**2. Clinical ASA resistance**

The antithrombotic effect of ASA has been primarily attributed to the irreversible blockade of the cyclooxygenase- 1 (COX-1) enzyme in platelets that leads to attenuation in the pro‐ duction of an important platelet agonist, thromboxane A2 TXA2 (1; 2). ASA irreversibly in‐ hibits cycloxygenase-1 by acetylating a serine residue at position 529, thereby preventing the conversion of arachidonic acid to unstable prostaglandine intermediate PGH2, which is con‐ verted to thromboxane TxA2, a potent vasoconstrictor and platelet agonist [22]. The finding that a considerable number of patients show an impaired antiplatelet effect of ASA in CAD patients, eminently after CABG threw new light into the discussion concerning poor paten‐ cy rates of bypass grafts: the early period after CABG shows a coincidence of an increased risk for bypass thrombosis (amongst others, due to platelet activation and endothelial cell disruption of the graft) and an increased prevalence of ASA resistance [5]. In recent years,

© 2013 Kammerer; licensee InTech. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2013 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

an increasing number of reports about ASA resistance have led to a growing concern among clinicians and patients about the efficacy of ASA treatment (6; 7; 8; 9), although one study group could not reveal any ASA resistance after CABG [10]. ASA resistance can be defined clinically as an ischemic event while on ASA therapy. Various studies have evaluated the antiplatelet effect of ASA therapy and have reported the prevalence of ASA resistance 0.4% - 35% of cardiovascular [11, 18] and 5 - 65% of stroke patients [19, 20].

detecting ASA resistance can not be used interchangeably. Simple linear regression analysis revealed significant association among CEPI-CT, AA TPA and AA IPA and collagen IPA Table 2 [14]. In the majority of cases AA IPA (impedance platelet aggregation induced by

**Collagen**

NS

CEPI-CT, collagen/epinephrine closure times; TPA, turbidimetric platelet aggregation; AATPA, turbidimetric platelet aggregation induced by arachidonic acid; collagen TPA, turbidimetric platelet aggregation induced by collagen; IPA, impedance platelet aggregation; AAIPA, impedance platelet aggregation induced by arachidonic acid; collagen IPA,

**Table 2.** Linear regression analysis (Spearman rank correlation coefficients, levels of significance (*P<0.01*)) determined

The clean comparison between both different procedures of CABG: on- and off-pump sur‐ gery is unperformed, the role of using extracorporeal circulation as potential destroyer of cell components for ASA Response uncertain. ASA resistence is a transient phenomenon during the early postoperatively period in approximately 30% of OPCAB patients, whereby

The new age antiplatelet therapy with clopidogrel, prasugrel or ticagrelor seems be effective in most cardiology diseases (Platelet Inhibition and Patient Outcomes = PLATO Study) like acute coronary syndrome (ACS), unstable angina pectoris, myocardial infarction (non-STE‐ MI or STEMI) with non- and invasive procedures [13], however is not standard medication for patients after CABG procedure like ASA. Clopidogrel (75mg/day) is a prodrug, which needs to be metabolized in the liver to active metabolites catalysed by Cytochrom-P450- Oxygenase CYP 3A4 and 3A5, which irreversibly inactivate the platelet ADP receptor P2Y12. Different to ASA clopidogrel does to influent the thienopyridins not cyclooxygenase and thromboxan formation. Platelet inhibition in patients group with response to clopidogrel was enhanced by switching to ticagrelol therapy and all clopidogrel. A few studies have re‐ vealed important individual heterogeneity in platelet response to clopidogrel in patients

*p<0,0001 p<0,0001 p=0001*

**AAIPA**

Aspirin Therapy Resistance in Coronary Artery Bypass Grafting

**TPA IPA**

*r=0,38\* r=0,43\* r=0,28 p<0,0001 p<0,0001 p=0,0006*

*r=0,35 r=0,31*

**Collagen**

http://dx.doi.org/10.5772/54414

189

*r=0,22 p=0,006*

*r=0,52 p<0,0001*

arachidonic acid) [16, 17] and ADP-induced platelet aggregation [4] were utilized.

**AATPA**

*r=0,49\**

**Collagen TPA** NS

in 42 CABG patients before, 1h and 24 h after 300 mg of aspirin intravenously (n=126)

**CEPI-CT**

**AATPA**

**AAIPA**

\*confirmed by multiple regression analysis

impedance platelet aggregation induced by collagen.

the ASA response was revered by 6 months [16, 17].

ASA failure has been attributed to many causes, including insufficient dosage, reduced ab‐ sorption or increased metabolism, diabetes mellitus, genes polymorphisms, cell-cell and drug-drug interactions and poor compliance [12]. Recent findings have suggested that the pyrazolinone analgesic metamizol, ibuprofen and other nonsteroidal analgesic anti-inflam‐ matory drugs, but not diclofenac, may prevent the irreversible inhibition of platelet throm‐ boxane formation by ASA [15]. The variation suggests about many more treatment failures with ASA therapy (including incompliance of patients) can be explained by a reduced anti‐ platelet effect for pharmacological reasons Table 1.

