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Emerging Concepts in the Response to Antiplatelet Therapy

Matthew J. Price, MD Co-Director, Cardiac Catheterization Laboratory Division of Cardiovascular Diseases, Scripps Clinic, La Jolla, California
January 2006
However, luminal thrombosis after coronary plaque rupture is the proximate cause of acute coronary syndromes (unstable angina, non-ST elevation myocardial infarction, and ST-elevation myocardial infarction). Coronary thrombosis is also as an important cause of adverse events during and following percutaneous coronary intervention (PCI). Agents that inhibit platelet activity have thus become the cornerstone of the medical management of patients with cardiovascular disease and of patients undergoing PCI. Despite anti-platelet therapy, cardiovascular events still occur in a substantial number of at-risk patients. Indeed, nearly 10% of patients with an acute coronary syndrome treated with aspirin and clopidogrel will suffer another cardiovascular event during the ensuing year.1 Stent thrombosis occurs in approximately 0.1% of patients despite aspirin and clopidogrel therapy, and though a rare event, it carries with it substantial morbidity and mortality. Why do some patients have recurrent cardiovascular events or stent thrombosis on clopidogrel therapy and others do not? Could variation in the response to aspirin and clopidogrel, and in turn, persistent platelet reactivity be partially responsible? And if so, can patients with a poor response to anti-platelet therapy be identified? A basic understanding of platelet biology is essential to understand the interplay between platelet function and the response to anti-platelet therapy. Platelet activation occurs through the binding of agonists (stimulants) to specific receptors on the platelet membrane. This agonist causes the platelet to release intracellular granules that contain pro-thrombotic and vasoconstrictive agents, as well as additional platelet agonists, the release of which result in a positive feedback loop enhancing platelet activation and promoting platelet aggregation. through the binding of agonists (stimulants) to specific receptors on the platelet membrane. This agonist causes the platelet to release intracellular granules that contain pro-thrombotic and vasoconstrictive agents, as well as additional platelet agonists, the release of which result in a positive feedback loop enhancing platelet activation and promoting platelet aggregation. This process of platelet activation and aggregation drives forward the clotting cascade, the cross-linking of fibrin and the formation and stabilization of clot. Major platelet agonists include thromboxane A2, ADP, and thrombin. There are two main classes of oral anti-platelet agents commonly used today: aspirin and the thienopyridines (clopidogrel and ticlopidine). Since ticlopidine is associated with frequent and often serious side effects, clopidogrel has become the thienopyridine of choice. Aspirin works by irreversibly inhibiting the platelet cyclooxygenase enzyme, thereby preventing the metabolism of arachadonic acid and in turn the production of thromboxane A2. The thienopyridines irreversibly bind to a major subtype of the ADP receptor, P2Y12, and inhibit the ability of ADP to stimulate and maintain platelet activation and aggregation. The rupture of a vulnerable atherosclerotic plaque within the coronary artery liberates a large amount of platelet agonists in addition to pro-coagulants that contribute to the formation of an occlusive thrombus, leading to an acute coronary syndrome.2 Balloon angioplasty and stenting of an obstructive coronary lesion during PCI mechanically cause plaque rupture. As with spontaneous plaque rupture, this can lead to thrombosis; in turn, this may result in distal atherothrombotic embolism, periprocedural myocardial infarction and, in the most severe of situations, abrupt vessel closure. After stent placement, platelet activation and subsequent aggregation within the stent and at the site of vascular injury can lead to clot formation and in turn acute stent thrombosis, resulting in a large myocardial infarction or death. Given the pro-stimulatory environment induced by PCI, administration of aspirin is mandatory prior to the procedure unless the patient has a significant allergy. Clinical trials have demonstrated that aspirin and clopidogrel reduce recurrent events after acute coronary syndrome, improve outcomes after acute myocardial infarction, decrease post-procedural myocardial infarction after PCI, and prevent stent thrombosis. For these reasons, aspirin and clopidogrel have become essential tools in the management of patients with cardiovascular disease. The effect of aspirin or clopidogrel on platelet function can be measured by a variety of techniques. Generally speaking, a specific agonist (arachadonic acid in the case of aspirin or ADP in the case of clopidogrel) is added to a specially prepared blood sample, and the degree of platelet aggregation is determined by the amount of light transmission through the test sample compared to a reference sample (a process called light transmission aggregometry, or LTA). In a subject treated with clopidogrel, for example, ADP-induced platelet aggregation should be reduced. In the past, aspirin and clopidogrel responsiveness have not been routinely measured because platelet aggregometry is a time- consuming, labor-intensive process that is difficult to perform. Although LTA is the gold standard for the measurement of platelet reactivity, a simple, easy to use point-of-care assay is now available for measuring the response to aspirin and, more recently, to clopidogrel, enabling the measurement of platelet activity in the everyday, clinical setting (Figure 1). The results of these point-of-care assays correlate well with findings on LTA (VerifyNow P2Y12 Assay package insert). A growing body of data has demonstrated that a percentage of patients may have a relatively limited response to the inhibitory effects of aspirin. Aspirin resistance (using various definitions) has been shown to occur in 5 to 40% of people and has shown to be predictive of adverse outcomes. In a study of 151 patients undergoing non-urgent PCI, aspirin resistance based on the point-of-care VerifyNow ASA assay (Accumetrics Inc., San Diego CA) was present in 20% of the patients and was a significant predictor of peri-procedural myonecrosis.3 Aspirin resistance identified by the VerifyNow ASA assay also predicts microvascular dysfunction after PCI, possibly due to enhanced distal embolization resulting from impaired aspirin-mediated platelet inhibition.4 A lower dose of aspirin has been also been associated with a higher frequency of resistance in patients with cardiovascular disease.5 Studies of platelet function have led many operators to reassess traditional dosing regimens for clopidogrel. The approved dosage of clopidogrel for acute coronary syndrome is a 300-mg loading dose followed by maintenance therapy of 75-mg daily. Loading prior to PCI has been shown to improve outcomes as long as the dose is given early enough. A loading dose of 600-mg reduces the time to peak inhibition and has been shown to improve outcomes compared to 300-mg when it is given at least 4 hours prior to PCI,6 but this dose is not FDA-approved. Studies of platelet reactivity have established that there is substantial variability in the functional response to clopidogrel between individuals, regardless of dose. For example, several hours after receiving a 300-mg loading dose of clopidogrel, one patient may have nearly complete inhibition of ADP-induced platelet aggregation (reflecting a strong response to clopidogrel), while another may have nearly no inhibition at all (reflecting a weak response.) Differences in the response to clopidogrel may be due to individual differences in absorption, metabolism, genetic polymorphisms of the P2Y12 receptor, baseline platelet reactivity, and compliance. As many as 30% of patients undergoing PCI may have a very limited response to a 300-mg clopidogrel loading dose (less than 10% decrease in platelet aggregation).7 This sub-optimal response is associated with worse outcomes. Among patients treated for an acute myocardial infarction, 40% of those individuals whose response to clopidogrel was below the 25th percentile had a recurrent cardiovascular event over the ensuing 6 months, while none of the patients above the 50th percentile had events.8 Incomplete P2Y12 receptor inhibition (the target of clopidogrel) is also a risk factor for subacute stent thrombosis.9 Also, drugs that inhibit or induce the cytochrome P450 3A4 metabolism of clopidogrel to its active form may cause variability in clopidogrel’s anti-platelet effects. We and others have shown that increasing the loading dose to 600-mg or 900-mg shortens the time to, and increases the magnitude of, maximal inhibition compared to 300-mg, but there still remains substantial variation in the response among individuals that can be readily identified with the VerifyNow P2Y12 assay (unpublished data, in submission). Variation in the level of platelet inhibition also exists in patients on daily maintenance therapy of 75-mg of clopidogrel, and this variation may potentially contribute to recurrent cardiovascular events. Indeed, additional platelet inhibition can be achieved in patients on chronic clopidogrel therapy with an additional bolus of 600-mg, suggesting that clopidogrel doses higher than 75-mg daily might be needed during chronic therapy in some patients.10 The current availability of a point-of-care platelet function assay now makes it feasible to monitor patients’ responses in the routine clinical setting. At Scripps Clinic, we are currently accruing a prospective registry of 1000 patients undergoing complex PCI with drug-eluting stents (the Scripps DES Real World Registry), and are using point-of-care assays to analyze baseline platelet reactivity and the post-procedural response to aspirin and clopidogrel. This registry will provide crucial information regarding the impact of anti-platelet resistance and different anti-platelet dosing regimens on short- and long-term outcomes following complex PCI with drug-eluting stents. Future studies will help determine the proper role of routine measurement of platelet inhibition in patients taking clopidogrel, and whether individual tailoring of clopidogrel therapy for low-responders (e.g., increasing dosage) will improve outcomes. The current AHA guidelines for PCI state that in patients in whom stent thrombosis would be catastrophic or lethal (unprotected left main, last remaining vessel) platelet function studies may be considered and the dose of clopidogrel increased to 150mg/day if less than 50% inhibition is demonstrated. However, given the substantial morbidity and mortality of any stent thrombosis regardless of anatomic site, identification of all at-risk patients may be beneficial, but this approach requires further investigation. While anti-platelet therapy with clopidogrel is a cornerstone of therapy for patients with cardiovascular disease and those receiving coronary stents, it also represents a hurdle in the care of such patients who require cardiac surgery. Pre-operative clopidogrel use is associated with increased transfusions, higher rates of re-operation for bleeding, and prolonged hospital stay, leading to increased health-care costs and patient morbidity. It is therefore common practice to stop clopidogrel for 5 to 7 days prior to surgery to allow full platelet recovery. Since pre-loading with clopidogrel several hours prior to PCI improves outcomes, patients often have received a large dose of clopidogrel prior to the discovery of surgical disease on coronary angiography, mandating costly delays prior to surgical revascularization. We have shown that the time to recovery of platelet function after discontinuation of daily clopidogrel may vary among subjects: more than 50% of subjects may recover platelet function within 3 days, while a small minority continues to have persistent platelet inhibition at 5 days after discontinuation (unpublished data). Therefore, monitoring of platelet inhibition may potentially reduce surgical delays for patients taking clopidogrel, and identify those who are at higher risk for bleeding complications despite prolonged discontinuation. In conclusion, the analysis of platelet reactivity has contributed significantly to our evolving approach to anti-platelet therapy in patients with cardiovascular disease. While the currently approved dosage of clopidogrel is a 300-mg loading bolus followed by 75-mg daily therapy, a 600-mg dose prior to PCI is associated with greater acute platelet inhibition and improved clinical outcomes. During maintenance therapy of 75-mg daily, additional boluses of clopidogrel can provide additional platelet inhibition. Regardless of dose, a percentage of patients are low- or non-responders, which may identify a subset of patients at risk for adverse outcomes. Clinicians can identify these patients in the acute and out-patient settings with recently available point-of-care assays. Point-of-care monitoring may also allow patients on chronic clopidogrel therapy to undergo major surgery in a safe and timely manner. Future studies must test whether clinical outcomes can be improved by routine monitoring of platelet function and individual tailoring of anti-platelet therapy. The author can be contacted at: price.matthew@scrippshealth.org
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2. Price MJ, Shah PK. Biology of the vulnerable plaque: part one. Cath Lab Digest. 2002; 10(5)

