Thienopyridine Pretreatment in Non-ST Elevation ACS
Thienopyridine Pretreatment in Non-ST Elevation ACS
Objective. To investigate the effect of pretreatment with P2Y12 receptor inhibitors compared with no pretreatment on efficacy and safety of treatment of non-ST elevation acute coronary syndrome (ACS).
Data Sources. Two reviewers independently searched Medline, Embase, Cochrane Controlled Trials, and BioMed Central databases for randomized placebo controlled trials and observational studies from August 2001 to March 2014.
Study Eligibility. Studies must have reported both all-cause mortality (primary efficacy endpoint) and major bleeding (safety endpoint) outcomes.
Data Extraction. Data on sample size, characteristics, drug dose and delay of administration, and outcomes were independently extracted and analyzed.
Data Synthesis. A random-effect model was applied. The analysis was performed (i) in all patients independently of the management strategy and (ii) only in patients undergoing percutaneous coronary intervention.
Results. Of the 393 titles identified, seven (four randomized controlled trials, one observational analysis from a randomized controlled trial, and three observational studies) met the inclusion criteria. No study was identified for ticagrelor or cangrelor, and analyses were thus limited to thienopyridines. A total of 32,383 non-ST elevation ACS patients were included, 18,711 coming from randomized controlled trials. Of these, 55% underwent percutaneous coronary intervention (PCI). Pretreatment was not associated with a significant lower risk of mortality in all patients (odds ratio 0.90 (95% confidence interval 0.75 to 1.07), P=0.24), in particular when considering only the randomized controlled trials (odds ratio 0.90 (0.71 to 1.14), P=0.39). Similar results were observed in the cohort of patients undergoing PCI. A significant 30-45% excess of major bleeding was consistently observed in all patients (odds ratio 1.32 (1.16 to 1.49), P<0.0001) and in those undergoing PCI, as well as in the subset analyses of randomized controlled trials of these two cohorts of patients. There was a reduction in major adverse cardiovascular events in the analysis of all patients (odds ratio 0.84 (0.72 to 0.98), P=0.02), driven by the old clopidogrel studies (CURE and CREDO), but the difference was not significant for the cohort of patients undergoing PCI. Stent thrombosis, stroke, and urgent revascularization did not differ between groups (pretreatment v no pretreatment). The results were consistent for both thienopyridines and confirmed in sensitivity analyses.
Limitations. Analysis was not performed on individual patient's data.
Conclusion. In patients presenting with non-ST elevation ACS, pretreatment with thienopyridines is associated with no significant reduction of mortality but with a significant excess of major bleeding no matter the strategy adopted, invasive or not. Our results do not support a strategy of routine pretreatment in patients with non-ST elevation ACS.
Non-ST elevation acute coronary syndrome (ACS) holds a significant burden in global healthcare systems with a one year incidence of more than 1.5/1000 people. In real world management, two thirds of patients presenting with a non-ST elevation ACS have coronary angiography performed, a third have coronary stenting, and 7-10% have coronary bypass surgery. Despite optimal evidence based treatment, these patients have worse mid-term and long term prognoses than patients with ST elevation ACS, with more frequent recurrent ischemic events and a twofold higher death rate at two years.
Dual antiplatelet therapy with aspirin and a P2Y12 receptor antagonist has been the cornerstone of the treatment of ACS, managed either medically or invasively. This is based on the single randomized CURE study, in which clopidogrel (300 mg pretreatment loading dose, 75 mg maintenance dose) for a mean duration of nine months reduced ischemic endpoints by 20% in non-ST elevation ACS patients medically managed. In the CREDO trial, in which two thirds of enrolled patients had non-ST elevation ACS, significant superiority of pretreatment in patients undergoing percutaneous coronary intervention (PCI) was not demonstrated but was suggested only in subgroup analyses. These trials were conducted 15 years ago when clinical practice was different in many ways.
The rationale for pretreatment with oral P2Y12 inhibitors is based on the need for a strong antiplatelet effect in non-ST elevation ACS patients scheduled for PCI, and the delay of action of these drugs, clopidogrel in particular, which provide a low and slow platelet inhibition in many patients.
