day and titrated upwards in 100mg increments every 3-4 weeks according to the serum urate concentrations, to a maximum of 900mg once per day. As second-line options, oral febuxostat could be started at 80 mg and if required increased to the maximum dose of 120 mg once per day or benzbromarone could be started at 50 mg and titrated up in 50 mg increments to a maximum of 200 mg once per day. Combination urate-lowering therapy (xanthine oxidase inhibitor plus uricosuric) could be used as the final treatment option.

By contrast, the usual care group could discuss treatment of flares at the baseline and annual assessments, but all other enquiries were directed to their GP.

The primary outcome was the percentage of patients who had achieved serum urate concentrations less than 360 μmol/L at 2 years. Secondary outcomes were other serum urate measures (percentage of patients who had achieved serum urate concentrations <360 μmol/L at 1 year, <300 μmol/L at 1 and 2 years, and group mean serum urate concentrations at 1 and 2 years); frequency of gout flares during years 1 and 2; the percentage of patients with tophi overall; the median number of tophi and the maximum diameter of the largest tophus at 1 and 2 years among patients with tophi at baseline; quality of life (physical and mental components) and Gout Impact Scale at 1 and 2 years; and cost-effectiveness, calculated as cost per quality-adjusted life-year (QALY) gained.

A total of 6,806 questionnaires were sent by GP practices with 41% (2,815) being returned. 1,071 reported have flares in the last 12 months and were willing to be contacted further. From these, 505 patients were randomised. In addition, a small number (12) of participants were identified from advertisements giving a total randomised population of 517, comprising 255 assigned to nurse-led care and 262 assigned to usual GP-led care.

The two groups were similar in terms of baseline characteristics. Most were middle-aged white men with average gout duration of 12 years. 203 (39%) were taking urate-lowering therapy at baseline and only around 20% had a serum urate concentration less than 360 μmol/L.

Of 517 patients who started the study, 482 (93%) completed 1 year and 441 (85%) completed 2 years. At 2 years, multiple imputation showed that 95% of participants in the nurse-led group had achieved serum urate concentrations less than 360 μmol/L compared with 30% in the usual care group (RR 3·18, 95% CI 2·42–4·18). A similar difference was seen after 1 year. Use of urate-lowering therapy increased in both groups, but was significantly higher in the nurse-led group: at 2 years, 96% of patients in the nurse-led group were using urate-lowering therapy compared to 56% in the usual-care group. The nurse-led group showed improvements compared to usual care in a range of the secondary outcomes, including flare frequency, presence of tophi and quality of life.

The authors conclude that nurse-led care can achieve high uptake of urate-lowering therapy and good adherence at 2 years. 95% of participants in the nurse-led group achieved the recommended target serum urate concentration of less than 360 μmol/L and patient-centred outcomes, including flare frequency, presence of tophi, and quality of life, improved significantly compared with those in the usual-care group.

You can read the full report here

Childhood eczema is a common condition that can have a substantial impact on quality of life for children and their families. Clinical guidelines recommend that total emollient therapy forms the main treatment with emollients applied by three ways, leave on creams, soap substitutes and bath emollients. There is evidence for the effectiveness of leave on emollients and clinical consensus on the use of soap substitutes, but uncertainty exists about the effectiveness of bath emollients with a lack of reliable evidence. Despite this lack of evidence, bath additives are widely prescribed at a cost of £23m per annum in the NHS in England.

The present trial was a pragmatic, multicentre, open-label parallel group design comparing emollient bath additives in addition to standard eczema care with standard care alone on childhood eczema. Participants were recruited from 96 general practices in Wales and England and eligible children were aged 1-11 years and excluded children with inactive or very mild eczema and who bathed less than once per week. Participants in the intervention group were prescribed bath additives and asked to use them regularly for 12 months. The control group were asked not to use bath additives for 12 months. The primary outcome was eczema severity measured by the patient oriented eczema measure (POEM) reported by parents or carers weekly over 16 weeks.

