Clinical trial NCT06635707: Efficacy and Safety Study of Urapidil Alone or With Esmolol in Treating Acute Hypertensive Intracerebral Hemorrhage
Official title: The Study on the Efficacy and Safety of Using Urapidil Alone or in Combination With Esmolol for the Treatment of Acute Hypertensive Intracerebral Hemorrhage: A Prospective, Open-label, Observational, Multicenter Research
Study type: OBSERVATIONAL
Overall status: NOT_YET_RECRUITING
Conditions: Hypertensive Intracerebral Hemorrhage
Lead sponsor: Qianfoshan Hospital
Sponsor class: OTHER
First posted: 2024-10-10
Enrollment: 600
Sex: ALL
Minimum age (years): 18
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: PROSPECTIVE
Sampling method: PROBABILITY_SAMPLE
Study population: Sample collection will be conducted for participants in the study of hypertensive intracerebral hemorrhage.

Recruitment Locations: The First Affiliated Hospital of Shandong First Medical University (Shandong Qianfoshan Hospital), along with various other sub-centers.

Brief summary: The objective of this study is to investigate the efficacy and safety of urapidil monotherapy versus the combination of esmolol in treating participants with acute hypertensive intracerebral hemorrhage through a prospective, open-label, observational, multicenter clinical trial, aiming to provide guidance for clinicians in formulating rational treatment plans.

Detailed description: Hypertensive intracerebral hemorrhage (HICH) is a prevalent and severe condition that poses significant challenges to the medical community due to its harmful nature and complexity. Over the past few decades, there has been considerable controversy surrounding blood pressure management strategies for patients with acute HICH. Both hypertension and hypotension following cerebral hemorrhage are associated with adverse outcomes. Multiple trials aimed at reducing blood pressure in patients with acute cerebral hemorrhage have been conducted, and among patients recruited within six hours of symptom onset, blood pressure reduction has been linked to decreased hematoma expansion. Current international guidelines from the European Stroke Organization, the American Heart Association (AHA)/American Stroke Association, and the Canadian Stroke Best Practice Recommendations support the prompt reduction of systolic blood pressure to 140 mmHg after symptom onset, aiming to maintain systolic blood pressure between 130 and 150 mmHg. However, for certain patients, such as those with extremely high blood pressure after ICH (systolic blood pressure \>220 mmHg), a more individualized approach is necessary. Notably, patients with very high blood pressure (systolic blood pressure \>220 mmHg) were not included in these trials, and reducing systolic blood pressure to 140 mmHg in this population may be harmful, associated with higher rates of neurological deterioration and adverse renal events.

Elevated blood pressure (BP) is common in patients with acute spontaneous intracerebral hemorrhage (ICH) and is closely related to hematoma growth, which is a crucial independent predictor of clinical deterioration and outcomes in ICH patients. Previous studies have shown that hematoma growth primarily occurs within the first six hours after spontaneous cerebral hemorrhage. Consequently, early blood pressure reduction may be beneficial in preventing hematoma growth. Research indicates that ICH patients who achieve target blood pressure more quickly are less likely to experience hematoma growth. Specifically, patients who reach a target systolic blood pressure (SBP) of \<140 mmHg within the first hour after randomization exhibit a lower absolute hematoma growth rate. Studies have supported the benefit of shortening the time to achieve target blood pressure in ICH patients, corroborating these findings. Hematoma growth is primarily attributed to ongoing bleeding and secondary vascular rupture, occurring predominantly within the first six hours after ICH onset, particularly during the initial 2-3 hours, with a gradual decline in frequency over time.

Changes in the autonomic nervous system (ANS) have been previously observed in acute stroke patients, characterized by impaired cardiovascular regulation and altered balance between sympathetic and parasympathetic nerves. Clinically significantly, autonomic dysfunction is associated with poor prognosis, increased mortality, or sudden death after stroke. Variations in heart rate variability (HRV) and baroreceptor sensitivity (BRS) have traditionally been considered surrogate markers of cardiovascular ANS modulation. Previous studies on HRV in acute brain injury have primarily focused on ischemic cerebral infarction or traumatic brain injury (TBI). In both TBI and ischemic cerebral infarction, HRV parameters have shown independent associations with outcomes.

