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Aspirin and Clopidogrel Drug Response in Patients Undergoing Percutaneous Coronary Intervention

Aspirin and Clopidogrel Drug Response in Patients Undergoing Percutaneous Coronary Intervention. Eli I. Lev, MD; Rajnikant T. Patel, MD; Kelly J. Maresh, RN, BSN; Sasidhar Guthikonda, MD; Juan Granada, MD; Timothy DeLao, MLT; Paul F. Bray, MD; Neal S. Kleiman, MD. Published in

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Aspirin and Clopidogrel Drug Response in Patients Undergoing Percutaneous Coronary Intervention

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  1. Aspirin and Clopidogrel Drug Response in Patients Undergoing Percutaneous Coronary Intervention Eli I. Lev, MD; Rajnikant T. Patel, MD; Kelly J. Maresh, RN, BSN; Sasidhar Guthikonda, MD; Juan Granada, MD; Timothy DeLao, MLT; Paul F. Bray, MD; Neal S. Kleiman, MD Published in Journal of the American College of Cardiology 2006

  2. Aspirin and Clopidogrel Drug Response: Background • Treatment with aspirin and clopidogrel has become the standard therapy in patients undergoing PCI with stenting; yet responses to these drugs vary widely among individuals. • Data concerning the concurrent responses to both drugs are limited. • The objective of this study was to prospectively evaluate the response to clopidogrel among aspirin-sensitive patients compared with aspirin-resistant patients, and to distinguish factors that affect the responses to either drug in patients undergoing elective PCI. Lev et al., JACC 2006 Jan;47(1):27-33.

  3. Aspirin and Clopidogrel Response: Study Design 150 patients undergoing elective PCI , who received aspirin 81-325 mg daily but not clopidogrel ≥1 week prior to PCI, no thienopyridine or GP IIb/IIIa for a week prior to enrollmentand excluding those with: acute myocardial infarction within 1 week; contraindications to aspirin, bivalirudin, or clopidogrel; thrombocytopenia; anemia; or renal failure. Prospective. Elective PCI with Stenting + Standard course of IV bivalirudin bolus (0.75 mg/kg) followed by infusion (1.75 mg/kg/h) until PCI completion Post-PCI: 300 mg clopidogrel and 325 mg oral aspirin in cath lab followed by 75 mg clopidogrel and 325 mg aspirin daily Aspirin-sensitive Aspirin-resistant • Primary Endpoint: Response to clopidogrel in aspirin-resistant and aspirin-sensitive patients Lev et al., JACC 2006 Jan;47(1):27-33.

  4. Aspirin and Clopidogrel Response: Methods • Platelet Aggregation: -Turbidimetric platelet aggregation in platelet-rich plasma with platelet count adjusted to 250x103/mm3. -Degree of aggregation was defined as the maximal light transmission ≤6 min after agonist was added. Platelet-poor plasma used as reference. • Platelet Activation: -Platelet activation was determined by assessing platelet surface expression of activated GP IIb/IIIa receptors and P-selectin in response to ADP stimulation using flow cytometry. • Rapid Platelet Function Assay-Aspirin (RPFA-ASA): -Results expressed as aspirin reaction units (ARU). ARU ≥550 indicates detection of aspirin-induced platelet dysfunction. (RPFA-ASA did not use AA as agonist). Lev et al., JACC 2006 Jan;47(1):27-33.

  5. Aspirin and Clopidogrel Response: Methods cont. • Definitions: -Clopidogrel resistance: absolute difference between baseline and post-treatment aggregation ≤10% in response to both 5 and 20 μmol/L ADP. -ASA resistance definition (incorporated previously used criteria) required two of the following three: 1) 0.5mg/ml AA-induced platelet aggregation ≥20%; 2) 5 μmol/L ADP-induced platelet aggregation ≥70%; and 3) RPFA-ASA ARU ≥550. -Additional definitions to allow comparison with prior studies: 1) Criteria 1 + 2 2) Criterion 3 - Baseline blood samples used to determine ASA resistance Lev et al., JACC 2006 Jan;47(1):27-33.

  6. Aspirin and Clopidogrel Drug Response: Resistance Rates Clopidogrel Resistance (% of patients) • Clopidogrel resistance was evident in 36 patients (24%). % patients Lev et al., JACC 2006 Jan;47(1):27-33.

  7. % patients n=23 n=19 n=14 Aspirin and Clopidogrel Drug Response: Resistance Rates • Using the primary definition (having ≥2 of the criteria), 19 patients were observed to ASA-resistant (12.7%, p=0.01). • The definition requiring the presence of criteria 1 & 2 (≥AA induced aggregation and ≥70% 5 μmol/L ADP-induced aggregation), 14 patients were ASA resistant (9.3%, p=0.02). • Under the definition requiring criterion 3 (RPFA-ASA ARU ≥550), 23 patients were ASA-resistant (15.3%, p=0.01). Aspirin Resistance (% of patients) p=0.01 p=0.01 p=0.02 Lev et al., JACC 2006 Jan;47(1):27-33.

  8. Aspirin and Clopidogrel Drug Response: Resistance Rates Clopidogrel resistance among ASA-resistant and ASA-sensitive patients (% of patients) • Regardless of which ASA resistance definition was used, 50% of patients were resistant to both ASA and clopidogrel; while 20% were sensitive to ASA but resistant to clopidogrel. p=0.02 % of patients Lev et al., JACC 2006 Jan;47(1):27-33.

