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Stroke
Derek Taylor

Case study and questions

Day 1 Mr DF, a 62-year-old-man, was admitted to hospital after col-

lapsing and experiencing a brief loss of consciousness 3 hours earlier. On
admission he was fully conscious and apyrexial. He had lost voluntary
movement in both his left arm and his left leg. His blood pressure was
160/100 mmHg. His previous medical history included hypertension, for
which he had been prescribed bendroflumethiazide 2.5 mg daily for 6
years. He had also been on carbamazepine 400 mg twice a day for 10 years
for epilepsy. He lived at home with his wife, and smoked 15 cigarettes per
day and occasionally drank alcohol.
His serum biochemistry results were:

■ Sodium 137 mmol/L (reference ■ Urea 4.7 mmol/L (2.5–7.0)

range 135–145) ■ Creatinine 95 micromol/L
■ Potassium 4.9 mmol/L (3.5–5.0) (50–130)

A diagnosis of ischaemic stroke was made. Mr DF was prescribed

aspirin 300 mg orally and transferred to the Acute Stroke Unit. A computed
tomography (CT) scan was ordered.

Q1 What risk factors did Mr DF have for developing a stroke?

Q2 What is the rationale for ordering a CT scan?
Q3 When should aspirin be administered if benefit is to be obtained and what
dose should be given?
Q4 Should Mr DF be prescribed prophylaxis against peptic ulceration?
Q5 What other agents, apart from aspirin, have been shown to be of benefit in
the treatment of ischaemic stroke?
Q6 Would Mr DF be a suitable candidate for a thrombolytic agent?
Q7 What metabolic parameters should be monitored closely?
Q8 What supportive treatment does Mr DF require?
Q9 Should the carbamazepine therapy be discontinued?
Q10 How should Mr DF’s hypertension be managed?
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Day 3 Mr DF was still experiencing loss of movement and hemiplegic

pain in his left arm and leg. He also had difficulty swallowing and was
therefore referred to the physiotherapist, speech and language therapist
and dietitian. A nasogastric tube was inserted.

Q11 Outline a pharmaceutical care plan for Mr DF.

Q12 How would you recommend his pain be managed?
Q13 What other complications associated with his stroke might Mr DF
experience?
Q14 What problems might occur when administering Mr DF’s medication via
the nasogastric tube?
Q15 What advice would you give to the nursing staff to overcome these
problems?

Day 9 Mr DF was transferred to a rehabilitation ward. His blood pressure

was 150/100 mmHg and he was therefore prescribed perindopril 2 mg
daily. His serum cholesterol level was 5.2 mmol/L.

Q16 Should Mr DF be started on warfarin?

Q17 What are the alternative antiplatelet agents to aspirin?
Q18 What is the rationale for the initiation of an angiotensin-converting enzyme
inhibitor (ACEI)?
Q19 Should a statin be prescribed for Mr DF?

Day 23 Mr DF’s swallow reflex had partially returned. Therefore, he was

started on a puréed diet during the day and given fluids overnight via the
nasogastric tube.

Day 44 Mr DF had regained most of his limb function and his swal-
low reflex had almost fully returned. His nasogastric tube was therefore
removed and he was discharged home on a soft diet. His medication on
discharge was:

■ Clopidogrel 75 mg orally daily ■ Amitriptyline 50 mg tablet at

■ Bendroflumethiazide 2.5 mg night
orally daily ■ Perindopril tablets 4 mg daily
■ Carbamazepine suspension ■ Simvastatin 40 mg at night
400 mg twice a day

Q20 What lifestyle changes would you recommend?

Q21 How could the pharmacist contribute to Mr DF’s discharge?
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Answers

What risk factors did Mr DF have for developing a stroke?

A1 Hypertension, smoking and gender.

