Allopurinol in Patients With Refractory Angina to Improve Ischemic Symptoms (ARAMIS)

A Single-center, Randomized, Double-blind, Placebo-controlled Study of the Efficacy and Safety of Allopurinol in Improving Ischemic Symptoms in Patients With Refractory Angina.

Despite numerous advances in medical treatment and revascularization procedures for the treatment of patients with stable angina, debilitating symptoms that are unresponsive to conventional therapy may occur in patients unsuitable for revascularization, a condition known as refractory angina. Allopurinol, a methylxanthine oxidase inhibitor, is widely used in the treatment of gout and asymptomatic hyperuricemia. On the other hand, the anti-ischemic effects of allopurinol have been the subject of increasing interest. Therefore, the investigators will study the safety and efficacy of allopurinol in alleviating ischemic symptoms in patients with refractory angina already on optimal medical therapy.

Study Overview

• Status: Recruiting
• Conditions: Refractory Angina
• Intervention / Treatment: Drug: Allopurinol 300 MG; Drug: Placebo oral tablet

Detailed Description

One of the most common clinical presentations associated with coronary artery disease (CAD) is stable angina, which can be translated clinically into chest discomfort (or equivalent) evoked by different levels of physical activity depending on the extent of the disease. In the United States, it is estimated that 16.5 million individuals over 20 years of age have chronic ischemic heart disease, of which 3.4 million live with the diagnosis of angina pectoris. Refractory angina is a clinical condition characterized by the presence of debilitating symptoms secondary to CAD lasting more than three months in which the symptoms are attributed to objectively documented ischemia and not controlled with the combination of conventional antianginal agents and myocardial revascularization procedures. The estimated annual incidence of patients with refractory angina is between 50,000 and 200,000 new cases in the United States.

Allopurinol, a methylxanthine oxidase inhibitor, is widely used in the treatment of gout and asymptomatic hyperuricemia. The therapeutic potential of allopurinol in patients with cardiovascular disease has been the subject of increasing interest. In patients with CAD, the first study tested the role of allopurinol in improving exercise tolerance in 65 patients with stable angina documented by angiography and positive stress test for myocardial ischemia. After only six weeks of treatment, patients who received allopurinol showed a statistically significant increase in ergometry parameters, including time for ST-segment depression, total exercise time, and time until the onset of angina. There were no reports of adverse events. Considerable decrease in inflammatory markers and oxidative stress indicators has been demonstrated in patients with acute myocardial infarction receiving allopurinol versus placebo with a significant reduction in the risk of cardiovascular events in 2 years (10% vs. 30%, respectively). Therefore, the investigators will test the hypothesis that the use of allopurinol increases exercise tolerance and reduces angina attacks compared to placebo after 16 weeks of follow-up in patients with refractory angina.

Patients will be randomly selected to receive a placebo or allopurinol (600mg od) for 16 weeks. At baseline and after 16 weeks of treatment, exercise tolerance will be assessed through the cardiopulmonary exercising test, and myocardial ischemia will be determined using an exercise echocardiogram protocol. Biomarkers of oxidative stress will be measured in the blood and urine; endothelial-dependent vasodilation will be assessed using the reactive hyperemia protocol at the brachial artery.

For the sample size calculation, the investigators chose the primary outcome as "total exercise time (TTE) after intervention" based on the study by Noman et al. (Lancet 2010;375:2161-7). Thus, assuming that μ1 (allopurinol) = 396sec, μ2 (placebo) = 319sec and σ = 63sec, the investigators concluded that to be able to detect a difference between groups with 95% confidence (1-alfa) and 90% power (1-beta), 17 patients are needed in each study group. If the investigators consider a screen failure rate at 20%, a total of 40 patients will be needed, randomized 1:1.

• Study Type: Interventional
• Enrollment (Anticipated): 40
• Phase: Phase 2; Phase 3

Contacts and Locations

• Study Contact: Name: Luis Henrique W Gowdak, MD, PhD; Phone Number: 5929 +55-11-26615000; Email: luis.gowdak@incor.usp.br
• Study Contact Backup: Name: Renato P Azevedo, MD; Phone Number: +55-11-32877441; Email: renatoslz@yahoo.com.br

Study Locations

• Brazil
  • SP
    • Sao Paulo, SP, Brazil, 05403-000
      • Recruiting
      • Heart Institute
      • Principal Investigator: Luis Henrique W Gowdak, MD, PhD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Clinical diagnosis of stable angina in functional class (CCS) ≥ 2 for at least three months in patients taking maximally tolerated doses of at least three classes of antianginal agents
• Documentation of myocardial ischemia by any provocative functional test (exercise test, stress echocardiogram, myocardial perfusion scintigraphy or cardiac resonance)
• Signature of the Informed Consent Form

