Randomized Trial of Atenolol Versus Losartan in children and Young Adults With Marfan Syndrome - Pediatric Heart Network

Description:

The current trial sought to compare outcomes after administration of losartan vs. atenolol in patients with known Marfan’s syndrome.

Hypothesis:

Losartan would be associated with a reduction in the rate of aortic enlargement in patients with known Marfan’s syndrome compared with atenolol.

Study Design

  • Randomized
  • Blinded
  • Parallel

Patient Populations:

  • Age 6 months to 25 years
  • Diagnosis of Marfan’s Syndrome by original Ghent criteria
  • ARz >3.0

    Number screened: 701
    Number of enrollees: 608
    Duration of follow-up: 3 years
    Mean patient age: 11.5 years
    Percentage female: 40%

Exclusions:

  • Prior or impending aortic surgery
  • Aortic-root diameter >5 cm
  • Aortic dissection
  • Loeys-Dietz or Sphrintzen-Goldberg syndromes
  • Therapeutic use of angiotensin-converting enzyme inhibitor, beta-blocker, or angiotensin-receptor blocker
  • Intolerance or contraindication to beta-blocker or angiotensin-receptor blocker

Primary Endpoints:

  • Rate of aortic root enlargement, expressed as annual change in aortic root z-score measured by echocardiography

Drug/Procedures Used:

Patients with Marfan’s syndrome were randomized to receive either losartan or atenolol. Losartan was administered at a maximum dose of 1.4 mg/kg/day (max 100 mg). Atenolol was administered at a maximum dose of 4 mg/kg/day (max 250 mg), with a goal of ≥20% decrease in mean heart rate by 24-hour recording. Randomization to atenolol or losartan was stratified by: a) Growing children vs. adult (male ≥16 years, female ≥15 years), and b) baseline BSA-adjusted maximum aortic root diameter z-score (ARz) <4.5 versus ≥4.5.

Concomitant Medications:

Prior use of beta-blockers (57%)

Principal Findings:

A total of 608 patients were randomized, 303 to atenolol and 305 to losartan. Baseline characteristics were fairly similar between the two arms. About 25% of patients were adults. Aortic root dimensions were approximately 3.4 cm on magnetic resonance imaging at baseline, with a max ARz score of 4.0 cm. Confirmed FBN1 mutation was observed in 30% of patients. Achieved doses for atenolol were 2.7 mg/kg/day (151 mg for adults) and 1.3 mg/kg/day (85 mg/day for adults).

Mean diastolic blood pressure was significantly lower in the atenolol arm compared with atenolol at 3 years (54 vs. 56 mm Hg, p = 0.04). The primary endpoint of baseline adjusted annual rate of change in the aortic root z-score was similar between the atenolol and losartan arms (-0.139 vs. -0.11 SD units/year, p = 0.08). The slopes for both lines were significantly <0, indicating a decrease in ARz in both arms. Younger patients had a greater decrease in ARz in both arms. Estimated rate of increase in aortic root absolute diameter was also similar between the two arms (0.069 vs. 0.075 cm/year, p = 0.2). Annual change in aortic annulus diameter was lower with atenolol (0.015 vs. 0.03 cm, p = 0.002). Freedom from aortic dissection, surgery, or death was similar between the two arms (3.4% vs 6.4%, p = 0.10). Possible or probable drug-related side effects were higher with losartan (204 vs. 163 events, p = 0.03), but serious adverse events were similar.

Interpretation:

The results of this trial indicate that rate of aortic root dilation at 3 years was similar with the use of high-dose atenolol or losartan in patients with Marfan’s syndrome, with some favorable effects of atenolol on aortic annulus diameter change. The dose of atenolol used in this trial is higher than conventionally used and also higher than studied before by most studies. The effect appeared to be more pronounced in younger patients.

Marfan’s syndrome is a connective tissue disorder, which includes vascular manifestations such as aortic dilation/aneurysms. Frequently, aortic dissection and sudden death are the first presentations. The underlying genetic cause is abnormality of the fibrillin-1 gene, which results in structural dysfunction of media due to regulatory dysfunction (i.e., upregulation of transforming growth factor [TGF]-beta). Losartan, by blocking TGF-beta, is thought to have favorable effects on aortic dimensions. The current trial suggests that both atenolol and losartan may be equally effective.

A couple of caveats exist. Since the majority of these patients are younger, it is unknown if life-long therapy therapy is safe/can be recommended based on this trial. Second, the long-term clinical impact of treatment on aortic outcomes will need to be ascertained in future studies. It is also unknown (though likely) that this is a class effect of angiotensin-receptor blockers/beta-blockers, and not unique to losartan/atenolol alone, but this will need to be studied further.

References:

Lacro RV, Dietz, HC, Sleeper LA, et al., on behalf of othe Pediatric Heart Network. Atenolol vs Losartan in Children and Young Adults With Marfan’s Syndrome. N Engl J Med 2014;Nov 18:[Eub ahead of print].

Presented by Dr. Ronald V. Lacro at the American Heart Association Scientific Sessions, Chicago, IL, November 18, 2014.

Clinical Topics: Arrhythmias and Clinical EP, Cardiac Surgery, Congenital Heart Disease and Pediatric Cardiology, Noninvasive Imaging, Vascular Medicine, SCD/Ventricular Arrhythmias, Aortic Surgery, Cardiac Surgery and Arrhythmias, Cardiac Surgery and CHD & Pediatrics, Congenital Heart Disease, CHD & Pediatrics and Arrhythmias, CHD & Pediatrics and Imaging, CHD & Pediatrics and Prevention, Magnetic Resonance Imaging

Keywords: Losartan, Angiotensin Receptor Antagonists, Atenolol, Blood Pressure, Heart Rate, Magnetic Resonance Imaging, Up-Regulation, Aortic Aneurysm, Mutation, Transforming Growth Factor beta, Adrenergic beta-Antagonists, Marfan Syndrome, Death, Sudden, Cardiac, AHA Annual Scientific Sessions


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