Applied Radiology

Dr. Simpson received his MD from East Carolina University (ECU) School of Medicine, Greenville, NC. He is currently in the ECU Deptartment of Cardiology.

Antiplatelet therapy is continuing to become an integral part of pharmacotherapy during percutaneous coronary interventions (PCI). The ongoing development of novel antiplatelet therapies continues to improve procedural and clinical outcomes during PCI. This review will provide clinically relevant information regarding commonly used antiplatelet drugs and the clinical research supporting their use during PCI.

Aspirin

Aspirin blocks the formation of prostaglandin endoperoxides and thromboxane A2 by inhibiting prostaglandin G/H synthase and the cyclo-oxygenase pathway. In an anucleate platelet, this is a permanent effect. Aspirin prior to PCI reduces the risk of abrupt coronary vessel closure by 50% to 75%. ^1,2 Other benefits of aspirin therapy include: the prevention of coronary artery disease and stroke; improved outcome in chronic stable angina, unstable angina, and acute myocardial infarction ³ ; and the maintenance of saphrenous vein graft patency after coronary artery bypass surgery. ⁴ The risk of bleeding is increased with aspirin. ^5,6 There has been no proven beneficial effect regarding restenosis.

The optimal dose, timing, and duration of administration of aspirin are unknown. The standard regimen consists of 325 mg at least 24 hrs prior to an elective intervention and continuing indefinitely. For emergency procedures, 4 baby aspirins should be chewed and swallowed (81 mg each). For patients who are allergic to aspirin, begin clopidogrel, 75 mg daily beginning 3 to 5 days prior to the intervention.

Aspirin does have its limitations. It does not block platelet aggregation caused by thrombin, catecholamines, adenosine diphosphate (ADP), serotonin, or shear stress. Recent studies suggest that 8% to 12% of patients with coronary artery disease may be unresponsive to the antiplatelet effects of aspirin. ⁷ Bedside platelet functioning may assist in identifying those aspirin nonresponders.

Ticlopidine

Ticlopidine is a thienopyridine that blocks ADP-induced platelet activation by interfering with the signaling between the low-affinity platelet ADP receptor and the subsequent processes of platelet activation, including activation of the platelet glycoprotein (GP) IIb/IIIa receptor. Ticlopidine also inhibits platelet aggregation in response to collagen, thrombin, and shear stress by inhibiting ADP amplification mechanisms for platelet activation. Thienopyridines, such as ticlopidine and clopidogrel, are much more effective than aspirin in inhibiting shear-induced platelet activation, which is an important cause of thrombosis in coronary artery disease. In a randomized trial of percutaneous transluminal coronary angioplasty (PTCA), ticlopidine (250 mg bid) resulted in fewer ischemic complications than aspirin plus dipyridamole (2% vs. 5%). ⁸ Several other trials have demonstrated superiority of aspirin plus ticlopidine versus aspirin plus warfarin in reducing ischemic and hemorrhagic complications following stenting. These trials include STARS, ⁹ ISAR ^10,11 (Intracoronary Stenting and Antithrombotic Regimen), FANTASTIC ¹² (Full Anticoagulation versus Aspirin and Ticlopidine), and MATTIS ¹³ (Multicenter Aspirin and Ticlopidine Trial after Intracoronary Stenting). Ticlopidine has also been shown to reduce the risk of death and nonfatal MI in unstable angina, ¹⁴ prevent stroke in patients with transient ischemic attacks (TIAs), ¹⁵ and has been used for aspirin-allergic or intolerant patients.

The recommended dosage of ticlopidine is 250 mg PO bid for at least 3 days prior to intervention to obtain maximal antiplatelet effect. The onset of action is 48 to 72 hours, and full antiplatelet effects are evident in 5 to 7 days. Oral loading of 500 mg PO bid for 48 hours may accelerate the antiplatelet effects and may provide some benefit in emergency situations. The antiplatelet effects subside over 1 to 2 weeks. The benefits of ticlopidine beyond 2 weeks after stenting is questionable.

An important side effect of ticlopidine is reversible neutropenia, which occurs in 0.5% to 2% of patients after 4 weeks of use. ¹⁶ It is recommended that a complete blood count be monitored every 2 weeks during the first few months of therapy. Ticlopidine has an associated incidence of thrombotic thrombocytopenic purpura estimated at 0.02%. Most cases occur during the 3rd or 4th week of therapy. Complaints of nausea, vomiting, and diarrhea associated with ticlopidine can usually be minimized by taking it with food. The use of ticlopidine has been greatly diminished because of its side effect profile compared with that of clopidogrel.

