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Balancing safety and efficacy: recent clinical evidence optimizing outcomes in patients with intermediate to high-risk non-ST-segment elevated acute coronary syndrome

Marco Valgimigli
DOI: http://dx.doi.org/10.1093/eurheartj/suq021 D14-D23 First published online: 2 September 2010

Abstract

Significant developments have taken place over the past 15 years with respect to greater understanding of ischaemic risk in non-ST-segment elevation (NSTE) acute coronary syndrome (ACS) and respective management strategies. This includes recognition of the clinical benefit of an early invasive strategy and of the value of addressing various antiplatelet targets in the approach to pharmacotherapy. The guidelines focused on management of NSTE-ACS advocate the role of dual antiplatelet therapy with a recommendation for triple antiplatelet therapy, including a glycoprotein (GP) IIb/IIIa inhibitor (GPI), in patients who are determined to be at an elevated risk for ischaemic events. This may include those who are elderly, have a history of diabetes and/or renal impairment, and have elevated cardiac biomarkers (e.g. troponin) or ST-segment deviation at diagnosis. While triple antiplatelet therapy has demonstrated significant improvement in clinical outcomes in patients with NSTE-ACS, there is concern over the potential for an increase in haemorrhagic complications. Newer pharmacotherapies such as prasugrel and ticagrelor have demonstrated significantly greater efficacy as compared with clopidogrel in patients with NSTE-ACS deemed as high risk, although the incidence of certain bleeding complications was significantly increased with both of these agents. Additionally, efficacy has not yet been proved when compared with higher doses of clopidogrel, which has been shown to offer significant clinical benefits in patients who underwent percutaneous coronary intervention. Thus, a regimen of triple antiplatelet therapy including a GPI should remain a strong consideration for standard therapy in patients at high risk for ischaemic events, even in the prasugrel and ticagrelor era.

  • Non-ST-segment elevation acute coronary syndrome
  • Platelet
  • Antiplatelet therapy
  • Clopidogrel
  • Prasugrel
  • Ticagrelor
  • Glycoprotein IIb/IIIa inhibitor
  • Abciximab
  • Tirofiban
  • Eptifibatide
  • High risk

Introduction

The past decade has been a time of great exploration with respect to managing patients with non-ST-segment elevation (NSTE)-acute coronary syndrome (ACS), particularly those at a high risk of ischaemic events. Much of this has been in the form of strategies featuring intense antiplatelet therapy, as it is quite apparent that enhanced platelet activity is a key culprit in the development and growth of the underlying thrombosis involving both the epicardial and myocardial vessels.

It has been shown that improving outcome in NSTE-ACS, specifically among patients who undergo an invasive strategy, requires a significant level of platelet inhibition.1 However, impeding platelet activity increases the risk of bleeding as well as thrombocytopenia. Striking a balance between efficacy and safety has been a significant focus of recent trials evaluating novel and existing pharmacological agents.

This article will discuss the role of a multi-modal approach to antiplatelet therapy designed to optimize efficacy while addressing safety.

Current recommendations for antiplatelet therapy in non-ST-segment elevation acute coronary syndrome

The central role of heightened platelet activity in the pathophysiology of NSTE-ACS supports the designation of antiplatelet therapy, including aspirin, thienopyridines, and glycoprotein (GP) IIb/IIIa inhibitors (GPI), as a cornerstone of management. The guidelines put forth by the American College of Cardiology (ACC)/American Heart Association (AHA) and European Society of Cardiology (ESC) advocate at the very least, dual antiplatelet therapy, and in patients determined as at an elevated risk for ischaemic complications managed with an early invasive strategy, triple antiplatelet therapy.2,3

Oral antiplatelet agents

It is a long-standing recommendation that all patients with NSTE-ACS should receive aspirin. More recently, however, there has been a growing role for dual antiplatelet therapy including a thienopyridine. It is strongly advocated that clopidogrel also be administered concurrently with aspirin, starting with a minimum loading dose of 300 mg.2,3 The basis for this recommendation is supported by results from studies such as PCI-CURE.4 PCI-CURE demonstrated a significant 30% relative risk reduction (RRR) in the composite of cardiovascular death, MI, or urgent target vessel revascularization (TVR) at 30 days with aspirin plus a clopidogrel regimen including 300 mg loading and 75 mg maintenance doses as compared with aspirin alone (6.4 vs. 4.5%; P = 0.03) in patients with NSTE-ACS who underwent percutaneous coronary intervention (PCI).

