Treatment of Coronary Heart Disease With Amiloride
Condition: Coronary Heart Disease
MeSH terms: Heart Diseases; Coronary Disease; Coronary Artery Disease; Myocardial Ischemia
Study type: Interventional
Phase: Phase 2/Phase 3

Summary: 
      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.
    

Detailed description: 
      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

      METHODS

      (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.
    

Intervention name(s): Amiloride; Nitrates, clopidogrel, aspirin, statins
Intervention type(s): Drug; Drug
Intervention description(s): 5mg/daily for 12th months; Comparative Efficacious Research
Other intervention name(s): Nitrates (40mg/daily) for 12 months; Clopidogrel(75mg/daily)for 12 months; Aspirin (80mg/daily) for 12 months; Statins (20mg/daily) for 12 months; Nitrates (40mg/daily) for 12 months; Clopidogrel(75mg/daily)for 12 months; Aspirin (80mg/daily) for 12 months; Statins (20mg/daily) for 12 months
Intervention MeSH terms: Aspirin; Amiloride; Clopidogrel; Hydroxymethylglutaryl-CoA Reductase Inhibitors
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Single (Participant)
Primary purpose: Treatment