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Fibrinolytic No Help for Microvascular Obstruction in PCI

Low-dose adjunctive alteplase (Activase) administered early during primary percutaneous coronary intervention (PCI) was no help in reducing microvascular obstruction, researchers found in the randomized T-TIME trial.

With a 20-mg dose of alteplase by intracoronary infusion, microvascular obstruction still averaged 3.5% of left ventricular (LV) mass on contrast-enhanced cardiac MRI on days 2-7 following PCI, which was no different than if the patient had gotten placebo (2.3% of LV mass, P=0.32). Similarly, alteplase 10 mg also did not improve upon placebo (2.6% vs 2.3%, P=0.74).

Also similar between groups was the rate of major adverse cardiac events out to 3 months, counting cardiac death, non-fatal myocardial infarction (MI), heart failure hospitalization (10.1% placebo vs 12.9% low alteplase vs 8.2% high alteplase), reported Colin Berry, PhD, of the British Heart Foundation Glasgow Cardiovascular Research Centre in Scotland, and colleagues in the January 1/8 issue of JAMA.

The investigators concluded that low-dose intracoronary fibrinolytic therapy given during PCI — soon after coronary reperfusion and before stent implant — does not reduce microvascular obstruction. “The undesired procoagulant effect of fibrinolytic therapy through thrombin activation may have led to microvascular thrombosis, limiting the efficacy of the intervention,” the team suggested.

“Microvascular dysfunction in MI patients is driven primarily by duration and severity of the ischemia, as well as embolization of atheroma, platelet-rich and thrombin-rich blood clots during PCI. Only the latter might be benefited by alteplase, so I would have guessed it unlikely that this intervention might help,” commented Stephen Ellis, MD, of the Cleveland Clinic, who was not involved in the study.

Also asked for his perspective, James Blankenship, MD, of Geisinger Medical Center in Danville, Pennsylvania, told MedPage Today that he was “absolutely not surprised” by the findings. “Microvascular obstruction correlates with infarct size, and dozens of studies over the past 3 decades have tested and failed to find a strategy that when administered along with primary PCI decreases infarct size. We can now add intra-coronary tPA to this list,” he said.

Berry’s group conducted T-TIME at 11 hospitals in the U.K. Trial participants were patients presenting within 6 hours of ST-segment elevation MI who were subsequently randomized to placebo (n=151), alteplase 10 mg (n=144), or alteplase 20 mg (n=145). The group was 15% women, and the mean age was 60.5 years.

“It is difficult to recruit these patients and accomplish the studies, but the investigators did it with a remarkably low drop-out rate,” Blankenship noted.

An important caveat of the study was that recruitment stopped early because of futility.

Over a decade ago, the ASSENT-4 and FINESSE trials had found no benefit to facilitated PCI — the former even showing an increased rate of mortality and heart attacks with this strategy.

“These results may be explained by comparatively inadequate anticoagulation and, potentially, formation of fibrin and thrombus in the group treated with tenecteplase [TNKase]. The importance of effective anticoagulation to mitigate the prothrombotic effects of fibrinolytic therapy with alteplase has been reported previously,” Berry and colleagues argued.

It’s not the end for thrombolytics in PCI, however, as the authors noted two ongoing phase 3 trials with reduced alteplase (STRIVE) and tenecteplase (RESTORE-MI).

The study was supported by grants from the National Institute for Health Research (NIHR).

Berry reported research grants from the NIHR Efficacy and Mechanism Evaluation Programme and British Heart Foundation; non-financial support from Boehringer-Ingelheim during the conduct of the study; institutional research support from Abbott Vascular, AstraZeneca, Boehringer-Ingelheim, HeartFlow, GlaxoSmithKline, Novartis, Philips, and Siemens Healthcare; and serving as chair of the clinical trials committee of the Society for Cardiovascular Magnetic Resonance and as treasurer of the British Society of Cardiovascular Magnetic Resonance.