Since PCI-CURE, studies have evaluated higher loading doses of clopidogrel.58 For example, in the Antiplatelet therapy for Reduction of Myocardial Damage during Angioplasty (ARMYDA)-2 trial, a regimen including a 600 mg loading dose of clopidogrel administered at 6 h prior to PCI demonstrated a significant benefit with respect to death, myocardial infarction (MI), or TVR in patients undergoing elective PCI, as compared with one utilizing 300 mg, also received at 6 h before PCI (12 vs. 4.0%; P = 0.041).5 It may be gleaned from this trial that 600 mg will provide a more rapid and intense platelet inhibition as compared with 300 mg. It is therefore suggested that a 600 mg loading dose be administered when there is the need for more rapid platelet inhibition.3 Yet, the results of these phase II studies have not been entirely confirmed by the Clopidogrel Optimal Loading Dose Usage to Reduce Recurrent Events-Optimal Antiplatelet Strategy for Interventions (CURRENT-OASIS 7) trial, in which a ‘double-dose regimen’ comprising 600 mg clopidogrel followed 150 mg/day for 7 days (then 75 mg/day) failed to improve the ischaemic outcome in the intent to treat patient population when compared with clopidgrel administered at the standard dose (loading dose 300 mg/maintenance 75 mg/day).9 Additionally, the rate of major bleeding complications was also significantly increased with the double-dose regimen.

Glycoprotein IIb/IIIa inhibitors

In patients managed invasively, concomitant administration of aspirin plus either clopidogrel or a GPI is optimal. Nevertheless, if a patient is considered high risk, triple antiplatelet therapy is advisable.3 Triple antiplatelet therapy including aspirin, clopidogrel, and a GPI has shown to be very beneficial in high-risk patients with NSTE-ACS, even those who have are pre-treated with high-dose (600 mg) clopidogrel. Results from ISAR-REACT 2 revealed that in patients with high-risk NSTE-ACS managed with an early invasive strategy, the addition of a GPI (abciximab) to aspirin and high-dose clopidogrel significantly reduced the incidence of clinical events as evidenced by the results for the combined endpoint of death, MI, or TVR (11.9 vs. 8.9%; P = 0.03).8 Moreover, this was driven mainly by a significant decrease in the rate of this composite endpoint in the subgroups of patients that were either troponin positive or age ≤70. This is a stark contrast from the ISAR-REACT study which also evaluated the value of a GPI on top of pre-treatment with ASA and high-dose clopidogrel (600 mg), though had enrolled only low-risk patients undergoing elective PCI.7 In ISAR-REACT, a significant benefit was not gained with the addition of abciximab. The results of these two trials underscore the importance of risk segmentation and the value of treating patients at high risk for ischaemic complications (e.g. troponin-positive) with a regimen including intensive antiplatelet therapy. Similarly, the ADVANCE trial demonstrated an enhanced benefit of tirofiban in a high-risk patient population.10 ADVANCE was a double-blind, placebo-controlled trial designed to determine the safety and efficacy of post-angiography tirofiban using the 25 µg/kg dose bolus regimen in high-risk patients undergoing PCI. A total of 202 patients undergoing PCI and exhibiting high-risk characteristics were enrolled. These included the presence of at least one coronary narrowing ≥70% amenable to coronary stenting and the presence of diabetes, planned multi-vessel intervention (stenting of two or more lesions of least 70% coronary stenosis in different coronary vessels), or the presence of NSTE-ACS. Patients in ADVANCE were pre-treated with a thienopyridine (ticlopidine 500 mg as a loading dose and then 250 mg twice daily or clopidogrel 300 mg orally as a loading dose and then 75 mg/day) and then randomized to either tirofiban or placebo immediately prior to PCI. Fifty-five per cent of patients in ADVANCE were enrolled due to NSTE-ACS. In the overall study population, the cumulative incidence of the primary endpoint of death, MI, TVR, or bailout use of GPI was 35 and 20% in placebo and tirofiban groups, respectively [hazard ratio (HR), 0.51, 95% CI, 0.29–0.88; P = 0.01]. As seen in Table 1, this difference was mainly due to the non-significant differences in MI and bailout use of GPIs with tirofiban, which were directionally consistent with other trials of tirofiban.

