In descending order our patients will die of cancer, heart disease, respiratory disease and stroke—the fourth largest cause of death. Although Scotland has the highest rate of stroke in the UK their incidence of new cerebrovascular disease (CVD) has dropped by nearly 22% in the last 10 years, age standardised mortality rates for CVD have dropped by nearly 42% in the last 10 years and by 5.7% in the last year.2


Acute CVA
Stroke is defined by the World Health Organization as a clinical syndrome consisting of rapidly developing clinical signs of focal (or global in case of coma) disturbance of cerebral function lasting more than 24 hours or leading to death with no apparent cause other than a vascular origin. There has been a huge publicity campaign to educate the public about symptoms of stroke; the FAST test is abnormal in 80% of strokes and it encourages people to assess for stroke and phone 999.
The GP attending an acute stroke patient arranges 999 ambulance transfer to secondary care where the patient will be assessed and transferred to an acute stroke unit. The GP should take a careful history and examination and be prepared to perform resuscitation. The history may be of other atheromatous illnesses or of thunderclap headache.
Hypertension is a leading cause of stroke and smoking, diabetes, high salt intake, obesity, inactivity, alcoholism, atrial fibrillation (AF), hypercholesterolaemia, coagulation disorders including medications are other common risk factors. The GP should check the patient for hypoglycaemia using the practice glucometer and, provided they are not reliant on a hypoxic drive, give oxygen if finger oximetry is below 94%.
On arrival at secondary care the type of stroke is determined by imaging. There are different forms of CT and MRI imaging, which can be undertaken of the brain and carotids, both initially and subsequently, and have provided a lot of information about stroke evolution and tissue necrosis—some of which is salvageable. It is now recognised that a cerebral infarct can undergo secondary haemorrhagic change and it is hoped to predict more accurately those patients who may subsequently haemorrhage after fibrinolytic therapy for ischaemic stroke by scanning.3 The impetus to provide a brain image within one hour is with a view to performing fibrinolysis on suitable ischaemic strokes in order to reduce mortality and morbidity. 85% of strokes are ischaemic due to embolism or thrombosis in arteries, 10% are due to intracerebral haemorrhage (ICH) and 5% are due to subarachnoid haemorrhage (SAH).
Patients suffering an ICH on warfarin require treatment to return their INR to normal using vitamin K and prothrombin complex concentrate (PCC). There is no specific antidote to the novel oral anticoagulants (NOACs) so haematology opinion is required to restore coagulation for these patients. 50% of SAH patients die although outlook is improved if there is a particular aneurysm causing the bleed with neurosurgical intervention by embolisation or surgical clipping within 48 hours.4
Carotid dissection is an unusual cause of stroke occurring in younger patients and sometimes with a history of neck trauma. The treatment is the same as for ischaemic stroke: there is no evidence of increased adversity with fibrinolysis or anticoagulation or antiplatelet therapy. Patients with antiphospholipid syndrome should also be treated in the same way as other patients with ischaemic stroke. Patients with a cerebral venous thrombosis however are treated with anticoagulation by heparin and then warfarin as standard venous thrombosis therapy.4

Ischaemic stroke
Acute ischaemic stroke has a mortality of up to 30% in the first month and is the leading cause of disability in the elderly, affecting a million of the UK population. Of those who survive a stroke 60–70% die within three years.5 Although stroke can occur at any age many of these patients are very elderly; in England and Wales in 2012 about 11,000 people died of cerebrovascular disease aged 75–84 compared to over 18,000 in the 85 plus age group.6
For the majority of patients who arrive in secondary care with their ischaemic stroke there is no evidence that warfarin is helpful and therapy revolves around possible fibrinolysis for a minority and antiplatelet therapy for other patients. Some patients however will be on warfarin due to other conditions (like heart valve disease or AF) and suffer a stroke. The patient’s anticoagulation may have been sub-therapeutic or conversely excessive and action is to ascertain INR levels and brain scan to decide if the patient has an ischaemic stroke or ICH.
Patients already on warfarin who suffer an ischaemic stroke will have less incidence of deep vein thrombosis (DVT) and pulmonary embolism (PE) and recurrent ischaemic stroke but an increase in ICH and other bleeds7 and clinical decision making considers their anticoagulant control and risks. Most of these patients will be transferred to aspirin therapy for 1–2 weeks in order to reduce the risk of ICH during possible haemorrhagic transformation of their ischaemic stroke and then re-anticoagulated with warfarin. This requires an individualised patient risk assessment, which will change over the initial admission days and is the skill of their secondary care specialist.

