Keywords: Anti-platelet; ischaemic stroke; TIA Replaces: Version 3

Transcription

1 Title: Protocol for the use of anti-platelet therapy following ischaemic stroke and transient ischaemic attack (TIA): Secondary prevention of recurrent stroke and other occlusive vascular events Authors Name: Dr Jane Wainwright Updated by: Karen Inston (Stroke Pharmacist) June 2011 Contact Name: Dr Jane Wainwright Contact Phone No: Ext Departments/Groups This Document Applies to: Neurosciences Scope: Trustwide Classification: Protocol Keywords: Anti-platelet; ischaemic stroke; TIA Replaces: Version 3 To be read in conjunction with the following documents: National Institute for Health and Clinical Excellence Clopidogrel and Modified Release Dipyridamole for the Prevention of Occlusive Vascular Events. Review of NICE technology appraisal no. 90. December Available at Unique Identifier: 184TD(C)37 Review Date: June 2013 Issue Status: Approved Issue No: 4 Issue Date: July 2011 Authorised by: Medicines Management Group (MMG) Authorisation Date: June 2011 Document for Public Display: Yes After this document is withdrawn from use it must be kept in an archive for 10 years. Archive: Stroke Date added to Archive: Officer responsible for archive: Page 1 of 18

2 Policy Statement These guidelines are intended to clarify and guide the selection of the most appropriate antiplatelet agent after ischaemic stroke and transient ischaemic attack (TIA), and are based on the best available evidence at the present time. However it remains the responsibility of anyone prescribing these drugs to ensure there are no additional contraindications to the medicines prescribed. If advice is needed this can be sought from the authors or a clinical pharmacist. 1. Guidelines 1.0 Introduction Patients who have suffered an ischaemic stroke or TIA are at high risk of another vascular event, primarily recurrent stroke, but also other occlusive vascular events like myocardial infarction. Secondary prevention is based on warfarin therapy for selected patients with cardioembolic strokes (most frequently atrial fibrillation) and antiplatelet agents for other aetiologies. In addition, vascular risk factors such as arterial hypertension, hyperlipidaemia, diabetes and smoking should be addressed appropriately. These guidelines are for the use of antiplatelet therapy after ischaemic stroke or TIA. They do not apply to the treatment of haemorrhagic stroke. A separate protocol should be referred to for patients who are eligible for thrombolysis. 1.1 Recommendations Acute phase: aspirin 300 mg daily Aspirin should be given as soon as possible after the onset of ischaemic stroke, but certainly within 48 hours, after haemorrhage has been excluded by appropriate brain imaging. If the patient cannot swallow, it can be given rectally. The dose is 300 mg daily for the first 14 days following nonhaemorrhagic stroke. If the neurological deficit resolves within 24 hours (this is classified as TIA), aspirin 300mg should be discontinued after the first dose and treatment should be changed to a combination of modified release dipyridamole and aspirin (as Asasantin retard 1 capsule twice daily). Patients presenting within up to 6 hours post onset of symptoms might be eligible for thrombolysis: they should not receive aspirin until the stroke physician has confirmed they will not be receiving thrombolysis. Page 2 of 18

