Biomarker Guided Therapies in Stage A/B Heart Failure

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT02230891
Recruitment Status : Active, not recruiting
First Posted : September 3, 2014
Last Update Posted : December 3, 2018
Baylor College of Medicine
Information provided by (Responsible Party):
VA Office of Research and Development

Brief Summary:
Despite advances in cardiovascular care, the occurrence of heart failure (HF) is steadily increasing. The increase in HF rates poses enormous challenges, as once an individual becomes symptomatic or requires hospitalization with HF, the prognosis remains poor. Therefore, prevention of HF is essential. HF prevention is a critical issue as HF risk factors that include common medical conditions such as hypertension and diabetes are also increasing. However, not everyone with these risk factors develops HF. Using novel blood tests, the investigators propose to identify and treat subjects at higher HF risk to see if the investigators can stabilize or improve ultrasound measures known to be associated with HF risk. This study will enroll only Veterans.

Condition or disease Intervention/treatment Phase
Hypertension Diabetes Cardiovascular Disease Drug: Carvedilol Drug: Spironolactone Phase 2

Detailed Description:

Recently the investigators have shown that HF risk prediction can be improved using cardiac troponin T measured with a novel high-sensitivity assay (hs-cTnT) and N-terminal pro-B-type natriuretic peptide (NT-proBNP). Furthermore, hs-cTnT seems to identify individuals at higher risk among those with established risk factors (such as hypertension) for HF. In preliminary results, the investigators have shown that individuals with systolic blood pressure of 120-129 mm Hg and elevated hs-cTnT have a higher rate of incident HF than those with systolic blood pressure of 140-159 mm Hg and undetectable hs-cTnT. Therefore, the investigators believe that by using hs-cTnT to estimate HF risk the investigators can identify individuals in whom aggressive modification of risk factors such as high blood pressure will be associated with a favorable risk-benefit ratio.

The investigators' objective/specific aim therefore is to evaluate if treatment of selected subjects with Stage A or B HF (i.e., those with hs-cTnT >5 ng/L and an estimated 10-year HF hospitalization risk of >5%) who have reasonably well-controlled blood pressure with antihypertensive agents (carvedilol or spironolactone) will be associated with improvement of surrogate markers associated with incident HF (i.e., speckle-tracked cardiac and vascular strain). Carvedilol and spironolactone were chosen for the following reasons: a) they are not routinely used as first-line antihypertensive agents; b) beta-blockade was associated with decreases in hs-cTnT in the preliminary analysis of subjects with established HF; and c) the mechanism of actions of carvedilol and spironolactone provide a sound scientific rationale for use in prevention of HF.

Using a prospective open-label blinded end point (PROBE) design, the investigators propose to randomize 210 subjects aged >40 years with systolic blood pressure between 120-155 mm Hg, cardiac troponin T (measured with a novel high-sensitivity assay) level >5 ng/L, and 10-year HF risk >5% (estimated using a validated laboratory model including demographic factors, NT-proBNP, and hs-cTnT) to receive carvedilol (nonselective beta-blocker), spironolactone (aldosterone antagonist), or usual care for 18 months. The primary end point will be change in global longitudinal systolic myocardial strain estimated using 2D speckle tracking. Additionally, changes in vascular strain and biomarkers will be evaluated. This study will help us identify whether both or either of the medications can be further tested in large randomized clinical trials to prevent the incidence of HF.

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 210 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Prevention
Official Title: Biomarker Guided Therapies in Stage A/B Heart Failure
Actual Study Start Date : October 1, 2014
Estimated Primary Completion Date : December 31, 2018
Estimated Study Completion Date : March 31, 2020

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Heart Failure

Arm Intervention/treatment
Active Comparator: Carvedilol
Approximately 70 subjects will be randomized to carvedilol
Drug: Carvedilol
Carvedilol is a non selective beta blocker

Active Comparator: Spironolactone
Approximately 70 subjects will be randomized to spironolactone
Drug: Spironolactone
Spironolactone is an aldosterone antagonist and can lower blood pressure/ is used in heart failure

No Intervention: Usual care
Approximately 70 subjects will be randomized to usual care/ standard care by primary care providers

Primary Outcome Measures :
  1. Cardiac Strain [ Time Frame: 18 months ]
    Change in myocardial speckle tracked strain (longitudinal strain) after 18 months of therapy

Secondary Outcome Measures :
  1. Change in biomarkers [ Time Frame: 18 months ]
    Change in levels of high sensitivity troponin and NT-proBNP after 18 months of therapy in blood samples. Additional time points when these measures will be assessed will also be tested

  2. arterial stiffness [ Time Frame: 18 months ]
    Changes in arterial stiffness over 18 months, cardio-vascular interaction will also be tested

