Several observational studies, randomized controlled trials, and meta-analyses suggested that pretreatment with clopidogrel in addition to aspirin could reduce the rate of ischemic events, especially in the setting of acute coronary syndromes. Newer P2Y12 inhibitors like prasugrel and ticagrelor, which provide faster and stronger platelet inhibition compared with clopidogrel, would enhance the benefits of pretreatment. However, 2 recent randomized trials, A Comparison of Prasugrel at PCI or Time of Diagnosis of Non-ST Elevation Myocardial Infarction and the Administration of Ticagrelor in the Cath Lab or in the Ambulance for New ST Elevation Myocardial Infarction to Open the Coronary Artery studies, aimed at assessing the effects of the timing of administration of novel P2Y12 inhibitors in acute coronary syndromes, failed to meet their primary end points. In this report, we review clinical data on pretreatment with dual oral antiplatelet therapy and comment on some criticisms raised from recent trials.
Early treatment with dual antiplatelet therapy (DAPT) is an established and important adjunct to percutaneous coronary intervention (PCI), and it is currently recommended for patients with acute coronary syndromes (ACS), even in those not receiving revascularization. In the light of recent clinical trials, which investigated the role of early treatment with novel oral antiplatelet agents, we review the current state of systematic pretreatment (defined as treatment before the anatomy is defined by angiography) with DAPT.
We performed a computerized literature search of Medline and Pubmed databases for published reports from January 1980 to December 2014 using the following predefined search terms pretreatment, clopidogrel, prasugrel, ticagrelor, or loading dose or preload or timing or upstream, with no language restrictions. References from reviews and selected reports were also reviewed for potential relevant citations. The search strategy retrieved 354 citations after removing duplicates. Among these citations, 36 reports were selected for full-text review.
The Origin of Pretreatment With DAPT
At first, periprocedural administration of DAPT—based on aspirin and ticlopidine—led to a 86% relative risk reduction (RRR) in stent thrombosis, with an associated benefit on ischemic events and major bleeding compared with aspirin and phenprocoumon, an anticoagulant, in patients who underwent elective PCI. Further investigation also demonstrated a reduced incidence of cardiovascular (CV) events, confirming the periprocedural advantages of ticlopidine. Thereafter, accumulated data showed that clopidogrel was preferable over ticlopidine because of better tolerability and at least equivalent efficacy. The Clopidogrel in Unstable Angina to Prevent Recurrent Events (CURE) trial has shown an early and persistent benefit of clopidogrel over placebo when added early to aspirin in patients with non–ST-elevation ACS. The most evident benefit of pretreatment with clopidogrel was showed in the PCI-CURE trial, in which patients in each treatment arms were given DAPT for 1 month after PCI. In this cohort of patients, clopidogrel pretreatment compared with placebo was associated with a significant 30% RRR in the cumulative incidence of CV death, myocardial infarction (MI), or urgent target-vessel revascularization at 28 days and a 31% RRR in the rate of CV death or MI at 1 year. This advantage in the composite ischemic end point was already evident some days after the administration of clopidogrel, which occurred at ∼6 days before PCI. This finding appears of major importance because a prespecified analysis of the Clopidogrel for the Reduction of Events During Observation trial showed that a drug with a slow onset of action, such as clopidogrel, exerts an adequate antiplatelet effect only after a long period of administration. Indeed, clopidogrel is a prodrug, and even with a 300-mg loading dose, there is an approximately 6-hour delay before the onset of substantial ADP receptor antagonism. The effectiveness of clopidogrel depends on generation of the active metabolite that are catalyzed by enzymes of the cytochrome P450 system, principally CYP2C19. Variants of the CYP2C19 gene have been identified that are associated with impaired antiplatelet effects, as measured by ex vivo platelet aggregation assays, and with higher CV event rates after ACS and PCI procedures. These findings may limit the efficacy of clopidogrel in the pretreatment setting, even if higher loading doses are used.