View this table:
Table 1

ADVANCE: clinical outcomes at 6 months

Clinical EventTirofiban (n = 101)Placebo (n = 101)Hazard ratioP-value
Primary endpoint (%)20350.51 (0.88–1.29)0.01
Death/MI/TVR (%)20310.57 (0.99–0.33)0.048
Death (%)211.7 (19–0.15)0.6
MI (%)4110.34 (1.08–0.11)0.052
TVR14190.64 (1.28–0.32)0.29
Bailout GPI use (%)040.15 (1.29–0.01)0.08
MI/bailout GPI (%)4150.23 (0.75–0.08)0.01
Death/MI/bailout GPI (%)6160.35 (0.88–0.13)0.03

On the basis of the Kaplan–Meier survival analysis demonstrating the proportion of survival free of the primary endpoint, at month 6 the HR was 0.51 (95% CI, 0.29–0.88; P = 0.01 by the log-rank test). As shown in Figure 1, significant reductions in the primary endpoint were observed in patients with NSTE-ACS or diabetes. These results suggest that tirofiban is apparently more effective in patients with ACS than in stable ones.

Figure 1

ADVANCE subgroup analysis: Hazard risk of primary endpoint according to the presence or absence of ACS as an indication to PCI or a history of diabetes. Reproduced with permission from Valgimigli et al.10

Early administration of GPIs in non-ST-segment elevation acute coronary syndrome

Treatment with GPIs in addition to aspirin and heparin, with initiation immediately after admission, reduces the potential for ischaemic complications that may occur in NSTE-ACS patients treated medically as well as in patients subsequently scheduled to undergo PCI.11 That said, the ESC recommends that in patients with NSTE-ACS determined to be high-risk (diabetes, troponin-positive, ST-segment deviations at baseline) either tirofiban or eptifibatide be initiated early in addition to oral antiplatelet agents.3 The exclusion of abciximab from this statement is owing to the results of the Global Use of Strategies To Open occluded arteries (GUSTO)-IV ACS trial in which abciximab and placebo were compared in patients with NSTE-ACS who had been experiencing a 24–48 h delay to the catheterization laboratory.12 Besides a diagnosis of NSTE-ACS, patients were required to also exhibit high-risk features including either positive cardiac troponin T/I or persistent ST-segment depression. At 30 days, there was no statistically significant difference in the primary endpoint of death or MI with either abciximab regimen (24 or 48 hours), as compared with placebo, (8.0 vs. 8.2 vs. 9.1%; P = NS). Additionally, patients treated with the abciximab 48 h regimen experienced significant increases in the rates of TIMI major bleeding (0.3 vs. 1.0%; P < 0.05), TIMI minor bleeding (2.0 vs. 4.0%; P < 0.05) and transfusion (0.7 vs. 1.3%; P < 0.05). The rate of thrombocytopenia (platelet count <100,000/l) was significantly higher in both abciximab groups as compared with placebo (1.0 vs. 5.0 vs. 7.0%; P < 0.05). Additionally, analysis of mortality rates over the course of 1 year demonstrated a significant increase in mortality as compared with placebo at 48 h in patients receiving the abciximab 48 h regimen (0.3 vs. 0.9%; P = 0.008).13

The Early GP IIb/IIIa Inhibition in Patients With Non-ST-Segment Elevation Acute Coronary Syndrome (EARLY-ACS) set out to determine whether pre-angiography administration of the double-bolus regimen (180 µg/kg ×2) eptifibatide would be superior to provisional use (of the same dosing regimen) administered post-angiography, in the catheterization laboratory, with respect to reducing clinical events within 96 h in patients with high-risk NSTE-ACS managed with an early invasive strategy.14 The results of EARLY-ACS showed that at 96 h, there was no significant benefit with pre-angiography eptifibatide with respect to the primary endpoint [all-cause mortality, MI, recurrent ischaemia requiring urgent revascularization (RIUR), or thrombotic bailout (TBO)] (10.0 vs. 9.3%; P = 0.23) or the component endpoints of death, MI, RIUR, or TBO. This endured at 30 days, in which no significant differences were demonstrated in the composite of death or MI (12.3 vs. 11.2%; P = 0.079) between routine pre-angiography and provisional eptifibatide. Additionally, bleeding complications at 5 days were significantly higher in the routine pre-angiography eptifibatide group as manifested by increases in the rates of all [including coronary artery bypass graft (CABG)-related] TIMI major (1.8 vs. 2.6%; P = 0.015), TIMI minor (1.7 vs. 3.6%; P < 0.001), and GUSTO minor (4.3 vs. 6.8%; P < 0.001) bleeding. Additionally, significant increases were observed in the rates of non-CABG-related TIMI major bleeding (0.8 vs. 1.6%; P < 0.001) and transfusions (6.7 vs. 8.6%; P = 0.001) with the administration of pre-angiography eptifibatide, compared with delayed eptifibatide.

It should be recognized, however, that results of the subgroup analysis indicated that with respect to death or MI at 30 days, patients who demonstrated the greatest benefit with routine pre-angiography eptifibatide tended to be younger, diabetic, and/or troponin-positive. The primary endpoint was also reduced with pre-angiography eptifibatide in the patients who underwent PCI as in this subgroup, when eptifibatide was initiated early, the rate of the primary endpoint was 8.0%, whereas it was 10.0% with delayed eptifibatide.

