COzaar in Marfan PAtients Reduces aortic Enlargement - COMPARE

Jul 07, 2020
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Author/Summarized by Author:
Dharam J. Kumbhani, MD, SM, FACC
Summary Reviewer:
Deepak L. Bhatt, MD, MPH, MBA, FACC
Trial Sponsor:
Dutch Heart Association and Interuniversity Cardiology Institute of the Netherlands
Date Presented:
01/01/2013
Date Published:
06/15/2020
Date Updated:
07/07/2020
Original Posted Date:
09/02/2013
References

Contribution To Literature:

The COMPARE trial demonstrated that losartan reduces the rate of aortic root enlargement as compared with placebo in patients with Marfan’s syndrome.

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.

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.

Long-term follow-up: Median duration: 8 years, follow-up available for 75 losartan users vs. 78 controls. Age was younger and beta-blocker use was higher among losartan users. For losartan vs. control: death: 0 vs. 5 (p = 0.014); aortic dissection: 3 vs. 11 (p = 0.013); composite endpoint: 14 vs. 26 (p = 0.019).

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. On long-term follow-up, clinical outcomes were also better among losartan users, although systematic follow-up was not available for all randomized 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 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:

van Andel MM, Indrakusuma R, Jalalzadeh H, et al. Long-term clinical outcomes of losartan in patients with Marfan syndrome: follow-up of the multicentre randomized controlled COMPARE trial. Eur Heart J 2020;Jun 15:[Epub ahead of print].

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;34:3491-500.

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

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


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