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Biomarker Guided Therapies in Stage A/B Heart Failure

Information source: Department of Veterans Affairs
ClinicalTrials.gov processed this data on August 23, 2015
Link to the current ClinicalTrials.gov record.

Condition(s) targeted: Hypertension; Diabetes; Cardiovascular Disease

Intervention: Carvedilol (Drug); Spironolactone (Drug)

Phase: Phase 2

Status: Recruiting

Sponsored by: Department of Veterans Affairs

Official(s) and/or principal investigator(s):
Vijay Nambi, MBBS, Principal Investigator, Affiliation: Michael E. DeBakey VA Medical Center, Houston, TX

Overall contact:
William Wehner, Phone: (713) 794-7966, Email: William.Wehner@va.gov

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, we propose to identify and treat subjects at higher HF risk to see if we can stabilize or improve ultrasound measures known to be associated with HF risk. This study will enroll only veterans.

Clinical Details

Official title: Biomarker Guided Therapies in Stage A/B Heart Failure

Study design: Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Prevention

Primary outcome: Cardiac Strain

Secondary outcome:

Change in biomarkers

arterial stiffness

Detailed description: Recently we 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, we 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, we believe that by using hs-cTnT to estimate HF risk we can identify individuals in whom aggressive modification of risk factors such as high blood pressure will be associated with a favorable risk-benefit ratio. Our 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 our 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, we propose to randomize 210 subjects aged >40 years with systolic blood pressure between 125-150 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.

Eligibility

Minimum age: 40 Years. Maximum age: 85 Years. Gender(s): Both.

Criteria:

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 8%) 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 125-150 mmHg at PCP visit and prerandomization visit (i. e., 2 separate

confirmations of the same). If there is discordance between the PCP visit and pre-randomization we 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). If diabetic the systolic blood pressure should be 125-140 mmHg

- Estimated 10-yr HF risk (based on ARIC HF Lab model) greater than 5%

- Provides informed consent

Exclusion Criteria: The exclusion criteria include

- 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 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, ALT

or 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 immnuosuppressed 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

Locations and Contacts

William Wehner, Phone: (713) 794-7966, Email: William.Wehner@va.gov

Michael E. DeBakey VA Medical Center, Houston, TX, Houston, Texas 77030, United States; Recruiting
William Wehner, Phone: 713-794-7966, Email: William.Wehner@va.gov
Vijay Nambi, MBBS, Email: Vijay.Nambi@va.gov
Vijay Nambi, MBBS, Principal Investigator
Additional Information

Starting date: October 2014
Last updated: August 14, 2015

Page last updated: August 23, 2015

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