Treatment of Coronary Heart Disease With Amiloride
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|ClinicalTrials.gov Identifier: NCT01231165|
Recruitment Status : Completed
First Posted : November 1, 2010
Last Update Posted : June 11, 2012
|First Submitted Date ICMJE||October 29, 2010|
|First Posted Date ICMJE||November 1, 2010|
|Last Update Posted Date||June 11, 2012|
|Study Start Date ICMJE||February 2009|
|Actual Primary Completion Date||May 2010 (Final data collection date for primary outcome measure)|
|Current Primary Outcome Measures ICMJE
|Original Primary Outcome Measures ICMJE
|Change History||Complete list of historical versions of study NCT01231165 on ClinicalTrials.gov Archive Site|
|Current Secondary Outcome Measures ICMJE||Not Provided|
|Original Secondary Outcome Measures ICMJE
||Exchanging RBC K uptake [ Time Frame: three months ]|
|Current Other Outcome Measures ICMJE||Not Provided|
|Original Other Outcome Measures ICMJE||Not Provided|
|Brief Title ICMJE||Treatment of Coronary Heart Disease With Amiloride|
|Official Title ICMJE||Comparative Randomized Single-blind Trial of Amiloride in Coronary Heart Disease|
Treatment of coronary artery disease is a major health care problem across the entire word, and the United States. Unfortunately, despite a number of medical advances, diagnostic procedure, or epidemiological studies, the treatment of these patients remain complex, and and at times frustrating. In fact, the COURAGE trial conducted in 50 centers across United States and Canada documented that drug treatment, coronary interventions or both were not effective solution in coronary artery diseases.
A novel approach has recently been developed, based on the critical role of the potassium (K) content in red-blood-cell in myocardial oxygenation, since oxygen and K binding by hemoglobin (red-blood-cell) occurs simultaneously in blood passing through the lungs, whereas in the organs as the heart, the hemoglobin release both Oxygen and K ions.
This apparently simple mechanisms occurs in human blood in all individuals but could be altered in subjects with acquired or hereditable defect in red-blood-cell K content. The purpose of this trial, thus, will be to evaluate the pharmacological effects of Amiloride on RBC K-uptake and transport and its impact on reversion of angina, electrocardiographic changes of myocardial ischemia and electrical regeneration of the heart in subjects with coronary artery diseases.
The Problem: Treatment of Cardiovascular Diseases (CVD) is a major health care problem across the entire word, and particularly in the United States, Japan and European Countries (1). In fact, these life-threatening disorders are a major cause of emergency medical care and hospitalization in the United States, and according the National Center for Health Statistics (NCHS) there were approximately 1,565,000 hospitalizations for primary or secondary diagnosis of an acute coronary syndrome (ACS), 669,000 for unstable angina (UA) and 896,000 for myocardial infarction (MI). In the 2003, NCHS reported 4,497,000 visits to emergency departments for primary diagnosis of CVD, wherein the average age of a person having a first heart attack is calculated at 65.8 years for men and 70.4 years for women (2)
Although the treatment of angina, chest pain secondary to coronary heart disease (stable chronic angina) and one of the most common and early symptom of Coronary Heart Disease (CHD) can be tracked as far as 1880's, it still represents a medically unresolved problem. Indeed, treatment of angina in particular, as well as associated condition as ACS, UA, and MI, involves a large number of life-style recommendations, dietetic advice, drugs, coronary artery intervention, or coronary bypass surgery aimed to improve symptoms, quality of life of patients, and even primary or secondary prevention of the stable chronic angina. Unfortunately, despite a century of medical advances and epidemiological studies, the current approach to CVD and coronary heart disease remain complex, and at times frustrating.
Among the proposals to treat stable chronic angina new aspects have been considered, including the single "polypill" agent (aspirin + statin + 3 blood pressure lowering agents in half dose, and folic acid), Simvastatin and intravascular ultrasound study, or intra-coronary angiogenesis therapy (3-5). However, most of them are unpractical, whereas it is difficult to determine whether these changes will translate to meaningful reductions in clinical events, or whether results in highly selected patient populations can be matched to the real-world of prevention and treatment of coronary artery syndromes.
Further, a recent large clinical trial, COURAGE study (6), conducted in 50 hospital centers in the United States and Canada showed that optimal drug treatment and percutaneous coronary interventions for stable coronary heart disease, was not more effective than optimal medical therapy alone for preventing cardiovascular events, hospitalization or death, suggesting that drugs, surgical procedures or both were not a statistically effective solution for stable chronic angina. By inference, a therapeutic approach for mot severe coronary syndromes as UA, post- myocardial infarction angina, or aggravated angina episodes, seems to be a more distant goal.
