Strategies for Aggressive Central Afterload Reduction in Patients With Heart Failure (SACAR)

This study has been completed.
Sponsor:
Collaborator:
AtCor Medical, Inc.
Information provided by (Responsible Party):
Barry Borlaug, Mayo Clinic
ClinicalTrials.gov Identifier:
NCT00588692
First received: December 21, 2007
Last updated: April 7, 2014
Last verified: April 2014
  Purpose

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.


Condition Intervention
Heart Failure
Device: SphygmoCor

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Single Blind (Investigator)
Primary Purpose: Treatment
Official Title: Strategies for Aggressive Central Afterload Reduction in Patients With Heart Failure

Resource links provided by NLM:


Further study details as provided by Mayo Clinic:

Primary Outcome Measures:
  • Change in Peak Oxygen Uptake (VO2) During Maximal Effort Exercise Stress Test According to Ejection Fraction Subgroups [ Time Frame: baseline, 6 months ] [ Designated as safety issue: No ]
    Peak oxygen uptake (VO2) is the maximum rate of oxygen consumption as measured during incremental exercise, most typically on a motorized treadmill. Maximal oxygen consumption reflects the aerobic physical fitness of the individual. VO2 data was obtained via standard breath-by-breath expired gas analysis. Ejection Fraction Subgroups are based on participants reported at baseline.

  • Change in Aortic Augmentation Index (AIx) According to Ejection Fraction Subgroups [ Time Frame: baseline, 6 months ] [ Designated as safety issue: No ]

    Aortic stiffness increases with aging, further augmenting cardiac load. One important repercussion of aortic stiffening is an increase in pulse wave velocity. As the outgoing pressure wave caused by ventricular ejection encounters zones of impedance mismatch, it is partially reflected backward, summing with the incident wave, to increase central aortic blood pressure. The magnitude of this systolic pressure wave reflection can be quantified by AIx.

    Aortic pressures were assessed in the seated position after 5 minutes rest. Aortic pulse waveform analysis was performed using a noninvasive, high-fidelity hand held tonometer placed over the radial artery. The built-in, custom software was then used to convert radial pressure waveforms to central aortic waveforms, which more accurately reflect LV afterload. The ratio of this augmented pressure to aortic pulse pressure is defined as the augmentation index (AIx).



Secondary Outcome Measures:
  • Change in Heart Rate [ Time Frame: baseline, six months ] [ Designated as safety issue: No ]
  • Change in Left Ventricle (LV) End Diastolic Volume [ Time Frame: baseline, 6 months ] [ Designated as safety issue: No ]

    End-diastolic volume (EDV) is the volume of blood in the right and/or left ventricle at end load or filling in (diastole). An increase in EDV increases the preload on the heart and, through the Frank-Starling mechanism of the heart, increases the amount of blood ejected from the ventricle during systole (stroke volume).

    Ventricular Data was derived from comprehensive echo-Doppler/Tissue Doppler Echo (TDE) study performed at rest, during and immediately after exercise, along with noninvasive blood pressure assessment (GE Vivid7). LV EDV was determined from the apical 4 and 2 chamber views using Simpson's method of discs, along with ejection fraction (EF).


  • Change in LV End Systolic Volume [ Time Frame: baseline, 6 months ] [ Designated as safety issue: No ]

    End-systolic volume (ESV) is the volume of blood in a ventricle at the end of contraction, or systole, and the beginning of filling, or diastole. ESV is the lowest volume of blood in the ventricle at any point in the cardiac cycle. End systolic volume can be used clinically as a measurement of the adequacy of cardiac emptying, related to systolic function.

    Ventricular Data was derived from comprehensive echo-Doppler/Tissue Doppler Echo (TDE) study performed at rest, during and immediately after exercise, along with noninvasive blood pressure assessment (GE Vivid7). LV end systolic volumes was determined from the apical 4 and 2 chamber views using Simpson's method of discs, along with EF.


  • Change in LV Ejection Fraction [ Time Frame: baseline, 6 months ] [ Designated as safety issue: No ]

    The ejection fraction is the percentage of the volume in the left ventricle ejected during a cardiac cycle. The normal ejection fraction is 55 to 75 percent. EF = (EDV ‑ ESV) / EDV where EF = ejection fraction, EDV = volume of blood in the left ventricle at end‑diastole, ESV = volume of blood in the left ventricle at end‑systole.

    Ventricular Data was derived from comprehensive echo-Doppler/Tissue Doppler Echo (TDE) study performed at rest, during and immediately after exercise, along with noninvasive blood pressure assessment (GE Vivid7).


  • Change in Stroke Volume [ Time Frame: baseline, 6 months ] [ Designated as safety issue: No ]
    Stroke volume (SV) is the volume of blood pumped from one ventricle of the heart with each beat. SV was determined from pulse wave (PW) and continuous wave (CW) Doppler in the LV outflow tract.

  • Change in Mitral E Velocity [ Time Frame: baseline, 6 months ] [ Designated as safety issue: No ]
    The Mitral E velocity is the speed at which blood fills the ventricle. It is determined by echocardiography, an ultrasound-based cardiac imaging modality.

