MAGMA and EXHALTED Trials Seek Ways to Monitor Disease Progression and Improve Outcomes

Trials employ novel imaging technologies for high-risk cases

Innovations in Cardiovascular Medicine & Surgery - Fall 2018

 Sanjay Rajagopalan, MD

 Mirela Dobre, MD, MPH

Physicians of the Harrington Heart & Vascular Institute at University Hospitals Cleveland Medical Center are harnessing sophisticated imaging technologies in their investigation of cardiovascular risk factors. Co-principal investigators, Sanjay Rajagopalan, MD, Chief, Division of Cardiovascular Medicine, UH Cleveland Medical Center, Co-Chair, Clinical Executive Committee, UH Harrington Heart & Vascular Institute; Director, Cardiovascular Research Institute and Clinical Professor of Medicine, Case Western Reserve University School of Medicine, and Mirela Dobre, MD, MPH, Department of Nephrology, are continuing their work on two trials funded through the National Institutes of Health that study high-risk patient populations to find broadly applicable solutions for monitoring disease progression and improving patient outcomes.

MAGMA Study

The MAGMA (Mineralocorticoid Receptor Antagonism Clinical Evaluation in Atherosclerosis) study is investigating the efficacy of the mineralocorticoid receptor (MR) antagonist drug spironolactone (Aldactone) to slow atherosclerosis in patients with type 2 diabetes mellitus (T2DM) and chronic kidney disease. Research shows that MR activation plays an essential role in inflammation and organ damage.

“Initially used as a drug for heart failure, we have shown in a series of investigations that spironolactone could be effective in reducing atherosclerosis plaque thickness,” Dr. Rajagopalan says. “In rabbit models fed a high-fat diet, the drug had favorable outcomes reducing atherosclerosis and inflammation and improving vascular function.”

To be eligible for the study, patients must not be in heart failure and must exhibit impaired kidney function, as measured by a glomerular filtration rate (GFR) of

Patients enrolled in the double-blind trial are randomized 1:1 to placebo or spironolactone (12.5 mg with eventual escalation to 25 mg daily over a 4-week period). Patients who are ineligible for the MAGMA trial because they exhibit hyperkalemia on spironolactone or RAAS blocker can be considered for the MAGMA Add-On trial, an open-label study of patiromer (Veltassa), which works by binding excess potassium in the gut. “In MAGMA Add-On, we are testing the efficacy of simultaneously treating patients with the drug patiromer to control hyperkalemia, enabling them to tolerate spironolactone and participate in the investigation.”

The co-primary efficacy endpoint is percentage change in total atheroma volume in thoracic aorta and left ventricular mass at 52 weeks in patients treated with spironolactone vs placebo. “Using sophisticated three-dimensional imaging methodologies, we are able to quantify the thickness of the arterial wall over time,” says Dr. Rajagopalan. Secondary endpoints include 24-hour mean systolic blood pressure, central aortic blood pressure and insulin resistance (HOMA-IR) at six weeks. Additionally, investigators are studying changes in candidate miRNAs that regulate expression of NR3C2 (MR gene), as well as measuring monocyte/macrophage polarization.

EXHALTED Study

The EXHALTED (Exercise MRI Evaluation of HIV-Pulmonary Arterial Hypertension Longitudinal Determinants) study is a 24-month investigation utilizing University Hospitals Cleveland Medical Center’s advanced MRI-compatible exercise platform (ExMR) in conjunction with cardiopulmonary testing to delineate pulmonary arterial hypertension (PAH) from other causes of cardiovascular dysfunction.

Data from the trial will identify individuals with exercise-induced PAH who are at high risk of developing resting PAH, and provide longitudinal estimates of progression of PAH and right ventricular function. Furthermore, the study is facilitating analysis of inflammatory variables that may aid in earlier identification of patients.

Trial participants must have a confirmed diagnosis of HIV, a Karnofsky score >70 on at least one occasion within the prior two weeks, and meet at least one of the following criteria:

• Unexplained persistent or progressively worsened dyspnea for at least six weeks
• Previously documented sPAP>35mmHg and/or abnormal RV on echo
• Established diagnosis of HIV-PAV.

“PAH is a serious cause of dyspnea and exercise limitation in patients with HIV,” Dr. Rajagopalan says. “The exact reason for dyspnea may be difficult to diagnose using routine physical exam or conventional methods available to the clinician. With novel imaging and software tools, we are able to analyze the underlying causes of shortness of breath.”

The trial utilizes high-resolution MRI immediately prior to and post exercise, paired with cardiopulmonary exercise testing (CPET), to provide a highly detailed assessment of heart and lung function.

“UH is one of a couple locations worldwide utilizing this methodology for exercise cardiopulmonary testing,” Dr. Rajagopalan says. “In the future, this technology will hopefully replace more invasive testing, such as exercise right heart catheterization, and pave the way for novel diagnostic strategies for a broad spectrum of disorders.”

In 2019, University Hospitals Harrington Heart & Vascular Institute will add the LODE MR Ergometer Pedal, enabling MRI scans while patients pedal to visualize heart function as exercise occurs. The MR ergometer is compatible up to 3 Tesla.

For more information on these studies, or details on other clinical trials available through University Hospitals Harrington Heart & Vascular Institute, contact Stacey Mazzurco, RN, Director, Clinical Trials, at Stacey.Mazzurco@UHhospitals.org or 216-844-3130.