Clopidogrel

Clopidogrel is another thienopyridine derivative, analogous to ticlopidine, which blocks ADP-induced platelet activation by irreversibly modifying the ADP receptor. Compared with ticlopidine, clopidogrel has a longer duration of action, a faster onset of action, and is associated with fewer hematologic effects. In a randomized blinded trial, Clopidogrel versus Aspirin in Patients at Risk of Ischemic Events (CAPRIE), ¹⁷ there was no difference in neutropenia between aspirin and clopidogrel. In the Clopidogrel Aspirin Stent International Cooperative Study (CLASSICS) ¹⁸ trial of patients undergoing elective stenting, clopidogrel was tolerated better than ticlopidine without sacrificing clinical efficacy. The combined use of aspirin plus clopidogrel in acute coronary syndromes was recently evaluated in the CURE (Clopidogrel in Unstable angina to prevent Recurrent Events) trial. There was a highly significant 20% relative reduction in the primary composite end points of cardiovascular death, MI, or stroke. Benefits were noted within 30 days and increased further beyond 30 days, demonstrating the importance of long-term therapy. ¹⁹ There was a 1% increase in major bleeding with clopidogel that was controlled easily with transfusions with no increase in fatal bleeding. This suggests that patients with acute coronary syndromes should be considered for antiplatelet therapy with aspirin plus clopidogrel.

The dosage of clopidogrel is 75 mg daily. The full antiplatelet effect is achieved in 5 days. A loading dose of 300 mg was used in the CLASSICS, CREDO (Clopidogrel for Reduction of Events During extended Observation), and CURE studies. The ideal dose and duration of clopidogrel plus aspirin following stenting should be answered by the CREDO study.

The most frequent side effects of clopidogrel (¾ 5% of cases) include purpura, diarrhea, rash, and pruritis. Clopidogrel is not associated with an increased risk of neutropenia, so routine hematologic monitoring is not required. A recent report documented 1 case of suspected thrombotic thrombocytopenic purpura (TTP) among 3000 patients exposed to clopidogrel. The overall incidence of TTP is substantially lower than that associated with ticlopidine. Clopidogrel is metabolized in the liver but has little impact on hepatic enzyme induction. Caution is recommended when clopidogrel is used in combination with nonsteroidal anti-inflammatory drugs or warfarin due to increased risk of bleeding.

Dipyridamole

Dipyridamole increases platelet c-AMP and causes direct release of prostacyclin from the endothelium, but its antiplatelet mechanism of action is incompletely understood.

The half-life of dipyridamole is 10 days and it is metabolized primarily in the liver. In PTCA patients, 2 studies of parenteral dipyridamole plus aspirin reported fewer ischemic complications compared with aspirin alone, but a randomized trial of oral dipyridamole failed to demonstrate benefit. ²⁰ The oral dose of dipyridamole is 75 mg bid for 6 months. Side effects of dipyridamole include exacerbation of angina, headaches, hypertension, and tachycardia. The risk of GI bleeding increases with the use of aspirin. At the present time, dipyridamole is not recommended routinely for coronary intervention.

Activation of the platelet GP IIb/IIIa receptor complex constitutes the final common pathway for platelet aggregation and is a critical event in arterial thrombosis. Potent GP IIb/IIIa receptor antagonists have been shown to improve event-free survival in a variety of interventional and noninterventional settings. The agents abciximab, eptifibatide, and tirofiban have been evaluated more thoroughly than others and are the most widely used.

Abciximab

Abciximab is a noncompetitive antagonist that binds 1:1 to the GP IIb/IIIa receptor molecule to induce a conformational change that renders its fibrinogen-binding site inactive. From a clinical standpoint, noncompetitive inhibitors have a longer biological half-life, more cross-reactivity with other cell-surface receptors, and more permanent binding than competitive inhibitors.

Abciximab has been studied in several large-scale, placebo-controlled randomized trials in PTCA, stenting, acute MI, and acute coronary syndromes.The PTCA trials were: EPIC (Evaluation of Platelet IIb/IIIa Inhibition for Prevention of Ischemic Complication), EPILOG (Evaluation in PTCA to Improve Long-term Outcome with Abciximab GP IIb/IIIa Blockade), and CAPTURE (c7E3 Fab Antiplatelet Therapy in Unstable Refractory Angina). EPISTENT (Evaluation of Platelet IIb/IIIA Inhibitor for Stenting) was a trial in stenting.

