Clinical Trials of Losartan to Block Aneurysm Growth in Marfan Syndrome

Hofmann Bowman MA, Eagle KA, Milewicz DM.
Update on Clinical Trials of Losartan With and Without Beta-Blockers to Block Aneurysm Growth in Patients With Marfan Syndrome: A Review. JAMA Cardiol 2019;May 8:[Epub ahead of print].

The following are key points to remember from this update on clinical trials of losartan with and without beta-blockers to block aneurysm growth in patients with Marfan syndrome:

  1. Thoracic aortic aneurysms leading to acute aortic dissections are a significant cause of morbidity and mortality despite significant advances in surgical treatment, the mainstay of therapy for thoracic aortic aneurysms.
  2. We now have a better understanding of molecular mechanisms that lead to aneurysm formation and dissections of the thoracic aorta.
  3. The major risk factors for the disease are increased hemodynamic forces, usually due to poorly controlled hypertension, and heritable genetic variants.
  4. The altered genes predisposing to thoracic aortic disease decrease vascular smooth muscle cell contraction, decrease transforming growth factor β signaling, or alter the extracellular matrix.
  5. Preclinical studies showed promising results for losartan as a potential therapy to attenuate aortic dilation in mice models of Marfan syndrome. However, several clinical trials did not conclusively confirm that losartan attenuated aortic aneurysm expansion better than beta-blockers.
  6. 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.
  7. The largest trial to date, 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 beta-blockers, suggesting that this study may have been underpowered to assess adverse aortic outcomes.
  8. Of note, the evidence for beta-blocker therapy to reduce morbidity and mortality in Marfan syndrome is limited to a single small, prospective, randomized, and nonblinded clinical trial. A 2007 meta-analysis of six studies that enrolled a total of 802 patients with Marfan syndrome found no difference between beta-blocker therapy and no treatment with regard to clinical outcomes of mortality and morbidity.
  9. At this time, the management of hypertension remains a central target for all physicians caring for patients with thoracic aortic disease.
  10. Based on limited data, it appears reasonable to use beta-blockers as a first-line therapy for thoracic aortic disease with the addition of losartan or other angiotensin-receptor blockers only if a second drug is needed for blood pressure control.
  11. There is some evidence that drugs that lower blood pressure by decreasing smooth muscle cell contraction (e.g., hydralazine, calcium channel blockers) should not be considered the first line of therapy.
  12. Available data or lack of data underscore 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.

Clinical Topics: Cardiac Surgery, Congenital Heart Disease and Pediatric Cardiology, Prevention, Vascular Medicine, Aortic Surgery, Cardiac Surgery and Arrhythmias, Cardiac Surgery and CHD and Pediatrics, Congenital Heart Disease, CHD and Pediatrics and Arrhythmias, CHD and Pediatrics and Prevention, CHD and Pediatrics and Quality Improvement, Hypertension

Keywords: Adrenergic beta-Antagonists, Aneurysm, Dissecting, Angiotensin Receptor Antagonists, Aortic Aneurysm, Aortic Aneurysm, Thoracic, Aortic Diseases, Blood Pressure, Calcium Channel Blockers, Dilatation, Extracellular Matrix, Heart Defects, Congenital, Hydralazine, Hypertension, Losartan, Marfan Syndrome, Muscle, Smooth, Vascular, Myocytes, Smooth Muscle, Primary Prevention, Risk Factors, Transforming Growth Factors, Vascular Diseases

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