Fibrinolysis
Fibrinolysis is the current hope for reducing disability but is only administered to 5–6% of patients in the UK with ischaemic stroke.1 Fibrinolysis is given using alteplase, which activates plasminogen to produce plasmin and so degrades fibrin at the thrombus—it was historically the therapy for acute myocardial infarction (MI) prior to percutaneous coronary intervention (PCI).
Ideally fibrinolysis is administered to any suitable ischaemic stroke if there are no contraindications within three hours and to suitable under 80 year olds between three and 4.5 hours and at individual discretion up to six hours after start of the ischaemic stroke.4 Side-effects of altepase are haemorrhage (up to 6%), acute coronary syndrome, pulmonary oedema and arrhythmias. The primary cause of death due to alteplase is ICH and it is not possible to define which patients are most at risk. Cost per treatment is £300–£600.8 It has not been shown to reduce all cause mortality at three months compared to placebo but has been shown to reduce disability.7 After 24 hours patients are started on antiplatelet therapy.
An alternative to fibrinolysis is mechanical clot extraction but NICE states that it has not yet been shown to benefit patients. Patients unsuitable for fibrinolysis who might benefit can be entered into a trail of mechanical thrombectomy after detailed discussion with the patient or carer.9 This prospective trial is starting to recruit and will compare thrombectomy with and without IV alteplase (the PISTE study).
The majority of patients however who suffer an ischaemic stroke will not receive fibrinolysis but will be treated with an antiplatelet agent. This is given within 24 hours and is 300mg of aspirin as a cyclo-oxygenase (COX) inhibitor, orally or if they have swallowing problems either by enteral tube or per rectum. COX inhibition prevents production of prostaglandin, prostacyclin and thromboxane. These factors usually act to cause vasoconstriction, platelet activation and aggregation. The patient then continues with aspirin 300mg a day for two weeks at which time a decision is made to continue an antiplatelet therapy (usually clopidogrel) or change to warfarin if indicated.
Patients with dyspepsia can be tried on a proton pump inhibitor to see if they can tolerate the aspirin. An alternative to early aspirin is clopidogrel, a platelet ADP inhibitor which acts to prevent platelets binding to fibrin. Dipyridamole, a phosphodiesterase inhibitor, blocks metabolism of AMP at vascular endothelium and red cells and prevents platelet aggregation and promotes vasodilation. It can be used alone or combined with aspirin as asasantin retard given twice daily.
For patients post ischaemic stroke the preferred antiplatelet at discharge for GPs to continue is clopidogrel. The CAPRIE study suggested it reduced stroke rates compared to aspirin.5 Clopidogrel is also used in patients with peripheral artery disease, those with multivascular disease and post MI with aspirin or as an option if aspirin is not tolerated. It is a prodrug and is metabolised in the liver via the CYP450 enzyme complex. Although in dyspeptic patients a proton pump inhibitor can be added, omeprazole and esomeprazole are not recommended due to liver interactions reducing its antiplatelet action. Side effects of clopidogrel may be rash, diarrhoea and bleeding and it is contraindicated in liver and renal failure.
If clopidogrel is not tolerated then asasantin retard is an alternative and if this cannot be tolerated then dipyridamole can be used alone. Use of an antiplatelet drug has been shown to reduce stroke by 25 per 1,000 patients treated for 29 months.4
Patients are mobilised early but some may require prophylaxis against venous thromboembolism. 


Patients with TIA
In the UK about 98,000 people have a first ischaemic stroke, about 46,000–65,000 have a TIA and 146,000 have a myocardial infarction per annum.5 A TIA is defined as stroke symptoms or signs which go within 24 hours. The symptoms and signs therefore are identical to a stroke and patients should be immediately admitted from general practice. Sometimes the TIA has resolved and the patient can be assessed as at high or low risk of stroke post TIA using the ABCD2 criteria. There are a maximum of 7 points and a score of 0–3 has a two day risk of stroke of 1% whilst a score of 4 or more has a two day risk of stroke of over 4%10 and requires 300mg of aspirin by the GP and hospital assessment within 24 hours.
At the TIA clinic patients have assessment and treatment of risk factors and carotid artery patency with a view to carotid endarterectomy within two weeks in suitable patients. They receive anticoagulation if in AF or with heart valve disease or other indications. 26% are admitted to a stroke unit. Otherwise patients receive asasantin if tolerated and indicated.
The risk of stroke using a 24 hour rapid access TIA clinic has been reduced to 1.6% at 90 days.7 Patients with recurrent TIAs, even with a low ABCD2 risk score, should be seen urgently by secondary care specialists. Clopidogrel is not currently licensed for use post TIA so NICE suggests asasantin retard or dipyridamole alone for long-term prevention of TIA. Clopidogrel is indicated in patients with multivascular disease.8 However the intercollegiate UK stroke guideline recommends treating ischaemic stroke and TIA in the same way using clopidogrel first line in both. Aspirin alone is not as effective as asasantin retard and combining aspirin and clopidogrel (as used post MI) has not been shown to be superior to aspirin or clopidogrel alone but increases bleeding risk.4


