**Pharmacotherapy During Percutaneous Coronary Interventions**

David C. Yang and Dmitriy N. Feldman *Greenberg Division of Cardiology, New York Presbyterian Hospital, Weill Cornell Medical College, New York, NY USA* 

#### **1. Introduction**

212 Coronary Interventions

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in diabetic patients undergoing elective cardiac catheterization or PCI: role of volume-to-creatinine clearance ratio and iodine dose-to-creatinine clearance ratio. *J Med Assoc Thai,* Vol.93 Suppl 1, (Jan), pp. S29-34, ISSN 0125-2208 (Print), 0125-2208

Farahani A, Sadigh G, Perkovic V (2009). Systematic review: sodium bicarbonate treatment regimens for the prevention of contrast-induced nephropathy. *Ann Intern Med,* Vol.151, No.9, (Nov 3), pp. 631-638, ISSN 1539-3704 (Electronic), 0003-4819 Percutaneous arterial catheterization and transluminal dilatation of stenotic vessels were first described by Charles T. Dotter and Melvin P. Judkins in their seminal paper published in 1964 (1). With the advent of contemporary coronary angioplasty and stenting techniques for patients with coronary artery disease (CAD) and acute coronary syndromes (ACS), the procedure has now been termed percutaneous coronary intervention (PCI). While PCI has done much in the modern era to improve patient outcomes in the face of acute myocardial infarction as well as in disabling cardiac angina, its benefits can still be limited by periprocedural complications such as acute vessel closure and stent thrombosis as well as conditions occurring after 30 days post-PCI, such as in-stent restenosis or late stent thrombosis. Additionally, catheter and wire associated thrombus formation can occur during PCI in the absence of adequate anticoagulation. Excess anticoagulation on the other hand carries a risk of major gastrointestinal or intracranial bleeding as well as vascular access bleeding complications. Stent thrombosis is a rare, but serious complication of PCI and usually presents as death or ST-elevation myocardial infarction. Coronary stents are generally made of stainless steel or cobalt chromium alloys rendering them thrombogenic until they are completely covered by endothelial tissue. The timing of complete endothelialization is variable and depends on whether the implanted stent is bare metal or drug-eluting, as well as which type of anti-proliferative drug the stent is coated with. Stent thrombosis can be described based on its timing relative to stent placement and is associated with a number of different risk factors (Table 1). Acute stent thrombosis occurs within 24 hours of PCI and in one pooled analysis, approximately 80 percent of all bare metal stent (BMS) thromboses occurred within this acute period (2). Subacute stent thrombosis occurs up to 30 days after PCI and this time period encompasses the majority of all thrombotic events observed in both BMS and drug-eluting stents (DES) (3). Stent thrombosis after 30 days and up to one year post-PCI is referred to as late stent thrombosis and seems to occur with equal frequency in BMS and DES, particularly in the absence or cessation of dual antiplatelet therapy with aspirin or clopidogrel (4-5). Occurring even less commonly at greater than one year post-PCI, very late stent thrombosis appears to be associated with DES more than BMS and is thought to be related to delayed neo-intimal coverage as well as ongoing vessel inflammation (6). Current ACC/AHA guidelines make a number of recommendations regarding the concurrent use of antiplatelet, antithrombotic, and

Pharmacotherapy During Percutaneous Coronary Interventions 215

testing below). Ticlopidine was the first widely used thienopyridine that began to have an antiplatelet effect within 24 to 48 hours after its administration. The STAIG trial was one of the first multicenter trials to evaluate the role of thienopyridines, particularly ticlopidine, in ACS (22). 652 patients with UA were randomized within 48 hours of presentation to conventional medical therapy alone versus ticlopidine in addition to conventional treatment. Ticlopidine use was associated with a reduction in vascular mortality by 46.8% (4.8% vs. 8.9%) and MI by 53.2% (5.1% vs. 10.9%). Further randomized trials such as STARS, MATTIS, ISAR, and FANTASTIC compared antiplatelet therapy with ticlopidine and aspirin to conventional anticoagulant therapy with heparin or warfarin in PCI with bare metal stenting and demonstrated a clear reduction in stent thrombosis, death, MI, or emergent CABG (23-26). Ticlopidine use, however, has been associated with significant side effects including thrombocytopenia, neutropenia and thrombotic thrombocytopenic purpura-hemolytic uremic syndrome (TTP-HUS); thus it is crucial that biweekly monitoring

of blood counts be performed for four months after initiation of ticlopidine (27-28).