  • Change in Mitral E/A Ratio [ Time Frame: baseline, 6 months ] [ Designated as safety issue: No ]
    The E/A ratio is a marker of the function of the left ventricle of the heart; it is determined by echocardiography, an ultrasound-based cardiac imaging modality. Abnormalities in the E/A ratio on Doppler echocardiography suggest that the left ventricle, which pumps blood into the circulation, cannot fill with blood properly in the period between contractions. The E/A ratio is the ratio of peak early transmitral inflow velocity and peak late mitral inflow velocity.

  • Change in Mitral E Wave Deceleration Time [ Time Frame: baseline, 6 months ] [ Designated as safety issue: No ]
    The deceleration time (DT) is the time taken from the maximum E point to baseline. Normally in adults it is less than 220 milliseconds. The DT was measured by pulse wave doppler.

  • Change in Brachial Systolic Blood Pressure (BP) [ Time Frame: baseline, 6 months ] [ Designated as safety issue: No ]

    Blood pressure is a measure of the force of the blood flowing against the walls of your arteries as it moves through your body.

    There are two numbers in a blood pressure reading. This tells how high in millimeters the pressure of your blood raises a column of mercury. The numbers usually are expressed in the form of a fraction; an example of a blood pressure reading is 120/80 mm Hg. The first, or top, number (120 in the example) is the systolic pressure. The systolic pressure is the measure of your blood pressure as the heart contracts and pumps blood. The second or lower number is the diastolic pressure and is the measure taken when your heart is at rest (80 in the example)

    Brachial systolic BP was determined by a standard oscillometric device (Dinemap, Critikon).


  • Change in Brachial Diastolic BP [ Time Frame: baseline, 6 months ] [ Designated as safety issue: No ]

    Blood pressure is a measure of the force of the blood flowing against the walls of your arteries as it moves through your body.

    There are two numbers in a blood pressure reading. This tells how high in millimeters the pressure of your blood raises a column of mercury. The numbers usually are expressed in the form of a fraction; an example of a blood pressure reading is 120/80 mm Hg. The first, or top, number (120 in the example) is the systolic pressure. The systolic pressure is the measure of your blood pressure as the heart contracts and pumps blood. The second or lower number is the diastolic pressure and is the measure taken when your heart is at rest (80 in the example)

    Brachial diastolic BP was determined by a standard oscillometric device (Dinemap, Critikon).


  • Change in Central Systolic BP [ Time Frame: baseline, 6 months ] [ Designated as safety issue: No ]
    Central blood pressure (CBP) is the pressure in the aorta, which is the large artery into which the heart pumps. This was determined by noninvasive radial tonometry, which undergoes transfer function using customized software to derive CBP tracings.

  • Change in Central Diastolic BP [ Time Frame: baseline, 6 months ] [ Designated as safety issue: No ]
    Central blood pressure (CBP) is the pressure in the aorta, which is the large artery into which the heart pumps. This was determined by noninvasive radial tonometry, which undergoes transfer function using customized software to derive CBP tracings.

  • Change in Augmentation Index [ Time Frame: baseline, 6 months ] [ Designated as safety issue: No ]

    Aortic stiffness increases with aging, further augmenting cardiac load. One important repercussion of aortic stiffening is an increase in pulse wave velocity. As the outgoing pressure wave caused by ventricular ejection encounters zones of impedance mismatch, it is partially reflected backward, summing with the incident wave, to increase central aortic blood pressure. The magnitude of this systolic pressure wave reflection can be quantified by AIx.

    Aortic pressures were assessed in the seated position after 5 minutes rest. Aortic pulse waveform analysis was performed using a noninvasive, high-fidelity hand held tonometer placed over the radial artery. The built-in, custom software was then used to convert radial pressure waveforms to central aortic waveforms, which more accurately reflect LV afterload. The ratio of this augmented pressure to aortic pulse pressure is defined as the augmentation index (AIx).


  • Change in Arterial Elastance [ Time Frame: baseline, 6 months ] [ Designated as safety issue: No ]
    Elastance is a measure of the tendency of a hollow organ to recoil toward its original dimensions upon removal of a distending or compressing force. Effective arterial elastance was determined by the ratio of end systolic BP/stroke volume (SV).


Enrollment: 60
Study Start Date: July 2007
Study Completion Date: December 2012
Primary Completion Date: November 2012 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: SphygmoCor Unblinded
The use of the sphygmocor values will determine medication adjustments to optimize HF treatment.
Device: 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.
Placebo Comparator: SphygmoCor Blinded
Sphygmocor values will be blinded to the investigator.
Device: 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.

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

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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)
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00588692

Locations
United States, Arizona
University of Arizona
Phoenix, Arizona, United States, 85004
United States, Minnesota
Mayo Clinic
Rochester, Minnesota, United States, 55905
Sponsors and Collaborators
Mayo Clinic
AtCor Medical, Inc.
Investigators
Principal Investigator: Barry A. Borlaug, MD Staff Physician, Mayo Clinic
  More Information

Additional Information:
No publications provided

Responsible Party: Barry Borlaug, MD, Mayo Clinic
ClinicalTrials.gov Identifier: NCT00588692     History of Changes
Other Study ID Numbers: 07-002008
Study First Received: December 21, 2007
Results First Received: January 30, 2014
Last Updated: April 7, 2014
Health Authority: United States: Institutional Review Board

Keywords provided by Mayo Clinic:
Heart Failure
Afterload Reduction
Sphygmocor

Additional relevant MeSH terms:
Heart Failure
Cardiovascular Diseases
Heart Diseases

ClinicalTrials.gov processed this record on October 23, 2014