Mortality Benefit With Prasugrel in CABG Cohort
Mortality Benefit With Prasugrel in CABG Cohort
Current American College of Cardiology/American Heart Association guidelines recommend the early use of adenosine diphosphate receptor P2Y12 inhibitors in patients with ACS in whom PCI is anticipated. The guidelines also recommend delaying elective CABG for ≥5 days after the last dose of clopidogrel and 7 days after the last dose of prasugrel, if possible. However, these guidelines are based on consensus opinions, and there are concerns that a delay of CABG to reduce bleeding risk may come at the expense of increased risk of myocardial injury/MI and/or stent thrombosis while awaiting surgery. Concern about CABG-related bleeding and difficulty in accurately identifying which patients will require CABG potentially limits early initiation of platelet inhibition along with the potential benefits of thienopyridines in non–ST-segment elevation MI ACS. This retrospective analysis of the patients undergoing CABG in the TRITON–TIMI 38 trial is the first characterization of outcomes in patients receiving prasugrel followed by a CABG procedure, and provides information about the relationship between residual antiplatelet drug activity, perioperative bleeding, and mortality. Overall, this study supports the perception that an increase in residual antiplatelet drug effect increases bleeding and transfusion; however, an increase in residual antiplatelet effect was also shown to be associated with a reduction of mortality hazard in patients treated with prasugrel compared with clopidogrel. Multivariate analyses and standard mortality risk-adjustment methods indicate that this difference is not related to any other potential confounders.
This finding of increased bleeding is also consistent with other studies of antiplatelet agents in which CABG was safely performed during periods of drug effect, presumably for clinical indications obviating surgical delay. Both abciximab and clopidogrel have been shown to have increased bleeding and transfusion outcomes compared with aspirin alone, whereas ticagrelor had similar bleeding and transfusion rates compared with clopidogrel. The observation of increased bleeding, transfusion, and re-exploration observed with the use of prasugrel in patients who require surgical intervention is an important finding for clinicians who are managing these patients in the perioperative setting. A better understanding of the bleeding risk will allow clinicians to be ready with respect to the potential for volume resuscitation, platelet therapy, or other hemostatic therapy for those patients who develop life-threatening bleeding after cardiac surgery.
Similar to prasugrel in the current study, abciximab and ticagrelor have been associated with improved CABG survival versus the comparator. As with these 2 agents, the survival differences are noted primarily in the first 30 days, suggesting that perioperative events related to surgery are affected by residual and continued antiplatelet therapy. The specific mechanism for this survival advantage was unclear for either abciximab or ticagrelor, and the event rates in the current study for other ischemic endpoints and infection endpoints were too small to add understanding given the sample size of this study. This is the first study, to the best of our knowledge, to use standard risk-adjustment methods to confirm that the comparative risk is not related to other potential confounding factors.
First, this study was a retrospective analysis involving patients who were randomized to receive either clopidogrel or prasugrel before an indication for CABG emerged. In this setting, there are possible unknown confounders influencing the baseline risk of CABG that differ between the study arms and may not be corrected for by the methods used. For example, the incidence of COPD and off-pump CABG performance differed between study groups despite investigator blinding to the study drug. The presence of COPD is an incorporated risk factor in the STS and EuroSCORE algorithms but the utilization of cardiopulmonary bypass could not be adjusted for with these tools. Postoperative bleeding is known to be affected by cardiopulmonary bypass and will be further explored, but mortality outcome is not similarly affected. Second, the decision to perform CABG and factors related to the timing of CABG are unknown and were therefore not characterized in this analysis. This decision, combined with the relatively small number of patients in various states of study drug "washout," makes these data difficult to translate into definitive recommendations regarding optimal decision making. In addition, small subgroup size limits the statistical power associated with comparisons between prasugrel and clopidogrel, and the imputation of missing values may potentially limit the risk-adjustment. Finally, the study design of the parent randomized trial, with the stated goal of PCI that was based on knowledge of the coronary anatomy before randomization, resulted in a CABG population enriched with 1- and 2-vessel coronary artery disease. Thus, the results are less generalizable to the typical population of patients referred for bypass surgery in whom 3-vessel disease predominates or in patients who undergo complex or multiple operative procedures. Despite these limitations, this study provides important additional information to surgeons and cardiologists as they determine the appropriate antiplatelet agent to enhance outcomes after PCI, and the impact on overall patient outcome if CABG is eventually selected as the desired revascularization strategy.
