Chapter 21 Marini Acute Coronary Syndromes

441

CHAPTER 21 • Acute Coronary Syndromes

Clopidogrel, Ticlopidine, and Prasugrel These agents, which are used in conjunction with aspirin for dual antiplatelet therapy, belong to the thienopyridine class. They prevent platelet aggrega- tion by noncompetitive inhibition of the adenosine diphosphate (ADP) binding to the type 2 puriner- gic (P2Y 12 ) receptor, thereby inhibiting the activa- tion of the glycoprotein IIb/IIIa receptor complex. Because ticlopidine requires 3 to 6 days of therapy for full antiplatelet effect and carries small but noteworthy risks of neutropenia (2.5%) and throm- botic thrombocytopenic purpura–hemolytic uremia syndrome (TTP–HUS), it has been replaced by safer and effective ADP receptor agents, such as clopidogrel. Clopidogrel has been extensively studied in patients with ACS and in those who have received intracoronary stents. The life-threatening adverse effects seen with ticlopidine are far fewer with clopidogrel. In the CURE trial, clopidogrel use in ACS was found to significantly reduce risk of car- diovascular events (mostly reinfarctions) compared to aspirin alone. The usefulness of clopidogrel as an agent in reducing risk of cardiovascular events in patients who have received coronary stents has been clearly demonstrated in the PCI-CURE and CREDO trials. Clopidogrel is usually given as an oral bolus of 300 mg, followed thereafter at a dose of 75 mg once daily. The antiplatelet effects of clopidogrel are seen within hours. Significant blood levels may be achieved sooner with a larger bolus dose of the medication (600 or 1,200 mg). Along with ASA (81 mg once daily), it is given for a month after the implantation of bare-metal coronary stents and for at least 3 to 6 months after insertion of drug-eluting coronary stents. In patients with ACS, clopidogrel can be continued for 9 to 12 months. In some individuals at high risk for future cardiovas- cular events, clopidogrel with low-dose aspirin may be continued indefinitely if there are no contraindi- cations and if cost is not an issue. There is a slight but significant increase in risk of bleeding with combination of clopidogrel and aspirin (3% to 5% risk of major bleeding), particularly in the elderly population. Prasugrel and ticagrelor are recently introduced oral thienopyridine ADP receptor antagonists avail- able for patients with ACS. They are both more powerful antiplatelet agents than clopidogrel and achieve platelet-inhibiting effects more quickly.

oxygen demand can outstrip supply and ischemia can worsen. Therefore, caution must be exercised to avoid hypotension or excessive tachycardia when using calcium channel antagonists. Antiplatelet Therapy Aspirin Most patients with NSTE-ACS have an ulcerated atherosclerotic plaque covered by a subocclusive accumulation of platelets, thrombin, and red blood cells. Typically, these patients have platelet-rich or “white clot.” Therefore, aggressive antiplatelet therapies are indicated in stabilizing them. Aspirin (162 to 325 mg daily) should be initiated immedi- ately for all patients with ACS unless compelling contraindications exist. Cyclooxygenase-1 (COX- 1)-mediated platelet aggregation is inhibited within 15 minutes when non–enteric-coated tab- lets are chewed and swallowed. Aspirin reduces synthesis of both thromboxane A2 (TXA-2) and prostacyclin. TXA-2 is a powerful promoter of platelet aggregation. Prostacyclin, on the other hand, promotes vasodilation and inhibits platelet aggregation. Low-dose aspirin preferentially inhib- its TXA-2 synthesis, and endothelial prostacyclin synthesis is inhibited by high-dose aspirin. In the VA cooperative study, Canadian multicenter trial, and RISC trial, aspirin was found to reduce the risk of death and AMI by approximately 50% in patients with NSTE-ACS. In a large meta-analy- sis by the Antithrombotic Trialist’s Collaboration, aspirin reduced risk of death, MI, and stroke by about 46%. The benefits of aspirin may persist for years with continued therapy. The risk of recurrent events is reduced by at least 25%. The risk of coro- nary reocclusion after PCIs is reduced by about 50% with use of aspirin. At the low doses (75 to 150 mg) needed for platelet inhibition, few hem- orrhagic or gastrointestinal side effects occur. At a lower dose, aspirin caused 2.5% major bleeds with 1% requiring transfusions. Aspirin resistance is seen in about 5% to 10% of patients, and these individuals are at increased risk for cardiovascular events. Although inhibition of platelet aggregation may complicate subsequent coronary artery sur- gery, aspirin-related clotting defects are reversible with platelet transfusions. Dipyridamole does not enhance the protective effect of aspirin in coro- nary ischemia, but clopidogrel and ticlopidine do complement the anti-ischemic effect of aspirin.