Inhibitors in Non ST-Segment Elevation Acute Coronary Syndrome Clinically Justified?

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1 Controversies in Cardiovascular Medicine Is Pretreatment With P2Y 12 Inhibitors in Non ST-Segment Elevation Acute Coronary Syndrome Clinically Justified? Pretreatment With P2Y 12 Inhibitors in Non ST-Segment Elevation Acute Coronary Syndrome Is Clinically Justified Marco Valgimigli, MD, PhD, FESC My advice is to never do tomorrow what you can do today. Procrastination is the thief of time. 1 Charles Dickens ( ) The modulation of the P2Y 12 receptor, carried out in the late 1990s with ticlopidine in patients with recent transient or focal cerebral or retinal ischemia 2 or with clopidogrel in patients with recent ischemic stroke, myocardial infarction (MI), or symptomatic peripheral arterial disease 3 resulted in a significant reduction in ischemic fatal or nonfatal end points compared with aspirin monotherapy. Response by Collet et al on p 1903 P2Y 12 inhibitors have subsequently become the reference therapy in addition to aspirin for the prevention of acute and subacute stent thrombosis in patients undergoing coronary stent-based intervention. This dual-pathway antiplatelet therapy was shown to be more effective than aspirin alone and more effective and safer than aspirin and vitamin K antagonists. 4 6 In this context, the achievement of more potent and consistent inhibition of the target receptor through prasugrel 7 or ticagrelor 8 has resulted in further improvements of the ischemic outcomes. Finally, clopidogrel 9 and ticagrelor, 8 but not prasugrel, 7,10 have been shown to provide additional ischemic benefit on top of aspirin in patients with acute coronary syndromes, regardless of the final revascularization strategy. In light of the multiple chemical and pharmacological differences existing between the 3 currently available oral P2Y 12 inhibitors, including potency, 11 consistency and reversibility of the P2Y 12 inhibition, 12 binding site in the target receptor, and off-target effects, 13,14 caution should be used in interpreting the value of these compounds as class effects. This concern is further corroborated by apparent discrepancies in study results noted throughout head-to-head comparisons. 7,8 Because the clinical value of antithrombotic relies largely on the balance between ischemic benefit and bleeding risk in a given patient population, the results of each individual study cannot be extrapolated to different clinical contexts, nor it should be assumed that the net clinical benefit observed for specific P2Y 12 inhibitor can be directly transferred to other P2Y 12 inhibitors. Hence, the value and risks of pretreatment with P2Y 12 inhibitors cannot be regarded as a class effect, and drug-specific net clinical benefit needs to be interpreted in the context in which it was generated within clinical studies. Moving P2Y 12 Inhibition Upstream: The Inception of Pretreatment The Clopidogrel in Unstable Angina to Prevent Recurrent Ischemic Events (CURE) study tested the effect of upstream clopidogrel administration in patients with non STsegment elevation acute coronary syndrome (NSTE-ACS) The opinions expressed in this article are not necessarily those of the editors or of the American Heart Association. From the Thoraxcenter, Erasmus Medical Center, Rotterdam, The Netherlands. This article is Part I of a 2-part article. Part II appears on p Correspondence to Marco Valgimigli, MD, PhD, FESC, Thoraxcenter, Ba 587, Erasmus MC, Rotterdam, The Netherlands. m.valgimigli@erasmusmc.nl (Circulation. 2014;130: ) 2014 American Heart Association, Inc. Circulation is available at DOI: /CIRCULATIONAHA

2 1892 Circulation November 18, 2014 who were hospitalized within 24 hours after the onset of symptoms. 9 A loading dose of clopidogrel (300 mg) or placebo was administered immediately, followed by clopidogrel (75 mg/d) or placebo for 3 to 12 months (mean treatment duration, 9 months). Before CURE, clopidogrel or ticlopidine was administered at the end of percutaneous coronary intervention (PCI) if a stent was inserted. 4 6 The goal was uniquely to prevent stent thrombosis. 4 6 The CURE study showed that upstream clopidogrel administration mitigated the risk of ischemic nonfatal complications, including decreasing the rate of MI both before and after PCI in patients who received this intervention. Overall, 582 patients (9.3%) in the clopidogrel group experienced a primary outcome, consisting of death resulting from cardiovascular causes, nonfatal MI, or stroke, compared with 719 (11.4%) in the placebo group (relative risk [RR], 0.80; 95% confidence interval [CI], ). 9 From randomization to 30 days, 343 patients (5.4%) developed cardiovascular death, MI, or stroke in the placebo group compared with 270 (4.3%) in the clopidogrel group (RR, 0.79, 95% CI, ; P<0.004). Additionally, there were reductions in in-hospital refractory ischemia (8.7% versus 9.3%), recurrent angina (20.9% versus 22.9%), and heart failure (3.7% versus 4.4%). 9 The effect of early clopidogrel administration was consistent across subgroups, with no signal of interaction across the final management strategy, including medical therapy, PCI, or coronary artery bypass graft surgery (CABG). 9 Starting a P2Y 12 inhibitor upfront carries a hypothetical risk of overtreatment in patients in whom the diagnosis is uncertain. It may be perceived that waiting until the coronary anatomy is known may allow the identification of a more selected patient population with confirmed disease. Importantly, however, the diagnosis of ACS should not be based on findings at angiogram. The absence of lumen obstruction at coronary angiography should not rule out the diagnosis because, in the presence of positive vessel remodeling, plaque rupture or erosion is frequently overlooked at coronary angiography, which is also A B C Figure 1. A, Effects of clopidogrel compared with placebo within the first week of randomization in the Clopidogrel in Unstable Angina to Prevent Recurrent Ischemic Events (CURE) study. B, Effects of clopidogrel compared with placebo in the first 24 hours after randomization in the CURE study. C, Cardiovascular (CV) death, myocardial infarction (MI), stroke, or severe ischemia (SI) within first 24 hours after randomization. CVA indicates cerebrovascular accident; GUSTO, Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries; NNTB, number needed to treat for benefit; NNTH, number needed to treat for harm; RI, regional ischemia; RR, relative risk; and TIMI, Thrombolysis in Myocardial Infarction.

