Thienopyridine Pretreatment in Non-ST Elevation ACS
Thienopyridine Pretreatment in Non-ST Elevation ACS
Pretreatment with P2Y12 receptor antagonists (here thienopyridines, in the absence of data for the other drugs of the same class) is not associated globally with a favorable risk-benefit ratio in patients with non-ST elevation ACS. We were unable to show a benefit on mortality, but there was significant harm with a consistent excess of major bleeding across all the analyses. The modest reduction of major adverse cardiovascular events was driven by the old randomized studies of clopidogrel and the observational studies with clopidogrel, but not confirmed in the more recent randomized studies using clopidogrel. Surprisingly, this effect on major adverse cardiovascular events was not driven by the cohort of patients who underwent percutaneous coronary intervention (PCI), in which we may have expected a particular benefit of pretreatment.
This work focused on patients with non-ST elevation ACS, independently of the management strategy and study drug used for pretreatment. Pretreatment with thienopyridines evaluated in more than 30,000 patients presenting with non-ST elevation ACS was not associated with a reduction in all cause death. The 16% reduction in major adverse cardiovascular events was driven by a (non-significant) reduction of myocardial infarction—a diagnosis based on an elevation of cardiac markers which may be related to the initial event, the procedure of revascularization, or, more rarely, to a recurrent event. This reduction in major adverse cardiovascular events was balanced by a 27-43% excess of major bleeding depending on the analysis performed. Unfortunately, we were unable to define a subgroup that may benefit more from pretreatment, like the PCI cohort, which did not perform better in this analysis, alike in the recent ACCOAST study. Pretreatment in patients who finally underwent PCI was associated with little effect on major adverse cardiovascular events (17% odds reduction, P=0.06) and an excess of major bleeding of a larger magnitude (23% odds excess, P=0.048). This may explain the absence of effect observed on survival.
The concept of pretreatment was introduced for patients with non-ST elevation ACS after the CURE study. This study already showed a similar pattern (reduction in myocardial infarction and excess of major bleeding) but with a conservative management strategy and only 21% of patients undergoing PCI (82% of stents), for which only the control group had four weeks of clopidogrel 75 mg after PCI. Consequently, CURE and its sub-study PCI-CURE did not really evaluate pretreatment, a treatment given before scheduled catheterization or PCI, but evaluated dual antiplatelet therapy in patients managed medically with a minority undergoing delayed catheterization, often several days after admission. The addition of more recent studies in this meta-analysis, including observational studies, allows better representation of contemporary practice with more frequent intervention and faster access to the catheterization laboratory, but also with more heterogeneity.
Examining the randomized studies only or all the studies did not modify the results, with a questionable risk-benefit balance and no impact on mortality despite an analysis performed on more than 32,000 patients. The benefit observed on major adverse cardiovascular events in all patients with non-ST elevation ACS was driven by the observational studies and the two oldest randomized trials with clopidogrel. The results were at odds with the two recent randomized trials with clopidogrel and the one with prasugrel. It is difficult to sort out the benefit of pretreatment on major adverse cardiovascular events in the current era, with rapid access of patients to the catheterization laboratory and use of modern techniques of revascularization. Similar results were also found in patients with stable coronary artery disease who underwent elective PCI, where pretreatment with clopidogrel did not confer any ischemic benefit but significantly increased bleedings complications.
Routine pretreatment is even more questionable nowadays, when patients reach the catheterization laboratory within 3-4 hours of admission, a delay that does not allow adequate platelet inhibition with clopidogrel in case of PCI but still exposes all patients, sometimes unnecessarily, to the risk of bleeding for several days after loading. The advantage of pretreatment is also less obvious with the availability of the new P2Y12 antagonists that have a rapid onset of action, are indicated in non-ST elevation ACS, and can be used after coronary artery disease has been diagnosed and the indication of PCI confirmed, as tested now in three large trials. Indeed, cangrelor, an intravenous P2Y12 antagonist of immediate action, showed superiority over clopidogrel in patients undergoing PCI with an excellent safety profile. Prasugrel, which has a faster and stronger antiplatelet effect than clopidogrel, also showed the valididy of a strategy of later administration once the coronary anatomy has been defined.
