Version May 2024
INTRODUCTION — Intracoronary thrombosis and the attendant risk of myocardial ischemia or infarction may occur soon after percutaneous coronary intervention with stent implantation. Trauma to the coronary endothelium (with the exposure of tissue factors to blood) and placement of metal (which is procoagulant) stents are causative. Stent thrombosis can be a life-threatening event. (See "Coronary artery stent thrombosis: Clinical presentation and management" and "Coronary artery stent thrombosis: Incidence and risk factors".)
Antithrombotic therapy, with both antiplatelet and anticoagulant medications, is used to reduce the risk. Early studies of antithrombotic therapy demonstrated a reduction in early stent thrombosis. (See "Periprocedural complications of percutaneous coronary intervention" and "Coronary artery stent thrombosis: Incidence and risk factors".)
The clinical trials evaluating antithrombotic therapy at the time of stent implantation will be reviewed here. Recommendations for the use of such therapy in stable patients and the use of antiplatelet and anticoagulant strategies in patients with acute coronary syndromes are discussed separately. (See "Antithrombotic therapy for elective percutaneous coronary intervention: General use" and "Acute ST-elevation myocardial infarction: Antiplatelet therapy" and "Acute non-ST-elevation acute coronary syndromes: Early antiplatelet therapy" and "Anticoagulant therapy in non-ST elevation acute coronary syndromes" and "Acute ST-elevation myocardial infarction: Management of anticoagulation".)
The discussion of and the recommendations for long-term dual antiplatelet therapy is found elsewhere. (See "Coronary artery stent thrombosis: Incidence and risk factors".)
ANTIPLATELET THERAPY — All patients receive periprocedural aspirin and a P2Y12 receptor blocker. A glycoprotein (GP) IIb/IIIa inhibitor is given to some patients.
Aspirin — Aspirin is recommended for all patients with coronary artery disease. (See "Aspirin for the secondary prevention of atherosclerotic cardiovascular disease".)
Aspirin is specifically recommended for patients undergoing coronary stenting, based primarily upon data from early randomized trials of aspirin or aspirin plus dipyridamole compared to placebo in patients undergoing percutaneous transluminal coronary (balloon) angioplasty [1,2].
The benefit from aspirin seen in the above trials [1,2] was found in an observational study of 65,175 patients who underwent percutaneous coronary intervention (PCI) between 2010 and 2011 [3]. In this population, 7.1 percent of patients were not given aspirin within 24 hours before the procedure. In a (1:1) propensity-matched analysis of 4640 individuals who did and 4640 who did not receive aspirin, the absence of aspirin was associated with a higher rate of death (3.9 versus 2.8 percent; odds ratio [OR] 1.89, 95% confidence interval [CI] 1.32-2.71) and stroke (0.5 versus 0.1 percent; OR 4.24, 95% CI 1.59-12.11).
P2Y12 receptor blockers — The thienopyridines clopidogrel, ticlopidine, and prasugrel and the non-thienopyridines ticagrelor and cangrelor achieve their antiplatelet effect by inhibiting the P2Y12 receptor, resulting in reduced platelet activation and subsequent aggregation [4].
Ticlopidine or clopidogrel (on top of aspirin therapy) have been extensively evaluated in stable patients undergoing stent implantation.
Ticlopidine — Early randomized trials found that ticlopidine plus aspirin was more effective than aspirin alone for preventing stent thrombosis in patients receiving bare metal stents [5-11]. However, ticlopidine is rarely used in clinical practice, as hematologic side effects limit its use. (See "Drug-induced neutropenia and agranulocytosis", section on 'Ticlopidine' and "Antithrombotic therapy for elective percutaneous coronary intervention: General use", section on 'P2Y12 receptor blockers'.)
Clopidogrel
Efficacy and safety — Clopidogrel has been shown to have equal efficacy to ticlopidine in terms of major cardiac events [12-16] and a lower rate of major side effects [12,13,17,18].