3 For those patients who are thrombolysed, aspirin 300mg daily should be initiated 24 hours post thrombolysis provided that a repeat CT scan has excluded haemorrhage. If patients are in atrial fibrillation, full anticoagulation with heparin or warfarin should usually be started no earlier then 14 days after the onset of symptoms. Aspirin 300 mg daily should be used initially. Exceptions are patients whose neurological deficit resolves quickly (i.e. TIA) or who are thought to have only a small area of infarction based on the CT scan and/or clinical picture. Anticoagulation can be started earlier on an individual basis in these patients. Aspirin 300mg should be continued until a therapeutic INR is achieved (i.e. INR>/=2.0). Patients who are already on warfarin for atrial fibrillation should usually be given aspirin 300 mg daily for up to 14 days before warfarin treatment is continued. Anticoagulant treatment is normally withheld during this time to prevent haemorrhagic transformation of an infarct. Note that the exact timing of re-introduction of warfarin may vary depending on the severity of the stroke and the balance of other risk factors. Aspirin 300mg should be continued until a therapeutic INR is achieved (i.e. INR>/=2.0). Patients who are on warfarin for mechanical prosthetic heart valves will need to stay anticoagulated. This can be warfarin, low molecular weight heparin or unfractionated heparin, but the method should be discussed with the stroke consultant and /or cardiologist in every case. Patients with true aspirin hypersensitivity or intolerance should receive clopidogrel 75 mg daily after an initial loading dose of 300mg Evidence Aspirin is the only antiplatelet agent that has been evaluated for the treatment of acute ischaemic stroke. The International Stroke Trial, IST (1) and the Chinese Acute Stroke Trial, CAST (2) have established that early aspirin provides benefit with regards to reduction of death and thromboembolic complications. In these trials, aspirin led to the avoidance of approximately 9 nonfatal strokes or deaths for every 1000 early-treated patients. The effects were similar in patients with or without atrial fibrillation. The early use of anticoagulation reduces the incidence of recurrent ischaemic stroke and pulmonary emboli. However, this benefit is offset by an increase in intracranial and major extracranial haemorrhage (3), and is thus not routinely recommended Secondary prevention: Page 3 of 18

4 Current NICE guidelines (4) recommend clopidogrel 75mg daily to prevent not related to atrial fibrillation. Modified-release dipyridamole in combination with aspirin (Asasantin retard) is recommended as an option to prevent : for people who have had a transient ischaemic attack (TIA) or for people who have had an ischaemic stroke only if clopidogrel is contraindicated or not tolerated. Modified-release dipyridamole alone is recommended as an option to prevent for: people who have had an ischaemic stroke only if aspirin and clopidogrel are contraindicated or not tolerated or for people who have had a TIA only if aspirin is contraindicated or not tolerated. Patients who are in atrial fibrillation (chronic or paroxysmal) should be anticoagulated with a target INR of 2.5. Patients with atrial fibrillation who have contraindications to anticoagulation should receive aspirin at 300 mg daily long term, as lower doses are not effective in this setting (5). See appendix 1 for a treatment summary Summary of Evidence The NICE review of technology appraisal no. 90 published in December 2010 (4) updated its recommendations for antiplatelet therapy for the secondary prevention of based on the evidence from four randomised controlled trials (RCTs) CAPRIE (6), ESPS-2 (7), ESPRIT (8) and PRoFESS (9). The superiority of modified-release dipyridamole combined with aspirin over aspirin alone in terms of reducing stroke risk has been demonstrated by the ESPS-2 (7) and ESPRIT (8) trials. The major limitation for the use of MR dipyridamole are side effects (see below). In the ESPRIT study, 34% of patients using dipyridamole had to discontinue its use, mainly due to headache. The ESPS-2 trial reported no statistically significant differences in stroke risk reduction comparing modified-release dipyridamole alone with aspirin. The recent PRoFESS trial (9) reported no statistically significant difference in terms of stroke recurrence rate between modified release dipyridamole plus aspirin compared with clopidogrel. NICE therefore recommend generic clopidogrel 75mg daily as a cost-effective option for the secondary prevention Page 4 of 18

