Low-Dose Alteplase During Primary Percutaneous Coronary Intervention According to Ischemic Time
Key result
Intracoronary alteplase during primary PCI fails to reduce microvascular obstruction in STEMI.
- mean increase in square root-transformed MVO per 10-mg increase in alteplase dose: 0.15
- 95% CI -0.12 to 0.42
- P=0.28
- n=440
Why the study?
Microvascular obstruction affects one-half of patients with STEMI and confers an adverse prognosis, but whether low-dose intracoronary alteplase efficacy and safety associate with ischemic time was unknown.
Does low-dose intracoronary alteplase reduce microvascular obstruction in patients with ST-segment elevation myocardial infarction undergoing primary percutaneous coronary intervention?
Key Points
- To determine whether the efficacy and safety of low-dose intracoronary alteplase administered early after reperfusion varies according to ischemic time in patients undergoing primary percutaneous coronary intervention.
- In a prospective, multicenter, parallel-group trial across 11 U.K. hospitals (N=440), patients presenting with STEMI within 6 h of symptom onset were randomized 1:1:1 to placebo (n=151), alteplase 10 mg (n=144), or alteplase 20 mg (n=145).
- Patients were categorized by pre-specified ischemic time (<2 h, n=107; ≥2 h but <4 h, n=235; ≥4 h to 6 h, n=98), and study drug was infused into the culprit coronary artery after reperfusion during primary PCI.
- The primary outcome was microvascular obstruction (percentage of left ventricular mass) quantified by cardiac magnetic resonance imaging at 2 to 7 days post-STEMI (available for 396 of 440 patients).
- Overall, there was no association between alteplase dose and microvascular obstruction (placebo: 2.32 ± 4.31%, 10 mg: 2.61 ± 4.49%, 20 mg: 3.48 ± 5.83%; p for trend = 0.128; linear regression p = 0.28).
- In patients with an ischemic time of ≥4 to 6 h, alteplase increased mean microvascular obstruction from 1.14% with placebo to 3.11% with 10 mg and 5.20% with 20 mg (p = 0.009 for trend; interaction p = 0.018).
Study Design
Type
RCT (n=440)
Blinding
Double-blind, placebo-controlled
Randomization
1:1:1 randomized, permuted blocks of length 6, stratified by location of STEMI and study site
Multicenter
Yes
Structured PICO
Does low-dose intracoronary alteplase reduce microvascular obstruction in patients with ST-segment elevation myocardial infarction undergoing primary percutaneous coronary intervention?
P
Population
440 patients with STEMI presenting within 6 hours of symptom onset undergoing primary percutaneous coronary intervention, followed for 3 months.
I
Intervention
Low-dose intracoronary alteplase (10 mg or 20 mg) manually infused immediately after successful reperfusion of the infarct-related artery and before stent implantation during primary percutaneous coronary intervention.
C
Comparator
Matching placebo manually infused immediately after successful reperfusion and before stent implantation during primary percutaneous coronary intervention.
O
Outcome
Amount of microvascular obstruction (MVO) (percentage of left ventricular mass) quantified by cardiac magnetic resonance imaging at 2 to 7 days.surrogate
Main Result
Mean Difference: 0.15 (95% CI -0.12–0.42)
p-value: p=0.28
Adjunctive low-dose intracoronary alteplase during primary PCI for STEMI does not reduce microvascular obstruction overall and may worsen it in patients with longer ischemic times (≥4 to 6 hours).
Limitations
- Study was discontinued early when pre-specified futility criteria were met
- No adjustment for multiplicity was made in the subgroup analysis
- Decision to explore treatment effects as trends across treatment groups was made post hoc
- Trial was stopped early for futility based on a pre-specified analysis
- No adjustments were made for multiple testing in the subgroup analyses, which should be viewed as exploratory
Key expert perspectives
Captured external expert commentary on this paper, strongest first. Original sources are linked where available.
“Failed myocardial reperfusion — in other words, microvascular obstruction — is a predictor of all-cause death and HF. There is no treatment for this problem and, therefore, presents an unmet therapeutic need.”
“The total ischemic time is an unreliable estimate based on symptom onset and baseline Q in the distribution of the MI is actually prognostically more useful. Additionally, the window of 2 to 7 days for MRI acquisition was wide and had this time frame been tighter, the data may have been different.”
Implication
Caution against low-dose intracoronary alteplase in STEMI with ischemic time ≥4–6 h; challenges adjunctive thrombolysis for microvascular protection in prolonged ischemia.
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).
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Published by ENLIGHTEN (Jurnal Bimbingan dan Konseling Islam) · CC BYCite This Study
McCartney et al. (2020) conducted an RCT in ST-segment elevation myocardial infarction (STEMI) (n=440). Alteplase vs. Placebo was evaluated on Amount of microvascular obstruction (MVO) (percentage of left ventricular mass) quantified by cardiac magnetic resonance imaging at 2 to 7 days (mean increase in square root-transformed MVO per 10-mg increase in alteplase dose: 0.15, 95% CI -0.12 to 0.42, p=0.28). In patients with STEMI and an ischemic time ≥4 to 6 hours, adjunctive low-dose intracoronary alteplase during primary PCI increased microvascular obstruction compared to placebo.