Добавил:
Sekretar
kiopkiopkiop18@yandex.ru
t.me/Prokururor I Вовсе не секретарь, но почту проверяю
Опубликованный материал нарушает ваши авторские права? Сообщите нам.
Вуз:
Предмет:
Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5267_Библиотеки_им_академика_М_И_Перельмана
.pdf
cost effective among all the interventions assessed at different levels of WTP for one
unit of outcome gained (in this case one standard deviation of the CIS). CEACs
showed that medication management had a higher probability of being cost effective
compared with routine community care at any level of WTP.
The results of the above studies indicate that medication management is likely to
be a cost-effective intervention from the perspective of a third-party payer in the US.
The authors acknowledged as a limitation of their analyses the fact that they did not
address potential longer-term costs and benefits associated with treatment, as well as
broader societal costs, such as parental absence from work and related productivity
losses, costs of special education services, and costs of other social services, includ-
ing the juvenile justice system. Another limitation of the analysis, as stated in Foster
and colleagues (2007), was the inability to generalise the results in other settings, as
routine community care may vary considerably across different sites. It must be noted
that routine community care described in the study included quite intensive psychoso-
cial therapy (as indicated by high respective costs associated with routine community
care), as well as provision of medication, mainly stimulants, in two-thirds of the study
population; hence the intervention described in the MTA study may have been more
intensive than community care received routinely in the UK.
Schlander and colleagues (2006a, 2006b, 2006c) evaluated the relative cost effec-
tiveness of the interventions examined in the MTA study in the context of four
European countries, including the UK. Resource use estimates still reflected US prac-
tice (taken from the MTA trial), but country-specific unit costs were employed. The
perspective of the analysis referring to the UK was that of the NHS (direct medical
expenditures). Costs for all countries were calculated in local currencies and then
converted to 2005 Euros (€). In addition to previous sub-group distinctions, the
authors provided results for children with ADHD combined type (according to DSM-
IV), hyperkinetic/ conduct disorder (according to ICD-10), pure ADHD (without coex-
isting conditions), and pure hyperkinetic disorder (without coexisting conditions). The
outcome measures used in the economic analyses were the number of children with
ADHD normalised, the CIS ES, and also the QALYs gained by treatment. This section
provides the results from the comparison between medication management and routine
community care. Results from the comparisons across medication management, inten-
sive behavioural therapy and combination therapy are presented in Chapter 11.
The ICER of medication management versus routine community care per
normalised child in the UK was found to be approximately €3,720 for ADHD
combined type, €3,540 for pure ADHD, €4,000 for hyperkinetic/conduct disorder,
and €1,520 for pure hyperkinetic disorder (or £2,565, £2,440, £2,760, and £1,050
respectively, using a conversion rate of 1UK£ 1.45€). When the measure of
outcome was the CIS ES, then the ICER of medication management versus routine
community care was estimated at roughly €3,000 for ADHD combined type, €2,775
for pure ADHD, €6,730 for hyperkinetic/conduct disorder, and €160 for pure hyper-
kinetic disorder (or £2,070, £1,915, £4,655, and £110 respectively, at a conversion
rate of 1UK£ 1.45€). CEACs demonstrated that for the majority of sub-populations
examined, medication management had a higher probability of being cost effective
compared with routine community care at any level of WTP. For children with
Pharmacological treatment
299
hyperkinetic/conduct disorder, routine community care was likely to be more cost
effective than medication management for low levels of WTP, that is, for up to roughly
€6,000 (£4,100) per CIS ES. It was also found that for children with externalising
coexisting conditions routine community care was likely to be more cost effective than
medication management up to a WTP of approximately €4,000 (£2,700) per child
normalised.