Pretreatment in Stable Versus Unstable Patients: Two Different Scenarios
Several studies have evaluated the efficacy of early DAPT administration in different clinical settings, including ACS and stable coronary artery disease (CAD), likely raising confusion on pretreatment strategies. In patients with ACS, an antiplatelet treatment must be established as soon as a diagnosis is made because the physiopathology of ACS is based on plaque instability and thrombus formation—a condition dependent on platelets, especially in early phases. In contrast, in patients with stable CAD who are scheduled for PCI, the pathophysiology of disease is completely different, CV risk is low, and periprocedural ischemic events are much less frequent than in ACS. Indeed, most studies on pretreatment of patients with stable CAD have failed to show a clear signal of benefit ( Table 1 ). Consistently, the most recent guidelines issued by the American College of Cardiology/American Heart Association and the European Society of Cardiology on stable CAD do not recommend the use of clopidogrel in patients with unknown coronary anatomy. Conversely, several randomized controlled trials and observational studies suggested that systematic pretreatment with clopidogrel in addition to aspirin could reduce the rate of ischemic events in patients with ACS ( Table 2 ). Negative studies in this setting include the post hoc analysis of the Acute Catheterization and Urgent Intervention Triage Strategy trial and the retrospective analysis of the Cornell Angioplasty Registry. As a matter of fact, the Acute Catheterization and Urgent Intervention Triage Strategy trial presents several biases including the open-label allocation that may have contributed to undetected imbalances in the underlying risk of patients in the different cohorts of clopidogrel pretreatment. In the retrospective analysis of the single-center Cornell Registry, ischemic events in “adequately pretreated” (300 mg ≥12 hours or 600 mg >2 hours or chronic use of clopidogrel) patients who had undergone PCI for ACS were not lower, compared with those receiving clopidogrel in the cath lab. Because 90% of the patients in the “adequately pretreated” group were in fact on chronic clopidogrel treatment, there were significant differences in baseline characteristics between the 2 groups (e.g., history of AMI, CAD, or diabetes were much more frequent in the “pretreated” group, p <0.001), making adequate comparisons difficult. Of note, however, major bleeding was not more frequent in “pretreated” patients. In the setting of ST-elevation myocardial infarction (STEMI), where a short interval between diagnosis and PCI is required, the efficacy of early DAPT administration is even more uncertain, particularly when clopidogrel is used. Nevertheless, a prespecified analysis of the Clopidogrel as Adjunctive Reperfusion Therapy (CLARITY)-Thrombolysis In Myocardial Infarction (TIMI) 28 trial on 1,863 patients who underwent PCI after successful thrombolysis, the PCI-CLARITY, showed that clopidogrel pretreatment was associated with a highly significant 41% RRR in the primary end point, a composite of CV death, MI, or stroke at 30 days without an increase in major bleeding complications compared with treatment at the time of intervention; the context, however, was clearly different from that of primary PCI. Three years later, a collaborative meta-analysis of the results of 3 randomized trials of clopidogrel pretreatment (PCI-CURE, Clopidogrel for the Reduction of Events During Observation, and PCI-CLARITY) suggested that clopidogrel administration before PCI was beneficial and safe in patients with ACS. A more recent meta-analysis that analyzed data from observational studies, post hoc analyses, and 6 randomized controlled trials involving patients with CAD (stable or ACS) showed that clopidogrel pretreatment was associated with a lower risk of major cardiac events (9.83% vs 12.35%; odds ratio [OR] 0.77; 95% confidence interval [CI] 0.66 to 0.89, p <0.001) without increasing the rate of major bleedings (3.57% vs 3.08%; OR 1.18; 95% CI 0.93 to 1.50, p = 0.18). A favorable trend was also observed for all-cause mortality (OR 0.80; 95% CI 0.57 to 1.11, p = 0.17, in randomized controlled trials). Notably, clopidogrel pretreatment was particularly effective in reducing major coronary events in patients with a diagnosis of STEMI (OR 0.54; 95% CI 0.36 to 0.81, p = 0.003) and in those with non–ST elevation (NSTE)-ACS (OR 0.78; 95% CI 0.66 to 0.91, p = 0.002) but not in the low-risk population of elective PCI. This finding reflects the different pathophysiological processes, which underlie stable CAD and ACS. In this latter context, a pretreatment exerts the most evident benefits, especially when there is a sufficient time interval between hospital admission and coronary angiography.