5 of over the combination of aspirin and dipyridamole (4) Combination therapy Aspirin plus warfarin - there is no clear indication for the combination of warfarin and aspirin, and it should be used only in exceptional circumstances after specialist advice. Aspirin plus clopidogrel - the addition of clopidogrel 75 mg to aspirin 75 mg has not been shown to lead to a significant reduction in major vascular events after ischaemic stroke. However, there is a clearly increased risk of lifethreatening or major bleeding events (10,11). Combination treatment is not recommended after stroke. Possible exceptions are when combination treatment is indicated for treatment of an acute coronary syndrome Aspirin failure No evidence is available to guide antiplatelet treatment in patients who develop an ischaemic stroke while on aspirin or clopidogrel. This has been termed aspirin failure, although some authorities discourage the use of this term. Generally, it would be unclear whether a patient with a stroke while on aspirin would not have suffered an earlier, or more severe, stroke without it. However, there is some evidence that patients who develop a stroke while on aspirin fare worse than comparable aspirin naïve patients (12,13). Thus, switching to an alternative antiplatelet agent or addition of dipyridamole is occasionally advised by a consultant stroke physician Contraindications, cautions, side-effects Aspirin: Contraindications: proven hypersensitivity; active peptic ulceration; haemophilia and other bleeding disorders; breast feeding. Cautions: previous peptic ulceration, asthma, uncontrolled hypertension, renal and hepatic impairment, pregnancy. Side-effects: bronchospasm, gastrointestinal and other haemorrhage (14). Comments: Patients with true aspirin hypersensitivity should receive clopidogrel 75 mg daily. Aspirin may lead to dyspepsia that may or may not be associated with peptic ulceration and gastrointestinal bleeding. Page 5 of 18

6 Some patients with mild dyspepsia might benefit from having aspirin at meal times or enteric coated aspirin. However, there is no evidence that the latter reduces the incidence of gastrointestinal bleeding. In patients with a history of severe dyspepsia induced by low-dose aspirin, NICE recommends treatment with clopidogrel, based on the results of the CAPRIE study (6), which showed that clopidogrel is associated with a significantly lower risk of dyspepsia and gastrointestinal bleeding compared to aspirin. However, note that the absolute effect of this is small (NNT 38 and 149 respectively) and the dose of aspirin used in the study was 325mg compared to clopidogrel 75mg Clopidogrel Contraindications: active bleeding, breast feeding Cautions: increased risk of bleeding, renal impairment, pregnancy Side-effects: dyspepsia, abdominal pain, diarrhoea, bleeding, others (14) Dipyridamole Cautions: severe coronary artery disease, including unstable angina and/or recent MI, left ventricular outflow obstruction or haemodynamic instability, breast feeding, myasthenia gravis, migraine Side-effects: headache (may be severe), hypotension, flushes and tachycardia, gastrointestinal effects, hypersensitivity reactions (14) Gastrointestinal (GI) protection For all patients on anti-platelet therapy or combination (dual anti-platelet / antiplatelet plus anti-coagulant) consider risk of GI bleed and possible need for ranitidine or a PPI (e.g. lansoprazole). It may be prudent to AVOID omeprazole if the patient is on clopidogrel due to the current debate in the literature on a possible interaction between omeprazole and clopidogrel. 2. Policy Implementation Plan Implementation is the responsibility of consultant medical staff and senior nurses on the Acute Stroke Unit. The changes to previous guidelines in terms of antiplatelet choice will be disseminated to the stroke team via the stroke clinical governance meetings and through continued education and feedback. Wider dissemination to medical staff dealing with patients with a stroke history admitted via other areas will be undertaken via the MMG. The change in local policy will be further publicised via the Primary Care Trust (PCT) MMG. The lead pharmacist for stroke will disseminate the changes to the pharmacy team. Page 6 of 18

7 The stroke team audit acute use of anti-platelets in stroke prospectively for all patients admitted with a stroke diagnosis as part of our commitment to SINAP (the Stroke Improvement National Audit Programme). Longer term use of antiplatelet agents at time of discharge post-stroke will be audited in April 2012 as part of the biannual mandatory audit from the Royal College of Physicians. Additionally to this we will audit in November 2011 and 2012 in the out-patient setting to ensure compliance with the policy. 3. Monitoring and Review This document will be reviewed on a two yearly basis or amended in the light of any new evidence. Approval for any alterations will be gained from the Medicines Management Group and appropriate level of hospital management. Effectiveness of implementation will be assessed as outlined above with yearly audit. Feedback of results will be via the Clinical Governance framework. Page 7 of 18