Schlander and colleagues (2006a) also provided a range of ICERs across the four
European countries considered, with outcomes expressed in QALYs. However, no
outcomes specific to the UK were available in the poster presentation. Using the
reported costs per child treated in the UK context, the proportions of children
normalised in the MTA study in the various sub-populations, and utility weights
reported by Coghill and colleagues (2004), it was possible to estimate the incremen-
tal cost per QALY of medication management versus routine community care in the
UK context. The estimated ICERs were £33,490 per QALY for ADHD combined
type, £32,150 per QALY for pure ADHD, £36,590 per QALY for hyperkinetic/
conduct disorder, and £13,990 per QALY for pure hyperkinetic disorder. In order to
estimate QALYs associated with any treatment option it was assumed that improve-
ment in HRQoL occurred at time zero for responders. It must be noted that decrement
in HRQoL from medication was not considered.
The above results suggest that medication management may actually not
be a cost-effective option for children with ADHD in the UK, according to the cost-
effectiveness threshold set by NICE (2006c), apart from the sub-population of
children with pure hyperkinetic disorder. However, this analysis is characterised by
important limitations, as resource use estimates in both medication management and
routine community care arms reflect clinical practice in the US setting, and may not
be representative of UK practice. Therefore, the results of all economic analyses
related to the MTA study, even those referring to the UK context in terms of unit costs
used, need to be interpreted with caution.
10.16.4 Pharmacological treatment in adults with ADHD
The systematic search of the economic literature identified no studies evaluating the
cost effectiveness of pharmacological interventions for adults with ADHD. Therefore,
it was decided to develop an economic model in order to assess the relative cost effec-
tiveness of potential first-line medications in this population. Clinical evidence was
available for four medications: methylphenidate, atomoxetine, dexamfetamine and
bupropion. Given that dexamfetamine and bupropion are not licensed for the treat-
ment of adults with ADHD and after taking into account the lack of experience in
using these two medications routinely for this purpose, the GDG deemed that the
most appropriate comparison would be between methylphenidate, atomoxetine
23
and
Pharmacological treatment
300
23
In adolescents whose symptoms persist into adulthood and who have shown clear benefit from treatment,
it may be appropriate to continue treatment into adulthood. However, start of treatment with atomoxetine
in adults is not appropriate.
no treatment. As discussed in Chapter 7, clinical effectiveness data in the form of
dichotomous outcomes, such as response rates to treatment, are the most suitable to
utilise in a cost-utility analysis, where the measure of outcome is expressed in
QALYs. However, no clinical studies of atomoxetine reporting dichotomous
outcomes were identified in the systematic search of the literature for adults with
ADHD. Subsequently, an attempt was made to undertake an economic analysis based
on studies reporting outcomes as changes in scores on scales measuring ADHD
symptoms. Again, the clinical data were sparse and heterogeneous, and did not permit
the development of a decision-analytic model that would allow for a comparison
between methylphenidate and atomoxetine. More specifically, there were no head-to-
head comparisons between methylphenidate and atomoxetine for adults with ADHD.
The economic analysis would need to be based on indirect comparisons between
the two drugs, with placebo being the common comparator in the available clinical
studies. Two studies assessed the clinical effectiveness of methylphenidate versus
placebo. SPENCER2005 expressed outcome as a mean score of Adult ADHD
Investigator System Report Scale (AISRS) at endpoint of analysis; KOOIJ2004
expressed outcome as mean score of the ADHD-RS at endpoint of analysis. On the
other hand, the three trials comparing atomoxetine to placebo in adults with ADHD
(MICHELSON2003a, MICHELSON2003b, and WERNICKE 2004b) measured the
mean change in CAARS from baseline to endpoint of analysis. It is evident that the
scales used and the time points of measuring outcomes were different between the
studies of methylphenidate and those of atomoxetine. Using these studies in an
economic analysis would introduce bias, would require a number of assumptions and
would, consequently, result in conclusions with high uncertainty.