Three trials in acute MI were: ADMIRAL (Abciximab before Direct angioplasty and stenting in Myocardial Infarction Regarding Acute and Long-term follow-up); RAPPORT (ReoPro and Primary PTCA Organization and Randomized Trial); CADILLAC (Controlled Abciximab and Device Investigation to Lower Late Angioplasty Complications); and GUSTO IV ACS (Global Utilization of Streptokinase and t-PA for occluded coronary arteries trial IV in Acute Coronary Syndromes). The TARGET trial (Do Tirofiban and ReoPro Give similar Efficacy Trial) has recently been completed. EPIC, EPILOG, EPISTENT, and CAPTURE all demonstrated 35% to 57% reduction in the primary end point (death, MI, TLR) favoring abciximab. Although EPIC reported more bleeding complications with abciximab, EPILOG demonstrated that low-dose, weight-adjusted heparin (70 U/kg to achieve an ACT 200 to 250 seconds) plus abciximab could reduce the risk of bleeding significantly without sacrificing efficacy. Furthermore, benefits observed in high-risk PTCA patients in EPIC were extended to high- and low-risk PTCA and stent patients in EPILOG and EPISTENT. Importantly, EPIC continues to demonstrate sustained benefit of abciximab at 30 days, 6 months, and 3 years. ^21-23 EPILOG has shown persistent benefit at 1 year ²⁴ ; and EPISTENT reported sustained benefit at 6 months ²⁵ and at 1 year (mortality 1% vs. 2.4%). ²⁶ Angiographic restenosis was also lower in diabetics treated with abciximab. ²⁷

In contrast to the abciximab bolus 12-hour infusion utilized in EPIC, EPILOG, and EPISTENT, CAPTURE patients received 18- to 24-hour infusion before and a 1-hour infusion after the intervention; initial benefit at 30 days was not sustained at 6 months, ²⁸ suggesting that a 12-hour infusion after intervention may be important for prolonged clinical benefit.

In patients with acute MI undergoing primary PTCA or stenting, three trials of abciximab have reported inconsistent results: In RAPPORT, ²⁹ abciximab was associated with a nonsignificant 17% reduction in late major adverse cardiac events (MACE) after primary PTCA. In ADMIRAL, ³⁰ abciximab was associated with a significant 47% reduction in late MACE after primary stenting. In CADILLAC, ³¹ patients were randomized to primary PTCA versus stenting, with or without abcximab. Similar to RAPPORT, the 21% reduction in late MACE was not significant, and in contrast to ADMIRAL, abciximab offered no incremental benefit after primary stenting. The TARGET trial reported significantly better results for abciximab compared with tirofiban for stent patients (death, MI, or urgent revascularization at 30 days), especially those presenting with an acute coronary syndrome.

The recommended dose for abciximab for percutaneous intervention is an IV bolus of 0.25 µg/kg/min, followed by an constant infusion of 0.125 µg/kg/min (max 10 µg/min), for 12 hours post-intervention. All patients should receive standard aspirin therapy. The recommended heparin dose is 70 U/kg IV to maintain an ACT of 200 to 250 seconds. No further heparin is needed postintervention, and sheaths should be removed when ACT is 150 to 175 seconds. Abciximab does not need to be discontinued for sheath removal.

A number of safety concerns have been raised about the use of GP IIb/IIIa antagonists in general and about abciximab in particular. Most of these concerns are related to the risks of bleeding complications, the potential requirement for emergency coronary artery bypass graft (CABG) surgery, severe thrombocytopenia, and potential drug reactions. Virtually all of these concerns are readily prevented and/or treated and are not felt to be significant obstacles to the use of GP IIb/IIIa inhibitors.

Independent predictors of bleeding include MI, low body weight, old age, longer procedural times, repeat PTCA, and failed intervention. In abciximab trials utilizing low-dose heparin, early sheath removal, and ACT 200 to 250 seconds (EPILOG, CAPTURE, and EPISTENT), there were no reported differences in major or minor bleeding compared with placebo. Importantly, patients do not have a higher incidence of intracranial hemorrhage when treated with abciximab compared with placebo.