| Study | Design | Oral APLT agent | Loading dose and timing | Mean time of Pre-Rx (hrs) | n | Primary endpoint | Time to endpoint (days) | Primary endpoint met |
|---|---|---|---|---|---|---|---|---|
| CREDO , 2002 | Randomized, prospective, multicenter, double-blind, placebo-controlled | Clopidogrel | 300 mg vs placebo (upstream) | 9.8 | 2116 | Death, MI, uTVR | 28 | NO |
| Chan et al. , 2003 | Post-hoc analysis of the TARGET trial | Clopidogrel | 300 mg (upstream) vs 300 mg (downstream) on top of GPI | 2.1 | 4809 | Death, MI, uTVR | 30 | YES |
| Saw et al. , 2004 | Post-hoc analysis of the REPLACE-2 trial | Clopidogrel | 300 mg (upstream) vs 300 mg (downstream) | 6-48 | 5919 | Death, MI, uTVR, major bleeding | 30 | NO |
| Kandzari et al. , 2004 | Post-hoc analysis of the ISAR-REACT trial | Clopidogrel | 600 mg at 2-3 hrs, 3-6 hrs, 6-12 hrs, >12 hrs | 7.4 | 2159 | Death, MI, uTVR | 30 | NO |
| van der Heijden et al. , 2004 | Randomized, prospective, single-center, open-label | Clopidogrel | 300 mg (upstream) vs 300 mg (downstream) | 72 | 203 | Rise in troponin I or CK-MB levels after PCI | 1 | NO |
| Szuk et al. , 2007 | Observational, prospective, multicenter | Clopidogrel | 300 mg (upstream) vs 300 mg (downstream) | 18 | 4160 | Death, MI, uTVR | 30 | YES |
| PRAGUE-8 , 2008 | Randomized, prospective, multicenter, open-label | Clopidogrel | 600 mg (upstream) vs 600 mg (downstream) | ≥6 | 1028 | Death, stroke, uTVR, periprocedural MI | 7 | NO |
| Davlouros et al. , 2009 | Randomized, prospective, single-center, open-label | Clopidogrel | 900 mg (upstream) vs 900 mg (downstream) | 2 | 199 | Death, stroke, periprocedural MI, uTVR | 30 | NO |
| ARMYDA PRELOAD , 2010 | Randomized, prospective, multicenter, open-label | Clopidogrel | 600 mg (upstream) vs 600 mg (downstream) | 6 | 409 | Cardiac death, MI, uTVR | 30 | NO |
| Amin et al. , 2011 | Retrospective analysis from the EVENT Registry | Clopidogrel | upstream vs downstream | >2 | 1913 | In-hospital death and MI | — | NO |
| Study | Design | Oral APLT agent | Loading dose and timing | Setting | Mean time of Pre-Rx | n | Primary endpoint | Time to endpoint (days) | Primary endpoint met |
|---|---|---|---|---|---|---|---|---|---|
| PCI CURE , 2001 | Randomized, prospective, multicenter, double-blind | Clopidogrel | 300 mg vs placebo (upstream) | NSTE-ACS | 10 days | 2658 | CV death, MI, uTVR | 30 | YES |
| PCI CLARITY , 2005 | Pre-specified analysis of the CLARITY-TIMI 28 trial | Clopidogrel | 300 mg vs placebo (upstream) | Recent STEMI | 3 days | 1863 | CV death, MI, stroke | 30 | YES |
| Lev et al. , 2008 | Observational, prospective, single-center | Clopidogrel | 300/600 mg (upstream) vs 300/600 mg (downstream) | STEMI | 1.5 hrs | 292 | Post-procedural TMPG | — | YES |
| Lincoff et al. , 2008 | Post-hoc analysis of the ACUITY trial | Clopidogrel | ≥300 mg (upstream) vs ≥300 mg (downstream) | NSTE-ACS | n/a | 7789 | Death, MI, uTVR | 30 | NO |
| Fefer et al. , 2009 | Observational, prospective, single-center | Clopidogrel | 300/600 mg (upstream) vs 300/600 mg (downstream) | STEMI | 69 min | 383 | Recurrent ACS, stent thrombosis, congestive HF, or death | 30 | YES |
| Feldman et al. , 2010 | Retrospective analysis from the Cornell Registry | Clopidogrel | 300/600 mg (upstream) vs 300/600 mg (downstream) | NSTE-ACS | ≥2 or ≥12 hrs | 1041 | Death | 365 | NO |
| Dorler et al. , 2011 | Observational, prospective, multicenter | Clopidogrel | ≥300 mg (upstream) vs ≥300 mg (downstream) | STEMI | 106 min | 5955 | In-hospital outcome | — | YES |
| Koul et al. , 2011 | Retrospective analysis from the SCAAR Registry | Clopidogrel | ≥300 mg (upstream) vs ≥300 mg (downstream) | STEMI | n/a | 13847 | Death or MI | 365 | YES |
| Wang et al. , 2011 | Post-hoc analysis of the EARLY-ACS trial | Clopidogrel | ≥300 mg (upstream) vs ≥300 mg (downstream) | NSTE-ACS | 21.4 hrs | 9166 | Death or MI | 30 | YES |