In the CLASSICS trial, the adverse event rate (major bleeding complications, thrombocytopenia, neutropenia, or early discontinuation of drug for a noncardiac adverse event) was significantly lower in the patients treated with clopidogrel (4.6 versus 9.1 percent with ticlopidine) [12]. (See "Antithrombotic therapy for elective percutaneous coronary intervention: General use", section on 'Problems with clopidogrel use'.)
Timing and dose — The CREDO trial confirmed the benefit of pretreatment with clopidogrel in more than 2100 patients undergoing elective PCI (almost all with stenting) [19]. The patients were randomly assigned to pretreatment with placebo or clopidogrel at a loading dose of 300 mg 3 to 24 hours before the procedure; after the procedure, all patients received clopidogrel (75 mg/day) for 28 days; clopidogrel or placebo, according to original randomization, was then given for the remainder of one year. All received aspirin for the duration of the study, and more than 40 percent of patients also received concomitant therapy with an intravenous GP IIb/IIIa inhibitor. The following results were noted:
●At 28 days, clopidogrel therapy was associated with a nonsignificant reduction in the combined end point of death, myocardial infarction (MI), or urgent target vessel revascularization (6.8 versus 8.3 percent, relative risk [RR] reduction 18.5 percent, 95% CI 14.2-41.8). In a prespecified subset analysis, a strong trend for reduction in these events was seen when clopidogrel was begun ≥6 hours before the procedure (RR reduction 38.6 percent, 95% CI -1.6 to +62.9 percent), with no benefit with shorter pretreatment intervals.
●At one year, the combined end point of MI, stroke, and death was significantly reduced by loading and long-term clopidogrel (8.5 versus 11.5 percent with placebo, RR reduction 26.9 percent, 95% CI 3.9-44.4).
●A subsequent subgroup analysis showed that the benefit of the clopidogrel loading dose was first significant when given at least 15 hours before PCI and was greatest when given at least 24 hours before PCI [20]. The absolute risk reduction in patients with ≥15 hours of clopidogrel pretreatment was 6.2 percent compared to placebo pretreatment in the same time interval (3.5 versus 9.7 percent). The risk reduction with prolonged clopidogrel pretreatment was greatest in patients who did not receive a GP IIb/IIIa inhibitor.
For patients who cannot receive clopidogrel within 15 hours of the procedure, this time limitation may be overcome by giving a clopidogrel loading dose of more than 300 mg, the dose used in CREDO. Evidence for efficacy within two to three hours of administration of 600 mg comes from the following observations:
●The time dependence of platelet inhibition after 600 mg of clopidogrel was evaluated in an unselected cohort of 1001 patients scheduled for possible PCI [21]. The maximum antiplatelet effect using several in vitro measures was seen by two hours.
●The ISAR-REACT trial evaluated the efficacy of abciximab in 2159 patients undergoing elective PCI [22]. All patients were pretreated with 600 mg of clopidogrel at least two hours before PCI. When the study subjects were grouped into four subsets based upon duration of clopidogrel pretreatment (two to three hours, three to six hours, 6 to 12 hours, and >12 hours), there was no significant difference among the four groups in the incidence of death, MI, or urgent revascularization at 30 days or in the rate of major bleeding.
The higher loading dose also may improve outcomes [23,24]. This was suggested in the ARMYDA-2 trial in which 255 patients (75 percent stable angina, 25 percent non-ST elevation acute coronary syndrome [ACS]) scheduled to undergo PCI were randomly assigned to a 300 or 600 mg loading dose four to eight hours before the procedure [23]. All but two patients received a stent and only 13 percent were treated with a GP IIb/IIIa inhibitor.
The primary end point (death, MI, or target vessel revascularization) occurred significantly less often with the 600 mg loading dose (4 versus 12 percent), a difference that was entirely due to a lower rate of periprocedural MI (4.0 versus 11.6 percent, adjusted odds ratio 0.48). Major bleeding did not occur in either group, but the authors could not comment on bleeding risk if emergency coronary artery bypass graft surgery (CABG) were required.
