Introduction and Hypothesis. The role of inflammation is widely recognized in the pathogenesis of coronary artery disease. Research on animal models had shown the potential benefits of targeting specific inflammatory pathways. However, studies on human subjects are limited with small number of patients and no head-to-head comparisons. Methods. We conducted a network meta-analysis of randomized controlled trials that studied the effects of anti-inflammatory medications on cardiovascular outcomes of coronary artery disease patients. We searched the electronic database until March 2020 for relevant studies. Results. Nineteen trials examining the efficacy of eight anti-inflammatory medications (pexelizumab, anakinra, colchicine, darapladib, varespladib, canakinumab, inclacumab, and losmapimod) were selected for analysis. Overall, there is no statistically significant difference in all-cause mortality, cardiovascular mortality, revascularization, and major cardio and cerebrovascular events (MACCE) with the use of anti-inflammatory drugs. However, we found the use of colchicine significantly reduces the odds of developing stroke by approximately 75% (OR 0.26, CI 0.10-0.63). Colchicine use was also associated with a lower risk of revascularization and MACCE compared to the other agents. Our subgroup analyses comparing the timing of medication initiation (within 7 days vs. >7 days) and clinical presentation (ACS vs. non-ACS) revealed a significant reduction in the risk of recurrent MI in the group that received medication after seven days (OR 0.92, CI 0.86-0.99) and the non-ACS group (OR 0.88, CI 0.80-0.98). Conclusion. Although many anti-inflammatory medications have failed to reduce adverse cardiovascular outcomes in the CAD population, selected medications show promise among subgroups of patients without ACS or after the first week following an acute ischemic event. Future studies examining the proper timing and targetable anti-inflammatory pathways are warranted.
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Ahmed Abdel-Latif is supported by the NIH R01 grant # HL124266.
The following supplementary materials are available for download as the additional file listed at the end of this record:
Supplemental Table 1: bias risk assessment of the studies. Supplemental Figure 1: forest plot for network meta-analysis comparing the relative efficacy of each anti-inflammatory medication on all-cause death. Use of pexelizumab is associated with lower risk of all-cause mortality in comparison with veraspladib (OR 0.62, CI 0.37–0.99). Supplemental Figure 2: forest plot for network meta-analysis comparing the relative efficacies of each anti-inflammatory medication on cardiovascular death. Supplemental Figure 3: forest plot for network meta-analysis of myocardial infarction. Uses of canakinumab, colchicine, darapladib, and pexelizumab were associated with lower risk of recurrent myocardial infarction in comparison with anakinra (OR 0.20, CI 0.04–0.79; OR 0.21, CI 0.04–0.83; OR 0.22, CI 0.04–0.81; and OR 0.22, CI 0.05–0.82, respectively). Supplemental Figure 4: forest plot for network meta-analysis of revascularization. Use of colchicine significantly reduced the risk of revascularization in comparison to both anakinra and darapladib (OR 0.31, CI 0.11–0.84 and OR 0.52, CI 0.29–0.93, respectively). Supplemental Figure 5: forest plot for network meta-analysis of stroke. Use of colchicine was associated with significant reduced risk of stroke events after myocardial infarction in comparison to several anti-inflammatory medications including: darapladib (OR 0.23, CI 0.07-0.57), pexelizumab (OR 0.23, CI 0.07-0.64), losmapimod (OR 0.25, CI 0.07-0.85), canakinumab (OR 0.30, CI 0.09-0.81), and veraspladib (OR 0.26, CI 0.07-0.97). Supplemental Figure 6: forest plot for network meta-analysis comparing the relative efficacy of each anti-inflammatory medication on major adverse cardiac and cerebrovascular events (MAACE). Colchicine use was associated with significantly lower risk of MACCE when compared to darapladib (OR 0.69, CI 0.44-0.98), losmapimod (OR 0.60, CI 0.37-0.93), anakinra (OR 0.28 CI 0.10–0.70), and varespladib (OR 0.53, CI 0.32-0.83). Both canakinumab and pexelizumab were associated with reduced risk of MACCE (OR 0.37, CI 0.13–0.95 and OR 0.39, CI 0.14–0.96, respectively). Supplemental Figure 7: network plot of treatments included in this network meta-analysis. Circles represent the intervention as a node in the network, lines represent direct comparisons using randomized clinical trials (RCTs), and the thickness of lines corresponds to the number of (RCTs) included in each comparison. Supplemental Figure 8: funnel plots of odds ratios and standard errors to assess the publication bias of all-cause mortality, cardiac mortality, revascularization, stroke, recurrent myocardial infarction, and major adverse cardiac and cerebrovascular events (MACCE). Supplemental Figure 9: consistency plot for all-cause mortality, cardiac mortality, revascularization, stroke, recurrent myocardial infarction, and major adverse cardiac and cerebrovascular events (MACCE).
Wudexi, Ivan; Shokri, Elica; Abo-Aly, Mohamed; Shindo, Kazuhiro; and Abdel-Latif, Ahmed, "Comparative Effectiveness of Anti-Inflammatory Drug Treatments in Coronary Heart Disease Patients: A Systematic Review and Network Meta-Analysis" (2021). Gill Heart & Vascular Institute Faculty Publications. 23.