Pretreatment with P2Y 12 Inhibitors in Non–ST-Segment–Elevation Acute Coronary Syndrome: An Outdated and Harmful Strategy
2014; Lippincott Williams & Wilkins; Volume: 130; Issue: 21 Linguagem: Inglês
10.1161/circulationaha.114.011320
ISSN1524-4539
AutoresJean‐Philippe Collet, Johanne Silvain, Anne Bellemain-Appaix, Gilles Montalescot,
Tópico(s)Acute Myocardial Infarction Research
ResumoHomeCirculationVol. 130, No. 21Pretreatment with P2Y12 Inhibitors in Non–ST-Segment–Elevation Acute Coronary Syndrome: An Outdated and Harmful Strategy Free AccessResearch ArticlePDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessResearch ArticlePDF/EPUBPretreatment with P2Y12 Inhibitors in Non–ST-Segment–Elevation Acute Coronary Syndrome: An Outdated and Harmful Strategy Jean-Philippe Collet, MD, PhD, Johanne Silvain, MD, PhD, Anne Bellemain-Appaix, MD and Gilles Montalescot, MD, PhD Jean-Philippe ColletJean-Philippe Collet From the Institut de Cardiologie, Centre Hospitalier Universitaire Pitié-Salpêtriėre (ACTION Study Group, AP-HP, Université Paris 6), Paris, France (J.-P.C., J.S., and G.M.); and Department of Cardiology, Hospital La Fontonne, Antibes, France (A.B.-A.). , Johanne SilvainJohanne Silvain From the Institut de Cardiologie, Centre Hospitalier Universitaire Pitié-Salpêtriėre (ACTION Study Group, AP-HP, Université Paris 6), Paris, France (J.-P.C., J.S., and G.M.); and Department of Cardiology, Hospital La Fontonne, Antibes, France (A.B.-A.). , Anne Bellemain-AppaixAnne Bellemain-Appaix From the Institut de Cardiologie, Centre Hospitalier Universitaire Pitié-Salpêtriėre (ACTION Study Group, AP-HP, Université Paris 6), Paris, France (J.-P.C., J.S., and G.M.); and Department of Cardiology, Hospital La Fontonne, Antibes, France (A.B.-A.). and Gilles MontalescotGilles Montalescot From the Institut de Cardiologie, Centre Hospitalier Universitaire Pitié-Salpêtriėre (ACTION Study Group, AP-HP, Université Paris 6), Paris, France (J.-P.C., J.S., and G.M.); and Department of Cardiology, Hospital La Fontonne, Antibes, France (A.B.-A.). Originally published18 Nov 2014https://doi.org/10.1161/CIRCULATIONAHA.114.011320Circulation. 2014;130:1904–1914Coronary plaque rupture that occurs during the acute coronary syndrome (ACS) results in the deposition and activation of platelets and the formation of thrombi. The platelet mediators thromboxane A2 and ADP have been demonstrated to play a dominant role in the initiation and propagation of coronary thrombosis, representing key therapeutic targets in the management of ACS. Early inhibition of these biomarkers with oral administration of aspirin and a P2Y12 receptor inhibitor together with anticoagulation has been recommended to avoid complete thrombotic occlusion, which may occur during the initial platelet response to vascular injury when the diagnosis of non–ST-segment–elevation ACS (NSTE-ACS) is made or after percutaneous coronary intervention (PCI). An early invasive strategy of cardiac catheterization and revascularization is recommended in patients in whom the thrombotic burden is the highest. A routine invasive versus selective invasive strategy was shown to reduce the rates of death and myocardial infarction, with the most pronounced difference in these high-risk patients.1 In particular, an early catheterization followed by coronary intervention on the first day of hospitalization was shown to be safe and superior in terms of lower risk of recurrent ACS (−41%) and shorter hospital stay (−28%).2 The strategy of "sooner is better" for catheterization suggests also having the same strategy for antiplatelet strategy, which has remained unproven. Guidelines have recommended early initiation of dual antiplatelet therapy, a combination of aspirin and clopidogrel, as soon as possible when the diagnosis of high-risk NSTE-ACS is made, although the timing of loading remained unclear.3,4 This concept of treatment of NSTE-ACS at the time of presentation or admission is known as pretreatment, a treatment given when the diagnosis is suspected and always before the coronary status is known to confirm the diagnosis of coronary artery disease (CAD) and to make the decisions about revascularization. The slow onset of action of clopidogrel and the proven relation between high on-treatment platelet reactivity and clinical outcome