Trial DesignRationale and design of a randomized clinical trial of β-blocker therapy (atenolol) versus angiotensin II receptor blocker therapy (losartan) in individuals with Marfan syndrome
Section snippets
The Marfan syndrome
Marfan syndrome (MFS) is a systemic disorder of connective tissue with autosomal dominant inheritance and a prevalence of approximately 1 per 5000 population.1 The cardinal features of this disorder involve the ocular, musculoskeletal, and cardiovascular systems. Cardiovascular disease, including aortic root dilation, aortic dissection, and myxomatous mitral valve changes, is the leading cause of mortality in MFS. Although early diagnosis and refined medical and surgical management have
Etiology of MFS
Marfan syndrome is caused by mutations in FBN1, the gene encoding fibrillin 1.5 More than 600 FBN1 mutations have been reported.6 Because fibrillin 1 is an important component of the extracellular matrix microfibril,7, 8 this protein was initially thought to play mainly a structural role in connective tissue. Structural abnormalities leading to weakness in connective tissue seemed to explain some clinical findings such as lens dislocation, joint hypermobility, lung bullae, and aortic dissection
Current medical approach to aortic root dilation in MFS
The aortic root diameter at the sinuses of Valsalva is considered the best predictor of adverse cardiovascular outcome.4 The optimal medical therapy for aortic root dilation has been a matter of vigorous debate.17, 18, 19, 20, 21, 22 Because several, although not all, studies have shown that therapy with β-adrenergic blockers (BBs) reduces the rate of aortic growth,17, 18, 19, 20 many clinicians consider BB to be the standard of care. The presumed mechanisms—decreasing proximal aortic shear
Pharmacologic trials in mouse models of MFS
Numerous studies describe the ability of the angiotensin receptor blocker (ARB), losartan, to achieve clinically relevant inhibition of TGF-β signaling in vivo (reviewed in Habashi et al16). In several disease states, including chronic renal disease and cardiomyopathy, antifibrotic effects of losartan, independent of hemodynamic effects, have been directly linked to TGF-β inhibition.
To test the hypothesis that angiotensin II type 1 blockade decreases aortic damage, Habashi et al16 randomized
Rationale for this trial
Despite the major advances in the medical and surgical management of MFS, morbidity persists. Existing medical therapies do not target the pathogenic basis for MFS; these therapies simply aim to reduce hemodynamic stress on predisposed tissue. Angiotensin receptor blocker therapy has the theoretical advantage of modifying the abnormal tissue directly by antagonism of TGF-β. The compelling results of losartan therapy in mice prompted a desire to translate these results systematically to humans.
Study overview
This trial is designed to test the hypothesis that ARB therapy with known TGF-β antagonism will reduce the rates of aortic root diameter growth and progression of aortic regurgitation compared to BB therapy. We will enroll 604 children and young adults who will be randomly assigned to receive BB (atenolol) or ARB (losartan) for 36 months. This study was designed by the National Heart, Lung, and Blood Institute (NHLBI)–funded Pediatric Heart Network (PHN)24 and will be conducted at 14 clinical
Statistical considerations
Longitudinal data from 2 participating centers were used to estimate rate of change and covariance structure of the primary outcome. Data for potentially eligible patients were also collected from participating clinical centers to characterize the expected study population. Estimates from these analyses were used to calculate target sample size.
The potential decrease in z score change rate is greater in those who have not attained maximum height (children, defined here as those <16 years of age
Choice of primary outcome
The major clinical cardiovascular end points for individuals with MFS are aortic root surgery, aortic dissection, and death. It is fortunate that aortic dissection and death are rare in children and young adults with MFS, but this also means that a trial designed to assess differences in these events would require an impractical number of patients and years. The decision to intervene surgically is a function of aortic root size or growth rate and is relatively standardized. Therefore, a primary
Conclusions
The appeal of a trial of losartan therapy in patients with MFS reflects its rational derivation from disease pathogenesis, its novel mechanism of action, and its performance in validated mouse models of MFS. One of the primary goals of the PHN is to promote evidence-based clinical care. Given the widespread publicity and excitement regarding the performance of losartan in animal models and the lack of practical barriers for its widespread clinical application, we sought to take advantage of a
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Cited by (0)
This work was supported by U01 HL068285 (Lacro); U01 HL068270 (Wruck, Mahony, Colan, Klein), U01 HL068269 (Li), U01 HL068292 (Minich), U01 HL068290 (Printz, Devereux, Roman), U01 HL068288 (Bradley), U01 HL068281 (Saul), and U01 HL068279 (Paridon, Pyeritz) from the National Heart, Lung, and Blood Institute (Bethesda, MD), the Howard Hughes Medical Institute (Baltimore, MD) (Dietz); the National Marfan Foundation (Port Washington, NY) (Dietz); and the Smilow Center for Marfan Syndrome Research (Baltimore, MD) (Dietz).