Due to the unfavorable side effect profile of ticlopidine, interest began to develop in clopidogrel as a potential thienopyridine alternative. The efficacy of clopidogrel in the treatment of CAD had already been demonstrated in the CAPRIE trial in which clopidogrel use significantly reduced the combined endpoint of ischemic stroke, MI and vascular death in patients with atherosclerotic disease (29). Clopidogrel's overall safety benefit as compared to ticlopidine was then convincingly demonstrated in the CLASSICS trial and a metaanalysis later found that clopidogrel use was at least as efficacious as ticlopidine with fewer major adverse cardiac events (MACE) as well as a lower incidence of mortality (30-31). Based on these findings, clopidogrel replaced ticlopidine as the thienopyridine of choice in combination with aspirin as standard therapy after PCI. Several landmark trials then fully expanded the application of clopidogrel therapy to ACS and PCI. Investigators in the CURE trial found a 20% reduction in the primary combined endpoint of cardiovascular death, MI, or stroke (9.3% vs. 11.4%) in 12,562 patients with NSTE-ACS when treated with combined aspirin and clopidogrel as compared to aspirin alone (32). When the subset of patients undergoing PCI was analyzed separately in the PCI-CURE substudy, pre-treatment with clopidogrel plus aspirin prior to PCI led to both immediate and long-term benefits in reducing ischemic vascular events and death (33-34). The CREDO trial later confirmed the benefit of upstream clopidogrel therapy in more than 2,100 patients who were randomized to receive either clopidogrel at a 300 mg loading dose or placebo 3 to 24 hours before elective PCI, followed by 75 mg/day for 28 days in both groups and then either clopidogrel or placebo out to one year according to the original randomization (35). The results from CREDO also proved the benefits of long-term clopidogrel therapy by finding a 26.9% relative risk reduction in the combined end point of death, MI, or stroke at one year (8.5% vs. 11.5%, 95% CI 3.9-44.4). Two additional randomized trials, CLARITY-TIMI 28 and COMMIT/CCS-2, then demonstrated that clopidogrel therapy when added to aspirin also improved outcomes in patients with STEMI being treated with fibrinolytics and heparin

With the role of clopidogrel now clearly defined in all forms of ACS as well as PCI, the timing and dose of clopidogrel pre-treatment for PCI came under question. In a pre-

**2.3 Clopidogrel** 

(36-37).

thrombolytic pharmacotherapy during PCI to prevent such complications. The goal of this chapter will be to describe different therapeutic agents available to clinicians during PCI and to summarize the most current guidelines regarding their use.

#### **2. Anti-platelet agents**

#### **2.1 Aspirin**

Aspirin causes an irreversible inactivation of the cyclooxygenase-1 enzyme required for prostaglandin and thromboxane synthesis, which in turn diminishes platelet aggregation. The use of aspirin for secondary prevention has been shown to decrease overall mortality in patients with established CAD or a CAD equivalent such as diabetes (7-10). Meanwhile, the net benefit for its use in primary prevention is less certain and needs to be weighed against individual risk for major gastrointestinal or extra-cranial bleeding (11). Extensive studies have also shown significant reductions in mortality and morbidity with the use of aspirin in unstable angina (UA) as well as in both non-ST-elevation myocardial infarction (NSTEMI) and ST-elevation myocardial infarction (STEMI). In one of the earliest trials from the Results of a Veterans Administration Cooperative Study, Lewis et al. reported a 51% reduction in incidence of death or acute MI as well as a 50% reduction in rates of nonfatal MI in patients with UA who received aspirin (12). These findings were reproduced in subsequent studies and helped to solidify the role for the use of aspirin in UA (13-14). The RISC trial evaluated the role of aspirin in both NSTEMI and UA patients and again demonstrated that aspirin was associated with a significant reduction in the combined endpoint of death and MI with differences persisting beyond one-year providing evidence for the long-term benefit of aspirin in NSTE-ACS (15). The landmark trial ISIS-2 then expanded the role of aspirin use to standard therapy in STEMI (16). ISIS-2 randomized 17,187 patients presenting with acute STEMI to streptokinase, aspirin, both therapies, or neither, and demonstrated an additive effect of aspirin to thrombolytic therapy. Currently, the ACC/AHA guidelines for the management of UA, NSTEMI and STEMI recommend immediate treatment with aspirin for all patients for indefinite duration (17). The recommendations for the use of aspirin in PCI with stenting are derived from several early clinical trials in which treatment with high dose aspirin (650 mg to 990 mg/day) along with dipyridamole or ticlopidine in percutaneous transluminal coronary angioplasty (PTCA) was compared to placebo. Patients who were treated with aspirin-based regimens uniformly had better outcomes with significant reductions in peri-procedural complications including abrupt vessel closure, dissection or MI (18-19). Pre-treatment with aspirin monotherapy was tested against aspirin plus dipyridamole and shown to have an independent beneficial effect (20). Subsequent studies comparing high-dose versus low-dose aspirin (1500 mg vs. 80 mg/day) prior to PTCA showed no difference in the incidence of MI or in the rate of major complications and restenosis (21). The most current ACC/AHA recommendations for the use of aspirin in PCI are that higher dose aspirin (300 mg to 325 mg) be given at least 2 hours before PCI as well as for at least 1 month after BMS implantation, 3 months after sirolimus-eluting stent implantation, and 6 months after paclitaxel-eluting stent implantation (17).