8 References 1. International Stroke Trial Collaborative Group. The International Stroke Trial (IST): a randomised controlled trial of aspirin, subcutaneous heparin, both or neither among patients with acute ischaemic stroke. Lancet 1997; 349: CAST: randomised placebo-controlled trtial of early aspirin use in 20,000 patients with acute ischaemic stroke. CAST (Chinese Acute Stroke Trial) Collaborative Group. Lancet 1997; 349: Gubitz G, Sandercock P, Counsell C. Anticoagulants for acute ischaemic stroke. Cochrane Database Systematic Review 2004; CD National Institute for Health and Clinical Excellence Clopidogrel and Modified Release Dipyridamole for the Prevention of Occlusive Vascular Events. Review of NICE technology appraisal no. 90. December Available at 5. Saxena R, Koudstaal PJ. Anticoagulants versus antiplatelet therapy for preventing stroke in patients with non rheumatic atrial fibrillation and a history of stroke or transient ischemic attack. Cochrane Review 2006 Issue 2. ISSN CAPRIE Steering Committee. A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). Lancet 1996; 348: Diener H, Cunha L, Forbes C, Sivenius J, Smets P, Lowenthal A: European Stroke Prevention Study 2. Dipyridamole and acetylsalicylic acid in the secondary prevention of stroke. J Neurol Sci 1996; 143: The ESPRIT Study Group. Aspirin plus dipyridamole versus aspirin alone after cerebral ischaemia of arterial origin (ESPRIT): randomised controlled trial. Lancet 2006;367: Diener HC, Sacco RL, Yusuf S, et al. Effects of aspirin plus extendedrelease dipyridamole versus clopidogrel and telmisartan on disability and cognitive function after recurrent stroke in patients with ischaemic stroke in the Prevention Regimen for Effectively Avoiding Second Strokes (PRoFESS) trial: a double-blind, active and placebo-controlled study. Lancet Neurol 2008; 7: Deepak L. Bhatt, M.D., Keith A.A. Fox, M.B., Ch.B., Werner Hacke, M.D.,et al for the CHARISMA Investigators Clopidogrel and Aspirin versus Aspirin Alone for the Prevention of Atherothrombotic Events N Engl J Med 2006;354 Page 8 of 18

9 11. Diener HC, Bogousslavsky J, Brass LM et al. Aspirin and clopidogrel compared 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: Mohr JP, Sciacca RR, Thompson JL et al. Aspirin failure in the warfarin aspirin recurrent stroke study. Program and abstracts of the 28 th International Stroke Conference 2003; Abstract Mohr JP, Thompson JL, Lazar RM et al. A comparison of warfarin and aspirin for the prevention of recurrent ischaemic stroke. N Engl J Med 2001; 345: Joint Formulary Committee (2011). British National Formulary. 61 st edition. London: British Medical Association and Royal Pharmaceutical Society of Great Britain. Page 9 of 18

10 Appendix 1: Choice of anti-platelet agent/anticoagulation following non-haemorrhagic stroke Acute ischaemic stroke (CT rules out haemorrhage)? YES Mechanical prosthetic heart valve requiring long term anticoagulation? NO YES Aspirin 300 mg daily for 14 days unless contraindicated OR Clopidogrel 300mg stat then 75 mg daily if aspirin hypersensitivity/ intolerance* Continue anticoagulation may need modification (see 1.1.1) Seek specialist advice from Stroke Consultant or Cardiologist 14 days post non-haemorrhagic stroke: Atrial fibrillation (persistent or paroxysmal)? YES NO Contra-indications to anticoagulation? NO Prescribe warfarin from day 14 with target INR 2.5. Continue aspirin 300mg until INR therapeutic (i.e. INR>/=2.0) *in cases of recent ACS or where a patient has a drug-eluting coronary stent dual therapy may need to continue liaise with cardiology team YES Consider aspirin 300mg daily long term 1 st line: Clopidogrel 75mg daily 2 nd line: Asasantin MR 1 capsule BD (if clopidogrel not tolerated or contraindicated) 3 rd line: Dipyridamole MR 200mg BD (if clopidogrel and aspirin not tolerated or contraindicated). Consider risk factors: Treat arterial hypertension to target Smoking cessation Treat dyslipidaemia to target Diabetes control Is carotid Doppler indicated? Page 10 of 18

