To Unload, or Not to Unload, That Is the Question

There are no solutions, only tradeoffs. In acute myocardial infarction, we have tradeoffs between coronary supply and myocardial demand. In terms of supply, we have made significant progress by reducing ischemic time but see a plateau of benefit at 90 minutes. In terms of demand, we currently utilize pharmacotherapy which may be too little too late, especially in patients with large infarct size who have progressed to cardiogenic shock and cannot tolerate these therapies.

We see these trends in the outcomes data. While advances in restoring supply have led to high short-term survival rates, long-term outcomes remain challenging due to the incidence of heart failure which reaches nearly 75% at 5 years (1). In-hospital mortality for cardiogenic shock remains abysmal despite advances in reperfusion. Thus, it is paramount that we find therapies capable of limiting infarct size without compromising systemic perfusion.

Mechanical unloading is one option that has been shown to reduce infarct size in preclinical studies since the 1980s. Translating the efficacy of preclinical studies to effectiveness in the real world, however, remains a work in progress. The initial roadblock was inadequate technology. In 2008, the FDA approved the Impella, a percutaneous transaxial flow pump, for mechanical circulatory support. It has been demonstrated to be a safe and effective option for mechanical unloading. It is now approved for use in high-risk PCI and cardiogenic shock. Other percutaneous left ventricular assist devices are under investigation.

The next roadblock was to develop best practices. Prospective observational data from the National Cardiogenic Shock Initiative (NCSI) and the INOVA-SHOCK registries have demonstrated a significant improvement in mortality with a protocolized approach to managing cardiogenic shock and initiating mechanical support with Impella (2, 3). In an area of marked heterogeneity among practice patterns, resource utilization, and patient populations, establishing an effective protocol for management was a necessary precursor for overcoming the next roadblock, prospective randomized data.

Enter RECOVER IV, the topic of this year’s keynote address at the Houston Shock Symposium by Dr. Gregg Stone. It is a randomized controlled trial in which patients with AMI cardiogenic shock will be randomized to the active treatment group with hemodynamic support prior to PCI with Impella using the NCSI study protocol, or the control group with standard of care including any kind of pharmacologic or mechanical circulatory support other than the Impella including IABP or ECMO. The primary endpoint is all-cause mortality at 30 days. Secondary endpoints include MACCE at 30 days, days alive out of the hospital at six months, recovery of LV function, need for durable VAD or heart transplant, and quality of life metrics (4).

The NCSI protocol utilized in this study helps to address clinical best practices, but ethical issues remain the greatest roadblock for cardiogenic shock research. Many previous trials have been terminated due to struggles with enrollment and consent. The traditional process of informed consent is not compatible with the acuity of cardiogenic shock, particularly considering that altered mental status is a hallmark of systemic hypoperfusion. Consequently, there is limited prospective clinical research in these contexts to guide evidence-based practice. RECOVER IV has taken historic measures to overcome this roadblock as the first US cardiogenic shock trial to utilize the exception from informed consent (EFIC) pathway. This strategy was approved by the FDA in 1996 and is intended to facilitate research in emergency settings, where obtaining informed consent may not be feasible due to the critical nature of the medical condition and the limited time available for intervention (5). With this major step towards addressing ethical roadblocks, RECOVER IV aims to enroll 560 patients.

In an area starved for data, there is optimism that the ongoing trials regarding unloading will provide valuable insights. Besides RECOVER IV, the DTU-STEMI trial and UNLOAD-ECMO trial are randomizing patients to mechanical unloading with Impella versus standard of care in different clinical situations related to cardiogenic shock. These trials will advance our understanding of the tradeoffs we make between supply and demand in AMI and cardiogenic shock. Armed with this knowledge, we have a chance to progress towards improved myocardial recovery and long-term outcomes.

Dr. Shiva Patlolla is a cardiology fellow at Baylor University Medical Center and served as a CardioNerds Conference Scholar for the 2023 Houston Shock Symposium. To learn more about shock, enjoy the open access Journal of Shock & Hemodynamics (JoSH), the official Journal of the Annual Houston Shock Symposium.

Save the date! The 2024 Houston Shock Symposium will be held in Houston, TX on March 22-24^th, 2024.

References:

1. Safi M, Aronson D, Bachar GN, et al. Declining In-Hospital Mortality and Increasing Heart Failure Incidence in Elderly Patients With First Myocardial Infarction. Arch Intern Med. 2006;166(14):1486-1491. doi:10.1001/archinte.166.14.1486
2. Tehrani B, Truesdell A, Singh R, Murphy C, Saulino P. Implementation of a Cardiogenic Shock Team and Clinical Outcomes (INOVA-SHOCK Registry): Observational and Retrospective Study. JMIR Res Protoc. 2018;7(6):e160. Published 2018 Jun 28. doi:10.2196/resprot.9761
3. Basir MB, Kapur NK, Patel K, et al. Improved Outcomes Associated with the use of Shock Protocols: Updates from the National Cardiogenic Shock Initiative. Catheter Cardiovasc Interv. 2019;93(7):1173-1183. doi:10.1002/ccd.28307
4. gov [Internet]. Bethesda (MD): National Library of Medicine (US). Identifier NCT05506449, Early Impella® Support in Patients With ST-Segment Elevation Myocardial Infarction Complicated by Cardiogenic Shock: The RECOVER IV Trial; 2021. [cited 2023 April 21]. Available from: https://clinicaltrials.gov/ct2/show/NCT05506449
5. S. Food and Drug Administration. 21 CFR 50.24 – Protection of Human Subjects. Accessed September 19, 2021. https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/cfrsearch.cfm?fr=50.24.