*Drug-related* ASA / Clopidogrel resistance


*Disease-relatedASA* / Clopidogrel *resistance*


#### **3. ASA response tests**

The common using tests platelet function analyzer (PFA-100TM) closure times (CT); turbidi‐ metric platelet aggregation (TPA) and impedance platelet aggregation (IPA) depending of platelet and leukocyte counts, Hb, fibrinogen and von Willebrand factor collagen binding assay (VWF:CBA), the best valid laboratory procedure was not been determinate to screen for ASA or clopidogrel resistance. One of the studies on on-pump CABG patients agrees with previous findings suggesting that different platelet function assays that are suitable for

**Table 1.** Mechanisms of ASA / Clopidogrel resistance

detecting ASA resistance can not be used interchangeably. Simple linear regression analysis revealed significant association among CEPI-CT, AA TPA and AA IPA and collagen IPA Table 2 [14]. In the majority of cases AA IPA (impedance platelet aggregation induced by arachidonic acid) [16, 17] and ADP-induced platelet aggregation [4] were utilized.


\*confirmed by multiple regression analysis

an increasing number of reports about ASA resistance have led to a growing concern among clinicians and patients about the efficacy of ASA treatment (6; 7; 8; 9), although one study group could not reveal any ASA resistance after CABG [10]. ASA resistance can be defined clinically as an ischemic event while on ASA therapy. Various studies have evaluated the antiplatelet effect of ASA therapy and have reported the prevalence of ASA resistance 0.4% -

ASA failure has been attributed to many causes, including insufficient dosage, reduced ab‐ sorption or increased metabolism, diabetes mellitus, genes polymorphisms, cell-cell and drug-drug interactions and poor compliance [12]. Recent findings have suggested that the pyrazolinone analgesic metamizol, ibuprofen and other nonsteroidal analgesic anti-inflam‐ matory drugs, but not diclofenac, may prevent the irreversible inhibition of platelet throm‐ boxane formation by ASA [15]. The variation suggests about many more treatment failures with ASA therapy (including incompliance of patients) can be explained by a reduced anti‐

35% of cardiovascular [11, 18] and 5 - 65% of stroke patients [19, 20].

• Prevention of binding to the Ser529 by other NSAID (Ibuprofen, Indomethacin, Naproxen)

• Gene polymorphism(s) (COX-1, COX-2, Thromboxan-A2-synthase, Glycoprotein Ia / IIb-, -Ib / V / IX and IIb / IIIa

The common using tests platelet function analyzer (PFA-100TM) closure times (CT); turbidi‐ metric platelet aggregation (TPA) and impedance platelet aggregation (IPA) depending of platelet and leukocyte counts, Hb, fibrinogen and von Willebrand factor collagen binding assay (VWF:CBA), the best valid laboratory procedure was not been determinate to screen for ASA or clopidogrel resistance. One of the studies on on-pump CABG patients agrees with previous findings suggesting that different platelet function assays that are suitable for

platelet effect for pharmacological reasons Table 1.

• Insufficient bioavailability (low dose-effect relationship)

receptor, Collagen, v.-Willebrand factor and factor VIII)

• Platelet hyperreactivity due to ASA-insensitive mechanisms

**Table 1.** Mechanisms of ASA / Clopidogrel resistance

• Alternative metabolism of thromboxan-A2-biosynthesis (ASA resistance) • Changing of enteral resoption and biotransformation (Clopidogrel resistance)

*Drug-related* ASA / Clopidogrel resistance

• Pharmacokinetics / Pharmacodynamics

• Exogenous toxins (diabetes mellitus, smoking) • Impaired sensitivity of platelet COX-1 (CABG)

*Disease-relatedASA* / Clopidogrel *resistance*

• Changes in the collagen receptor • Platelet "sensitizing" by Isoprostanes

**3. ASA response tests**

• Incompliance (23)

188 Artery Bypass

CEPI-CT, collagen/epinephrine closure times; TPA, turbidimetric platelet aggregation; AATPA, turbidimetric platelet aggregation induced by arachidonic acid; collagen TPA, turbidimetric platelet aggregation induced by collagen; IPA, impedance platelet aggregation; AAIPA, impedance platelet aggregation induced by arachidonic acid; collagen IPA, impedance platelet aggregation induced by collagen.

**Table 2.** Linear regression analysis (Spearman rank correlation coefficients, levels of significance (*P<0.01*)) determined in 42 CABG patients before, 1h and 24 h after 300 mg of aspirin intravenously (n=126)

The clean comparison between both different procedures of CABG: on- and off-pump sur‐ gery is unperformed, the role of using extracorporeal circulation as potential destroyer of cell components for ASA Response uncertain. ASA resistence is a transient phenomenon during the early postoperatively period in approximately 30% of OPCAB patients, whereby the ASA response was revered by 6 months [16, 17].

