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Randomized Controlled Trial
. 2023 Oct 13;77(8):1166-1175.
doi: 10.1093/cid/ciad310.

Randomized Placebo-Controlled Trial to Evaluate Effects of Eplerenone on Myocardial Perfusion and Function Among Persons With Human Immunodeficiency Virus (HIV)-Results From the MIRACLE HIV Study

Suman Srinivasa  1 , Allie R Walpert  1 , Teressa S Thomas  1 , Daniel M Huck  2 , Michael Jerosch-Herold  3 , Sabeeh Islam  3 , Michael T Lu  4 , Tricia H Burdo  5 , Christopher R deFilippi  6 , Carolyn N Dunderdale  1 , Meghan Feldpausch  1 , Sanjna Iyengar  1 , Grace Shen  1 , Stephen Baak  5 , Martin Torriani  7 , Gregory K Robbins  8 , Hang Lee  9 , Raymond Kwong  3 , Marcelo DiCarli  2 , Gail K Adler  10 , Steven K Grinspoon  1
Affiliations
Randomized Controlled Trial

Randomized Placebo-Controlled Trial to Evaluate Effects of Eplerenone on Myocardial Perfusion and Function Among Persons With Human Immunodeficiency Virus (HIV)-Results From the MIRACLE HIV Study

Suman Srinivasa et al. Clin Infect Dis. .

Abstract

Background: Increased renin angiotensin aldosterone system (RAAS) activity may contribute to excess cardiovascular disease in people with HIV (PWH). We investigated how RAAS blockade may improve myocardial perfusion, injury, and function among well-treated PWH.

Methods: Forty PWH, on stable ART, without known heart disease were randomized to eplerenone 50 mg PO BID (n = 20) or identical placebo (n = 20) for 12 months. The primary endpoints were (1) myocardial perfusion assessed by coronary flow reserve (CFR) on cardiac PET or stress myocardial blood flow (sMBF) on cardiac MRI or (2) myocardial inflammation by extracellular mass index (ECMi) on cardiac MRI.

Results: Beneficial effects on myocardial perfusion were seen for sMBF by cardiac MRI (mean [SD]: 0.09 [0.56] vs -0.53 [0.68] mL/min/g; P = .03) but not CFR by cardiac PET (0.01 [0.64] vs -0.07 [0.48]; P = .72, eplerenone vs placebo). Eplerenone improved parameters of myocardial function on cardiac MRI including left ventricular end diastolic volume (-13 [28] vs 10 [26] mL; P = .03) and global circumferential strain (GCS; median [interquartile range 25th-75th]: -1.3% [-2.9%-1.0%] vs 2.3% [-0.4%-4.1%]; P = .03), eplerenone versus placebo respectively. On cardiac MRI, improvement in sMBF related to improvement in global circumferential strain (ρ = -0.65, P = .057) among those treated with eplerenone. Selecting for those with impaired myocardial perfusion (CFR <2.5 and/or sMBF <1.8), there was a treatment effect of eplerenone versus placebo to improve CFR (0.28 [0.27] vs -0.05 [0.36]; P = .04). Eplerenone prevented a small increase in troponin (0.00 [-0.13-0.00] vs 0.00 [0.00-0.74] ng/L; P = .03) without effects on ECMi (0.9 [-2.3-4.3] vs -0.7 [-2.2--0.1] g/m2; P = .38). CD4+ T-cell count (127 [-38-286] vs -6 [-168-53] cells/μL; P = .02) increased in the eplerenone- versus placebo-treated groups.

Conclusions: RAAS blockade with eplerenone benefitted key indices and prevented worsening of myocardial perfusion, injury, and function among PWH with subclinical cardiac disease when compared with placebo.

Clinical trials registration: NCT02740179 (https://clinicaltrials.gov/ct2/show/NCT02740179?term=NCT02740179&draw=2&rank=1).

Keywords: HIV; eplerenone; myocardial blood flow; myocardial dysfunction; renin-angiotensin-aldosterone system.

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Conflict of interest statement

Potential conflicts of interest. S. S. was the recipient of a Gilead Sciences Research Scholars award. M. T. L. has received research funding from KOWA, MedImmune, AstraZeneca, Ionis, and Johnson & Johnson Innovation. T. H. B. is a paid member of the Scientific Advisory Board and has equity in Excision BioTherapeutics, Inc. C. R. d. receives consulting fees from Abbott Diagnostics, Quidel/Ortho, Roche Diagnostics, and Siemens Diagnostics. G. K. R. has received trials support from Leonard Meron Biosciences and consulting fees from Teradyne for clinical trial design and from SEED for COVID consulting. He is also an unpaid panel member of the Department of Health and Human Services (DHHS) Opportunistic Infections guidelines review committee and has provided expert medical review testimony for Tufts Medical Center. G. K. R. also reports unpaid participation on a Data Safety Monitoring Board or Advisory Board for Arterial Inflammation and Coronary Microvascular Dysfunction among Women with HIV: Missing Pieces to the MI Risk Puzzle (grant number R01HL146267). S. K. G. has received research funding from KOWA, Gilead, ViiV, and Theratechnologies and received consulting fees from Theratechnologies and ViiV. He is a member of the Scientific Advisory Board of Marathon Asset Management. M. D. reports grants or contracts paid to institutions from Gilead Sciences and Spectrum Dynamics; consulting fees from Sanofi and MedTrace Pharma; and receipt of equipment, materials, drugs, medical writing, gifts, or other services from Amgen. All disclosures are unrelated to this manuscript. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.

Figures

Figure 1.
Figure 1.
Flowchart of the participants in the study. One hundred and ten participants were assessed for eligibility. Seventy participants were excluded, as 53 did not meet the inclusion criteria per protocol, 10 declined to participate, and 7 were lost to follow-up. A total of 40 participants were randomized and evenly allocated to the eplerenone and placebo treatment arms. Within the eplerenone arm, 1 participant declined to participate further and 5 other participants discontinued intervention, leaving 14 participants for the primary analysis. Within the placebo arm, 1 participant discontinued intervention, leaving 19 participants for the primary analysis. Abbreviations: CTA, computed tomography angiography; VAT, visceral adipose tissue.
Figure 2.
Figure 2.
Change in stress myocardial blood flow and global circumferential strain on cardiac MRI over 12 months among treatment groups. A, The bar graph shows the mean change in stress myocardial blood flow measured on cardiac MRI among those treated with eplerenone versus placebo. Error bars represent the standard deviation. B, The box plot shows the median change in global circumferential strain measured on cardiac MRI among those treated with eplerenone versus placebo. The box plot represents the 25th and 75th percentile, and the line within the box represents the median. Abbreviation: MRI, magnetic resonance imaging.
Figure 3.
Figure 3.
Change in CFR over 12 months by impaired versus normal total flow capacity on cardiac PET among treatment groups. A, Participants categorized based on integrating CFR and maximal MBF both obtained by cardiac PET to assess total flow capacity identify unique prognostic at-risk phenotypes for CVD. B, The bar graph shows the mean change in CFR stratified by impaired total flow capacity (groups 1–3) versus normal total flow capacity (group 4) in the eplerenone- versus placebo-treated groups. Eplerenone significantly improves mean CFR among those participants with impaired total flow capacity. Abbreviations: CFR, coronary flow reserve; MBF, myocardial blood flow; PET, positron emission tomography.
See this image and copyright information in PMC

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