Aspirin Dosing Cardiac Events and Bleeding Events
This is the first meta-analysis to our knowledge that investigates the role of maintenance aspirin dose in patients with ACS and the occurrence of thrombotic or bleeding events following SI or MT. We analyzed data from 136 primary publications and 289,330 patients; and the results suggest that there was no difference in the rate of thrombotic events between the ASA doses studied, even after adjusting for select confounders.
There were only 2 randomized clinical trials that directly addressed long-term maintenance doses of ASA in ACS patients. Therefore, we pooled the evidence available from studies that included ASA in the immediate post-ACS care period and reported clinical outcomes according to categories of ASA doses. The data suggest that published studies do not indicate a clear clinical difference in the occurrence of stroke, MACE, or MI in patients with ACS who were treated with either low or high doses of ASA for 1 to 6 months. In light of the paucity of comparative ASA dosing trials in ACS patients, we performed a supplemental targeted search using similar search terms without primary ACS treatment regimen terminology (ie, SI, CABG, or MT) to ensure that our approach did not exclude key trials comparing ASA doses in ACS patients with mixed primary treatments. The supplemental search results confirmed that our search and screening strategy did not prevent a meaningful comparative analysis.
Our results are consistent with the recently published CURRENT OASIS 7 trial in which ACS patients who were scheduled to undergo angiography within 72 hours of hospital arrival were treated in a factorial design with low- or high-dose ASA and clopidogrel for 30 days. There were no significant differences in outcomes between these 2 groups except for an increased risk of minor bleeding in the higher-dose ASA group. The section of our review that focused on ACS patients who received stent placement had similar patient and treatment characteristics to the CURRENT OASIS 7 trial and also showed no significant difference between ASA groups on major bleeding, or MACE at 1 month or 6 months. Although the CURRENT OASIS 7 study was published after our search cutoff date, we performed a sensitivity analysis that confirmed that our results and conclusions would not change if we incorporated the CURRENT OASIS 7 data.
The CURE study (inclusive of the PCI-CURE substudy) was the only study included in our review that stratified analysis by low (≤100 mg), medium (101–199 mg), and high (≥200 mg) ASA dose, although this was a post hoc analysis. Again, in line with our overall findings and with the CURRENT OASIS 7 trial, the CURE trial found no differences in primary outcome variables among ASA doses, but instead reported significantly more patients experiencing major bleeding and life-threatening bleeding events in groups with higher ASA dose.
We performed meta-regression analyses in an attempt to adjust for potential confounders. The ASA dose did not show a statistically significant difference on the outcomes analyzed for clinical outcome at either 1 or 6 months when adjusted for age, sex, or year of publication. However, similar to Peters et al (2003), who found an increase in bleeding events with higher ASA doses, the results for major bleeding at 1 month suggested that the difference in proportions of patients who experienced major bleeding would be significantly higher among those who received high-dose ASA compared with those who received low-dose ASA in studies evaluating patients who received MT.
Although we attempted to represent all patients treated for ACS, we did not find enough data to allow us to assess ASA dose and clinical outcomes in patients who underwent CABG surgery as primary treatment. Although CABG is used widely in the management of ACS patients with major occlusions, given the severity of the procedure and the alternatives, there are fewer publications that report outcomes specifically for patients undergoing CABG procedures in ACS-only populations. In addition, given the known risks of bleeding associated with high-dose ASA, use of the lowest effective dose is warranted.
As with all observational analyses, interpretation is limited to associations without the ability to deduce attribution. Our analysis of summary level data compromised the precision of our meta analysis and did not allow us to perform time-to-event analyses. In addition, randomization to various other non–ASA-based treatment protocols contributed to heterogeneity in the data. Some of the factors contributing to heterogeneity included differences in enrolment procedures, MT regimens and timing of administration, and study designs (RCTs, cohort studies, and retrospective studies), and some inconsistencies in the definitions of bleeding and MACE. Similarly, publications did not always define the make-up of the ACS populations such that it was a challenge to fully understand and, therefore, control for the severity and types of ACS patients. In addition, both the definitive and adjunct treatments for ACS varied. Although the meta-regression was aimed at addressing some of the heterogeneity by adjusting for potential confounders that are reported consistently, because of the differences in the format in which age was reported, our meta-regression results did not include the roughly 40,000 patients of the ISIS 3 trial. Unfortunately, because of the inconsistent reporting of other likely confounders mentioned above, our regression analysis was not able to adjust for many of the potential drivers of the data heterogeneity.