Following the CURE and CREDO studies, clopidogrel pretreatment has been generalized for non-ST elevation ACS management with a Class I-B recommendation in the European and US guidelines, with the paradigm that "sooner is better." However, there has been no specific trial randomizing non-ST elevation ACS patients for clopidogrel pretreatment versus no pretreatment before routine catheterization as performed nowadays. Moreover, the time from hospital admission to catheterization has been considerably shortened in the past 10 years. The risk-benefit of pretreatment can now be reevaluated, considering the changes in practice and the accumulation of studies since the seminal publication of the CURE study allowing evaluation of low frequency but hard endpoints such as mortality and major bleeding. Indeed, pretreatment, a treatment administered before the coronary angiogram, may be detrimental in patients finally oriented towards coronary artery bypass graft surgery, which is performed within five days of clopidogrel loading in 87% of cases, with associated higher perioperative transfusion rates of blood products and a twofold increase of reoperation for bleeding complications. Patients medically managed may also not benefit from pretreatment, especially when there is no significant coronary disease or an alternate diagnosis for the clinical presentation. Finally, a few randomized studies have questioned the risk-benefit of pretreatment in patients undergoing PCI, and, in a meta-analysis performed in 37,814 patients undergoing PCI (elective, urgent, or primary), we found no benefit of clopidogrel pretreatment on mortality.
The recent randomized ACCOAST trial demonstrated the absence of benefit of pretreatment with prasugrel in non-ST elevation ACS patients invasively managed. Moreover, there was hazard associated with pretreatment, suggesting an unfavorable risk-benefit of systematic pretreatment for patients with non-ST elevation ACS.
We decided to evaluate the risk-benefit of routine pretreatment with P2Y12 receptor inhibitors administered to patients with non-ST elevation ACS independently of the treatment strategy applied, medical or invasive. We included in the present meta-analysis not only randomized placebo controlled trials but also registries; we evaluated the global effect independently of revascularization (all patients included in the analysis) and the effect only in patients undergoing PCI, to evaluate potential differences according to the management strategy used.
Abstract and Introduction
Abstract
Objective. To investigate the effect of pretreatment with P2Y12 receptor inhibitors compared with no pretreatment on efficacy and safety of treatment of non-ST elevation acute coronary syndrome (ACS).
Data Sources. Two reviewers independently searched Medline, Embase, Cochrane Controlled Trials, and BioMed Central databases for randomized placebo controlled trials and observational studies from August 2001 to March 2014.
Study Eligibility. Studies must have reported both all-cause mortality (primary efficacy endpoint) and major bleeding (safety endpoint) outcomes.
Data Extraction. Data on sample size, characteristics, drug dose and delay of administration, and outcomes were independently extracted and analyzed.
Data Synthesis. A random-effect model was applied. The analysis was performed (i) in all patients independently of the management strategy and (ii) only in patients undergoing percutaneous coronary intervention.
Results. Of the 393 titles identified, seven (four randomized controlled trials, one observational analysis from a randomized controlled trial, and three observational studies) met the inclusion criteria. No study was identified for ticagrelor or cangrelor, and analyses were thus limited to thienopyridines. A total of 32,383 non-ST elevation ACS patients were included, 18,711 coming from randomized controlled trials. Of these, 55% underwent percutaneous coronary intervention (PCI). Pretreatment was not associated with a significant lower risk of mortality in all patients (odds ratio 0.90 (95% confidence interval 0.75 to 1.07), P=0.24), in particular when considering only the randomized controlled trials (odds ratio 0.90 (0.71 to 1.14), P=0.39). Similar results were observed in the cohort of patients undergoing PCI. A significant 30-45% excess of major bleeding was consistently observed in all patients (odds ratio 1.32 (1.16 to 1.49), P<0.0001) and in those undergoing PCI, as well as in the subset analyses of randomized controlled trials of these two cohorts of patients. There was a reduction in major adverse cardiovascular events in the analysis of all patients (odds ratio 0.84 (0.72 to 0.98), P=0.02), driven by the old clopidogrel studies (CURE and CREDO), but the difference was not significant for the cohort of patients undergoing PCI. Stent thrombosis, stroke, and urgent revascularization did not differ between groups (pretreatment v no pretreatment). The results were consistent for both thienopyridines and confirmed in sensitivity analyses.