The results of EARLY-ACS might cast some doubt on the utility of upstream initiation of GPIs inhibitors in high-risk patients. Nonetheless, a review of earlier trials including EVEREST provides validation for such treatment.15

Similar to EARLY-ACS, the EVEREST trial compared an upstream GPI regimen with a downstream (at time of PCI) strategy in high-risk NSTE-ACS patients managed with PCI. However, in EVEREST, an upstream regimen of a small-molecule agent (tirofiban) was compared with both a downstream regimen of the same agent as well as a different one. Upstream tirofiban using 0.4 µg/kg/min for 30 min followed by infusion of 0.1 µg/kg/min was evaluated against downstream tirofiban (25 µg/kg for 3 min followed by infusion of 0.15 µg/kg/min) and downstream abciximab, with respect to tissue level perfusion and troponin I release The vast majority of patients were administered clopidogrel loading with 300 mg. The results of EVEREST determined that upstream tirofiban produced significantly better myocardial perfusion as evidenced by significantly lower rates of TIMI myocardial perfusion grade 0/1 both before (28.1 vs. 66.7 vs. 71%, respectively; P = 0.0009) and after PCI (6.2 vs. 20 vs. 35.5%, respectively; P = 0.015) as compared with post-angiography tirofiban and abciximab. This was also evident with respect to myocardial contrast echocardiography score index (0.88 ± 0.18 vs. 0.77 ± 0.32 vs. 0.71 ± 0.30, respectively; P < 0.05). The incidence of post-procedural cardiac troponin I (cTn)I elevation was also significantly reduced in the upstream tirofiban group compared with the (post-angiography) 25 µg/kg dose bolus tirofiban and abciximab groups (9.4 vs. 30 vs. 38.7%, respectively; P = 0.018). The cTnI levels after PCI were significantly decreased with pre-angiography tirofiban compared with (post-angiography) 25 µg/kg bolus tirofiban (3.8 ± 4.1 vs. 7.2 ± 12; P = 0.015) and abciximab (3.8 ± 4.1 vs. 9 ± 13.8; P = 0.0002).

Results of the Platelet Receptor Inhibition for Ischemic Syndrome Management in Patients Limited by Unstable Signs and Symptoms (PRISM-PLUS) demonstrated a significant reduction in the composite endpoint of death or MI at 7 days (8.3 vs. 4.9%; P = 0.006) with the combination of tirofiban (using 0.4 µg/kg/min loading dose regimen) plus unfractionated heparin (UFH) as compared with UFH alone. This effect persisted to 30 days (11.9 vs. 8.7%; P = 0.027).16

Consistent to that seen in EARLY-ACS, results of subgroup analyses revealed that patients who exhibited high-risk characteristics including diabetes, elevated troponin at baseline, and ST-segment deviation yielded significant benefits with the addition of tirofiban to UFH.

Diabetes

Of the 1570 patients randomized to receive either tirofiban plus UFH (n = 773) or UFH alone (n = 797) in PRISM-PLUS, 23% had a baseline diagnosis of diabetes.16 A pre-specified analysis of the diabetic subgroup was conducted, as shown in Table 2. Relative to those who were administered UFH alone, there was a significant reduction in the composite of death or MI in patients treated with tirofiban plus UFH. This was noted at 48 h and at 7, 30, and 180 days.17

View this table:
Table 2

PRISM-PLUS: clinical events in the diabetic subgroup

EventTirofiban (n = 773)Placebo (n = 797)P-value
Death or MI
 48 h0%3.1%0.003
 7 days1.2%9.3%0.005
 30 days4.7%15.5%0.002
 180 days11.2%19.2%0.003

The investigators discussed the limitations of their analysis and the need to assess the data as being suggestive rather than definitive. Nevertheless, the results observed with an 89% RRR in death or MI at 7 days (absolute reduction 8.1%) and a relative 70% reduction at 30 days (absolute reduction 10.8%) were deemed as substantial. They also commented on the clinical implications of their analysis and suggested that treatment with tirofiban may be of benefit in diabetic patients by preventing the ischaemic complications of ACS. Although the benefit was present in medically managed patients, it was of a greater magnitude in the setting of revascularization procedures (PCI and CABG), which are associated with increased morbidity and mortality in diabetic patients.

Troponin-positive

In an analysis of 110 patients enrolled in PRISM-PLUS, it was demonstrated that among those patients with elevated serum cTnI (>0.5 ng/mL), there was a non-significant difference in the rate of death or MI at 30 days in the tirofiban plus UFH group (20.6 vs. 3.6%; P = 0.06; RRR, 83%).18 These results were directionally consistent with other trials of GPIs in troponin-positive NSTE-ACS patients. Among the cTnI-negative patients (cTnI <0.5 ng/mL), the rates of death or MI at 30 days were not significantly different in the two treatment groups.

ST-segment deviation

In PRISM-PLUS, patients with evidence of ST-segment deviations on electrocardiogram demonstrated a significant benefit with treatment with tirofiban plus UFH with respect to the composite endpoint of all-cause death, MI, or refractory ischaemia at 7 days.16 This was observed regardless of whether the deviation was in the form of ST-segment depression (21.7 vs. 16.6%; P ≤ 0.05) or elevation (17.4 vs. 7.7%; P ≤ 0.05).

Renal impaired

The effect of tirofiban plus UFH as compared with UFH alone was examined in a subgroup of 1537 renal-impaired patients in PRISM-PLUS.19 This analysis did not include patients with severe renal insufficiency (defined as a serum creatinine ≥2.5 mg/dL) as they were excluded from PRISM-PLUS. Irrespective of creatinine clearance (CrCl), treatment with tirofiban significantly reduced the composite endpoint of death, MI, or refractory ischaemia at 48 h [odds ratio (OR) 0.68 (95% confidence interval, CI, 0.46–1.0); P = 0.05], 7 days [OR, 0.68 (95% CI, 0.52–0.88); P = 0.003], 30 days [OR, 0.78 (95% CI, 0.63–0.98); P = 0.03], and 6 months (OR, 0.81; 95% CI, 0.68–0.98; P = 0.03). The risk of death or MI was also significantly decreased at all time points examined. For TIMI-defined major bleeding, neither the effects of renal insufficiency nor the addition of tirofiban to UFH resulted in statistically significant increases in major bleeding rates (P = 0.35 and 0.20, respectively).

Using the PRISM-PLUS bleeding definition, the rates of all bleeding increased with decreases in CrCl (P < 0.001 for trend), and the addition of tirofiban to UFH resulted in statistically significant increases in bleeding (P < 0.001) that were consistent across levels of CrCl (Figure 2). The proportional odds for any form of bleeding among the patients in PRISM-PLUS as a function of CrCl were determined and it was found that irrespective of treatment assignment, renal insufficiency was a significant risk for bleeding (lowest vs. highest CrCl category: OR, 1.57; P < 0.001). In addition, irrespective of renal function, the addition of tirofiban to UFH resulted in an incremental risk for bleeding (P < 0.001), but bleeding was not amplified by the addition of tirofiban to UFH in patients with renal insufficiency. This finding should be considered specific to tirofiban as unlike eptifibatide, tirofiban has both renal and hepatic clearance which allows for dose adjustment only in patients with severe renal impairment (i.e. CrCl <30 mL/min).

Figure 2

Proportional odds for any severity of bleeding among patients in PRISM-PLUS treated with tirofiban and heparin (combination vs. heparin, expressed as a function of CrCl (in mL/min). Though declining renal function and overall use of tirofiban (in the overall study population) was significantly associated with haemorrhage, (P < 0.001 and P < 0.001, respectively), the addition of tirofiban in the presence of renal insufficiency was not accompanied by an incremental increase in risk for haemorrhage. Adapted with permission from Januzzi et al.19

Elderly

An analysis was conducted to determine the interaction between age, prognosis, and bleeding risk in patients with NSTE-ACS enrolled in PRISM-PLUS.20 Age was considered a continuous and categoric (<60, 61–70, and ≥71 years) variable for the purposes of this analysis. The combination of tirofiban plus UFH significantly reduced the odds of the composite endpoint at 7 days, 30 days, and 6 months. Death or MI was also significantly reduced with tirofiban plus UFH at all time points (48 h, 7 days, 30 days, and 6 months).

Using the PRISM-PLUS definition of bleeding, the rates of all forms of bleeding increased concomitantly with age [OR, 1.29 per decade increase in age (95% CI, 1.19–1.40); P < 0.0001]. The use of tirofiban also resulted in statistically significant increases in mild to moderate bleeding [OR, 1.71 (95% CI 1.41 to 2.06); P < 0.0001] which were consistent across the age range studied; however, severe or life-threatening bleeding was uncommon in patients treated with tirofiban and were not statistically more common in the oldest patients relative to the rest of the study patients. The odds of any form of bleeding as a function of age demonstrated that, irrespective of age, therapy with tirofiban resulted in a higher bleeding risk, but bleeding was not incrementally amplified in older patients (OR, 1.33 vs. 1.34; P = NS).

