Adjunctive Pharmacology for Cardiac Catheterization
Kevin Croce
Daniel I. Simon
An important part of interventional catheterization involves mastery of a broad range of drugs that includes anticoagulant, antiplatelet, vasoactive, sedative, and antiarrhythmic agents. There is little doubt that refinements in antiplatelet (e.g., ADP receptor antagonists) and anticoagulant (e.g., bivalirudin) adjunctive pharmacology have contributed significantly to the improvements in percutaneous coronary intervention (PCI) success, safety, and durability over the last decade, and this chapter focuses on evidence-based recommendations for antithrombotic therapy during PCI highlighting the guidelines from the American College of Cardiology Foundation/ American Heart Association/Society for Cardiac Angiography and Interventions (ACCF/AHA/SCAI).1
ANTIPLATELET AGENTS
The three classes of antiplatelet agents that are approved for use in PCI patients include cyclooxygenase inhibitors (aspirin), platelet P2Y12 ADP receptor antagonists (ticlopidine, clopidogrel, prasugrel, ticagrelor), and glycoprotein (GP) IIb/IIIa inhibitors. These agents are commonly used in combination to reduce pre-, intra-, and post-procedural adverse cardiovascular events in patients undergoing PCI. In addition, current guidelines recommend dual antiplatelet therapy with aspirin and an ADP receptor antagonist for all PCI patients based on reduction of ischemic events and stent thrombosis following coronary intervention.1, 2, 3, 4
Aspirin
Mechanism of Action and Pharmacokinetics
Aspirin (acetylsalicylic acid, aspirin) exerts its antiplatelet effect primarily by interfering with the biosynthesis of cyclic prostanoids (e.g., thromboxane A2, TXA2). Aspirin irreversibly inhibits the cyclooxygenase activity of prostaglandin H synthase 1 (Cox-1) and prostaglandin H synthase 2 (Cox-2) which produce intermediate compounds that are used to generate several prostanoids including arachidonic acid-derived TXA2, which promotes platelet aggregation.5,6 Aspirin irreversibly acetylates key serine residues on Cox-1 and Cox-2 and prevents conversion of arachidonic acid to prostanoid precursors. The platelet activating prostanoid TXA is mainly produced by Cox-1 while the vasodilator and platelet inhibitor prostacyclin (PGI2) is primarily produced by Cox-2. Higher aspirin doses are required to inhibit Cox-2 compared to Cox-1, which is the reason why aspirin exerts antiplatelet effects at half the dose that is required for analgesia (80 to 100 mg versus 325 mg). Aspirin is rapidly absorbed in the upper gastrointestinal tract (GI) and plasma levels peak <40 minutes after administration.7 Aspirin-mediated platelet inhibition is seen within 40 to 60 minutes of ingestion, and Cox is irreversibly inhibited for the life of the platelet (7 to 10 days).7
Dosing for Percutaneous Coronary Intervention
The optimal aspirin dose for PCI is not firmly established, but randomized trials have shown inhibition of Cox-1 at doses ranging between 50 and 100 mg/day.8 Clinical studies have demonstrated that aspirin doses of 75 to 150 mg are as effective as higher doses for the prevention of cardiovascular events.9 When given in combination with warfarin or the ADP receptor antagonist class of antiplatelet agents, the aspirin dose should probably be lowered to 80 to 100 mg based on a post-hoc analysis of data from the Clopidogrel in Unstable angina to prevent Recurrent Events (CURE) study in which similar efficacy, but less major bleeding, was seen in the low-dose (<100 mg) aspirin group.10
The CURRENT/OASIS-7 (Clopidogrel Optimal Loading Dose Usage to Reduce Recurrent Events/Organization to Assess Strategies in Ischemic Syndromes) trial was the first prospective randomized study to compare low-dose versus high-dose aspirin in acute coronary syndrome (ACS) patients undergoing coronary angiography.11 Patients were randomized in a 2 × 2 factorial manner to open-label low-dose (75 to 100 mg daily) versus high-dose (300 to 325 mg daily) aspirin and to standard dose (300 mg loading dose followed by 75 mg daily thereafter) or high dose (600 mg loading dose followed by 150 mg daily for 7 days and then 75 mg daily thereafter) clopidogrel for 1 month. With regard to aspirin dose, the results of CURRENT/OASIS-7 did not show significant differences in efficacy between low- and high-dose aspirin. Although there was a trend toward increased GI bleeding in the high-dose aspirin group (0.38% versus 0.24%; P = 0.051), there were no differences in major bleeding.
Evidence for Use in Percutaneous Coronary Intervention Patients
Aspirin is a cornerstone treatment of coronary artery disease (CAD) because four randomized trials have demonstrated that aspirin therapy results in approximately 50% reduction in the risk of death or myocardial infarction (MI) in patients with unstable angina (UA) and non-ST segment elevation myocardial infarction (NSTEMI).12, 13, 14, 15 The Swedish angina pectoris aspirin trial, in which 2,035 patients were allocated to receive 75 mg aspirin daily or placebo,16 showed that aspirin therapy led to significant reductions in death and MI in several patient subsets; UA (46% reduction), stable angina (33% reduction), and patients undergoing coronary angioplasty (53% reduction).
The benefits of aspirin in reducing cardiovascular death, MI, and stroke in patients with CAD17 has led to the near universal use of this medication in PCI patients. PCI with balloon angioplasty or intracoronary stenting results in local vascular trauma, endothelial denudation, and platelet and fibrin deposition, and thus early trials showed a 3.5% to 8.6% risk of abrupt vessel closure or subacute thrombosis.18 The initial studies examining aspirin in PCI included combined antiplatelet regimens with dipyridamole, which reduced the incidence of periprocedural MI during PCI by 77% compared to placebo when administered 24 hours prior to balloon angioplasty and continued for 4 to 7 months.19 Dipyridamole, however, was shown to provide no additional benefit beyond that conveyed by aspirin alone during elective angioplasty.20 Aspirin has been shown to be particularly effective in patients undergoing intracoronary stent placement, especially in combination with platelet P2Y12 ADP receptor antagonists.21, 22, 23
Adverse Reactions
Because of its antiplatelet effects, aspirin increases the risk of bleeding. Metaanalysis studies have demonstrated a 60% increase in the risk of a major extracranial bleed with aspirin therapy, although aspirin does not appear to increase the risk of fatal bleeding.9,24 Aspirin sensitivity includes anaphylactoid reactions, respiratory sensitivity, and cutaneous sensitivity (urticaria and/or angioedema). Aspirin allergic patients that require aspirin therapy for PCI and stenting can be desensitized so that they can tolerate dual antiplatelet therapy following stent implantation.25,26
Guideline Recommendations
The 2011 ACCF/AHA/SCAI Guidelines for Percutaneous Coronary Intervention specifically addresses aspirin in the context of dual antiplatelet therapy following PCI. The recommendations are as follows:
1. Patients already taking daily aspirin therapy should take 81 mg to 325 mg before PCI. (Class 1, level of
evidence: B)
2. Patients not on aspirin therapy should be given nonenteric aspirin 325 mg before PCI. (Class 1, level of evidence: B)
3. After PCI, use of aspirin should be continued indefinitely (Class 1, level of evidence: A).
Of note, aspirin dose should be reduced to 81 to 100 mg when used concomitantly with ticagrelor.27
ADP Receptor Antagonists
Mechanism of Action and Pharmacokinetics
ADP receptor antagonists attenuate platelet activation by selectively and irreversibly (clopidogrel, prasugrel, ticlopidine) or reversibly (ticagrelor) binding and inhibiting the platelet P2Y12 ADP receptor, which plays a critical role in orchestrating platelet activation and aggregation.28 P2Y12 receptor activation results in sustained platelet aggregation and stabilization of the platelet aggregate. When given in combination with aspirin, ADP receptor antagonists inhibit platelet aggregation to a greater extent than either agent alone.29 Currently four ADP receptor antagonists are approved for clinical use in the United States (ticlopidine, clopidogrel, prasugrel, and ticagrelor). An additional intravenous ADP receptor antagonist, cangrelor, is currently under clinical investigation. Cangrelor has rapid onset and offset, and although it does not does not appear to be superior to oral regimens in the PCI setting,30 it is currently being evaluated in bridging patients to cardiac surgery.31,32
Ticlopidine
Ticlopidine is the first-generation ADP receptor antagonist that was approved for use as an antiplatelet agent in 1991. Ticlopidine is a thienopyridine class ADP receptor antagonist, which is an inactive prodrug that requires conversion by hepatic cytochrome P450-3A4 enzymes to produce active metabolites.33,34 The inhibition of platelet aggregation by ticlopidine is concentration dependent35 and ticlopidine metabolites bind irreversibly to the P2Y12 receptor resulting in
inhibition for the life of the platelet. Administration of ticlopidine results in maximal platelet inhibition 2 days after the initiation of therapy. However, due to safety concerns (mainly high rates of neutropenia) and twice daily dosing, ticlopidine has been largely replaced by clopidogrel (a second-generation thienopyridine) due to its better safety profile.36
inhibition for the life of the platelet. Administration of ticlopidine results in maximal platelet inhibition 2 days after the initiation of therapy. However, due to safety concerns (mainly high rates of neutropenia) and twice daily dosing, ticlopidine has been largely replaced by clopidogrel (a second-generation thienopyridine) due to its better safety profile.36
Clopidogrel
The second-generation thienopyridine clopidogrel differs structurally from ticlopidine by the addition of a carboxymethyl group. Clopidogrel is also a prodrug that requires hepatic cytochrome P450-3A4 conversion to produce active metabolites.33,34 Eighty-five percent of clopidogrel is hydrolyzed by human carboxylesterase-1 into an inactive metabolite, and the remaining 15% of clopidogrel then undergoes a two-step hepatic cytochrome P450 (CYP)-dependent oxidation process. The activation processes involved in clopidogrel metabolism lead to a delay in peak antiplatelet effect that varies from 6 to 9 hours depending on the loading dose. Clopidogrel is six times more potent than ticlopidine and these two drugs do not share common metabolites.37 The inhibition of platelet aggregation by clopidogrel is concentration dependent and irreversible.35 Following cessation of clopidogrel therapy, platelet function recovers in 5 to 7 days due to the synthesis of new platelets.38