#### **2.2 Ticlopidine**

Thienopyridines block the adenosine diphosphate (ADP) receptor P2Y12 on platelet surfaces thereby decreasing platelet activation and aggregation (see section on platelet function testing below). Ticlopidine was the first widely used thienopyridine that began to have an antiplatelet effect within 24 to 48 hours after its administration. The STAIG trial was one of the first multicenter trials to evaluate the role of thienopyridines, particularly ticlopidine, in ACS (22). 652 patients with UA were randomized within 48 hours of presentation to conventional medical therapy alone versus ticlopidine in addition to conventional treatment. Ticlopidine use was associated with a reduction in vascular mortality by 46.8% (4.8% vs. 8.9%) and MI by 53.2% (5.1% vs. 10.9%). Further randomized trials such as STARS, MATTIS, ISAR, and FANTASTIC compared antiplatelet therapy with ticlopidine and aspirin to conventional anticoagulant therapy with heparin or warfarin in PCI with bare metal stenting and demonstrated a clear reduction in stent thrombosis, death, MI, or emergent CABG (23-26). Ticlopidine use, however, has been associated with significant side effects including thrombocytopenia, neutropenia and thrombotic thrombocytopenic purpura-hemolytic uremic syndrome (TTP-HUS); thus it is crucial that biweekly monitoring of blood counts be performed for four months after initiation of ticlopidine (27-28).

#### **2.3 Clopidogrel**

214 Coronary Interventions

thrombolytic pharmacotherapy during PCI to prevent such complications. The goal of this chapter will be to describe different therapeutic agents available to clinicians during PCI and

Aspirin causes an irreversible inactivation of the cyclooxygenase-1 enzyme required for prostaglandin and thromboxane synthesis, which in turn diminishes platelet aggregation. The use of aspirin for secondary prevention has been shown to decrease overall mortality in patients with established CAD or a CAD equivalent such as diabetes (7-10). Meanwhile, the net benefit for its use in primary prevention is less certain and needs to be weighed against individual risk for major gastrointestinal or extra-cranial bleeding (11). Extensive studies have also shown significant reductions in mortality and morbidity with the use of aspirin in unstable angina (UA) as well as in both non-ST-elevation myocardial infarction (NSTEMI) and ST-elevation myocardial infarction (STEMI). In one of the earliest trials from the Results of a Veterans Administration Cooperative Study, Lewis et al. reported a 51% reduction in incidence of death or acute MI as well as a 50% reduction in rates of nonfatal MI in patients with UA who received aspirin (12). These findings were reproduced in subsequent studies and helped to solidify the role for the use of aspirin in UA (13-14). The RISC trial evaluated the role of aspirin in both NSTEMI and UA patients and again demonstrated that aspirin was associated with a significant reduction in the combined endpoint of death and MI with differences persisting beyond one-year providing evidence for the long-term benefit of aspirin in NSTE-ACS (15). The landmark trial ISIS-2 then expanded the role of aspirin use to standard therapy in STEMI (16). ISIS-2 randomized 17,187 patients presenting with acute STEMI to streptokinase, aspirin, both therapies, or neither, and demonstrated an additive effect of aspirin to thrombolytic therapy. Currently, the ACC/AHA guidelines for the management of UA, NSTEMI and STEMI recommend immediate treatment with aspirin for all patients for indefinite duration (17). The recommendations for the use of aspirin in PCI with stenting are derived from several early clinical trials in which treatment with high dose aspirin (650 mg to 990 mg/day) along with dipyridamole or ticlopidine in percutaneous transluminal coronary angioplasty (PTCA) was compared to placebo. Patients who were treated with aspirin-based regimens uniformly had better outcomes with significant reductions in peri-procedural complications including abrupt vessel closure, dissection or MI (18-19). Pre-treatment with aspirin monotherapy was tested against aspirin plus dipyridamole and shown to have an independent beneficial effect (20). Subsequent studies comparing high-dose versus low-dose aspirin (1500 mg vs. 80 mg/day) prior to PTCA showed no difference in the incidence of MI or in the rate of major complications and restenosis (21). The most current ACC/AHA recommendations for the use of aspirin in PCI are that higher dose aspirin (300 mg to 325 mg) be given at least 2 hours before PCI as well as for at least 1 month after BMS implantation, 3 months after sirolimus-eluting stent

implantation, and 6 months after paclitaxel-eluting stent implantation (17).

Thienopyridines block the adenosine diphosphate (ADP) receptor P2Y12 on platelet surfaces thereby decreasing platelet activation and aggregation (see section on platelet function

to summarize the most current guidelines regarding their use.