Physiological Basis for Innovation: For more than a century, the extremely rapid coupled tissue O2/CO2 gas exchange and ion H/K transport by Hemoglobin (Hb) in red blood cell (RBC) has been well known for scientific community, the so-called Bohr/Haldane Effect (7). Since then, it has been noted and confirmed that RBC have a critical role to maintain normal vascular function, blood flow and tissue oxygenation and acid-base regulation. These functional roles of RBC include a nitric oxide (NO) transport, NO synthetasa, and regulation of platelet aggregation, vascular rheology, and endothelial function (8). Indeed, recent studies have demonstrated that erythrocyte serves as a regulator of vascular tone and tissue perfusion, whereas the hemoglobin and RBC itself may be sensors for the oxygen tissue requirement (9).
In this context, the evidence that erythrocytes are the major intravascular storage of nitrites (10), and that nitroglycerin effects on erythrocyte rheology and oxygen unloading in myocardial ischemia are mediated by S-Nitrosohemoglobin (11) implies that RBC K exchange should be preserved in subjects with CHD, especially if a hereditable defect in RBC K transport exists (12). Unfortunately, and despite such multiple integrated functions to maintain tissue oxygenation in health and diseases states, the role of RBC has never been considered in the therapeutic approach of stable chronic angina (13). However, our recent observation that reversal of an abnormal low RBC K content in hypertensive patients receiving low doses of pyrazinoylguanidine hydrochloride (amiloride HCl, 5 mg), and calcium gluconolactate was associated with a better control of BP, and regression of the ST-T alterations related to LVH or coronary heart disease (14), strongly support a novel mechanistic approaches to improve blood flow and myocardium oxygen transport in stable chronic angina.
Informed consent will be obtained in each patient, and the Review board committee of the Docent Institute of Urology, University of Carabobo Medical School, Valencia, will approve the trial. This trial is a continuation of the Protocol ID UIC-3 2007 (Novel Treatment for Coronary Artery Disease, NCT 01228214) and will be also registered in the ClinicalTrials.gov
(I) Clinical Methods
At the inclusion period and in each clinical visit all subjects had measurements of BP, HR, body weight/height and measurement of body resistance and reactance for Body Composition Analysis of Total Body water and extra-cellular spaces, Fat-Free-Mass, Fat Mass. Number of anginal episodes, and functional anginal class (CCS) will be recorded in each case.
(II) Laboratory Methods
All patients will have routine measurement of Ion Transport Studies, which includes a 12-hour night (7 pm- 7 am) urine collection, followed by fasting state for measurement of plasma (Na, K, Cl, Mg++, Ionized calcium), RBC (Na, K, H2O content), and urine (Na, K, Cl, Mg++, calcium) electrolytes, along with plasma and urine osmolality, at entry, 4-week, and at 3, 8 and 12-months period.
(III) Cardiovascular Studies
All subjects All subjects had resting 12-lead ECG at entry, and non-invasive hemodynamic and PWA (DynaPulse200M, San Diego, CA) for Aortic Stiffness (Augmentation index, and Travel-Time-Reflected-Wave), Systemic and Brachial Artery Resistance and Compliances, obtained at entry and during clinical visits, including possible emergency attention. EchoC, or Doppler studies will be evaluated at baseline, 6-month, and 12-month periods.
|Study Type ICMJE||Interventional|
|Study Phase||Phase 2
|Study Design ICMJE||Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single (Participant)
Primary Purpose: Treatment
|Condition ICMJE||Coronary Heart Disease|
* Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
|Recruitment Status ICMJE||Completed|
|Actual Enrollment ICMJE
|Original Actual Enrollment ICMJE
|Actual Study Completion Date||February 2011|
|Actual Primary Completion Date||May 2010 (Final data collection date for primary outcome measure)|
|Eligibility Criteria ICMJE||
|Ages||35 Years to 75 Years (Adult, Senior)|
|Accepts Healthy Volunteers||No|
|Contacts ICMJE||Contact information is only displayed when the study is recruiting subjects|
|Listed Location Countries ICMJE||Venezuela|
|Removed Location Countries|
|NCT Number ICMJE||NCT01231165|
|Other Study ID Numbers ICMJE||UIC-5 2008|
|Has Data Monitoring Committee||No|
|U.S. FDA-regulated Product||Not Provided|
|IPD Sharing Statement||Not Provided|
|Responsible Party||Antonio Delgado Leon, MD, University of Carabobo|
|Study Sponsor ICMJE||University of Carabobo|
|PRS Account||University of Carabobo|
|Verification Date||April 2012|
ICMJE Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP