COzaar in Marfan PAtients Reduces aortic Enlargement - COMPARE

Description:

Data from murine models of Marfan’s syndrome suggest that losartan, which blocks the action of transforming growth factor (TGF)-beta, may result in improvements in aortic dimensions. The current trial sought to compare outcomes after administration of losartan versus placebo 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.

Study Design

  • Placebo Controlled
  • Randomized
  • Blinded
  • Parallel

Patient Populations:

  • Marfan’s syndrome

    Number of enrollees: 233
    Duration of follow-up: 3 years
    Mean patient age: 41 years
    Percentage female: 47%

Exclusions:

  • More than one vascular prosthesis at baseline
  • Established contraindication or indication for losartan/ARB use

Primary Endpoints:

  • Rate of aortic root enlargement measured by computed tomography or MRI at 3 years

Secondary Endpoints:

  • Total aortic volume expansion rate
  • Cardiovascular mortality/aortic dissection/prophylactic aortic surgery

Drug/Procedures Used:

Patients with Marfan’s syndrome were randomized to receive either losartan or placebo. Losartan was started at 50 mg daily and then up-titrated to 100 mg daily after 2 weeks if well-tolerated (achieved in 54% of patients).

Concomitant Medications:

Beta-blockers (73%)

Principal Findings:

A total of 233 patients were randomized, 116 to losartan and 117 to placebo. Baseline characteristics were fairly similar between the two arms. Approximately 27% had undergone prior aortic root replacement. Baseline blood pressure was 125/74 mm Hg. Aortic root dimensions were approximately 4.4 cm on magnetic resonance imaging (MRI) at baseline, with nearly 44% having an aortic root diameter >4.5 cm.

Mean arterial blood pressure was significantly lower in the losartan arm by about 3 mm Hg when compared with placebo (p = 0.032). The primary endpoint of aortic root enlargement at 3 years was significantly lower in the losartan arm compared with placebo (0.77 mm vs. 1.35 mm, p = 0.014). The proportion of patients with no growth of the aortic root over this period was also higher (50% vs. 31%, p = 0.022). In the subset of patients with prior aortic root replacement, enlargement of the aortic arch was reduced (0.5 mm vs. 1.01 mm, p = 0.033). There was no difference in the rate of elective aortic surgery (10 vs. 9 patients) or aortic dissections (0 vs. 2 patients). No differences for the primary endpoint were noted whether or not patients were on beta-blockers at baseline.

Interpretation:

The results of the COMPARE trial indicate that losartan reduces the rate of aortic root enlargement as compared with placebo in patients with Marfan’s syndrome. The majority of these patients were also on a beta-blocker. This finding thus confirms data from murine models demonstrating improvements in aortic dimensions with losartan use.

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 TGF-beta. Losartan, by blocking TGF-beta, thus appears to have favorable effects on aortic dimensions. A couple of caveats exist. Since the majority of these patients are younger (frequently in the second and third decade of life), it is unknown if life-long losartan therapy is safe/can be recommended based on this trial. Second, the long-term clinical impact of losartan 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 (ARBs), and not unique to losartan alone, but this will need to be studied further.

References:

Groenink M, den Hartog AW, Franken R, et al. Losartan reduces aortic dilatation rate in adults with Marfan syndrome: a randomized controlled trial. Eur Heart J 2013;Sep 2:[Epub ahead of print].

Presented by Dr. Maarten Groenink at the European Society of Cardiology Congress, Amsterdam, Holland, September 2, 2013.

Clinical Topics: Cardiac Surgery, Congenital Heart Disease and Pediatric Cardiology, Noninvasive Imaging, Cardiac Surgery and CHD & Pediatrics, Congenital Heart Disease, CHD & Pediatrics and Imaging, CHD & Pediatrics and Prevention, Magnetic Resonance Imaging

Keywords: Transforming Growth Factor beta, Angiotensin Receptor Antagonists, Losartan, Microfilament Proteins, Marfan Syndrome, Death, Sudden, Blood Pressure, Magnetic Resonance Imaging


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