3 Valgimigli Pretreatment in NSTE-ACS 1893 known to be an insensitive tool for the detection of coronary thrombus. 15 Further subdivision of the data indicated a consistent early benefit within the first 7 days (Figure 1A). Detailed examination of the data during the first 24 hours after randomization (Figure 1B) indicated a 20% RR reduction in the primary outcome and a 34% RR reduction in the expanded composite, which included refractory ischemia. 9 The latter difference was statistically significant (P<0.003) even within this relatively brief period (Figure 1C). Even when the potential risks in terms of bleeding complications were appraised, the benefit of early clopidogrel administration outweighed the risks at 24 hours or 7 days after randomization (Figure 1A and 1B). Effect of Previous Clopidogrel Administration in NSTE-ACS Patients Undergoing CABG Of the patients recruited in CURE, 2072 underwent CABG. 16 The median time from randomization to CABG was 25.5 days. The time to CABG for those undergoing the procedure during the initial hospitalization was 12 days. The primary outcome occurred in 16.2% of placebo-treated and 14.5% of clopidogrel-treated patients undergoing CABG. For those undergoing surgical revascularization during hospitalization, 16.4% of the placebo-treated and 13.4% of the clopidogrel-treated patients experienced cardiovascular death, MI, or stroke. 16 These findings are consistent with the treatment effect observed in the entire CURE trial. 16 Among patients undergoing CABG, benefits were observed mainly before the procedure; 71 patients in the placebo group (6.7%) experienced a primary end point compared with 57 in the clopidogrel group (5.6%; RR, 0.82; 95% CI, ). 9,16 For patients proceeding to CABG during hospitalization, the effect of pretreatment tended to be even greater (4.7% for placebo and 2.9% for clopidogrel patients). 16 These findings suggest a marked benefit of early clopidogrel administration in patients with more advanced and unstable coronary artery disease requiring surgical revascularization within the index hospitalization. 16 Of patients who underwent CABG, 80 placebo (7.5%) and 97 clopidogrel (9.6%) patients experienced major bleeding (RR, 1.27; 95% CI, ; P=0.095). Of these, 60 placebo (5.7%) and 71 clopidogrel (7.0%) patients fulfilled the CURE criteria for life-threatening bleeding (RR, 1.24; 95% CI, ; P=0.20). 16 An absolute excess of 2.8% more patients (n=10) experienced life-threatening bleeding within 7 days after CABG surgery among those who continued the study drug 5 days before CABG. However, there were no excess (2 fewer) lifethreatening bleeds for those stopping the study drug >5 days before CABG. 16 Considering life-threatening or non lifethreatening major bleeds, 24 of 454 placebo-treated patients (5.3%) and 20 of 456 clopidogrel-treated patients (4.4%) experienced such events (RR, 0.83; 95% CI, ). When the Thrombolysis in Myocardial Infarction (TIMI) criteria for major bleeding (within 7 days) were applied, 25 placebo (2.4%) and 22 clopidogrel (2.2%) patients fulfilled the criteria (RR, 0.90; 95% CI, ), a trend for a risk reduction. 16 Risks and benefits overall may be considered by combining the primary end point and life-threatening or major bleeding. In patients undergoing CABG at any time point after randomization, the corresponding numbers were 19.7% in the placebo versus 19.3% in the clopidogrel group. 16 Hence, the findings of the CURE trial suggest benefit toward reduction of nonfatal ischemic end points in patients who underwent CABG, especially those undergoing surgery within hospitalization, in whom the composite ischemic end point was almost halved before intervention. There was an increase in bleeding events in the surgical group in clopidogrel-treated patients, which overall did not outweigh the ischemic benefit and was confined to patients who underwent surgery within 5 days after stopping the treatment. The applicability of study results to contemporary practice most likely reflects the logistics of each institution, including the availability of a surgical facility on site, time to catheterization, and average time delay from catheterization to surgical treatment, as well as the overall proportion of patients with NSTE-ACS who are referred for surgical revascularization compared with medical therapy and PCI. Because surgical revascularization is confined to a minority of patients with NSTE-ACS, especially during index hospitalization, 17 avoiding pretreatment in all NSTE-ACS patients on the basis of the concern for bleeding in those undergoing CABG is poorly justifiable. First, the excess of bleeding is confined to those undergoing surgery within 5 days after stopping therapy, and even considering those, the net clinical benefit remains in favor of pretreatment. 16 Second, omitting pretreatment to all patients because of concern for bleeding in the surgical group would also deprive the benefit of pretreatment to the vast majority of patients undergoing medical therapy and PCI, in whom the benefit largely outweighs the risks. Finally, the contemporary availability of ticagrelor, with its fast offset of action, makes pretreatment less problematic in patients undergoing surgery, as discussed below. Effect of Previous Clopidogrel Administration in NSTE-ACS Patients Undergoing PCI Overall, 2658 patients in the CURE trial underwent PCI. 18 A total of 1730 PCIs were done during the initial hospitalization and 928 after discharge. During the initial hospital stay, the median number of days before PCI was 6 days in both groups and 10 days overall. 18 Given the design of the CURE study, which allowed open-label P2Y 12 inhibition in all patients undergoing PCI, regardless of the randomization scheme, the PCI population offers the unique opportunity to tease out the effect of pretreatment from that of continuing the treatment after stent implantation. Indeed, about a quarter of patients in each group received open-label thienopyridines before PCI, and >80% received them after PCI for a median of 30 days (interquartile range, days). 18 Before PCI, significantly fewer patients on clopidogrel than

4 1894 Circulation November 18, 2014 Figure 2. A, Cumulative hazard rates of cardiovascular (CV) death, myocardial infarction (MI), and urgent target vessel revascularization in stented patients who did not receive open-label thienopyridine before percutaneous coronary intervention (PCI). All patients received openlabel thienopyridine after PCI for a median of 30 days. B, Cumulative hazard rates (Kaplan Meier plot) for CV death/nonfatal MI from randomization (rand) to the end of follow-up by timing of PCI. Clopidogrel was associated with a consistently lower incidence of CV death/nonfatal infarction in all 3 patients groups. Benefit was greater in those undergoing PCI <48 hours after randomization. PCI indicates percutaneous coronary intervention; and RR, relative risk. on placebo had an MI or the composite of MI or refractory ischemia. 18 Significantly fewer patients in the clopidogrel group than in the placebo group had a primary outcome of cardiovascular death, MI, or urgent revascularization by 30 days after PCI. 18 The composite of cardiovascular death or MI was also lower in the clopidogrel group. Remarkably, the risk of Q-wave MI was reduced by as much as 65% in the clopidogrel group (2.4% versus 0.8%; RR, 0.35; 95% CI, ), suggesting that only 63 patients would need to be treated upstream with clopidogrel to avoid this event. An appraisal of the potential risks of early clopidogrel administration in this patient population showed no difference in major or minor bleeding between the groups at 30 days and an identical need for transfusion at 1.1%. 18 Authors have disclosed the 30-day results of the study of patients who underwent stenting during hospitalization and thus received open-label thienopyridine for a median of 30 days after PCI (Figure 2A). 19 As shown, in the 30 days after PCI, when treatment between the 2 groups was virtually identical, the events curves continued to separate, which implies that this divergence was indeed attributable to the effects of pretreatment. Although one may question the relatively long duration of clopidogrel pretreatment in the PCI CURE trial and thus the generalizability of this finding to contemporary practice, the benefit of upstream P2Y 12 inhibition was shown to be consistent regardless of delay to PCI. Mortality alone was low in all subgroups and not altered by administration of clopidogrel. On the other hand, the incidence of MI was low in patients randomized to clopidogrel, particularly in the pre-pci Figure 3. Relationship between the duration of clopidogrel treatment before percutaneous coronary intervention and log odds of the primary end point of death, myocardial infarction (MI), and urgent target vessel revascularization (UTVR) in the Clopidogrel for the Reduction of Events During Observation (CREDO) Trial. Dotted line indicates placebo; and solid line, clopidogrel.

5 Valgimigli Pretreatment in NSTE-ACS 1895 period and particularly in patients undergoing early (0.6% versus 2.1%) or in-hospital (2.0% versus 4.0%) intervention 20 (Figure 2B). Thus, the analysis of timing does not support the interpretation that the positive results of PCI CURE were artificially driven by a long delay to PCI and an extensive duration of pretreatment. 20 The Clopidogrel for the Reduction of Events During Observation (CREDO) trial recruited 2116 patients undergoing planned PCI or at high likelihood to undergo PCI and randomly assigned them to receive a 300-mg clopidogrel loading dose or matching placebo 3 to 24 hours before the procedure. 21 Immediately after PCI, both groups received 75 mg clopidogrel through day 28. Despite fewer events being noted for each component of the primary end point, consisting of death, MI, or urgent target vessel revascularization, in the clopidogrel group, a nonsignificant 18.5% relative reduction was observed at 28 days in the experimental arm (6.8% versus 8.3%). 21 An interaction was noted for the duration of pretreatment. In a prespecified analysis of patients in whom therapy was initiated at least 6 hours before PCI, those randomized to clopidogrel experienced a 38.6% (95% CI, 1.6% to 62.9%; P=0.051) RR reduction in the primary end point. Linear splines were subsequently used to summarize the effect of the time of pretreatment as a continuous variable 22 (Figure 3). For patients randomized to placebo, there was no relationship between the duration of pretreatment and the occurrence of the primary end point, whereas longer durations of pretreatment in patients randomized to clopidogrel were associated with improved outcomes 22 (Figure 3). The difference in outcomes between placebo- and clopidogrel-pretreated patients started to diverge after 10 hours of pretreatment duration, with a 58.8% (P=0.028) reduction in the primary end point in patients pretreated with clopidogrel 15 hours compared with those treated with placebo. 22 Major nonprocedural bleeding at 28 days was low and did not differ in the 2 groups, whereas there was a numerically but not statistically significant increase in procedural bleedings in the clopidogrel arm (4.7% versus 3.3%; P=0.11). 22 Few other studies with relatively small sample size, focusing largely on stable coronary disease patients, further randomized patients to receive clopidogrel upstream or at the time of PCI. 23 A recent systematic review of the literature identified 15 articles: 6 randomized, controlled trials; 2 observational analyses of randomized, controlled trials; and 7 observational studies. 24 It was shown that clopidogrel pretreatment was associated with a lower risk of major cardiac events (9.83% versus 12.35%; odds ratio, 0.77; P<0.001). 24 There was no significant association between pretreatment and major bleeding overall (3.57% versus 3.08%; odds ratio, 1.18; P=0.18). 23 Similarly, there was a nonsignificant 20% risk reduction of death (absolute risk, 1.54% versus 1.97%; odds ratio, 0.80; P=0.17). 24 An analysis stratified on the basis of clinical presentation, including stable coronary artery disease, NSTE-ACS, and ST-segment elevation MI (STEMI), showed a clear signal for interaction between clopidogrel pretreatment and mortality (interaction P=0.02) or for major cardiac events (interaction P=0.08), implying that the benefit of upstream P2Y 12 administration may be greater in patients presenting unstable/thrombotic coronary lesion 24 (Figure 4). No such an interaction was noted for major bleeding events. This meta-analysis has been interpreted as proof for a lack of benefit for clopidogrel pretreatment based on the absence of a clear mortality benefit compared with clopidogrel Figure 4. Clinical presentation and subgroup analysis of the patients included in the meta-analysis. NSTE ACS indicates Non ST-Segment Elevation Acute Coronary Syndrome; PCI, percutaneous coronary intervention; and STEMI, ST-segment elevation MI.

6 1896 Circulation November 18, 2014 downstream administration. 24 The reasons why this appears to be an invalid criticism are as follows: First, clopidogrel has never been shown in contemporary practice to improve mortality even compared with placebo. Second, this pooled analysis included multiple studies focusing on patients with stable coronary artery disease in whom fatal events are extremely rare and thus unlikely to be further reduced by concomitant medications. Third, the difference in timing of clopidogrel administration included only a few hours or minutes in some of the included studies. Unraveling the Evidence for Prasugrel as a Pretreatment Option in NSTE- ACS: From TRITON to ACCOAST Current evidence does not support the upstream use of prasugrel in patients with NSTE-ACS. In the Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition With Prasugrel (TRITON)-TIMI 38, NSTE-ACS patients were eligible only if coronary angiography supported the indication to proceed to PCI. 7 Moreover, patients previously exposed to clopidogrel were excluded. 7 Pretreatment with 300 mg clopidogrel was allowed only in patients with STEMI undergoing primary PCI, but this treatment strategy was not allowed for patients with STEMI undergoing delayed (ie, >12 hours) intervention. 7 Hence, only a minority of patients (18% of the overall patient population) were exposed to P2Y 12 inhibitors before coronary angiography. 7 A Comparison of Prasugrel at PCI or Time of Diagnosis in Patients With Non-ST Elevation Myocardial Infarction (ACCOAST) trial enrolled 4033 patients with non-stemi who were scheduled to undergo coronary angiography within 2 to 48 hours after randomization. 25 Patients were randomly assigned to receive prasugrel (a 30-mg loading dose) before the angiography or placebo. When PCI was indicated, an additional 30 mg prasugrel was given in the pretreatment group at the time of PCI, and 60 mg prasugrel was given in the control group. The rate of the primary efficacy end point, a composite of death resulting from a cardiovascular causes, MI, stroke, urgent revascularization, or glycoprotein IIb/IIIa inhibitor through day 7, did not differ significantly between the 2 groups (hazard ratio with pretreatment, 1.02; 95% CI, ; P=0.81). 25 The rate of the key safety end point of TIMI major bleeding episodes, whether related or not related to CABG, through day 7 was increased with pretreatment (hazard ratio, 1.90; 95% CI, ; P=0.006). 25 The rates of TIMI major bleeding and life-threatening bleeding not related to CABG were increased by factors of 3 and 6, respectively. Pretreatment did not reduce the rate of the primary outcome even among patients undergoing PCI (69% of the patients) but increased the rate of TIMI major bleeding at 7 days. 25 The results of the ACCOAST trial are being tentatively interpreted as demonstration that the upstream administration of any P2Y 12 inhibitor is not beneficial and may result in an unfavorable safety profile. Yet, when these study findings are applied to clinical practice, it is of paramount importance to critically examine some key features of the ACCOAST trial. Moreover, the distinctive pharmacokinetic/pharmacodynamics profile of prasugrel questions the transferability of study results to other P2Y 12 inhibitors. 12,26 Safety of Prasugrel Pretreatment in the ACCOAST Study The key safety end point of the study, consisting of CABG- or non CABG-related TIMI major bleeding, showed an excess of 25 bleeding events in the pretreatment group, with a number needed to treat for harm in the range of In the pretreatment group, patients undergoing CABG contributed similarly to the excess of bleeding complications compared with those undergoing PCI (ie, roughly each of these 2 subgroups added 40% of all extra bleeding events), whereas the remaining 20% of extra bleeding events were observed in medically treated patients. 25 As expected, almost all extra bleeding events in the pretreatment group were CABG- and non CABG-related in the CABG and non-cabg groups (ie, PCI plus medically managed patients), respectively. 25 It is reasonable to speculate that a pretreatment strategy based on clopidogrel or ticagrelor administration may have dramatically reduced the bleeding hazard of pretreatment in the surgical cohort. In TRITON- TIMI 38, patients undergoing CABG in the prasugrel group showed an almost 5-fold increase in CABG-related bleeding compared with clopidogrel-treated patients (13.4% versus 3.2%; hazard ratio, 4.73; 95% CI, ; P<0.001). 7 On the other hand, the risk of TIMI-defined CABG bleeding was not increased in the ticagrelor compared with the clopidogrel group in Platelet Inhibition and Patient Outcomes (PLATO; 5.3% versus 5.8%, hazard ratio, 0.94; 95% CI, ; P=0.32). 8 The differential safety profiles of P2Y 12 inhibitors observed in head-to-head studies among patients undergoing CABG may be explained by the lower potency in terms of platelet inhibition of clopidogrel versus prasugrel and by the quicker offset of action of ticagrelor, a reversible P2Y 12 inhibitor, as opposed to prasugrel, an irreversible P2Y 12 inhibitor. 12,26 Unlike clopidogrel and ticagrelor, prasugrel is not indicated for the treatment of medically managed patients, which is justified by their exclusion from the TIMI 38 study and by the null findings provided in the Targeted Platelet Inhibition to Clarify the Optimal Strategy to Medically Manage Acute Coronary Syndromes (TRILOGY). 7,10 Hence, in the medically managed cohort of the ACCOAST study, which made up a quarter of the overall patient population (n=1014), pretreatment with prasugrel was compared with no protocol-mandated P2Y 12 inhibition. 25 This may have additionally skewed the safety results in disfavor of pretreatment with prasugrel. Moreover, because prasugrel therapy remains off-label outside the PCI cohort of ACS patients, liberal administration of this drug even in patients who will not finally undergo PCI triggers ethical considerations in terms of excessive bleeding risks that are currently not justified by clear ischemic benefit. Although the ACCOAST study was designed well before the results of TRILOGY became available, the null outcome

7 Valgimigli Pretreatment in NSTE-ACS 1897 of the latter study also contributes to endangering the conceptual value of pretreatment with prasugrel beyond the negative results of the former investigation. It is interesting to note that although patients with previous stroke or transient ischemic attack were formally excluded from inclusion, patients with advanced age (ie, 75 years) or low body weight (ie, <60 kg) were not excluded, making up 23% of the overall patient population. 25 Consistent with the results of TIMI 38, this relatively limited patient population contributed substantially to the bleeding hazard noted in the pretreatment group in that 13 of 25 overall extra bleeding events (ie, 52%) in the pretreatment compared with the nopretreatment group were noted in patients fulfilling at least 1 of these criteria. 25 When the role of access site is finally considered in the safety profile of pretreatment with prasugrel, transradial intervention failed to affect the bleeding hazard compared with transfemoral access (interaction P=0.66). 25 Indeed, in the pretreatment group, the absolute excess of bleeding complications was numerically greater even in patients undergoing transradial (n=14) as opposed transfemoral (n=11) access. 25 Yet, the risk of non-cabg major bleeding was rather low in transradially treated patients in both study groups (6 versus 2 patients, corresponding to a proportion of 0.69% versus 0.24%), with an absolute difference in bleeding in the range of 0.5%, leading to a number needed to treat for harm of On the other hand, in patients undergoing transfemoral access, non-cabg bleeding events were noted in 20 patients (1.75%) in the pretreatment group as opposed to 7 (0.62%) in the nopretreatment group, with an absolute difference in the range of 1.1% and a corresponding number needed to treat for harm of Vascular access site bleeding apparently explained only 7 of 18 overall extra non-cabg bleeding complications in the pretreatment group. 25 On the other hand, it should be noted that retroperitoneal hemorrhages were included in the socalled other category, which itself contributed to as many as 8 extra bleeding complications noted in the experimental study arm. Although it remains unclear how many of these so-called other bleeding events were attributable to retroperitoneal hemorrhages, vascular bleeding events at the site of arterial puncture were most likely the most frequent type of adverse events in the non-cabg category, disfavoring pretreatment. In summary, the ACCOAST study shows that the bleeding hazard noted with prasugrel pretreatment is the result of more CABG-related bleeding, especially in the radial group, and higher vascular access site related events, especially the transfemoral group. The fact that CABG bleeding events in the radial group were numerically higher than in the femoral group most likely reflects a chance finding because it has no plausible biological explanation. Hence, the association of ticagrelor, which does not increase CABG-related bleeding compared with clopidogrel, 8 and radial intervention, which reduces vascular access site compared with transfemoral access site, 27,28 appears to be a reasonable treatment strategy to optimize benefit versus risks of pretreatment. Efficacy of Prasugrel Pretreatment in the ACCOAST Study The lack of efficacy of pretreatment with prasugrel noted in the ACCOAST trial has been the most unexpected finding of the trial. The rate of the primary efficacy end point, a composite of death resulting from cardiovascular causes, MI, stroke, urgent revascularization, or glycoprotein IIb/IIIa inhibitor rescue therapy (glycoprotein IIb/IIIa bailout) through day 7, did not differ significantly between the 2 groups (hazard ratio with pretreatment, 1.02; 95% CI, ; P=0.81). In an examination of the effect of prasugrel pretreatment on cardiovascular mortality or stroke rates, there was no signal of harm, with crude event rates numerically favoring this treatment option. 25 On the other hand, the risk of MI was slightly higher in the pretreatment group, albeit not significantly, which drove the neutral results of the trial. 25 Hence, the ACCOAST study failed to show that prasugrel pretreatment reduced the risk of MI, which was most likely the end point expected to drive superiority of the tested treatment strategy. A key question for the correct interpretation of study results is whether the lack of treatment benefit observed here with prasugrel reflects a true finding. There are some important methodological considerations that should be factored in before assuming prasugrel pretreatment to be completely ineffective in reducing periprocedural ischemic events. Patients were eligible for the study if their troponin level was at least 1.5 higher the upper limit of normal (qualifying MI). 25 MIs included as primary efficacy end points had to be distinct from the qualifying MI event. The definition of MI was based on the Joint European Society of Cardiology/ American College of Cardiology Foundation/American Heart Association/World Health Federation Task Force for the Redefinition of Myocardial Infarction criteria. 29 Yet, troponin was not the preferred biomarker to diagnose MI because of its slow kinetics and the expected short delay from qualifying MI (troponin-positive subjects) to PCI. An MI in the study was defined as creatine kinase-mb or total creatine kinase >3 times the upper limit of normal within 48 hours after PCI. If the pre-pci creatine kinase-mb or total creatine kinase level was higher than the upper limit of normal, there also needed to be either the demonstration of a falling creatine kinase-mb or total creatine kinase level before the onset of the suspected event or a subsequent at least 20% peak of the cardiac biomarker. Importantly, this definition of MI was based on an expected median delay from randomization to PCI of 12 hours, as clearly stated in the study protocol. 25 Actually, PCI was performed at a median time of 4.3 hours after the initial loading dose. 25 This means that the duration of pretreatment and the time for biomarkers to be washed out after the index MI, thus

8 1898 Circulation November 18, 2014 A B Figure 5. A hypothetical patient experiencing a myocardial infarction and subsequently being recruited in a study testing the value of a drug given at the time of percutaneous coronary intervention (PCI; A) or testing the value of the same drug given early after hospital admission (B). Gray bars denote the time and value of biomarker assessment over time. R indicates randomization; and Sx, symptom onset. creating of a window of opportunity to detect a second ischemic insult, were 3-fold shorter than expected. It is difficult to justify clinically why such a rapid invasive management was offered to patients in the study, considering that roughly 20% of patients only presented a Global Registry of Acute Coronary Events (GRACE) score of at least 140. Registry data show that time from hospital admission and catheterization varies greatly in current practice. 30 Hence, the benefit of pretreatment may have been largely underestimated in the ACCOAST trial, in which an almost immediate invasive approach was implemented regardless of baseline risk status. The Timing of Intervention in Acute Coronary Syndrome (TIMACS) trial randomized NSTE-ACS patients to undergo either routine early intervention (coronary angiography 24 hours after randomization) or delayed intervention (coronary angiography 36 hours after randomization). 31 Coronary angiography was performed in the early intervention group after a median time after randomization of 14 hours. 31 There was no significant benefit in favor of the early intervention group. 31 In a post hoc analysis, patients with high GRACE score (>140) showed a significant 35% risk reduction of the primary end point, whereas in patients with a lower GRACE score, no benefit was observed, with a nonsignificant 12% risk increase disfavoring the early intervention group (P for interaction=0.01). 31 The different timing of randomization with respect to symptom onset and coronary intervention may explain the lack of MI benefit of prasugrel pretreatment in the ACCOAST study and may potentially clarify some apparently discrepant findings reported in TIMI 38 and PLATO. In TIMI 38, NSTE-ACS patients were eligible to randomization only after angiography, once the decision to proceed to PCI was made, which occurred at least 24 hours after symptom onset in 5976 patients (60.2%). 7 Hence, delayed randomization in this study allowed more time for cardiac enzymes to decline after the index MI while enhancing the discriminatory capacity to detect a new rise in biomarkers during or after postrandomization coronary intervention. Interestingly, in TIMI 38, the beneficial effect of the more potent P2Y 12 inhibitor, that is, prasugrel, in preventing ischemic events emerged immediately after randomization. In PLATO, which endorsed study drug administration as early as possible and well before coronary angiography, that is, similar to ACCOAST, patients were exposed to study drug early after hospital admission, which occurred >20 hours after symptom onset in less than a quarter of patients only. 8 In PLATO and in ACCOAST, at variance with TRITON, the more potent P2Y 12 failed to provide instantaneous benefit. This may reflect the issue of identifying a new biomarker rise in the context of an ongoing or recent MI. Figure 5 illustrates how time from symptom onset to randomization and PCI can play a key role in determining the capability of the study to discern the index from a postrandomization MI event. Hence, the appraisal of the treatment delay from the onset of symptoms to drug exposure and subsequent PCI should be taken into great account when assessing the potential value of a given treatment strategy on outcomes such as periprocedural MIs that is almost entirely dependent on the kinetics of the biomarkers. Ultimately, a modified definition of MIs in such contexts or the identification of a novel cardiac biomarker with faster kinetic in both the rising and falling phase may be needed in the future to better ascertain the effect of early treatment in patients with recent MI who are managed with an early invasive strategy. From PLATO to Clinical Practice: When Should Ticagrelor Be Started in NSTE-ACS patients? In PLATO, patients were randomly assigned to ticagrelor or clopidogrel as early as possible after the index event, not >24 hours after the event. Hence, ticagrelor was compared with clopidogrel by adopting a study design that closely resembled the design that led to approval for clopidogrel in the CURE study, that is, the initiation of the P2Y 12 inhibitor as soon as

9 Valgimigli Pretreatment in NSTE-ACS 1899 Figure 6. Bleeding stratified by revascularization in the Non ST- Segment Elevation Acute Coronary Syndrome (NSTE-ACS) cohort of the Platelet Inhibition and Patient Outcomes (PLATO) trial. Kaplan Meier estimate of (A) time to major bleeding according to the PLATO criteria from day 10 postrandomization and (B) time to non coronary artery bypass graft (CABG) major bleeding. PCI indicates percutaneous coronary intervention. possible after hospital admission regardless of the final treatment strategy. In the study, patients (72.0%) were specified by the investigator at the time of randomization as planned to be managed with an invasive strategy, which was actually carried out at a median delay of 0.6 hour (interquartile range, hours) after randomization. PCI was performed in individuals (76.8%) and CABG in 782 (5.8%). Median time to PCI was 2.4 hours ( hours) after both randomization and study drug administration in patients with non-stemi, whereas time to CABG was 6 days (3 10 days). The time from onset of symptoms to start of study drug was 15.3 hours ( hours) for those with non ST-segment elevation MI or unstable angina. It may be argued that PLATO cannot prove the clinical usefulness of pretreating patients with ticagrelor, given the lack of a control arm in which the same drug was administered at the time of PCI. Moreover, it should be emphasized that the potent P2Y 12 inhibitor was compared with placebo in ACCOAST and not with clopidogrel in the pretreatment setting such as in PLATO, thus potentially disfavoring the potent P2Y 12 inhibitor in terms of bleeding by study design. Yet, at variance with prasugrel in the ACCOAST study, the chosen strategy of implementing ticagrelor therapy as soon as possible was not shown to increase overall or early (ie, 30 days) non-cabg major bleeding events compared with clopidogrel (Figure 6) while leading at 30 days to a consistent ischemic and mortality benefit. 8 In the NSTE- ACS population of PLATO, CABG bleeding events were even numerically lower in the ticagrelor arm compared with the clopidogrel group, whereas inspection of the distribution of non-cabg bleeding in the 2 study arms over time clearly shows that the event rate was almost identical in the first days after randomization (Figure 6) and that more long-term than early exposure to the potent P2Y 12 inhibitor justified a significant increase in nonprocedural bleeding in the study. 32 Finally, an important finding that at least indirectly supports the value of ticagrelor in the upstream setting is the remarkable mortality advantage observed in the surgical cohort of patients exposed to early ticagrelor compared with early clopidogrel, which in a post hoc analysis was especially evident in patients undergoing early surgery after drug discontinuation. 33,34 In summary, the use of ticagrelor in clinical practice should not deviate from the way the drug has been tested in clinical trials and subsequently approved for clinical use. Failure in clinical practice to comply with the existing evidence would create hazardous uncertainty about the efficacy and safety profile of the treatment. When Should a P2Y 12 Inhibitor Be Started According to the American College of Cardiology Foundation/ American Heart Association and European Society of Cardiology Guidelines? The Table summarizes the 3 most recent sets of recommendations from the American College of Cardiology Foundation/ American Heart Association and European Society of Cardiology for the use of P2Y 12 inhibitors in NSTE-ACS. The American guidelines have remained remarkably consistent, endorsing with a Class I recommendation the upstream use of a P2Y 12 inhibitor (clopidogrel in 2007, 35 ticagrelor or clopidogrel in and ). A dual antiplatelet therapy strategy has been advocated as the favorite upstream therapy in patients with NSTE-ACS, regardless of the in-hospital management strategy (ie, routine invasive or conservative). Although aspirin has been regarded as the mainstay antiplatelet therapy, the choice of the second antiplatelet therapy included either 1 P2Y 12 inhibitor among ticagrelor or clopidogrel or 1 of the small-molecule glycoprotein IIb/IIIa inhibitors, tirofiban or eptifibatide. Triple antiplatelet therapy, consisting of aspirin, ticagrelor or clopidogrel, and tirofiban

10 1900 Circulation November 18, 2014 Table. Recommendations From American College of Cardiology/American Heart Association and European Society of Cardiology NSTE-ACS Guidelines on Early Use of P2Y 12 Inhibitors Year of Publication Recommendations on (Pre)Treatment With Oral P2Y 12 Inhibitors American College of Cardiology Foundation/American Heart Association guidelines For UA/NSTEMI patients in whom an initial invasive strategy is selected, antiplatelet therapy in addition to aspirin should be initiated before diagnostic angiography (upstream) with either clopidogrel (loading dose followed by daily maintenance dose) or an intravenous GP IIb/IIIa inhibitor (Class I; LOE A). For UA/NSTEMI patients in whom an initial conservative (ie, noninvasive) strategy is selected, clopidogrel (loading dose followed by daily maintenance dose) should be added to aspirin and anticoagulant therapy as soon as possible after admission and administered for at least 1 mo (Class I; LOE A) and ideally up to 1 y (LOE B). For UA/NSTEMI patients in whom an initial invasive strategy is selected, it is reasonable to initiate antiplatelet therapy with both clopidogrel (loading dose followed by daily maintenance dose) and an intravenous GP IIb/IIIa inhibitor (Class IIa; LOE B) Focused update 36 Patients with definite UA/NSTEMI at medium or high risk and in whom an initial invasive strategy is selected should receive dual antiplatelet therapy on presentation (LOE A). Aspirin should be initiated on presentation (Class I; LOE A) The choice of a second antiplatelet therapy to be added to aspirin on presentation includes 1 of the following: Before PCI: clopidogrel (Class I; LOE B) or an intravenous GP IIb/IIIa inhibitor (Class I; LOE A). Intravenous eptifibatide and tirofiban are the preferred GP IIb/IIIa inhibitors. At the time of PCI: clopidogrel if not started before PCI (Class I; LOE A), prasugrel (Class I; LOE B), or an intravenous GP IIb/IIIa inhibitor (Class I; LOE A). For UA/NSTEMI patients in whom an initial conservative (ie, noninvasive) strategy is selected, clopidogrel (loading dose followed by daily maintenance dose) should be added to aspirin and anticoagulant therapy as soon as possible after admission and administered for at least 1 mo (Class I; LOE A) and ideally up to 1 y (Class I; LOE B). For UA/NSTEMI patients in whom an initial conservative (ie, noninvasive) strategy is selected, clopidogrel (loading dose followed by daily maintenance dose) should be added to aspirin and anticoagulant therapy as soon as possible after admission and administered for at least 1 mo and ideally up to 1 y (Class I; LOE B) Focused update 37 Patients with definite UA/NSTEMI at medium or high risk and in whom an initial invasive strategy is selected should receive dual antiplatelet therapy on presentation (Class I; LOE A). Aspirin should be initiated on presentation (Class I; LOE A). The choice of a second antiplatelet therapy to be added to aspirin on presentation includes 1 of the following (note that there are no data for therapy with 2 concurrent P2Y 12 receptor inhibitors, and this is not recommended in the case of aspirin allergy): Before PCI: clopidogrel (Class I; LOE B), ticagrelor (Class I; LOE B), or an intravenous GP IIb/IIIa inhibitor (Class I; LOE A). Intravenous eptifibatide and tirofiban are the preferred GP IIb/IIIa inhibitors (Class I; LOE B). At the time of PCI: clopidogrel if not started before PCI (Class I; LOE A), prasugrel (Class I; LOE B), ticagrelor (Class I; LOE B), or an intravenous GP IIb/IIIa inhibitor (Class I; LOE A). For UA/NSTEMI patients in whom an initial conservative (ie, noninvasive) strategy is selected, clopidogrel or ticagrelor (loading dose followed by daily maintenance dose) should be added to aspirin and anticoagulant therapy as soon as possible after admission and administered for up to 12 mo (Class I; LOE B). European Society of Cardiology guidelines Clopidogrel should be given to ACS patients scheduled for angiography unless there is a likelihood that the patient will proceed to urgent surgery (within 5 d). Clopidogrel may also be recommended for immediate and long-term therapy in patients who do not tolerate aspirin (CAPRIE) and is recommended in patients receiving a stent (Class I; LOE B) Pretreatment of unselected patients with clopidogrel before angiography results in better outcome of PCI. The approach of postponing clopidogrel administration until coronary anatomy in patients submitted to very early invasive angiography is not based on evidence. The potential advantage of this approach is to avoid increased bleeding risk in patients requiring immediate surgery. However, this situation is rare, and surgery frequently can be deferred for a few days. Therefore, postponing clopidogrel until after angiography cannot be recommended because the highest rates of events are observed in the early phase of NSTE-ACS. In patients who cannot be given clopidogrel before PCI, GP IIb/IIIa inhibitors should be administered A P2Y 12 inhibitor should be added to aspirin as soon as possible and maintained over 12 mo, unless there are contraindication such as excessive risk of bleeding (Class I; LOE A). Ticagrelor (180-mg loading dose, 90 mg twice daily) is recommended for all patients at moderate to high risk of ischemic events (eg, elevated troponins), regardless of initial treatment strategy and including those pretreated with clopidogrel (which should be discontinued when ticagrelor is begun; Class I; LOE B). Prasugrel (60-mg loading dose, 10-mg daily dose) is recommended for P2Y 12 inhibitor naïve patients (especially diabetics) in whom the coronary anatomy is known and who are proceeding to PCI unless there is a high risk of life-threatening bleeding or other contraindications (Class I; LOE B). ACS indicates acute coronary syndrome; CAPRIE, Clopidogrel Versus Aspirin in Patients at Risk of Ischaemic Events; GP glycoprotein; LOE, level of evidence; NSTE- ACS, non ST-segment elevation acute coronary syndrome; NSTEMI, non ST-segment elevation myocardial infarction; PCI, percutaneous coronary intervention; and UA, unstable angina.

11 Valgimigli Pretreatment in NSTE-ACS 1901 or eptifibatide, has also been contemplated with a Class IIa recommendation. The 2002 European Society of Cardiology guidelines advocated the use of early clopidogrel in NSTE- ACS patients but cautioned against its use in patients at high likelihood of undergoing CABG. 38 The 2007 guidelines, likely reflecting the 2004 CABG subanalysis of the CURE study, stated that the approach of postponing clopidogrel administration until coronary anatomy is known in patients submitted to very early invasive angiography is not based on evidence. The potential advantage of this approach is to avoid increased bleeding risk in patients requiring immediate surgery. However, this situation is rare, and frequently surgery can be deferred for a few days. Therefore, postponing clopidogrel to after angiography cannot be recommended, because the highest rates of events are observed in the early phase of NSTE-ACS. 39 Finally, the 2011 European Society of Cardiology guidelines indicated that a P2Y 12 inhibitor, including ticagrelor as first choice or clopidogrel as second choice, should be started in NSTE-ACS patients as soon as possible, regardless of the final treatment strategy. 40 Conclusions There is abundant evidence suggesting that clopidogrel and ticagrelor should be started as soon as possible after hospital admission in NSTE-ACS patients. The value of early implementation of P2Y 12 inhibition in the upstream setting has been derived from the results of the CURE study, which showed consistent ischemic benefit across patient subgroups, including PCI, medical therapy, or surgical revascularization. This benefit was not offset by a bleeding liability, which was largely confined to patients undergoing surgery within 5 days of clopidogrel discontinuation. Ticagrelor has been compared with clopidogrel in the upstream setting in the PLATO study, which showed a reduction in the composite ischemic end point, including overall and cardiac mortality, and no overall increase in any major bleeding events. CABG bleeding complications were numerically lower in the ticagrelor group compared with the clopidogrel group, whereas non-cabg hemorrhages did not disfavor ticagrelor early after randomization, implying that long-term more than early exposure to the drug be potentially responsible for the overall nonprocedural bleeding hazard noted in the study. What remains to be further investigated is the exact timing of ticagrelor administration to optimize net clinical benefit. Considering that ticagrelor has a much quicker onset of action compared with clopidogrel, a shorter pretreatment duration, as indeed tested in PLATO, may be sufficient to minimize ischemic recurrences. At variance with clopidogrel and ticagrelor, prasugrel should be confined to patients undergoing PCI, and this therapy should be implemented only immediately before PCI, on the basis of the ACCOAST study. 25 The consistent bleeding liability noted with prasugrel in patients undergoing CABG 7 and the lack of clear benefit of prasugrel in medically managed patients 10 support this conclusion. The lack of ischemic benefit noted with prasugrel pretreatment in patients undergoing almost immediate invasive management should not bring into question the well-known value of early platelet inhibition in ACS patients or the value of other P2Y 12 inhibitors in this setting. Only studies resolving the complexity of discriminating multiple temporarily connected MI events based on biomarker assessment or other innovative methodology would qualify for unraveling the value of pretreatment in contemporary early invasive strategy based practice. Disclosures Dr Valgimigli has received fees for lecturing from or has served on the advisory board of Abbott Vascular, Alvimedica, AstraZeneca, Correvio, The Medicines Company, Medtronic, and Terumo. References 1. Dickens C. Sketches of Young Men. My Advice is to never do tomorrow what you can do today. Procrastination is the thief of time. Copyright Group; Hass WK, Easton JD, Adams HP Jr, Pryse-Phillips W, Molony BA, Anderson S, Kamm B. A randomized trial comparing ticlopidine hydrochloride with aspirin for the prevention of stroke in high-risk patients: Ticlopidine Aspirin Stroke Study Group. N Engl J Med. 1989;321: CAPRIE Steering Committee. A randomised, blinded, trial of Clopidogrel Versus Aspirin in Patients at Risk of Ischaemic Events (CAPRIE): CAPRIE Steering Committee. Lancet. 1996;348: Bertrand ME, Legrand V, Boland J, Fleck E, Bonnier J, Emmanuelson H, Vrolix M, Missault L, Chierchia S, Casaccia M, Niccoli L, Oto A, White C, Webb-Peploe M, Van Belle E, McFadden EP. Randomized multicenter comparison of conventional anticoagulation versus antiplatelet therapy in unplanned and elective coronary stenting: the Full Anticoagulation Versus Aspirin and Ticlopidine (FANTASTIC) study. Circulation. 1998;98: Leon MB, Baim DS, Popma JJ, Gordon PC, Cutlip DE, Ho KK, Giambartolomei A, Diver DJ, Lasorda DM, Williams DO, Pocock SJ, Kuntz RE. A clinical trial comparing three antithrombotic-drug regimens after coronary-artery stenting: Stent Anticoagulation Restenosis Study Investigators. N Engl J Med. 1998;339: Schömig A, Neumann FJ, Kastrati A, Schühlen H, Blasini R, Hadamitzky M, Walter H, Zitzmann-Roth EM, Richardt G, Alt E, Schmitt C, Ulm K. A randomized comparison of antiplatelet and anticoagulant therapy after the placement of coronary-artery stents. N Engl J Med. 1996;334: Wiviott SD, Braunwald E, McCabe CH, Montalescot G, Ruzyllo W, Gottlieb S, Neumann FJ, Ardissino D, De Servi S, Murphy SA, Riesmeyer J, Weerakkody G, Gibson CM, Antman EM; TRITON-TIMI 38 Investigators. Prasugrel versus clopidogrel in patients with acute coronary syndromes. N Engl J Med. 2007;357: Wallentin L, Becker RC, Budaj A, Cannon CP, Emanuelsson H, Held C, Horrow J, Husted S, James S, Katus H, Mahaffey KW, Scirica BM, Skene A, Steg PG, Storey RF, Harrington RA, Freij A, Thorsén M; PLATO Investigators. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med. 2009;361: Yusuf S, Zhao F, Mehta SR, Chrolavicius S, Tognoni G, Fox KK; Clopidogrel in Unstable Angina to Prevent Recurrent Events Trial Investigators. Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. N Engl J Med. 2001;345: Roe MT, Armstrong PW, Fox KA, White HD, Prabhakaran D, Goodman SG, Cornel JH, Bhatt DL, Clemmensen P, Martinez F, Ardissino D, Nicolau JC, Boden WE, Gurbel PA, Ruzyllo W, Dalby AJ, McGuire DK, Leiva- Pons JL, Parkhomenko A, Gottlieb S, Topacio GO, Hamm C, Pavlides G, Goudev AR, Oto A, Tseng CD, Merkely B, Gasparovic V, Corbalan R, Cinteză M, McLendon RC, Winters KJ, Brown EB, Lokhnygina Y, Aylward PE, Huber K, Hochman JS, Ohman EM; TRILOGY ACS