Thrombocytopenia is a potential safety concern with GP IIb/IIIa antagonists, which may increase bleeding complications. ³² The incidence of thrombocytopenia appears to be higher with abciximab compared with tirofiban and eptifibatide. The incidence of mild thrombocytopenia (<100,000/mm ³ ) was 2.6% to 5.6% and severe thrombocytopenia (<50,000/mm ³ ) was 0.9% to 1.6%. ³³ Unlike heparin-induced thrombocytopenia (HIT), abciximab-associated thrombocytopenia responds within days of discontinuing the drug and responds quickly to platelet transfusions. In contrast, severe thrombocytopenia after abciximab retreatment (which is 2 to 3 times more frequent than after first time use) may not respond promptly to platelet transfusions. If retreatment with abciximab is performed, early platelet counts should be obtained with rapid discontinuation of the drug if platelet count falls.

The risk of bleeding during emergency CABG is potentiated by abciximab and heparin. ^34,35 The hemostatic defect due to abciximab is largely reversible with platelet transfusions, but the benefit is not immediate or complete due to persistent platelet-bound abciximab. Transfused platelets serve as a "sink" to remove excess drug from affected platelets, and it may take 3 hours to completely reverse the antiplatelet effect. ^36,37 In the EPIC, EPILOG, and EPISTENT trials, ^38,39 the risk of major bleeding or blood transfusion in emergency CABG patients receiving antecedent abciximab was similar to that of those receiving placebo, although abciximab patients required more platelet transfusions.

Eptifibatide

Eptifibatide is a synthetic cyclic K-G-D (lysine-glysine-aspartic acid) heptapeptide and a competitive antagonist for GP IIb/IIIa receptor. Unlike abciximab, eptifibatide has a short half-life (2.5 hours), ⁴⁰ is very specific for the GP IIb/IIIa receptor, and does not cross-react with the vitronectin receptor. Platelet function returns to normal within 4 hours after drug discontinuation.

The use of eptifibatide during coronary intervention was studied in the IMPACT-II (Integrilin to Minimize Platelet Aggregation and Coronary Thrombosis), PURSUIT (Platelet glycoprotein IIb/IIIa in Unstable angina: Receptor Suppression Using Integrilin Therapy), and ESPRIT (Enhanced Suppression of the Platelet IIb/IIIa Receptor with Integrin Therapy) trials. In IMPACT-II, there was a nonsignificant 19% reduction in the composite primary end point (death, MI, revascularization, or bailout coronary stent) at 30 days in the low-dose and high-dose eptifibitide groups. ⁴¹ There was no difference in major bleeding or blood transfusion. In PURSUIT, 10,948 patients with unstable angina or non-Q-wave MI received aspirin and intravenous (IV) heparin and were randomly assigned to eptifibitide (180 µg/kg bolus and 2.0 µg/kg/min infusion) or placebo. ⁴² In a subgroup of 1250 patients undergoing percutaneous intervention within 72 hours of randomization, eptifibitide reduced the 30-day incidence of death and MI by 31% ( P = 0.01). In ESPRIT, the dose of eptifibatide was further modified to include a second bolus, 10 minutes after the first. ⁴³ In an elective coronary stent population, this second bolus was associated with a 37% reduction in ischemic events at 48 hours, which persisted at 30 days and at 6 months.

The FDA-approved dose of eptifibitide is 135 µg/kg immediately before intervention followed by a continuous infusion of 0.5 µg/kg/min for 12 to 24 hours. The current recommended dose due to the concerns of IMPACT-II and the favorable response in PURSUIT is 180 µg/kg IV bolus X 2 (10 minutes apart) followed by a constant infusion at 2.0 µg/kg/min.

Eptifibitide was not associated with an increased risk of major bleeding in IMPACT-II, PURSUIT, and ESPRIT. In contrast to abciximab, there may be less need to reduce the heparin dose, there is no known immune response, and the incidence of thrombocytopenia is similar to placebo. Eptifibatide should be discontinued in patients requiring emergency CABG. Antiplatelet effects resolve in 4 to 6 hours and platelet transfusion is ineffective. Drug clearance is longer in renal impaired patients.

Tirofiban

Tirofiban is a synthetic, small molecule nonpeptide competitive antagonist of the GP IIb/IIIa receptor. Similar to eptifibatide, it is rapidly reversible, highly selective, and does not cross-react with the vitronectin receptor.