11 Endorsed by: Name of Lead Clinician/Manager or Committee Chair Dr Paul Chadwick Dr Craig Smith Position of Endorser or Name of Endorsing Committee Medicines Management Committee Stroke Clinical Governance Lead Date June 2011 June 2011 Page 11 of 18

12 Record of Changes to Document Version 4 Changes approved in this document by: Date: June 2011 Medicines Management Group Section Amendment Deletion Addition Reason Number Title Addition of transient ischaemic attack (TIA) to title 1.11 If the neurological deficit resolves within 24 hours (this is classified as Transient Ischaemic Attack (TIA), patients may be continued on a combination of modified release dipyridamole and aspirin (Asasantin retard 1 capsule twice daily) following a single dose of aspirin 300 mg. continued on aspirin 75mg daily TIA included in title and main text. continued on a combination of modified release dipyridamole and aspirin (Asasantin retard 1 capsule twice daily) Continue aspirin 300mg until INR therapeutic (i.e. INR>/=2.0) No separate policytreatment of TIA is included in guidelines. NICE guidance update (Ref. 4) Clearer guidelines for warfarin initiation For those patients who are thrombolysed, aspirin 300mg daily should be initiated 24 hours post thrombolysis provided that a repeat CT scan has excluded haemorrhage. Reflects current practice 1.13 Secondary prevention after 14 days. Change to antiplatelet recommendations Asasantin retard 1 st line for secondary prevention Patients with true aspirin hypersensitivity or intolerance should receive clopidogrel 75 mg daily after an initial loading dose of 300mg. Clopidogrel 75mg daily to prevent occlusive vascular events not related to atrial fibrillation. NICE guidelines update (Ref. 4) Version 4 [June 2011] Form 10b Asasantin retard is only recommended: for people who have had a transient ischaemic attack (TIA) or Page 12 of 18

13 for people who have had an ischaemic stroke only if clopidogrel is contraindicated or not tolerated Evidence Some additional comments removed as no longer fit with main text Asasantin for 2 years then switch to aspirin alone. In patients with a history of gastrointestinal haemorrhage not associated with Helicobacter pylori, the addition of a proton pump inhibitor to low dose aspirin is superior to clopidogrel in preventing recurrent gastrointestinal haemorrhage (14). It seems reasonable to give aspirin and omeprazole rather than clopidogrel in patients with a history of GI bleeding (8). Modified-release dipyridamole alone is recommended for: people who have had an ischaemic stroke only if aspirin and clopidogrel are contraindicated or not tolerated or for people who have had a TIA only if aspirin is contraindicated or not tolerated. Update of evidence including NICE guidelines and PRoFESS trial consider risk of GI bleed and possible need for ranitidine or a PPI (e.g. lansoprazole). It may be prudent to AVOID omeprazole if the patient is on clopidogrel due to the current debate in the literature on a Update of guidelines in line with current evidence No longer fits with guidelines Update in line with current evidence Page 13 of 18

