Esmolol in acute ischemic stroke thrombolysis: Benefits confined to atrial fibrillation and hypertensive patients

Abstract

This editorial comments on the retrospective study by Papamichalis et al published in the recent issue of World Journal of Clinical Cases, examining esmolol use during the acute phase of ischemic stroke in 149 patients undergoing intravenous thrombolysis. The study raises a clinically important question: Does heart rate control with esmolol improve or worsen outcomes after thrombolysis? The findings challenge the routine use of esmolol in this setting. Current guidelines from the American Heart Association/American Stroke Association recommend lowering blood pressure to below 185/110 mmHg before intravenous thrombolysis, but provide no guidance on the preferred pharmacological agent. Esmolol, a short-acting beta-1 selective blocker, reduces cardiac output and may compromise cerebral perfusion pressure in patients with already compromised cerebrovascular autoregulation. The observation that esmolol was associated with poor outcomes in patients without atrial fibrillation or hypertension, yet appeared neutral in those with atrial fibrillation or established hypertension, suggests that underlying cardiac and vascular physiology significantly modifies drug response. This subgroup-dependent effect has direct clinical implications. Indiscriminate beta-blockade in the acute stroke window may be harmful, particularly in patients without a clear hemodynamic indication. These data support a personalized, indication-driven approach to blood pressure pharmacotherapy before thrombolysis, and highlight the urgent need for prospective trials in this underexplored area.

Key Words: Esmolol; Acute ischemic stroke; Intravenous thrombolysis; Blood pressure management; Atrial fibrillation; Hypertension; Cerebral perfusion; Beta-blocker

Core Tip: Esmolol, an ultrashort-acting beta-1 selective blocker, is increasingly used for pre-thrombolysis blood pressure control in acute ischemic stroke, but evidence for its safety in this setting is limited. In a study of 149 patients with acute ischemic stroke undergoing intravenous thrombolysis, Papamichalis et al report that esmolol-treated patients showed significantly worse 3-month functional outcomes, defined by modified Rankin Scale score > 2, compared with untreated patients. Subgroup analyses revealed that this harm was confined to patients without atrial fibrillation and those without a history of hypertension, while outcomes were not significantly different in patients with atrial fibrillation or established hypertension. These data support individualized antihypertensive selection and underscore the need for prospective trials in this underexplored but clinically critical area.

This editorial refers to “Correlation between esmolol usage in the acute phase of ischemic stroke and outcomes of patients undergoing intravenous thrombolysis” by Papamichalis et al, 2026; https://doi.org/10.12998/wjcc.v14.i8.117167.

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INTRODUCTION

Ischemic stroke remains one of the leading causes of death and disability worldwide, with intravenous thrombolysis (IVT) using alteplase or tenecteplase representing the cornerstone of acute pharmacological management when administered within 4.5 hours of symptom onset[1,2]. A necessary prerequisite for eligibility is adequate blood pressure control: Systolic blood pressure must be below 185 mmHg and diastolic blood pressure below 110 mmHg before administration, and maintained below 180/105 mmHg for 24 hours afterward[3]. Blood pressure is commonly elevated at stroke onset and requires active pharmacological intervention in a substantial proportion of candidates.

Despite the clarity of the blood pressure targets, the choice of antihypertensive agent remains a contested and largely unresolved clinical question. Intravenous labetalol, nicardipine, and esmolol are among the most commonly used agents, and current guidelines do not establish superiority of one over another[3]. Esmolol, an ultrashort-acting cardioselective beta-1 adrenoreceptor antagonist with a half-life of approximately 9 minutes, is metabolized by red blood cell esterases and offers the advantage of rapid reversibility[4,5]. These pharmacokinetic properties make it highly attractive in time-sensitive emergency settings. However, esmolol’s primary mechanism of action, reduction of heart rate, cardiac contractility, and cardiac output, raises a legitimate concern about its adequacy in maintaining cerebral perfusion in the already-compromised ischemic brain.