Role of clopidogrel loading in upstream glycoprotein IIb/IIIa inhibitor therapy

Finally, the absence of clopidogrel pre-treatment in the PRISM-PLUS study as compared with EARLY-ACS should not lead to trivialize the value of upstream GPIs in preventing ischaemic events in high-risk ACS. Patients who received optimal clopidogrel exposure prior to PCI in EARLY-ACS derived a significant reduction of the composite endpoint of death or MI at 30 days [adjusted HR, 0.85 (95% CI, 0.73–0.99)], which was not reproduced in patients who were not exposed to upstream clopidogrel [adjusted HR, 1.02 (95% CI, 0.80–1.30)].21 This interesting finding may indeed suggest that in the management of patients with NSTE-ACS, upstream GPIs and exposure to upstream clopidogrel might indeed be a synergistic strategy to prevent ischaemic complications rather than alternative and mutually exclusive treatments.

Bleeding events and outcomes

Bleeding events, as determined by means of several definitions, have been correlated with significant increases in ischaemic complications and mortality in patients with ACS.2224 Results from a pooled analysis of data from two randomized trials totalling 15 454 patients with ACS showed significant stepwise increases in the risk of the 30-day and 6-month composite of death or MI with worsening bleeding as defined by GUSTO [mild HR, 1.20 (95% CI, 1.05–1.37); moderate HR, 3.28 (95% CI, 2.88–3.73); severe HR, 5.57 (95% CI, 4.33–7.17)] and an increased risk with all three levels of TIMI bleeding [minimal HR, 1.84 (95% CI, 1.63–2.08); minor HR, 1.64 (95% CI, 1.31–2.04); major HR, 1.45 (95% CI, 1.23–1.70)].22 An analysis of data from 24 045 patients with ACS enrolled in the GRACE registry revealed that after adjustment for a variety of potential confounders, major bleeding was significantly associated with an increased risk of in-hospital death (adjusted OR 1.64, 95% CI, 1.18–2.28).23 Moreover, in the Acute Catheterization and Urgent Intervention Triage strategy (ACUITY) trial, patients with NSTE-ACS who experienced major bleeding experienced higher rates of 30-day mortality (7.3 vs. 1.2%, P < 0.0001), vs. those without major bleeding.24 Major bleeding was also an independent predictor of 30-day mortality [OR, 7.55 (95% CI, 4.68–12.18); P<0.0001].

Owing to the increased risk of CABG-related bleeding in patients treated with clopidogrel, it is recommended that CABG surgery (if warranted) should be postponed for 5–7 days in patients treated with clopidogrel.3 Addressing this potential safety concern may result in clopidogrel being delayed until after the coronary anatomy has been assessed. However, even with a considerable loading dose such as 600 mg, it is extremely unlikely that at the time of PCI, platelet inhibition will achieve the level necessary to have a positive impact on clinical events.

Review of contemporary trials of antiplatelet therapy in non-ST-segment elevation acute coronary syndrome: balancing efficacy and safety

In the effort to further optimize efficacy while ameliorating adverse bleeding events, trials have assessed the benefit of different regimens for existing agents as well as novel therapies in high-risk patients who are invasively managed. As noted earlier, in CURRENT OASIS-7, the intent-to-treat population did not meet the primary endpoint of death, MI, or stroke at 30 days.9 However, the patients who underwent PCI (60% of the study population) demonstrated a significant reduction in death, MI, or stroke at 30 days with the double-dose regimen (4.5 vs. 3.9%; P = 0.036) which was driven by a significant reduction in the rate of MI (2.6 vs. 2.0%; P = 0.012).

The effects of prasugrel and clopidogrel on platelet function were compared in the Platelet Activation and Aggregation-Thrombolysis in Myocardial Infarction (PRINCIPLE)-TIMI 44 trial.25 In this crossover study, when compared with 600 mg of clopidogrel, the percent inhibition of platelet activity (% IPA) of a 60 mg prasugrel loading dose was significantly higher at 30 min (4.9 vs. 30.8%) and maintained through 24 h (32.6 vs. 69.3%) (all P < 0.0001). At 15 days after the initiation of maintenance therapy, % IPA was also significantly higher in patients receiving prasugrel 10 mg/day compared with clopidogrel 150 mg/day (45.4 vs. 61.9%; P < 0.0001). Nonetheless, neither drug achieved ≥70% platelet inhibition.

