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Heparin 30-40,000

7 d

3 vs 15%



ASA, acetylsalicylic acid (aspirin); MI, myocardial infarctions.

ASA, acetylsalicylic acid (aspirin); MI, myocardial infarctions.

difference between the two groups in the incidence of the composite end point or its components (48). However, this issue was recently addressed by the Aspirin in Carotid Endarterectomy trial, which involved more than 2800 patients undergoing carotid endarterectomy (49). Patients randomly received either low-dose aspirin (81 or 325 mg) or high-dose aspirin (650 or 1300 mg) daily. The risk of death, myocardial infarction, or stroke were lower among patients who received either of the two lower doses of aspirin compared to the higher doses, both at 30 d (5.4 vs 7.0%, p = 0.07 [relative risk (RR) = 1.31]) and at 3 mo (6.2 vs 8.4%, p = 0.03 [RR = 1.34]). Therefore, this is the first direct evidence to support low doses of aspirin (81-325 mg daily). Given the weight of evidence against a dose-response effect of aspirin, in addition to apparent dose-related tol-erability of aspirin therapy, as well as the theoretical concern about an imbalance between TXA2 and PGI2 production, it seems appropriate to favor the lower doses of aspirin shown to be effective for a given indication. In consequence, because the ISIS-2 trial conclusively established the efficacy of a 162 mg aspirin dose in patients with suspected myocardial infarction, it appears reasonable to administer 160-325 mg of aspirin to patients with non-ST-segment elevation ACS.

Aspirin Resistance

About 5-40% of patients have been reported to manifest a new and vaguely defined entity called "aspirin resistance" (33,50-53). The wide range of reported frequencies of this condition possibly reflect the various definitions and methods and criteria that have been used to define it. Aspirin resistance has been variously defined in pharmacodynamic studies as failure of aspirin to prolong bleeding time or failure to reduce 12-HETE production (33); or failure of aspirin to reduce platelet aggregation by a certain percentage (depending on the agonist being used); or as having normal platelet aggregation despite aspirin therapy in newer platelet-function analyzers, such as the PFA-100 (53). The variability among these assays may be significant, and the findings have not been universally reproducible. Aspirin resistance has also been clinically defined as having a new cardiovascular event despite aspirin therapy. Thus, several problems may be encountered while trying to define this entity. In addition, it has also been proposed that more than being aspirin-resistant, some individuals may simply be more sensitive to a certain platelet agonist and, therefore, require higher aspirin doses to achieve a similar antiplatelet effect (54).

Regardless of how aspirin resistance is defined, it is apparent that a group of patients may not be deriving any benefit from aspirin therapy at the usual doses. Therefore, the question is whether aspirin resistance has an impact on the outcome of patients. Two studies have reported that aspirin resistance is clinically relevant. In one of these studies, patients who suffered a stroke were given 500 mg of aspirin 3 X daily. Based on the modified Wu and Hoak platelet function test, 40% of patients were found to be aspirin "non-responders." After a 2-yr follow-up period, aspirin nonresponders had a 20-fold higher rate of cardiovascular death, myocardial infarction, or recurrent stroke compared to aspirin responders (52). In a second study, compared to aspirin responders, patients who failed to fully respond to aspirin therapy had a greater frequency of vessel reocclusion after percutaneous transluminal ileofemoral angioplasty (55).

What the appropriate management of patients with aspirin resistance should be is currently somewhat speculative. Whether higher aspirin doses should be prescribed or aspirin should be substituted with a thienopyridine is not known. However, based on the findings of the Clopidogrel vs Aspirin in Patients at Risk of Ischaemic Events (CAPRIE) trial (56), in which clopidogrel alone was at least as efficacious and safe compared to aspirin in patients with vascular disease, the substitution of aspirin for a thienopyridine (specifically clopidogrel) would seem sound.

Limitations and Adverse Effects of Aspirin Therapy

Side effects are seen infrequently with low-dose aspirin therapy and can easily be monitored. The major side effects of aspirin are gastrointestinal symptoms, which occur more frequent with higher aspirin doses (49,57) Gastrointestinal bleeding, however, appears to be equally likely to occur at any dose (58). In a small number of patients (4%), particularly those with adult onset asthma, aspirin may cause bronchospasm and angioedema.

Concerns have been raised regarding a possible negative interaction between aspirin and angiotensin-converting enzyme (ACE) inhibitors. ACE inhibitors increase plasma levels of bradykinin, which is a potent stimulus for prostacyclin production, and may partly explain the favorable effects of this class of drugs. By blocking the cyclooxyge-nase enzyme, aspirin may also block prostacyclin production and blunt some of the effects of ACE inhibitors. Aspirin was seen to prevent several of the beneficial hemo-dynamic effects normally seen with ACE inhibitor therapy in patients with severe heart failure (59). In addition, post hoc analyses of two large-scale multicenter trials suggested that aspirin attenuated the improved survival seen with ACE inhibitors in patients with moderate-to-severe heart failure (60,61). In contradistinction, an analysis of more than 11,500 patients did not observe the purported negative interaction between aspirin and ACE inhibitors (62). Because of the potential implications in the health of millions of patients taking both ACE inhibitors and aspirin, this issue will have to be directly addressed in a prospective fashion.