Bearing in mind the comments above, economic considerations are important in
the formulation of clinical practice recommendations. Medication has been shown to
be cost effective in children with ADHD when compared with no treatment. The
economic analysis undertaken to support the NICE TA on the use of methylphenidate,
atomoxetine and dexamfetamine in children and adolescents with ADHD (NICE,
2006b) concluded that all sequences of drug monotherapies examined were more cost
effective than no treatment (King et al., 2006). The results from this analysis,
presented in Table 31, showed that some strategies dominated no treatment, and the
rest were more effective than no treatment at a cost below £6,500 per QALY in all
cases. The effect sizes of drugs in adults with ADHD are overall somewhat lower than
the respective effect sizes in children with the same condition, although comparison
between the two populations is in some cases difficult, given the variety characteris-
ing outcome measurement in the trials included in the systematic review of clinical
evidence. Nevertheless, it was considered that the relative magnitude of effect size of
medication in adults (compared with children) was such that the ICER of medication
as a whole versus no treatment was unlikely to exceed the cost-effectiveness thresh-
old of £20,000 per QALY set by NICE (NICE, 2006c), and therefore provision of
medication in adults with ADHD was estimated to be a cost-effective intervention.
In order to compare methylphenidate and atomoxetine, a rough cost analysis was
attempted to measure the costs associated with provision of these two drugs in
adults with ADHD. Assuming that the healthcare professional costs for titration and
Pharmacological treatment
301
monitoring are similar, the drug acquisition costs over a year were estimated for the
two medications. Provision of generic, IR methylphenidate at a daily dose of 60 mg
costs £30 per month or £360 per year (Joint Formulary Committee, 2008). MR
methylphenidate at a daily dose of 72 mg costs £81 per month or £972 per year
(British Medical Association & the Royal Pharmaceutical Society of Great Britain
[2007], Concerta XL
®
). Atomoxetine at a dose of 80 mg daily costs £129 per month
or £1,548 per year (British Medical Association & the Royal Pharmaceutical Society
of Great Britain [2007], Strattera
®
). Atomoxetine is therefore more expensive than
methylphenidate in terms of drug acquisition costs.
The interpretation of all available clinical evidence indicated that methylphenidate
is likely to be more effective than atomoxetine in adults with ADHD. Consequently,
methylphenidate is possibly a dominant option over atomoxetine as a first-line phar-
macological treatment in adults with ADHD. However, other factors need to be
assessed, such as the presence of intolerable side effects that lead to discontinuation
of treatment and initiation of second-line therapy; the management of other side
effects; the acceptability of a drug that affects continuation rates; and compliance.
These additional factors may affect the relative cost effectiveness of methylphenidate
and atomoxetine.
10.17 FROM EVIDENCE TO RECOMMENDATIONS
On the whole, the evidence indicates that methylphenidate in the treatment of chil-
dren and adults with ADHD has moderate to high beneficial effects on ADHD core
symptoms and conduct problems. The evidence for atomoxetine as a treatment of
ADHD in children and adults suggests a moderate beneficial effect on ADHD core
symptoms and conduct problems. Two studies involved a head-to-head compari-
son between methylphenidate and atomoxetine and the results indicated that
methylphenidate had more beneficial effects in children with ADHD.
Only lower-level evidence was found for the use of dexamfetamine in children
with ADHD. For adults with ADHD, one study showed high beneficial effect of
dexamfetamine on clinical improvement. However, the use of dexamfetamine in
clinical practice is marginal and is not licensed for adults with ADHD.
For pre-school children there is no evidence that drug treatment is effective in the
treatment of ADHD.
The review of the economic evidence demonstrated that drug treatments are cost
effective compared with no treatment in children with ADHD. The relative cost effec-
tiveness of different medications cannot be established owing mainly to the uncer-
tainty characterising clinical-effectiveness data and the difficulty in synthesising
available evidence. It must also be noted that long-term benefits and harms from
medication have not been taken into account in the assessment of cost effectiveness
as relevant data were not available or not suitable for a modelling exercise.
Medication in adults is likely to be cost effective too, considering that the effect size
of medication in adults with ADHD is significant and only moderately lower than that
in children. Medication management was shown to be a cost-effective intervention in
Pharmacological treatment
302
the US. However, the cost effectiveness results of the MTA study cannot be extrapo-
lated to the UK context without caution, as the interventions assessed and the clinical
practice in the US are likely to differ substantially from respective interventions and
clinical practice in the UK.