14 2.0 There will be review of the effectiveness of this implementation as part of the Stroke Clinical Audit Forward Programme, baseline audit having been done in Results of the next audit will be presented both at Stroke and Neurology meetings and at Clinical Governance meetings. possible interaction between omeprazole and clopidogrel. Implementation is the responsibility of consultant medical staff and senior nurses on the Acute Stroke Unit. The changes to previous guidelines in terms of antiplatelet choice will be disseminated to the stroke team via the stroke clinical governance meetings and through continued education and feedback. Wider dissemination to medical staff dealing with patients with a stroke history admitted via other areas will be undertaken via the MMG. The change in local policy will be further publicised via the Primary Care Trust (PCT) MMG. The lead pharmacist for stroke will disseminate the changes to the pharmacy team. The stroke team audit acute use of anti-platelets in stroke prospectively for all patients admitted with a stroke diagnosis as part of our commitment to SINAP (the Stroke Improvement National Audit Programme). Longer term use of antiplatelet agents at time of discharge post-stroke will be audited in April 2012 as part of the biannual mandatory audit from the Royal College of Physicians. Additionally to this we will audit in November 2011 and Updated with current practice Page 14 of 18

15 Appendix 1 Flowchart amended to fit with change in guidelines 2012 in the outpatient setting to ensure compliance with the policy. In line with change to NICE guidelines Page 15 of 18

16 Screening Equality Analysis Outcomes (Policies/Procedures/PGD s) The Trust is required to ensure that all our policies/procedures meet the requirements of its service users, that it is accessible to all relevant groups and does not impact negatively on any groups by age religion/belief, disability, sex, sexual orientation, martial status, pregnancy, carers, transgender or social/economic. Have you been trained to carryout this assessment? YES If 'no' contact Equality Team for details. Name of policy or document : Protocol for the use of anti-platelet therapy following ischaemic stroke and transient ischaemic attack (TIA): Secondary prevention of recurrent stroke and other occlusive vascular events 1) a) Whom is this document or policy aimed at? b) What are the demographics of your target group? c) How will you ensure that this policy is cascaded to the target group? 2) a) Is there any evidence to suggest that different groups have different needs in relation to this policy or document (e.g. health/employment inequality outcomes) (NB If you do not have any evidence you should put in the end of this document how you will start to undertake this analysis?) b) What action have you taken to reduce these inequalities? Patients who have had an ischaemic stroke or TIA and are eligible for antiplatelet therapy as secondary prevention. This protocol only applies to patients eligible for anti-platelet therapy following ischaemic stroke or TIA. It does not apply to the treatment of haemorrhagic stroke. A separate protocol should be referred to for patients who are eligible for thrombolysis. All patients will be assessed for treatment in line with the protocol. See protocol implementation plan for full details. No N/A 3) a) Does the document require any decision to be made which could result in some individuals receiving different treatment, care, outcomes to other groups/individuals? No Page 16 of 18

17 b) if yes, on what basis would this decision be made? (It must be objectively justified) c) Have you included where you may need to include reasonable adjustments for disabled users or staff to ensure they receive the same outcomes? 4) a) Have you undertaken any consultation/involvement with service users or other groups in relation to this policy? b) If yes, what format did this take? face/face or questionnaire? (please provide evidence of this) c)has any amendments been made as a result? N/A N/A No N/A N/A 5) a) Are you aware of any complaints from service users in relation to the application of this policy? No b) If yes, how was the issue resolved? Has this policy been amended as a result? Page 17 of 18

18 6a) Are you aware of any complaints from service users in relation to the application of this policy? No b) If yes, how was the issue resolved? Has this policy been amended as a result? 6) a) Looking at all of the above information is there any evidence to indicate that any groups listed below have different needs, experiences or priorities in relation to this document? Age Disability Gender Marital Status Racial group Religious belief Sexual orientation Pregnancy Carers Transgender Socio/economic Yes No unsure b) How will these differences be reduced or eliminated by this policy? N/A 7) If any impact has been highlighted by this assessment, you will need to undertake a full equality impact assessment: Will this policy require a full impact assessment? No (delete) (if yes please contact Equality Team, 62598/67204, for further guidance) High/Medium/Low signed Karen Inston (Stroke Pharmacist) date: June 2011 Page 18 of 18