The following mechanisms may contribute to the apparently better outcome with the 600 mg loading dose:
●A 300 mg loading dose would not be fully active when given four to eight hours before PCI [22].
●A 600 mg loading dose produces a greater maximal antiplatelet effect [24-28], an earlier antiplatelet effect (the degree of platelet inhibition at two hours is greater than the maximal effect with 300 mg, which is also seen later) [27], and may diminish the likelihood of both clopidogrel resistance [29] and of a reduced antiplatelet effect in patients taking drugs that are metabolized by CYP3A4 [21,30]. (See "Clopidogrel resistance and clopidogrel treatment failure", section on 'Definitions'.)
The need to give clopidogrel hours before PCI is potentially problematic for patients referred for diagnostic coronary arteriography, since many of these patients do not have coronary artery disease requiring intervention and some will have disease requiring early CABG. Both of these groups would therefore be unnecessarily exposed to any bleeding risk associated with clopidogrel therapy. These issues were addressed in the PRAGUE-8 and ARMYDA-5 PRELOAD trials:
●In PRAGUE-8, 1028 stable patients were randomly assigned to clopidogrel 600 mg given either more than six hours before or immediately after elective coronary arteriography in patients undergoing PCI [31]. PCI was performed in 29 percent of patients and CABG in 12 percent. There was no significant difference between the two regimens in a combined primary clinical end point (death/MI, stroke, transient ischemic attack, repeat PCI, 0.8 versus 1.0 percent), but there was a statistically significant increase in the rate of bleeding (mostly minor) in those who received the earlier clopidogrel dose (3.5 versus 1.4 percent). However, there were several important limitations of this trial, including the small number of patients undergoing PCI and a higher-than-expected rate of bleeding complications [32].
●In ARMYDA-5 PRELOAD, 409 patients (61 percent with stable angina, 39 percent with non-ST elevation MI) were randomly assigned to clopidogrel 600 mg either four to eight hours before or immediately after coronary angiography (but before PCI) [33]. There was no significant difference in the 30-day incidence of major adverse cardiac events of cardiac death, MI, or unplanned target vessel revascularization (10.3 versus 8.8 percent) nor was there a difference in the rates of either risk of bleeding/vascular complications (7.8 versus 5.4 percent). A post-hoc subgroup analysis of the patients with stable angina showed no significant difference in these events.
The issue of whether patients already taking clopidogrel 75 daily need to be reloaded at the time of PCI is discussed elsewhere. (See "Antithrombotic therapy for elective percutaneous coronary intervention: General use", section on 'P2Y12 receptor blockers'.)
The duration of dual antiplatelet therapy is an important issue that is discussed separately. (See "Antithrombotic therapy for elective percutaneous coronary intervention: General use", section on 'P2Y12 receptor blockers'.)
Cangrelor — Cangrelor is an intravenous (non-thienopyridine) adenosine triphosphate analogue that blocks the adenosine diphosphate P2Y12 receptor. Advantages of cangrelor, which might improve clinical outcomes over other antiplatelet agents, are its rapid onset of action and rapid return of platelet function after cessation. Our recommendations for the use of cangrelor in patients undergoing PCI, based on the studies below, are found elsewhere. (See "Antithrombotic therapy for elective percutaneous coronary intervention: General use", section on 'P2Y12 receptor blockers' and "Acute ST-elevation myocardial infarction: Antiplatelet therapy", section on 'Patients receiving primary PCI' and "Acute non-ST-elevation acute coronary syndromes: Early antiplatelet therapy", section on 'P2Y12 use'.)
Two early trials evaluated cangrelor in patients undergoing PCI and both failed to show clinical superiority to clopidogrel [34,35]. In both trials, which enrolled patients with ACS or stable angina requiring PCI, cangrelor infusion was given for two hours or for the duration of the procedure, whichever was longer:
●In the CHAMPION PLATFORM trial, over 5000 patients were randomly assigned to either cangrelor infusion or placebo 30 minutes before PCI, followed by 600 mg of clopidogrel after the procedure in both groups [34]. There was no significant difference in the primary composite end point (death, MI, or ischemia-driven revascularization) at 48 hours (7.0 versus 8.0 percent, respectively).