As presented in Chapter 11, an economic analysis undertaken for this guideline
comparing psychological, pharmacological and combined treatments for children
with ADHD indicated that group behavioural therapy or group CBT for school-age
children were more cost effective than medication. Combined therapies were not cost
effective, as they incurred very high costs for a rather low additional effect. Again in
this case, long-term benefits and harms from medication and psychological therapy
were not considered in the economic analysis, as data appropriate to inform the
economic model did not exist. A similar assessment of the cost effectiveness of
psychological versus pharmacological interventions in adults with ADHD was not
possible because of a complete lack of relevant clinical data.
10.18 RECOMMENDATIONS
10.18.1 Treatment for pre-school children
10.18.1.1 Drug treatment is not recommended for pre-school children with ADHD.
10.18.2 Treatment for school-age children with moderate ADHD
10.18.2.1 Drug treatment is not indicated as the first-line treatment for all school-
age children and young people with ADHD. It should be reserved for
those with severe symptoms and impairment or for those with moderate
levels of impairment who have refused non-drug interventions, or whose
symptoms have not responded sufficiently to parent-training/education
programmes or group psychological treatment.
10.18.2.2 Following treatment with a parent-training/education programme, chil-
dren and young people with ADHD and persisting significant impairment
should be offered drug treatment.
10.18.3 Treatment for school-age children with severe ADHD (hyperkinetic
disorder) and severe impairment
10.18.3.1 In school-age children and young people with severe ADHD, drug treat-
ment should be offered as the first-line treatment. Parents should also be
offered a group-based parent-training/education programme. (Key priority)
10.18.3.2 Drug treatment should only be initiated by an appropriately qualified
healthcare professional with expertise in ADHD and should be based
on a comprehensive assessment and diagnosis. Continued prescribing
Pharmacological treatment
303
and monitoring of drug therapy may be performed by general practition-
ers, under shared care arrangements
24
.
10.18.3.3 If drug treatment is not accepted by the child or young person with severe
ADHD, or their parents or carers, healthcare professionals should advise
parents or carers and the child or young person about the benefits and supe-
riority of drug treatment in this group. If drug treatment is still not
accepted, a group parent-training/education programme should be offered.
10.18.3.4 If a group parent-training/education programme is not effective for a
child or young person with severe ADHD, and if drug treatment has not
been accepted, discuss the possibility of drug treatment again or other
psychological treatment (group CBT and/or social skills training), high-
lighting the clear benefits and superiority of drug treatment in children
or young people with severe ADHD.
10.18.4 Pre-drug treatment assessment
10.18.4.1 Before starting drug treatment, children and young people with ADHD
should have a full pre-treatment assessment, which should include:
● full mental health and social assessment
● full history and physical examination, including:
– assessment of history of exercise syncope, undue breathlessness
and other cardiovascular symptoms
– heart rate and blood pressure (plotted on a centile chart)
– height and weight (plotted on a growth chart)
– family history of cardiac disease and examination of the cardio-
vascular system
● an electrocardiogram (ECG) if there is past medical or family history
of serious cardiac disease, a history of sudden death in young family
members or abnormal findings on cardiac examination
● risk assessment for substance misuse and drug diversion (where the
drug is passed on to others for non-prescription use).
10.18.4.2 Drug treatment for children and young people with ADHD should always
form part of a comprehensive treatment plan that includes psychological,
behavioural and educational advice and interventions. (Key priority)
10.18.5 Choice of drug for children and young people with ADHD
10.18.5.1 Where drug treatment is considered appropriate, methylphenidate,
atomoxetine and dexamfetamine are recommended, within their licensed
Pharmacological treatment
304
24
This recommendation is taken from TA98 (NICE, 2006b). At the time of publication, methylphenidate
and atomoxetine did not have UK marketing authorisation for use in children younger than 6 years.
Informed consent should be obtained and documented.
indications, as options for the management of ADHD in children and
adolescents
25
.
10.18.5.2 The decision regarding which product to use should be based on the
following:
● the presence of comorbid conditions (for example, tic disorders,
Tourette’s syndrome, epilepsy)
● the different adverse effects of the drugs
● specific issues regarding compliance identified for the individual
child or adolescent, for example problems created by the need to
administer a mid-day treatment dose at school
● the potential for drug diversion (where the medication is forwarded
on to others for non-prescription uses) and/or misuse
● the preferences of the child/adolescent and/or his or her parent or
guardian
26
.