led to the development of the more potent P2Y12 receptor inhibitors prasugrel and ticagrelor.5,6 These second-generation agents were found to be superior to clopidogrel in preventing recurrent ischemic events in ACS patients.7,8 Pooled analysis confirms that these newer P2Y12 inhibitors provide more effective suppression of ischemic events and reduced mortality, with an increase in major bleeding events among patients receiving PCI.9 However, the timing of loading was not tested in these pivotal trials. It remained a matter of debate until the first modern randomized study of systematic early pretreatment was performed in high-risk NSTE-ACS patients, identified by a relevant rise/fall in troponin or dynamic ST/ T-wave changes (symptomatic or silent) or Global Registry of Acute Coronary Events (GRACE) score >140 and undergoing a rapid invasive strategy. Despite providing better inhibition of platelet function at the time of catheterization, pretreatment with prasugrel was associated with no hint of clinical benefit but significant excess of major bleeding.10 These unexpected findings shed a new light on the management of high-risk NSTE-ACS. Concerns have been raised as to whether these data are relevant to our routine practice. Should pretreatment be banned in NSTE-ACS? Is there a true harm of pretreatment, or is it a study design–related finding? Is it a class effect or only drug related?Response by Valgimigli on p 1914Where Is the Concept of Pretreatment Coming From?The concept of pretreatment with P2Y12 receptor blockers is based on the observation that the risk of PCI depends on the intraprocedural level of platelet inhibition. It has been accepted and recommended on the basis of evidence from the results of 3 randomized studies in which death or myocardial infarction was reduced (odds ratio [OR], 0.71; 95% confidence interval [CI], 0.56–0.89).11–13 Of importance, these studies were performed >15 years ago when time to angiogram was much longer than it is now and PCI was even discouraged in some trials.11 This concept was born with the PCI–Clopidogrel in Unstable Angina to Prevent Recurrent Events Trial (PCI-CURE) substudy representing only 20% of the main population in which clopidogrel pretreatment of high-risk NSTE-ACS patients (300-mg loading dose with a median of 10 days before catheterization) was associated with a 30% reduction of the composite end point of cardiovascular death, myocardial infarction, and urgent target vessel revascularization at 30 days without a significant difference in major bleeding.12 It was also tested in the Clopidogrel for the Reduction of Events During Observation (CREDO) trial, a negative study for pretreatment despite the bias that most patients were selected not before but after the angiogram was obtained. The 90% rate of PCI in CREDO does not reflect, of course, the true rate of PCI in stable or stabilized patients scheduled for angiography but reflects the selection bias.14 Randomization in this study does not really address the issue of pretreatment, a treatment given before the coronary status of the patient is known. Despite this bias, the study was negative for preloading, and only post hoc analyses suggested an interaction between the timing of pretreatment and the protection against adverse cardiovascular events in stable patients undergoing scheduled angioplasty (Figure 1).14,15 This does not address the question of pretreatment in a patient presenting with a working diagnosis of NSTE-ACS and no information on the coronary status, which is the real question for the clinician. Finally, in the Clopidogrel as Adjunctive Reperfusion Therapy (CLARITY)–PCI substudy, there was a significant decrease in major coronary events with no increased risk of bleeding in patients undergoing secondary PCI after fibrinolysis associated with clopidogrel pretreatment. However, this ST-segment–elevation myocardial infarction (STEMI) population cannot be compared with the NSTE-ACS population. These benefits on major adverse cardiovascular events have been confirmed in a meta-analysis of these studies, but no significant reduction in mortality or increase in bleeding was observed.16,17Download figureDownload PowerPointFigure 1. Timing and risk of events of loading in the CREDO study.15Since then, administration of clopidogrel before PCI has become the standard of care, and a higher loading dose of 600 mg for PCI for patients with NSTE-ACS has a Class IB recommendation when ticagrelor or prasugrel is not an option.3 This is based on studies that have examined a 300-mg clopidogrel loading dose versus a ≥600-mg clopidogrel loading dose, suggesting that a high dose among patients undergoing PCI was associated with a lower rate of cardiac death or myocardial infarction (OR, 0.54; 95% CI, 0.32–0.90; P=0.02), especially among higher-risk patients.18 This double dose was associated with a significant reduction in cardiovascular death, myocardial infarction, or stroke in the prespecified but not randomized subgroup analysis of patients undergoing PCI (3.9% versus 4.5%; adjusted hazard ratio [HR], 0.86; 95% CI, 0.74–0.99; P=0.039) in the Clopidogrel Optimal Loading Dose Usage to Reduce Recurrent Events/Optimal Antiplatelet Strategy for Interventions (CURRENT-OASIS 7) study.19 Protocol-defined major bleeding was increased with double-dose clopidogrel (1.6% versus 1.1%; adjusted HR, 1.41; 95% CI, 1.09–1.83; P=0.009).20 Higher dose of clopidogrel had a consistent effect in the stratified analysis according to NSTE-ACS versus STEMI (P for interaction=0.817) in the CURRENT-OASIS 7 study, including those undergoing PCI (3.6% versus 4.2%; HR, 0.87; 95% CI, 0.72–1.06; P=0.167), but pretreatment per se was not tested in this mega-trial.20Why Is Pretreatment of NSTE-ACS With Clopidogrel Questionable?Clinical Evidence Is WeakAlthough initiation of P2Y12 receptor inhibitors as soon as possible after the diagnosis of NSTE-ACS (Class IA) or at presentation when a planned invasive strategy is chosen (Class IB) has previously been strongly recommended by the 2011 European Society of Cardiology NSTE-ACS guidelines3 and the 2011 American College of Cardiology Foundation/American Heart Association focused update of the NSTE-ACS guidelines,4 respectively, recent clinical trial evidence directly examining this practice has raised doubts about its effectiveness. First, most of the evidence for pretreatment comes from subgroup analyses of trials not designed to test the pretreatment hypothesis. Second, in these trials, an early invasive management was not the common practice. Third, a comprehensive meta-analysis evaluating the association of clopidogrel pretreatment versus no treatment for mortality and major bleeding among patients undergoing PCI17,21. reported a significant increase in Thrombolysis in Myocardial Infarction (TIMI) major bleeds (OR, 1.28; 95% CI, 1.12–1.46; P=0.0002) and a neutral effect on mortality in NSTE-ACS patients (Figure 2A).12,14,22–26 The significant reduction in major cardiovascular events (OR, 0.81; 95% CI, 0.70–0.94; P=0.006) should be acknowledged. However, this benefit was driven mainly by periprocedural myocardial infarction, a controversial end point. Of importance, similar trends were observed in elective PCI in that 15% to 40% of NSTE-ACS patients were stabilized27–29 (Figure 2B).Download figureDownload PowerPointFigure 2. Meta-analysis of randomized trials of pretreatment in non–ST-segment–elevation acute coronary syndrome (NSTE-ACS)12,14,22,25,26 (A) and in elective percutaneous coronary intervention (PCI), including stabilized NSTE-ACS patients (B).27–29 ARMYDA indicates Antiplatelet Therapy for Reduction of Myocardial Damage During Angioplasty; CI, confidence interval; CREDO, Clopidogrel for the Reduction of Events During Observation; CURE, Clopidogrel in Unstable Angina to Prevent Recurrent Events; MACE, major adverse cardiac events; MI, myocardial infarction; OR, odds ratio; TARGET, Do Tirofiban and ReoPro Give Similar Efficacy Outcome Trial; and Tx, treatment.One may argue that the lack of mortality benefit in this patient subset is a concern. However, the few individual studies addressing pretreatment in NSTE-ACS were not designed to test survival. On the other hand, the meta-analysis was powered for survival and did not show any hint of benefit (Figure 2A and 2B). More important, the low baseline platelet reactivity in these stable patients and the moderate level of inhibition of clopidogrel for both loading and maintenance doses (Figure 3), with a modest absolute difference of 25 in platelet reactivity units in pretreatment versus no pretreatment, outline the limitation of pretreatment with clopidogrel.27Download figureDownload PowerPointFigure 3. Pharmacodynamic profile of platelet inhibition according to pretreatment with 600 mg clopidogrel and 60 mg prasugrel.10,27 LD indicates loading dose.Practical ConcernsThere are other arguments not supportive of a systematic clopidogrel pretreatment in NSTE-ACS patients who are eligible for an early invasive management. First, most of the serious events, in particular death, do not occur in the catheterization laboratory but are delayed by days or weeks when clopidogrel is effective. Second, systematic pretreatment exposes up to one third of elective patients with normal angiograms30 to bleeding risk with therefore no benefit to be expected on survival.31 Third, the likely need for surgical revascularization is difficult to predict,32 and there is evidence for significant increases in major bleeding complications (relative risk, 1.48; 95% CI, 0.72–3.04), reoperation for bleeding (relative risk, 1.88; 95% CI, 1.37–2.58), red blood cell transfusion (relative risk, 1.23; 95% CI, 1.10–1.37), and death (relative risk, 1.33; 95% CI, 1.02–1.67) in observational registries when coronary artery bypass graft surgery is performed in patients on dual antiplatelet therapy compared with withholding therapy.33A flow chart of the management of NSTE-ACS patients in the real world (Figure 4) shows that up to 10% of patients with non-STEMI (NSTEMI), almost 25% of female patients have no significant CAD when angiography is done, and an even greater proportion of patients with unstable angina would be expected not to have CAD.30,34 Compared with STEMI or stable CAD, PCI appears to be a less frequent option in NSTE-ACS patients, further highlighting the need for careful risk stratification. In particular, coronary angiography has a key role in that it helps to identify patients with ACS mediated by mechanisms other than plaque rupture and patients presenting with increased cardiac biomarkers or ST/T changes not related to ACS.35Download figureDownload PowerPointFigure 4. Non–ST-segment–elevation acute coronary syndrome (NSTE-ACS) in the real world of all-comers.30,31,34 CABG indicates coronary artery bypass graft surgery; NSTEMI, non–ST-segment–elevation myocardial infarction; PCI, percutaneous coronary intervention; Pre-TTT, pretreatment; SCAD, stable coronary artery disease; and STEMI, ST-segment–elevation myocardial infarction.Pretreatment With More Potent Oral P2Y12 InhibitorsThe European Society of Cardiology/American College of Cardiology/American Heart Association guidelines for the management of NSTE-ACS also raise the issue of whether the limitation of pretreatment with clopidogrel applies to more potent P2Y12 inhibitors.4 Although pretreatment was not tested in the Platelet Inhibition and Patient Outcomes (PLATO) trial, the benefits of ticagrelor compared with clopidogrel in NSTE-ACS (n=11 080) were independent of whether revascularization was performed in the first 10 days after randomization.36 More important, patients with normal high-sensitivity cardiac troponin T at randomization did not seem to benefit from ticagrelor, further suggesting that systematic pretreatment of low-risk patients should not be recommended before the coronary anatomy is known.37No Hint of Clinical Benefit of Prasugrel Pretreatment: The ACCOAST TrialA Comparison of Prasugrel at PCI or Time of Diagnosis in Patients With Non-ST Elevation Myocardial Infarction (ACCOAST) trial was launched because of the lack of data demonstrating the incremental benefit of more potent P2Y12 inhibition among high-risk NSTE-ACS patients on one hand and clinical evidence supporting the earlier and even emergent PCI treatment of these high-risk patients on the other hand.38,39 It is the first and only study evaluating pretreatment with a P2Y12 in high-risk NSTE-ACS patients managed invasively. It was a randomized comparison of pretreatment with prasugrel 30 mg and a further 30 mg before PCI with initiation of prasugrel 60 mg after diagnostic angiography but before PCI among 4033 patients with NSTEMI (Figure 5). By 7 days, patients randomized to the pretreatment arm experienced no reduction in the risk of cardiovascular death, recurrent myocardial infarction, stroke, urgent revascularization, and bailout use of glycoprotein IIb/IIIa inhibition (HR, 1.02; 95% CI, 0.84–1.25; P=0.81), with no benefits emerging by 30 days.10 This was shown despite the proven biological efficacy of prasugrel within the first hour of oral intake of 30 mg in the pretreated patients (Figure 3). There was a rapid onset of action of prasugrel 30 mg pretreatment with a profound inhibition of the P2Y12 pathway at the time of PCI, a treatment effect much more powerful than 600 mg clopidogrel within the same time frame (Figure 3). In addition, this lack of effect on ischemic events was very consistent regardless of patients' baseline characteristics and was observed in high-risk patients defined according to a GRACE risk score of ≥140. ACCOAST demonstrated that a stronger platelet inhibition in NSTEMI patients does not reduce ischemic events occurring just before or within a few hours after PCI. These findings are consistent with the outcomes of other randomized studies exploring early initiation of intravenous glycoprotein IIb/IIIa inhibition among patients with ACS,40,41 a Class III recommendation,3 and in the CREDO trial with clopidogrel in which pretreatment was started in general after the coronary angiogram in patients undergoing elective PCI.14Download figureDownload PowerPointFigure 5. Flow chart of A Comparison of Prasugrel at PCI or Time of Diagnosis in Patients With Non-ST Elevation Myocardial Infarction (ACCOAST) study. CABG indicates coronary artery bypass graft surgery; CV, cardiovascular; GP, glycoprotein; MI, myocardial infarction; NSTEMI, non–ST-segment–elevation myocardial infarction; ULN, upper limit of normal; and Urg Revasc, urgent revascularization.Harm of Prasugrel Pretreatment Regardless of Interventional ManagementUnexpectedly, TIMI major bleeding criteria were significantly increased among patients randomized to the pretreatment arm by 7 days (pretreatment, 2.6% versus no pretreatment, 1.4%; HR, 1.90; 95% CI, 1.19–3.02; P=0.006). The highest rates of bleeding were seen among patients receiving surgical revascularization and are in line with the meta-analysis of observational and randomized studies of patients receiving clopidogrel who subsequently require coronary artery bypass graft surgery, demonstrating a consistently increased need for reoperation for bleeding and mortality with the use of clopidogrel.42 However, TIMI major bleeding episodes not related to coronary artery bypass graft surgery were increased by 3-fold (1.4% versus 0.51%; HR, 2.69; 95% CI, 1.13–6.40), including an increase by a factor of 6 in life-threatening bleeding (0.86% versus 0.15%; HR, 5.93; 95% CI, 1.33–26.5), further confirming a consistent harm in the PCI cohort.Does ACCOAST Fit in the Real-Life Management of NSTE-ACS?The ACCOAST trial has been a matter of great debate because it calls for reappraisal of pretreatment strategies in NSTE-ACS patients, a common practice supported by guidelines, although evidence is weak. ACCOAST has been challenged with respect to its applicability. This trial was designed to demonstrate the superiority of pretreatment with a fast-acting oral P2Y12 inhibitor compared with no pretreatment in patients presenting with a strong suspicion of NSTE-ACS always associated with a rise of troponin. Randomization of pretreatment in PCI patients only (as in CREDO) would have been impossible because of logistic constraints and would not have examined the clinicians' question of whether they need to pretreat the patients at the time of presentation when the coronary status is not yet known. ACCOAST was also designed to fit within the real-life management of NSTE-ACS patients (Figure 5). The rate of medical-managed patients after the angiography in ACCOAST reflects what has been seen in other studies in which one third of patients did not need PCI (Figure 6A).22,43–46 Approximately 25% of patients were considered high risk on the basis of a GRACE score >140, and they did not benefit from pretreatment. Six percent of patients required surgical revascularization, a situation in which pretreatment may delay surgery or expose patients to perioperative bleeding.10 Some questions remain to be answered.Download figureDownload PowerPointFigure 6. Percentages of non–ST-segment–elevation acute coronary syndrome (NSTE-ACS) patients medically managed across different randomized trials (A) and corresponding median of delays to angiography/percutaneous coronary intervention (PCI; B). ACCOAST indicates A Comparison of Prasugrel at PCI or Time of Diagnosis in Patients With Non-ST Elevation Myocardial Infarction; ACS, acute coronary syndrome; ACUITY, Acute Catheterization and Urgent Intervention Triage Strategy; CHAMPION PHOENIX, A Clinical Trial Comparing Cangrelor to Clopidogrel Standard Therapy in Subjects Who Require Percutaneous Coronary Intervention (PCI); CURRENT-OASIS 7, Clopidogrel Optimal Loading Dose Usage to Reduce Recurrent Events/Optimal Antiplatelet Strategy for Interventions; NSTEMI, non–ST-segment–elevation myocardial infarction; PLATO, Platelet Inhibition and Patient Outcomes; TIMACS, Early Versus Delayed Timing of Intervention in Patients With Acute Coronary Syndromes; and TRACER, Trial to Assess the Effects of Vorapaxar (SCH 530348; MK-5348) in Preventing Heart Attack and Stroke in Participants With Acute Coronary Syndrome. *The study includes patients with ST-segment–elevation myocardial infarction, a group with a high rate of primary PCI.Time Delays in ACCOAST Were Too ShortIn ACCOAST, the median duration of pretreatment was 4.3 hours, although patients could undergo angiography up to 48 hours after randomization. This short time delay may be perceived as a limitation for the applicability of ACCOAST in the real-life setting. However, as shown in Figure 6B, this time delay is similar to what was observed in contemporary ACS studies,2,43–46 which are used to recommend rapid invasive management in high-risk NSTEMI. In addition, no interaction was observed between time delay from randomization to angiography and outcome, outlining that the lack of benefit of pretreatment is consistent regardless of time delay. Patients waited up to 48 hours for catheterization, and there was no benefit of pretreatment for those who waited the longest. Indeed, patients in the fourth quartile of delay from prasugrel loading to catheterization who waited 14 to 48 hours had no benefit on the primary end point of pretreatment (HR, 0.92; 95% CI, 0.61–1.38; P=0.68).Should Complex Lesions Be Pretreated?This is the dilemma of all interventional cardiologists who fear the downside of a waiting pharmacological strategy. However, this no long pertains to pretreatment. In that specific situation, use of cangrelor or glycoprotein IIb/IIIa inhibitors for ad hoc PCI is a possible option. On-table loading with a new oral P2Y12 inhibitor is also a good option (the Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition With Prasugrel [TRITON] strategy). Finally, delaying the procedure by 2 to 3 hours or more is still possible to allow full pretreatment when the anatomy is known to be at high risk for PCI.The lack of effective platelet inhibition at the time of PCI in patients with complex anatomy or intracoronary thrombus is associated with increased ischemic complications at 30 days (Figure 7A).47 In ACCOAST-PCI, the subgroup of patients with intracoronary thrombus (21%) was prespecified and had a 3-fold higher primary end point than patients without thrombus (HR, 3.01; 95% CI, 2.42–3.71; P<0.001).48 However, there was no impact of prasugrel pretreatment on the presence of thrombus before PCI or on the occurrence of stent thrombosis after PCI (Figure 7B). This suggests that waiting for coronary angiogram avoids the use of dual antiplatelet therapy when not indicated and refines risk stratification of a potential PCI procedure without additional risk. This implies improving logistical organization toward an accelerated access to angiography as soon as possible, as outlined in Figure 8.Download figureDownload PowerPointFigure 7. Impact of thrombus on outcome (A)47 and in A Comparison of Prasugrel at PCI or Time of Diagnosis in Patients With Non-ST Elevation Myocardial Infarction (ACCOAST; B).48 DVE indicates distal vascular embolization; GP, glycoprotein; HR, hazard ratio; MACE, major adverse cardiac events; and PCI, percutaneous coronary intervention.Download figureDownload PowerPointFigure 8. P2Y12 inhibitor pathway in patients with non–ST-segment–elevation acute coronary syndrome (NSTE-ACS) at low/intermediate risk according to timing of angiography (angio) and bleeding risk. Patients presenting with ongoing ischemia are not considered. CABG indicates coronary artery bypass graft surgery; CAD, coronary artery disease; inh., inhibitor; and PCI, percutaneous coronary intervention.Such a "wait and see" approach provides flexibility and should be reassuring for interventional cardiologists. First, angiography without pretreatment allows a refinement in risk stratification without additional harm and is safe. Second, these data are in line with those from the TRILOGY ACS trial in which prasugrel did not reduce cardiovascular events among patients who were given drug treatment for NSTE-ACS compared with clopidogrel but did not increase bleeding.49 Similar to the findings in ACCOAST, these findings were not a result of inadequate platelet inhibition, and the TRILOGY ACS Platelet Function Substudy confirmed that patients given prasugrel had lower platelet reactivity, yet treatment was not significantly associated with fewer ischemic outcomes.50 However, when coronary angiography was performed and anatomic CAD was confirmed, a more intensive antiplatelet strategy with prasugrel was found to be beneficial, a finding also supporting the ACCOAST results.51 The angiogram is key in NSTE-ACS for deciding to use strong PY12 inhibition with one of the new agents available.Radial Access May Obviate the Excess of Bleeding Associated With PretreatmentACCOAST is a contemporary trial reflecting current management of high-risk NSTEMI. Invasive management was rapid, and radial access was the preferred strategy, although its mortality benefit remains unproven in NSTE-ACS.52 In ACCOAST, radial access was associated with a 60% lower bleeding rates compared with femoral access, a finding in line with other large studies.53 PCI-related bleeding events occurred early and represented the dominant location of TIMI major bleedings (9 of 21). Of interest, the safety hazard of pretreatment was observed regardless of radial versus femoral approach (no significant interaction). In addition, the multivariate analysis for TIMI major bleeding identified femoral (versus radial) access (HR, 3.01; 95% CI, 1.13–8.00; P=0.027) and treatment group (HR, 2.77; 95% CI, 1.16–6.60; P=0.022) as the 2 strongest independent correlates of bleeding complications in PCI patients. This suggests that the use of the radial approach to prevent the excess of bleeding associated with pretreatment with prasugrel is not a valid argument. Pretreatment is still associated with an excess of bleeding complications in radial patients. Only the locations of the bleeding differed compared with femoral patients.Dosing StrategiesOne may argue that pretreatment with 30 mg has not been tested before and is questionable with respect to its potential efficacy to avoid early ischemic events. Pharmacodynamic evaluation does not support such an argument, as shown in Figure 4. Onset of action of this dose was very fast, and all patients were within the optimal range of P2Y12 inhibition at the time of PCI. In addition, this dose regimen has been tested in previous pharmacodynamic/pharmacokinetic studies and has been shown to be safe and biologically efficient in the TRILOGY ACS trial.49,50Should This Apply to Ticagrelor?Ticagrelor is an oral, reversibly binding P2Y12 inhibitor with a short plasma half-life. Like prasugrel, ticagrelor has a more rapid and consistent onset of action compared with clopidogrel, but it also has a faster offset of action with more rapid recovery of platelet function.54 In patients with STEMI undergoing primary PCI, both ticagrelor and prasugrel exhibit an initial delay in the onset of their antiplatelet action without a difference in reducing platelet reactivity within the first 24 hours after loading.55 Ticagrelor has been successfully tested versus clopidogrel in ACS patients regardless of medical versus invasive intervention but not pretreatment versus no pretreatment.8 In the PLATO study, all patients were pretreated before the angiogram. Although prehospital treatment with ticagrelor in patients with STEMI undergoing primary PCI appears to be safe but with no improvement in pre-PCI coronary reperfusion,56 its risk/benefit in NSTE-ACS is unknown. Therefore, a strategy of systematic pretreatment should not be encouraged when there is harm with prasugrel, a P2Y12 in
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