●In the CHAMPION PCI trial, almost 8000 patients were randomly assigned to either cangrelor infusion or 600 mg of clopidogrel given 30 minutes before PCI [35]. Using an identical primary end point as CHAMPION PLATFORM, there was no significant difference between cangrelor and clopidogrel (7.5 versus 7.1 percent respectively) at 48 hours.
A third trial, CHAMPION PHOENIX, randomly assigned 11,145 patients undergoing urgent or elective PCI to receive a bolus and infusion of cangrelor or a loading dose of either 600 or 300 mg of clopidogrel [36]. At 48 hours, the rate of the composite primary efficacy end point (death, MI, ischemia-driven revascularization, or stent thrombosis) occurred less often in the cangrelor group (4.7 versus 5.9 percent; adjusted odds ratio 0.78, 95% CI 0.66-0.93). There was no significant difference in the rate of the primary safety end point of severe or life-threatening bleeding at 48 hours (0.16 versus 0.11 percent; odds ratio 1.50, 95% CI 0.53-4.22). In a sensitivity analysis published separately, cangrelor reduced the incidence of MI at 48 hours (3.8 versus 4.7 percent; odds ratio 0.80, 95% CI 0.67-0.97) [37].
In a pooled analysis of patient-level data from the three CHAMPION trials (12 percent ST-elevation MI, 57 percent non-ST elevation ACS, and 31 percent stable disease), cangrelor, compared to control (clopidogrel or placebo), lowered the rate of primary composite efficacy end point of death, MI, ischemia-driven revascularization, or stent thrombosis at 48 hours (3.8 versus 4.7 percent; odds ratio 0.81, 95% CI 0.71-0.91) [38]. Mild, but not major, bleeding was increased with cangrelor (16.8 versus 13.0 percent).
Cangrelor was approved for use by the United States Food and Drug Administration in June of 2015 as an adjunct to PCI in patients who have not been treated with a P2Y12 platelet inhibitor and who are not being given a glycoprotein IIb/IIIa inhibitor [39,40].
Ticagrelor and prasugrel — Two platelet P2Y12 receptor blockers, ticagrelor and prasugrel, have been evaluated in patients with ACS. The relevant trials and our recommendations for their use are presented separately. (See "Acute non-ST-elevation acute coronary syndromes: Early antiplatelet therapy", section on 'Summary and recommendations' and "Acute ST-elevation myocardial infarction: Antiplatelet therapy", section on 'Summary and recommendations' and "Acute ST-elevation myocardial infarction: Antiplatelet therapy", section on 'Patients receiving primary PCI' and "Acute non-ST-elevation acute coronary syndromes: Early antiplatelet therapy".)
Cilostazol — Cilostazol is approved for the treatment of intermittent claudication and its use has been associated with a reduction in the rate of restenosis after coronary stent placement. (See "Management of claudication due to peripheral artery disease", section on 'Cilostazol'.)
As an inhibitor of type III phosphodiesterase in platelets, cilostazol is an effective antiplatelet agent. (See "Platelet biology and mechanism of anti-platelet drugs".) Triple antiplatelet therapy with aspirin, clopidogrel, and cilostazol compared to dual antiplatelet therapy with aspirin and clopidogrel has been evaluated in a few studies of patients with either stable or unstable coronary disease. In each of the studies below, cilostazol was given with a loading dose of 200 mg and then maintained at 100 mg twice daily, unless otherwise stated.
Short-term outcomes were evaluated in two studies and no difference between double and triple antiplatelet therapy was found [41,42]. Longer-term outcomes come from one randomized trial and two observational studies:
●In an open-label, randomized trial of 1212 patients with ACS undergoing stent placement with either bare metal stents or drug-eluting stents (DES), patients were treated with either aspirin and clopidogrel or cilostazol (for six months; no loading dose given) in addition to aspirin and clopidogrel [43]. At one year, the primary end point (composite of cardiac death, nonfatal MI, stroke, or target vessel revascularization) occurred significantly less often in the group that received cilostazol (10.3 versus 15.1 percent; hazard ratio 0.65, 95% CI 0.41-0.91).