It has recently been recognized that there is significant response variability in the degree of platelet inhibition achieved with clopidogrel and the topic of clopidogrel response variability has been reviewed extensively.39, 40, 41 The degree of platelet inhibition achieved with clopidogrel is affected by several clinical factors, such as compliance, age, ethnicity, body weight, diabetes, dyslipidemia, renal function, MI presentation, congestive heart failure, and interaction with drugs that alter prodrug conversion.42, 43, 44, 45, 46, 47 In addition, specific polymorphisms that reduce the activity of hepatic CYP2C19 enzymes (e.g., CYP2C19*2 and CYP2C19*3) decrease hepatic conversion of clopidogrel, and carriers of these reducedfunction CYP2C19 alleles have significantly lower levels of active metabolite, diminished platelet inhibition, and higher rates of adverse cardiovascular events and stent thrombosis following PCI.46 The prevalence of CYP2C19 polymorphisms is significant, and varies from 30% to 60% depending on ethnic background.48, 49, 50 Polymorphisms in genes that influence GI absorption, such as ABCB1, also influence platelet inhibition by clopidogrel,51,52 and medications that inhibit CYP activity such as certain proton pump inhibitors appear to decrease clopidogrel efficacy by diminishing clopidogrel conversion to the active metabolite.53 The clinical importance of ABCB1 polymorphisms and clopidogrel drug-drug interactions (e.g., atorvastatin and omeprazole) remain uncertain with regard to their effect on cardiovascular outcomes in PCI patients. In some countries where access to the newer ADP receptor antagonists prasugrel and ticagrelor is limited, the antiplatelet agent cilostazol is added to aspirin and clopidogrel to treat clopidogrel hyporesponders. Cilostazol is a phosphodiesterase-3 inhibitor that increases platelet inhibition in pharmacodynamic studies where poor clopidogrel responders were treated with triple aspirin, clopidogrel, and cilostazol therapy.54,55
Prasugrel
Compared to ticlopidine and clopidogrel, the third-generation irreversible thienopyridine ADP receptor antagonist prasugrel has more rapid onset of action (1 to 2 hours), achieves a greater degree of platelet inhibition, has fewer drug-drug interactions, and less interindividual response variability (Figure 5.1).48,56,57 Prasugrel is also a prodrug; however, compared to clopidogrel, prasugrel conversion occurs via more efficient hepatic oxidation pathways that result in rapid metabolite production and peak platelet inhibition 30 to 60 minutes after loading dose administration.48,56,57 Prasugrel activity is not altered by genetic polymorphisms in hepatic CYP2C19 enzymes.48
Ticagrelor
The third-generation non-thienopyridine ADP receptor antagonist ticagrelor is a reversibly binding, direct acting, noncompetitive agent. Ticagrelor and prasugrel are similar in the timing of their onset of action (<60 minutes), and both of these newer agents provide a greater degree of platelet inhibition with less interindividual variability compared to clopidogrel.58 Ticagrelor is not a prodrug and thus does not require hepatic conversion to an active metabolite. In addition, because ticagrelor is a reversible inhibitor, platelet function normalizes within 3 to 5 days following the last dose, which is faster compared to irreversible thienopyridine agents.59
Dosing for Percutaneous Coronary Intervention
In the setting of PCI, ticlopidine is administered 250 mg twice daily with antiplatelet doses of aspirin. The recommended loading dose of clopidogrel is 600 mg in the setting of PCI which is followed by 75 mg daily.1 In patients undergoing PCI, the clopidogrel loading dose should be given as early as possible.1 Pretreatment with clopidogrel prior to PCI improves 30-day outcomes compared to no pretreatment60,61 and, owing to the delay in the onset of clopidogrel action, the benefit of pretreatment is greatest when clopidogrel is administered more than 6 hours prior to the start of the PCI.62 Several clinical studies have demonstrated that increased loading (900 mg) and maintenance doses of clopidogrel can increase platelet inhibition in patients who are slow clopidogrel metabolizers or in patients who have high on-treatment platelet reactivity on standard dose clopidogrel.63, 64, 65 Higher clopidogrel dosing has been shown to shorten the onset of action, reduce interindividual variability, and improve early outcomes without increasing bleeding.63, 64, 65 Despite the ability of high maintenance dose clopidogrel to increase platelet inhibition, high maintenance dosing strategies have
not consistently improved cardiovascular outcomes when patients with poor clopidogrel response are prospectively identified with platelet function testing.66 In the setting of PCI, prasugrel is administered with a 60 mg loading dose followed by 10 mg daily. Because of the rapid onset of action, prasugrel preloading was not routinely done prior to diagnostic angiography in clinical studies.67 Ticagrelor dosing for PCI is accomplished with a 180 mg load followed by 90 mg twice daily. When prescribing ticagrelor, aspirin should be used at low 81 to 100 mg doses because ticagrelor had reduced clinical efficacy in clinical trials when coadministered with highdose aspirin.27,58
not consistently improved cardiovascular outcomes when patients with poor clopidogrel response are prospectively identified with platelet function testing.66 In the setting of PCI, prasugrel is administered with a 60 mg loading dose followed by 10 mg daily. Because of the rapid onset of action, prasugrel preloading was not routinely done prior to diagnostic angiography in clinical studies.67 Ticagrelor dosing for PCI is accomplished with a 180 mg load followed by 90 mg twice daily. When prescribing ticagrelor, aspirin should be used at low 81 to 100 mg doses because ticagrelor had reduced clinical efficacy in clinical trials when coadministered with highdose aspirin.27,58
 Figure 5.1 Relationship between inhibition of platelet activation by clopidogrel (300 mg) versus prasugrel (60 mg) in response to 20 pmol/L adenosine diphosphate (ADP) 24 hours after loading. Subjects were administered both clopidogrel and prasugrel in a crossover fashion. These data illustrate the point that clopidogrel has significant interindividual variability compared with prasugrel. (From Brandt JT, et al. A comparison of prasugrel and clopidogrel loading doses on platelet function: magnitude of platelet inhibition is related to active metabolite formation. Am Heart J 2007;153:66.) |
Evidence for Use in Percutaneous Coronary Intervention Patients
The early experience with coronary stenting was notable for unacceptably high rates of subacute stent thrombosis that occurred in 3% to 5% of patients and was associated with MI, need for urgent coronary artery bypass grafting (CABG), and/or death. Aggressive anticoagulation regimens (including intravenous heparin and dextran, warfarin, and dipyridamole) to minimize the risk of stent thrombosis led to frequent bleeding complications and prolonged hospitalizations.68 When aspirin is used in combination with a thienopyridine, several studies have demonstrated up to 5-fold reductions in acute and subacute stent thrombosis compared with either aspirin alone, warfarin, heparin, or long-term low-molecularweight heparin (LMWH)22,70 (Figure 5.2).
