Mechanical Thrombectomy for All Large Core Infarcts: Would Hippocrates Agree?

The recent publication of a series of randomized controlled trials (RCTs),1-6 along with their meta-analysis,7 has reignited one of the most contentious discussions in acute stroke management: Should mechanical thrombectomy (MT) be offered routinely to acute stroke patients presenting with large core infarcts? Historically, patients with extensive early ischemic changes were excluded from thrombectomy trials because of the presumption of poor outcomes and a high risk of complications such as hemorrhagic transformation or malignant edema. Yet, a new wave of evidence—particularly from Randomized Clinical Trial of Endovascular Therapy for Acute Large Vessel Occlusion with Large Ischemic Core, Randomized Controlled Trial to Optimize Patient's Selection for Endovascular Treatment in Acute Ischemic Stroke (SELECT-2), Study of Endovascular Therapy in Acute Anterior Circulation Large Vessel Occlusive Patients with a Large Infarct Core, and Thrombectomy for Emergent Salvage of Large Anterior Circulation Ischemic Stroke—challenges these previous assumptions, suggesting that patients with large ischemic cores can still derive clinical benefit from MT, especially when treated promptly and with careful selection criteria.1-3,5 The Randomized Clinical Trial of Endovascular Therapy for Acute Large Vessel Occlusion with Large Ischemic Core trial demonstrated benefit in patients with a low Alberta Stroke Programme Early computed tomography (CT) Score of 3–5 who were treated within 6 hours of onset.1 SELECT-2 included patients with ischemic core volumes of up to 150 mL—identified either by Alberta Stroke Programme Early CT Score or perfusion imaging—and showed a shift toward better functional outcomes.3 The Study of Endovascular Therapy in Acute Anterior Circulation Large Vessel Occlusive Patients with a Large Infarct Core trial, which focused on a cohort of Chinese patients, similarly demonstrated benefit in patients with large infarcts, confirmed by CT perfusion or MRI core volume measurements.2 Although the Thrombectomy for Emergent Salvage of Large Anterior Circulation Ischemic Stroke trial yielded neutral results, it trended toward benefit and underscored that infarct volume should not serve as the sole criterion for excluding patients from MT.5 Taken together, these results strongly support that infarct volume alone does not predict futility. However, is futility an appropriate or even a humane metric for patients suffering from devastating impairment because of acute large vessel occlusions? The magnitude of absolute benefit—defined as the number of patients achieving functional improvement—is substantial. What is lacking, however, is an agreed upon definition for acceptable functional improvement. Although several trials have examined prethrombectomy infarct volume, consideration of patient age, comorbidities, premorbid modified Rankin scale (mRS) score, infarct location, and collateral circulation is critical in assessing the likelihood of significant functional recovery. Moreover, infarct volume estimation is inherently imprecise, as CT perfusion and diffusion-weighted MRI can lead clinicians to overestimate infarct size in the hyperacute phase due to transient perfusion deficits, edema, or selective neuronal dysfunction. This so-called “ghost infarct” phenomenon reminds us that imaging must always be interpreted within clinical context.8 The SELECT-2 subgroup analysis highlighted the relevance of infarct “quality,” where the presence of hypodensity—not core size per se—served as a treatment effect modifier.9 This again underscores that infarct location, composition, and topography are critical to outcomes—particularly when eloquent cortical areas or deep nuclei are involved. As the clinical evidence base for MT continues to expand, we must now ask about the appropriateness of intervention. Enhanced technical feasibility has increased recanalization rates, but we must pause and consider: Would Hippocrates agree? Are we not compelled to act in the patient's best interest and first do no harm (primum non nocere)? This principle is not passive; it demands active discernment. In the context of large core infarcts, where clinical decisions are often urgent and outcomes are uncertain, the expanding indications for MT require not only sound judgment but also ethical clarity. Is it humane to offer MT to an 80-year-old with a completed stroke resulting in conductive aphasia in the hopes of preserving some right leg movement? If the patient was to remain aphasic and the hemiplegia improve to dense hemiparesis, is that truly a “good” functional outcome? The recent RCTs on this topic have expanded the boundaries of acceptable patient selection,1-6 but they have not resolved the deeper ethical question concerning true meaningful recovery. Is shifting a patient from an mRS score of 6 to 5, or from 5 to 4, an act of healing or merely the prolongation of a life in dependency? For some patients—particularly those who are younger or previously fully independent (mRS score of 0)—survival with severe neurological deficits and complete dependence on others may be perceived as a personally and existentially unacceptable outcome.10,11 These distinctions are not captured by imaging thresholds or outcome scales, and although evidence exists that there are patients who say an mRS score of 4-5 is a fate worse than death, physicians must practice individualized, morally grounded clinical judgment. We must remain nimble in our assessments of quality of life, as these parameters are personal. Furthermore, the promise of future neurorestorative technologies may eventually broaden the population of stroke patients who derive substantive benefits from successful thrombectomy. The concept of medical futility, once considered a fixed and largely quantitative threshold, must be redefined. Traditionally, futility has been understood as an unacceptably low likelihood of achieving an outcome the patient can meaningfully appreciate.12 An intervention may be successful by clinical standards and still fail ethically whether it imposes a quality of life the patient would not have chosen. This ethical issue is especially salient in the context of MT for large core infarcts, where treatment decisions are often made in rapid succession, without the opportunity for direct patient or family member input. In such scenarios, clarifying what constitutes “benefit” is not a theoretical concern—it is a clinical and ethical necessity. These decisions should not be guided solely by aggregated RCT data or institutional algorithms but must also integrate individualized assessments of patient values and the anticipated quality of life after intervention. It is imperative that stroke physicians develop a common language, where we painstakingly depict the most likely functional result after thrombectomy. We must avoid conversations about opening vessels and salvaging tissue. Rather, the focus must be on the patient's long-term functional status that can be achieved with a successful procedure. For example, we have all had conversations with patients or their families explaining that, “even if we can successfully open the vessel, your mother won't be able to understand or speak and will likely not have functional use of her right arm and leg, but we may prevent death from brain swelling.” Only with transparency and honesty can we hope to be the best advocates for our patients. Severe disability not only affects the individual patient, it also has socioeconomic and healthcare resource consequences because of sequelae from long-term disability. Clinicians may soon begin to weigh financial burden against human life, as outcomes of mRS scores of 4 or 5 carry enormous implications for health systems, families, caregivers, and patients. The costs of lifelong institutional care, mechanical assistance, and dependency can be measured by economic metrics but never in existential emotional burden. In conclusion, the debate is no longer whether MT can be performed in patients with large core infarcts. The question is how we define “benefit” in a way that respects individual patient values, preserves human dignity, and remains consistent with the foundational principles of medical practice as guided by Hippocratic code: primum non nocere. So again, we ask, would Hippocrates agree? Maybe, but only if we practice medicine with the discerning judgment of what we should do as stewards of patient care. A decade ago, the question was whether we should intervene on select patients with large vessel occlusion. The question has evolved to “who should we not intervene on to avoid prolonged unacceptable human suffering and hence ‘do no harm’”? Clinical trials should more deeply examine longer term outcomes, including patient-reported and family-reported outcome measures on quality of life. We must also look beyond recanalization to trials on cellular and functional therapies, as well as more tailored and sophisticated rehabilitation paradigms.