Clinical Use of Aspirin in Patients with non-ST-Elevation ACS

Aspirin remains the cornerstone of anti-platelet therapy for patients with non-ST-elevation ACS. It should be administered as early as possible to all patients, unless there is history of severe intolerance. The American Heart Association/American College of Cardiology guidelines give a Class I recommendation for the administration of 162 mg to 325 mg of aspirin in the acute setting to patients (with no contraindications to aspirin) presenting with non-ST-segment elevation ACS, preferably chewing the first dose of a rapidly absorbable, nonenteric coated formulation to rapidly establish a high blood level; and thereafter, 75-160 mg of aspirin (enteric or nonenteric) per day, indefinitely. A thienopyridine, preferably clopidogrel, should be administered to patients who are unable to take aspirin because of hypersensitivity or severe gastrointestinal intolerance (63).


ADP was identified more than 40 yr ago as a mediator derived from erythrocytes that could affect platelet adhesion and aggregation (64). In fact, in the thrombotic milieu, ADP is released from erythrocytes that are lysed as they are subjected to high shear stress that may result from a severely stenotic lesion. In addition, ADP is present in platelet dense granules and is released upon activation, thus amplifying the aggregation and activation responses in both, an autocrine and paracrine fashion. ADP acts in syn ergy with other platelet agonists and potentiates most aggregation responses, even of weak agonists, such as serotonin, epinephrine (65), or chemokines (66). Thus, ADP is a necessary cofactor for the normal activation and aggregation of platelets. Further observations pointing to the central role of ADP in hemostasis is the profound impact ADP-removing enzymes have on platelet aggregation (68), or the bleeding diatheses observed in patients with genetic defects of ADP receptors, or in those who have dense granules deficient in ADF (68). Therefore, it is not surprising that platelet ADP receptors are potential targets for antithrombotic or pharmacologic interventions.

Platelet ADP Receptors

Transduction of the signal elicited by ADP involves a rise in free cytoplasmic calcium due to an influx of this cation from the extracellular medium, as well as the mobilization of the internal calcium stores and a concomitant inhibition of adenylyl cyclase (68). Although, based on pharmacological studies, MacFarlane proposed in 1983 the existence of two distinct ADP receptors, one mediating platelet shape change and aggregation and the other the inhibition of adenylyl cyclase (69), it was not until quite recently that the main platelet ADP receptors, which are essential in the normal aggregation process, were cloned and further characterized. These receptors can be divided into two groups: the G protein-coupled receptors, termed P2Y, and the ion-gated channel receptors termed P2X.

P2Yj, a G protein-coupled receptor that activates Gq, was the first of the P2 (puriner-gic) receptors to be cloned (70). Nevertheless, it soon became apparent that another ADP receptor was involved in ADP-induced platelet aggregation, as selective antagonists to P2Y1 had no effect whatsoever on ADP-induced inhibition of platelet adenylyl cyclase, which is stimulated by anti-aggregatory mediators, such as prostacyclin or nitric oxide. Indeed, several groups nearly simultaneously published their observations showing that P2Y1 is necessary but not sufficient for platelet aggregation (71,72). Definitive evidence of the existence of an ADP receptor coupled to adenylyl cyclase inhibition came from studies using P2Y1 knock-out mice, in which platelet shape change and aggregation in response to ADP were abolished, whereas adenylyl cyclase production of cyclic AMP was unaffected (73).

The ADP receptor that remained to be identified was expected to also be of the purinoceptor P2Y superfamily, since ADP is known to activate the heterotrimeric Gi2 protein. Depending on the author, this receptor was termed P2YADP, P2TAC, or P2cyc (68). Very recently, this elusive receptor was cloned (74). Sequence analysis identified the new receptor of the P2Y family and termed it P2Y12. As expected, ADP stimulation of cells expressing only P2Y12 led to adenylyl cyclase inhibition, a phenomenon reversed by treatment of these cells with selective P2Y12 antagonists (74,75). Even though P2Y12 was very recently identified, this is the receptor targeted by the clinically used platelet ADP receptor antagonists, the thienopyridines: ticlopidine and clopidogrel.

The third ADP receptor expressed on platelets is P2X1, an ATP-gated ion channel and a member of the ionotropic receptor superfamily involved in platelet shape-change upon stimulation (76). This receptor is responsible for the rapid entry of calcium ions from the extracellular medium to the platelet upon ADP cell stimulation and is broadly expressed on a variety of tissues, specifically on excitable cells such as neurons and muscle cells. As opposed to the P2Y receptors, mice deficient in P2X1 demonstrate no obvious hemostatic defects (77). Future studies will define the precise role of this recep-

Table 3

Platelet Purinergic Receptorsa

Table 3

Platelet Purinergic Receptorsa

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