The CURE study randomized 12,562 patients who presented within 24 hours of symptoms to receive clopidogrel 300 mg load, followed by 75 mg daily and aspirin versus aspirin and placebo.70 There was a significant reduction (9.3% versus 11.4%, RRR 20%, P < 0.001) in the primary endpoint (death from cardiovascular cause, nonfatal MI, or stroke) in the group receiving clopidogrel. The benefit with clopidogrel was noted early (within 24 hours of treatment), was sustained at 1 year, and was observed in all patients with ACSs regardless of their level of risk.71 In a prespecified substudy of CURE, patients who underwent PCI and were randomized to clopidogrel had a 31% relative risk reduction in death and MI compared to placebo-treated PCI patients.60 Furthermore, long-term (9 to 12 months) compared to short-term (4 weeks) clopidogrel therapy post PCI was associated with a 31% lower rate of cardiovascular death, MI, or revascularization (P = 0.03).
The clopidogrel to reduce events during observation (CREDO) trial demonstrated the benefit of clopidogrel
pretreatment and long-term therapy in a relatively stable CAD population undergoing stenting.61 Patients were randomly assigned to receive a 300 mg clopidogrel loading dose or placebo, 3 to 24 hours before PCI, followed by clopidogrel 75 mg daily for 28 days post PCI. Patients loaded with clopidogrel were continued on active drug from day 28 through 12 months and those patients in the control group received placebo. There was a significant 27% (P = 0.02) reduction in death, MI, or stroke in patients receiving clopidogrel, suggesting that clopidogrel therapy in addition to aspirin should be continued for a minimum of 9 months post PCI.
pretreatment and long-term therapy in a relatively stable CAD population undergoing stenting.61 Patients were randomly assigned to receive a 300 mg clopidogrel loading dose or placebo, 3 to 24 hours before PCI, followed by clopidogrel 75 mg daily for 28 days post PCI. Patients loaded with clopidogrel were continued on active drug from day 28 through 12 months and those patients in the control group received placebo. There was a significant 27% (P = 0.02) reduction in death, MI, or stroke in patients receiving clopidogrel, suggesting that clopidogrel therapy in addition to aspirin should be continued for a minimum of 9 months post PCI.
 Figure 5.2 Comparison of major adverse clinical events (MACE %) after bare-metal stenting in the CLASSICS, ISAR, FANTASTIC, STARS, and MATTIS trials. These events largely reflect the incidence of subacute stent thrombosis. OAC indicates oral anticoagulants; ASA, acetylsalicylic acid (aspirin); and LD, loading dose. (From Bertrand ME, et al. Double-Blind Study of the Safety of Clopidogrel with and without a Loading Dose in Combination with Aspirin Compared with Ticlopidine in Combination with Aspirin after Coronary Stenting study (CLASSICS). Circulation 2000;102:628.) |
In CURE, there was a significant increase in major bleeding in those receiving clopidogrel compared to placebo (3.7% versus 2.7%, P = 0.001), which was most notable in patients requiring CABG.71 In contrast, CREDO only showed a trend toward more Thrombolysis in Myocardial Infarction (TIMI) major bleeding with clopidogrel compared to placebo (8.8% versus 6.7%, P = 0.07), and no excess bleeds among patients undergoing CABG.61 These findings have led to the recommendation to delay elective CABG for 5 days after stopping clopidogrel, and possibly avoiding preloading of clopidogrel in unstable angina (UA)/NSTEMI patients until after the coronary anatomy is identified and the need for CABG excluded. However, it is important to emphasize that the risk-benefit of pretreatment needs to be established for each individual patient, recognizing the consistent and substantial benefit of clopidogrel pretreatment in reducing the risk of death and MI.
Prasugrel was compared head to head with clopidogrel in the Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel-Thrombolysis in Myocardial Infarction (TRITON-TIMI) 38 trial, which tested the hypothesis that a newer antiplatelet agent with greater potency and less variable response would reduce ischemic events compared to standard-dose clopidogrel.67 The study randomized 13,608 patients with moderate-to-high-risk ACS (10,074 with UA or non-ST-elevation MI and 3,534 with ST-elevation MI) undergoing PCI to prasugrel (60 mg loading dose, 10 mg QD) or clopidogrel (300 mg loading dose, 75 mg QD) for a duration of 6 to 15 months (median duration 14 months). The primary efficacy endpoint was death from cardiovascular causes, nonfatal MI, or nonfatal stroke and the primary safety endpoint was non-CABG TIMI major bleeding. The primary efficacy endpoint occurred in 9.9% of patients receiving prasugrel and 12.1% of patients receiving clopidogrel (hazard ratio [HR] for prasugrel versus clopidogrel, 0.81; 95% confidence interval [CI], 0.73 to 0.90; P < 0.001). There were significant reductions in the prasugrel group in the rates of MI (prasugrel, 7.4% versus clopidogrel, 9.7%; P < 0.001), urgent target-vessel revascularization (prasugrel, 2.5% versus clopidogrel, 3.7%; P < 0.001), and stent thrombosis (prasugrel, 1.1% versus clopidogrel, 2.4%; P < 0.001). These improvements in cardiovascular outcomes led the FDA to approve prasugrel for use in ACS patients undergoing PCI in 2009.
The reversible ADP receptor antagonist ticagrelor was also compared head to head against clopidogrel in The Study of Platelet Inhibition and Patient Outcomes (PLATO) trial. PLATO randomized 18,624 patients admitted to the hospital with an ACS to ticagrelor (180 mg loading dose, 90 mg twice daily thereafter) versus clopidogrel (300 to 600 mg loading dose, 75 mg daily thereafter) and examined the rate of adverse cardiovascular events up to 12 months.58 The primary endpoint, a composite of death from vascular causes, MI, or stroke occurred in 9.8% of patients receiving ticagrelor as compared with 11.7% of those receiving clopidogrel (HR, 0.84; 95% CI, 0.77 to 0.92; P < 0.001). In secondary endpoint analyses, ticagrelor reduced the rate of MI (5.8%
in the ticagrelor group versus 6.9% in the clopidogrel group, P = 0.005) and death from vascular causes (4.0% versus 5.1%, P = 0.001). The FDA approved ticagrelor for ACS patients in 2011.
in the ticagrelor group versus 6.9% in the clopidogrel group, P = 0.005) and death from vascular causes (4.0% versus 5.1%, P = 0.001). The FDA approved ticagrelor for ACS patients in 2011.
