1. North of Tyne anti-platelet guidelines: use in primary care Jane S Skinner Consultant Community Cardiologist

2. Purpose of the presentation To summarise key points for treatment with anti-platelet agents in primary care North of Tyne To include some key evidence to support the recommendations

3. Which anti-platelet agents are prescribed in primary care? Aspirin Thienopyridines –Clopidogrel –Prasugrel Dipyridamole

4. Indications for anti-platelet agents in primary care Secondary prevention in atheromatous vascular disease –Coronary disease –Cerebrovascular disease –Peripheral arterial disease Atrial fibrillation Primary prevention

5. Secondary prevention Aspirin 75 mg daily –First line, long term treatment –Not enteric coated –In some patients a higher dose may be recommended from specialist care eg after CABG Clopiodgrel 75 mg od –Only if aspirin is contra-indicated eg allergy Combination anti-platelet agents

6. Absolute effects of anti-platelet therapy on vascular events 0 5 10 15 20 25 Previous MIAcute MIPrevious stroke/TIA Acute stroke Other high risk 13.5% 17.0% 10.4% 14.2% 17.8% 21.4% 8.2% 9.1% 8.1% 10.2% Adjusted % vascular events ATC BMJ 2002;324:71 Anti-platelet Placebo Mean months of treatment27 129 0.7 22 Aspirin reduced the risk of serious vascular events (non-fatal MI, non fatal stroke or vascular death) by about a quarter (ATC BMJ 2002;324:71) In a more recent meta-analysis aspirin reduced the risk of serious vascular events by 19% (Lancet 2009;373:1849-60)

7. 19,185 patients recent acute MI, recent acute ischaemic stroke or symptomatic PAD Aspirin 325 mg od versus clopidogrel 75 mg od CAPRIE Lancet 1996;348:1329-39 Annual risk of a major vascular event 5.32% with clopidogrel vs 5.83% with aspirin No major differences in terms of safety

8. Dyspepsia with aspirin Review and modify other contributory factors –Excess alcohol –NSAIDs, steroids Investigate if appropriate Take aspirin with food Reduce aspirin dose to 75 mg od Use aspirin in combination with a PPI Do not switch to enteric coated

9. Recurrent GI bleeding; aspirin plus PPI vs clopidogrel 0 2 4 6 8 10 Recurrent ulcer bleedingLower GI bleeding Probability of recurrent bleeding at 12 months (%) Aspirin 80mg od plus esomeprazole 20mg bd (n=159) Clopidogrel 75mg od plus placebo (n=161) NEJM 2005;352:238-44

10. Key messages in long term secondary prevention Aspirin first line –Individual high risk patients, clopidogrel on consultant recommendation Allergic to aspirin –Consider clopidogrel Dyspepsia with aspirin –Routine measures –Consider the addition of a PPI History of upper GI bleeding or ulcer with aspirin –Heal ulcer, HP erradication –Addition of PPI to aspirin

11. Combination anti-platelet agents Aspirin plus thienopyridine –Clopidogrel –Prasugrel Aspirin plus dipyridamole

12. PLATELET ACTIVATION Cyclo-oxygense Plaque rupture Other sources Eg damaged endothelium ADP RELEASE PLATELET ADP RECEPTOR PLATELET AGGREGATION ASPIRIN THIENOPYRIDINE

13. Groups to consider Coronary artery disease Cerebrovascular disease After a recent acute vascular event After intervention

14. Patients with acute MI Thienopyridine plus aspirin –ST elevation MI and unstable angina / non ST elevation MI –With or without percutaneous coronary intervention (PCI) –Irrespective of type of stent Bare metal or drug eluting Routinely for 12 months

15. NEJM 2001;345:494 Aspirin vs aspirin plus clopidogrel in ACS without ST elevation Clopidogrel + ASA 3 3 6 6 9 9 Placebo + ASA Months of Follow-Up 11.4% 9.3% 20% RRR P < 0.001 N = 12,562 20% RRR P < 0.001 N = 12,562 0 0 12 0.00 0.02 0.04 0.06 0.08 0.10 0.12 0.14 Cumulative Hazard Rate Δ2.1% Excess of 1 life-threatening and 6 major bleeds per 1000 patients treated with clopidogrel

16. Stable patients having elective PCI Aspirin 75 mg od plus Bare metal stent –Clopidogrel 75 mg od for 1 month (up to 12 months on cardiologist advice) Drug eluting stent –Clopidogrel 75 mg od for 12 months then review Left main stem stent –Clopidogrel 75 mg od lifelong unless advised by a cardiologist

17. Clopidogrel or prasugrel in combination with aspirin? Clopidogrel in many Prasugrel –May be substituted for clopidogrel in some, always started in hospital Prasugrel only in selected patients having PCI –Primary PCI for STEMI –Stent thrombosis occurred whilst treated with clopidgrel –Diabetes –Not if higher risk of bleeding, or after previous stroke