Exclusion Criteria:

• Left ventricular dysfunction defined by LVEF < 30% on transthoracic echocardiogram
• Significant concomitant valve disease
• Chronic renal failure stage 4 or 5 (GFR < 30mL/min/1.73m2 calculated by the MDRD equation
• Significant liver dysfunction (Child-Pugh class C) or MELD value ≥ 15 calculated from creatinine, total bilirubin, and INR values
• Current use of warfarin
• Prior use of allopurinol within three months of randomization
• Pregnant and lactating women

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Allopurinol; Allopurinol 300mg P.O. once daily for four weeks followed by allopurinol 300mg P.O. twice daily for 12 weeks.	Drug: Allopurinol 300 MG; Allopurinol 300mg once daily for four weeks followed by allopurinol 300mg twice daily for 12 weeks; Other Names: Zyloric
Placebo Comparator: Placebo; Placebo pills indistinguishable from the active comparator given P.O. once daily for four weeks, followed by twice daily for 12 weeks.	Drug: Placebo oral tablet; Placebo 300mg once daily for four weeks followed by allopurinol 300mg twice daily for 12 weeks; Other Names: Placebo

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Increase in total exercise time (seconds) assessed by CPET	Total exercise duration during a maximal, symptom-limited cardiopulmonary exercise testing	16 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of angina attacks per week	Frequency of patient-reported daily diary of angina	16 weeks
Short-acting nitrates intake per week	Frequency of patient-reported short-acting nitrates intake for symptom-relief	16 weeks
Relative decrease in stress-induced myocardial ischemia during exercise echocardiogram	% of change in myocardial ischemia burden assessed during exercise echocardiogram stress test compared to baseline	16 weeks
Relative change in the levels of oxidative stress biomarkers	% of change in the level of biomarkers of stress oxidative (nitrotyrosine, malondialdehyde and of reduced glutathione) compared to baseline	16 weeks
Relative change in endothelium-dependent vasodilation during reactive hyperemia in the forearm	% of improvement in endothelium-dependent vasodilation assessed during reactive hyperemia (brachial artery) compared to baseline	16 weeks

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of participants with treatment-related adverse events as assessed by CTCAE v5.0	All AE will be recorded during the 16 week period of the trial	16 weeks

Collaborators and Investigators

• Sponsor: Ministry of Health, Brazil
• Collaborators: Fundação de Amparo à Pesquisa do Estado de São Paulo; InCor Heart Institute
• Investigators: Principal Investigator: Luis Henrique W Gowdak, MD, PhD, Heart Institute (InCor-HCFMUSP)

Publications and helpful links

General Publications

• Noman A, Ang DS, Ogston S, Lang CC, Struthers AD. Effect of high-dose allopurinol on exercise in patients with chronic stable angina: a randomised, placebo controlled crossover trial. Lancet. 2010 Jun 19;375(9732):2161-7. doi: 10.1016/S0140-6736(10)60391-1. Epub 2010 Jun 9.

Study record dates

Study Major Dates

• Study Start (Anticipated): March 3, 2021
• Primary Completion (Anticipated): September 30, 2021
• Study Completion (Anticipated): December 31, 2021

Study Registration Dates

• First Submitted: April 23, 2020
• First Submitted That Met QC Criteria: April 27, 2020
• First Posted (Actual): April 30, 2020

Study Record Updates

• Last Update Posted (Actual): February 24, 2021
• Last Update Submitted That Met QC Criteria: February 23, 2021
• Last Verified: February 1, 2021

More Information

Terms related to this study

• Keywords: treatment; coronary artery disease; angina; allopurinol; oxidative stress; myocardial ischemia; cardiopulmonary exercising test; stress echocardiogram
• Additional Relevant MeSH Terms: Myocardial Ischemia; Heart Diseases; Cardiovascular Diseases; Vascular Diseases; Pain; Neurologic Manifestations; Chest Pain; Angina Pectoris; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antirheumatic Agents; Antimetabolites; Protective Agents; Antioxidants; Free Radical Scavengers; Gout Suppressants; Allopurinol
• Other Study ID Numbers: SDC 4781/18/132; 2018/22588-3 (Other Grant/Funding Number: Fundação de Amparo à Pesquisa do Estado de São Paulo)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No
• IPD Plan Description: We must abide by the local regulations.

Drug and device information, study documents

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