Discussion
This is the first meta-analysis to our knowledge that investigates the role of maintenance aspirin dose in patients with ACS and the occurrence of thrombotic or bleeding events following SI or MT. We analyzed data from 136 primary publications and 289,330 patients; and the results suggest that there was no difference in the rate of thrombotic events between the ASA doses studied, even after adjusting for select confounders.
There were only 2 randomized clinical trials that directly addressed long-term maintenance doses of ASA in ACS patients. Therefore, we pooled the evidence available from studies that included ASA in the immediate post-ACS care period and reported clinical outcomes according to categories of ASA doses. The data suggest that published studies do not indicate a clear clinical difference in the occurrence of stroke, MACE, or MI in patients with ACS who were treated with either low or high doses of ASA for 1 to 6 months. In light of the paucity of comparative ASA dosing trials in ACS patients, we performed a supplemental targeted search using similar search terms without primary ACS treatment regimen terminology (ie, SI, CABG, or MT) to ensure that our approach did not exclude key trials comparing ASA doses in ACS patients with mixed primary treatments. The supplemental search results confirmed that our search and screening strategy did not prevent a meaningful comparative analysis.
Our results are consistent with the recently published CURRENT OASIS 7 trial in which ACS patients who were scheduled to undergo angiography within 72 hours of hospital arrival were treated in a factorial design with low- or high-dose ASA and clopidogrel for 30 days. There were no significant differences in outcomes between these 2 groups except for an increased risk of minor bleeding in the higher-dose ASA group. The section of our review that focused on ACS patients who received stent placement had similar patient and treatment characteristics to the CURRENT OASIS 7 trial and also showed no significant difference between ASA groups on major bleeding, or MACE at 1 month or 6 months. Although the CURRENT OASIS 7 study was published after our search cutoff date, we performed a sensitivity analysis that confirmed that our results and conclusions would not change if we incorporated the CURRENT OASIS 7 data.
The CURE study (inclusive of the PCI-CURE substudy) was the only study included in our review that stratified analysis by low (≤100 mg), medium (101–199 mg), and high (≥200 mg) ASA dose, although this was a post hoc analysis. Again, in line with our overall findings and with the CURRENT OASIS 7 trial, the CURE trial found no differences in primary outcome variables among ASA doses, but instead reported significantly more patients experiencing major bleeding and life-threatening bleeding events in groups with higher ASA dose.
We performed meta-regression analyses in an attempt to adjust for potential confounders. The ASA dose did not show a statistically significant difference on the outcomes analyzed for clinical outcome at either 1 or 6 months when adjusted for age, sex, or year of publication. However, similar to Peters et al (2003), who found an increase in bleeding events with higher ASA doses, the results for major bleeding at 1 month suggested that the difference in proportions of patients who experienced major bleeding would be significantly higher among those who received high-dose ASA compared with those who received low-dose ASA in studies evaluating patients who received MT.
Although we attempted to represent all patients treated for ACS, we did not find enough data to allow us to assess ASA dose and clinical outcomes in patients who underwent CABG surgery as primary treatment. Although CABG is used widely in the management of ACS patients with major occlusions, given the severity of the procedure and the alternatives, there are fewer publications that report outcomes specifically for patients undergoing CABG procedures in ACS-only populations. In addition, given the known risks of bleeding associated with high-dose ASA, use of the lowest effective dose is warranted.
Limitations
As with all observational analyses, interpretation is limited to associations without the ability to deduce attribution. Our analysis of summary level data compromised the precision of our meta analysis and did not allow us to perform time-to-event analyses. In addition, randomization to various other non–ASA-based treatment protocols contributed to heterogeneity in the data. Some of the factors contributing to heterogeneity included differences in enrolment procedures, MT regimens and timing of administration, and study designs (RCTs, cohort studies, and retrospective studies), and some inconsistencies in the definitions of bleeding and MACE. Similarly, publications did not always define the make-up of the ACS populations such that it was a challenge to fully understand and, therefore, control for the severity and types of ACS patients. In addition, both the definitive and adjunct treatments for ACS varied. Although the meta-regression was aimed at addressing some of the heterogeneity by adjusting for potential confounders that are reported consistently, because of the differences in the format in which age was reported, our meta-regression results did not include the roughly 40,000 patients of the ISIS 3 trial. Unfortunately, because of the inconsistent reporting of other likely confounders mentioned above, our regression analysis was not able to adjust for many of the potential drivers of the data heterogeneity.
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