**2. Anti-platelet agents** 

**2.1 Aspirin** 

**2.2 Ticlopidine** 

Due to the unfavorable side effect profile of ticlopidine, interest began to develop in clopidogrel as a potential thienopyridine alternative. The efficacy of clopidogrel in the treatment of CAD had already been demonstrated in the CAPRIE trial in which clopidogrel use significantly reduced the combined endpoint of ischemic stroke, MI and vascular death in patients with atherosclerotic disease (29). Clopidogrel's overall safety benefit as compared to ticlopidine was then convincingly demonstrated in the CLASSICS trial and a metaanalysis later found that clopidogrel use was at least as efficacious as ticlopidine with fewer major adverse cardiac events (MACE) as well as a lower incidence of mortality (30-31). Based on these findings, clopidogrel replaced ticlopidine as the thienopyridine of choice in combination with aspirin as standard therapy after PCI. Several landmark trials then fully expanded the application of clopidogrel therapy to ACS and PCI. Investigators in the CURE trial found a 20% reduction in the primary combined endpoint of cardiovascular death, MI, or stroke (9.3% vs. 11.4%) in 12,562 patients with NSTE-ACS when treated with combined aspirin and clopidogrel as compared to aspirin alone (32). When the subset of patients undergoing PCI was analyzed separately in the PCI-CURE substudy, pre-treatment with clopidogrel plus aspirin prior to PCI led to both immediate and long-term benefits in reducing ischemic vascular events and death (33-34). The CREDO trial later confirmed the benefit of upstream clopidogrel therapy in more than 2,100 patients who were randomized to receive either clopidogrel at a 300 mg loading dose or placebo 3 to 24 hours before elective PCI, followed by 75 mg/day for 28 days in both groups and then either clopidogrel or placebo out to one year according to the original randomization (35). The results from CREDO also proved the benefits of long-term clopidogrel therapy by finding a 26.9% relative risk reduction in the combined end point of death, MI, or stroke at one year (8.5% vs. 11.5%, 95% CI 3.9-44.4). Two additional randomized trials, CLARITY-TIMI 28 and COMMIT/CCS-2, then demonstrated that clopidogrel therapy when added to aspirin also improved outcomes in patients with STEMI being treated with fibrinolytics and heparin (36-37).

With the role of clopidogrel now clearly defined in all forms of ACS as well as PCI, the timing and dose of clopidogrel pre-treatment for PCI came under question. In a pre-

Pharmacotherapy During Percutaneous Coronary Interventions 217

With regards to timing of double-dose clopidogrel pre-treatment, the ISAR-REACT trial showed that among 2,159 patients undergoing PCI, a clopidogrel 600 mg loading dose could be given as early as as 2 hours prior to PCI without detrimental effects when compared to longer durations of pre-treatment (2 to 3 hours, 3 to 6 hours, 6 to 12 hours, > 12 hours) (48). Similarly, the PRAGUE-8 and ARMYDA-5 PRELOAD trials reported no differences in outcomes when clopidogrel 600 mg was given to patients with stable angina or NSTE-ACS either before (mean of 19 and 6 hours respectively) or immediately after diagnostic coronary

The RELOAD and ARMYDA-4 RELOAD trials attempted to address the question of whether an additional loading dose of clopidogrel was required prior to PCI in stable and ACS patients who were already receiving chronic clopidogrel therapy (51-52). The trials found that although clopidogrel reloading produced significantly greater levels of platelet inhibition, there was no difference in the primary endpoint of MACE. A subgroup analysis, however, showed that when reloaded with clopidogrel 600 mg, there was a significant benefit in patients with ACS who underwent PCI. While there is not enough evidence to make definitive recommendations regarding this issue, it may be reasonable to reload patients receiving chronic clopidogrel therapy with clopidogrel 600 mg prior to PCI for ACS

Despite the increasing use of higher doses of clopidogrel, there are still many cases of breakthrough thrombotic events in patients receiving standard dual antiplatelet therapy (32). Limitations of clopidogrel therapy are thought to be due to its delayed onset of action, modest platelet inhibition effects, and a wide range of inter-individual variability with regards to platelet responsiveness. Prasugrel is a third-generation thienopyridine and like clopidogrel, also requires biotransformation to its active metabolite before binding to P2Y12 receptors and inhibiting platelet aggregation. In contrast to clopidogrel however, prasugrel has been shown to achieve greater levels of platelet inhibition more rapidly and more consistently among healthy individuals as well as in patients with CAD and those who are undergoing PCI (53-55). The JUMBO-TIMI 26 trial was a phase 2 randomized study of 904 patients designed to assess the safety of prasugrel when administered at the time of PCI and the results of this trial showed no difference in the rates of clinically significant bleeding events (56). In PRINCIPLE-TIMI 44, 201 subjects were randomized to either prasugrel 60 mg or clopidogrel 600 mg as a loading dose one half hour prior to elective PCI, and then to either prasugrel 10 mg or clopidogrel 150 mg as a maintenance dose (57). The prasugrel groups were found to achieve significantly greater levels of platelet inhibition in both the loading and maintenance phases. To assess prasugrel's clinical efficacy, the landmark TRITON-TIMI 38 trial enrolled 13,608 patients with moderate- to high-risk ACS (including both NSTE-ACS and STEMI) undergoing PCI and randomly assigned patients to either prasugrel (60 mg loading dose followed by 10 mg maintenance dose) or clopidogrel (300 mg loading dose followed by 75 mg maintenance dose) (58). At 15 month follow-up, prasugrel reduced the composite endpoint of death, nonfatal MI or nonfatal stroke by 20% in comparison to clopidogrel (9.9% vs. 12.1%; HR 0.81; 95% CI 0.73-0.90; p<0.001) with the majority of the difference driven by lower rates of nonfatal MI (7.4% vs. 9.7%). Stent thrombosis was also significantly reduced with prasugrel (1.1% vs. 2.4%; p<0.001), however,

angiography, but prior to PCI (49-50).

or if their risk for stent thrombosis is high.

**2.4 Prasugrel** 

specified sub-group analysis, the PCI-CLARITY trial found that early treatment with clopidogrel (300 mg) led to significantly better outcomes in all time groups ranging from within 6 hours before PCI to as far as 96 hours ahead of PCI (38). A substudy from CREDO, however, found that the benefit was only seen if clopidogrel (300 mg) was given 10 to 12 hours before PCI and did not become significant unless given >15 hours prior to PCI, with a maximum effect seen at 24 hours (39).

Since pre-treatment with clopidogrel for >15 hours prior to PCI is not always practical in situations of ACS or ad hoc decisions to stent at the time of diagnostic angiography, the issue was raised as to whether higher loading doses of clopidogrel could be beneficial by increasing the level of platelet inhibition or by decreasing the time required until its maximum antiplatelet effects were achieved. In an unselected cohort of over 1,000 patients, who were given a 600 mg dose of clopidogrel, in vitro studies found that maximum platelet inhibition was seen by two hours and additional testing showed that clopidogrel 600 mg dosing seemed to achieve more intense levels of peak platelet inhibition when compared with the conventional 300 mg dose (40-41). Several large studies then sought to evaluate whether these pharmacodynamic differences could translate into improved patient outcomes. The ARMYDA-2 trial randomized 255 patients with stable angina or NSTE-ACS to either 600 mg or 300 mg of clopidogrel given four to eight hours prior to PCI (42). By 30 days, the composite endpoint of death, MI, or target vessel revascularization (TVR) occurred in only 4% of the 600 mg group as compared to 12% in the 300-mg group, a difference that was entirely driven by rates of peri-procedural MI (p <0.05). No differences were reported in the rates of major bleeding between the two groups. The benefit of a clopidogrel 600 mg loading dose was seen again in a subgroup analysis from the HORIZONS-AMI trial in which 3,602 patients with STEMI undergoing primary PCI were randomized to either bivalirudin or unfractionated heparin (UFH) plus a glycoprotein (GP) IIb/IIIa inhibitor (43). Clopidogrel loading doses of either 300 mg (1,153 patients) or 600 mg (2,158 patients) were chosen at the clinician's discretion and after multivariable analysis, the 600 mg dose was found to be an independent predictor of lower rates of 30-day MACE without higher bleeding. The CURRENT-OASIS 7 trial then randomized over 25,000 patients with ACS (29.2% STEMI) who were referred for an invasive strategy and compared the regimen of double dose clopidogrel (600 mg loading dose followed by 150 mg daily for six days and then 75 mg daily thereafter) versus standard dose clopidogrel (300 mg loading dose followed by 75 mg daily) (44). The investigators found that while there was no significant difference in the primary outcome of cardiovascular death, MI or stroke at 30 days (4.2% in the double dose group vs. 4.4% in the standard dose group; HR 0.94; 95% CI 0.83-1.06; p =0.30), double dose clopidogrel was associated with a significant reduction in the secondary outcome of stent thrombosis in the greater than 17,000 patients who underwent PCI (1.6% vs. 2.3%; HR 0.68; 95% CI 0.55-0.85; p=0.001). Notably, major bleeding occurred significantly more in the double dose group (2.5% vs. 2.0%; HR 1.24; 95% CI 1.05-1.46; p=0.01). Several subsequent smaller studies including ISAR-CHOICE, ALBION, and PREPAIR have attempted to look at whether even higher loading doses of clopidogrel (900 mg and 1200 mg) might carry additional benefit when compared to the 600 mg and 300 mg doses (45-47). These studies found that while treatment with increasing doses of clopidogrel did in fact result in greater levels of platelet inhibition, clinical endpoints such as MACE and troponin release were not statistically different. At this point, larger prospective trials evaluating clinical outcomes are needed before clopidogrel loading doses above 600 mg can be justified. With regards to timing of double-dose clopidogrel pre-treatment, the ISAR-REACT trial showed that among 2,159 patients undergoing PCI, a clopidogrel 600 mg loading dose could be given as early as as 2 hours prior to PCI without detrimental effects when compared to longer durations of pre-treatment (2 to 3 hours, 3 to 6 hours, 6 to 12 hours, > 12 hours) (48). Similarly, the PRAGUE-8 and ARMYDA-5 PRELOAD trials reported no differences in outcomes when clopidogrel 600 mg was given to patients with stable angina or NSTE-ACS either before (mean of 19 and 6 hours respectively) or immediately after diagnostic coronary angiography, but prior to PCI (49-50).

