Clopidogrel

1. Clopidogrel

2. Options for local implementationNPC. Key therapeutic topics – Medicines management options for local implementation. Second Update July 2011 Review, and where appropriate revise, prescribing and duration of treatment of clopidogrel to ensure it is in line with NICE guidance. Treatment with clopidogrel should be started with the least costly licensed preparation: in practice, this means generic clopidogrel.

3. Key questions • What does NICE say about when clopidogrel should be used? • How long should it be used for? • How does clopidogrel compare to other antiplatelets? • How are we doing with clopidogrel and antiplatelet prescribing?

4. Clopidogrel – changes in NICE guidanceNICE. TA210. December 2010NPC. MeReC Rapid Review No. 2353 Changes in NICE guidance on clopidogrel (and MR dipyridamole) for the prevention of occlusive vascular events have been introduced in technology appraisal guidance 210, which replaces the NICE guidance(TA90) issued in 2005

5. Clopidogrel – after an ischaemic strokeNICE. TA210. December 2010NPC. MeReC Rapid Review No. 2353 Implications of changes to NICE guidance: Clopidogrel* alone now recommended no specified limit on duration of treatment MR dipyridamole plus aspirin only if clopidogrel contraindicated / not tolerated, combination treatment no longer limited to two years MR dipyridamole alone only if aspirin or clopidogrel cannot be used as above because they are contraindicated or not tolerated no limit on duration of treatment. * Treatment with clopidogrel should be started with the least costly licensed preparation: in practice, this means generic clopidogrel.

6. Clopidogrel – after peripheral arterial disease (PAD) or multivascular diseaseNICE. TA210. December 2010NPC. MeReC Rapid Review No. 2353 Implications of changes to NICE guidance: Clopidogrel* alone now recommended as a treatment option for patients with PAD or multivascular disease.  * Treatment with clopidogrel should be started with the least costly licensed preparation: in practice, this means generic clopidogrel.

7. Clopidogrel – after a TIANICE. TA210. December 2010NPC. MeReC Rapid Review No. 2353 Implications of changes to NICE guidance: MR dipyridamole plus aspirin: still recommended after a TIA, now no recommended limit on the duration of treatment MR dipyridamole monotherapy: after TIA only if aspirin is contraindicated or not tolerated, with no limit on duration of treatment No recommendations are made about clopidogrel after a TIA because it is not licensed for this indication.

8. Clopidogrel –after an MINICE. TA210. December 2010NPC. MeReC Rapid Review No. 2353 Implications of changes to NICE guidance: Recommendations about aspirin as treatment of choice post MI not affected new guidance TA210: Aspirin is treatment of first choice post MI Clopidogrel* recommended after an MI, only if aspirin contraindicated or not tolerated * Treatment with clopidogrel should be started with the least costly licensed preparation: in practice, this means generic clopidogrel.

9. Clopidogrel in combination with aspirin? NICE recommends clopidogrel in combination with aspirin in the following circumstances: for 12 months after most recent acute episode of non-ST-segment-elevation acute coronary syndrome (NICE. CG94. March 2010) for at least 4 weeks in patients treated with a combination of aspirin and clopidogrel during the first 24 hours after an ST-segment-elevation MI (NICE CG 48(May 2007)) following coronary or carotid interventions e.g. stenting In general, low-dose aspirin is prescribed with clopidogrel (or prasugrel▼ in specific circumstances – see accompanying notes) for 12 months after the procedure. Such drugs should be used in accordance with the device-specific instructions for use (NICE TA71(October 2003), NICE TA1529(July2008) and NICE TA182(October 2009)). Thereafter, standard treatment including low-dose aspirin should be given, unless there are other indications to continue dual antiplatelet therapy.

10. Four factors influencing prescribing decisionsBarber N. BMJ 1995; 310: 923-5 EFFECTIVE SAFE Beneficence Non-malificence PATIENT FACTORS COST Justice Patient autonomy

11. Double-blind randomised controlled trial (RCT) including 19,185 patients 9,599 received clopidogrel 75mg daily 9,586 received aspirin 325mg daily Received treatment for one to three years Average rate per year of stroke, MI or vascular death: 5.32% with clopidogrel 5.83% with aspirin ARR=0.51, RRR 8.7%, P=0.043 NNT with clopidogrel instead of aspirin to prevent such an event ~ 200, for a year. Effectiveness evidence: How does aspirin compare with clopidogrel in occlusive vascular events?Lancet 1996;348:1329–39 (CAPRIE)

