Review of the TAPAS trial

Thrombus Aspiration during Primary Percutaneous Coronary Intervention

N Engl J Med 2008;358:557-567

Background: ST-segment elevation myocardial infarction (STEMI) is caused by disruption of an atherosclerotic plaque, leading to intraluminal thrombosis that partially or completely blocks the coronary artery. Opening the blocked artery using percutaneous coronary intervention (PCI) restores blood flow and is the standard of therapy for these patients. In many patients, spontaneous embolization or embolization caused by thrombus fragmentation during PCI can lead to small thrombi migrating distally and obstructing the coronary microcirculation. This is associated with increased infarct size, reduction in left ventricular recovery and increased risk of mortality.

Several devices designed to retrieve intracoronary thrombus have been developed and have demonstrated improved coronary reperfusion in small studies. The Thrombus Aspiration during Percutaneous Coronary Intervention in Acute Myocardial Infarction Study (TAPAS) sought to compare the efficacy of thrombus aspiration versus conventional PCI in patients with STEMI.

Patients: Eligible patients were recruited from a single center in Netherlands. Patients had STEMI with symptoms lasting more than 30 minutes but less than 12 hours. The EKG criteria were ST-segment elevation of >1mm in at least two leads.

Patients were excluded if they had rescue PCI after thrombolysis or if life expectancy was less than 6 months.

Baseline characteristics: The trial randomized 1,071 patients – 535 randomized to thrombus aspiration and 536 randomized to conventional PCI.

The average age of patients was 63 years and 70% were men. Approximately 35% had hypertension, 12% had diabetes, 25% had hyperlipidemia, 10% had prior myocardial infarction, and 47% were current smokers.

Infarct-related vessel was the left anterior descending artery in 43% of the patients, the left circumflex artery in 17% and the right coronary artery in 38%.

Procedures: Patients were randomly assigned in a 1:1 ratio to undergo thrombus aspiration during PCI or conventional PCI. All placed stents were bare-metal stents.

Before PCI, patients received 500 mg of aspirin, 600mg of clopidogrel and 5000 IU of heparin. Patients also received the glycoprotein IIb/IIIa inhibitor abciximab, if not contraindicated, and additional heparin during the procedure.

Endpoints: The primary end point was the postprocedural frequency of a myocardial blush grade of 0 or 1. Secondary end points included complete resolution of ST-segment elevation and the absence of persistent ST-segment deviation. Clinical endpoints were also assessed as part of the secondary endpoints and included target-vessel revascularization, reinfarction or death, at 30 days.

A 12-lead EKG was obtained at presentation and again at 30 to 60 minutes after PCI, and the ST-segments on the postprocedural EKG were compared with those at presentation.

Not to readers: Myocardial blush is a qualitative angiographic method used to assess microvascular perfusion during coronary angiography. It evaluates how well contrast dye penetrates the myocardium. The grading of myocardial blush was: 0: no myocardial blush, 1: minimal myocardial blush or contrast density, 2: moderate myocardial blush or contrast density but less than that obtained during angiography of a contralateral or ipsilateral non–infarct-related coronary artery, and 3: normal myocardial blush or contrast density, similar to that obtained during angiography of a contralateral or ipsilateral non–infarct-related coronary artery. Persistent myocardial blush suggests leakage of contrast medium into the extravascular space and was given a grade of 0.

Analysis was performed based on the intention-to-treat principle. To achieve 80% power with a two-sided alpha of 0.05, a total of 1,080 patients would be needed to detect a 25% reduction in the primary endpoint with thrombus aspiration compared to conventional PCI. This calculation assumed a 30% rate of myocardial blush grade 0 or 1 in the conventional PCI group.

Results: Among the 1,161 patients screened for inclusion, 1,071 (92.2%) were randomized. Approximately, 94% of the patients in both groups underwent PCI. Among patients who underwent PCI in the thrombus aspiration group, 89% underwent thrombectomy. Among the patients who underwent thrombus aspiration, histopathological examination showed atherothrombotic material in 331 (72.9%) patients.

The primary outcome of myocardial blush grade 0 or 1 was significantly lower in the thrombus aspiration group (17.1% vs 26.3%, RR: 0.65, 95% CI: 0.51 - 0.83; p<0.001) [i.e. thrombus aspiration led to improved blood flow to the coronary microcirculation].

Complete ST-segment resolution was more frequent in the thrombus aspiration group (56.6% vs 44.2%; p<0.001). Similarly, more patients in the thrombus aspiration group had no persistent ST-segment deviation (53.1% vs 40.5%; p<0.001).

At 30 days, death was numerically lower in the thrombus aspiration group (2.1% vs 4.0%; p= 0.07), as well as reinfarction (0.8% vs 1.9%; p=0.11) and target-vessel revascularization (4.5% vs 5.8%; p= 0.34). The rates of death and major adverse cardiac events were significantly associated with myocardial blush grade, resolution of ST-segment elevation, and ST-segment deviation (P for association was 0.003 between death and myocardial blush grade and <0.001 for all other associations).

There were no significant subgroup interactions for the primary outcome.

Intraprocedural complications were not significantly different between groups, approximately 1% in both groups.

Conclusion: In patients with ST elevation myocardial infarction, thrombus aspiration during PCI as compared to conventional PCI, improved reperfusion as evident by myocardial blush. It also resulted in more resolution of ischemic EKG changes. The absolute treatment benefit for these endpoints was large – 9.2% for myocardial blush, 12.4% for ST-segment resolution and 12.6% for no persistent ST-segment deviation. There was a trend toward improvement in clinical outcomes, however, this was not statistically significant and the trial was not powered for these outcomes. These clinical outcomes were strongly associated with myocardial blush grade and EKG changes.

In the original publications, the authors overstated the clinical endpoints by saying that thrombus aspiration [results in better reperfusion and clinical outcomes than conventional PCI, irrespective of clinical and angiographic characteristics at baseline].

The trial enrolled most of the screened patients, enhancing its external validity. The primary outcome of this trial was a surrogate endpoint, which helps validate the pathophysiological mechanism of the treatment and informs the design of future larger trials powered to detect differences in hard clinical outcomes. While surrogate endpoints can provide valuable early insights, they do not always translate into actual clinical benefits. Therefore, relying solely on trials of surrogate outcomes to change clinical practice can be misleading and we do not recommend it.

Next, we will review a trial of thrombus aspiration in STEMI patients powered for hard endpoints. Will it be positive?

Note to Readers: Surrogate endpoints are sometimes used in clinical trials as substitutes for clinical outcomes, such as survival. Surrogate endpoints may include biomarkers, imaging findings, EKG changes, etc. These endpoints are selected based on their known correlation with clinical events. Utilizing surrogate endpoints enables trials to require smaller sample sizes and yield results more quickly.