Adverse Reactions
All of the ADP receptor antagonists increase the risk of bleeding. In CURE, clopidogrel use with aspirin was associated with an increase in bleeding compared to placebo with aspirin (3.7% versus 2.7%; relative risk, 1.38; P = 0.001)70 and in the Clopidogrel Aspirin Stent International Cooperative Study (CLASSICS) major peripheral or bleeding complication were similar between clopidogrel (1.3%) and ticlopidine (1.2%).36 Compared to clopidogrel, the more potent agents prasugrel and ticagrelor do increase bleeding in patients undergoing PCI.58,67 In TRITON TIMI38, prasugrel use was associated with increased life-threatening bleeding (prasugrel, 1.4% versus clopidogrel, 0.9%; P = 0.01), which included nonfatal bleeding (prasugrel, 1.1% versus clopidogrel, 0.9%; HR, 1.25; P = 0.23) and fatal bleeding (prasugrel, 0.4% versus clopidogrel, 0.1%; P = 0.002).67 Similarly, in PLATO ticagrelor caused a higher rate of major bleeding not related to CABG (ticagrelor, 4.5% versus clopidogrel, 3.8%, P = 0.03), including more instances of fatal intracranial bleeding.58
The incidence of adverse reaction to ticlopidine is significant; diarrhea, nausea, and vomiting are common with ticlopidine, occurring in 30% to 50% of recipients72 and neutropenia, which is a serious side effect, occurs in 1.3% to 2.1% compared with 0.10% with clopidogrel.73,74 With ticlopidine, most cases of neutropenia develop within the first 3 months of therapy and initially may be clinically silent. Complete blood counts should be performed every 2 weeks during the first 3 months of therapy.75 Bone marrow aplasia and thrombotic thrombocytopenic purpura (TTP) have been reported with ticlopidine.76, 77, 78 The estimated incidence of ticlopidineassociated TTP is 1 per 1,600 to 5,000 patients treated37,77,79 while the incidence of TTP with clopidogrel appears to be lower.77 Allergic or hematologic reactions to clopidogrel occur in approximately 1% of patients and limited information on switching thienopyridine in patients with adverse reactions is available.80 Desensitization protocols using escalating doses of oral clopidogrel have been proposed for clopidogrel-allergic patients;81 however, recent availability of the non-thienopyridine ticagrelor may provide an option for switching ADP receptor antagonist class rather than embarking on desensitization.
The incidence of adverse nonhemorrhagic reactions for prasugrel and clopidogrel are similar. Post hoc subgroup analysis of TRITON TIMI 38 identified less clinical efficacy and greater bleeding in patients with prior history of stroke or transient ischemic attack, in elderly patients (age > 75 years), in patients with low body weight (<60 kg), and in patients undergoing urgent CABG. Increased risk of bleeding in these subgroups resulted in an FDA black box warning stating that prasugrel should not be prescribed to patients with any history of stroke or transient ischemic attack or to patients with severe liver dysfunction. In addition, prasugrel is not recommended for elderly patients (age > 75 years) as this subgroup had increased risk of fatal and intracranial bleeding with uncertain benefit except in high-risk subsets (those with history of diabetes or prior MI). Prasugrel should also be avoided with concomitant use of medications that increase bleeding risk (i.e., Coumadin) and should be used with caution in patients with low body weight (<60 kg). The two most common nonhemorrhagic side effects seen with ticagrelor are dyspnea (ticagrelor, 13.8% versus clopidogrel 7.8%) and bradycardia/ ventricular pauses (ticagrelor 6.0% versus clopidogrel 3.5%).
Guideline Recommendations
The 2011 ACCF/AHA/SCAI Guidelines for Percutaneous Coronary Intervention specifically address oral ADP receptor antagonists for patients undergoing PCI. The recommendations are as follows:
1. A loading dose of a P2Y12 receptor inhibitor should be given to patients undergoing PCI with stenting (Level of Evidence: A).
Options include:
a. Clopidogrel 600 mg (ACS and non-ACS patients) (Class I, level of evidence: B)
b. Prasugrel 60 mg (ACS patients) (Class 1, level of evidence: B)
c. Ticagrelor 180 mg (ACS patients) (Class 1, level of evidence: B)
2. The duration of P2Y12 inhibitor therapy after stent implantation should generally be as follows:
a. In patients receiving a stent (BMS or DES) during PCI for ACS, P2Y12 inhibitor therapy should be given for at least 12 months. Options include clopidogrel 75 mg daily, prasugrel 10 mg daily, and ticagrelor 90 mg twice daily. (Class 1, level of evidence: B)
b. In patients receiving DES for a non-ACS indication, clopidogrel 75 mg daily should be given for at least 12 months if patients are not at high risk of bleeding. (Class 1, level of evidence: B)
c. In patients receiving BMS for a non-ACS indication, clopidogrel should be given for a minimum of 1 month and ideally up to 12 months (unless the patient is at increased risk of bleeding; then it should be given for a minimum of 2 weeks). (Class 1, level of evidence: B)
Intravenous Glycoprotein IIb/IIIa Inhibitors
Mechanism of Action and Pharmacokinetics
Platelet GP IIb/IIIa receptors mediate the “final common pathway” of platelet aggregation by binding fibrinogen and
other adhesive proteins that bridge adjacent platelets and have thus served as a primary focus of pharmacologic antiplatelet strategies. Three parental GP IIb/IIIa receptor antagonists abciximab (ReoPro), eptifibatide (Integrilin), and tirofiban (Aggrastat) are currently approved for clinical use by FDA.
other adhesive proteins that bridge adjacent platelets and have thus served as a primary focus of pharmacologic antiplatelet strategies. Three parental GP IIb/IIIa receptor antagonists abciximab (ReoPro), eptifibatide (Integrilin), and tirofiban (Aggrastat) are currently approved for clinical use by FDA.