| CIPAMI , 2012 | Randomized, prospective, single-center, open-label | Clopidogrel | 600 mg (upstream) vs ≥300 mg (downstream) | STEMI | 47 min | 654 | Pre-procedural TIMI 2/3 | — | NO |
| ACCOAST , 2013 | Randomized, prospective, multicenter, double-blind | Prasugrel | 30 mg (upstream)+30 mg (downstream) vs 60 mg (downstream) | NSTEMI | 4.4 hrs | 4033 | CV death, MI, stroke, uTVR, or GPI bailout | 7 | NO |
| LOAD & GO , 2013 | Randomized, prospective, single-center, open-label | Clopidogrel | 600/900 mg (upstream) vs 300 mg (downstream) | STEMI | 65 min | 168 | Post-procedural TMPG | — | NO |
| de Waha S, et al. , 2014 | Observational, prospective, single-center | Clopidogrel | 300 mg or 600 mg (upstream) vs 600 mg (downstream) | STEMI | 80 min | 423 | Infarct size and MO | — | YES |
| ATLANTIC , 2014 | Randomized, prospective, multicenter, double-blind | Ticagrelor | 180 mg (upstream) vs 180 mg (downstream) | STEMI | 48 min | 1862 | TIMI flow grade or ST-segment resolution pre-PCI | — | NO |
Pretreatment in Stable Versus Unstable Patients: Two Different Scenarios
Several studies have evaluated the efficacy of early DAPT administration in different clinical settings, including ACS and stable coronary artery disease (CAD), likely raising confusion on pretreatment strategies. In patients with ACS, an antiplatelet treatment must be established as soon as a diagnosis is made because the physiopathology of ACS is based on plaque instability and thrombus formation—a condition dependent on platelets, especially in early phases. In contrast, in patients with stable CAD who are scheduled for PCI, the pathophysiology of disease is completely different, CV risk is low, and periprocedural ischemic events are much less frequent than in ACS. Indeed, most studies on pretreatment of patients with stable CAD have failed to show a clear signal of benefit ( Table 1 ). Consistently, the most recent guidelines issued by the American College of Cardiology/American Heart Association and the European Society of Cardiology on stable CAD do not recommend the use of clopidogrel in patients with unknown coronary anatomy. Conversely, several randomized controlled trials and observational studies suggested that systematic pretreatment with clopidogrel in addition to aspirin could reduce the rate of ischemic events in patients with ACS ( Table 2 ). Negative studies in this setting include the post hoc analysis of the Acute Catheterization and Urgent Intervention Triage Strategy trial and the retrospective analysis of the Cornell Angioplasty Registry. As a matter of fact, the Acute Catheterization and Urgent Intervention Triage Strategy trial presents several biases including the open-label allocation that may have contributed to undetected imbalances in the underlying risk of patients in the different cohorts of clopidogrel pretreatment. In the retrospective analysis of the single-center Cornell Registry, ischemic events in “adequately pretreated” (300 mg ≥12 hours or 600 mg >2 hours or chronic use of clopidogrel) patients who had undergone PCI for ACS were not lower, compared with those receiving clopidogrel in the cath lab. Because 90% of the patients in the “adequately pretreated” group were in fact on chronic clopidogrel treatment, there were significant differences in baseline characteristics between the 2 groups (e.g., history of AMI, CAD, or diabetes were much more frequent in the “pretreated” group, p <0.001), making adequate comparisons difficult. Of note, however, major bleeding was not more frequent in “pretreated” patients. In the setting of ST-elevation myocardial infarction (STEMI), where a short interval between diagnosis and PCI is required, the efficacy of early DAPT administration is even more uncertain, particularly when clopidogrel is used. Nevertheless, a prespecified analysis of the Clopidogrel as Adjunctive Reperfusion Therapy (CLARITY)-Thrombolysis In Myocardial Infarction (TIMI) 28 trial on 1,863 patients who underwent PCI after successful thrombolysis, the PCI-CLARITY, showed that clopidogrel pretreatment was associated with a highly significant 41% RRR in the primary end point, a composite of CV death, MI, or stroke at 30 days without an increase in major bleeding complications compared with treatment at the time of intervention; the context, however, was clearly different from that of primary PCI. Three years later, a collaborative meta-analysis of the results of 3 randomized trials of clopidogrel pretreatment (PCI-CURE, Clopidogrel for the Reduction of Events During Observation, and PCI-CLARITY) suggested that clopidogrel administration before PCI was beneficial and safe in patients with ACS. A more recent meta-analysis that analyzed data from observational studies, post hoc analyses, and 6 randomized controlled trials involving patients with CAD (stable or ACS) showed that clopidogrel pretreatment was associated with a lower risk of major cardiac events (9.83% vs 12.35%; odds ratio [OR] 0.77; 95% confidence interval [CI] 0.66 to 0.89, p <0.001) without increasing the rate of major bleedings (3.57% vs 3.08%; OR 1.18; 95% CI 0.93 to 1.50, p = 0.18). A favorable trend was also observed for all-cause mortality (OR 0.80; 95% CI 0.57 to 1.11, p = 0.17, in randomized controlled trials). Notably, clopidogrel pretreatment was particularly effective in reducing major coronary events in patients with a diagnosis of STEMI (OR 0.54; 95% CI 0.36 to 0.81, p = 0.003) and in those with non–ST elevation (NSTE)-ACS (OR 0.78; 95% CI 0.66 to 0.91, p = 0.002) but not in the low-risk population of elective PCI. This finding reflects the different pathophysiological processes, which underlie stable CAD and ACS. In this latter context, a pretreatment exerts the most evident benefits, especially when there is a sufficient time interval between hospital admission and coronary angiography.
| Study | Design | Oral APLT agent | Loading dose and timing | Mean time of Pre-Rx (hrs) | n | Primary endpoint | Time to endpoint (days) | Primary endpoint met |
|---|---|---|---|---|---|---|---|---|
| CREDO , 2002 | Randomized, prospective, multicenter, double-blind, placebo-controlled | Clopidogrel | 300 mg vs placebo (upstream) | 9.8 | 2116 | Death, MI, uTVR | 28 | NO |
| Chan et al. , 2003 | Post-hoc analysis of the TARGET trial | Clopidogrel | 300 mg (upstream) vs 300 mg (downstream) on top of GPI | 2.1 | 4809 | Death, MI, uTVR | 30 | YES |
| Saw et al. , 2004 | Post-hoc analysis of the REPLACE-2 trial | Clopidogrel | 300 mg (upstream) vs 300 mg (downstream) | 6-48 | 5919 | Death, MI, uTVR, major bleeding | 30 | NO |
| Kandzari et al. , 2004 | Post-hoc analysis of the ISAR-REACT trial | Clopidogrel | 600 mg at 2-3 hrs, 3-6 hrs, 6-12 hrs, >12 hrs | 7.4 | 2159 | Death, MI, uTVR | 30 | NO |
| van der Heijden et al. , 2004 | Randomized, prospective, single-center, open-label | Clopidogrel | 300 mg (upstream) vs 300 mg (downstream) | 72 | 203 | Rise in troponin I or CK-MB levels after PCI | 1 | NO |
| Szuk et al. , 2007 | Observational, prospective, multicenter | Clopidogrel | 300 mg (upstream) vs 300 mg (downstream) | 18 | 4160 | Death, MI, uTVR | 30 | YES |
| PRAGUE-8 , 2008 | Randomized, prospective, multicenter, open-label | Clopidogrel | 600 mg (upstream) vs 600 mg (downstream) | ≥6 | 1028 | Death, stroke, uTVR, periprocedural MI | 7 | NO |
| Davlouros et al. , 2009 | Randomized, prospective, single-center, open-label | Clopidogrel | 900 mg (upstream) vs 900 mg (downstream) | 2 | 199 | Death, stroke, periprocedural MI, uTVR | 30 | NO |
| ARMYDA PRELOAD , 2010 | Randomized, prospective, multicenter, open-label | Clopidogrel | 600 mg (upstream) vs 600 mg (downstream) | 6 | 409 | Cardiac death, MI, uTVR | 30 | NO |
| Amin et al. , 2011 | Retrospective analysis from the EVENT Registry | Clopidogrel | upstream vs downstream | >2 | 1913 | In-hospital death and MI | — | NO |
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