Aspirin Aspirin ResistanceResistance

Issa Majed Ghanma MD.Issa Majed Ghanma MD.

Platelets Platelets FunctionFunction

- Platelets play an important role in - Platelets play an important role in homeostasis.homeostasis.

- they bind to collagen and to each - they bind to collagen and to each other forming a barrier to blood loss other forming a barrier to blood loss at the site of injury.at the site of injury.

Cont. Platelets Cont. Platelets FunctionFunction

they accelerate the rate of activation of they accelerate the rate of activation of coagulation proteins and release coagulation proteins and release

granules that promote further platelet granules that promote further platelet activation and healing.activation and healing.

Cont. Platelet Cont. Platelet FunctionFunction

- There are many important - There are many important platelets agonists:platelets agonists:

1- thrombin1- thrombin

2- thromboxane A2 2- thromboxane A2

3- ADP3- ADP

Antiplatelet Antiplatelet AgentsAgents

Several antiplatelet agents are Several antiplatelet agents are available that work at different sites of available that work at different sites of platelet activation:platelet activation:

1- Aspirin.1- Aspirin.

2- Clopidogrel .2- Clopidogrel .

3- dipyridamole . 3- dipyridamole .

4- thrombin inhibitors (bivalirudin, 4- thrombin inhibitors (bivalirudin, lepirudin).lepirudin).

5- IIb / IIIa receptor blockers. 5- IIb / IIIa receptor blockers.

The History of The History of AspirinAspirin

- Salicylates have been used to treat - Salicylates have been used to treat pain and inflammation associated with pain and inflammation associated with rheumatism.rheumatism.

- Industrial production of salicylic acid - Industrial production of salicylic acid started in 1859, however early started in 1859, however early preparation were associated with side preparation were associated with side effects, such as unpleasant taste and effects, such as unpleasant taste and dyspepsia.dyspepsia.

- Felix Hoffman of Friedrich Bayer & - Felix Hoffman of Friedrich Bayer & Co. developed a stable and better-Co. developed a stable and better-tolerated form of the drug tolerated form of the drug (acetylsalicylic acid). (acetylsalicylic acid).

Cont. Aspirin Cont. Aspirin HistoryHistory

1950… Reports linked 1950… Reports linked aspirin use with aspirin use with prolongation of bleeding prolongation of bleeding time. time.

1970… Aspirin 1970… Aspirin demonstrated to be a potent demonstrated to be a potent inhibitor of prostaglandin inhibitor of prostaglandin synthesis.synthesis.

Later …Later … It was confirmed It was confirmed that aspirin acetylates that aspirin acetylates serine 529 in the active site serine 529 in the active site of the cyclooxygenase-1 of the cyclooxygenase-1 enzyme enzyme (prostaglandin H2 synthase-(prostaglandin H2 synthase-1), permanently 1), permanently deactivating it and deactivating it and preventing thromboxane A2 preventing thromboxane A2 platelet activation.platelet activation.

These observations paved These observations paved the way for the clinical the way for the clinical investigation of aspirin's investigation of aspirin's antiplatelet effects in antiplatelet effects in preventing thrombotic preventing thrombotic events, such as ischemic events, such as ischemic strokes and acute strokes and acute myocardial infarction.myocardial infarction.

Mechanism Of Action Of Mechanism Of Action Of

AspirinAspirin Aspirin inhibit the Aspirin inhibit the cyclooxygenase (COX) cyclooxygenase (COX) activity of prostaglandin activity of prostaglandin (PG), which in turn blocks (PG), which in turn blocks the metabolism of the metabolism of arachidonic acid to cyclic arachidonic acid to cyclic prostanoids such as prostanoids such as thromboxane A2 (TXA2).thromboxane A2 (TXA2).

Aspirin Membrane Phospholipids

(Phospholipase A)

Arachidonic Acid

(COX-1/PGH-Synthase)

Prostaglandin G2

Prostaglandin H2

(HOX/PGH-Synthase)

(PGH-Synthase)

TXA2

-Increased platelet aggregation.

-Vasoconstriction.

Platelet COX-1 inhibition

Pharmacokinetics Of Pharmacokinetics Of AspirinAspirin

-Aspirin is rapidly absorbed from the -Aspirin is rapidly absorbed from the gastrointestinal tract and peak plasma gastrointestinal tract and peak plasma concentration are achieved in 30 to 40 concentration are achieved in 30 to 40 minutes.minutes.