10.18.5.3 When a decision has been made to treat children or young people with
ADHD with drugs, healthcare professionals should consider:
● methylphenidate for ADHD without significant comorbidity
● methylphenidate for ADHD with comorbid conduct disorder
● methylphenidate or atomoxetine when tics, Tourette’s syndrome,
anxiety disorder, stimulant misuse or risk of stimulant diversion are
present
● atomoxetine if methylphenidate has been tried and has been
ineffective at the maximum tolerated dose, or if the child or young
person is intolerant to low or moderate doses of methylphenidate.
(Key priority)
10.18.5.4 When prescribing methylphenidate for the treatment of children or young
people, modified-release preparations should be considered for the
following reasons:
● convenience
● improving adherence
● reducing stigma (because the child or young person does not need to
take medication at school)
● reducing problems schools have in storing and administering
controlled drugs
● their pharmacokinetic profiles.
Alternatively, immediate-release preparations may be considered if more
flexible dosing regimens are required, or during initial titration to deter-
mine correct dosing levels.
Pharmacological treatment
305
25
This recommendation is taken from TA98 (NICE, 2006b). At the time of publication, methylphenidate
and atomoxetine did not have UK marketing authorisation for use in children younger than 6 years.
Informed consent should be obtained and documented.
26
Ibid.
10.18.5.5 When starting drug treatment children and young people should be
monitored for side effects. In particular, those treated with atomoxetine
should be closely observed for agitation, irritability, suicidal thinking and
self-harming behaviour, and unusual changes in behaviour, particularly
during the initial months of treatment, or after a change in dose. Parents
and/or carers should be warned about the potential for suicidal thinking
and self-harming behaviour with atomoxetine and asked to report these
to their healthcare professionals. Parents or carers should also be warned
about the potential for liver damage in rare cases with atomoxetine
(usually presenting as abdominal pain, unexplained nausea, malaise,
darkening of the urine or jaundice).
10.18.5.6 If there is a choice of more than one appropriate drug, the product with
the lowest cost (taking into account the cost per dose and number of daily
doses) should be prescribed
27
.
10.18.5.7 Antipsychotics are not recommended for the treatment of ADHD in chil-
dren and young people.
10.18.6 Poor response to treatment
10.18.6.1 If there has been a poor response following parent-training/education
programmes and/or psychological treatment and treatment with
methylphenidate and atomoxetine in a child or young person with
ADHD, there should be a further review of:
● the diagnosis
● any coexisting conditions
● response to drug treatment, occurrence of side effects and treatment
adherence
● uptake and use of psychological interventions for the child or young
person and their parents or carers
● effects of stigma on treatment acceptability
● concerns related to school and/or family
● motivation of the child or young person and the parents or carers
● the child or young person’s diet.
10.18.6.2 Following review of poor response to treatment, a dose higher than
that licensed for methylphenidate or atomoxetine should be considered
following consultation with a tertiary or regional centre. This may exceed
‘British national formulary’ (BNF) recommendations: methylphenidate
can be increased to 0.7 mg/kg per dose up to three times a day or a
total daily dose of 2.1 mg/kg/day (up to a total maximum dose of 90 mg/day
for immediate release; or an equivalent dose of modified-release
Pharmacological treatment
306
27
Ibid.
methylphenidate
28
); atomoxetine may be increased to 1.8 mg/kg/day (up
to a total maximum dose of 120 mg/day). The prescriber should closely
monitor the child or young person for side effects.
10.18.6.3 Dexamfetamine should be considered in children and young people
whose ADHD is unresponsive to a maximum tolerated dose of
methylphenidate or atomoxetine.
