Time to train all doctors to look after seriously ill patients

Sarah A Ross, Clinical Research Fellow, Dept of Clinical Pharmacology, Aberdeen Royal Infirmary

Richard J Coleman, Consultant Neurologist, Dept of Neurology, Aberdeen Royal Infirmary

John Webster, Consultant Physician, Dept of Clinical Pharmacology, Aberdeen Royal Infirmary

Beta-interferon was licensed for the treatment of multiple sclerosis in 1996. Since then it has been a controversial therapy. Availability of treatment has been varied from region to region. We audited the use of beta-interferon in the Grampian region, which has the largest cohort of patients treated in Scotland. One hundred and thirty seven patients were treated up to the beginning of 2002, 12.5% of the local MS population. The number of patients given treatment in Grampian continues to increase. Very few patients have discontinued treatment. The results of this audit show that our patients were treated in line with current clinical guidelines. This has implications for the implementation of guidelines in the rest of Scotland, where much smaller numbers of patients have been treated thus far. (127)

Multiple sclerosis (MS) is a chronic disabling disease of the central nervous system. Scotland has a higher prevalence of MS than other parts of the UK. The prevalence of MS in Grampian region is approximately 203/100000[i], giving an estimated total number of 1100 patients in the Grampian area.

In the past therapeutic options have been limited, but recent trials have provided evidence that beta-interferon therapy may modify the course of the disease[ii] [iii] [iv]. Beta-interferon has been a controversial treatment in the UK because of its high cost and limited benefits. As a result the availability of this treatment has varied from region to region in the UK, a prime example of so-called "postcode prescribing".

When beta interferon first became available in 1995, Grampian Health Board decided to fund treatment within guidelines agreed with the neurologists at Aberdeen Royal Infirmary (Table i). These are similar to the subsequent Association of British Neurologists' guidelines[v] (Table ii). The Grampian guidelines applied to patients with relapsing remitting MS. When one of the products obtained a licence for use in secondary progressive MS, the guidelines were not extended and so this group of patients remained ineligible for treatment. Again, when glatiramir obtained a product licence, the guidelines were not extended and so this product was not used locally.

Grampian region in Scotland has a population of 541240 (April 2001 GHB figures). The region is served by the neurology department at Aberdeen Royal Infirmary. Over the period in question there have been at different times 2, 3 or 4 consultant neurologists based in Aberdeen (currently 3.4 whole time equivalents). The Aberdeen neurologists also provide neurological services for Highland, Orkney and Shetland regions. Specialist nurse support for patients with MS has been available since 1995, with initially one nurse, and more recently two (whole time equivalents).

We performed a case note audit of all the patients within the Grampian Health Board region who have been treated with beta-interferon. Patients from Highland, Orkney and Shetland Health Board Regions were not included in this study. Patients were identified from a database of patients receiving beta-interferon therapy. These names were verified with the MS nurses responsible for the initiation of beta-interferon treatment, ensuring that all appropriate patients were included. A proforma was used to collect information from patient medical records; the data recorded is listed in Table iii. The audit date was 1st Feb 2002.

A total of 137 patients living in Grampian were treated with beta-interferon between Jan 1995 and Jan 2002. 20 patients were treated as part of clinical trials, the majority of whom (19) continued treatment after the end of the trial, even though they did not all fulfil the prescribing criteria.

Gender - Of the 137 patients, 109 were women, 28 men, a ratio of approximately 4:1.

Age - Mean age of patients at diagnosis was 32 years. Mean age at initiation of therapy was 36 years, with a range of 18 to 53. Local guidelines initially suggested that patients between 18 and 50 should be eligible for therapy, but the upper age limit was later withdrawn.

Payment for treatment - The majority of patients in Grampian who have been treated with beta-interferon have been funded through the NHS, including the 20 patients who had had trial medication, for whom special arrangements were made. However, two patients in the audit had received private treatment.

Duration of therapy – at the time of the audit, the mean duration of treatment was 2 years 7 months, with a range of 1 month to 7 years.

MS Category - The twenty patients who were involved in clinical trials were excluded from this part of the audit, as treatment was not initiated on the basis of clinical guidelines. Of the other 117, 6 patients had secondary progressive multiple sclerosis and 2 did not have a clear MS category from case note audit. Two of the patients with secondary progressive disease paid for their own treatment and so were not subject to the agreed criteria.

Walking - The clinical criteria for beta-interferon treatment includes a stipulation that patients should be ambulant (able to walk 100 metres without aid or rest). It appears that the definition of "ambulant" initially stipulated in the Grampian guidelines has not been strictly adhered to; a measured walking distance was not recorded in the notes. With time, it appears that the definition of ambulant in the ABN guidelines has been adopted (able to walk independently). From the information available in case records, only two patients were not thought to be ambulant at the time of treatment initiation.

Relapses - It is generally agreed that a patient should have had at least 2 significant relapses in the 2 years prior to treatment. Of the 115 patients who were not privately funded or involved in trials, 6 patients did not have the number of relapses recorded in their notes. A further 2 had only one relapse documented and therefore did not meet the treatment criteria. The majority of patients had 2 or 3 relapses in the preceding 2 years, but one patient had more than 5. A trend towards earlier treatment with beta-interferon was seen over time as the therapy became more established. It has become common for therapy to be started if a second episode, a disease-defining relapse, occurs within 2 years of the first episode.

Preparations - Most patients in the Grampian area have been treated with Betaferon given by alternate day subcutaneous injection. Others opted for Avonex, intramuscularly once a week. Only one patient has used Rebif, the other licensed preparation. No patients received glatiramir (Copaxone).

Stopping medication - Of the 137 patients, only 21 have stopped beta-interferon therapy. Others have suspended treatment for example because of side effects, to switch preparation or in anticipation of pregnancy. 9 patients have stopped treatment due to secondary progression of their MS, as recommended by the ABN guidelines. The majority of the other patients (7) stopped due to side effects, including two who had serious soft tissue infections. Other reasons for stopping treatment included leaving the UK (1), severe alcoholic liver disease leading to death (1), a dislike of self-injecting (1) and the perception of no effect from the medication (1).

Six of the 21 patients who stopped treatment were male. Mean age of those stopping therapy was 42. There was no difference in the dates of diagnosis or initiation between patients who continued and did not continue therapy. Mean duration of treatment in those who subsequently stopped beta-interferon altogether was 1.57 years.

Side effects - Reported side effects were in line with those in other studies, namely flu-like symptoms and injection site problems. Depression was often cited as a side effect, however it is unclear whether this is causally related to treatment. Two serious soft tissue infections occurred, necessitating surgical debridement and significant tissue loss in one patient. Changes in menstrual cycle were noted by a number of women. (Table iv)

Recommendations for safety monitoring of beta-interferon include three monthly liver function tests and full blood counts. After the first year of treatment, this can be relaxed to six monthly. Many of our patients did not have blood tests done at these exact intervals. Minor liver function test abnormalities were noted in 60 of 130 patients for whom there were results available, but no patients had medication stopped as a result. The highest GGT and AAT were less than 7 times the locally used normal range. No changes in bilirubin or albumin were seen. Haematological abnormalities were seen in 83 patients. As expected, these were mostly lymphopenia. Two patients were noted to be significantly polycythaemic and in one of these the cause was thought to be beta-interferon although this has not been definitively confirmed. In all only 22 patients had completely normal monitoring blood tests during therapy.

It is not possible to assess the efficacy of beta-interferon from a retrospective audit. However, valuable information is obtained about the numbers of patients who are being treated and whether they are suitable for beta-interferon therapy. Most patients were treated in line with both local and national guidelines. The purpose of this audit was not to accertain whether all patients who met the treatment criteria were treated. However the data does suggest that a significant proportion of the MS population is suitable for treatment under these guidelines, which may have implications for other geographical areas in Britain.

The ABN guidelines also provide some guidance for the use of beta-interferon in secondary progressive disease which our local guidelines exclude. There is some evidence to support prescribing for this group of patients, but this comes from only one trial[vi]. Using beta-interferon in secondary progressive disease would greatly enlarge the population being given this drug with the inherent cost implications.

The percentage of patients who have been treated with beta-interferon in Grampian (approx. 12.5%, currently treated 10.5%) is significantly higher than the average estimated for the UK (1.8%), but not as high as estimated for the USA or some European nations eg Italy (17.5%), Germany (10%) (Schering figures 1999). The high percentage of patients treated in Grampian compared to the rest of the UK is no doubt due to the attitude adopted by Grampian Health Board in funding treatment at an early stage after launch, as well as the involvement of the neurology department in clinical trials.

The total number of patients being treated with beta-interferon in Grampian has continued to rise and shows no sign of slowing (Table vi, Figure 2). If prescribing practice does not alter then, at some point, a "steady state" will be reached where the number starting treatment is equal to the number stopping; this steady state has not yet been reached in Grampian after 6 years of prescribing. This may be because criteria for stopping therapy were not clearly agreed in advance. There is no satisfactory measure of treatment efficacy particularly when the natural history of MS is so variable. There may also be a reluctance on the part of patients to give up a treatment which has become so politicised.

The annual spend on beta-interferon in Grampian region has increased year on year. In the 1997-98 financial year the total expenditure was £205070. In 2001-02, this was £878549 (Figure 1). This accounts for 70% on average of the total annual spend on beta-interferon in Scotland, although the population of Grampian is approximately 10% of Scotland as a whole.

Those patients who have stopped treatment in our region did so for a number of reasons. Three had adverse events which were sufficiently serious to cause a medical decision to be made to stop treatment. One further patient became seriously ill with another condition. A number of patients stopped therapy in discussion with their consultant once a diagnosis of secondary progression had been made. Patients who chose to stop treatment did so if for whatever reason they felt it was not helping. This group did however have two noticable demographic differences from the total population. The average age of the patients who stopped therapy was 42, 10 years higher than the population average. This may be merely a reflection of patients who are older being more likely to have progression of their MS. Proportionally more men than women discontinued treatment; 6 out of 28 men stopped treatment compared with 15 out of 109 women.

The monitoring of blood tests in our patients was less than optimal. Often there was uncertainty surrounding who was responsible for ensuring that blood tests were undertaken. For example patients were asked to attend their GP for a blood test, but if they failed to do so this was not apparent until their next hospital appointment.

Patients were more likely to get their bloods checked if they saw the MS nurses at the clinic. Clinic letters did not always ask the GP to check bloods. Greater clarification would also reduce these tests. Given that little action is taken in most patients cases while the majority of patients have some blood abnormalities, it may be that tests of this frequency are not perceived as important. Now that beta-interferon has become more established, it may be time to reconsider these recommendations.

Our data are of value to those preparing budgets for drug expenditure in Grampian. There may be wider implications, however. In 2002, a "risk sharing scheme" was introduced into the UK whereby some of the costs to the NHS of supplying disease modifying drugs for multiple sclerosis might be defrayed through an arrangement with the pharmaceutical companies. The operational details of this scheme are just emerging, though the indications are that these are complex and somewhat lacking in transparency. The essence would appear to be that costs will be refunded to the NHS in the event that treatment is unsuccessful. Our data were not acquired specifically to address this issue, but suggest to us that any reimbursement to the NHS is likely to be relatively small. The numbers of patients in Grampian discontinuing beta-interferon because of lack of efficacy or side effects of treatment was less than 10% of the total starting. Many other difficulties can be foreseen. The timescale over which such decisions can be made may be prolonged in patients with relatively infrequent relapses. The distinction between failure of treatment and spontaneous relapse or progression of disease can be extremely difficult.

At the time of the audit, we were aware of huge regional differences in beta-interferon use within Scotland. Virtually all patients in Grampian who qualified on clinical criteria were offered a trial of one of the drugs. In Tayside, the regional prescribing budget for beta-interferon was approximately 10% of that in Grampian. Limited prescribing was also allowed in Glasgow, whereas these drugs were not included in the prescribing formulary in Lothian. These differences are dramatically illustrated in figure 1, which shows that by far the largest proportion of beta-interferon prescribing in Scotland has been and continues to be borne in Grampian. Such data should be taken into account in the administration of the risk sharing scheme, which should be administered transparently to ensure equity of both availability and funding of these drugs. Such an arrangement is particularly desirable in use of a treatment which may be efficacious, but which is of such marginal cost-effectiveness.

Overall, our results suggest that in Grampian, Beta-interferon for MS has been used in a way very close to that utilised in the initial trials and as recommended by National Guidelines. There is little doubt that financial constraints have had an influence on prescribing, resulting in highly uneven availability across the country. The advent of the NHS risk-sharing scheme may change this dramatically, and continuing audit of this form of treatment will be highly desirable.

Dr Caroline Hinds, Prescribing Adviser, Grampian Primary Healthcare Trust who provided data on national prescribing of beta interferons using information supplied by Primary Care Information Unit, ISD Scotland.

RJC has been an investigator in clinical trials of beta interferon in multiple sclerosis sponsored by Schering Health.

Support for specialist nurse and management of the local multiple sclerosis database was provided by Schering Health and Biogen.

References

[i] Scottish Needs Assessment Programme Report on Multiple Sclerosis. Office for Public Health in Scotland. 2000.

[ii]The IFNB multiple sclerosis study group. Interferon beta-1b is effective in relapsing-remitting multiple sclerosis; clinical results of a multicentre, randomised, double-blind, placebo-controlled trial. Neurology 1993; 43: 655-61.

[iii] Jacobs LD, Cookfair DL, Rudick RA et al. Intramuscular interferon beta-1a for disease progression in relapsing multiple sclerosis: the multiple sclerosis collaborative research group (MSCRG). Ann Neurol 1996; 39: 285-294.

[iv] Ebers Gc, Hommes O, Hughes RAC et al. Randomised double-blind placebo-controlled study of interferon beta-1a in relapsing/remitting multiple sclerosis. Lancet 1998; 352: 1498-504.

[v] Association of British Neurologists. Guidelines for the use of beta interferons and glatiramer acetate in multiple sclerosis. January 2001.

[vi] European Study Group on Interferon-1b in Secondary Progressive MS. Placebo-controlled multicentre randomised trial of interferon-1b in treatment of disability in secondary progressive multiple sclerosis. Lancet 1998; 352: 1491-97.

Beta-Interferon Use in Multiple Sclerosis: Audit of Practice in Grampian