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Management of aspirin resistance

11 February 2008

In the last decade the wonderful drug of the 20th century, aspirin, is studied

again in clinical studies but this time for its failure in the prevention of vascular

thrombotic events called as aspirin resistance. Researchers defined aspirin

resistance clinically and/or with the aid of laboratory techniques. Possible

mechanisms of aspirin resistance are also well described previously. The

hallmark of aspirin resistance studies is its implication on clinical outcomes in

patients with cardiovascular diseases. Recent studies established that patients

who developed a new acute coronary syndrome under aspirin therapy are at

higher risk (1, 2). Prior aspirin use is also a component of TIMI risk score which

guides us in the management of acute coronary syndromes (3). Aspirin

resistances impact on clinical outcomes are established previosuly in differentpatient groups (1, 4, 5).

The major limitations of studies on aspirin resistance are; use of different

methods which makes difficult to compare the results, insufficient monitorization

of compliance and differences in diagnostic criteria of aspirin resistance. We

need also to make a concensus on the definition of aspirin resistance.

Development or determination of an optimal platelet function analyzer or method

is also necessary to standardize the results. This method should be cheap,

accurate, available and applicable in every hospital.

We need to discuss also the monitorization of aspirin compliance in patients with

cardiovascular diseases. A fast diagnostic tool consisted of a platelet function

test, blood an/or urine salycilate and/or thromboxane level may serve us in daily

clinical practise. I think that a such diagnostic tool should be used at least in

patients with higher risk of aspirin resistance (eg elder patients, patients with an

acute coronary syndrome or diabetes or intracoronary stent restenosis).

None of the recent studies advised the cessation of aspirin in case of aspirin

resistance. Aspririn therapy should be continued in aspirin resistant subjects and

management of aspirin resistant subjects should be based on clinical evidence.

We have aditional antiplatelet agents which may be used in aspirin resistant

subjects. Prasugrel is one of these hopeful molecules and its effectiveness is

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proven in aspirin-treated subjects with coronary artery disease. Prasugrel 60/10

mg provided faster onset and greater inhibition of P2Y(12) receptor-mediated

platelet aggregation than clopidogrel 600/75 mg, because of greater and more

efficient generation of the active metabolite (6).

1. Pamukcu B, Oflaz H, Oncul A, et al. The role of aspirin resistance on outcome

in patients with acute coronary syndrome and the effect of clopidogrel therapy in

the prevention of major cardiovascular events. J Thromb Thrombolysis. 2006

Oct;22(2):103-10.

2. Hobikoglu GF, Norgaz T, Aksu H, et al. High frequency of aspirin resistance in

patients with acute coronary syndrome. Tohoku J Exp Med. 2005 Sep;207(1):59-

64.

3. Antman EM, Cohen M, Bernink PJLM, et al. The TIMI Risk Score for Unstable

Angina/NonST Elevation MI. A Method for Prognostication and Therapeutic

Decision Making. JAMA. 2000;284:835-842.

4. Pamukcu B, Oflaz H, Onur I, et al. Clinical relevance of aspirin resistance in

patients with stable coronary artery disease: a prospective follow-up study

(PROSPECTAR). Blood Coagul Fibrinolysis. 2007 Mar;18(2):187-92.

5. Sztriha LK, Sas K, Vecsei L. Aspirin resistance in stroke: 2004. J Neurol Sci.

2005 Mar 15;229-230:163-9. Epub 2004 Dec 23. Review.

6. Wallentin L, Varenhorst C, James S, et al. Prasugrel achieves greater and

faster P2Y12receptor-mediated platelet inhibition than clopidogrel due to more

efficient generation of its active metabolite in aspirin-treated patients with

coronary artery disease. Eur Heart J. 2008 Jan;29(1):21-30. Epub 2007 Nov 30.

Anti-platelets in acute coronary syndromes: too much of a

good thing?

2 April 2007

Dear Sir,

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The editorial comment by Khavandi and Walker provides a timely reminder of the

need for careful assessment of risk in patients presenting with an acute coronary

syndrome to identify those would benefit from early angiography and

revascularization.1 Their conclusion that glycoprotein IIb/IIIa inhibitors (GPI) are

underused in high-risk patients is however based on outdated trial data. All the

landmark trials establishing the role of GPI in non ST-segment elevation acute

coronary syndrome were conducted in the era before the routine use of

clopidogrel. Whereas the benefits of clopidogrel in patients with acute coronary

syndrome have been demonstrated across all levels of risk, irrespective of PCI,

the benefits of GPI appear more pronounced in those managed invasively.

Clinical outcome data on initial or upstream use of GPI in the era of clopidogrel

are lacking. The National Institute for Clinical Excellence (NICE) guidance on the

use of GPI of September 2002 recommends the use of a small-molecule GPI

(tirofiban or eptifibatide) in addition to aspirin and unfractionated heparin in high-

risk acute coronary syndrome patients, with no mention of the role of concomitant

clopidogrel.2 The Clopidogrel in Unstable angina to prevent Recurrent Events

(CURE) trial and its PCI sub-study were published in August 2001, too late to

inform NICE guidance.3,4 The high-risk group of acute coronary syndrome

patients in whom post-hoc analysis showed benefit from upstream use of GPI

were entirely clopidogrel nave.5

The Boersma meta-analysis on the use of GPI in acute coronary syndromes

quoted in the editorial was influential in forming guidance, but none of the six

landmark trials analysed patients treated with clopidogrel.6 Furthermore, the

relatively modest benefit in terms of reduction in recurrent MI was confined to a

group of troponin positive patients, most of whom subsequently underwent PCI.

Indeed addition of GPI to aspirin and heparin conferred less protection from

death or myocardial infarction (1% absolute reduction from 11.8% to 10.8%) than

did addition of clopidogrel to aspirin in CURE (8.6% death or recurrent MI forclopidogrel and aspirin versus 10.5% aspirin alone, relative risk , 0.81,

p

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platelet medications increase the risk of bleeding. No randomized, controlled

clinical trial has specifically addressed the issue of upstream quadruple anti-

platelet therapy (aspirin, low molecular- weight heparin, clopidogrel plus

upstream GPI). The US National registry of 38,000 patients with non ST-segment

myocardial infarction has cast doubt on the benefits of upstream GPI: the

addition of upstream glycoprotein IIb/IIIa inhibitor to aspirin, heparin and

clopidogrel significantly increased the combined risk of mortality, re-infarction or

major bleeding compared to aspirin, heparin and clopidogrel alone in

conservatively managed patients (17.8% versus 12.4%, OR 1.61, p

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Addition of other antiplatelet drugs to aspirinAddition to aspirin of an antiplatelet drug that prevents platelet aggregation

through some other pathway may well produce a further reduction in the risk of

serious vascular events. This has now been shown for short term treatment.

Large randomised trials among patients having percutaneous coronary

interventions have found that adding a short intravenous infusion of glycoprotein

IIb/IIIa antagonist reduces the risk of early arterial or stent thrombosis. 43 In the

present meta-analysis, evidence of benefit was limited to a follow up of only

around one month, but recently published studies show that the benefit of

glycoprotein IIb/IIIa antagonists is maintained for at least six months (and

possibly longer).5153 Despite this, the oral IIb/IIIa-antagonists have not been found

to add to the effects of aspirin.54

Similarly, the addition of dipyridamole to aspirin has not been shown clearly to

produce additional reductions in serious vascular events, although one trial

suggested that there may be a worthwhile further reduction in stroke.17 Reasons

for this apparent effect on stroke in that study include the possibility that the

newer (and more bioavailable) formulation of dipyridamole was more effective

than the older preparation. It is also plausible that these findings (which were not

supported by other studies) arose largely or wholly by the play of chance, or were

due to an insufficient daily aspirin dose or a slight antihypertensive effect of

dipyridamole. Dipyridamole is being tested further in the European and Australian

stroke prevention in reversible ischaemia trial.55

Clopidogrel and ticlopidine, which are both thienopyridines, act by blocking ADP

dependent activation of platelets. The effects of their antiplatelet properties on

occlusive vascular events could therefore be complementary to those of aspirin,

which inhibits thromboxane dependent activation. A large trial that assessed the

effects of adding clopidogrel to aspirin among patients with unstable anginarecently reported promising results,42 and the second Chinese cardiac study is

assessing this question among patients with acute myocardial infarction.56 Long

term studies of the effects of adding clopidogrel to aspirin might also be useful

among other types of patients at high risk of occlusive vascular disease. Such

studies could also examine the important question of whether adding clopidogrel

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is effective in patients who were taking aspirin when the event occurred (so

called aspirin failures).

In the high risk setting of percutaneous coronary intervention or among high risk

patients with an acute coronary syndrome, intensification of antiplatelet therapy

by adding an intravenous glycoprotein IIb/IIIa antagonist or thienopyridine to

aspirin may be appropriate. In other circumstances, however, aspirin at a dose of

75-150 mg daily is likely to be an appropriate antiplatelet regimen unless patients

have a definite contraindication to aspirinfor example, definite allergy or

appreciable gastric symptoms even with low dose aspirin. Clopidogrel might be

an appropriate alternative in such patients.

Benefits exceed hazards in most high riskpatientsOur results suggest that among individuals at high risk of occlusive vascular

disease, the proportional risk reductions with antiplatelet therapy are roughly

similar in most categories of patient (although they are smaller in acute stroke).

