Efficacy of Phentolamine in Prevention of Contrast-Associated Acute Kidney Injury After Complex PCI

Protective Efficacy of Phentolamine in Patients at High Risk of Contrast-Associated Acute Kidney Injury After Complex Percutaneous Coronary Intervention

To evaluate the efficacy and safety of phentolamine in prevention of CA-AKI following complex PCI in patients at high risk of CA-AKI.

Study Overview

• Status: Recruiting
• Conditions: Coronary Artery Disease; Acute Coronary Syndrome; Adrenergic Receptor Antagonist Adverse Reaction; CA-AKI - Contrast-Associated Acute Kidney Injury
• Intervention / Treatment: Drug: Phentolamine

Detailed Description

Coronary angiography is accepted as the gold standard diagnostic procedure in the management of coronary artery disease (CAD). It involves the visualization of the coronary arteries using contrast dye and dynamic X-ray imaging and allows for the identification of suitable lesions for percutaneous coronary intervention (PCI). PCI has more importance when performed as an emergency procedure during acute coronary syndromes (ACS) providing immediate relief of symptoms, preventing myocardial damage and reducing mortality rates despite its potential complications. These complications varies in its incidence including arrhythmias, coronary dissection, bleeding at the access site, allergy to contrast agent and kidney injury with varying risk on patient condition.

Contrast-associate acute kidney injury (CA-AKI), formerly termed contrast-induced nephropathy (CIN), is a significant complication of PCI and the third most common cause of renal failure in hospitalized patients. It is defined as a rise in creatinine of ≥ 50% of baseline or 0.3 mg/dL from the pre-contrast value within 48-72 hours of intravascular administration of a contrast medium, which is usually reversible acute kidney injury. The development of CA-AKI despite successful percutaneous coronary procedures is associated with prolonged hospitalization, an increase in health expenditure, and increased short and long-term mortality for most patients. Therefore, early risk prediction and management is crucial.

Over the past few decades, a number of risk scores have been introduced to predict contrast-associated acute kidney injury after PCI. The most commonly used is Mehran score that was introduced in 2004 for its simplicity and availability but it excluded patients with acute myocardial infarction. However, it recently updated with larger population and more emphasis on patient's ACS presentation and procedural features and reintroduced in 2021 as Mehran 2 CA-AKI Risk Score.

Exact pathophysiological mechanism of CA-AKI is not known and includes complex cascades of events. The most important elements of pathophysiological mechanism of CA-AKI seem to be the medullary hypoxia due to contrast-induced medullary vasoconstriction and direct renal tubular cytotoxicity, in addition to oxidative stress and the increase in blood and renal tubular viscosity which are complementary events that further exacerbates CA-AKI.

Several clinical interventions aimed to reduce the incidence of CA-AKI targeting various aspects of the pathophysiology including volume expansion with intravenous fluid, administration of N-acetylcysteine, sodium bicarbonate, vitamin E, statins and vasodilator agents with different protective efficacy but only few of them had been approved for clinical practice.

Vasodilators agents like nicorandil showed a statistically significant lower odds of developing CA-AKI with periprocedural hydration and the vasodilator agent nicorandil versus periprocedural hydration only (OR: 0.173). Also, a recent clinical trial has demonstrated encouraging results regarding the renoprotective effects of phentolamine in chronic coronary syndrome following PCI with odds ratio 0.04 of CA-AKI in phentolamine group in comparison to control group.

Phentolamine, a non-selective alpha-adrenergic antagonist, is primarily used for the treatment of conditions involving excessive sympathetic activity. While it is not a commonly used medication in the management of CAD, it used in various cardiovascular urgent conditions as in hypertensive crisis and in the treatment of cocaine-induced ACS which counteract the excessive sympathetic stimulation and reduce peripheral vascular resistance in conjunction with other treatments to alleviate symptoms and improve hemodynamics with less incidence of tachycardia associated with other vasodilators e.g. nitroglycerin.

This clinical trial will investigate the potential of phentolamine as a renoprotective agent following complex PCI by evaluating the impact of phentolamine on renal outcomes and its safety which may significantly impact clinical practice by guiding the use of phentolamine as an adjuvant therapy, ultimately improving patient outcomes and reducing the burden of CA-AKI in high-risk population.

• Study Type: Interventional
• Enrollment (Estimated): 60
• Phase: Phase 2; Phase 3

Contacts and Locations

• Study Contact: Name: Mohammed Soliman; Phone Number: +201032137563; Email: Mohammed_Mostafa@med.helwan.edu.eg

Study Locations

• Egypt
  • Cairo
    • Badr, Cairo, Egypt
      • Recruiting
      • Badr University Hospital
      • Contact: Mohammed Soliman, MBBCH; Phone Number: +201032137563; Email: Mohammed_Mostafa@med.helwan.edu.eg

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Patients admitted to CCU with CAD.
• Patients underwent successful complex PCI defined as multivessel disease, more than two lesions, high coronary lesion complexity, chronic total occlusion, lesion length >30 mm, or bifurcation.
• Patients at high or very high risk for CA-AKI based on Mehran-2 CA-AKI Risk Score (Model 2).

Exclusion Criteria:

• Patients with end stage renal disease on regular dialysis.
• Patients with failed PCI revascularization.
• Patients presented with STEMI and underwent primary PCI.
• Patients presented with high risk NSTEMI defined as elevated cardiac enzymes with chest pain refractory to medications and/or dynamic ST changes.
• Patients presented with cardiogenic shock.
• Patients presented with any degree of heart block.
• Patients with of history of asthma or hypersensitive for phentolamine.
• Patients on α-blockers, barbiturates or antipsychotic treatment.
• Patients intolerant to phentolamin with significant hemodynamic changes defined as >20% drop of systolic blood pressure (SBP) or >20% increase of heart rate (HR) after loading dose of phentolamine.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
No Intervention: Control group; Patients will receive conventional management including high dose atorvastatin and isotonic (0.9%) saline intravenous (IV) infusion at a rate of 1 ml/kg/hr for 12 hours or reduced to 0.5 ml/kg/hr if the patient's LVEF < 40% or overt heart failure.
Experimental: Phentolamine group; In addition to the conventional management, patients will receive phentolamine infusion.	Drug: Phentolamine; In addition to the conventional management, patients will receive phentolamine (Rogitamine; Egypharma) infusion at a rate of 0.5 μgm/kg/min for the first 15 minutes after a bolus dose of 5 mg. If significant hemodynamic change occurred, the infusion then will be discontinued and the patient will be excluded. Otherwise, the dose will be uptitrated gradually 0.5-2 ugm/kg/min and the infusion will be continue for 12 hours.; Other Names: Rogitamine

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Rate of CA-AKI	A rise in creatinine of ≥ 50% of baseline or 0.3 mg/dL from the pre-contrast value within 48-72 hours of intravascular administration of a contrast medium.	3 days post-PCI

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Peak of serum creatinine elevation	Maximum level of serum creatinine reached in patients who developed CA-AKI	7 days
Duration of CA-AKI	Duration of CA-AKI in patients who developed CA-AKI	14 days
Change in HR	Change in heart rate	12 hours post-PCI
Change in SBP	Change in systolic blood pressure	12 hours post-PCI
Change in DBP	Change in diastolic blood pressure	12 hours post-PCI
Urine output	Urine output per hour post-PCI	12 hours post-PCI
Rate of RRT	Rate of patients needed renal replacement therapy	7 days
Rate of MACE	Composite rate of myocardial injury, non-fatal MI, non-fatal stroke, and all-cause mortality.	30 days post-PCI
Rate of rehospitalization	Unplanned hospitalization during the first month post-PCI	30 days post-PCI
Duration of hospitalization	Duration of hospitalization post-PCI until hospital discharge	14 days