Patients with AF
AF has a prevalence of 0.7% for 55–59 year olds, increasing to 17.8% in the 85 years plus age group with an overall prevalence of 5.5% for the over 55s. AF is the commonest cause of embolic stroke, and patients in AF who present with a TIA or ischaemic stroke have a risk of recurrent ischaemic stroke of 12% in the first year and 5% per year thereafter. Treatment with warfarin reduces this risk from 12% to 4%, treatment with aspirin is less effective.11 There are now a number of NOACs also used in AF antithrombotic therapy.
Patients in AF may complain of dizziness, palpitations, chest discomfort, breathlessness or commonly be asymptomatic. Electronic BP monitors alert GPs, practice nurses and assistant practitioners to irregular pulse rates and so have encouraged detection of asymptomatic AF by GPs but once diagnosed NICE recommends BP measurement in AF patients to be monitored manually.12
Practice investigations include an ECG to ensure AF rather than another arrhythmia, a common differential diagnosis in the elderly is multiple ectopic beats and in order to assess rate. Causes which GPs seek on history and examination are: hypertensive heart disease, heart valve problems, especially mitral rheumatic valve stenosis (common in the past), and thyrotoxicosis. The patient’s medication should be reviewed for arrhythmogenic medications and a history of alcohol excess taken. The patient may have had a recent ACS provoking AF, there is an incidence of silent MI in the elderly and diabetics but there may be changes present on the ECG or a raised troponin.
Sick sinus syndrome, also known as tachy-brady syndrome, due to carotid sinus dysfunction is more common in the elderly and can cause paroxysmal AF interspersed with normal pulse or episodic ventricular pauses. AF can also develop with any lung condition eg. pneumonia, severe illness or post-operatively, especially post-thoracotomy or post-CABG. Further investigation will vary from sending the patient to hospital to exclude ACS to arranging rhythm monitoring and also checking electrolytes and thyroid function tests. Echocardiography may be indicated to exclude a valvular cause as valvular AF is referred to secondary care and requires warfarin therapy usually. Lone AF refers to AF with a normal heart.
70% of ventricular filling occurs passively in diastole so there may be up to 30% reduction in cardiac output due to lack of efficient atrial contraction. In addition if the patient is tachycardic, cardiac output will fall further so the patient may develop heart failure. The treatment of rate problems is to rate limit the heart, often using β-blockers or rate limiting calcium channel blockers (verapamil or diltiazem). The fibrillation of the atria allows thrombus formation in the atria, especially the left atrial appendage, this can then embolise via the left ventricle and aorta to the brain and cause an ischaemic stroke. The rate of stroke in patients with AF who are not anticoagulated is in the range of 6–9% per year.13 Stroke risk is similar among patients with paroxysmal, persistent and permanent AF. Patients with nonvalvular AF are risk stratified
to assess their risk of stroke and need for anticoagulation—for this GPs use CHADS2 as outlined in 2013-4 QOF points AF002, AF003 and AF004.14
NICE is currently updating its AF guideline, collating itx technology appraisals on NOACs, the 2006 NICE AF guidance and almost certainly incorporating the European Society of Cardiology guideline15 for using CHA2DS2-VASc rather than CHADS2. Using CHA2DS2-VASc there are a group of patients with no risk factors who are under 65 years old and do not require anticoagulation. Other patients should be informed of their calculated risk of stroke and offered anticoagulation unless they have contraindications. Patients who have already had an ischaemic stroke, a TIA or other thromboembolism (it is a matter of chance whether the embolism from the AF enters the cerebral or other circulation from the aorta) have a risk of recurrent stroke of 12% pa.14 CHADS2 and CHA2DS2VASc can be downloaded to the practice computer or kept as a free app on a smart phone. A number of apps also assess bleeding risk eg. AF-STROKE app (free).
The NOACs are alternatives to warfarin but aspirin is less effective in stroke prevention, its benefit mainly being related to that on vascular disease. The NOACs currently authorised for use in the UK and USA are dabigatran, rivaroxaban or apixaban.
Patients having cardioversion to sinus rhythm are anticoagulated with warfarin for a few weeks after procedure but if considered at high risk of recurrent AF, anticoagulation is continued indefinitely.
Many of the factors which increase the risk of stroke in AF such as age and hypertension also increase bleeding risk. HAS-BLED16 has become a popular bleeding risk score and incorporates Hypertension, Abnormal renal/liver function, Stroke, Bleeding history or predisposition, Labile INR, Elderly (>65 years), Drugs/alcohol use. It perhaps doesn’t focus on the common GP risk assessments of polypharmacy, diet, bowel function, activities, falls and forgetfulness. Definitions of major bleeding vary between studies and patients. In the HASBLED study the risk of major bleeding in a year for patients with AF on warfarin was 1.5%.
Warfarin reduces the risk of stroke to about 1.4% from an overall risk of 4.5%.17 The risks of major bleeding with warfarin in asymptomatic patients with AF were 1% in the control group and 1.3% on warfarin.14 Most patients in UK and advanced health care nations appear to spend a disappointing “gold standard” of 70% of their time in the therapeutic INR range but some studies report INR control at about 55%: this may reflect both over or under anticoagulation.
In a study comparing dabigatran, the direct thrombin inhibitor, with warfarin the mean age was 71 years old and the mean CHADS2 score 2.18 Dabigatran prevents fibrinogen cleaving to form fibrin, inactivating F13 and preventing platelets aggregating to fibrin. It is liver metabolised and so the dose is reduced in patients on particular drugs like verapamil or amiodarone. The dose is reduced in the elderly. Aspirin was used concomitantly with each drug in about 20% of patients for various reasons. The rate of major bleeding was 3.36% per year in the warfarin group, 2.71% per year in the group on 110mg of dabigatran and 3.11% per year in the group on 150mg of dabigatran. Rates of hemorrhagic stroke were 0.38% per year in the warfarin group, 0.12% per year in the 110mg of dabigatran group and 0.10% per year in the 150mg group. There was more dyspepsia in the dabigatran group (5.8% versus 11.8%) and no differences in numbers of patients with raised ALTs. The rates of stroke or systemic embolisation were low and similar in both groups at <2%. The rates of discontinuation for dabigatran doses are approximated to 21% and for warfarin 17% at two years. NICE has a technology appraisal supporting its use in prevention of ischaemic stroke in patients with AF.19
There are two F10 inhibitors, which prevent the cleavage of prothrombin to form thrombin, licensed for prevention of ischaemic stroke in patients with AF. One is rivaroxaban,20 which is renal excreted and in studies about 14% of people experience adverse reactions. Bleeding occurred in 3.3% and anaemia in 1%. It also can cause a rise in ALT. It’s large trial, ROCKET-AF, compared rivaroxaban to warfarin. Over 50% of patients had suffered previous stroke, TIA or systemic emboli. The rate of recurrent events in the rivaroxaban group was 1.8% and 2.2% in the warfarin group.
Just over 20% of patients stopped their therapy for various reasons before the end of the trial in both groups and there was no significant difference in bleeding events: there was a significant reduction in fatal bleeds and ICH with rivaroxaban but more gastrointestinal bleeds.21 Apixaban is also recommended in AF patients and has a reduced dose for those over 80, patients weighing below 60kg and those with renal impairment. It has been shown to be more effective than warfarin in reducing the incidence of stroke and systemic embolisation and also had a reduced rate of bleeding complications.22


Patients wanting HRT or COC
GPs should consider that the older woman wanting contraception runs a higher risk of ischaemic stroke if taking the combined oral contraception (COC) pill rather than progesterone pill or none-hormonal methods like condoms and IUCD. Women who are on HRT are also at increased risk of ischaemic stroke. Tibolone increases stroke risk. Transdermal HRT may offer a lesser risk to the patient. Given this it seems reasonable that patients who have had a stroke or who are at high risk of stroke and adamant that they want to take the combined pill for contraception or postmenopausal HRT are referred for a specialist assessment.


The last article in this anticoagulant and fibrinolytic series will explore the vast improvements in outcomes for the haemophiliac patient.


Conflict of interest: none declared


References 

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2. Stroke Statistics Update Year Ending 31 March 2012. www.isdscotland.scot.nhs.uk/Health-Topics/Stroke

3. Nour M. and  Liebeskind D S. Brain Imaging in Stroke: Insight Beyond Diagnosis. Neurotherapeutics. 2011; 8(3): 330–39. www.ncbi.nlm.nih.gov 

4. National Clinical Guideline for Stroke prepared by the Intercollegiate Stroke Working Party 4th Edition September 2012. Royal College of  Physicians.

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15. The Task Force for the Management of Atrial Fibrillation of the European Society of Cardiology (ESC). Guidelines for the management of atrial fibrillation. European Heart Journal 2010; 31: 2369–429

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20 Atrial fibrillation (stroke prevention) – rivaroxaban. May 2012. NICE TA256.  www.nice.org.uk

21. Patel M R, Mahaffey K W, Garg J, Pan G et al Rivaroxaban versus Warfarin in Nonvalvular Atrial Fibrillation. N Engl J Med 2011; 365: 883–91

22. Stroke and systemic embolism (prevention, non-valvular atrial fibrillation) – apixaban.  NICE TA 275.February 2013. www.nice.org.uk