A total of 12,504 letters of invitation were sent to parents or carers and 1,451 responses were received. Overall, 662 met the eligibility criteria and were approached to participate and a total of 483 entered the trial. One participant subsequently withdrew giving a total randomised of 482 participants, comprising 264 participants in the intervention arm and 218 in the control arm. The groups were well balanced on a range of baseline characteristics. By contrast, the groups were clearly different according to bath additive use with 93% of participants in the intervention arm using bath additives all of the time or more than half of the time and in the control arm 92% of participants never used bath additives or used them less than half of the time.

The baseline POEM score was 9.5 (SD 5.7) in the bath additives group and 10.1 (SD 5.8) in the no bath additives group (POEM score range 0-28, the higher the score the more severe the eczema). The mean POEM score over the 16 week period was 7.5 (SD 6.0) in the bath additives group and 8.4 (SD 6.0) in the no bath additives group. No statistically significant difference was found in weekly POEM scores between the two groups over the 16 week period. In addition, no significant differences were seen between the groups for a range of secondary outcomes, including number of eczema exacerbations, or prescribing of flare up medication.

The authors conclude that the trial provides strong evidence that emollient bath additives provide minimal or no additional benefit beyond standard eczema care in the management of eczema in children.

You can read the full report here.

Shoulder pain is common and subacromial decompression for subacromial shoulder pain is one of the commonest surgical procedures in orthopaedics. Despite a lack of reliable evidence for its effectiveness, the number of patients undergoing subacromial decompression has substantially increased in recent years; in 2000 around 2,500 patients in the UK underwent subacromial decompression and by 2010 this had increased to more than 21,000.

The present trial was a multicentre, randomised, pragmatic, parallel group, placebo controlled, three group trial at 30 hospital sites in the UK. The intervention arm was arthroscopic subacromial compression. The placebo surgical intervention was investigational arthroscopy only where no bone and tissue were removed. The third arm was a no treatment arm. Patients in the surgical arms were masked to their treatment assignment, but patients in the no treatment arm were unblinded. Blinded outcome assessment was done in all groups.

Eligible participants had to have subacromial shoulder pain of at least 3 months duration with intact rotator cuff tendons, be eligible for arthroscopic surgery, and to have previously completed a non-surgical management programme that included both exercise therapy and at least one steroid injection. The primary outcome measure was the Oxford Shoulder Score (a patient reported questionnaire and an effective measure of change in pain and function in shoulders over time) at 6 months. The main analysis was according to intention-to-treat.

A total of 313 participants were randomised comprising 106 patients to decompression surgery, 103 assigned to arthroscopy and 104 assigned to no treatment. At 6 months, data for the Oxford Shoulder Score were available for 90 patients assigned to decompression, 94 to arthroscopy, and 90 to no treatment. Mean Oxford Shoulder Score did not differ between the two surgical groups at 6 months (decompression 32·7 points [SD 11·6] vs arthroscopy 34·2 points [9·2]; mean difference −1·3 points (95% CI −3·9 to 1·3, p=0·3141). Both surgical groups showed a small benefit over no treatment (mean 29·4 points [SD 11·9], decompression was higher by 2·8 points [95% CI 0·5–5·2], p=0·0186; mean difference vs arthroscopy by 4·2 points [1·8–6·6], p=0·0014) but these differences were not clinically important. A range of secondary outcomes, comprising further shoulder pain scales and more general quality of life, showed the same pattern of results as the primary outcome.

In conclusion, the authors state that in patients with persistent subacromial shoulder pain due to impingement, improvement in Oxford Shoulder Scores with arthroscopic subacromial decompression did not differ to that achieved with arthroscopy only (placebo surgery). Although both types of surgery provide greater symptom improvement than no treatment, this difference was of uncertain clinical significance. The difference between surgery and no treatment might be due to a surgical placebo effect, or possibly caused by other factors, including rest and/or post-operative physiotherapy. There were also no differences in outcome between the two surgical groups at any time point. This finding suggests that the treatment effect is not due to the principal clinical justification for the surgery, which is the removal of bone, bursa, and soft tissue to relieve impingement on the underlying tendons during movement of the arm.