Urapidil (URA) is a selective α1-adrenoceptor antagonist that also acts as a central 5-HT1A receptor agonist, exerting both peripheral and central hypotensive effects. The hypotensive effect of URA is dose-dependent and may vary among individuals. URA demonstrates a self-limiting hypotensive effect, even at high doses, without causing severe hypotension. It reduces cardiac preload and afterload, decreases myocardial oxygen consumption, and increases cardiac output without causing reflex tachycardia or affecting heart rate. Additionally, URA does not increase intracranial pressure, does not impair hemodynamics in the middle cerebral artery, and is conducive to maintaining cerebral perfusion pressure. Furthermore, URA enhances renal blood flow, reduces renal vascular resistance, does not increase shunt fraction, and does not decrease arterial oxygen partial pressure.

Esmolol is an ultra-short-acting, highly selective β1-blocker that competitively antagonizes β1 receptors in myocardial cells. It exerts its pharmacological effects by blocking the activity of adrenaline and noradrenaline. At high doses, it may also block β2 receptors in airway and vascular smooth muscle. At therapeutic doses, esmolol has no intrinsic sympathomimetic activity or membrane-stabilizing effects. When administered intravenously, it takes effect within 60 seconds and its pharmacological effects disappear within 10 to 30 minutes after infusion cessation. Electrophysiological studies suggest that esmolol exhibits typical β1-blocker effects, including reduced heart rate, prolonged sinus cycle length, prolonged sinus node recovery time, prolonged AH interval and antegrade Wenckebach period, slowed conduction in atrial and ventricular myocardium and cardiac conduction system, and prolonged refractoriness. By blocking sympathetic excitation, esmolol lowers the threshold for ventricular fibrillation (VF).

Patients with acute HICH often experience increased heart rate and uncontrolled blood pressure. Previous studies have shown that the time taken to normalize blood pressure and heart rate variability are correlated with adverse outcomes in patients. The present study aims to evaluate the effectiveness of urapidil alone and in combination with esmolol in reducing blood pressure and controlling heart rate in patients with acute.

Eligibility criteria: Inclusion Criteria:

1. Participants in the study of acute hypertensive intracerebral hemorrhage aged between 18 and 80 years old;
2. Participants with acute intracerebral hemorrhage (basal ganglia hemorrhage \< 50ml) confirmed by imaging within 6 hours of onset;
3. Participants with systolic blood pressure \> 140mmHg upon admission;
4. Participants who have signed the informed consent form.

Exclusion Criteria:

1. Participants in the cerebral hemorrhage study who decline to have their disease management information collected and used and/or refuse to undergo subsequent follow-ups;
2. Participants with allergies to the medication in question;
3. Participants in the study of secondary cerebral hemorrhage resulting from tumors, vascular malformations, aneurysms, trauma, post-thrombolytic therapy, or cerebral arteriovenous thrombosis;
4. Participants undergoing anticoagulant therapy or with coagulation disorders;
5. Pregnant women;
6. Participants with multiple organ failure;
7. Participants deemed unsuitable for enrollment by the research staff due to other factors.

Primary outcomes:
measure: Modified Rankin Scale (mRS)
timeFrame: Three months after the onset of the disease
Secondary outcomes:
measure: Changes in the volume of acute intracranial hematoma
timeFrame: First seven days of hospitalization
measure: Heart rate variability
timeFrame: First seven days of hospitalization
measure: Time taken for blood pressure to reach target levels after administering antihypertensive medications
timeFrame: First 24 hours after hospitalization
measure: Modified Rankin Scale (mRS) score
timeFrame: Seventh day after the onset of the disease
measure: In-hospital mortality rate
timeFrame: From date of randomization until the date of death from any cause, assessed up to 3 months
measure: Mortality rate within 3 months of onset
timeFrame: Three months after the onset of the disease
measure: Adverse events
timeFrame: During hospitalization(up to 8 weeks)
measure: Incidence of seizures
timeFrame: During hospitalization(up to 8 weeks)
measure: length of hospital stay
timeFrame: From date of randomization until the date of discharge from hospital for any reason, assessed up to 3 months
Other outcomes:
Locations:
Study officials:
affiliation: Qianfoshan Hospital
name: Jianjun Wang, Ph.D.
role: STUDY_DIRECTOR
affiliation: Qianfoshan Hospital
name: Xueyan Cui, Ph.D.
role: STUDY_DIRECTOR
References: