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Update on Clinical Trials of Losartan With and Without β-Blockers to Block Aneurysm Growth in Patients With Marfan Syndrome A Review

Educational Objective
To detail the evidence regarding the utility of β-blockers and angiotensin receptor blockers for the treatment of thoracic aortic aneurysm in patients with Marfan syndrome.
1 Credit CME
Abstract

Importance  Thoracic aortic aneurysms leading to acute aortic dissections are a major cause of morbidity and mortality despite significant advances in surgical treatment, which remains the main intervention to prevent type A dissections. In the past 2 decades progress has been made toward a better understanding of molecular mechanisms that lead to aneurysm formation and dissections of the thoracic aorta. This focused review emphasizes the results of clinical trials using β-blocker, losartan potassium, and irbesartan in patients with Marfan syndrome and comments briefly on mechanisms of aortic remodeling, including fibrosis and transforming growth factor β signaling.

Observation  The major risk factors for the disease are increased hemodynamic forces, typically owing to poorly controlled hypertension, and heritable genetic variants. The altered genes predisposing to thoracic aortic disease have been shown or are predicted to decrease vascular smooth muscle cell contraction, decrease transforming growth factor β signaling, or alter the extracellular matrix. Preclinical models of Marfan syndrome showed promising results for losartan as a potential therapy to attenuate aortic dilation in mice. However, several clinical trials did not conclusively confirm that losartan attenuated aortic aneurysm expansion better than β-blockers. Most importantly, clinical trials assessing whether losartan therapy not only reduces aortic growth but also improves adverse aortic outcomes, including dissection, need for surgery, and death, have not been conducted. The largest trial to date to our knowledge, the Pediatric Heart Network trial, sponsored by the National Heart, Lung, and Blood Institute, showed a nonsignificant increase in adverse aortic outcomes, with almost a doubling of adverse events in patients randomized to losartan treatment compared with β-blockers, suggesting that this study was underpowered to assess adverse aortic outcomes. On the other hand, the evidence for β-blocker therapy to reduce morbidity and mortality in Marfan syndrome is limited to a single small, prospective randomized and nonblinded clinical trial.

Conclusions and Relevance  Taken together, these data emphasize the need for clinical trials adequately powered to assess both aortic aneurysm growth and adverse aortic outcomes to identify effective medical therapies for Marfan syndrome and other aortopathies.

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Article Information

Accepted for Publication: March 4, 2019.

Corresponding Author: Marion A. Hofmann Bowman, MD, PhD, 2547 Frankel Cardiovascular Center, University of Michigan, 1500 E Medical Center Dr, SPC 5853, Ann Arbor, MI 48109 (mhofmann@med.umich.edu).

Published Online: May 8, 2019. doi:10.1001/jamacardio.2019.1176

Author Contributions: Drs Hofmann Bowman and Milewicz had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: All authors.

Acquisition, analysis, or interpretation of data: Hofmann Bowman.

Drafting of the manuscript: Hofmann Bowman, Milewicz.

Critical revision of the manuscript for important intellectual content: Hofmann Bowman, Eagle.

Obtained funding: Milewicz.

Administrative, technical, or material support: Hofmann Bowman.

Supervision: Hofmann Bowman, Eagle.

Conflict of Interest Disclosures: None reported.

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