Information from the National Library of Medicine

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Ages Eligible for Study:   40 Years to 85 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

Inclusion Criteria:

Only Veterans are eligible to participate. Other inclusion criteria include

  • Age greater than 40 years
  • One of the following in order to establish Stage A HF a. Hypertension b. Diabetes mellitus (controlled: defined as hemoglobin A1c less than 9%) c. Obesity (defined as BMI greater than 30 kg/m2) d. Metabolic syndrome (using the National Cholesterol Education Panel definition) e. Left ventricular hypertrophy (by ECG) f. Coronary or cerebrovascular arterial disease
  • Troponin T measured by the high sensitivity assay of greater than 5ng/L
  • Systolic BP 120-155 mmHg at primary care provider (PCP) visit and prerandomization visit (i.e., 2 separate confirmations of the same). If there is discordance between the PCP visit and pre-randomization the investigators will bring patient back to recheck his BP and use that as the tie breaker. Not orthostatic with measurements (defined as a fall in systolic BP greater than 20 mmHg when subjects assume an upright position). - Estimated 10-yr HF risk (based on Atherosclerosis Risk in Communities [ARIC] HF Lab model) greater than 5%
  • Provides informed consent

Exclusion Criteria:

The exclusion criteria include

  • Active Atrial fibrillation
  • History of chest/ neck radiation
  • High-risk chronic obstructive pulmonary disease (COPD) (GOLD classification 3-4 with greater than equal to 2 COPD exacerbations in the last 12 months)
  • Known allergy to carvedilol or spironolactone
  • Renal insufficiency with estimated Glomerular Filtration Rate (eGFR) less than 60 ml/min
  • Serum potassium greater than 5 meq/L
  • Current use of carvedilol, spironolactone, any other beta-blockers or aldosterone antagonists
  • Signs of clinical HF on initial examination (pulmonary rales/crackles, elevated jugular venous pulse with S3/S4 on auscultation)
  • Left ventricular ejection fraction <50% by echo
  • Moderate or greater valve stenosis or regurgitation
  • Hypertrophic cardiomyopathy
  • Exposure to known cardiotoxic chemotherapy
  • Poor echo image quality
  • Right ventricular dysfunction more than mild
  • Any valvular dysfunction that is more than mild
  • Any life-threatening disease expected to result in death within the next 2 years
  • Active severe liver disease (evaluated at Visit 1): cirrhosis, active hepatitis, aspartate transaminase (ALT) or alanine transaminase (AST) greater than 3 x ULN, or biliary obstruction with hyperbilirubinemia (total bilirubin greater than 2 x ULN).
  • Participation in another clinical trial involving an investigational agent within 90 days prior to randomization
  • Any condition or therapy which, in the opinion of the investigator, might pose a risk to the patient or make participation in the study not in the patient s best interest
  • Drug or alcohol abuse within the past 6 months, and unable/unwilling to abstain from drug abuse and excessive alcohol consumption during the study. Excessive alcohol consumption is on average greater than 2 units of alcohol per day. A unit of alcohol is defined as a 12-ounce (350 mL) beer, 5-ounce (150 mL) wine, or 1.5-ounce (45 mL) of 80 ]proof alcohol for drinks.
  • Mental/psychological impairment or any other reason to expect patient difficulty in complying with the requirements of the study.
  • Any immunosuppressed condition where intercurrent illnesses may affect interpretation of study results
  • Pregnant women or any woman planning a pregnancy during the study period
  • Not meeting any of the inclusion criteria

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT02230891

United States, Texas
Michael E. DeBakey VA Medical Center, Houston, TX
Houston, Texas, United States, 77030
Sponsors and Collaborators
VA Office of Research and Development
Baylor College of Medicine
Principal Investigator: Vijay Nambi, MBBS Michael E. DeBakey VA Medical Center, Houston, TX

Responsible Party: VA Office of Research and Development Identifier: NCT02230891     History of Changes
Other Study ID Numbers: CLNB-009-13F
First Posted: September 3, 2014    Key Record Dates
Last Update Posted: December 3, 2018
Last Verified: November 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No

Keywords provided by VA Office of Research and Development:
heart failure

Additional relevant MeSH terms:
Heart Failure
Cardiovascular Diseases
Heart Diseases
Adrenergic beta-Antagonists
Adrenergic Antagonists
Adrenergic Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action
Physiological Effects of Drugs
Antihypertensive Agents
Vasodilator Agents
Adrenergic alpha-1 Receptor Antagonists
Adrenergic alpha-Antagonists
Mineralocorticoid Receptor Antagonists
Hormone Antagonists
Hormones, Hormone Substitutes, and Hormone Antagonists
Diuretics, Potassium Sparing
Natriuretic Agents