Hypertension is the major risk factor for stroke. Current trial data suggest
that lowering blood pressure by 5–6 mmHg diastolic and 10–12 mmHg
systolic for 2–3 years may reduce the annual risk of stroke from 7% to
4.8%. Smoking increases the risk of stroke by around 50% and men are
25–30% more likely to have a stroke than women.
Other risk factors, which are not present in Mr DF, include alcohol
abuse, drug abuse, cardiovascular disease (especially atrial fibrillation),
diabetes mellitus, migraine headaches and previous transient ischaemic
attacks.
What is the rationale for ordering a CT scan?

A2 To differentiate between an ischaemic stroke and a haemorrhagic

stroke.
In all, 69% of strokes are the result of an infarct in the brain (ischaemic),
13% are due to intracerebral haemorrhage, 6% due to subarachnoid
haemorrhage, with the remaining 12% being of uncertain type. A haem-
orrhagic stroke must be excluded by brain imaging before the prescribing
of thrombolytics or anticoagulants can be considered.

When should aspirin be administered if benefit is to be obtained and

what dose should be given?

A3 Aspirin 150–300 mg orally should be given within 24 hours.

The rationale for aspirin treatment in the acute phase of ischaemic stroke
is to prevent further occlusion of blood supply to surrounding areas of
brain tissue. A dose of 150–300 mg aspirin should be administered as
soon as possible after the onset of stroke symptoms if a diagnosis of
haemorrhage is considered unlikely. The initial diagnosis of an ischaemic
stroke is a clinical decision, and studies have shown that aspirin may be
administered before a brain scan has been undertaken; however, a brain
scan must always be undertaken before commencing anticoagulation
or thrombolysis, due to the significantly increased risk of intracerebral
haemorrhage with these therapies.
This use of aspirin is supported by two large studies of the treatment
of acute ischaemic stroke: the International Stroke Trial (IST) and the
Chinese Acute Stroke Trial (CAST). In the IST, those patients treated
with aspirin 300 mg daily for 14 days had significantly fewer recurrent
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ischaemic strokes (2.8% versus 3.9%, 2P < 0.001) and no significant excess
of haemorrhagic strokes (0.9% versus 0.8%) within 14 days, compared
with placebo. However, the reductions in deaths within 14 days (9.0%
versus 9.4%) and the numbers of patients dead or dependent after 6
months (62.2% versus 63.5%, 2P = 0.07) were not significant. In the
CAST, those patients treated with aspirin 160 mg/day for up to 4 weeks
(started within 48 hours of stroke onset) showed a small but significant
reduction in recurrent ischaemic stroke rate (1.6% versus 2.1%, 2P = 0.01)
and a non-significant increase in haemorrhagic strokes (1.1% versus 0.9%,
2P > 0.1) after 4 weeks, compared with placebo. Overall mortality in the
CAST, after 4 weeks, was shown to fall from 3.9% to 3.3% (2P = 0.04).
The authors concluded that, when the results of these two studies are
combined, aspirin started early in hospital produces a small but definite
net benefit, with about nine fewer deaths or non-fatal strokes per 1000
patients in the first few weeks (2P = 0.001) and about 13 fewer dead or
dependent per 1000 patients at 6 months (2P < 0.01).
In line with the evidence from these trials, aspirin should be
administered at a dose of 150–300 mg daily for at least the first 14 days
after an ischaemic stroke. After this period, long-term antithrombotic
treatment should be initiated. People being discharged before 2 weeks
have elapsed can be started on long-term antithrombotic treatments at
the point of discharge.

Should Mr DF be prescribed prophylaxis against peptic ulceration?

A4 No.
Mr DF does not have a history of peptic ulcer disease. The incidence of
major gastrointestinal bleeds with aspirin, at the doses used for cardio-
vascular protection, is 2–3%. There is still some debate over the relative
risk-to-benefit ratio (for gastrointestinal bleeds) between using higher
doses (>300 mg) and lower doses (<150 mg) of aspirin.
If prophylaxis is required, a maintenance dose of a proton pump
inhibitor (PPI) may be prescribed, e.g. lansoprazole 15 mg daily. The
current National Institute for Health and Clinical Excellence (NICE)
guidelines recommend the use of low-dose PPI therapy for patients with a
history of ulcers but not for those patients with a history of dyspepsia.