●In the KAMIR registry of patients with ST-elevation MI treated with primary PCI using DES, there were 2569 individuals who received aspirin and clopidogrel and 1634 who received cilostazol (for at least one month) in addition to aspirin and clopidogrel [44]. At eight months, patients who received cilostazol had significantly lower rates of cardiac death (2.0 versus 3.2 percent; adjusted odds ratio [OR] 0.52, 95% CI 0.32-0.84), and total major adverse cardiac events (all-cause mortality, nonfatal MI, and repeat PCI or revascularization procedure) (7.6 versus 9.3 percent; adjusted OR 0.74, 95% CI 0.58-0.95).
●In the DECREASE registry of patients with stable or unstable coronary disease who underwent stenting with DES, 1443 received aspirin and clopidogrel and 1656 received cilostazol for at least four weeks in addition to aspirin and clopidogrel [45]. At 12 months, there was no significant difference between the two groups in combined rate of death, MI, or stent thrombosis. However, the hazard ratios for MI or stent thrombosis were significantly lower in those who received all three antiplatelet agents (0.23, 95% CI 0.08-0.70 and 0.14, 95% CI 0.04-0.52, respectively).
In all studies, there was no significant difference in the rate of major bleeding between groups.
GP IIb/IIIa inhibitors — The efficacy of GP IIb/IIIa inhibitors in elective stenting was addressed in the EPISTENT and ESPRIT trials of patients undergoing elective stenting who were treated with aspirin and ticlopidine [46-51]. While these studies showed improved clinical outcomes at 30 days and one year, comparing a GP IIb/IIIa inhibitor to placebo, they were performed in an era prior to the routine use of P2Y12 inhibitor loading, more potent P2Y12 receptor inhibitors, and the use of direct thrombin inhibitors as anticoagulants. (See 'P2Y12 receptor blockers' above.)
A GP IIb/IIIa inhibitor may not provide any additional benefit in patients pretreated with clopidogrel. This was demonstrated in the ISAR-REACT trial, in which 2159 patients with stable native vessel coronary disease and no major comorbidities underwent elective PCI (90 percent with stenting) at least two hours after pretreatment with 600 mg of clopidogrel (median duration of pretreatment 7.4 hours) [52]. The study subjects were randomly assigned to abciximab plus heparin (70 units/kg) or placebo plus heparin (100 to 140 units/kg). At 30 days, there was no difference in the incidence of death, MI, or urgent target vessel revascularization between abciximab and placebo (4 percent in each group). Major bleeding complications occurred in 1 percent of each group. A later follow-up at one year continued to show no effect of abciximab on death or MI [53].
Comparison of different agents — The relative clinical efficacy of abciximab, tirofiban, and eptifibatide at currently recommended doses has been uncertain for patients undergoing PCI. The efficacy of any of the agents appears to be closely related to the degree of platelet inhibition achieved during and in the initial period after PCI [54-56]. This effect is clearly related to the potency of the initial bolus dose. The degree of platelet inhibition is similar at two hours after initiation of therapy [54], but the dosing regimen of tirofiban (10 mcg/kg bolus followed by 0.15 mcg/kg per min infusion) often produces a lesser degree of platelet inhibition compared to the other two agents in the clinically important period of 15 to 60 minutes after intervention [55,57].
The only trial that has directly compared the relative efficacy of two GP IIb/IIIa inhibitors was the TARGET trial, in which 4809 patients who underwent nonemergent stent-based PCI were randomly assigned to abciximab (0.25 mg/kg bolus followed by 0.125 mcg/kg [maximum 10 mcg/min] for 12 hours) or tirofiban (10 mcg/kg bolus followed by 0.15 mcg/kg for 18 to 24 hours) [58]. Abciximab was significantly superior to tirofiban in the composite end point of death, infarction, or the need for urgent revascularization at 30 days (6 versus 7.6 percent, hazard ratio 0.79) (figure 1). The magnitude and direction of the effect were similar for each component of the composite end point, but the benefit was due primarily to fewer MIs (5.4 versus 6.9 percent). The superiority of abciximab was independent of age, sex, or the use of clopidogrel pretreatment.
Subgroup analysis revealed the benefit of abciximab was limited to patients undergoing stenting for an ACS, in whom platelet activation is more marked, and to nondiabetics, since the outcomes at 30 days were similar with the two drugs in diabetics [59]. However, these subgroup results should be interpreted with caution, given the increased probability of a chance occurrence with multiple looks at the data.
By six months of follow-up, there was no significant difference in the combined end point or the individual end points between the two drugs (figure 2) [60]. The 1.6 percent absolute benefit and 21 percent relative reduction in the combined end point at 30 days with abciximab had fallen to nonsignificant levels (0.5 percent and 4 percent, respectively). Although there remained a significant benefit with abciximab in the subgroup of patients with an ACS at six months, this effect was no longer present at one year [61].
In summary, the only benefit from abciximab in TARGET appeared to be a reduction in procedure-related MI, primarily in patients with an ACS [60]. This difference was evident in the early periprocedural period and may have been due to less effective platelet inhibition with tirofiban with the dosage regimen used (10 mcg/kg bolus followed by 0.15 mcg/kg per min for 18 to 24 hours) [60].
Two other studies also demonstrated reduced response to tirofiban using the 10 mcg/kg bolus. In one, the proportion of patients in whom there was ≥80 percent inhibition of platelet activation at 15 minutes was significantly higher with abciximab than tirofiban (93 versus 60 percent); eptifibatide was as effective as abciximab [55]. In the second, abciximab achieved >90 percent inhibition of maximal platelet aggregation during the first 15 to 60 minutes, a critical interval after intervention-induced vascular injury, compared to only 61 to 66 percent inhibition with tirofiban [57].
A high-dose bolus regimen of tirofiban before high-risk PCI (25 mcg/kg bolus over three minutes, followed by 0.15 mcg/kg per min for 18 hours) was evaluated in the ADVANCE trial, in which 202 patients were randomly assigned to tirofiban or placebo in addition to aspirin, clopidogrel, and heparin [62]. The primary end point of death, MI, urgent target vessel revascularization, or bailout GP IIb/IIIa inhibitor therapy was significantly lower with tirofiban (20 versus 35 percent). This high-dose bolus with a 12-hour infusion was also used in the EVEREST trial cited above [63], and is being compared with abciximab in the TENACITY trial
The United States Food and Drug administration’s approved dosing for tirofiban, for its approved use in unstable angina/non-ST elevation myocardial infarction, is a 25 mcg/kg bolus within five minutes and then 0.15 mcg/kg/min for up to 18 hrs. The infusion rate is reduced 50 percent in patients with creatinine clearance of less than or equal to 60 mL/min.
ANTICOAGULANT THERAPY — Unfractionated heparin (UFH; with or without glycoprotein [GP] IIb/IIIa inhibitors), low molecular weight heparin, direct thrombin inhibitors, and oral anticoagulants have been studied in patients undergoing percutaneous coronary intervention (PCI). All patients undergoing PCI receive one of these.
Heparin — Intravenous UFH is given during the procedure to prevent acute vessel closure due to thrombosis [64]. This practice was initiated when percutaneous transluminal coronary angioplasty was the procedure of choice and has been continued with the routine use of intracoronary stents. The dosing of heparin and the role of activated clotting time (ACT) monitoring during heparin therapy is discussed separately. (See "Antithrombotic therapy for elective percutaneous coronary intervention: General use", section on 'Heparin'.)