Abciximab
Abciximab is a humanized Fab fragment engineered from the murine monoclonal antibody 7E3 directed against GP IIb/IIIa.82 Unlike small-molecule agents, abciximab interacts with the GP IIb/IIIa receptor at sites distinct from the ligand-binding RGD sequence site, and exerts its inhibitory effect noncompetitively.83 The antibody has unique pharmacokinetics, with the majority of the drug cleared from plasma within 26 minutes, but much slower clearance from the body with a functional half-life up to 7 days.84 Because of the high affinity of abciximab for GP IIb/IIIa receptors, the number of abciximab molecules bound to platelets is considerably higher than the free plasma pool of the drug for the duration of treatment, and platelet-associated abciximab can be detected for more than 14 days after the infusion is stopped.85 The use of intracoronary GP IIb/IIIa antagonists has been advocated by some interventional cardiologists largely on the basis of smaller angiographic trials. Interestingly, the recent Intracoronary Aabciximab and Aspiration Thrombectomy in Patients with Large Anterior Myocardial Infarction (INFUSE-AMI) trial indeed indicates that intracoronary abciximab in the setting of primary PCI for STEMI improved left ventricular function to a greater extent than aspiration thrombectomy.86
Eptifibatide
The cyclic heptapeptide eptifibatide is based on barbourin, a 73-amino acid peptide isolated from the venom of the Southeastern pygmy rattlesnake Sistrurus miliarius barbouri.87 With the recommended bolus (180 µg/kg followed by second 180 µg/kg bolus) and infusion (2 µg/kg/minute) regimen, peak plasma levels are established shortly after the bolus dose, and slightly lower concentration are subsequently maintained throughout the infusion period. Plasma concentrations decrease rapidly after the infusion is discontinued and eptifibatide has an elimination half-life of 2.5 hours, with the majority of the drug eliminated through renal mechanisms.88 A lower infusion dose (1 µg/kg/minute) of eptifibatide is recommended in patients with creatinine clearance less than 50 mL/minute. Substantial recovery of platelet aggregation is apparent within 4 hours of discontinuing the infusion.89
Tirofiban
Tirofiban is a peptidomimetic inhibitor that occupies the binding pocket on GP IIb/IIIa and thereby competitively inhibits platelet aggregation mediated by fibrinogen or von Willebrand factor.90 The stoichiometry of both eptifibatide and tirofiban needed to achieve full platelet inhibition is >100 molecules of drug per GP IIb/IIIa receptor. This compares with a stoichiometry of 1.5 molecules of abciximab for each receptor.88 Like eptifibatide, substantial recovery of platelet aggregation is apparent within 4 hours of stopping the infusion.89 Pharmacodynamic studies have led to the development of high loading dose tirofiban regimens that appear to be more efficacious than the FDA-approved regimen.91, 92, 93
Dosing for Percutaneous Coronary Intervention
Preclinical and clinical pharmacodynamic studies suggest that 80% inhibition of platelet aggregation by light transmission aggregometry should be the target for clinically effective antiplatelet activity.94 The level of platelet inhibition varies between the three GP IIb/IIIa inhibitors following the recommended bolus and infusions.95 In general, the bolus and infusion regimen of abciximab and the double bolus and infusion regimen of eptifibatide are associated with rapid and profound inhibition of platelet function.95, 96, 97 Several studies have documented that the FDA-approved bolus and infusion regimen for tirofiban achieves suboptimal levels of platelet inhibition for up to 4 to 6 hours, and this suboptimal level of inhibition likely accounts for inferior clinical results in the PCI setting.97
The clinical relevance of these pharmacodynamic observations was tested in the TARGET (Tirofiban and ReoPro Give Similar Efficacy) trial, which randomized 5,308 patients to tirofiban (10 µg/kg bolus followed by an infusion of 0.15 µg/kg/ minute for 18 to 24 hours post PCI) or abciximab before undergoing PCI with the intent to perform stenting.98 The primary endpoint was a composite of death, nonfatal MI, or urgent target vessel revascularization (TVR) at 30 days. The primary endpoint (6.0% versus 7.6%, P = 0.038) as well as the incidence of MI (5.4% versus 6.9%, P = 0.04) were significantly lower in the abciximab group compared to the tirofiban group, respectively. There was no significant difference in the rate of major bleeding between the two groups. Increasing the tirofiban bolus 2.5-fold (25 mg/kg) appears to enhance platelet inhibition and improve PCI outcomes compared to the FDA-approved dosing regimen.99 The degree of platelet inhibition appears central to the efficacy of GP IIb/IIIa inhibitors; achieving >95% platelet inhibition 10 minutes after the bolus in patients undergoing PCI was associated with a 55% reduction in MACE compared to those patients with <95% platelet inhibition.100
Evidence for Use in Percutaneous Coronary Intervention Patients
The landmark trial demonstrating efficacy of GP IIb/IIIa inhibition in the balloon angioplasty setting is the Evaluation of IIb/IIIa platelet receptor antagonist 7E3 in Preventing Ischemic Complications (EPIC) trial.104 In this study, high-risk patients undergoing balloon angioplasty were randomized to abciximab bolus and infusion versus abciximab bolus alone versus placebo. The group treated with abciximab bolus and
infusion had a 35% lower rate of death, MI, or unplanned urgent revascularization at 30 days compared to the placebo group (8.3% versus 12.8%, P = 0.008). No significant benefit with abciximab bolus alone was observed, suggesting that shorter duration of platelet inhibition was insufficient to favorably affect clinical outcomes. Major bleeding complications occurred in an unacceptably high proportion of patients treated with abciximab compared to placebo (major bleeding 14% versus 7%, transfusion 15% versus 7%, respectively). Procedural modifications, including performing front-wall arterial access only, reducing arterial sheath size from 8F to 6F, reducing heparin dosing to target activated clotting time (ACT) 200 to 250 seconds rather than >300 seconds, removing sheaths as soon as possible (ACT < 180 seconds) rather than overnight, and abandoning the use of routine venous sheaths, successfully reduced major bleeding complications to less than 1.0% to 1.5% in subsequent trials.
