Download Stroke long-term management

Vol 3
July/August 2011
Clinical Pharmacist
Stroke
long-term management
By Rowan Tolhurst, DipGPP, and Ian Rowlands,
DipClinPharm, MRPharmS
T
he long-term management of patients who have
suffered a stroke can be divided into two main
areas — managing the sequelae of the stroke and
preventing another vascular event.
In addition to considering what medicines are
appropriate for the long-term management of stroke,
pharmacists must also be aware of practical considerations
around medicines administration. For example, they need
to consider who is going to be administering a patient’s
medicines. Can the patient do it or will he or she need the
help of a carer? Does the patient have issues with manual
dexterity, swallowing or memory, which may affect his or
her ability to effectively and safely take medicines?
SUMMARY
An important component of the long-term treatment of patients who have
suffered a stroke is managing sequelae, including swallowing difficulties,
depression, spasticity, dry mouth and excessive saliva production.
Another key consideration is the prevention of secondary vascular
events. For all types of stroke, good control of blood pressure reduces the
risk of subsequent strokes. For patients who have suffered an ischaemic
stroke, anti-platelet therapy (or anticoagulation in specific circumstances,
such as for patients with atrial fibrillation) and cholesterol reduction are
also important for secondary prevention.
and most effective method of doing so. Speech and
language therapists play a key role in the assessment and
management of swallowing difficulties, and can identify
patients who require input from a pharmacist to help tailor
drug therapy to their swallowing requirements. Speech and
language therapists are also highly involved with patients
who have disorders of saliva production.
Sequelae of stroke
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Swallowing difficulties For many patients who
experience swallowing difficulties (dysphagia) in the acute
phase after stroke, the problem will become chronic.
Stroke is the most common indication for patients
receiving home enteral tube feeding.1 Whatever the care
setting, it is essential that medicines are administered in
the safest way possible. For most drugs used after stroke,
administration via a feeding tube will be off licence. Every
effort should be made to rationalise therapies and to
prescribe the most appropriate formulation to help
administration; proprietary liquids and dispersible tablets
are preferable but few products come in these
formulations. If crushing tablets is the only solution,
ensure that nursing staff or carers are advised on the safest
Excessive saliva production In normal circumstances,
a person with excessive saliva production (sialorrhoea) will
compensate by increasing swallowing.2 For stroke patients,
there may be a loss of control of facial and oral muscles,
which can lead to drooling. If there is co-existing
dysphagia, an increase in saliva production may also put
the patient at an increased risk of aspiration. If patients are
aware that they are drooling then it can be very upsetting
for them, and also for carers and family members.
There is a lack of pharmaceutical options available to
treat sialorrhoea. Antimuscarinics inhibit parasympathetic
stimulation of the salivary glands and reduce salivary
secretion and are the cornerstone of pharmacological
treatment. The application of hyoscine patches can be
effective, but prolonged use may be limited by central side
effects such as confusion and restlessness, especially in
elderly patients and those who require more than one
patch to be applied at a time. Higher doses of hyoscine
may also predispose patients to cardiac effects, namely
Rowan Tolhurst is senior clinical pharmacist for
stroke services at King’s College Hospital NHS
Foundation Trust and Ian Rowlands is lead
pharmacist for stroke services at Imperial College
Healthcare NHS Trust.
E: [email protected]
CLINICAL FOCUS
Dry mouth, depression and spasticity are common sequelae of stroke. Managing these problems and
preventing further vascular events are the main considerations in the long-term care of stroke patients
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Clinical Pharmacist
July/August 2011
Vol 3
tachycardia, which is undesirable in this patient group.
This is an unlicensed indication for hyoscine patches.
Glycopyrronium bromide is believed to have fewer
cardiac and central effects than hyoscine, but oral
glycopyrronium has variable gastrointestinal absorption
and preparations are not readily available in the UK. If
available, glycopyrronium may be started orally at 500µg
one to three times daily and titrated to effect.2 In some
cases, the injectable solution is administered via patients’
feeding tubes, but this is an off-licence use and
inappropriate outside the hospital environment.
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CLINICAL FOCUS
210
Dry mouth About 61% of patients who suffer a stroke will
experience dry mouth (xerostomia).3 Dry mouth can be
caused by reduced innervation of the salivary glands (due
to the stroke), increased mouth breathing or decreased oral
intake. It is also important to consider medicines as a cause
of dry mouth, particularly those with antimuscarinic
activity. Xerostomia can cause patients discomfort,
increase the risk of oral and dental infections and
contribute to swallowing difficulties. Application of
artificial saliva can help relieve symptoms, and meticulous
oral hygiene is essential to prevent infection.
Hypertension is an independent risk factor for recurrent stroke
focal spasticity in one or two joints should be treated with
intramuscular botulinum toxin.5 However, patient access to
this treatment might be limited by the lack of availability
of specialist services to provide it. Some patients will
benefit from skeletal muscle relaxants such as baclofen or
tizanidine, but the use of these medicines is limited by side
effects (particularly drowsiness and a lack of specificity for
the affected muscle groups) and they should only be used
under specialist supervision.
Depression Approximately a third of patients will suffer
from depression after a stroke4 (although this figure may
underestimate the prevalence because it can be hard to
assess mood in patients with communication difficulties or
neurological impairment). Appropriate and effective
treatment of post-stroke depression is essential given the
impact that it may have on a patient’s successful
rehabilitation and, therefore, on the outcome of stroke.
According to the “National clinical guideline for
stroke”, all patients entering stroke rehabilitation should
be screened for depression using a validated tool and
observed regularly during and on finishing rehabilitation
for mood changes.5
Despite the observed frequency of post-stroke
depression, there is a relative lack of data on its treatment.
A Cochrane review on the subject concludes that
antidepressants may have a small but significant treatment
effect on depression after stroke, but that their usage needs
to be balanced against a significantly increased risk of
adverse events.6 Most data are from studies using selective
serotonin reuptake inhibitors, but no consensus is available
on which one of these is the most effective. Although the
evidence base to support treatment is lacking, it is
inappropriate to deny antidepressant treatment to patients
who require it. If indicated, antidepressants can be used
with caution, with patients undergoing regular monitoring
for efficacy and adverse effects. It should also be borne in
mind that patient anxiety may be increased after stroke,
and the initial effects of antidepressant therapy could
worsen this.
Spasticity Spasticity has been estimated to affect 38% of
patients after stroke.7 Increased muscular tone, abnormal
posture and spasms can cause pain, limit the functional
ability of limbs and impair patients’ ability to participate in
rehabilitation and carry out activities of daily living.
The “National clinical guideline for stroke”
recommends that patients who are affected by persistent
❝
IT IS ALSO
IMPORTANT TO
CONSIDER
MEDICINES AS A
CAUSE OF DRY
MOUTH,
PARTICULARLY
THOSE WITH
ANTIMUSCARINIC
ACTIVITY
❞
Seizures Post-stroke seizures are a common problem:
early-onset seizures affect about 2–33% and late-onset
seizures about 3–67% of patients who have suffered an
ischaemic stroke.8 Identification and diagnosis can be
difficult because of the similarity of stroke and seizure
symptoms.
Treatment of post-stroke seizures is controversial.
There is a lack of evidence to support the routine use of
antiepileptic drugs to prevent post-stroke seizures;9
however, if patients suffer recurrent seizures and a
diagnosis of epilepsy is confirmed, it is widely accepted
that treatment should be initiated.
The choice of medicine will depend on the patient, the
type of seizure, the side effect profile of the antiepileptic
drug and any potential interactions with other medicines.
Antiepileptic drugs that cover a broad range of seizure
types, such as sodium valproate and levetiracetam, are
commonly used in practice. Phenytoin is less frequently
used because of drug interactions (particularly with
warfarin) and the perceived increased likelihood of
drowsiness and confusion.
Secondary prevention
People with a history of ischaemic stroke or transient
ischaemic attack (TIA) are at a high risk of all vascular
events, such as myocardial infarction, and are at particular
risk of subsequent stroke — the risk is about 10% in the
first year and 5–7% each year thereafter.10 One in four
strokes are second strokes. Therefore, secondary
prevention measures are an important part of the longterm management of stroke patients.
Antiplatelet medicines All patients who have had an
ischaemic stroke should be considered for antiplatelet
Vol 3
Anticoagulation Warfarin should not be used routinely
for secondary prevention in ischaemic stroke patients.