  9. Aspirin and Clopidogrel Drug Response: Resistance Rates AA-induced aggregation before and 20-24 hours after witnessed ASA dose in: ASA-resistant patients (%) p=0.2 ASA-sensitive patients (%) p=0.3 10.5 +/- 4.7% 10 +/- 3.7% 20.2 +/- 4.5% 18.8 +/- 2.9% % patients % patients • AA-induced aggregation was compared pre- and post-PCI among aspirin-resistant and aspirin-sensitive patients in order to evaluate the affect of previous medication compliance on aspirin resistance. • The differences were insignificant. Lev et al., JACC 2006 Jan;47(1):27-33.

  10. Aspirin and Clopidogrel Drug Response: Patient Characteristics Dual Drug resistance and ASA resistance in men and women (%) • Men were less likely to be dual-drug resistant compared with women (26.9% vs. 67.7%, p=0.02). • Aspirin resistant patients were more commonly women and had diabetes. • More specifically, 8 of the 103 men compared with 11 of the 47 women were ASA-resistant (7.8% vs. 23.4%, p=0.01). • No differences were found between clopidogrel-resistant versus clopidogrel-sensitive patients. p=0.02 p=0.01 % n=8 n=11 Lev et al., JACC 2006 Jan;47(1):27-33.

  11. Aspirin and Clopidogrel Drug Response: Response to Clopidogrel ADP-induced aggregation in ASA-resistant vs. ASA-sensitive patients (%) • Aspirin-resistant patients had a higher percentage of post-clopidogrel ADP-induced aggregation than aspirin-sensitive patients (5 μmol/L ADP: 78.9% vs. 18.3%, p=0.001 and 20 μmol/L ADP: 73.4% vs. 19.1%, p=0.001). • There was a significant difference in the change of ADP-induced aggregation compared with tertiles of AA-induced aggregation (5 μmol/L ADP, p=0.006 and 20 μmol/L ADP, p=0.0001). 5 μmol/L 20 μmol/L p=0.001 p=0.001 % Lev et al., JACC 2006 Jan;47(1):27-33.

  12. Aspirin and Clopidogrel Drug Response: Markers of Myonecrosis CK-MB elevation above the upper limit of normal (%) • CK-MB elevation was present more often in patients who were ASA-resistant than in those that were ASA-sensitive (38.9% vs.18.3%, p=0.04) and in dual-resistant compared with dual sensitive patients (44.4% vs. 15.8%, p=0.05). • Similarly, CK-MB levels trended toward more frequent elevations among clopidogrel-resistant compared with clopidogrel-sensitive patients (32.4% vs. 17.3, p=0.06). p=0.04 p=0.06 p=0.05 % patients with CK-MB elevation ASA-Resistant ASA-Sensitive Clopidogrel-Resistant Clopidogrel-Sensitive Dual- Resistant Dual-Sensitive Lev et al., JACC 2006 Jan;47(1):27-33.

  13. Aspirin and Clopidogrel Drug Response: Limitations • This study was powered to examine the different responses that aspirin-resistant and aspirin-sensitive patients exhibit while being treated with clopidogrel; however, the sample size was not large enough to estimate the risk of myonecrosis associated with dual drug resistance. • Since the antiplatelet effects of aspirin and clopidogrel were only assessed at two time points during one 24 hour period, they may not reflect the possible temporal fluctuations among individual responses. • Among all patients the first blood sample was obtained from an arterial access site; whereas, the second was from a venous access site. • The loading dose of clopidogrel was 300 mg, which is the dose that most clinical efficacy data have been obtained with, but recent studies have indicated that a 600 mg loading dose not only produces a more rapid and pronounced early response, but also reduces the rate of clopidogrel resistance. Lev et al., JACC 2006 Jan;47(1):27-33.

  14. Aspirin and Clopidogrel Drug Response: Summary • This is the first study to differentiate the response to clopidogrel among aspirin-resistant and aspirin-sensitive patients. • Also, it is the first to study antiplatelet drug response among a direct thrombin inhibitor instead of unfractionated heparin. • ASA resistance was present in 9% to 15% of patients depending on its definition and there was clopidogrel resistance in 24%. • Approiximately half of the patients who were ASA-resistant were also resistant to clopidogrel. • Both aspirin resistance and dual drug resistance were more commonly observed in women, which may help explain the recently reported failure of ASA to produce beneficial primary prevention effects in women. Lev et al., JACC 2006 Jan;47(1):27-33.

  15. Aspirin and Clopidogrel Drug Response: Summary cont. • An additional clinical factor associated with aspirin resistance is diabetes and platelets have been shown to have a reduced response to aspirin in patients with type 2 diabetes. • Three possible mechanisms may explain the lower response to clopidogrel in aspirin-resistant patients: 1) a global increase in platelet reactivity; 2) an increase in platelet turnover, which may cause the release of young platelets that are still able to form thromboxane A2 through non-cyclooxygenase-1-dependent pathways and respond to ADP regardless of ASA and clopidogrel treatment, or 3) poor compliance, which is not likely since both the clopidogrel loading dose and ASA were administered in the cath lab. • Furthermore, as demonstrated by the elevated CK-MB levels in ASA-resistant and dual-resistant patients and the tendency of clopidogrel-resistant patients to have more frequent CK-MB elevation, this study extends the evidence of an association between adverse clinical events and resistance to ASA and clopidogrel. Lev et al., JACC 2006 Jan;47(1):27-33.

  16. Aspirin and Clopidogrel Drug Response: Summary cont. • The high occurrence of elevated CK-MB levels found post-PCI in the dual drug-resistant group suggests these patients may be at high risk for thorombotic complications and should be confirmed in a larger study. • The low response to clopidogrel among aspirin-resistant patients is clinically important since clopidogrel has been suggested as an alternative treatment for aspirin-resistant patients. This finding suggests that other platelet inhibitors that would act on additional targets should be developed and evaluated. Lev et al., JACC 2006 Jan;47(1):27-33.

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