We acknowledge several limitations to our study. As with any meta-analysis, several biases may have interfered with the final results, for which precautions and limitations have been described elsewhere. Confidence intervals are wide, and definite conclusion cannot been made solely on point estimates without taking the variability about them into consideration. In addition, confounding by indication, although controlled, cannot be excluded in registries, and we found significant heterogeneity between observational studies on clopidogrel, which may limit conclusions. This heterogeneity might be due to differences in clinical presentation (non-ST elevation ACS at low or higher risk), in bleeding risk, and in the dose and timing of clopidogrel pretreatment ( Table 1 ). However, the global results using all studies available were confirmed in the more robust subgroup of randomized controlled trials and the pre-specified sensitivity analyses.
Another limitation relates to the 300 mg clopidogrel loading dose, where we cannot exclude the possibility that a higher dose, which is known to confer faster and stronger platelet inhibition, would have given a different result. However, the only study in this meta-analysis that used a 600 mg loading dose did not favor pretreatment, and the CURRENT study did not confirm the superiority of 600 mg over 300 mg of clopidogrel in the global management of non-ST elevation ACS. Because no data are available for ticagrelor, conclusions cannot be drawn for this drug. Postponing treatment to after the coronary angiogram is certainly acceptable in patients reaching the catheterization laboratory within 48 hours after admission, as in the studies that tested this hypothesis, but not in patients with longer waiting periods or for emergent cases (ST-elevation-like patients) who were not enrolled in these studies.
In conclusion, our meta-analysis shows that in patients with non-ST elevation ACS, pretreatment with thienopyridines is not associated with a lower risk of mortality globally or more specifically in patients undergoing PCI. The reduction of ischemic endpoints is modest and counterbalanced by an increase in major bleeding, no matter the final management strategy with or without PCI. The concept of systematic and immediate pretreatment with P2Y12 antagonists in patients admitted with non-ST elevation ACS needs to be reconsidered.
Discussion
Principal Findings
Pretreatment with P2Y12 receptor antagonists (here thienopyridines, in the absence of data for the other drugs of the same class) is not associated globally with a favorable risk-benefit ratio in patients with non-ST elevation ACS. We were unable to show a benefit on mortality, but there was significant harm with a consistent excess of major bleeding across all the analyses. The modest reduction of major adverse cardiovascular events was driven by the old randomized studies of clopidogrel and the observational studies with clopidogrel, but not confirmed in the more recent randomized studies using clopidogrel. Surprisingly, this effect on major adverse cardiovascular events was not driven by the cohort of patients who underwent percutaneous coronary intervention (PCI), in which we may have expected a particular benefit of pretreatment.
This work focused on patients with non-ST elevation ACS, independently of the management strategy and study drug used for pretreatment. Pretreatment with thienopyridines evaluated in more than 30,000 patients presenting with non-ST elevation ACS was not associated with a reduction in all cause death. The 16% reduction in major adverse cardiovascular events was driven by a (non-significant) reduction of myocardial infarction—a diagnosis based on an elevation of cardiac markers which may be related to the initial event, the procedure of revascularization, or, more rarely, to a recurrent event. This reduction in major adverse cardiovascular events was balanced by a 27-43% excess of major bleeding depending on the analysis performed. Unfortunately, we were unable to define a subgroup that may benefit more from pretreatment, like the PCI cohort, which did not perform better in this analysis, alike in the recent ACCOAST study. Pretreatment in patients who finally underwent PCI was associated with little effect on major adverse cardiovascular events (17% odds reduction, P=0.06) and an excess of major bleeding of a larger magnitude (23% odds excess, P=0.048). This may explain the absence of effect observed on survival.
