North of Tyne anti-platelet guidelines: use in primary care

Jane S Skinner

Consultant Community Cardiologist

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

Which anti-platelet agents are prescribed in primary care?

• Aspirin

• Thienopyridines– Clopidogrel– Prasugrel

• Dipyridamole

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

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

Absolute effects of anti-platelet therapy on vascular events

0

5

10

15

20

25

Previous MI Acute MI Previous 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%

Adj

uste

d %

vas

cula

r ev

ents

ATC BMJ 2002;324:71

Anti-plateletPlacebo

Mean months of treatment 27 1 29 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)

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 aspirinNo major differences in terms of safety

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

Recurrent GI bleeding; aspirin plus PPI vs clopidogrel

0

2

4

6

8

10

Recurrent ulcer bleeding Lower 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

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

Combination anti-platelet agents

• Aspirin plus thienopyridine– Clopidogrel– Prasugrel

• Aspirin plus dipyridamole

PLATELET ACTIVATION

Cyclo-oxygense

Plaque ruptureOther sources

Eg damaged endothelium

ADP RELEASE ADP RELEASE ADP RELEASE

PLATELET ADP RECEPTOR

PLATELET AGGREGATION

ASPIRIN

THIENOPYRIDINE

Groups to consider

• Coronary artery disease

• Cerebrovascular disease

• After a recent acute vascular event

• After intervention

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

NEJM 2001;345:494NEJM 2001;345:494

Aspirin vs aspirin plus clopidogrel in ACS without ST elevation

Aspirin vs aspirin plus clopidogrel in ACS without ST elevation

Clopidogrel + ASA

Clopidogrel + ASA

33 66 99

Placebo + ASA

Placebo + ASA

Months of Follow-UpMonths of Follow-Up

11.4%11.4%

9.3%9.3%

20% RRRP < 0.001

N = 12,562

20% RRRP < 0.001

N = 12,562

00 12120.000.00

0.020.02

0.040.04

0.060.06

0.080.08

0.100.10

0.120.12

0.140.14

Cu

mu

lati

ve H

azar

d R

ate

Cu

mu

lati

ve H

azar

d R

ate Δ2.1%Δ2.1%

Excess of 1 life-threatening and 6 major bleeds per 1000 patients treated with clopidogrelExcess of 1 life-threatening and 6 major bleeds per 1000 patients treated with clopidogrel

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

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

0

5

10

15

0 90 180 270 360 450

HR 0.81(0.73-0.90)P=0.0004

Prasugrel

Clopidogrel

Days

End

poin

t (%

)

12.1

9.9

HR 1.32(1.03-1.68)P=0.03

Prasugrel

Clopidogrel1.82.4

1o EP: CV Death / MI / Stroke

TIMI Major NonCABG Bleeds

TITAN

Wiviott et al., NEJM 2007; 357: 2001-5

TRITON-TIMI 38

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 bleeding2.1% clopidogrel vs 1.3% placebo

Initiation of combination treatment with aspirin and clopidogrel is not

recommended in stable patients with vascular disease

MHRA Drug Safety Update July 2009

MHRA Drug Safety Update April 2010

MHRA Drug safety update April 2010

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

CV

dea

th, M

I or

str

oke

Days

CLOPIDOGREL PPI vs no PPI: Adj HR 0.94, 95% CI 0.80-1.11

PPI use at randomization (n= 4529)

Clopidogrel

Prasugrel

PRASUGREL PPI 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

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

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

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

ESPRIT main results

ESPRIT Lancet 2006;367:1665-73

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

MATCH Lancet 2004;364:331-337

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

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

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

ATT collaboration. Lancet 2009;373:1849-60

ATT collaboration. Lancet 2009;373:1849-60

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

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

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

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

Summary

• Anti-platelet agents for prevention in patients with or at risk of vascular disease– Indications – Risks

• Single agents

• Combination agents