infusion had a 35% lower rate of death, MI, or unplanned urgent revascularization at 30 days compared to the placebo group (8.3% versus 12.8%, P = 0.008). No significant benefit with abciximab bolus alone was observed, suggesting that shorter duration of platelet inhibition was insufficient to favorably affect clinical outcomes. Major bleeding complications occurred in an unacceptably high proportion of patients treated with abciximab compared to placebo (major bleeding 14% versus 7%, transfusion 15% versus 7%, respectively). Procedural modifications, including performing front-wall arterial access only, reducing arterial sheath size from 8F to 6F, reducing heparin dosing to target activated clotting time (ACT) 200 to 250 seconds rather than >300 seconds, removing sheaths as soon as possible (ACT < 180 seconds) rather than overnight, and abandoning the use of routine venous sheaths, successfully reduced major bleeding complications to less than 1.0% to 1.5% in subsequent trials.
The benefit of GP IIb/IIIa inhibition patients undergoing elective stent placement has been shown in two large, randomized controlled trials.101,102 The Evaluation of IIb/IIIa inhibitor for Stenting (EPISTENT) trial randomized 2,399 patients to stent plus placebo, stent plus abciximab, or balloon angioplasty plus abciximab.103 The primary 30-day endpoint, a combination of death, MI, or urgent revascularization, occurred in 10.8% of patients in the stent plus placebo group, 5.3% of those in the stent plus abciximab group (HR 0.48; P < 0.001), and 6.9% in the group undergoing balloon angioplasty plus abciximab (HR 0.63; P = 0.007). These benefits were maintained at 6 months104 and 1 year,105 with a significant reduction in 1-year mortality in patients treated with stent plus abciximab compared with stent without the IIb/IIIa inhibitor (2.4% versus 1.0%, P = 0.037). No significant differences in bleeding complications were noted among the various groups.
The Enhanced Suppression of the Platelet IIb/IIIa Receptor with Integrilin Therapy (ESPRIT) trial randomized 2,064 patients undergoing stenting to eptifibatide (180 µg/kg bolus followed by a 2.0 µg/kg/hour infusion, with a second bolus of 180 µg/kg given 10 minutes after the first bolus) or placebo.102 In this trial, patients were administered a loading dose of clopidogrel or ticlopidine on the day of the procedure. The trial was terminated early for efficacy. The primary endpoint—a composite of death, MI, urgent revascularization, or thrombotic bailout at 48 hours—was reduced by 37% with eptifibatide (10.5% versus 6.6%, P = 0.0017). Death or MI at 48 hours was significantly reduced with eptifibatide compared to placebo (5.5% versus 9.2%, RRR = 40%, P = 0.0013). These benefits were maintained at 6 months106 and 1 year.107 Major bleeding was rare, but occurred more frequently in patients receiving eptifibatide compared to placebo (1.3% versus 0.4%, respectively; P = 0.027).
Three large, randomized clinical trials have evaluated each of the three GP IIb/IIIa inhibitors in UA/NSTEMI patients undergoing PCI. In the c7E3 Fab Antiplatelet Therapy in Unstable Refractory Angina (CAPTURE) trial, patients (n = 1,265) with refractory angina undergoing PCI were randomly assigned to receive abciximab 18 to 24 hours prior to PCI and for 1 hour after completion of the procedure or placebo.108 MACE was reduced in the abciximab group compared to placebo (15.9% versus 11.3%, P = 0.012, respectively). There was a significant increase in major bleeding (1.9% versus 3.8%, P = 0.043) and the need for transfusion (3.4% versus 7.1%, P = 0.005) in the abciximab group compared to placebo. The Platelet Receptor Inhibition in Ischemic Syndrome Management in Patients Limited by Unstable Sign and Symptoms (PRISM-PLUS) trial randomized 1,915 patients with UA/NSTEMI to tirofiban alone, tirofiban plus heparin, or placebo infusion plus heparin.101 The combination of tirofiban and heparin led to a 32% risk reduction in the rate of death, MI, or recurrent refractory ischemia at 7 days compared with heparin alone (12.9% versus 17.9%, respectively, P = 0.004). Tirofiban was also beneficial in the subgroup of patients undergoing PCI (RRR of death or MI at 30 days = 0.44).
In the Platelet Glycoprotein IIb/IIIa in UA: Receptor Suppression Using Integrilin Therapy (PURSUIT) trial, 10,948 patients with UA/NSTEMI were randomized to eptifibatide or placebo.109 The primary endpoint of 30-day death or MI was reduced in those patients receiving eptifibatide versus placebo (14.2% versus 15.7%, P = 0.042, respectively). This treatment benefit was more pronounced among patients undergoing PCI within 72 hours of presentation (11.6% versus 16.7%, P = 0.01, respectively). Moderate or severe hemorrhage was more common in the eptifibatide group (12.8% versus 9.9%, P < 0.001, respectively).