Discussion
Current American College of Cardiology/American Heart Association guidelines recommend the early use of adenosine diphosphate receptor P2Y12 inhibitors in patients with ACS in whom PCI is anticipated. The guidelines also recommend delaying elective CABG for ≥5 days after the last dose of clopidogrel and 7 days after the last dose of prasugrel, if possible. However, these guidelines are based on consensus opinions, and there are concerns that a delay of CABG to reduce bleeding risk may come at the expense of increased risk of myocardial injury/MI and/or stent thrombosis while awaiting surgery. Concern about CABG-related bleeding and difficulty in accurately identifying which patients will require CABG potentially limits early initiation of platelet inhibition along with the potential benefits of thienopyridines in non–ST-segment elevation MI ACS. This retrospective analysis of the patients undergoing CABG in the TRITON–TIMI 38 trial is the first characterization of outcomes in patients receiving prasugrel followed by a CABG procedure, and provides information about the relationship between residual antiplatelet drug activity, perioperative bleeding, and mortality. Overall, this study supports the perception that an increase in residual antiplatelet drug effect increases bleeding and transfusion; however, an increase in residual antiplatelet effect was also shown to be associated with a reduction of mortality hazard in patients treated with prasugrel compared with clopidogrel. Multivariate analyses and standard mortality risk-adjustment methods indicate that this difference is not related to any other potential confounders.
This finding of increased bleeding is also consistent with other studies of antiplatelet agents in which CABG was safely performed during periods of drug effect, presumably for clinical indications obviating surgical delay. Both abciximab and clopidogrel have been shown to have increased bleeding and transfusion outcomes compared with aspirin alone, whereas ticagrelor had similar bleeding and transfusion rates compared with clopidogrel. The observation of increased bleeding, transfusion, and re-exploration observed with the use of prasugrel in patients who require surgical intervention is an important finding for clinicians who are managing these patients in the perioperative setting. A better understanding of the bleeding risk will allow clinicians to be ready with respect to the potential for volume resuscitation, platelet therapy, or other hemostatic therapy for those patients who develop life-threatening bleeding after cardiac surgery.
Similar to prasugrel in the current study, abciximab and ticagrelor have been associated with improved CABG survival versus the comparator. As with these 2 agents, the survival differences are noted primarily in the first 30 days, suggesting that perioperative events related to surgery are affected by residual and continued antiplatelet therapy. The specific mechanism for this survival advantage was unclear for either abciximab or ticagrelor, and the event rates in the current study for other ischemic endpoints and infection endpoints were too small to add understanding given the sample size of this study. This is the first study, to the best of our knowledge, to use standard risk-adjustment methods to confirm that the comparative risk is not related to other potential confounding factors.
Study Limitations
First, this study was a retrospective analysis involving patients who were randomized to receive either clopidogrel or prasugrel before an indication for CABG emerged. In this setting, there are possible unknown confounders influencing the baseline risk of CABG that differ between the study arms and may not be corrected for by the methods used. For example, the incidence of COPD and off-pump CABG performance differed between study groups despite investigator blinding to the study drug. The presence of COPD is an incorporated risk factor in the STS and EuroSCORE algorithms but the utilization of cardiopulmonary bypass could not be adjusted for with these tools. Postoperative bleeding is known to be affected by cardiopulmonary bypass and will be further explored, but mortality outcome is not similarly affected. Second, the decision to perform CABG and factors related to the timing of CABG are unknown and were therefore not characterized in this analysis. This decision, combined with the relatively small number of patients in various states of study drug "washout," makes these data difficult to translate into definitive recommendations regarding optimal decision making. In addition, small subgroup size limits the statistical power associated with comparisons between prasugrel and clopidogrel, and the imputation of missing values may potentially limit the risk-adjustment. Finally, the study design of the parent randomized trial, with the stated goal of PCI that was based on knowledge of the coronary anatomy before randomization, resulted in a CABG population enriched with 1- and 2-vessel coronary artery disease. Thus, the results are less generalizable to the typical population of patients referred for bypass surgery in whom 3-vessel disease predominates or in patients who undergo complex or multiple operative procedures. Despite these limitations, this study provides important additional information to surgeons and cardiologists as they determine the appropriate antiplatelet agent to enhance outcomes after PCI, and the impact on overall patient outcome if CABG is eventually selected as the desired revascularization strategy.
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