What other agents, apart from aspirin, have been shown to be of benefit
in the treatment of ischaemic stroke?
A5 Thrombolytic agents.

The rationale behind the use of thrombolytics in the acute phase of an

ischaemic stroke is to accelerate reperfusion of the affected area in the
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brain. A number of multicentre clinical trials in recent years (e.g. NINDS,

ECASS-I, ECASS-II, Atlantis-A and B, CASES and SITS-MOST) have shown
significant benefit from alteplase, especially when administered within
3 hours of onset of stroke symptoms. However, the use of thrombolysis
in the treatment of acute ischaemic stroke is dependent on patients
reaching hospital as soon as possible, and the availability of out-of-hours
CT scanning to confirm the diagnosis.
In the National Institute of Neurological Disorders and Stroke rt-PA
Stroke Study Group Trial, patients who received alteplase (0.9 mg/kg to a
maximum dose of 90 mg) within 3 hours of ischaemic stroke onset were
shown to have a significantly better outcome (no or minimum disability)
at 3 months than those who received placebo. There was, unfortunately,
no significant reduction in mortality at 3 months (17% in the alteplase
group and 21% in the placebo group; P = 0.30). Trials with streptokinase
have been stopped early due to an increased incidence of early death in
patients, usually due to cerebral haemorrhage.
The IST indicated that the use of heparin did not confer any benefit
in the treatment of acute ischaemic stroke. In this trial, subcutaneous
heparin 5000 international units twice daily and 12 500 international
units twice daily were compared with placebo. Heparin therapy produced
a non-significant reduction in mortality within 14 days (9.0% versus 9.3%)
compared with placebo. Patients receiving heparin had significantly fewer
recurrent ischaemic strokes within 14 days (2.9% versus 3.8%, 2P =
0.005) but this was offset by a similar-sized increase in haemorrhagic
strokes (1.2% versus 0.4%, 2P < 0.00001). When compared with the low-
dose heparin regime, heparin 12 500 international units twice daily was
associated with significantly more transfused or fatal extracranial bleeds,
more haemorrhagic strokes, and more deaths or non-fatal strokes within
14 days (12.6% versus 10.8%, 2P = 0.007). Perhaps as a result of this,
at 6 months the number of patients dead or dependent was identical to
placebo (62.9%).

Would Mr DF be a suitable candidate for a thrombolytic agent?

A6 Thrombolysis can be administered up to 6 hours from the onset

of symptoms. Provided Mr DF has access to urgent brain scanning
and he has no other contraindications, he could be a candidate
for thrombolysis.

Mr DF did not present to hospital until 3 hours after the onset of his
symptoms. The product licence and the Royal College of Physician’s
National Clinical Guidelines for Stroke state that thrombolytic treatment
with a tissue plasminogen activator (tPA) should only be given if the
following criteria are met: tPA is administered within 3 hours of onset of
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stroke symptoms; haemorrhage has definitely been excluded (by CT scan);

and the patient is in a specialist centre with appropriate experience and
expertise in thrombolytic use. However, two recently published clinical
trials, ECAS-III and IST-3, have demonstrated the effectiveness of alteplase
given to patients with acute ischaemic stroke within 3–4.5 hours and
within 6 hours of symptom onset respectively.

What metabolic parameters should be monitored closely?

A7 Mr DF’s state of hydration, blood glucose level, temperature,

oxygenation and blood pressure.

(a) Hydration. His fluid balance, urea, creatinine and sodium levels
should be monitored closely. Excessive hydration can result in
hyponatraemia, which can force fluid into neurones and therefore
exacerbate damage from ischaemia. Hyponatraemia can also lead to
seizures, which may further affect the damaged neurones.
(b) Blood glucose level. Hypoglycaemia may lead to significantly worse
clinical outcomes. It is therefore important that Mr DF’s blood
glucose levels are kept within the normal range.
(c) Temperature. Any pyrexia, such as that linked with infection,
should be controlled with paracetamol, a fan and treatment of
the underlying cause.
(d) Oxygenation. The routine use of supplemental oxygenation is not
recommended and Mr DF should only receive supplemental oxygen
if his oxygen saturation falls below 95%.