In a recently published retrospective study in the World Journal of Clinical Cases, Papamichalis et al[6] investigated the correlation between esmolol use in the acute phase of ischemic stroke and outcomes in 149 patients undergoing IVT. Of these, 26 patients received esmolol during thrombolysis or within the first 72 hours of stroke onset (esmolol-treated group), and 123 did not (esmolol-untreated group). The primary outcome was the modified Rankin Scale (mRS) score at 3 months, a widely used, validated 7-point disability scale (0 = no symptoms; 6 = death), where mRS ≤ 2 denotes functional independence and mRS > 2 denotes unfavorable outcome. Secondary outcomes included length of stay (LOS), need for advanced critical or neurocritical care, primary adverse events (symptomatic intracranial hemorrhage, death, serious systemic bleeding, or new stroke), and 3-month mortality. Their study is timely and important: It is among the first to examine esmolol specifically within the thrombolysis context and to perform subgroup analyses stratified by atrial fibrillation (AF) status and hypertension history. In this editorial, we examine their findings in light of the existing literature, explore the mechanistic basis for the subgroup-dependent results, and propose how these data should inform clinical practice.

WHAT IS ALREADY KNOWN: BLOOD PRESSURE MANAGEMENT IN THE THROMBOLYSIS WINDOW

Blood pressure management in acute ischemic stroke is one of the most nuanced areas in emergency neurology. In patients not receiving IVT, permissive hypertension, tolerating systolic blood pressures up to 220 mmHg, is recommended to support collateral perfusion through the ischemic penumbra[3,7]. In patients eligible for IVT, however, this permissive approach is reversed: Active lowering to below 185/110 mmHg is mandated due to the risk of hemorrhagic transformation at higher pressures.

Despite this imperative, the evidence base for any specific antihypertensive agent in this setting is remarkably thin. The ENCHANTED trial, which randomized 2227 IVT-eligible patients to intensive (130-140 mmHg) vs guideline-standard (below 180 mmHg) blood pressure targets, found that intensive lowering did not improve functional outcome despite reducing intracranial hemorrhage[8]. This result highlighted the dual risk of both uncontrolled hypertension (hemorrhagic transformation) and excessive blood pressure reduction (worsening cerebral ischemia). The blood pressure-outcome relationship in acute ischemic stroke follows a U-shaped curve, with worse outcomes at both extremes[7,9].

Beta-blockers, including esmolol, have been used in this setting despite limited prospective evidence. A retrospective comparative study by Melekoğlu et al[10] found no difference in mortality or morbidity between esmolol and nicardipine for blood pressure control in hypertensive acute ischemic stroke patients, noting that while nicardipine achieved faster pressure reduction, outcomes were comparable between groups. This finding has been cited as supporting esmolol’s utility, but critically, this study was conducted in hypertensive patients specifically and did not evaluate patients without established hypertension or without AF.

The broader beta-blocker literature in acute stroke is also mixed. A meta-analysis by Balla et al[11], comprising more than 100000 patients, found no survival benefit from acute beta-blocker use after stroke and raised concerns that blood pressure suppression may reduce cerebral tissue perfusion in the acute ischemic phase. However, other observational data suggest that persistent beta-blocker therapy in patients with elevated heart rates after ischemic stroke significantly reduces long-term mortality, particularly in those with AF or coronary artery disease[12]. This distinction between acute initiation and continuation of pre-existing therapy is clinically critical and often overlooked.

LITERATURE GAPS THAT THE INDEX STUDY ADDRESSES

Several important knowledge gaps exist in this field. First, no prospective randomized trial has specifically examined esmolol vs other agents for pre-thrombolysis blood pressure control in acute ischemic stroke. All available data derive from retrospective cohorts or from trials in broader acute stroke populations. Second, prior studies have not examined whether the effect of esmolol varies according to underlying cardiac physiology, specifically AF status and chronic hypertension, both of which fundamentally alter the hemodynamic context in which esmolol operates. Third, the concept of cerebrovascular autoregulation impairment in acute ischemic stroke, which renders cerebral blood flow directly dependent on systemic perfusion pressure, has rarely been translated into agent-specific pharmacological recommendations.

The study by Papamichalis et al[6] directly addresses the second gap. By performing a priori-defined subgroup analyses stratified by AF and hypertension status, the authors have generated the first clinical dataset suggesting that esmolol’s effect is not uniform across the pre-thrombolysis population. This subgroup-level granularity is not present in any prior published dataset on esmolol in acute ischemic stroke.

MECHANISTIC BASIS FOR SUBGROUP-DEPENDENT EFFECTS

The physiological rationale for the differential effects of esmolol across subgroups deserves careful analysis. Esmolol exerts its antihypertensive effect primarily through negative chronotropy and inotropy at the beta-1 adrenoreceptor, resulting in reduced heart rate, myocardial contractility, and cardiac output[4,5]. This reduction in cardiac output can translate directly into reduced cerebral perfusion pressure, particularly in patients with impaired cerebrovascular autoregulation, a well-documented consequence of acute ischemic stroke[13,14].

