Physicians' Press - Innovative Medical Publishing - Interventional Cardiology Self-Assessment & Review

SELF-ASSESSMENT QUESTIONS: ORAL ANTIPLATELET AGENTS

a. Aspirin blocks the cyclo-oxygenase pathway by inhibiting prostaglandin G/H synthase, preventing formation of prostaglandin endoperoxides and thromboxane A2
b. Aspirin inhibits platelet aggregation induced by shear-stress
c. Aspirin inhibits platelet adherence to vascular subendothelium

Questions 2-9 list characteristics of specific antiplatelet agents. For each characteristic below, choose one or more of the following:

2. Inhibits thrombin-induced platelet aggregation
3. More effective than aspirin at blocking ADP-induced platelet aggregation
4. Can be given to aspirin-allergic patients
5. More effective than aspirin in blocking platelet aggregation induced by shear-stress
6. Reduces the incidence of myocardial infarction and stroke in high-risk patients
7. Associated with irreversible neutropenia
8. Associated with an increased risk of thrombotic thrombocytopenic purpura (TTP)
9. May enhance aspirin’s effects by causing direct release of prostacyclin from vascular endothelium

Answers: 2 (b,c); 3 (b,c); 4 (b,c); 5 (b,c); 6 (a,b,c); 7 (d); 8 (b,c); 9 (b,c)
Oral antiplatelet therapy has become the cornerstone of preventing abrupt closure during percutaneous coronary intervention, and has replaced warfarin-based regimens .

Aspirin (ASA). Aspirin blocks the cyclo-oxygenase pathway (COX) by inhibiting prostaglandin G/H synthase, preventing formation of prostaglandin endoperoxides and thromboxane A2, a potent platelet aggregator. This effect is transient in nucleated cells, but is permanent for the life of anucleate platelets (10 days). Aspirin has no impact on thromboxane A2-independent platelet aggregation mediated by adenosine diphosphate (ADP), thrombin, serotonin, or shear stress. Preprocedural administration of aspirin reduces the risk of abrupt coronary occlusion by 50-75% and is standard therapy for all coronary interventional procedures. Other beneficial cardiovascular effects include the primary prevention of coronary artery disease; improved outcome in chronic stable angina, unstable angina, and acute MI; maintenance of saphenous vein graft patency after coronary bypass surgery; and reduction in stroke. For the aspirin-allergic patient, ticlopidine (250 mg orally twice daily starting at 3-5 days prior to intervention) or clopidogrel (75 mg daily starting 3-5 days prior to intervention) can be substituted; other antiplatelet drugs such as dipyridamole, sulfinpyrazone, and dextran have not been studied and are not routinely recommended. Patients with acute coronary syndromes may be resistant to aspirin, but the impact of higher doses has not been studied. Recent studies suggest that 8-12% of patients may be unresponsive to the antiplatelet effects of aspirin; bedside platelet function testing may soon facilitate the identification of such aspirin-non-responders.

Ticlopidine. Ticlopidine is a thienopyridine that blocks ADP-induced platelet activation by interfering with the signaling between the low-affinity platelet ADP receptor (P2T) and the subsequent processes of platelet activation, including the activation of platelet glycoprotein (GP) IIb/IIIa. By inhibiting ADP amplification mechanisms for platelet activation, ticlopidine inhibits platelet aggregation in response to collagen, thrombin, and shear-stress; enhances the antiaggregatory effects of prostacyclin; and promotes deaggregation of thrombin-activated platelets. Thus, the thienopyridines are much more effective than aspirin at inhibiting shear-induced platelet activation. Ticlopidine can be used in the aspirin-allergic or intolerant patient, to decrease death and nonfatal MI in unstable angina, and stroke in patients with TIA's (although clopidogrel has virtually replaced ticlopidine in the United States, due to its enhanced safety profile and based on the results of the CURE trial, see below). In patients with coronary artery disease, the combination of aspirin (50 mg/day) and ticlopidine (250 mg twice daily) demonstrated synergistic platelet inhibition. The most serious side effect of ticlopidine is reversible neutropenia, which occurs in 0.5-2% of patients after 4 weeks of use; complete blood counts are recommended every 2-4 weeks during the first few months of therapy. Sporadic cases of thrombotic thrombocytopenic purpura (TTP) have been reported.

Clopidogrel. Clopidogrel is another thienopyridine, analogous to ticlopidine, but is longer-acting, has faster onset of action, and is associated with fewer adverse side-effects. Clopidogrel has been evaluated in randomized trials vs. aspirin for secondary prevention (CAPRIE), vs. ticlopidine for coronary stenting (CLASSICS), and most recently in conjunction with aspirin vs. aspirin alone for non-ST-elevation acute coronary syndromes (CURE).

