Strategies for Aggressive Central Afterload Reduction in Patients With Heart Failure

NCT ID: NCT00588692

Last Updated: 2014-05-06

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: NA
• Total Enrollment: 60 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2007-07-31
• Study Completion Date: 2012-12-31

Brief Summary

Heart failure (HF) is the leading cause of hospitalization among Americans over the age of 65 years, affecting greater than 5 million in the U.S. alone. Significant improvements in morbidity and mortality have been achieved through the use of medications that antagonize adverse neurohormonal signaling pathways, particularly therapies that reduce left ventricular (LV) afterload.

Vascular stiffness increases with aging, contributing to the increase in cardiac load. One important repercussion of such stiffening is an increase in pulse wave velocity. As the incident pressure wave generated by cardiac ejection encounters zones of impedance mismatch (such as arterial bifurcations), part of the wave is reflected backward, summing with the incident wave, increasing central blood pressure (CBP). With normal aging, hypertension, and heart failure, increased wave velocity causes the reflected wave to reach the heart earlier, in mid to late systole, considerably increasing late-systolic load, impairing cardiac ejection, and diastolic relaxation in the ensuing cardiac cycle.

The magnitude of this reflected pressure wave can be quantified by the augmentation index (AIx). The use of vasoactive agents which antagonize this increase in late systolic load (and AIx) may prove useful in the treatment of heart failure, by facilitating cardiac ejection during late systole when reflected pressure waves predominate. However, it has never been conclusively shown in humans that CBP-targeted therapy is useful in the management of HF.

LV afterload, measured centrally in the ascending aorta, may differ considerably from brachial cuff-measured pressure, and has traditionally required invasive hemodynamic assessment to determine, limiting the applicability of techniques targeting CBP and late-systolic load. Recently, a novel, hand-held tonometer (SphygmoCor, Atcor Medical) has been developed for the noninvasive assessment of CBP. This pencil-like device is applied over the radial artery, and uses a validated mathematical transformation to derive central aortic pressure. This device has received FDA approval for clinical use in the assessment of central pressures. However, it remains unknown whether knowledge of CBP and late-systolic load (AIx) confers any clinically-significant incremental benefit in the management of patients with heart failure. The primary objective of the proposed investigation will be to determine if this assessment might have such a role.

Detailed Description

Research Design and Methods

Hypotheses Knowledge of central aortic pressure waveforms (central pressure therapy, CPT) will affect the intensity of antihypertensive medication prescription, and treatment decisions based upon this knowledge in turn will lead to an enhanced reduction in CBP and AIx. Finally, it is hypothesized that this reduction in AIx/CBP will lead to improved exercise performance and LV systolic and diastolic reserve function.

Basic Study Plan This is a single-blind, randomized, controlled, parallel group intervention study examining the effects of a novel, noninvasive diagnostic test for determining AIx and CBP (SphygmoCor, Atcor Medical) on medical care, blood pressure control, exercise performance, and LV functional reserve in patients with chronic heart failure (HF) and systolic dysfunction (25%<EF<50%) and with preserved systolic function (EF>50%). Eligible subjects will undergo resting echocardiogram, noninvasive CBP assessment, and metabolic exercise stress testing on a recumbent cycle ergometer to quantify exercise performance. Echocardiography and CBP assessment will be performed at rest, during graded exercise, and immediately after peak exercise to determine indexes of LV systolic and diastolic performance and changes in CBP. Subjects will then be randomized (1:1) to subsequent determination of CBP at 1 month heart failure clinic visits versus sham (tonometry information acquired, but not shared with investigator). Investigators will then make adjustments to subject's medical therapy and antihypertensive regimen based upon the additional data procured via the Sphygmocor device. Subjects randomized to sham will have adjustments made as per standard clinical judgment based upon brachial blood pressure assessment and other clinical variables. In addition to standard clinical assessment, each subject will undergo 6 minute walk test at each visit, administered by the study coordinator.