Strengths and Limitations of the Meta-analysis and Relations With Other Studies
The concept of pretreatment was introduced for patients with non-ST elevation ACS after the CURE study. This study already showed a similar pattern (reduction in myocardial infarction and excess of major bleeding) but with a conservative management strategy and only 21% of patients undergoing PCI (82% of stents), for which only the control group had four weeks of clopidogrel 75 mg after PCI. Consequently, CURE and its sub-study PCI-CURE did not really evaluate pretreatment, a treatment given before scheduled catheterization or PCI, but evaluated dual antiplatelet therapy in patients managed medically with a minority undergoing delayed catheterization, often several days after admission. The addition of more recent studies in this meta-analysis, including observational studies, allows better representation of contemporary practice with more frequent intervention and faster access to the catheterization laboratory, but also with more heterogeneity.
Examining the randomized studies only or all the studies did not modify the results, with a questionable risk-benefit balance and no impact on mortality despite an analysis performed on more than 32,000 patients. The benefit observed on major adverse cardiovascular events in all patients with non-ST elevation ACS was driven by the observational studies and the two oldest randomized trials with clopidogrel. The results were at odds with the two recent randomized trials with clopidogrel and the one with prasugrel. It is difficult to sort out the benefit of pretreatment on major adverse cardiovascular events in the current era, with rapid access of patients to the catheterization laboratory and use of modern techniques of revascularization. Similar results were also found in patients with stable coronary artery disease who underwent elective PCI, where pretreatment with clopidogrel did not confer any ischemic benefit but significantly increased bleedings complications.
Routine pretreatment is even more questionable nowadays, when patients reach the catheterization laboratory within 3-4 hours of admission, a delay that does not allow adequate platelet inhibition with clopidogrel in case of PCI but still exposes all patients, sometimes unnecessarily, to the risk of bleeding for several days after loading. The advantage of pretreatment is also less obvious with the availability of the new P2Y12 antagonists that have a rapid onset of action, are indicated in non-ST elevation ACS, and can be used after coronary artery disease has been diagnosed and the indication of PCI confirmed, as tested now in three large trials. Indeed, cangrelor, an intravenous P2Y12 antagonist of immediate action, showed superiority over clopidogrel in patients undergoing PCI with an excellent safety profile. Prasugrel, which has a faster and stronger antiplatelet effect than clopidogrel, also showed the valididy of a strategy of later administration once the coronary anatomy has been defined.
We acknowledge several limitations to our study. As with any meta-analysis, several biases may have interfered with the final results, for which precautions and limitations have been described elsewhere. Confidence intervals are wide, and definite conclusion cannot been made solely on point estimates without taking the variability about them into consideration. In addition, confounding by indication, although controlled, cannot be excluded in registries, and we found significant heterogeneity between observational studies on clopidogrel, which may limit conclusions. This heterogeneity might be due to differences in clinical presentation (non-ST elevation ACS at low or higher risk), in bleeding risk, and in the dose and timing of clopidogrel pretreatment ( Table 1 ). However, the global results using all studies available were confirmed in the more robust subgroup of randomized controlled trials and the pre-specified sensitivity analyses.
Another limitation relates to the 300 mg clopidogrel loading dose, where we cannot exclude the possibility that a higher dose, which is known to confer faster and stronger platelet inhibition, would have given a different result. However, the only study in this meta-analysis that used a 600 mg loading dose did not favor pretreatment, and the CURRENT study did not confirm the superiority of 600 mg over 300 mg of clopidogrel in the global management of non-ST elevation ACS. Because no data are available for ticagrelor, conclusions cannot be drawn for this drug. Postponing treatment to after the coronary angiogram is certainly acceptable in patients reaching the catheterization laboratory within 48 hours after admission, as in the studies that tested this hypothesis, but not in patients with longer waiting periods or for emergent cases (ST-elevation-like patients) who were not enrolled in these studies.
Conclusions and Policy Implications
In conclusion, our meta-analysis shows that in patients with non-ST elevation ACS, pretreatment with thienopyridines is not associated with a lower risk of mortality globally or more specifically in patients undergoing PCI. The reduction of ischemic endpoints is modest and counterbalanced by an increase in major bleeding, no matter the final management strategy with or without PCI. The concept of systematic and immediate pretreatment with P2Y12 antagonists in patients admitted with non-ST elevation ACS needs to be reconsidered.