CAPRIE Trial. Clopidogrel proved somewhat more effective than aspirin for secondary prevention in the Clopidogrel vs. Aspirin in Patients at Risk of Ischemic Events (CAPRIE) trial, in which 19,185 patients with atherosclerotic vascular disease – MI within 35 days, ischemic stroke within 6 months, or established peripheral arterial disease – were randomized to clopidogrel (75 mg/d) or aspirin (325 mg/d) for 1-3 years (ref). At 1.6 years, clopidogrel reduced the combined endpoint of new ischemic stroke, new MI, or other vascular death by 8.7% relative to aspirin (p = 0.045). Benefit was greatest in patients with peripheral artery disease. Aspirin was associated with more gastrointestinal bleeding, and the incidence of severe neutropenia was similar (0.1%) in both groups.

CLASSICS Trial. In the randomized CLASSICS trial of 1020 patients undergoing elective stenting, clopidogrel was better tolerated than ticlopidine without compromising clinical efficacy.

CURE Trial. Most recently,the potential synergistic effects of aspirin and clopidogrel on clinical outcome was recently evaluated in the Clopidogrel in Unstable Angina to Prevent Recurrent Events (CURE) trial. In this study, 12,562 patients with unstable angina or non-Q-wave MI were randomized to aspirin (75-325 mg/day) alone or aspirin plus clopidogrel (300 mg loading dose followed by 75 mg/day) for 3-12 months (average 9 months). Patients treated with IIb/IIIa inhibitors within 3 days or revascularization within 3 months were excluded from this study. As shown in Table 34.32 (below), clopidogrel resulted in a highly significant 20% relative reduction in the primary composite endpoint of cardiovascular death, MI, or stroke (9.3% vs. 11.5%, p = 0.00005). Benefits were evident within the first day, demonstrating the importance of early treatment, and were similar before and after 30 days, suggesting the need for long-term therapy. Although there was a 1% absolute increase in major bleeding with clopidogrel, these cases were effectively managed by blood transfusions, and there was no increase in fatal bleeding. When clopidogrel was discontinued < 5 days prior to CABG, there was no increased risk of major bleeding; however, when clopidogrel was stopped within 5 days of surgery, the risk of major bleeding was increased by 50%. Overall, it has been estimated that routine use of clopidogrel in addition to aspirin for non-ST-elevation ACS could prevent 100,000 cardiovascular deaths, myocardial infarctions, or strokes in the United States alone. These compelling data suggest that patients with non-ST-elevation ACS should immediately receive dual antiplatelet therapy with aspirin (75-325 mg/day) plus clopidogrel (loading dose of 300 mg followed by 75 mg/day). In CURE, 2658 of 12,562 patients underwent PCI at a median of 6 days after hospitalization. Pretreatment with clopidogrel plus aspirin resulted in a 30% reduction in cardiovascular death or MI before and after PCI compared to pretreatment with aspirin alone (12.6% vs. 8.8%, p = 0.002); most patients in the aspirin arm received open-label clopidogrel after PCI for 2-4 weeks. These data confirm the beneficial effects of dual antiplatelet therapy prior to PCI. Although not a pre-specified endpoint of the trial, clopidogrel use in patients also receiving IIb/IIIa inhibitors was not associated with an increase in major or life-threatening bleeding. The ongoing Clopidogrel for Reduction of Events During Observation (CREDO) trial will define the ideal dose and duration of clopidogrel when used with aspirin following stent implantation.

The safety profile of clopidogrel is similar to low-dose aspirin, with a rare incidence of thrombotic thrombocytopenic purpura. The most frequent side effects include diarrhea (4%), rash (4%), and pruritus (3%). Clopidogrel is not associated with an increased risk of neutropenia, so routine hematologic monitoring is not necessary for patients on chronic therapy. A recent report documented 11 cases of suspected TTP among 3 million patients exposed to clopidogrel, although the incidence of TTP is substantially lower than that associated with ticlopidine. Some patients on combined aspirin and clopidogrel therapy may develop severe platelet inhibition, which could be clinically important if CABG is needed; the rapid platelet aggregation assay can be used to assess the degree of antiplatelet activity in this instance. Clopidogrel is metabolized in the liver but has little impact on hepatic enzyme induction or drug metabolism. Caution is recommended when clopidogrel is used in combination with nonsteroidal anti-inflammatory drugs or warfarin due to the increased risk of bleeding.

ARCHIVE

The archives can be reached by returning to the Interventional Cardiology and Self-Assessment page and clicking on the individual archive links there.