Clopidogrel should be used at a dose of 75mg daily

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1 Statement in response to Royal College of Physicians National Clinical Guideline for Stroke () and NICE Technology Appraisal 210 (December 2010) Executive Summary: The NICE clinical guidance, Clopidogrel & Dipyridamole for the prevention of occlusive vascular events (TAG210) was published in December It recommended Clopidogrel for stroke and Dipyridamole for TIA, based on the licenced indication. Subsequently guidance published by the Royal College of Physicians advises the use of Clopidogrel for both stroke and TIA, based on the fact that it is the same disease process. The Medicines Management Board recommends that Clopidogrel is used for stroke and for TIA, contrary to the guidance published by NICE. Introduction In November 2012 the Royal College of Physicians published their fourth edition of the National Clinical Guideline for Stroke. The concise guideline contains 300 recommendations and includes 28 key recommendations identified by the Intercollegiate Stroke Working Party. Of these, number 5.5.1A states that For patients with ischaemic stroke or TIA in sinus rhythm, clopidogrel should be the standard antithrombotic treatment: Clopidogrel should be used at a dose of 75mg daily NICE guidance published December 2010 advises the use of Clopidogrel and Dipyridamole for the prevention of occlusive vascular events in people who have had a myocardial infarction, or have had an ischaemic stroke or who have peripheral vascular disease. This guidance differentiates treatment between ischaemic stroke and transient ischaemic attack

2 Epidemiology There are two main types of stroke. Ischaemic strokes happen when something blocks an artery that carries blood to the brain. There are several possible causes: a blood clot forms in a main artery to the brain a blood clot, air bubble or fat globule forms in a blood vessel and is carried to the brain there is a blockage in the tiny bloody vessels deep inside the brain. Haemorrhagic strokes happen when a blood vessel bursts and bleeds into the brain (a haemorrhage). The haemorrhage may be due to: a vessel bursting within the brain itself, or a blood vessel on the surface of the brain bleeding into the area between the brain and the skull. Sometimes the blockage in the blood supply to the brain is temporary, and a person will have the symptoms of a stroke for a short time. This is called a transient ischaemic attack (TIA) or mini stroke. A TIA is a sign that part of the brain is not getting enough blood, and there is a risk of a more serious stroke in future. As TIAs share the same underlying etiology as strokes the argument to treat and prevent future events underpins the decision by the RCP to recommend Clopidogrel for both stroke and TIA.

3 Clopidogrel Licence Clopidogrel is indicated in: Hydrochloride - Patients suffering from myocardial infarction (from a few days until less than 35 days), ischaemic stroke (from 7 days until less than 6 months) or established peripheral arterial disease. Besylate - Adult patients suffering from myocardial infarction (from a few days until less than 35 days), ischaemic stroke (from 7 days until less than 6 months) or established peripheral arterial disease. Hydrogen sulphate (brand) - Adult patients suffering from myocardial infarction (from a few days until less than 35 days), ischaemic stroke (from 7 days until less than 6 months) or established peripheral arterial disease. NICE TA210 - Clopidogrel and modified-release dipyridamole for the prevention of occlusive vascular events. The following statement is taken directly from the guideline, section The Guidance: 1.1. Clopidogrel is recommended as an option to prevent occlusive vascular events: For people who have had an ischaemic stroke or who have peripheral arterial disease or multivascular disease or For people who have had a myocardial infarction only if aspirin is contraindicated or not tolerated. This statement does not specify that treatment needs to be started within a specific time frame which would suggest that NICE are advocating the use of Clopidogrel outside of its licence. The following statements are taken directly from the guideline, section Clinical Effectiveness: The Committee heard from the patient experts that they considered that clopidogrel had fewer severe side effects than aspirin or modified-release dipyridamole The Committee discussed the results of the PRoFESS trial and considered that it had not shown that clopidogrel provided greater benefits than modified-release dipyridamole plus aspirin. But the Committee also considered that the trial had not shown that modified-release dipyridamole plus aspirin provided greater benefits than clopidogrel The Committee heard from the clinical specialists that people who have had a transient ischaemic attack are sometimes treated with clopidogrel. However, the Committee recognised that recommendations could not be made for the use of clopidogrel for people who have had a transient ischaemic attack because clopidogrel is not licensed for this indication. These statements would appear to be contradictory, the final one referring to the fact that NICE could not advocate recommending the use of a drug outside of its licence.

4 Costing Analysis Based on prices in BNF 64 (September 2012), the costs for 28 days treatment can be compared on the following chart: Further analysis against time based on 100 patients for 1 year, the costs can be compared on the following graph. An assumption has been made that those patients on Aspirin alone, Clopidogrel alone and Asasantin have 100% compliance. However, owing to the strong likelihood that compliance will wane in the Aspirin and Dipyridamole group because it is 2 tablets to be taken and one of those tablets could be identified by the patient as the cause of avoidable side effects, the rule has been applied that 50% of all patients will stop taking the Dipyridamole after one year. The result shows a slight decrease in gradient of the line but would in fact result in 37.5% of patients on sub-optimal therapy and at higher risk of stroke with the management costs of events in addition (this is not costed in):

5 The cost of using Clopidogrel is marginally more than Aspirin alone but considerably less than the treatment advised in the NICE guidance TA210. Conclusion The Medicines Management Board representing The East Lancashire Health Economy recommends that the National Guideline for Stroke published by the Royal College of Physicians be followed in preference to the NICE guidance TAG210 with reference to the use of Clopidogrel in TIA for the prevention of occlusive vascular events based on The same disease process is involved in stroke and TIA Clopidogrel is the most cost effective option, compared to Dipyridamole Clopidogrel is better tolerated than Dipyridamole, therefore likely to have better compliance Argument that NICE cannot advise use of Clopidogrel in TIA because it is off licence is not valid when the guidance advises the use of Clopidogrel in stroke and MI without time frames which is also off licence. NICE states that evidence does not show Clopidogrel to be superior to Dipyridamole in TIA, but neither does it show it to be inferior.