The new age antiplatelet therapy with clopidogrel, prasugrel or ticagrelor seems be effective in most cardiology diseases (Platelet Inhibition and Patient Outcomes = PLATO Study) like acute coronary syndrome (ACS), unstable angina pectoris, myocardial infarction (non-STE‐ MI or STEMI) with non- and invasive procedures [13], however is not standard medication for patients after CABG procedure like ASA. Clopidogrel (75mg/day) is a prodrug, which needs to be metabolized in the liver to active metabolites catalysed by Cytochrom-P450- Oxygenase CYP 3A4 and 3A5, which irreversibly inactivate the platelet ADP receptor P2Y12. Different to ASA clopidogrel does to influent the thienopyridins not cyclooxygenase and thromboxan formation. Platelet inhibition in patients group with response to clopidogrel was enhanced by switching to ticagrelol therapy and all clopidogrel. A few studies have re‐ vealed important individual heterogeneity in platelet response to clopidogrel in patients with stable coronary disease, but the clinical significance of this phenomenon has not yet been investigated. Matetzky showed in his study that in 15 out of 60 consecutive patients STEMI (25%) were resistant to clopidogrel and subsequently were at increased risk of recur‐ rent cardiovascular events in a 6-month follow-up [24].

**References**

Surg; 212:982–4

126(Suppl 3):600-8S

Drug Monit;27 :484–90

Surg; 212:982–4

40-6

in resistance. Thromb Res;115: 25–9

coronary artery bypass surgery. Circulation;108: 542–7

Study *Circulation*; 115;3156-64

[1] Patrono C, Coller B, FitzGerald GA, Hirsh J, Roth G. 2004 Platelet-active drugs: the relationships among dose, effectiveness, and side effects: the Seventh ACCP Confer‐

Aspirin Therapy Resistance in Coronary Artery Bypass Grafting

http://dx.doi.org/10.5772/54414

191

[2] Antithrombotic Trialists' Collaboration. 2002 Collaborative meta-analysis of random‐ ized trials of antiplatelet therapy for prevention of death, myocardial infarction, and

[3] Zimmermann N, Kienzle P, Weber AA, Winter J, Gams E, Schröder K, Hohlfeld T. 2001 Aspirin resistance after coronary artery bypass grafting. J Thorac Cardiovasc

[4] Gurbel PA, Bliden KP, DiChiara J, Newcomer J, Weng W, Neerchal NK, Gesheff T, Chaganti SK, Etherington A, Tantry US 2007 Evaluation of dose-related effects of As‐ pirin on platelet function: results from the Aspirin-induced platelet effect (ASPECT)

[5] Stein PD, Schunemann HJ, Dalen JE, Gutterman D. 2004 Antithrombotic therapy in patients with saphenous vein and internal mammary artery bypass grafts: The sev‐ enth ACCP conference on Antithrombotic and Thrombolytic therapy Chest;

[6] Golanski J, Chlopicki S, Golan´ ski R, Gresner P, Iwaszkiewicz, A, Watala C. 2005 Re‐ sistance to aspirin in patients after coronary artery bypass graftings is transient. Ther

[7] Yilmaz MB, Balbay Y, Caldir V, Ayez S, Guray Y, Guray U, Korkmaz S. 2005 Late sa‐ phenous vein graft occlusion in patients with coronary bypass: Possible role of aspir‐

[8] Zimmermann N, Kienzle P, Weber AA, Winter J, Gams E, Schröder K, Hohlfeld T. 2001 Aspirin resistance after coronary artery bypass grafting. J Thorac Cardiovasc

[9] Zimmermann N, Wenk A, Kim U, Kienzle P, Weber AA, Gams E, Schröder K, Hohl‐ feld T. 2003 Functional and biochemical evaluation of platelet aspirin resistance after

[10] Mengistu AM, Wolf MW, Boldt J, Röhm KD, Lang J, Piper SN. 2008 Evaluation of a new platelet function analyzer in cardiac surgery: a comparison of modified throm‐ boelastography and whole-blood aggregometry. J Cardiothorac Vasc Anesth.; 22 (1):

[11] Cox D, Maree AO, Dooley R, Byrne MF, Fitzgerald DJ. 2006 Effect of enteritic coating on antiplatelet activity of low-dose aspirin in healthy volunteers. Stroke; 37: 3153–58

ence on Antithrombotic and Thrombolytic Therapy. *Chest*; 126: 234–64

stroke in high-risk patients. *BMJ.* 324:71– 86

Non-Responders and Responders treated with ticagrelor will have platelet reactivity below the cut points associated with ischemic risk in the RESPOND Study [4]. Their resistance in cardiac surgery after using of extracorporeal circulation (on-pump) or without (off pump) is unidentified.

Regarding the PLATO trials (Platelet Inhibition and Patient Outcome by ticagrelol) under‐ went CABG endpoints were a non-significant reduction of the primary endpoint like total major bleeding [HR: 0.84 (95% CI = 0.60–1.16), p = 0.29], significant reduction of CV death [HR: 0.52 (95% CI = 0.32–0.85)] and all-cause death [HR: 0.49 (95%CI = 0.32– 0.77)] [13]. CABG-related major bleedings according to PLATO or TIMI bleeding definitions were ob‐ served very commonly during CABG.