-Significant platelet inhibition is noted -Significant platelet inhibition is noted within 60 minute of ingestion and a within 60 minute of ingestion and a single dose of 100mg of aspirin can single dose of 100mg of aspirin can completely block TXA2 production for completely block TXA2 production for the life of the platelet in most individual.the life of the platelet in most individual.

-The plasma half-life of aspirin -The plasma half-life of aspirin is only 20 minutes but the is only 20 minutes but the irreversible nature function irreversible nature function makes once-daily dosing makes once-daily dosing sufficient to maintain its sufficient to maintain its antithrombotic benefit.antithrombotic benefit.

Cont. Cont. Pharmacokinetics Pharmacokinetics

Of AspirinOf Aspirin

Aspirin EfficacyAspirin Efficacy- Aspirin plays an important role in - Aspirin plays an important role in primary and secondary prevention of primary and secondary prevention of vascular events.vascular events.

- Aspirin is very effective therapy for - Aspirin is very effective therapy for patients suffering an acute M.I, as patients suffering an acute M.I, as demonstrated by (ISIS-2) trial in which demonstrated by (ISIS-2) trial in which aspirin administration reduced aspirin administration reduced mortality by 23%, a comparable effect mortality by 23%, a comparable effect to thrombolytic therapy. to thrombolytic therapy.

People still have events People still have events while on ASA!!!while on ASA!!!

Do all patients respond in Do all patients respond in the same way?the same way?

Definition(s) of “APT Definition(s) of “APT

Resistance?”Resistance?” The fact that some patients may The fact that some patients may experience recurrent vascular events experience recurrent vascular events despite the use of APT should be despite the use of APT should be properly defined as “treatment failure” properly defined as “treatment failure” rather than “APT resistance” (multiple rather than “APT resistance” (multiple pathways mediate thrombotic events).pathways mediate thrombotic events).

APT Resistance/Non-APT Resistance/Non-responsiveness=failure to inhibit the responsiveness=failure to inhibit the targettargetAPT Resistance/Non-APT Resistance/Non-responsiveness≠clinical failure responsiveness≠clinical failure

Antiplatelet Drug Antiplatelet Drug ResistanceResistance

1- What do we know about it ?1- What do we know about it ?

2- How do we define it ?2- How do we define it ?

3- What do we do about it ?3- What do we do about it ?

AspirinAspirin ResistanceResistance

- Clinical observation of aspirin's - Clinical observation of aspirin's inability to protect individuals from inability to protect individuals from thrombotic complications. thrombotic complications.

- Laboratory phenomenon of absence of - Laboratory phenomenon of absence of aspirin's effect on one or more tests of aspirin's effect on one or more tests of platelets function. platelets function.

Aspirin Aspirin ResistanceResistance No… formal diagnostic No… formal diagnostic

criteria…but aspirin resistance criteria…but aspirin resistance generally describes the failure generally describes the failure of aspirin to produce an of aspirin to produce an expected biological response or expected biological response or the failure of aspirin to prevent the failure of aspirin to prevent atherothrombotic events. atherothrombotic events. Aspirin resistance has been Aspirin resistance has been reported to occur in 5% to 45% reported to occur in 5% to 45% of the general population.of the general population.

The exact prevalence of The exact prevalence of aspirin resistance remains aspirin resistance remains uncertain… but uncertain… but Measurement of platelet Measurement of platelet aggregation, platelet aggregation, platelet activation, and bleeding time activation, and bleeding time have all confirmed variability have all confirmed variability in patient's anti-thrombotic in patient's anti-thrombotic responses to aspirin therapy.responses to aspirin therapy.

