The recanalization after thrombolysis as surrogate for clinical outcomes in patients with ST‐segment elevation acute myocardial infarction: A systematic review and meta‐regression analysis of data from randomized controlled trials

Abstract

Thrombolytic therapy has been known to be effective in reducing clinical outcomes and increasing recanalization rate among patients with ST-segment elevation acute myocardial infarction (STEMI). However, whether post-thrombolysis recanalization could be used as a surrogate for clinical outcomes is unknown.Methods: We systematically searched PubMed, EMBASE and the Cochrane Library database to identify randomized controlled trials (RCT) that examined effects of thrombolytic agents in STEMI. Recanalization was defined as TIMI grade 2 or 3 flow.The primary outcome was in-hospital all-cause mortality. Secondary outcomes included in-hospital and 30-day recurrent myocardial infarction (re-MI), composite of death and re-MI, major bleeding and all bleeding. Random-effects meta-regression was used for analysis. Results:We identified 111 eligible study arms and 52 eligible comparisons from 58 RCTs involving 16 536 patients. Our analyses showed that among study arms recanalization rate was significantly inversely associated with the incidence of inhospital all-cause mortality (β: À0.07, 95% confidence interval [CI]: À0.13 to À0.02), re-MI (β: À0.09, 95%CI: À0.18 to À0.01) and the composite of death and re-MI (β: À0.17, 95%CI: À0.28 to À0.05), and positively associated with in-hospital all bleeding but not with major bleeding. Among paired comparisons, the difference in recanalization rate was associated with the corresponding difference in incidence of in-hospital all-cause mortality (β: À0.15, 95%CI: À0.28 to À0.01) but the relationship was not significant for any other outcome. Conclusion:Pooled evidence from RCTs suggest the potential use of recanalization as a surrogate for clinical outcomes in evaluating the efficacy of thrombolysis among patients with STEMI.

Tenecteplase versus alteplase in treatment of acute ST-segment elevation myocardial infarction: A randomized non-inferiority trial

“…There was no statistically significant difference between intervention groups in any safety endpoints. As recanalization has been a validated surrogate endpoint of clinical outcomes, [15] we could further extend our conclusion of the non-inferiority in reperfusion to that in clinical endpoints. Our experience indicated the importance of studies validating the surrogate endpoints for innovative drug development.…”

“…For the present study, the study treatment strategy of fibrinolysis in patients with STEMI has been studied intensively previously, allowing for a well-powered meta-analysis. [ 15 ] The systematic review and meta-analysis analyzed data from 58 RCTs with randomized controlled design, with 111 eligible study arms and 52 eligible comparisons involving a total of 16,536 patients, and the pooled evidence from these RCTs demonstrated that recanalization, defined by TIMI 2/3 flow, was a validated surrogate for clinical endpoints in evaluating the efficacy of fibrinolysis among patients with STEMI. [ 15 ] The results from multiple prospective studies conducted in Chinese patients with STEMI also suggested a significant relationship between the patency of infarct-related coronary arteries and clinical events.…”

“…[ 15 ] The systematic review and meta-analysis analyzed data from 58 RCTs with randomized controlled design, with 111 eligible study arms and 52 eligible comparisons involving a total of 16,536 patients, and the pooled evidence from these RCTs demonstrated that recanalization, defined by TIMI 2/3 flow, was a validated surrogate for clinical endpoints in evaluating the efficacy of fibrinolysis among patients with STEMI. [ 15 ] The results from multiple prospective studies conducted in Chinese patients with STEMI also suggested a significant relationship between the patency of infarct-related coronary arteries and clinical events. [ 22 , 23 ] Based on the findings from the systematic review and meta-analysis, we were able to change our primary outcome from MACCEs to recanalization.…”

“…Before replacement, a systematic review and meta-analysis on the association of post-fibrinolysis recanalization (defined by TIMI flow 2 or 3) and the risk of clinical outcomes was performed by retrieving data from all published randomized controlled trials (RCT) globally on the efficacy and safety of fibrinolytic agents, and the results strongly supported recanalization defined by TIMI flow 2 to 3 as a validated surrogate marker for clinical endpoints in evaluating the efficacy of fibrinolysis among patients with STEMI. [ 15 ]…”

“…Before replacement, a systematic review and metaanalysis on the association of post-fibrinolysis recanalization (defined by TIMI flow 2 or 3) and the risk of clinical outcomes was performed by retrieving data from all published randomized controlled trials (RCT) globally on the efficacy and safety of fibrinolytic agents, and the results strongly supported recanalization defined by TIMI flow 2 to 3 as a validated surrogate marker for clinical endpoints in evaluating the efficacy of fibrinolysis among patients with STEMI. [15] Considering that less than half of our participants had angiography and the approved association of clinically judged recanalization and TIMI flow-defined recanalization, [16,17] we used recanalization justified by a non-invasive clinical index as the secondary endpoint. The original primary endpoint, 30-day MACCEs and its components will also be reported but as exploratory endpoints.…”