N Engl J Med 2013;369:1587-1597
N Engl J Med 2014;371:1111-1120
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Background: In the TAPAS trial, thrombus aspiration in patients with ST elevation myocardial infarction (STEMI) improved coronary reperfusion as evident by coronary blush grade and electrocardiogram. The improvement in these surrogate endpoints was large and generated enthusiasm within the cardiology community regarding the potential of thrombus aspiration. While the trial demonstrated a trend toward improvement in clinical outcomes, this was not statistically significant and the trial was not powered for these clinical outcomes.
The Thrombus Aspiration in ST-Elevation Myocardial Infarction in Scandinavia (TASTE) trial was designed to assess the impact of thrombus aspiration in patients with STEMI, and was powered to detect differences in clinical endpoints.
Patients: Patients were included if they had chest pain suggestive of myocardial ischemia for at least 30 minutes but less than 24 hours before hospital admission, and if the EKG showed new ST-segment elevation or left bundle-branch block.
Patients were excluded if they couldn’t provide informed consent or if they needed emergency coronary artery bypass grafting.
The trial enrolled patients from all 29 PCI centers in Sweden, 1 in Iceland and 1 in Denmark.
Baseline characteristics: The trial randomized 7,244 patients – 3,621 randomized to thrombus aspiration and 3,623 randomized to conventional PCI.
The average age of patients was 66 years and 75% were men. Approximately 42% had hypertension, 12% had diabetes, 21% had hyperlipidemia, 12% had prior myocardial infarction, and 31% were current smokers.
Procedures: Patients were randomly assigned in a 1:1 ratio to undergo thrombus aspiration follow by PCI or conventional PCI. The study was open label.
The use of anticoagulants during PCI was left to the discretion of the treating physician. Stenting was encouraged with the type of stent left to the discretion of the physician. The administration of P2Y12 inhibitors was also left to the discretion of the physician. Lifelong treatment with aspirin was recommended in all patients.
Endpoints: The primary end point was all-cause death at 30 days. Data on mortality were obtained from the national population registry. The secondary end points, which were obtained from the SWEDEHEART registry and the national discharge registry, included 30-day rates of hospitalization for recurrent myocardial infarction, stent thrombosis, target-vessel revascularization, target-lesion revascularization, and the composite of all-cause mortality or recurrent myocardial infarction.
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 4,886 patients would be needed to detect a hazard ratio for death of at least 1.30 with PCI alone as compared with PCI plus thrombus aspiration. This calculation assumed the 30-day mortality with PCI alone to be 6.3%. Due to lower than expected mortality rate, the sample size was increased to 7,138 patients. The new sample size would detect an odds ratio for death with PCI alone as compared with PCI with thrombus aspiration of at least 1.5, assuming the 30-day mortality in the conventional PCI group to be 3.5%.
Results: Out of the 11,709 patients with STEMI in Sweden or Iceland, 4,697 (40.1%) were not enrolled in the trial. Of these patients not enrolled, 1,162 (24.7%) underwent thrombus aspiration. The median time from onset of symptoms to PCI was approximately 3 hours. No patients were lost to follow up with respect to the primary outcome. Among patients assigned to thrombus aspiration, 93.9% of the patients underwent the procedure. Among patients assigned to conventional PCI, 4.9% underwent thrombus aspiration.
The primary outcome of all-cause death at 30-days was similar between both treatment groups (2.8% with thrombus aspiration vs 3.0% with conventional PCI, HR: 0.94, 95% CI: 0.72 - 1.22; p= 0.63).
There were no statistically significant differences in any of the secondary outcomes at 30-days (incidence for thrombus aspiration mentioned first): Hospitalization for recurrent myocardial infarction (0.5% vs 0.9%), stent thrombosis (0.2% vs 0.5%), target-vessel revascularization (1.8% vs 2.2%), target-lesion revascularization (1.2% vs 1.6%), and the composite of all-cause death or recurrent myocardial infarction (3.3% vs 3.9%).
There was no difference in the incidence of stroke or neurological complications (0.5% in both groups), and no difference in the incidence of perforation or tamponade (0.4% in both groups).
Authors published a 1-year follow up study. At 1-year, there was no significant difference in all-cause death (5.3% with thrombus-aspiration group vs. 5.6% with conventional PCI, HR: 0.94, 95% CI: 0.78 - 1.15; p= 0.57). Similarly, no significant differences were observed for any of the secondary endpoints (incidence for thrombus aspiration mentioned first): Hospitalization for recurrent myocardial infarction (2.7% in both groups), stent thrombosis (0.7% vs 0.9%), target-vessel revascularization (4.4% vs 4.9%), target-lesion revascularization (3.2% vs 3.5%), and the composite of all-cause death or recurrent myocardial infarction (7.7% vs 8.1%).
There were no significant subgroup interactions for the primary outcome.
Conclusion: In patients with ST elevation myocardial infarction, thrombus aspiration during PCI as compared to conventional PCI, did not improve the primary outcome of all-cause at 30-days. It also did not significantly reduce the secondary outcomes at 30-days which included hospitalization for recurrent myocardial infarction, stent thrombosis, target-vessel revascularization, target-lesion revascularization, and the composite of all-cause death or recurrent myocardial infarction. Results remained unchanged at 1-year.
The TAPAS and TASTE trials highlight a critical lesson in research: Reliance on surrogate endpoints to guide medical practice can be misleading, even when surrogate outcomes suggest a substantial benefit, as seen in the TAPAS trial. Therefore, positive findings based on surrogate endpoints should always be validated by larger trials powered to assess clinical outcomes, before adopting them into clinical practice.
The TAPAS trial did impact clinical practice, with approximately 1 in 4 patients with STEMI in Sweden during the TASTE study period, who were not enrolled in the TASTE trial, underwent thrombus aspiration.
Another key takeaway is that results from smaller trials are not always replicated in larger studies. In TAPAS, thrombus aspiration was associated with a reduction in 30-day mortality, with a number needed to treat of approximately 53 patients. However, this finding was not statistically significant, raising questions about whether a larger sample size could have demonstrated a significant benefit. This assumption was refuted by the TASTE trial, highlighting the potential pitfalls of prematurely adopting interventions without robust evidence from sufficiently large trials.
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