Cont. Aspirin Cont. Aspirin ResistanceResistance

Platelet Function TestsPlatelet Function Tests

.. Platelet aggregation Platelet aggregation Light transmittance aggregometry (LTA)←gold standard Light transmittance aggregometry (LTA)←gold standard impedance platelet aggregation impedance platelet aggregation

.. Flow Cytometry Flow Cytometry GPIIb/IIIa receptors activation GPIIb/IIIa receptors activation P-selectin expression P-selectin expression Monocyte-platelet aggregates Monocyte-platelet aggregates

Vasodilator-associated stimulated phosphoprotein (VASP)Vasodilator-associated stimulated phosphoprotein (VASP)

. . Point-of-care Point-of-care Ultegra rapid platelet function analyzer (Verify Now)Ultegra rapid platelet function analyzer (Verify Now) Thromboelastagraph (TEG)Thromboelastagraph (TEG) Platelet worksPlatelet works Cone and platel(let) analyzer (IMPACT)Cone and platel(let) analyzer (IMPACT)

..Genetic testingGenetic testing

Potential mechanisms Potential mechanisms /causes of aspirin /causes of aspirin

resistanceresistance

Although the mechanism for Although the mechanism for aspirin resistance remains aspirin resistance remains uncertain, it is likely due to a uncertain, it is likely due to a combination of clinical, biological, combination of clinical, biological, and genetic properties affecting and genetic properties affecting platelet function.platelet function.

Aspirin Resistance Patient Aspirin Resistance Patient

ManagementManagement

- Educate patients on importance of - Educate patients on importance of compliancecompliance

- Eliminate interfering substances - Eliminate interfering substances (ibuprofen) (ibuprofen)

- Increase aspirin dose(?) (….increasing - Increase aspirin dose(?) (….increasing the dose of aspirin does not enhance the dose of aspirin does not enhance COX-1 inhibition)COX-1 inhibition)

- Use other anti-platelet medications - Use other anti-platelet medications (e.g. clopidogrel) (?) (….no scientific (e.g. clopidogrel) (?) (….no scientific evidence that switching to alternative evidence that switching to alternative treatment strategies improves treatment strategies improves outcomes).outcomes).

Main pointsMain points1-Aspirin is effective antiplatelet agent 1-Aspirin is effective antiplatelet agent with proven benefit in the prevention with proven benefit in the prevention of atherothrombotic complications of of atherothrombotic complications of cardiovascular; however, the absolute cardiovascular; however, the absolute risk of recurrent vascular events risk of recurrent vascular events among patients taking aspirin among patients taking aspirin relatively high.relatively high.

2-Although formal diagnostic criteria 2-Although formal diagnostic criteria are lacking, aspirin resistance are lacking, aspirin resistance generally describes the failure of generally describes the failure of aspirin to produce an expected aspirin to produce an expected biological response (ie, platelet biological response (ie, platelet inhibition) or to prevent inhibition) or to prevent atherothrombotic events atherothrombotic events

3-Aspirin resistance has been estimated 3-Aspirin resistance has been estimated to exist in anywhere from 5% to 45% of to exist in anywhere from 5% to 45% of the population, representing a the population, representing a phenomenon of possible clinical phenomenon of possible clinical significance.significance.

4-Traditionally, platelet aggregation has 4-Traditionally, platelet aggregation has been measured in platelet-rich plasma been measured in platelet-rich plasma using an optical aggregometer. Other using an optical aggregometer. Other effective means of analizing platelet effective means of analizing platelet function include the platelet function function include the platelet function analyzer (PFA)-100 and the rapid analyzer (PFA)-100 and the rapid platelet function assay (RPFA). platelet function assay (RPFA).

ConclusionsConclusions- Variability in individual responsiveness to - Variability in individual responsiveness to antiplatelet agents is an emerging clinical antiplatelet agents is an emerging clinical problem: poor responsiveness has been problem: poor responsiveness has been associated with an increased risk of ischemic associated with an increased risk of ischemic events, including stent thrombosis.events, including stent thrombosis.

- - WHATWHAT and and HOWHOW to measure antiplatelet to measure antiplatelet drug responsiveness still needs to be fully drug responsiveness still needs to be fully defined.defined.

- - WHATWHAT do we do with the results coming do we do with the results coming from the “test tube”? (No demonstration of an from the “test tube”? (No demonstration of an association with clinical events conditioning association with clinical events conditioning cost-effective changes in treatment).cost-effective changes in treatment).

- responsiveness to antiplatelet therapy - responsiveness to antiplatelet therapy should be evaluated for mainly investigation should be evaluated for mainly investigation purposes!!! purposes!!!

Thank YouThank You

AspirinAspirin Resistance: Resistance:Relative Risk Of Different Relative Risk Of Different

eventsevents Events Events Relative riskRelative risk

M.I or UAP M.I or UAP 3.8 3.8

Stroke or TIA Stroke or TIA 4.14.1