ST-elevation MI Door-To-Unload Pivotal Trial: Acute Cardiac Unloading and Myocardial Recovery

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In the concluding talk, Dr Kapur provided the rationale and discussed the trial design of the ST-elevation MI Door-To-Unload (STEMI-DTU) pivotal trial. He stated a few facts from the American Heart Association about MI and its prognosis. Nearly every 40 seconds, an American will have an MI, and the estimated annual incidence of new MI is 605,000.1 The estimated average number of years of life lost because of an MI death is 16.2. Approximately 35% of people who experience a coronary event in a given year will die as a result of it, and about 14% who experience an MI will die. He highlighted that the Swedish Web-system for Enhancement and Development of Evidence-Based Care in Heart Disease (SWEDEHEART) study shows that heart failure (HF) after MI increases mortality, and this is one of the reasons why the STEMI-DTU trial is needed.2,3 Studies have also shown that the size of the infarcts matter. For every 5% increase in myocardial infarct size, 1-year all-cause mortality increases by 19% and HF hospitalisation by 20%.4

He discussed the paradox of reperfusion therapy in MI by highlighting that reperfusion therapy to limit myocardial damage in STEMI may itself promote myocardial damage. A fundamental component of the paradox is the mandate for rapid reperfusion in STEMI.5,6 Data suggest that every 30-minute increase in ischaemic time is associated with increased 1-year mortality and infarct size. This raises the question of whether the ischaemic time increases in the STEMI-DTU trial due to delayed reperfusion in the Impella arm. Studies have suggested that during ischaemia without reperfusion, 100% of the area at risk (AAR) is infarcted.7 On the other hand, only 50% of the AAR is infarcted with ischaemia with timely reperfusion, and ischaemia with timely reperfusion with cardioprotection may reduce the infarct size to 25% of the AAR.7,8

Dr Kapur noted that the current approaches of management in STEMI have focused on reducing reperfusion injury, not ischaemic injury.9 He highlighted that left ventricle (LV) unloading with Impella uncouples ischaemia and reperfusion, thus reducing the fear of delaying reperfusion.10 He showcased the pre-clinical development of primary unloading from 2012 to 2019, which demonstrated that transvalvular LV unloading limits myocardial ischaemia and promotes a cardioprotective shift in myocardial biology.

Dr Kapur emphasised that in STEMI-DTU, delayed reperfusion is not equal to delayed treatment. He hypothesised that unloading the LV prior to reperfusion limits the potential ischaemic damage, thus the point of inhiation of haemodynamic support may be considered the onset of treatment. To test this hypothesis, adult male pigs subjected to left anterior descending artery (LAD) occlusion for 90 minutes were divided into two groups. In the no unloading group, LAD was occluded for an additional 120 minutes without reperfusion. In the unloading group, LAD was occluded for an additional 120 minutes with unloading using Impella and no reperfusion. The infarct size was 10% of the AAR in the no unloading group without reperfusion compared to 2–3% of the AAR in the unloaded group without reperfusion. Interestingly, the infarct size in the no unloading group increased from 10% to 30% of the AAR following reperfusion. Likewise, the infarct size also increased in the unloaded group from <3% to 18% of the AAR after reperfusion, but was significantly less than the no unloading group. These results suggest two important things. First, ischaemia-dependent damage is independent of reperfusion-dependent damage, and second, that unloading with Impella prior to reperfusion may differentially limit both.

The STEMI-DTU pilot trial assessing the feasibility and safety of primary LV unloading and delaying reperfusion was conducted before attempting a randomised control trial evaluating the efficacy of this approach.11 In the STEMI-DTU pilot trial, 50 patients presenting with anterior STEMI at 14 centres in the US were randomised to mechanical unloading with the Impella CP, followed by immediate reperfusion (U-IR) or LV unloading with a 30-minute delay to reperfusion (U-DR). The majority of the patients enrolled in the pilot trial had large anterior MI with high left ventricular end-diastolic pressure (LVEDP). Notably, no patient in the trial experienced no reflow after the percutaneous coronary intervention (PCI) compared to the expected rate of 25%. The successful STEMI-DTU pilot trial established safety, feasibility and compliance with no bailout PCI in the U-DR arm. A subgroup analysis of infarct size normalised to the myocardial AAR was performed in patients stratified by sum ST-segment elevation. A stepwise increase in infarct size normalised to the AAR was observed in the U-IR group compared with no such effect in the U-DR group. This result suggests that unloading and reperfusion limits infarct size, irrespective of the AAR by sum ST-segment elevation.

He further outlined the current trial design of the upcoming STEMI-DTU pivotal trial. When a patient with anterior STEMI presents to a DTU site, an iliac and femoral angiogram, LV-gram and LVEDP measurement are performed. The patients are then randomised to either the DTU arm (LV unloading with Impella CP, followed by reperfusion using PCI) or the door-to-balloon (DTB) arm (reperfusion as per current standard of care). In the DTU arm, Impella CP support is initiated first, followed by PCI. The patient will be supported with Impella CP for 4–6 hours post-PCI, and the subject will be taken to the catheterisation lab for Impella explant. In the DTB arm, patients will receive PCI after a coronary angiogram. The primary endpoint of the trial is infarct size as a percentage of LV mass at 3–5 days.

Secondary endpoints include clinical safety evaluation at 30 days, 6, 12, 18 and 24 months. The subjects will be followed up yearly until 60 months.

In conclusion, Dr Kapur emphasised that there is no delay to treatment in the STEMI-DTU trial. The biggest difference is that the treatment in STEMI-DTU begins with LV unloading with the ultimate goal to prevent HF after an acute MI by limiting infarct size and aid the process of myocardial recovery.


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