12. Effectiveness evidence: How does aspirin plus MR dipyridamole compare with clopidogrel?Sacco RL, et al. New Engl J Med 2008;359:1238–51NPC. MeReC Rapid Review No. 193 PRoFESS study supports previous evidence that any difference in the effectiveness of these two regimens in preventing further events in people who have had a stroke is likely to be extremely small at a population level N = 20,332 who had recent ischaemic stroke Aspirin 25mg plus MR dipyridamole 200mg twice daily vs. clopidogrel 75mg daily Duration — mean 2.5 years What did it find? No statistically significant difference in recurrent stroke (primary outcome) 9.0% combination vs. 8.8% clopidogrel, HR 1.01 (95%CI 0.92 to 1.11) More major haemorrhagic events in aspirin plus MR dipyridamole group 4.1% combination vs. 3.6% clopidogrel, HR 1.15 (95%CI 1.00 to 1.32) Post-hoc analysis found that the net risk of recurrent stroke or major haemorrhage was the same in both groups 11.7% combination vs. 11.4% clopidogrel, HR 1.03 (95%CI 0.95 to 1.11)

13. Cost: So what caused the changes in guidance for clopidogrel?NICE. TA210. Decemeber 2010NPC. MeReC Rapid Review No. 2353 Since the publication of the previous NICE guidance in 2005 (TA90), a key change has been the availability of generic formulations of clopidogrel. Consequently, for people who have had an ischaemic stroke, the cost effectiveness of treatment changed depending on whether the branded or generic price of clopidogrel was used. Treatment with clopidogrel should be started with the least costly licensed preparation: in practice, this means generic clopidogrel.

14. Patient factors: What does NICE say? NICE. TA210. December 2010 • In patients who have had an MI: • “…. For people with intolerance to aspirin, treatment with clopidogrel was likely to be the optimal treatment, compared with no preventive therapy” • Genuine aspirin intolerance, defined by hypersensitivity reactions or severe dyspepsia, should be differentiated from mild dyspeptic symptoms, which are common. • …“Contraindications to clopidogrel include severe liver impairment and active pathological bleeding such as peptic ulcer or intracranial haemorrhage. For full details of side effects and contraindications, see the summary of product characteristics.”

15. Safety evidence:Do clopidogrel and PPIs interact?MHRA/CHM. Drug Safety Update. Volume 3, issue 9. April 2010

16. To summarise

17. Trends in prescribing of antiplatelets in general practice in England No substantial increase in antiplatelet use, and no substantial change in choice of agent © Copyright NHSBSA 2011

18. Trends in spending on antiplatelets in general practice in England 60,000,000 Aspirin Clopidogrel Dipyridamole Others 50,000,000 40,000,000 30,000,000 NIC (£) 20,000,000 10,000,000 0 Quarter to Mar-06 Jun-06 Mar-07 Jun-07 Mar-08 Jun-08 Mar-09 Jun-09 Mar-10 Jun-10 Dec-05 Dec-06 Dec-07 Dec-08 Dec-09 Dec-10 Sep-06 Sep-07 Sep-08 Sep-09 Sep-10 N.B The price held for Dipyridamole 200mg m/r caps was incorrect during the quarter to December 2009, which accounts for the inflated NIC for this period Impact of introduction of generic clopidogrel on spend © Copyright NHSBSA 2011

19. Prescribing comparatorClopidogrel generic prescribing ratewww.nhsbsa.nhs.uk/PrescriptionServices/3334.aspx 99.73% 91.51% © Copyright NHSBSA 2011

20. Key messages (1) * Use least costly licensed preparation of clopidogrel: in practice, this means generic clopidogrel After an ischaemic stroke: Clopidogrel* alone (as antiplatelet monotherapy) is now recommended – no specified limit on duration of treatment MR dipyridamole plus aspirin now recommended only if clopidogrel contraindicated / not tolerated, with no two-year time limit for the dipyridamole component MR dipyridamole alone only if aspirin or clopidogrel cannot be used as above because they are contraindicated or not tolerated, with no limit on duration of treatment. For peripheral arterial disease (PAD) or multivascular disease: Clopidogrel* alone is now recommended as a treatment option

21. After a myocardial infarction (MI): Aspirin is treatment of first choice post MI Clopidogrel* recommended after an MI, only if aspirin contraindicated or not tolerated After a transient ischaemic attack (TIA): MR dipyridamole plus aspirin still recommended as first choice, now no recommended limit on the duration of treatment MR dipyridamole monotherapy is recommended after TIA only if aspirin contraindicated or not tolerated, now no limit on duration of treatment No recommendations are made about clopidogrel after a TIA because it is not licensed for this indication. Following an analysis of new data, the European Medicines Agency says: only concomitant use of clopidogrel and omeprazole or esomeprazole should now be discouraged for other PPIs, concomitant use can be considered if specifically indicated Key messages (2)