What supportive treatment does Mr DF require?

A8 He requires assessment of his level of consciousness, swallow

reflex, pressure sore and venous thromboembolism risk, nutri-
tional status, cognitive impairment, moving and handling needs,
and bladder and bowel management needs.

These parameters should be assessed and undertaken by suitably trained

staff as part of the formal admission procedure. Those patients with
identified swallowing needs should then have a specialist assessment of
swallowing, ideally within 24 hours, but no more than 72 hours after
admission. If Mr DF is unable to take adequate nutrition orally he should
receive early tube feeding with a nasogastric tube, ideally within 24 hours
of admission.
Dysphagia is common and occurs in about 45% of all stroke patients
admitted to hospital. It is associated with more severe strokes and worse
outcome. The presence of aspiration may be associated with an increased
risk of developing pneumonia after stroke. Malnutrition is also common
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and is found in about 15% of all patients admitted to hospital, increasing

to about 30% a week after admission.
Venous thromboembolism often occurs in the first week of a stroke,
most often in immobile patients with paralysis of the leg, but its impact
after stroke is still unclear. Studies have shown that deep-vein thrombosis
(DVT) occurs in up to 50% of patients with hemiplegia but clinically
apparent DVT probably occurs in fewer than 5%. Similarly, although
autopsy has identified pulmonary embolism (PE) in a large percentage of
patients who die, clinically evident PE occurs in only 1–2% of patients.
To minimise the risk of venous thromboembolism patients should be
adequately hydrated and mobilised as soon as possible following an
appropriate assessment (e.g. sitting balance and falls risk). The effective-
ness of compression stockings in the acute post-stroke phase is still being
assessed in clinical trials. Prophylactic anticoagulation should not be rou-
tinely used in either the acute or rehabilitation phases as it increases
the risk of cerebral haemorrhage; however, if a venous thromboem-
bolism has been diagnosed clinically, anticoagulant treatment should
be started.
Most patients presenting with moderate to severe stroke are inconti-
nent at presentation and may still be incontinent on discharge. This is a
major burden on carers and may impede rehabilitation. Management of
both bladder and bowel problems must therefore be seen as an essential
part of the rehabilitation process.

Should the carbamazepine therapy be discontinued?

A9 No.
Seizures may occur in up to 20% of stroke patients and, with his history
of epilepsy and the dangers of fitting in the acute post-stroke phase, Mr
DF should be continued on his carbamazepine therapy. He should remain
on the same dose but it should be administered using the suspension
formulation.
How should Mr DF’s hypertension be managed?

A10 Mr DF should be maintained on his bendroflumethiazide. There

should be no further attempts to reduce his blood pressure in the
acute phase of his stroke, unless his blood pressure continues to
increase.
Caution should be exercised in controlling Mr DF’s blood pressure acutely,
because decreasing the blood pressure too rapidly will compromise cere-
bral blood flow and expand the region of ischaemia and infarction,
whereas hypertension will place him at greater risk for cerebral haemor-
rhage, especially if a thrombolytic agent is used. Therefore, blood pressure
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manipulation is only recommended in acute stroke where there is a

hypertensive emergency or the patient has a serious concomitant med-
ical condition such as hypertensive encephalopathy, aortic dissection,
hypertensive nephropathy, pre-eclampsia, hypertensive cardiac failure or
in intracerebral haemorrhage with systolic blood pressure >200 mmHg.

Outline a pharmaceutical care plan for Mr DF.