Clinical trials that have investigated the use of warfarin for
secondary prevention in all ischaemic stroke patients have
not demonstrated any additional benefit with warfarin
treatment compared with aspirin and the incidence of
bleeding is much greater.17,18
However, for patients who have had an embolic
ischaemic stroke, anticoagulation with medicines such as
warfarin is the treatment of choice. (Some newer oral
Clinical Pharmacist
anticoagulants are likely to be licensed for the prevention
of stroke in the near future, see Box 1.)
Cardioembolic strokes account for about 20% of all
ischaemic strokes. Atrial fibrillation (AF) is the most
common cause of cardioembolic stroke (accounting for
12% of ischaemic strokes); other causes include prosthetic
heart valves, infective endocarditis, mural thrombus,
recent myocardial infarction, recent cardiac surgery,
cardiomyopathy and heart failure.
All patients with a history of cardioembolic ischaemic
stroke or TIA should be anticoagulated unless there is a
contraindication to treatment. Several clinical trials have
demonstrated the efficacy of warfarin for stroke prevention
for patients with AF. An analysis of pooled data from five
clinical trials comparing warfarin with placebo for primary
prevention of stroke showed a consistent decrease in the
risk of stroke, with an overall relative risk reduction of
68%.21 The “European atrial fibrillation trial” (EAFT)
confirmed that there was a similar benefit when warfarin
was used in the secondary prevention of stroke.22 Aspirin
has been shown to be less effective than warfarin,
decreasing the relative risk of stroke by 18% and 44%
when using 75mg daily and 300mg daily, respectively.21
The incidence of bleeding was found to be similar with
both doses of aspirin.
There is no evidence to guide when patients should be
anticoagulated after cardioembolic stroke. In EAFT, most
patients were anticoagulated 14 days after the stroke, but
most of these patients had suffered a minor stroke or TIA.22
The early use of anticoagulation for patients who have
suffered a large cardioembolic stroke, with or without
uncontrolled hypertension, may increase the risk of
haemorrhagic transformation of the initial infarct. In
practice, warfarin tends to be started 14 days after the
Box 1: Newer oral anticoagulants
The new factor Xa inhibitors, dabigatran and rivaroxaban, have been shown
to reduce the incidence of stroke for patients with atrial fibrillation (AF).
The RE-LY study compared dabigatran (110mg twice daily and 150mg
twice daily) with dose-adjusted open-label warfarin for stroke prevention in
patients with AF. The lower dose of dabigatran was as effective at
preventing stroke as warfarin and caused less bleeding. The higher dose of
dabigatran was more effective at preventing stroke than warfarin, with a
similar bleeding risk.19
The ROCKET-AF trial was a double-blind study that compared
rivaroxaban with dose-adjusted warfarin in patients with AF; the primary
endpoint was a composite of stroke and non-central nervous system
embolism. Results from the trial showed that rivaroxaban was non-inferior
to warfarin in the prevention of stroke with a comparable bleeding risk;
however, superiority of rivaroxaban over warfarin was not shown.20
The main advantages of factor Xa inhibitors are that they have simpler
dosing regimens and require less monitoring than warfarin. Based on the
above results, both drugs are likely to gain licences for the prevention of
stroke in patients with AF (such a licence for dabigatran is expected
imminently). The National Institute for Health and Clinical Excellence is
currently working on technology appraisals for both drugs for this
indication. Based on concerns surrounding compliance with factor Xa
inhibitors (since less intensive monitoring is required) and the high cost of
the drugs, it is likely that their use will be limited to patients who cannot
tolerate or are unsuitable for warfarin (ie, as a second-line approach).
211
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therapy to prevent secondary vascular events. Current
treatment options include clopidogrel, aspirin and
extended-release dipyridamole, all of which act via
different mechanisms to inhibit platelet aggregation.