3. Chen WH, Lee PY, Ng W, Tse HF, Lau CP. Aspirin resistance is associated with a high incidence of myonecrosis after non-urgent percutaneous coronary intervention despite clopidogrel pretreatment. J Am Coll Cardiol. 2004 Mar 17;43(6):1122-6

4. Chen WH, Lee PY, Ng W, Kwok JY, Cheng X, Lee SW, Tse HF, Lau CP. Relation of aspirin resistance to coronary flow reserve in patients undergoing elective percutaneous coronary intervention. Am J Cardiol. 2005 Sep 15;96(6):760-3.

5. Lee PY, Chen WH, Ng W, Cheng X, Kwok JY, Tse HF, Lau CP. Low-dose aspirin increases aspirin resistance in patients with coronary artery disease. Am J Med. 2005; 118(7):723-7.

6. Patti G, Colonna G, Pasceri V, et al. Randomized trial of high loading dose of clopidogrel for reduction of periprocedural myocardial infarction in patients undergoing coronary intervention: results from the ARMYDA-2 (Antiplatelet therapy for Reduction of MYocardial Damage during Angioplasty) study. Circulation 2005; 111(16):2099-2106.

7. Gurbel PA, Bliden KP, Hiatt BL, O’Connor CM. Clopidogrel for coronary stenting. Response variability, drug resistance and the effect of pretreatment platelet reactivity. Circulation 2003;107:2908-13.

8. Matetzky S, Shenkman B, Guetta V, et al. Clopidogrel resistance is associated with increased risk of recurrent atherothrombotic events in patients with acute myocardial infarction. Circulation. Jun 29 2004;109(25):3171-3175.

9. Gurbel PA, Bliden KP, Samara W, Yoho JA, Hayes K, Fissha MZ, Tantry US. Clopidogrel Effect on Platelet REactivity in Patients With Stent Thrombosis Results of the CREST Study. J Am Coll Cardiol. 2005 Nov 15; 46(10):1827-32.

10. Kastrati A, von Beckerath N, Joost A, et al. Loading with 600 mg clopidogrel in patients with coronary artery disease with and without chronic clopidogrel therapy. Circulation. Oct 5 2004;110(14):1916-1919.


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