18. 0 5 10 15 090180270360450 HR 0.81 (0.73-0.90) P=0.0004 Prasugrel Clopidogrel Days Endpoint (%) 12.1 9.9 HR 1.32 (1.03-1.68) P=0.03 Prasugrel Clopidogrel 1.8 2.4 1 o EP: CV Death / MI / Stroke TIMI Major NonCABG Bleeds TITAN Wiviott et al., NEJM 2007; 357: 2001-5 TRITON-TIMI 38

19. Aspirin vs aspirin and clopidogrel in stable patients CHARISMA New Engl J Med 2006;354 p=0.22 Primary Efficacy Outcome = MI, Stroke, or CV Death) Median follow up 28 mths Moderate bleeding 2.1% clopidogrel vs 1.3% placebo Initiation of combination treatment with aspirin and clopidogrel is not recommended in stable patients with vascular disease

20. MHRA Drug Safety Update July 2009 MHRA Drug Safety Update April 2010

21. MHRA Drug safety update April 2010

22. O’Donoghie et al. Lancet 2009;374:989-997

23. CV death, MI or stroke Days CLOPIDOGREL PPI vs no PPI: Adj HR 0.94, 95% CI 0.80-1.11 PPI use at randomization (n= 4529) Clopidogrel Prasugrel PRASUGRELPPI vs no PPI: Adj HR 1.00, 95% CI 0.84-1.20 Primary endpoint stratified by use of PPI O’Donoghie et al. Lancet 2009;374:989-997

24. Key messages for combination of aspirin and thienopyridine in CAD Initiated in hospital –After MI / unstable angina –After PCI Duration depends on: –Whether MI / unstable angina –Type of stent if elective PCI Not continued long term (beyond 12 months) with some exceptions –Advised by cardiologist Do not stop early without discussing with a cardiologist

25. Patients after acute ischaemic stroke Aspirin 75 mg od and dipyridamole MR 200 mg bd after acute ischaemic stroke Dipyridamole –For at least 2 years, but may be continued indefinitely –Relatively poorly tolerated: GI S/E, dizziness, myalgia, headache, hypotension, hot flushes and tachycardia –Might be limited to higher risk patients on specialist advice –No benefit in reducing coronary events If aspirin allergy / not tolerated –Clopiodgrel monotherapy not dipyridamole monotherapy

26. ESPRIT Patients –1363 aspirin plus dipyridamole 200mg bd (extended release in 83%) –1376 aspirin alone Mean dose aspirin 75 mg od (range 30 to 325) Mean follow up 3.5 years Primary outcome –Vascular death, non fatal MI, non fatal stroke, major bleeding complication ESPRIT Lancet 2006;367:1665-73

27. ESPRIT main results ESPRIT Lancet 2006;367:1665-73

28. MATCH 7599 patients Ischaemic stroke or TIA within last 3 months plus 1+ previous ischaemic stroke, MI, angina, diabetes, symptomatic PAD in last 3 years Aspirin plus placebo vs aspirin plus clopidogrel Primary outcome: ischaemic stroke, MI, vascular death, or rehospitalistation for acute ischaemic event MATCH Lancet 2004;364:331-337

30. Carotid stenting Planned in secondary care Aspirin 75 mg od plus clopidogrel 75 mg od for 4 weeks after the procedure –Aspirin long term Usually Aspirin 75 mg od plus clopidogrel 75 mg od for 7 days before the procedure

31. Key messages for anti-platelet agents in patients with acute ischaemic stroke / TIA National Clinical Guidelines for stroke Aspirin and dipyridamole standard secondary prevention treatment following ischaemic stroke For patients unable to tolerate dipyridamole –Aspirin alone For patients unable to tolerate aspirin –Clopidogrel alone

32. Primary prevention Not licensed Recent meta-analysis (ATT collaboration. Lancet 2009;373:1849-60) –12% proportional reduction in serious vascular events with aspirin compared to placebo, due mainly to a reduction in non fatal MI by 23% –Absolute reduction: 0.51% vs 0.57% per year –Increased risk of GI and major extracranial bleeds 0.1% vs 0.07% per year

33. ATT collaboration. Lancet 2009;373:1849-60

36. Key messages for aspirin in primary prevention Less frequently recommended now Might consider in those at very high risk, but only after considering the risks and benefits Only consider if blood pressure is controlled < 150/90 High risk patients intolerant of other preventative treatment such as statins may have more to gain

37. Anti-platelet agents and surgery Minor surgery –Low bleeding risk, bleeding can be easily managed –Anti-platelet agents do not need to be withdrawn Endoscopy patients Major surgery –Assess risks and benefits –Clopidogrel is more likely to cause significant bleeding problems –Seek specialist advice, especially with combination agents and with prior stents

38. Other issues Anti-platelet agents and anticoagulants Anti-platelet agents with NSAIDs Thromboembolic prophylaxis in patients with AF –Warfarin vs aspirin –Dependent on thrombo-embolic risk –Taking into account the risk of bleeding

39. Thrombo-embolic prophylaxis in AF: Anti-platelet agents vs anticoagulation Use ‘scoring’ system to assess risk of thrombo-embolism Take into account bleeding risk and patient preferences when agreeing treatment

40. Summary Anti-platelet agents for prevention in patients with or at risk of vascular disease –Indications –Risks Single agents Combination agents