The combination of aspirin and extended-release
dipyridamole has long been used for secondary prevention
after ischaemic stroke. The “European stroke prevention
study 2” compared the efficacy of monotherapy with
aspirin or extended-release dipyridamole, and a
combination of the two, with placebo for secondary
prevention of ischaemic stroke. The combination of aspirin
and extended-release dipyridamole reduced the risk of
stroke or death by 24%. The risk was reduced by 13% with
aspirin alone and by 15% with extended-release
dipyridamole monotherapy.11
The PROFESS trial aimed to prove that extendedrelease dipyridamole was non-inferior to clopidogrel
monotherapy for the secondary prevention of stroke, but
the predefined non-inferiority criteria were not met.12 In
addition, clopidogrel is associated with a lower incidence
of adverse effects than the combination of aspirin and
dipyridamole, which frequently causes headaches and
gastrointestinal disturbances.13
The National Institute for Health and Clinical
Excellence issued updated guidance in December 2010
that recommends clopidogrel monotherapy as the firstline agent for the secondary prevention of vascular events
for patients who have had an ischaemic stroke.14 The
combination of aspirin and extended-release dipyridamole
should be considered for patients who have suffered a TIA
or for people with ischaemic stroke in whom clopidogrel is
contraindicated or not tolerated.14 Extended-release
dipyridamole alone is an option for patients with
ischaemic stroke in whom clopidogrel and aspirin are
contraindicated or not tolerated or for patients with TIAs
in whom aspirin is contraindicated or not tolerated.14
The combination of aspirin and clopidogrel is not
routinely used for secondary prevention because the
reduction in vascular events is outweighed by an increased
risk of bleeding.15 However, in patients at high risk of
secondary vascular events, such as those with significant
carotid or cerebral stenosis, the combination of aspirin and
clopidogrel can be used in the short term (up to three
months post-stroke) when the patient is at the highest risk
of having a recurrent event.15,16
Antiplatelet medicines that are prescribed for
secondary prevention are usually started 14 days after the
acute event (ie, after the acute phase antiplatelet course
is complete) and should be continued indefinitely.
Occasionally, antiplatelets may be started earlier if the
patient is discharged from hospital within this period.
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acute event, although it can be started earlier or later
depending on the perceived risk of haemorrhagic
transformation for individual patients.
Cholesterol reduction The evidence for the strokerelated benefits of statin treatment originally came from
sub-group analyses of data from ischaemic heart disease
trials. In these analyses the addition of simvastatin 40mg
daily, irrespective of initial cholesterol levels, decreased
the risk of ischaemic stroke by 25%.23 In the first strokespecific statin trial atorvastatin was shown to decrease the
risk of stroke by 16%; 45 patients would need to be treated
for five years to prevent one stroke.24
Evidence suggests that the protective effects of statins
extend far beyond cholesterol reduction. Statins are
vasoprotective — they increase the bioavailability of nitric
oxide, improve endothelial function, stabilise
microvascular integrity and have anti-inflammatory
effects — which may be partially responsible for the
benefit of statin therapy in stroke prevention.25
However, statins have not been shown to reduce the
incidence of haemorrhagic stroke. Data from the recent
SPARCL study suggest that treatment with high-dose
atorvastatin could increase the risk of haemorrhagic stroke;
however, the statistical significance of the association
could not be determined due to the small number of
patients affected.24 Therefore, statins are not used for
secondary prevention in patients with a history of
haemorrhagic stroke, unless the patient also has
hyperlipidaemia requiring treatment.
Simvastatin 40mg daily remains the treatment of
choice, although cholesterol levels should be reviewed
regularly to ensure total cholesterol is <4mmol/L and low
density lipoprotein cholesterol is <2mmol/L.5 Highintensity statins should be considered if the desired levels
are not achieved.
Hypertension Hypertension is an independent risk factor
for recurrent stroke. The relationship between
hypertension and stroke risk is almost linear — the greater
the blood pressure, the greater the risk of stroke.
The use of perindopril plus indapamide for patients
with previous stroke or TIA over four years was shown to
decrease blood pressure by 12/5mmHg and the relative
risk of stroke by 43%. In this study a similar reduction in
stroke risk was seen for hypertensive and non-hypertensive
patients, and the risk of both ischaemic and haemorrhagic
strokes were reduced.26
Therefore, the use of low-dose antihypertensives
should be considered for all patients, even those who
are normotensive. Tight blood pressure control
(<130/80mmHg) is one of the single most important
interventions for secondary stroke prevention.
reduce microvascular complications (eg, nephropathy and
retinopathy) but there are fewer data on the effect of tight
glycaemic control on macrovascular complications
(including stroke). Analysis of data from randomised trials
suggests that improving glycaemic control will lead to a
reduction in vascular events.27 Although there are no
specific guidelines for the management of diabetes for
patients who have suffered strokes, improving glycaemic
control for these patients is recommended as part of
standard secondary prevention measures.
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