Low-Dose Alteplase During Primary Percutaneous Coronary Intervention According to Ischemic Time

BACKGROUND Microvascular obstruction affects one-half of patients with ST-segment elevation myocardial infarction and confers an adverse prognosis. OBJECTIVES This study aimed to determine whether the ef ﬁ cacy and safety of a therapeutic strategy involving low-dose intracoronary alteplase infused early after coronary reperfusion associates with ischemic time. METHODS This study was conducted in a prospective, multicenter, parallel group, 1:1:1 randomized, dose-ranging trial in patients undergoing primary percutaneous coronary intervention. Ischemic time, de ﬁ ned as the time from symptom onset to coronary reperfusion, was a pre-speci ﬁ ed subgroup of interest. Between March 17, 2016, and December 21, 2017, 440 patients, presenting with ST-segment elevation myocardial infarction within 6 h of symptom onset ( < 2 h, n ¼ 107; $ 2 h but < 4 h, n ¼ 235; $ 4 h to 6 h, n ¼ 98), were enrolled at 11 U.K. hospitals. Participants were randomly assigned to treatment with placebo (n ¼ 151), alteplase

P rimary percutaneous coronary intervention (PPCI) to emergently reopen the occluded coronary artery, restore blood flow, and secure vessel patency with a stent is the evidence-based standard of care for ST-segment elevation myocardial infarction (STEMI) (1). However, the success of PPCI is limited by failed microvascular reperfusion, which occurs in one-half of all treated patients (2,3). This complication, described as microvascular obstruction (MVO), is associated with adverse left ventricular remodeling and reduced left ventricular function and is independently predictive of cardiac prognosis (4).
During PPCI, distal embolization of thrombus within the lumen of the infarct-related coronary artery and microvascular thrombosis (5)(6)(7)(8)(9), notably of fibrin-rich microthrombi (6), contribute to MVO. Myocardial hemorrhage is closely related to MVO (3) and occurs when endothelial cell injury compromises capillary integrity leading to the extravasation of blood into the extracellular space. T 2 *-weighted cardiac magnetic resonance (CMR) is the established method to identify and evaluate myocardial hemorrhage in vivo, accumulation of paramagnetic hemoglobin breakdown products leads to a shortening of T 2 * relaxation times, resulting in a hypointense zone on imaging that represents tissue hemorrhage (9,10). Late gadoliniumenhanced CMR imaging is used to identify MVO, a dark area representing failed perfusion at the core of the bright infarct. Validation in swine established that the hypointense core on T 2 * imaging corresponds with severe capillary loss and destruction resulting in tissue hemorrhage, with excellent anatomical correlation between the localization and extent of MVO and myocardial hemorrhage (9).
Fibrinolytic therapy is an effective treatment for acute coronary thrombosis (11). A facilitated PCI strategy involving full-or half-dose adjunctive fibrinolytic therapy given before PCI with stenting improves coronary flow acutely (12,13). Similarly, in patients with an expected PCI-related delay, half-dose alteplase and timely PCI improves epicardial and myocardial flow when compared with PPCI alone. However, combination-facilitated PCI involving either full-dose (14) or half-dose lytic therapy (15) causes paradoxical activation of thrombin, clot formation, and bleeding.
In T-TIME (A Trial of Low-Dose Adjunctive Alteplase During Primary PCI), we hypothesized that a therapeutic strategy involving low-dose intracoronary fibrinolytic therapy with alteplase infused early after coronary reperfusion would reduce MVO. Patients with acute STEMI presenting <6 h after symptom onset and a large thrombus burden evident at initial coronary angiography were enrolled in a 3-arm dose-ranging design (10 or 20 mg of alteplase or placebo). The primary analysis determined that alteplase did not reduce the amount of MVO revealed by CMR imaging 2 to 7 days post-MI (primary outcome) and the secondary outcomes were consistent with this result (16).
Infarct size is influenced by ischemic time (17), as are the efficacies of primary reperfusion therapies, including systemic fibrinolysis (18) and primary PCI (19). In this pre-specified analysis, we hypothesized that the effects of adjunctive intracoronary administration of low-dose alteplase during PPCI could be associated with ischemic time. We assessed the as-   The participants are grouped by treatment group and ischemic time. Two patients (1 randomized to placebo and 1 randomized to 10 mg alteplase) received 20 mg alteplase because an incorrect treatment pack had been selected. Four patients were unable to complete the CMR examination meaning evaluable data for the primary outcome was not available: placebo group (n ¼ 1); 10 mg-alteplase group (n ¼ 2); 20 mg-alteplase group (n ¼ 1  Table 4).
There was no evidence of any treatment effects in relation to infarct size, or myocardial salvage index at 2 to 7 days or 3 months.  Table 3). There were no statistically significant interactions observed for fibrin D-dimers, prothrombin F1 þ 2 (a measure of thrombin activation), tissue plasminogen activator (a measure of endogenous tissue plasminogen activator and any circulating alteplase), plasminogen, or fibrinogen (Supplemental Table 4).

DISCUSSION
The principal findings from the T-TIME trial were that the intervention was feasible but not effective (16).
Adjunctive, low-dose intracoronary alteplase administered after coronary reperfusion and before stent implantation did not reduce the amount of MVO revealed by cardiac CMR 2 to 7 days post-STEMI.
In this pre-specified analysis, low-dose intra-  Values are mean AE SD or n (%), unless otherwise indicated. All outcomes were pre-specified. Treatment effect estimates derived from linear or logistic regression models, modelling the treatment effect as a linear trend across alteplase dose groups (0 mg vs. 10 mg vs. 20 mg). Interaction test p values reported from regression models with ischemic time included as a 3-level categorical variable and interaction with treatment effect. Treatment effect estimates and tests of interaction are based on models assuming a linear trend with alteplase dose. The p values and 95% CI have not been adjusted for multiplicity, therefore these analyses should be interpreted as exploratory and not definitive.          Abbreviations as in Table 2.  Values are mean AE SD or n (%), unless otherwise indicated. All outcomes were pre-specified. Treatment effect estimates derived from linear or logistic regression models, modelling the treatment effect as a linear trend across alteplase dose groups (0 mg vs. 10 mg vs. 20 mg). Interaction test p values reported from regression models with ischemic time included as a 3-level categorical variable and interaction with treatment effect. Treatment effect estimates and tests of interaction are based on models assuming a linear trend with alteplase dose. The p values and 95% CI have not been adjusted for multiplicity, therefore these analyses should be interpreted as exploratory and not definitive.
Abbreviations as in Table 2.
reperfused ST-segment elevation myocardial infarction. J Am Heart Assoc 2017;6:e005651. KEY WORDS fibrinolysis, microvascular obstruction, myocardial hemorrhage, primary percutaneous coronary intervention, STsegment elevation myocardial infarction APPENDIX For supplemental methods and tables, please see the online version of this paper.