Four trials support the use of abciximab in primary PCI for STEMI, reducing MACE at 30 days by 35% to 54%.110, 111, 112, 113 In the Abciximab before Direct Angioplasty and Stenting in Myocardial Infarction Regarding Acute and Long-Term Followup (ADMIRAL) trial, 300 patients with acute MI were randomized to abciximab plus stenting or stenting alone prior to angiography.112 At 30 days, the primary endpoint—a composite of death, reinfarction, or urgent TVR—occurred in 6% of the patients in the abciximab group, as compared with 14.6% of those in the placebo group (P = 0.01). This beneficial effect was sustained at 6 months (7.4% versus 15.9%, P = 0.02) in ADMIRAL, but not in the two other trials.110, 111, 112, 113
Upstream administration of GP IIb/IIIa inhibitors prior to PCI in patients presenting with STEMI has been studied in six trials. In a metaanalysis of these trials, TIMI grade 3 flow (20.3% [84/413] versus 12.2% [51/418]) was significantly more common in the early (prior to transfer to the cardiac catheterization laboratory) group compared with the late (catheterization laboratory) group (odds ratio [OR], 1.69; 95% CI, 1.28 to 2.22; P < 0.001; and OR, 1.85; 95% CI, 1.26 to 2.71; P < 0.001, respectively). The early administration of GP IIb/IIIa inhibitors was associated with a 28% reduction of mortality from 4.7% to 3.4%, which was not significant but consistent with similar trends for reinfarction and the composite ischemic endpoint. Thus, early administration of GP IIb/IIIa inhibitors in STEMI appeared to improve coronary patency with favorable trends for clinical outcomes. However,
the prospective, randomized EARLY-ACS trial showed no significant benefit of upstream initiation compared to cardiac catheterization laboratory initiation of eptifibatide.114
the prospective, randomized EARLY-ACS trial showed no significant benefit of upstream initiation compared to cardiac catheterization laboratory initiation of eptifibatide.114
GP IIb/IIIa inhibitors have been shown to reduce major adverse cardiac events (death, MI, and urgent revascularization) by 35% to 50% in patients undergoing PCI115 (Table 5.1). Although no single study demonstrated a significant reduction in mortality alone with GP IIb/IIIa inhibitors, a metaanalysis suggests that these agents as a class reduce death by 20% to 30%119 (Figure 5.3). The mechanism by which GP IIb/IIIa inhibitors reduce long-term mortality is unclear, and cannot be explained solely by their ability to reduce periprocedural death or MI. Investigators have postulated that this therapy may also be associated with significant anti-inflammatory properties that may favorably influence the course of atherothrombotic disease,116,117 a contention that remains unproven at this time.
Although GP IIb/IIIa inhibitors have demonstrated ability to reduce adverse cardiovascular events, in the modern era of thienopyridine use and stenting, the clinical benefit of routine GP IIb/IIIa inhibitors has been inconsistent. The CADILLAC (Controlled Abciximab and Device Investigation to Lower Late Angioplasty Complications) trial demonstrated that STEMI patients treated with stenting did not benefit as much as patients treated with balloon angioplasty.113 In lowrisk elective PCI patients that were preloaded with 600 mg of clopidogrel, abciximab increased bleeding and did not improve ischemic outcomes.118,119 Although there is no benefit to routine GP IIb/IIIa inhibitor use in thienopyridinetreated low-risk elective PCI cohorts, data do justify targeted GP IIb/IIIa inhibitor use in high-risk patients. In the Intracoronary Stenting and Antithrombotic Regimen: Rapid Early Action for Coronary Treatment-2 (ISAR-REACT-2) study abciximab reduced ischemic endpoints without increasing bleeding in high-risk ACS patients.120
Table 5.1 Outcomes of Patients Receiving Glycoprotein IIb/IIIa Inhibitors | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Although older studies demonstrated reduction in ischemia when GP IIb/IIIa inhibitors were used upstream before PCI,121,122 a recent study performed in the thienopyridine and stenting era showed that in ACS patients undergoing invasive management, upstream GP IIb/IIIa inhibitor use increased bleeding to the same degree that it reduced ischemic events compared to a strategy of provisional GP IIb/IIIa inhibitor use at the time of PCI.114 Similarly, the Facilitated Intervention with Enhanced Reperfusion Speed to Stop Events (FINESSE) trial demonstrated that in ST-segment elevation MI patients, early abciximab use increased bleeding without clinical benefit when compared to provisional use during PCI. Table 5.2 summarizes data from trials examining GP IIb/IIIa inhibitor use in the modern era of thienopyridine preloading and stenting.
Adverse Reactions
As outlined above, when GP IIb/IIIa inhibitors are utilized with dose-adjusted heparin and early sheath removal, studies demonstrate a 0 to 1% absolute increase in major bleeding that occurs primarily at femoral access sites.109,121, 122, 123, 124, 125, 126 In a metaanalysis of eight clinical trials, abciximab increased the incidence of mild thrombocytopenia (>50,000 < 100,000) compared to placebo group (4.2% versus 2.0%, P < 0.001; OR 2.13).127 Eptifibatide or tirofiban with heparin did not increase mild thrombocytopenia compared with placebo with heparin (OR 0.99). Patients receiving abciximab with heparin had more than twice the incidence of severe thrombocytopenia (defined as >20,000 and <50,000) than those receiving placebo with heparin (1.0% versus 0.4%, P = 0.01; OR 2.48). Eptifibatide or tirofiban with heparin did not cause a significant excess of severe thrombocytopenia compared with placebo with heparin (0.3% versus 0.2%, P = 0.16). ACS trials tended to report higher incidence of thrombocytopenia compared to PCI trials, perhaps because of longer heparin infusions producing heparin-induced thrombocytopenia (HIT).127
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