The RELOAD and ARMYDA-4 RELOAD trials attempted to address the question of whether an additional loading dose of clopidogrel was required prior to PCI in stable and ACS patients who were already receiving chronic clopidogrel therapy (51-52). The trials found that although clopidogrel reloading produced significantly greater levels of platelet inhibition, there was no difference in the primary endpoint of MACE. A subgroup analysis, however, showed that when reloaded with clopidogrel 600 mg, there was a significant benefit in patients with ACS who underwent PCI. While there is not enough evidence to make definitive recommendations regarding this issue, it may be reasonable to reload patients receiving chronic clopidogrel therapy with clopidogrel 600 mg prior to PCI for ACS or if their risk for stent thrombosis is high.

#### **2.4 Prasugrel**

216 Coronary Interventions

specified sub-group analysis, the PCI-CLARITY trial found that early treatment with clopidogrel (300 mg) led to significantly better outcomes in all time groups ranging from within 6 hours before PCI to as far as 96 hours ahead of PCI (38). A substudy from CREDO, however, found that the benefit was only seen if clopidogrel (300 mg) was given 10 to 12 hours before PCI and did not become significant unless given >15 hours prior to PCI, with a

Since pre-treatment with clopidogrel for >15 hours prior to PCI is not always practical in situations of ACS or ad hoc decisions to stent at the time of diagnostic angiography, the issue was raised as to whether higher loading doses of clopidogrel could be beneficial by increasing the level of platelet inhibition or by decreasing the time required until its maximum antiplatelet effects were achieved. In an unselected cohort of over 1,000 patients, who were given a 600 mg dose of clopidogrel, in vitro studies found that maximum platelet inhibition was seen by two hours and additional testing showed that clopidogrel 600 mg dosing seemed to achieve more intense levels of peak platelet inhibition when compared with the conventional 300 mg dose (40-41). Several large studies then sought to evaluate whether these pharmacodynamic differences could translate into improved patient outcomes. The ARMYDA-2 trial randomized 255 patients with stable angina or NSTE-ACS to either 600 mg or 300 mg of clopidogrel given four to eight hours prior to PCI (42). By 30 days, the composite endpoint of death, MI, or target vessel revascularization (TVR) occurred in only 4% of the 600 mg group as compared to 12% in the 300-mg group, a difference that was entirely driven by rates of peri-procedural MI (p <0.05). No differences were reported in the rates of major bleeding between the two groups. The benefit of a clopidogrel 600 mg loading dose was seen again in a subgroup analysis from the HORIZONS-AMI trial in which 3,602 patients with STEMI undergoing primary PCI were randomized to either bivalirudin or unfractionated heparin (UFH) plus a glycoprotein (GP) IIb/IIIa inhibitor (43). Clopidogrel loading doses of either 300 mg (1,153 patients) or 600 mg (2,158 patients) were chosen at the clinician's discretion and after multivariable analysis, the 600 mg dose was found to be an independent predictor of lower rates of 30-day MACE without higher bleeding. The CURRENT-OASIS 7 trial then randomized over 25,000 patients with ACS (29.2% STEMI) who were referred for an invasive strategy and compared the regimen of double dose clopidogrel (600 mg loading dose followed by 150 mg daily for six days and then 75 mg daily thereafter) versus standard dose clopidogrel (300 mg loading dose followed by 75 mg daily) (44). The investigators found that while there was no significant difference in the primary outcome of cardiovascular death, MI or stroke at 30 days (4.2% in the double dose group vs. 4.4% in the standard dose group; HR 0.94; 95% CI 0.83-1.06; p =0.30), double dose clopidogrel was associated with a significant reduction in the secondary outcome of stent thrombosis in the greater than 17,000 patients who underwent PCI (1.6% vs. 2.3%; HR 0.68; 95% CI 0.55-0.85; p=0.001). Notably, major bleeding occurred significantly more in the double dose group (2.5% vs. 2.0%; HR 1.24; 95% CI 1.05-1.46; p=0.01). Several subsequent smaller studies including ISAR-CHOICE, ALBION, and PREPAIR have attempted to look at whether even higher loading doses of clopidogrel (900 mg and 1200 mg) might carry additional benefit when compared to the 600 mg and 300 mg doses (45-47). These studies found that while treatment with increasing doses of clopidogrel did in fact result in greater levels of platelet inhibition, clinical endpoints such as MACE and troponin release were not statistically different. At this point, larger prospective trials evaluating clinical outcomes are needed before clopidogrel loading doses above 600 mg can be justified.

maximum effect seen at 24 hours (39).