The full report of the study can be found here.

Hypertension is a leading risk factor for cardiovascular disease. Despite effective medication the management of hypertension in primary remains suboptimal. Previous studies of self-monitoring, where patients monitor their own blood pressure and report back to their GP, have shown contradictory results in terms of effectiveness. The present trial aimed to assess the efficacy of self-monitored blood pressure, with or without telemonitoring, for antihypertensive titration in primary care, compared with usual care.

The design of the trial was a three-arm parallel group with self-monitoring, with or without telemonitoring and compared to usual care. Eligible hypertensive patients were older than 35, with a blood pressure higher than 140/90 mm Hg and willing to self-monitor their blood pressure. The trial duration was 12 months.

Participants randomly assigned to self-monitoring were taught to use a validated automated electronic sphygmomanometer (Omron M10-IT). They were asked to monitor their own blood pressure in their non-dominant arm, twice each morning and evening, for the first week of every month using standard recommendations and their GPs were asked to use the self-monitored measurements for titration of antihypertensive medication. A simple colour chart was used to train participants to attend their practice for a blood pressure check as a result of very high or very low readings. At the end of each monitoring week they were asked to record their readings on paper and send them for review to their practice in a reply-paid envelope.

Participants in the telemonitoring group were asked to send their results via a simple SMS text service. The telemonitoring system incorporated an algorithm that alerted participants to contact their surgery in the light of very high or very low readings, reminded them if insufficient readings were transmitted, prompted them to make contact with their practice if their average blood pressure was above target, and presented readings to attending clinicians via a web interface. This secure web page automatically calculated mean blood pressure for each monitoring week, highlighted very high or very low readings, and presented a graphical display of blood pressure measurements.

General practitioners were asked to review both self-monitoring and telemonitoring groups’ readings on a monthly basis and usual care patients as often as they wished. Blood pressure targets were based on current National Guidelines adjusted for self-monitoring: lower than 140/90 mm Hg (<135/85 mm Hg at home) for those younger than 80 years, lower than 150/90 mm Hg (<145/85 mm Hg at home) for those 80 years or older, and lower than 140/80 mm Hg (<135/75 mm Hg at home) for those with diabetes.

A total of 142 general practices participated recruiting a total of 1182 participants, of which 1003 (85%) were included in the primary analysis.

Systolic blood pressure at baseline was around 153 mm Hg in all groups and at 12 months the blood pressure was lower in all of the groups, with the largest reduction seen in the self-monitoring and telemonitoring groups: blood pressure at 12 months, usual care group 140.4 (SD 16.5, n=348), self-monitoring group 137.0 (16.7, n=328), telemonitoring group 136.0 (16.1, n=327). At 12 months, the adjusted mean difference in systolic blood pressure compared to usual care was significantly lower for both the self-monitoring (-3.5 [95% CI -5.8 to -1.2] p=0.0029) and telemonitoring (-4.7 [-7.0 to -2.4] p<0.0001) groups. There was no difference in the adjusted mean difference between the self-monitoring and telemonitoring groups (-1.2 [-.3.5 to 1.2] p=0.3219).

After 12 months, the number of prescribed antihypertensives was higher in the self-monitoring (1.63 [SD 0.89]) and telemonitoring groups (1.70 [0.88]) compared to the usual care group (1.55 [0.85]). The adjusted mean difference was significantly higher in both the self-monitoring group (0.11 [95% CI 0.02 to 0.19] p=0.0129) and telemonitoring group (0.13 [0.04 to 0.21] p=0.0038) compared to the usual care group.

The authors conclude that after one year patients whose medication was adjusted using self-monitoring, with or without telemonitoring, has significantly lower systolic blood pressure than those receiving treatment adjusted using clinic blood pressure.

You can read the full report here.