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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
- Source :
- JAMA cardiology. 4(7)
- Publication Year :
- 2019
-
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.
- Subjects :
- Losartan Potassium
Marfan syndrome
medicine.medical_specialty
Adrenergic beta-Antagonists
030204 cardiovascular system & hematology
Losartan
Marfan Syndrome
03 medical and health sciences
Aortic aneurysm
Mice
0302 clinical medicine
Aneurysm
Internal medicine
medicine.artery
medicine
Thoracic aorta
Animals
Humans
030212 general & internal medicine
Adverse effect
Clinical Trials as Topic
Aortic Aneurysm, Thoracic
business.industry
medicine.disease
Propranolol
Clinical trial
Disease Models, Animal
Treatment Outcome
cardiovascular system
Cardiology
Cardiology and Cardiovascular Medicine
business
Angiotensin II Type 1 Receptor Blockers
medicine.drug
Subjects
Details
- ISSN :
- 23806591
- Volume :
- 4
- Issue :
- 7
- Database :
- OpenAIRE
- Journal :
- JAMA cardiology
- Accession number :
- edsair.doi.dedup.....ac6e967cb3749e69f4b00439efe8b29c