At the 6 month follow up visit, subjects will undergo resting and exercise echo/CBP/metabolic stress testing exactly as performed at visit 1. The co-primary endpoints will be the change in central augmentation index (defined below) and change in peak oxygen uptake (VO2) from baseline. Secondary endpoints will include the changes in resting and exercise-induced CBP and brachial blood pressures, number of antihypertensive medications prescribed, resting and exercise change in LV systolic and diastolic function (see below), changes in: cardiac output, exercise time, anaerobic threshold, minute ventilation (VE) over carbon dioxide produced (VCO2) slope (ventilatory efficiency). There will be a total of 7 visits, the first and last for exercise testing; the intervening 5 visits will be routine heart failure clinic follow up appointments.

Conditions

Heart Failure

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: SINGLE

Study Groups

SphygmoCor Unblinded

The use of the sphygmocor values will determine medication adjustments to optimize HF treatment.

Group Type: ACTIVE_COMPARATOR

SphygmoCor

Intervention Type: DEVICE

The SphygmoCor, a hand-held tonometer will assess central blood pressure noninvasively. This pencil-like device is applied over the radial artery, and uses a validated mathematical transformation to derive central aortic pressure.

SphygmoCor Blinded

Sphygmocor values will be blinded to the investigator.

Group Type: PLACEBO_COMPARATOR

SphygmoCor

Intervention Type: DEVICE

The SphygmoCor, a hand-held tonometer will assess central blood pressure noninvasively. This pencil-like device is applied over the radial artery, and uses a validated mathematical transformation to derive central aortic pressure.

Interventions

SphygmoCor

The SphygmoCor, a hand-held tonometer will assess central blood pressure noninvasively. This pencil-like device is applied over the radial artery, and uses a validated mathematical transformation to derive central aortic pressure.

Intervention Type: DEVICE

Eligibility Criteria

Inclusion Criteria

• 18 years of age or greater
• Cardiac Ejection Fraction (EF) greater than or equal to 25% by echocardiography within 12 months
• Stable New York Heart Association (NYHA) class II or greater
• Heart Failure consultation within the last 18 months
• Ability to exercise on a cycle ergometer
• Stable angiotensin-converting enzyme inhibitors (ACEI) or angiotensin II receptor blockers (ARB) dosage for greater than 3 months

Exclusion Criteria

• Enrollment in a concurrent study that may confound the results of this study
• Subjects with medical conditions that would limit study participation
• Pregnancy
• Brachial Systolic Blood Pressure less than 110 mmHg
• Baseline AIx less than 15%
• Cardiac Surgery with 60 days of potential study enrollment
• Myocardial infarction within 30 days of potential study enrollment
• Hemodynamically significant valvular stenosis (greater than mild)
• Heart failure due to thyroid disease
• Active myocarditis or anemia defined as hemoglobin less than 9 mg/dl
• Presence of severe renal insufficiency with serum creatinine greater than 2.5 mg/dl
• Significant pulmonary hypertension or Cor pumonale
• Irregular heart rhythms
• Dyspnea due to pulmonary disease
• Uninterpretable echocardiographic images or radial tonometry data
• Significant competing cause for exercise intolerance (e.g., severe stable angina)

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

AtCor Medical, Inc.

INDUSTRY

Sponsor Role: collaborator

Mayo Clinic

OTHER

Sponsor Role: lead

Responsible Party

Barry Borlaug

MD

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Barry A. Borlaug, MD

Role: PRINCIPAL_INVESTIGATOR

Staff Physician, Mayo Clinic

Locations

University of Arizona

Phoenix, Arizona, United States

Mayo Clinic

Rochester, Minnesota, United States

Countries

United States

References

Wohlfahrt P, Melenovsky V, Redfield MM, Olson TP, Lin G, Abdelmoneim SS, Hametner B, Wassertheurer S, Borlaug BA. Aortic Waveform Analysis to Individualize Treatment in Heart Failure. Circ Heart Fail. 2017 Feb;10(2):e003516. doi: 10.1161/CIRCHEARTFAILURE.116.003516.

Reference Type: DERIVED

PMID: 28159826 (View on PubMed)

Borlaug BA, Olson TP, Abdelmoneim SS, Melenovsky V, Sorrell VL, Noonan K, Lin G, Redfield MM. A randomized pilot study of aortic waveform guided therapy in chronic heart failure. J Am Heart Assoc. 2014 Mar 20;3(2):e000745. doi: 10.1161/JAHA.113.000745.

Reference Type: DERIVED

PMID: 24650926 (View on PubMed)

Other Identifiers

07-002008

Identifier Type: -

Identifier Source: org_study_id