The effect of prasugrel as compared with clopidogrel was evaluated in the Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel—TRITON-(TIMI) 38 study. A significant reduction in the composite of CV death, MI, or stroke at 15 months in patients with ACS (including NSTE-ACS and STEMI) was demonstrated with prasugrel (loading dose 60 mg/maintenance dose 10 mg/day) when compared with clopidogrel (loading dose 300 mg/maintenance dose 75 mg/day) [12.1 vs. 9.9%; HR, 0.81 (95% CI, 0.73–0.90; P < 0.001)].26 This efficacy was accompanied by a significant increase in non-CABG-related TIMI major and minor bleeding, life-threatening and fatal bleeding, bleeding which required transfusion, and CABG-related TIMI major bleeding. It should be noted that similar to clopidogrel, prasugrel is an irreversible agent and, therefore, also requires a 7-day delay in CABG, if deemed necessary. The bleeding risk was most prominent in patients who had a history of stroke or transient ischaemic attack (TIA) as well as elderly (aged ≥75) or with a low body weight (<60 kg). To that end, prasugrel is contraindicated in specific patients, particularly those with a history of stroke or TIA.27 Remarkably, 54% of patients in TRITON-TIMI 38 received a GPI at some point during the index hospitalization.28 Analysis of this subgroup revealed that the use of triple antiplatelet therapy did not result in any significant increase in major bleeding. Another interesting point includes the fact that the effect of prasugrel on post-PCI ischaemic outcomes was largely influenced by the prevention of stent thrombosis-related MI (Type 4b), whereas PCI-related MIs, which were not due to stent thrombosis, were only marginally and not significantly reduced by prasugrel as compared with clopidogrel (Figure 3). This again emphasizes the still vital role of GPIs in the prevention of ischaemic complications even in the era of potent oral P2Y12 receptor blockers.

Figure 3

TRITON-TIMI 38: effect of prasugrel of type IV MI.

Ticagrelor is the first in a new class of antiplatelet agents known as the cyclo-pentyl-triazolo-pyrimidines (CPTPs). Ticagrelor is an oral non-thienopyridine adenosine diphosphate (ADP) receptor antagonist and selective inhibitor of P2Y12, although unlike clopidogrel and prasugrel, it is orally active and does therefore not require metabolism via the CYP 450 pathway. Ticagrelor is also reversible, resulting in the return of platelet activity within a few hours.29

Cyclo-pentyl-triazolo-pyrimidines (ticagrelor)

In the landmark PLATelet inhibition and patient Outcomes (PLATO) trial, ticagrelor (180 mg loading dose/90 mg b.i.d. maintenance) was compared in relation to clopidogrel (300 mg loading dose/75 mg/day maintenance) in patients who were hospitalized for an NSTE-ACS or STEMI. A significant reduction was evident with ticagrelor in the rate of the primary endpoint (death from vascular causes, MI, or stroke) at 12 months (11.7 vs. 9.8%; P ≤ 0.001).30 Protocol-defined (PLATO) major bleeding was not significantly different between the two groups (11.2 vs. 11.6%, clopidogrel and ticagrelor, respectively; P = 0.43), though there was a non-significant difference between clopidogrel and ticagrelor (respectively) in the overall rate of intracranial bleeding (0.2 vs. 0.3%; P = 0.06) and a significant increase with ticagrelor in the rate of intracranial fatal bleeding (0.01 vs. 0.1%; P = 0.03). It should also be noted that in the considerable number of patients in PLATO who were treated with a GPI (n = 4955), its use did not significantly impact the bleeding rates between ticagrelor and clopidogrel.

In PLATO, investigators evaluated additional safety endpoints including bradycardia, ventricular pauses, dyspnoea, serum uric acid, and creatinine. The rates of bradycardia, syncope, heart block, and pacemaker insertion were not significantly different between clopidogrel and ticagrelor. On the basis of the results of Holter monitoring, there was a significant increase with ticagrelor in ventricular pauses occurring within the first week after randomization and lasting ≥3 s (3.6 vs. 5.8%; P = 0.01). By 30 days, this difference was no longer significant. The ticagrelor arm experienced a significant increase in the rate of any dyspnoeic event, including events requiring the discontinuation of the study drug. There were also significant increases in serum uric acid and creatinine in patients treated with ticagrelor. These elevations were evident at 1 and 12 months, with differences between the two groups no longer evident at 1 month after the discontinuation of the study drug.

A study was performed comparing the onset and offset of IPA of ticagrelor (using the dose employed in PLATO) and a regimen involving a high loading dose of clopidogrel (600 mg/75 mg/day maintenance).31 Ticagrelor achieved greater IPA (20 µmol/L ADP, final extent) vs. clopidogrel at 0.5, 1, 2, 4, 8, and 24 h after loading and at 6 weeks (P < 0.0001 for all). Furthermore, at 2 h post-loading, a higher proportion of patients in the ticagrelor group achieved ≥50% IPA (98 vs. 31%, P < 0.0001) and ≥70% IPA (90 vs. 16%, P < 0.0001). Ticagrelor was also associated with a faster offset [4–72 h slope (% IPA/hour) −1.04 vs. −0.48, P < 0.0001]. At 24 h after the last dose, the mean IPA was not significantly different between the two groups.

Minimizing bleeding: impact of adjunctive anticoagulation, choice of vascular access, and use of bleeding risk stratification tools

Minimizing bleeding when using GPIs need not be limited to discontinuation of therapy. Rather, an increase in major bleeding is not inevitable with the use of GPIs. Decisions with respect to the dose, type, or regimen of the concomitant anticoagulant as well as vascular access can have an appreciable impact on the incidence of bleeding complications. For example, early trials of GPIs in patients undergoing PCI revealed significant increases in major bleeding when compared with placebo.32 It was soon confirmed through subsequent trials that indeed the non-weight-based dose of UFH used in these trials was fairly excessive and likely responsible for the bleeding rate apparent in the GPI arm.33 Treatment with GPIs utilizing a weight-based dosing of UFH has demonstrated no significant increase in major bleeding complications as compared with placebo, despite a marked improvement in clinical events.

Newer options for anticoagulation may be considered as well. A subanalysis of OASIS-5 indicated that that in patients with ACS treated with a GPI, despite similar clinical outcomes, fondaparinux was associated with significantly lower rates of bleeding than enoxaparin (Figure 4).34

Figure 4

OASIS 5: clinical outcomes and major bleeding in patients who received GP IIb/IIIa inhibitors.

Results from trials such as SYNERGY also suggest the potential influence of inconsistency in therapy on bleeding. In SYNERGY, patients who were switched from enoxaparin to UFH or vice versa experienced higher rates of both GUSTO severe and TIMI major bleeding than either non-crossover patients or the overall study population.35

Moreover, the approach used for vascular access in PCI may also further avert any excess bleeding when using these GPIs. A prospective registry compared a femoral with a transradial approach in 13 399 consecutive patients undergoing PCI and treated with GPIs.36 A significant reduction in in-hospital vascular access complications was observed in those in whom the transradial approach was used (1.5 vs. 0.6%; P = 0.001).

Lastly, determining who is at the greatest risk for haemorrhagic complications may also lessen the likelihood of such events in patients treated with GPIs. This may be achieved through utilization of specific risk stratification tools designed to predict bleeding events in patients with NSTE-ACS. One example is the Can Rapid Risk Stratification of Unstable Angina Patients Suppress Adverse Outcomes with Early Implementation of the ACC/AHA Guidelines (CRUSADE) risk score. This tool has been most recently validated in a Spanish study of 782 patients managed for NSTE-ACS employing contemporary approaches and therapies including antithrombotic therapy and cardiac catherization.37 The CRUSADE score demonstrated adequate calibration and excellent capacity to discriminate bleeding risk in patients treated with or without two or more antithrombotic agents and who did or did not undergo cardiac catheterization. A similar risk score was developed by Mehran et al.38 using the study populations of the ACUITY and HORIZONS-AMI trials. Applying a multi-variable logistic regression model, investigators identified independent predictors of non-CABG-related major bleeding at 30 days, including six baseline predictors and one treatment-related variable (anticoagulant regimen). Comprising these factors, this simple risk score ultimately identified patients at increased risk for non-CABG-related bleeding as well as subsequent 1-year mortality.

Conclusion

Though a regimen of triple antiplatelet therapy including a GPI has been shown to offer significant clinical benefit in patients with NSTE-ACS at an elevated risk of ischaemic complications, there has been a concerted effort towards the development of new oral agents which may be used in combination with aspirin alone. The impetus for such development has been a concern over the safety of triple antiplatelet therapy, particularly with respect to haemorrhagic complications, even though these regimens do not universally increase bleeding rates. While the currently available data on newer and novel agents, specifically prasugrel and ticagrelor, have appeared promising with respect to efficacy, it should be considered that substantial use of GPIs were used in the landmark trials which tested the incremental value of these agents over clopidogrel. The use of triple antiplatelet therapy failed to impact on higher bleeding complications.

In effect, GPIs remain the gold standard for prevention of ischaemic events during and before PCI, even in the era of potent oral antiplatelet therapies.

Funding

Supported by an unrestricted grant from Iroko Cardio, LLC.

Conflict of interest: M.V. has received speaking honoraria and research grants from Lilly and Iroko.

References

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