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

Abstract

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 efficacy 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, defined as the time from symptom onset to coronary reperfusion, was a pre-specified 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 = 107; ≥2 h but <4 h, n = 235; ≥4 h to 6 h, n = 98), were enrolled at 11 U.K. hospitals. Participants were randomly assigned to treatment with placebo (n = 151), alteplase 10 mg (n = 144), or alteplase 20 mg (n = 145). The primary outcome was the amount of microvascular obstruction (MVO) (percentage of left ventricular mass) quantified by cardiac magnetic resonance imaging at 2 to 7 days (available for 396 of 440).

Results: Overall, there was no association between alteplase dose and the extent of MVO (p for trend = 0.128). However, in patients with an ischemic time ≥4 to 6 h, alteplase increased the mean extent of MVO compared with placebo: 1.14% (placebo) versus 3.11% (10 mg) versus 5.20% (20 mg); p = 0.009 for the trend. The interaction between ischemic time and alteplase dose was statistically significant (p = 0.018).

Conclusion: In patients presenting with ST-segment elevation myocardial infarction and an ischemic time ≥4 to 6 h, adjunctive treatment with low-dose intracoronary alteplase during primary percutaneous coronary intervention was associated with increased MVO. Intracoronary alteplase may be harmful for this subgroup. (A Trial of Low-Dose Adjunctive Alteplase During Primary PCI [T-TIME]; NCT02257294).

Keywords: ST-segment elevation myocardial infarction; fibrinolysis; microvascular obstruction; myocardial hemorrhage; primary percutaneous coronary intervention.

Graphical abstract

Figure 1

T-TIME Flow Diagram 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 = 1); 10 mg–alteplase group (n = 2); 20 mg–alteplase group (n = 1). CMR = cardiac magnetic resonance; T-TIME = A Trial of Low-Dose Adjunctive Alteplase During Primary PCI.

Central Illustration

Efficacy of Intracoronary Alteplase and Mechanism of Increased Microvascular Injury in Patients With an Ischemic Time of ≥4 to 6 h The flow diagram groups participants by ischemic time into 3 categories (≥4 to 6 h, n = 98; ≥2 but <4 h, n = 235; <2 h, n = 107), those with an ischemic time of 4 h or more are subgrouped according to treatment group allocation (placebo, n = 29; 10 mg alteplase n = 38; 20 mg alteplase, n = 31). The effect of intracoronary alteplase on the extent of microvascular obstruction and myocardial hemorrhage is shown, including the effect estimates. The estimated mean difference on a square root scale is shown for the extent of microvascular obstruction and the estimated mean difference for myocardial hemorrhage. There was a statistically significant increase in microvascular obstruction and myocardial hemorrhage extent in those patients receiving alteplase. CI = confidence interval.

Figure 2

Clinical Case Examples Two patients, both with acute lateral ST-segment elevation myocardial infarction treated successfully with primary percutaneous coronary intervention. Each patient had TIMI (Thrombolysis In Myocardial Infarction) flow grade 0 at initial angiography and TIMI flow grade 3 (normal flow grade) at the end of percutaneous coronary intervention. The first with an ischemic time of 5 h and the second 3 h. Cardiac magnetic resonance (CMR) was performed at 3 days post-reperfusion. (A) Patient with hemorrhagic infarction on CMR. Diagnostic coronary angiogram demonstrated an occluded circumflex artery (yellow arrow). T₂*-CMR (far right) revealed myocardial hemorrhage (white arrow) within the infarct core. Late gadolinium-enhanced CMR revealed microvascular obstruction (middle, red arrow) within the bright area of infarction. The microvascular obstruction within the infarct core spatially corresponded with the myocardial hemorrhage. This represents a case of failed microvascular reperfusion despite successful percutaneous coronary intervention. (B) Patient with a lateral infarct but no CMR evidence of reperfusion injury. Diagnostic coronary angiogram demonstrated an occluded circumflex artery (yellow arrow). Late gadolinium-enhanced CMR revealed a lateral infarct with no evidence of microvascular obstruction and no evidence of hemorrhagic transformation on T₂*-CMR. This represents a case of successful microvascular reperfusion.