Clinical trial NCT00588692: Strategies for Aggressive Central Afterload Reduction in Patients With Heart Failure
Official title: Strategies for Aggressive Central Afterload Reduction in Patients With Heart Failure
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Heart Failure
Keywords: Heart Failure
Afterload Reduction
Sphygmocor
Lead sponsor: Mayo Clinic
Sponsor class: OTHER
Collaborators: name: AtCor Medical, Inc.
First posted: 2008-01-08
Enrollment: 60
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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)

Primary outcomes:
measure: Change in Peak Oxygen Uptake (VO2) During Maximal Effort Exercise Stress Test According to Ejection Fraction Subgroups
timeFrame: baseline, 6 months
measure: Change in Aortic Augmentation Index (AIx) According to Ejection Fraction Subgroups
timeFrame: baseline, 6 months
Secondary outcomes:
measure: Change in Heart Rate
timeFrame: baseline, six months
measure: Change in Left Ventricle (LV) End Diastolic Volume
timeFrame: baseline, 6 months
measure: Change in LV End Systolic Volume
timeFrame: baseline, 6 months
measure: Change in LV Ejection Fraction
timeFrame: baseline, 6 months
measure: Change in Stroke Volume
timeFrame: baseline, 6 months
measure: Change in Mitral E Velocity
timeFrame: baseline, 6 months
measure: Change in Mitral E/A Ratio
timeFrame: baseline, 6 months
measure: Change in Mitral E Wave Deceleration Time
timeFrame: baseline, 6 months
measure: Change in Brachial Systolic Blood Pressure (BP)
timeFrame: baseline, 6 months
measure: Change in Brachial Diastolic BP
timeFrame: baseline, 6 months
measure: Change in Central Systolic BP
timeFrame: baseline, 6 months
measure: Change in Central Diastolic BP
timeFrame: baseline, 6 months
measure: Change in Augmentation Index
timeFrame: baseline, 6 months
measure: Change in Arterial Elastance
timeFrame: baseline, 6 months
Other outcomes:
Locations:
city: Phoenix
country: United States
facility: University of Arizona
state: Arizona
city: Rochester
country: United States
facility: Mayo Clinic
state: Minnesota
Study officials:
affiliation: Staff Physician, Mayo Clinic
name: Barry A. Borlaug, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.