Limitations. Analysis was not performed on individual patient's data.
Conclusion. In patients presenting with non-ST elevation ACS, pretreatment with thienopyridines is associated with no significant reduction of mortality but with a significant excess of major bleeding no matter the strategy adopted, invasive or not. Our results do not support a strategy of routine pretreatment in patients with non-ST elevation ACS.
Introduction
Non-ST elevation acute coronary syndrome (ACS) holds a significant burden in global healthcare systems with a one year incidence of more than 1.5/1000 people. In real world management, two thirds of patients presenting with a non-ST elevation ACS have coronary angiography performed, a third have coronary stenting, and 7-10% have coronary bypass surgery. Despite optimal evidence based treatment, these patients have worse mid-term and long term prognoses than patients with ST elevation ACS, with more frequent recurrent ischemic events and a twofold higher death rate at two years.
Dual antiplatelet therapy with aspirin and a P2Y12 receptor antagonist has been the cornerstone of the treatment of ACS, managed either medically or invasively. This is based on the single randomized CURE study, in which clopidogrel (300 mg pretreatment loading dose, 75 mg maintenance dose) for a mean duration of nine months reduced ischemic endpoints by 20% in non-ST elevation ACS patients medically managed. In the CREDO trial, in which two thirds of enrolled patients had non-ST elevation ACS, significant superiority of pretreatment in patients undergoing percutaneous coronary intervention (PCI) was not demonstrated but was suggested only in subgroup analyses. These trials were conducted 15 years ago when clinical practice was different in many ways.
The rationale for pretreatment with oral P2Y12 inhibitors is based on the need for a strong antiplatelet effect in non-ST elevation ACS patients scheduled for PCI, and the delay of action of these drugs, clopidogrel in particular, which provide a low and slow platelet inhibition in many patients.
Following the CURE and CREDO studies, clopidogrel pretreatment has been generalized for non-ST elevation ACS management with a Class I-B recommendation in the European and US guidelines, with the paradigm that "sooner is better." However, there has been no specific trial randomizing non-ST elevation ACS patients for clopidogrel pretreatment versus no pretreatment before routine catheterization as performed nowadays. Moreover, the time from hospital admission to catheterization has been considerably shortened in the past 10 years. The risk-benefit of pretreatment can now be reevaluated, considering the changes in practice and the accumulation of studies since the seminal publication of the CURE study allowing evaluation of low frequency but hard endpoints such as mortality and major bleeding. Indeed, pretreatment, a treatment administered before the coronary angiogram, may be detrimental in patients finally oriented towards coronary artery bypass graft surgery, which is performed within five days of clopidogrel loading in 87% of cases, with associated higher perioperative transfusion rates of blood products and a twofold increase of reoperation for bleeding complications. Patients medically managed may also not benefit from pretreatment, especially when there is no significant coronary disease or an alternate diagnosis for the clinical presentation. Finally, a few randomized studies have questioned the risk-benefit of pretreatment in patients undergoing PCI, and, in a meta-analysis performed in 37,814 patients undergoing PCI (elective, urgent, or primary), we found no benefit of clopidogrel pretreatment on mortality.
The recent randomized ACCOAST trial demonstrated the absence of benefit of pretreatment with prasugrel in non-ST elevation ACS patients invasively managed. Moreover, there was hazard associated with pretreatment, suggesting an unfavorable risk-benefit of systematic pretreatment for patients with non-ST elevation ACS.
We decided to evaluate the risk-benefit of routine pretreatment with P2Y12 receptor inhibitors administered to patients with non-ST elevation ACS independently of the treatment strategy applied, medical or invasive. We included in the present meta-analysis not only randomized placebo controlled trials but also registries; we evaluated the global effect independently of revascularization (all patients included in the analysis) and the effect only in patients undergoing PCI, to evaluate potential differences according to the management strategy used.
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