10.18.6.4 In children and young people whose ADHD is unresponsive to
methylphenidate, atomoxetine and dexamfetamine, further treatment
should only follow after referral to tertiary services. Further treatment
may include the use of medication unlicensed for the treatment of ADHD
(such as bupropion, clonidine, modafinil and imipramine
29
) or combina-
tion treatments (including psychological treatments for the parent or
carer and the child or young person). The use of medication unlicensed
for ADHD should only be considered in the context of tertiary services.
10.18.6.5 A cardiovascular examination and ECG should be carried out before start-
ing treatment with clonidine in children or young people with ADHD.
10.18.7 Treatment of adults with ADHD
10.18.7.1 For adults with ADHD, drug treatment
30
should be the first-line treat-
ment unless the person would prefer a psychological approach.
Pharmacological treatment
307
28
Stimulant dose equivalents (mg)
IR-MPH: immediate-release methylphenidate; Concerta XL, Equasym XL and
Medikinet XL: brands of modified-release methylphenidate.
*licensed up to 54 mg.
29
At the time of publication, bupropion, clonidine, modafinil and imipramine did not have UK marketing
authorisation for use in children and young people with ADHD. Informed consent should be obtained and
documented.
30
At the time of publication, methylphenidate, dexamfetamine and atomoxetine did not have UK market-
ing authorisation for use in adults with ADHD. However, atomoxetine is licensed for adults with ADHD
when the drug has been started in childhood. Informed consent should be obtained and documented.
IR-MPH Concerta XL Equasym XL Medikinet XL
10 – 10 10
15 18 – –
20 – 20 20
30 36 30 30
–– – 40
45 54 – –
60 72* 60 –
10.18.7.2 Drug treatment for adults with ADHD should be started only under the guid-
ance of a psychiatrist, nurse prescriber specialising in ADHD, or other clini-
cal prescriber with training in the diagnosis and management of ADHD.
10.18.7.3 Before starting drug treatment for adults with ADHD a full assessment
should be completed, which should include:
● full mental health and social assessment
● full history and physical examination, including:
– assessment of history of exercise syncope, undue breathlessness
and other cardiovascular symptoms
– heart rate and blood pressure (plotted on a centile chart)
– weight
– family history of cardiac disease and examination of the cardio-
vascular system.
● an ECG if there is past medical or family history of serious cardiac
disease, a history of sudden death in young family members or abnor-
mal findings on cardiac examination
● risk assessment for substance misuse and drug diversion.
10.18.7.4 Drug treatment for adults with ADHD should always form part of a
comprehensive treatment programme that addresses psychological,
behavioural and occupational needs. (Key priority)
10.18.7.5 Following a decision to start drug treatment in adults with ADHD,
methylphenidate should normally be tried first. (Key priority)
10.18.7.6 Atomoxetine or dexamfetamine should be considered in adults unrespon-
sive or intolerant to an adequate trial of methylphenidate (this should
usually be about 6 weeks)
31
. Caution should be exercised when prescribing
dexamfetamine to those likely to be at risk of stimulant misuse or diversion.
10.18.7.7 When starting drug treatment, adults should be monitored for side
effects. In particular, people treated with atomoxetine should be observed
for agitation, irritability, suicidal thinking and self-harming behaviour,
and unusual changes in behaviour, particularly during the initial months
of treatment, or after a change in dose. They should also be warned of
potential liver damage in rare cases (usually presenting as abdominal
pain, unexplained nausea, malaise, darkening of the urine or jaundice).
Younger adults aged 30 years or younger should also be warned of the
potential of atomoxetine to increase agitation, anxiety, suicidal thinking
and self-harming behaviour in some people, especially during the first
few weeks of treatment.
10.18.7.8 Where there may be concern about the potential for drug misuse and
diversion (for example in prison services), atomoxetine may be consid-
ered as the first-line drug treatment for ADHD in adults
32
.
Pharmacological treatment
308
31
At the time of publication, methylphenidate, dexamfetamine and atomoxetine did not have UK market-
ing authorisation for use in adults with ADHD. However, atomoxetine is licensed for adults with ADHD
when the drug has been started in childhood. Informed consent should be obtained and documented.
32
Ibid.
Соседние файлы в папке Библиотека им академика М.И. Перельмана