A11 The pharmaceutical care plan for Mr DF should include the fol-
lowing:

(a) Antiplatelet therapy:

(i) Ensure antiplatelet agent is continued daily at the current dose.
(ii) Monitor for signs of gastric irritation.
(b) Dysphagia:
(i) Determine his swallow reflex after liaison with the speech and
language therapist.
(ii) Assess suitable alternative formulations if an enteral feeding
tube is in place.
(iii) Check timing of medication doses if on an enteral feed.
(c) Hypertension:
(i) Regular monitoring of blood pressure.
(ii) The optimal target blood pressure (in the rehabilitation
phase) for those patients with established cardiovascular
disease is 130/80 mmHg, with a maximum blood pressure of
140/90 mmHg.
(iii) Do not increase doses or prescribe new doses of antihyperten-
sives until at least 7 days after the initial stroke.
(d) Aggravating drug therapy. Centrally acting drugs should be avoided
if possible as they may compromise memory and cognition.
(e) Monitor other parameters:
(i) Urea and electrolytes.
(ii) Blood glucose.
(iii) Temperature.

How would you recommend his pain be managed?

A12 If the pain is genuinely a hemiplegic pain, a low dose of amitripty-

line should be prescribed.

It is very important that the correct cause of the pain is diagnosed. Other
possible causes of post-stroke limb problems may be muscular, spasticity or
joint-related. These types of pain may respond to careful manipulation and
physiotherapy. Appropriate medication, such as paracetamol, baclofen
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or intra-articular injections, may also be prescribed for each of these

problems, respectively.
If the pain is central in origin, a low dose of amitriptyline, e.g. 25 mg
at night, may be prescribed. This should be titrated at 25-mg intervals every
week, according to response. The patient should be monitored closely for
any signs of central nervous system suppression and therapy should not
be commenced until the patient is medically stable. Alternative options
include carbamazepine (which Mr DF is already on) or gabapentin.

What other complications associated with his stroke might Mr DF

experience?

A13 Agitation, delirium, stupor, coma, cerebral oedema, pneumonia,

pulmonary oedema, DVT, arrhythmias and depression.

Pneumonia, pulmonary oedema, DVT and arrhythmias after an ischaemic

stroke may be related to further infarction, haemorrhage or cerebral
oedema. Pneumonia and DVT are further exacerbated by inactivity, hence
the need to mobilise Mr DF as soon as possible.
Stroke patients often experience psychological reactions. The most
common reaction is depression, which occurs in 40–50% of patients.
If this depression interferes with recovery and rehabilitation, a selective
serotonin reuptake inhibitor may be prescribed.

What problems might occur when administering Mr DF’s medication via

the nasogastric tube?

A14 Carbamazepine may bind to the feeding tube and interact with
the enteral feed.
The first option when selecting alternative formulations for administra-
tion is to use a commercially available oral solution or dispersible tablet.
If this is not an option, the next step is to crush and fully disperse the
contents of the tablet or capsule. This should not be done with enteric-
coated or modified-release preparations as it may result in changes in
bioavailabilty with dangerous peaks or troughs, or blockage of the tube.
Carbamazepine suspension may bind to the material of the enteral
tubing or interact with the enteral feed itself. Both of these effects may
alter the bioavailabilty and clinical effectiveness of the medication.

What advice would you give to the nursing staff to overcome these
problems?

A15 The feed should be stopped at least 1 hour before the dose.
The carbamazepine suspension should be diluted with at least
30–60 mL of water and the tube flushed with at least an equal
volume after the dose. The enteral feed should not be restarted
until 2 hours after the dose.
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Should Mr DF be started on warfarin?

A16 No.
Anticoagulation should only be considered for patients whose ischaemic
stroke is believed to be cardioembolic in origin, e.g. those in valvular or
non-valvular atrial fibrillation. It should not be started until intracerebral
haemorrhage has been excluded by brain imaging, and usually only
after 14 days have elapsed. Meta-analysis of several trials into the use
of warfarin have suggested a relative risk of stroke in patients receiving
warfarin of 0.33 compared with placebo. This means that only one-third as
many strokes occurred in patients receiving warfarin compared with those
receiving placebo. There also appears to be a relative risk for deaths from
causes other than stroke of 0.57 in patients receiving warfarin compared
with placebo.

What are the alternative antiplatelet agents to aspirin?

A17 Clopidogrel or dipyridamole.

Current NICE guidelines recommend that clopidogrel should be pre-

scribed for all first-time ischaemic stroke patients. In those patients who
have had a transient ischaemic attack or if clopidogrel is contraindicated
or not tolerated, aspirin in combination with modified-release dipyri-
damole should be prescribed. The results of the PROFESS trial showed
that, while the reduction in further strokes was similar between clopi-
dogrel monotherapy and the aspirin and dipyridamole combination, the
incidence of major bleeding and adverse effects was significantly higher
with the combination of aspirin and dipyridamole compared with clopi-
dogrel monotherapy. Therefore, Mr DF should have his aspirin therapy
discontinued and clopidogrel 75 mg once a day added to his medication
regime once the acute phase of his stroke had finished (i.e. after the first
14 days post-stroke).
There is currently no evidence to support the combination of aspirin
and clopidogrel for routine secondary prevention after an ischaemic
stroke. The MATCH study demonstrated that a combination of aspirin
and clopidogrel did not produce a significantly greater reduction in
the risk of secondary stroke events compared with either agent as
monotherapy; however, the combination did produce a significantly
greater risk of life-threatening bleeding compared with either agent
as monotherapy.

What is the rationale for the initiation of an angiotensin-converting

enzyme inhibitor (ACEI)?

A18 To reduce the risk of Mr DF suffering a further stroke.

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The management of Mr DF’s hypertension should now be a priority,

with a target blood pressure of 130/80 mmHg; however his blood pressure
should only be reduced gradually and additional antihypertensives are
not normally prescribed until at least 7 days after a stroke as a sudden
drop in blood pressure could impair cerebral perfusion, which may impair
consciousness or result in further infarction.
In the PROGRESS study the combination of an ACEI (perindopril)
and a thiazide diuretic (indapamide) produced a stroke risk reduction of
43% compared with placebo in both hypertensive and non-hypertensive
patients. As Mr DF is already on bendroflumethiazide and still hyperten-
sive on day 9, it was decided to add in perindopril 2 mg daily and titrate
the dose upwards slowly as needed.
There is still debate as to whether the reduction in stroke risk
observed in the trial is a class effect, an effect unique to perindopril or
just the result of aggressive lowering of blood pressure. In the HOPE
study, ramipril reduced the risk of stroke by 33% in high-risk patients
with vascular disease or diabetes and one other risk factor. The resultant
cardiovascular benefit was greater than that attributable to a decrease in
blood pressure; however, HOPE was not specifically designed to examine
the prevention of further strokes after an initial stroke.

Should a statin be prescribed for Mr DF?

A19 Yes.
The Royal College of Physicians Stroke Guidelines state that a statin
should be considered for all patients with a total serum cholesterol
> 3.5 mmol/L following stroke. This statement is supported by the results
of the Heart Protection Study, in which simvastatin 40 mg daily led to
a relative risk reduction of about one-quarter in all groups of patients,
irrespective of their baseline serum cholesterol level.

What lifestyle changes would you recommend?

A20 Smoking cessation, reduction of alcohol intake, weight reduction

and moderate regular exercise.

Mr DF should be advised about the availability and use of nicotine

replacement therapy. A reduction in alcohol intake, regular, moderate
exercise and dietary advice may also reduce his cardiovascular risk.

How could the pharmacist contribute to Mr DF’s discharge?

A21 The pharmacist can contribute to the discharge by providing

pharmaceutical advice and support to the patient and carers.
There should also be effective liaison with his general practitioner
(GP) and community pharmacist.
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The pharmacist can contribute to Mr DF’s discharge in the following ways:

(a) Counselling. Mr DF should be given both written (patient informa-

tion leaflets and a reminder chart) and verbal information regarding
the purpose and use of his medicines. The importance of long-term
antiplatelet therapy and good control of his blood pressure and
cholesterol level should be stressed. Early treatment of acute stroke
appears to be the most important factor in determining outcome;
therefore Mr DF and his carers should be carefully instructed to seek
urgent medical attention if he experiences any weakness or paralysis,
speech impairment, numbness, blurred or sudden loss of vision or
altered level of consciousness.
(b) Compliance assessment. This must be assessed in the light of any
existing impairment of his manual dexterity or cognitive function as
a result of the stroke. Mr DF still has some restriction in movement in
his arm, which may impair the opening of his medication containers.
The use of any compliance aids must be with the consent of Mr DF
and his carers.
(c) Liaison with his GP and community pharmacist. Information
regarding medication changes (i.e. the prescribing of clopidogrel,
perindopril, simvastatin and amitriptyline), alternative formulations
of medicines (i.e. the carbamazepine suspension), nutritional prod-
ucts and compliance aids should be communicated to the patient’s
GP and community pharmacist.
(d) Liaison with patient support groups. Mr DF should be given
contact information for organisations that provide support and
information to both patients and carers, e.g., the Stroke Association,
Different Strokes and the National Stroke Association.

Further reading
CAST (Chinese Acute Stroke Trial) Collaborative Group. CAST: randomised
placebo-controlled trial of early aspirin use in 20 000 patients with
ischaemic stroke. Lancet 1997; 349: 1641–1649.
Clark WM, Wissman S, Albers GW et al. Recombinant tissue-type plasminogen
activator (alteplase) for ischaemic stroke 3 to 5 hours after symptom
onset. The ALTANTIS Study: a randomised controlled trial. Alteplase
Thrombolysis for Acute Noninterventional Therapy in Ischemic Stroke.
J Am Med Assoc 1999; 282: 2019–2026.
Diener HC, Bogusslavsky J, Brass LM et al. Aspirin and clopidogrel com-
pared with clopidogrel alone after recent ischaemic stroke or transient
ischaemic attack in high-risk patients (MATCH): randomised, double-
blind, placebo-controlled trial. Lancet 2004; 364: 331–337.
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Hacke W, Kaste M, Fieschi C et al. Intravenous thrombolysis with recombinant

tissue plasminogen activator for acute hemispheric stroke. The European
Cooperative Acute Stroke Study (ECASS). J Am Med Assoc 1995; 274:
1017–1025.
Hacke W, Kaste M, Fieschi C et al. Randomised double-blind placebo-
controlled trial of thrombolytic therapy with acute ischaemic stroke
(ECASS-II). Second European–Australian Acute Stroke Study Investiga-
tors. Lancet 1998; 352: 1245–1251.
Hacke W, Kaste M, Blumhki E et al. Thrombolysis with Alteplase 3 to 4.5
Hours after Acute Ischemic Stroke (ECASS-III). N Engl J Med 2008; 359:
1317–1329.
Heart Outcomes Prevention Evaluation Study Investigators. Effects of an
angiotensin-converting-enzyme inhibitor, ramipril on cardiovascular
events in high-risk patients. N Engl J Med 2000; 342: 145–153.
Hill MD, Buchan AM and Canadian Alteplase for Stroke Effectiveness Study
(CASES) Investigators. Thrombolysis for acute ischaemic stroke; results
of the Canadian Alteplase for Stroke Effectiveness Study. Can Med Assoc
J 2005; 172: 1307–1312.
Intercollegiate Working Party for Stroke. National Clinical Guidelines for Stroke,
3rd edn. Royal College of Physicians, London, 2008.
International Stroke Collaborative Group. The International Stroke Trial (IST):
a randomised trial of aspirin, subcutaneous heparin, both, or neither
among 19 435 patients with acute ischaemic stroke. Lancet 1997; 349:
1569–1581.
International Stroke Collaborative Group. The benefits and harms of intra-
venous thrombolysis with recombinant tissue plasminogen activator
within 6 h of acute ischaemic stroke (the third International Stroke Trial
[IST-3]): a randomised controlled trial. Lancet 2012; 379: 2352–2363.
MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin
in 20 536 high-risk individuals; a randomised placebo-controlled trial.
Lancet 2002; 306: 7–22.
PROFESS Study Group. Aspirin and extended release dipyridamole versus
clopidogrel for recurrent stroke. N Engl J Med 2008; 359: 1238–1251.
PROGRESS Collaborative Group. Randomised trial of a perindopril-based
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