Bleeding complications resulting from the combined use of potent antiplatelet and anticoagulant agents are a major risk of PCI. The issue of whether heparin is necessary in patients at very low risk of ischemic complications after PCI was addressed in the CIAO trial of 700 patients already taking aspirin and clopidogrel and undergoing elective PCI for an uncomplicated lesion; the patients were randomly assigned to either UFH (70 to 100 international units/kg) or no heparin [65,66]. Patients with calcified, bifurcation, or long lesions, as well as those with thrombus, small vessels, and bypass graft lesions, were excluded. No patients in either group received GP IIb/IIIa inhibitor therapy. The primary end point of death, MI, or urgent target vessel revascularization at 30 days occurred more frequently in the heparin group (3.7 versus 2.0 percent), but this difference was not statistically significant. Although there were fewer bleeding events in the no-heparin group, too few events occurred to permit important conclusions.
Despite the results of this small study, we believe that anticoagulant therapy should be used in all low-risk patients. While bleeding risk is recognized as a major safety issue and safer strategies require investigation, the omission of any anticoagulant is not prudent with the current level of evidence.
Low molecular weight heparin — Two studies have directly compared low molecular weight heparin to UFH in patients with stable coronary artery disease undergoing stenting and found no significant difference between the two:
●The STEEPLE safety trial randomly assigned 2528 patients presenting for elective PCI to enoxaparin (a single intravenous bolus of either 0.50 or 0.75 mg/kg before PCI) or UFH [67]. There was a higher mortality rate among patients receiving the 0.50 mg/kg dose of enoxaparin than in either of the other two groups, causing the data monitoring committee to recommend termination of this dose late in the trial. There was an observed reduction in the primary end point of major and minor bleeding in the 0.75 mg/kg group compared with UFH (6.5 versus 8.5 percent), but the difference was not statistically significant. The incidence of major bleeding, which was a secondary end point, was significantly reduced with enoxaparin.
●In a study of 291 patients undergoing elective or urgent PCI who were randomly assigned to enoxaparin or UFH (both groups received a glycoprotein IIb/IIIa inhibitor), there was no difference in the primary end point of bleeding, nor was there a difference in a composite of death, MI, or urgent target vessel revascularization at 48 hours or 30 days [68].
Bivalirudin — Bivalirudin, with or without a GP IIb/IIIa inhibitor, was an acceptable alternative to heparin therapy in two randomized trials of predominantly stable or low-risk ACS patients (REPLACE-2 and ISAR-REACT 3).
In the REPLACE-2 trial, 6010 patients (85 percent of whom received a stent) were randomly assigned to bivalirudin with provisional GP IIb/IIIa inhibitor therapy or to heparin with planned GP IIb/IIIa inhibitor therapy; almost all patients received clopidogrel pretreatment [69]. In the heparin arm, 97 percent received the "planned" GP IIb/IIIa inhibitor, while in the bivalirudin arm, only 7 percent received a "provisional" GP IIb/IIIa inhibitor, primarily for procedural or angiographic complications (eg, side branch closure, obstructive dissection, thrombus).
REPLACE-2 satisfied prespecified criteria for noninferiority (of bivalirudin) for the primary end point of death, MI, urgent revascularization, or in-hospital major bleeding and for the secondary end point of death, MI, or urgent revascularization. Interpretation and clinical application of the results of REPLACE-2 has centered on the following:
●Bivalirudin was associated with a significant reduction in protocol-defined major bleeding (2.4 versus 4.1 percent) compared to heparin plus a GP IIb/IIIa inhibitor. However, major bleeding by TIMI criteria was similar for the two groups (0.6 versus 0.9 percent), and it has been argued that heparin dosing and higher-than-usual procedural ACT values may have accounted in part for the increase in TIMI minor bleeding seen with heparin.
●The heparin plus GP IIb/IIIa inhibitor group had a nonsignificant reduction in post-procedure non-ST elevation myocardial infarction (MI; 5.8 versus 6.6 percent), driven mostly by a reduction in intermediate (creatine kinase MB fraction [CK-MB] greater than five times normal) and large (CK-MB greater than 10 times normal) MIs. The clinical significance of this trend is uncertain.
In a subsequent analysis of longer-term outcomes, the incidence of death, MI, or any revascularization at six months was comparable for patients treated with bivalirudin versus heparin plus GP IIb/IIIa inhibitor (18.8 versus 17.5 percent) [70]. Mortality at one year was also not significantly different (1.9 versus 2.5 percent).