In patients without AF and without a history of hypertension, baseline cardiac output is normal, and there is no pathological tachycardia for esmolol to correct. In this context, esmolol-induced reduction of cardiac output may represent an unnecessary and potentially harmful decrease in cerebral driving pressure. In the index study, only 8 of the 95 patients without AF received esmolol, a very small exposed subgroup. Despite this limitation, the esmolol-treated patients without AF demonstrated significantly worse outcomes: Increased LOS [9 days (range 1-52) vs 2 days (range 1-52); P = 0.006], greater need for advanced critical care (37.5% vs 6.9%; P = 0.026), higher rates of primary adverse events (25% vs 2.3%; P = 0.034), and significantly lower 90-day survival (62% vs 88%; P = 0.009 by Kaplan-Meier analysis). Among the 52 patients without hypertension, just 4 received esmolol, making this the most statistically underpowered subgroup; nevertheless, the direction and magnitude of harm were consistent. The ischemic penumbra, the metabolically vulnerable but still viable tissue surrounding the infarct core, depends critically on collateral perfusion, which is itself dependent on adequate systemic hemodynamics[13]. Compromising this hemodynamic support through excessive rate and output reduction may effectively expand the infarct core and worsen neurological outcomes.

In contrast, in patients with AF, rate control carries a specific and rational hemodynamic purpose. Rapid ventricular rates in AF, defined as rapid ventricular response, are associated with blood pressure instability, reduced diastolic filling time, and reduced cardiac output[15]. In the index study, 54 of 149 patients had AF, of whom 18 received esmolol. Crucially, outcomes including LOS, need for advanced critical care, adverse event rates, and 3-month mortality were not significantly different between esmolol-treated and untreated patients in this subgroup (all P > 0.05), and 90-day survival rates were similar (log-rank P = 0.807). In this population, esmolol may paradoxically improve cardiac output by slowing the ventricular rate and allowing adequate diastolic filling, thereby maintaining or even augmenting cerebral perfusion. This is consistent with data showing that delays in resuming rate-control therapy in AF patients after IVT are associated with prolonged intensive care stays[15]. Similarly, in patients with established hypertension, who comprised 97 of 149 patients, of whom 22 received esmolol, chronic adaptation of the cerebral vasculature shifts the autoregulatory curve rightward, meaning these patients require higher mean arterial pressures to maintain adequate cerebral blood flow[9,13,14]. In this subgroup, esmolol was associated only with a marginally longer LOS (4 days vs 3 days; P = 0.013), with no significant differences in critical care need, adverse events, functional outcome, or mortality. This relatively benign profile is consistent with the hypothesis that patients with chronic hypertension have developed sufficient vascular adaptation to tolerate modest blood pressure reduction. Antihypertensive therapy that gently reduces blood pressure in this population may be well tolerated because the autoregulatory plateau still encompasses perfusion pressures achieved. In contrast, patients without established hypertension have a narrower autoregulatory range, and any blood pressure reduction carries greater risk of falling below the lower limit of autoregulation.

There is also a neurohormonal dimension worth considering. The acute phase of ischemic stroke is associated with profound sympathoadrenal activation, which may paradoxically support cerebral perfusion by maintaining systemic vascular resistance[16]. Experimental and clinical data suggest that beta-blockade in the acute stroke setting may suppress this compensatory sympathetic response, with uncertain net effects on brain perfusion depending on the baseline cardiac and vascular status of the patient[11,16].

CLINICAL IMPLICATIONS AND PRECISION PHARMACOTHERAPY

The findings of Papamichalis et al[6] carry important clinical implications that warrant immediate consideration. The central message is that esmolol should not be regarded as a universally applicable antihypertensive for pre-thrombolysis blood pressure control. Its use appears safe, and potentially beneficial, when there is a clear hemodynamic indication, such as rapid ventricular response in AF. In the absence of such an indication, however, esmolol may cause net harm through cardiac output reduction in the vulnerable peri-infarct period.

This finding aligns conceptually with the broader literature on antihypertensive selection in acute stroke. The FAVOR study demonstrated that beta-blockers, when compared with angiotensin receptor blockers under similar brachial blood pressure control, resulted in worse central aortic hemodynamics and no cerebral blood flow advantage in ischemic stroke patients[17]. Furthermore, experimental data have shown that cardioselective beta-blockers including metoprolol may eliminate beta-1 receptor-mediated cerebrovascular dilation in cerebral arteries, potentially predisposing to dysregulation of cerebrovascular tone[18]. Whether esmolol shares this property at therapeutic doses has not been directly investigated.