Consequently, a patient's absolute risk is likely to be more important than the

proportional reduction in serious vascular events in determining the likely benefit

of antiplatelet therapy. In patients at particularly high risk of vascular events, the

benefits of antiplatelet therapy are large. For example, among 1000 patients with

acute myocardial infarction who are given one month of aspirin and then continue

to take low dose aspirin for some years, about 40 would avoid a serious vascular

event during the first month and about a further 40 would avoid a vascular event

in the next couple of years. Similar sized long term benefits are likely to be seen

if antiplatelet therapy is started soon after stroke or transient ischaemic attack

and continued long term. Even in patient populations at intermediate risk (2-3% a

year of serious occlusive vascular events) such as some patients with no

previous vascular event but with stable angina, atrial fibrillation, or peripheralarterial disease, antiplatelet therapy for a couple of years would be expected to

prevent about 10-15 vascular events for every 1000 patients treated.

The present evidence suggests that the proportional increase in the risk of major

bleeding of about one half is similar among a wide range of categories of patient.

Population based observational studies have found that regular use of aspirin (at

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a dose of 300 mg/day) is associated with around a twofold increased risk of

upper gastrointestinal bleeding (or perforation).57 It therefore seems likely that the

benefits of antiplatelet therapy will far outweigh any hazards unless the absolute

risk of bleeding is high (such as among haemodialysis patients) or the absolute

risk of a vascular event is low (as in apparently healthy people). Consequently,

unless some definite contraindication exists, antiplatelet therapy should be

considered routinely for all patients whose medical history implies a significant

risk of occlusive vascular disease over the next few months or years, and it

should generally be continued for as long as the risk remains high.

Potential for wider use of antiplatelet

therapy in high risk patientsRecent audits have shown that the use of antiplatelet therapy has increasedduring the past few years but that a substantial proportion of high risk patients

still do not receive it. For example, only about half (or less) of all patients with a

history of myocardial infarction, angina, or peripheral arterial disease are

currently receiving antiplatelet therapy, and rates tend to be lower in older people

despite their higher absolute risk.5860 Use of aspirin among patients with diabetes

is even more limited, with one survey suggesting that less than a quarter of those

with a clear history of coronary artery disease were taking regular aspirin,58 and

another study finding that only 7% of those without a history of coronary artery

disease were taking aspirin.60 Similarly, only about one third of patients with atrial

fibrillation receive oral anticoagulants, the most effective treatment for the

prevention of strokes in this condition. 6162 This may be because of the associated

risks of bleeding and the need for anticoagulation monitoring. But less than half

of such patients who are not taking anticoagulants receive antiplatelet therapy

despite the high risk of stroke (especially in elderly people). 6364

These results reinforce the value of ensuring that antiplatelet therapy with 75-150mg aspirin daily (or some other effective antiplatelet regimen) is considered

routinely for all such patients at high or intermediate risk of occlusive vascular

events (more than about 2% a year), irrespective of whether they have already

had a major vascular event. An unanswered question, however, is whether it is

possible to identify particular groups of apparently healthy people who may be at

increased risk of myocardial infarction or stroke and for whom the benefits of

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daily aspirin outweigh the hazards. This is currently being investigated in an

analysis of primary prevention trials. For most healthy individuals, however, for

whom the risk of a vascular event is likely to be substantially less than 1% a year,

daily aspirin may well be inappropriate.

Co-morbidities and ACS: Do they have a role in risk

stratification?

11 October 2006

Editor- Fox et al and the GRACE group have done this important and clinically

relevant study, presenting us with a remarkably easy to apply tool for risk

stratification at the point of diagnosis and aid appropriate identification of patients

for more intensive treatment incluiding reperfusion therapy compared to the

currently used TIMI scoring.(1) Given the patients in the GRACE registry spansthe spectrum of acute coronary syndrome and is based on an unselected

contemporary population, this predictive model do not have the limitations seen

with large clinical trial databases.

Of particular interest is the non-inclusion of co-morbidities like stroke, diabetes

and atrial fibrillation in the risk prediction tool, since as shown in this study, they

do attain statistical significance in both death and death/MI model(2). STROKE-

Death model: x2 of 69.2, CI 1.8 (1.56 to 2.10), Death/MI model x2 of 36.5, CI 1.4

(1.26 to 1.58); DIABETES - Death model x2 of 61.2, CI 1.5 (1.36 to 1.67),

Death/MI model: x2 of 29.4, CI 1.2 (1.15 to 1.35) and ATRIAL FIBRILLATION-

Death model: x2 of 152.8,CI 2.3 (2.00 to 2.60), Death/MI model- x2 of 46.9, CI

1.5 (1.33 to 1.66).

In the UKPDS study (3) a subgroup analysis suggested that reducing the HbA1C

value by 1% was associated with an 18% percent reduction in MI and a 15%

reduction in stroke.

Another interesting difference from the TIMI risk score is the usage of aspirin in

last 7 days not been tested, also prior coronary artery disease not attaining

statistical significance (2)- Coronary artery disease: Death model x2 of 13.4, CI

0.8 (0.72 to 0.91)and Death/MI model x2 of 78.1, CI 0.7 (0.63 to 0.74).

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This study will definitely help in initial and further management decisions of

patients presenting with acute coronary syndromes to A&E and MAU.

Prospective data on its usage will further consolidate the relevance of this risk

prediction tool.