This issue of how bivalirudin compares to heparin without GP IIb/IIIa inhibitor therapy in stable or low-risk ACS patients (biomarker negative) was addressed in the ISAR-REACT 3 trial [71]. In this study, 4570 patients pretreated with clopidogrel 600 mg at least two hours before the procedure were randomly assigned to anticoagulation with either bivalirudin (0.75 mg per kilogram bolus, followed by 1.75 mg/kg/hour infusion for the duration of the procedure) or a high dose of UFH (140 units/kg). After 30 days, the following findings were noted:
●There was no significant difference in the incidence of the composite primary end point of death, MI, urgent target-vessel revascularization due to myocardial ischemia, or major bleeding during the index hospitalization between the bivalirudin and heparin groups (8.3 versus 8.7 percent, respectively).
●The composite secondary end point of death, MI, or urgent target vessel revascularization due to myocardial ischemia was similar in the two groups (5.9 versus 5.0 percent, respectively).
●The incidence of protocol-defined major bleeding (using the same definition as in REPLACE-2) was significantly lower in the bivalirudin group (3.1 versus 4.6 percent). Most of this difference was attributable to a decrease in hemoglobin ≥3g/dL with an overt source. There was no significant difference in the rate of transfusion.
●At one year, there was no significant difference in the incidence of the primary composite end point (17.1 versus 17.5 percent, respectively) [72].
However, the applicability of ISAR-REACT 3 to current practice is somewhat uncertain, as the dose of heparin was higher than that recommended in United States and European guidelines [73,74]. (See "Antithrombotic therapy for elective percutaneous coronary intervention: General use", section on 'Heparin'.)
The ISAR-REACT 3A study addressed this issue by treating 2505 similar patients with a lower-dose heparin bolus (100 international units/kg) and comparing their outcomes to the historical groups in ISAR-REACT 3 [75]. At 30 days, the rate of the primary composite end point was not statistically different between the two heparin doses. The rate of major bleeding was lower (3.6 versus 4.6 percent) with the 100 international units/kg dose, but did not achieve statistical significance. In addition, the lower dose was noninferior to bivalirudin with regard to the primary composite outcome.
Fondaparinux — The heparin pentasaccharide analog fondaparinux is a selective inhibitor of factor Xa. It is rarely used at the time of PCI in stable patients [76]. (See "Fondaparinux: Dosing and adverse effects".)
Warfarin — Combined antiplatelet therapy with aspirin and thienopyridine produces significantly better outcomes than aspirin plus warfarin. In the STARS trial, for example, 1653 patients who received a stent were randomly assigned to aspirin, aspirin plus warfarin, or aspirin plus ticlopidine [5]. At 30 days, the incidence of the primary end point of events reflecting stent thrombosis (death, emergency coronary artery bypass graft surgery, Q wave myocardial infarction, or angiographically evident thrombosis) was significantly lower with aspirin plus ticlopidine (0.5 versus 2.7 with aspirin plus warfarin). (See 'Efficacy and safety' above and 'Timing and dose' above.)
The use of warfarin in patients who require both long-term anticoagulant and antiplatelet therapies is discussed below. (See "Periprocedural management of antithrombotic therapy in patients receiving long-term oral anticoagulation and undergoing percutaneous coronary intervention", section on 'Elective patients'.)
SUMMARY
●This topic reviews the studies that support the use of antithrombotic therapy, using both antiplatelet and anticoagulant drugs, during percutaneous coronary intervention with stenting. However, even with proper administration, thrombotic events can occur. In addition, clinically important bleeding is not uncommon. (See "Antithrombotic therapy for elective percutaneous coronary intervention: General use", section on 'Bleeding'.)
●Recommendations for the periprocedural use of antithrombotic therapy in patients with stable coronary disease are found elsewhere. (See "Antithrombotic therapy for elective percutaneous coronary intervention: General use", section on 'Summary and recommendations'.)
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