In practical terms, the decision to use esmolol for pre-thrombolysis blood pressure control should incorporate an individualized assessment that considers: The presence or absence of AF with rapid ventricular response; whether elevated blood pressure represents true hypertensive urgency or a compensatory physiological response to cerebral ischemia; the patient’s baseline blood pressure and cerebrovascular autoregulatory status; and the availability of alternative agents such as nicardipine or labetalol, which act through different mechanisms and may carry different cerebrovascular profiles.

It is also clinically important to distinguish between acute initiation of esmolol de novo and continuation of pre-existing beta-blocker therapy. Current evidence from large observational studies suggests that persistent continuation of beta-blockers in patients who were already taking them at stroke onset, particularly those with elevated heart rates or AF, is associated with reduced long-term mortality[12]. This is a distinct scenario from initiating esmolol acutely in a patient without prior beta-blocker exposure and without a clear rate-control indication.

LIMITATIONS AND FUTURE DIRECTIONS

While the study by Papamichalis et al[6] provides valuable hypothesis-generating data, several limitations must be acknowledged. As a single-center retrospective study of 149 patients, it is susceptible to selection bias, unmeasured confounding, and limited statistical power within subgroups. The specific dosing regimen, duration of esmolol infusion, and achieved blood pressure parameters in each subgroup are not uniformly reported, making it difficult to disentangle drug-specific effects from blood pressure-lowering magnitude. Outcome definitions, timing of assessment, and the functional scoring methodology also warrant scrutiny in any retrospective analysis.

Several specific confounders deserve explicit acknowledgment. First, although the median National Institutes of Health Stroke Scale (NIHSS) score was 11 in both the overall esmolol-treated and untreated groups, the range differed (3-23 vs 2-28), and NIHSS distribution across individual subgroups was not adjusted for in outcome analyses. NIHSS score is the single most powerful predictor of 90-day mRS and may have differed meaningfully within subgroups in ways that median values do not capture. Second, time-to-thrombolysis (symptom-to-needle time) was recorded in the study as the therapeutic window but was not reported as a covariate in subgroup outcome comparisons. It is an established independent determinant of both functional recovery and hemorrhagic transformation risk, and its distribution across esmolol-treated and untreated subgroups is unknown. Third, indication bias is a prominent concern: Esmolol was used significantly more often in patients with AF (69.2% vs 29.3%; P < 0.001) and hypertension (84.6% vs 61%; P = 0.022), both of which independently predict poor outcomes, meaning esmolol selection was driven by clinical severity markers. Although subgroup analyses were designed to address this, residual confounding within subgroups cannot be excluded. Fourth, and most critically for statistical interpretation, the esmolol-exposed subgroups were extremely small: Only 8 patients without AF and only 4 patients without hypertension received esmolol. Statistically significant findings in groups of this size must be regarded as hypothesis-generating and exploratory, not confirmatory, regardless of P-values. The absence of adjustment for multiple comparisons across subgroups further warrants caution.

The study nevertheless performs a valuable function: It provides the rationale and preliminary data to justify a prospective, randomized trial comparing esmolol with alternative antihypertensives for pre-thrombolysis blood pressure management. Such a trial should pre-specify stratification by AF status and hypertension history, measure cerebral hemodynamic parameters where feasible, and report outcome data at both 90 days and one year. The field of acute stroke pharmacotherapy is in urgent need of evidence on antihypertensive drug selection, a topic that has received disproportionately little attention compared with thrombolytic agents themselves.

CONCLUSION

The study by Papamichalis et al[6] contributes an important and clinically meaningful insight to the management of acute ischemic stroke: Esmolol is not a hemodynamically neutral antihypertensive in this setting. Its effects are conditioned by the patient’s underlying cardiac physiology. Where rate control serves a genuine purpose, as in AF with rapid ventricular response or in patients with established hypertension whose autoregulatory curves have shifted, esmolol may be well tolerated or even helpful. In patients without these indications, esmolol-induced reductions in cardiac output may compromise the cerebral perfusion that the ischemic penumbra depends upon for survival. Clinicians should approach pre-thrombolysis antihypertensive selection not as a single-agent default but as a precision decision informed by each patient’s hemodynamic profile. Prospective randomized trials are now needed to formally establish whether this individualized approach translates into improved neurological outcomes.