Collaborators and Investigators

• Sponsor: Helwan University
• Investigators: Study Chair: Yasser Sadek, Professor, Helwan University; Study Director: Arafa Gomaa, MD, Helwan University

Publications and helpful links

General Publications

• Mehran R, Owen R, Chiarito M, Baber U, Sartori S, Cao D, Nicolas J, Pivato CA, Nardin M, Krishnan P, Kini A, Sharma S, Pocock S, Dangas G. A contemporary simple risk score for prediction of contrast-associated acute kidney injury after percutaneous coronary intervention: derivation and validation from an observational registry. Lancet. 2021 Nov 27;398(10315):1974-1983. doi: 10.1016/S0140-6736(21)02326-6. Epub 2021 Nov 15.
• Ozkok S, Ozkok A. Contrast-induced acute kidney injury: A review of practical points. World J Nephrol. 2017 May 6;6(3):86-99. doi: 10.5527/wjn.v6.i3.86.
• Hamila MA, El Ghawaby H, Zaki M, Soliman M, Gabr K. Association of periprocedural phentolamine infusion with favorable outcome in patients with chronic kidney disease and chronic coronary syndrome undergoing coronary catheterization: a prospective randomized controlled pilot study. BMC Nephrol. 2022 Dec 31;23(1):416. doi: 10.1186/s12882-022-03050-9.
• Kelesoglu S, Yilmaz Y, Elcik D, Cetinkaya Z, Inanc MT, Dogan A, Oguzhan A, Kalay N. Systemic Immune Inflammation Index: A Novel Predictor of Contrast-Induced Nephropathy in Patients With Non-ST Segment Elevation Myocardial Infarction. Angiology. 2021 Oct;72(9):889-895. doi: 10.1177/00033197211007738. Epub 2021 Apr 8.
• Lu Y, Wang Y, Zhou B. Predicting long-term prognosis after percutaneous coronary intervention in patients with acute coronary syndromes: a prospective nested case-control analysis for county-level health services. Front Cardiovasc Med. 2023 Dec 4;10:1297527. doi: 10.3389/fcvm.2023.1297527. eCollection 2023.
• Walker H, Guthrie GD, Lambourg E, Traill P, Zealley I, Plumb A, Bell S. Systematic review and meta-analysis of prophylaxis use with intravenous contrast exposure to prevent contrast-induced nephropathy. Eur J Radiol. 2022 Aug;153:110368. doi: 10.1016/j.ejrad.2022.110368. Epub 2022 May 23.

Study record dates

Study Major Dates

• Study Start (Actual): March 7, 2024
• Primary Completion (Estimated): December 31, 2024
• Study Completion (Estimated): January 31, 2025

Study Registration Dates

• First Submitted: February 22, 2024
• First Submitted That Met QC Criteria: February 22, 2024
• First Posted (Actual): February 29, 2024

Study Record Updates

• Last Update Posted (Actual): March 18, 2024
• Last Update Submitted That Met QC Criteria: March 15, 2024
• Last Verified: March 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Myocardial Ischemia; Heart Diseases; Cardiovascular Diseases; Vascular Diseases; Arteriosclerosis; Arterial Occlusive Diseases; Kidney Diseases; Urologic Diseases; Renal Insufficiency; Coronary Disease; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases; Coronary Artery Disease; Wounds and Injuries; Acute Kidney Injury; Acute Coronary Syndrome; Physiological Effects of Drugs; Adrenergic Antagonists; Adrenergic Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Antihypertensive Agents; Adrenergic alpha-Antagonists; Phentolamine
• Other Study ID Numbers: Phentolamine for CA-AKI

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Master sheet of decoded data of the participants
• IPD Sharing Time Frame: 3 months after end of the study duration
• IPD Sharing Access Criteria: Supporting information will be added to the original study during publishing
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF; CSR

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No