Despite the increasing use of higher doses of clopidogrel, there are still many cases of breakthrough thrombotic events in patients receiving standard dual antiplatelet therapy (32). Limitations of clopidogrel therapy are thought to be due to its delayed onset of action, modest platelet inhibition effects, and a wide range of inter-individual variability with regards to platelet responsiveness. Prasugrel is a third-generation thienopyridine and like clopidogrel, also requires biotransformation to its active metabolite before binding to P2Y12 receptors and inhibiting platelet aggregation. In contrast to clopidogrel however, prasugrel has been shown to achieve greater levels of platelet inhibition more rapidly and more consistently among healthy individuals as well as in patients with CAD and those who are undergoing PCI (53-55). The JUMBO-TIMI 26 trial was a phase 2 randomized study of 904 patients designed to assess the safety of prasugrel when administered at the time of PCI and the results of this trial showed no difference in the rates of clinically significant bleeding events (56). In PRINCIPLE-TIMI 44, 201 subjects were randomized to either prasugrel 60 mg or clopidogrel 600 mg as a loading dose one half hour prior to elective PCI, and then to either prasugrel 10 mg or clopidogrel 150 mg as a maintenance dose (57). The prasugrel groups were found to achieve significantly greater levels of platelet inhibition in both the loading and maintenance phases. To assess prasugrel's clinical efficacy, the landmark TRITON-TIMI 38 trial enrolled 13,608 patients with moderate- to high-risk ACS (including both NSTE-ACS and STEMI) undergoing PCI and randomly assigned patients to either prasugrel (60 mg loading dose followed by 10 mg maintenance dose) or clopidogrel (300 mg loading dose followed by 75 mg maintenance dose) (58). At 15 month follow-up, prasugrel reduced the composite endpoint of death, nonfatal MI or nonfatal stroke by 20% in comparison to clopidogrel (9.9% vs. 12.1%; HR 0.81; 95% CI 0.73-0.90; p<0.001) with the majority of the difference driven by lower rates of nonfatal MI (7.4% vs. 9.7%). Stent thrombosis was also significantly reduced with prasugrel (1.1% vs. 2.4%; p<0.001), however,

Pharmacotherapy During Percutaneous Coronary Interventions 219

disease found that ticragrelor produced a more pronounced reduction in the primary endpoint when compared to patients with normal renal function as well as an overall

Unfractionated heparin (UFH) inhibits platelet aggregation and fibrin formation by accelerating the action of antithrombin, which in turn inactivates factors IIa, IXa, and Xa. The evidence for UFH therapy in UA and NSTE-ACS has been well defined in early trials such as RISC and ATACS (61-65), however, the benefits in acute STEMI are less clear. Current ACC/AHA guidelines on the management of acute STEMI recommend intravenous UFH therapy for all patients treated with a fibrin-specific fibrinolytic agent (alteplase, tenecteplase, reteplase) or a non-fibrin-specific agent (streptokinase, urokinase, anistreplase) if the risk for systemic embolization is high (large or anterior MI, atrial fibrillation, prior embolus, or known left ventricular thrombus). The goal for activated partial thromboplastin time (aPTT) should be 1.5 to 2.0 times control or between 50-70 seconds. The benefit of adjunctive UFH with fibrinolytic therapy is thought to be due to its effect on maintaining infarct vessel patency as there is limited data regarding any improvements in either mortality or reinfarction (66-69). In patients being referred for PCI, current guidelines recommend intravenous treatment with UFH (17). UFH use during PCI is believed to reduce the risk for acute vessel closure as well as catheter or wire thrombosis and has been extrapolated from data obtained from PTCA prior to the era of coronary stenting and dual anti-platelet therapy (70). The 2005 ACC/AHA/SCAI guidelines for PCI recommend that in patients not receiving a glycoprotein (GP) IIb/IIIa inhibitor, UFH should be given using a bolus of 70 to 100 IU/kg to target an activated clotting time (ACT) between 250 to 350 seconds. For patients who are receiving a GP IIb/IIIa inhibitor, heparin bolus should be lowered to 50 to 70 IU/kg to achieve an ACT of 200 to 250 seconds (71). Heparin monitoring during PCI is generally done with ACT instead of aPTT as the anticoagulation levels required during the procedure are frequently too high for aPTT to track. An alternative strategy endorsed by the 2005 European Society of Cardiology guidelines for PCI was a single bolus of 100 IU/kg without ACT monitoring (72). The routine use of UFH after uncomplicated procedures has not been shown to reduce stent thrombosis and is not recommended given its association with increased rates of bleeding and vascular access complications. UFH use can cause autoimmune heparin-induced thrombocytopenia, a rare but potentially lethal complication associated with thrombosis. Treatment includes prompt withdrawal of UFH or low molecular weight heparin (LMWH) and initiation of alternative

anticoagulation therapy (argatroban, lepirudin, bivalirudin).

Low-molecular-weight heparin (LMWH), like UFH, prevents clot propagation, but possesses several advantages over UFH due to different mechanisms of action. The ratio of anti-Xa/anti-IIa activity is significantly higher in LMWH compared to UFH, thereby inhibiting thrombin generation more effectively with potentially less bleeding. Suppression of the release of von Willebrand factor also augments LMWH's anticoagulant effect.

**3.2 Low-Molecular-Weight Heparin** 

decrease in total mortality (60).

**3. Anti-thrombotic agents 3.1 Unfractionated heparin** 

the risk for bleeding in all categories was significantly increased including major bleeding (2.4% vs. 1.8%; p=0.03), life-threatening bleeding (1.4% vs. 0.9%; p=0.01), and fatal hemorrhage (0.4% vs. 0.1%; p=0.002). Risk factors for bleeding included age ≥75 years, history of stroke or TIA, and body weight <60 kg. Overall mortality did not differ significantly between the treatment groups.

The 2009 ACC/AHA Joint STEMI/PCI updated guidelines recommend that in patients with ACS in whom PCI is planned, a loading dose of either clopidogrel of at least 300 to 600 mg (Class I, Level of Evidence C) or prasugrel 60 mg (provided there are no contraindications) (Class I, Level of Evidence B) be given as soon as possible. For STEMI patients who have received fibrinolytic therapy, clopidogrel at a loading dose of either 300 or 600 mg should be given followed by clopidogrel as the thienopyridine of choice for maintenance therapy (Class I, Level of Evidence C). The choice and duration of maintenance therapy for ACS patients receiving a BMS or DES should be either clopidogrel 75 mg daily (Class I, Level of Evidence B) or prasugrel 10 mg daily (provided there are no contraindications) (Class I, Level of Evidence B) for at least 12 months unless the risk of morbidity due to bleeding outweighs the anticipated benefit of thienopyridine therapy, at which point earlier discontinuation should be considered (Class I, Level of Evidence C). In patients in whom coronary artery bypass grafting (CABG) is planned and can be delayed, it is recommended that clopidogrel be withdrawn for at least 5 days (Class I, Level of Evidence B) and prasugrel for at least 7 days (Class I, Level of Evidence C) unless the need for revascularization and/or the net benefit of the thienopyridine outweighs the risks of bleeding (Class I, Level of Evidence C). Age ≥ 75 years, history of TIA or stroke, and active major bleeding are contraindications to prasugrel therapy. Body weight < 60 kg is a relative contraindication to prasugrel therapy and consideration of lowering the maintenance dose from 10 mg to 5 mg daily should be given, though the safety and efficacy of the 5 mg dose have not been established (17).

#### **2.5 Ticragrelor**

Ticragrelor is an oral antiplatelet agent from the cyclopentyltriazolopyrimidine class that reversibly binds the ADP-P2Y12 platelet receptor. Like prasugrel, it is known to produce a more rapid and intense reduction in platelet function when compared to clopidogrel. In the PLATO trial, 18,624 patients with ACS (38% STEMI) were randomized to either ticragrelor (180 mg loading dose followed by 90 mg twice daily) or clopidogrel (300 to 600 mg loading dose followed by 75 mg daily) in addition to chronic aspirin therapy (59). At 12 months, ticragrelor therapy was associated with a significant reduction in the primary efficacy endpoint of cardiovascular death, MI or stroke (9.8% vs. 11.7%; HR 0.84; 95% CI 0.77-0.92; p<0.001). Importantly, the rate of death from any cause was reduced in the ticagrelor group (4.5% vs. 5.9% with clopidogrel, p<0.001). Furthermore, there were no significant differences in the rates of major bleeding, although ticagrelor was associated with a higher rate of bleeding not related to CABG. The STEMI patients in PLATO, when analyzed separately, also showed a benefit of ticagrelor over clopidogrel with trends consistent with the overall PLATO trial. In addition, ticagrelor reduced rates of MI alone, total mortality, and stent thrombosis. The reductions in stent thrombosis (ST) for ticagrelor versus clopidogrel were 1.6% vs. 2.4% (definite ST, p=0.03), 2.6% vs. 3.4% (definite or probable ST), and 3.3% vs. 4.3% (definite, probable, or possible ST). A subgroup analysis of patients with chronic kidney disease found that ticragrelor produced a more pronounced reduction in the primary endpoint when compared to patients with normal renal function as well as an overall decrease in total mortality (60).