In the RESTORE trial, ^44,45 2139 patients with acute coronary syndromes undergoing PTCA or directional coronary atherectomy receiving aspirin and heparin were randomized to tirofiban (10 µg/kg bolus, 0.15 µg/kg/min infusion) or placebo for 36 hours. There was a 40% reduction in death, MI, and urgent revascularization (5.2% vs. 8.7%, P = 0.002) at 2 days, 30% reduction at 7 days (6.9% vs. 9.8%, P = 0.016), and a 24% reduction at 30 days (8.0% vs. 10.5%, P = 0.16). The composite end point (death, MI, and revascularization) at 6 months was similar to placebo (24.1% vs. 27.1%, P = 0.11). The TARGET trial was a direct head-to-head comparison of tirofiban versus abciximab in 4812 stent patients. Overall tirofiban was less effective than abciximab, with a 26% relative increase in the primary end point of death, MI, and urgent revascularization at 30 days (7.5% vs. 6.0%, P = 0.037). In the TACTICS-TIMI-18 (Treat Angina with Aggrastat [tirofiban] and determine Cost of Therapy with Invasive or Conservative Strategy-Thrombolysis In Myocardial Infarction) trial, ⁴⁶ 2220 patients with unstable angina or non-ST-elevation MI received aspirin, heparin, beta-blockers, and tirofiban upon hospital admission, followed by randomization to invasive management (catheterization within 4 to 48 hours and revascularization where feasible) versus conservative management (catheterization only for spontaneous or provocable ischemia). The primary end point of the trial (death, MI, or rehospitalization for ACS at 6 months) was reduced by 18% in the invasive arm (15.9% vs. 19.4%, P = 0.025). The beneficial effect was most pronounced in the patients with positive troponins (14% vs. 24%).

The dosage of tirofiban used in RESTORE and TARGET was 10 µg/kg bolus followed by an infusion of 0.15 µg/kg/min. In the PRISM-PLUS (Platelet receptor inhibition in ischemic syndrome management in patients limited by unstable signs and symptoms) trial, the dose was slightly different, a 0.4 µg/kg/min loading infusion for 30 minutes, followed by a 0.1 µg/kg/min maintenance infusion. In practice, physicians favor the high-dose regimen for patients undergoing coronary intervention. Therapy is usually continued for 12 to 24 hours after the completion of the procedure.

With tirofiban, there was no increase in major bleeding complications in the clinical trials, ^43,47 and, as with eptifibatide, there is no known immune response and the overall incidence of thrombocytopenia is low. If patients require emergency CABG, tirofiban should be discontinued; antiplatelet effects will resolve in 6 hours, but platelet transfusion is ineffective. Clearance is longer in patients with renal failure.

Trials of oral GP IIb/IIIa antagonists have been disappointing without obvious explanation. In the EXCITE (Evaluation of oral xemilofiban in controlling thrombotic events) trial, ⁴⁸ 7232 patients undergoing coronary intervention were randomized to xemilofiban or placebo. The primary end point (death, MI, and urgent intervention) was similar at 30 days and 6 months, although there appeared to be a benefit in diabetics. In OPUS (Orboifiban in Patients with Unstable coronary Syndrome)-TIMI 16, 10,302 patients with unstable ischemic syndromes were randomized to oral orbofiban or placebo. ⁴⁹ Enrollment was terminated because of excess 30-day mortality in the low-dose orbofiban group, although patients who underwent PCI appeared to benefit from orbofiban.

Conclusion

Antiplatelet medications have made, and will continue to make, a significant impact on PCI. After review of the evidence, the supported recommendations regarding antiplatelet medication and PCI (unless contraindicated) would be as follows: 1) all patients undergoing PCI should receive aspirin; 2) all patients receiving stents should be placed on clopidogrel; 3) the data is compelling for the routine use of IV GP IIb/IIIa antagonists during PCI with stenting and especially high risk PCI; 4) the routine use of GP IIb/IIIa antagonists during acute MI with primary stent is controversial; 5) there is potential benefit for the use of abciximab during acute MI (rescue PTCA after failed lytic therapy), but further study is needed; and 6) rescue use of GP IIb/IIIa antagonists after failed/suboptimal intervention has not been prospectively studied. Several small reports suggest potential benefit for "rescue use" in thrombus-containing lesions, stent thrombosis, and abrupt closure, but suggest less benefit in degenerated vein grafts.