COMMENTARY

Atenolol vs Losartan in Patients With Marfan Syndrome

Robert J. Widmer, MD, PhD; Juan Bowen, MD

Disclosures

November 18, 2014

Editorial Collaboration

Medscape &

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Robert J Widmer, MD, PhD: I'm Jay Widmer, cardiovascular fellow at the Mayo Clinic. Today on theheart.org, we will be discussing the recent, late-breaking trial published in the New England Journal of Medicine[1] comparing losartan vs atenolol for reducing aortic-dilatation rate in Marfan's syndrome. I am with my colleague, Dr Juan Bowan, who is director of the Marfan and thoracic aorta clinic at the Mayo Clinic. Lets start with the basics. What is Marfan's syndrome?

Juan Bowen, MD: Marfan's syndrome is a heritable disorder of connective tissue that affects about one in 5000 people. It was first described as a collection of physical characteristics. The cause wasn't known, although it was thought to be related to a structural protein. Eventually, a mutation in the fibrillin-1 gene was found in 1991, a component of elastic microfibrils, but later on it was found out that this particular protein is also a regulator of the TGF-beta pathway. So it has important effects on the morphogenesis of tissues.

Marfan's syndrome affects the cardiovascular system, the skeletal system, and the eye, but the dangerous consequences have to do with the cardiovascular system, primarily with aortic aneurysms in the proximal aorta.

Dr Widmer: What is the natural history of the patient with Marfan's syndrome?

Dr Bowen: Before we had effective therapy, patients with Marfan's syndrome often died very young, often in their 30s or even younger, and the cause of death was usually aortic dissection, sometimes heart failure from progressive aortic regurgitation. But therapy eventually improved in Marfan's syndrome, and today life expectancy in some patients can be normal or near normal.

Dr Widmer: What is the standard therapy that allows patients to have a normal life expectancy, and why is better treatment needed?

Dr Bowen: There are two components of therapy. The surgical treatment that was developed in the late 1960s gets the credit for the long survival that patients have today. At that time, surgeons had the insight that a composite aortic graft could be used to repair the aorta in a prophylactic way, and then survival jumped up, because that turned out to be a very effective therapy.

Today, those operations continue to be done, but there are refinements now, particularly the valve-sparing operation, which is a promising operation that has been used in recent years. But medical protection of the aorta with beta-blockers has been around since about the 1980s–1990s with reasonably good evidence that it works.

Today, patients receive medical aortic protection with beta-blockers, they undergo prophylactic repair of the aorta when their aortic roots reach certain dimensions, right around 5 cm, and they require lifelong monitoring with imaging. They also have noncardiovascular problems of the eye and the skeletal system.

Dr Widmer: Most of us use beta-blockers in our practice. If they are such effective therapies, why did we study an angiotensin-receptor blocker [ARB] in this trial?

Dr Bowen: There is an important insight that once the structure and the function of the fibrillin-1 molecule was understood in its relationship to the TGF-beta pathway, it was found that in an animal model (Marfan mice), the TGF-beta pathway was quite overactive. It turns out that you can block TGF-beta dysregulation by blocking the AT1 receptor, and angiotensin-converting enzyme (ACE) inhibitors block both AT1 and AT2, but ARBs block AT1.

In the animal model, losartan was a very effective therapy, and Marfan mice given losartan at a young age developed very well and did not have the serious aortic enlargement compared with wild-type mice. And when compared with propranolol-treated mice, the effects on the aorta were much better with losartan. This, of course, led to human trials, because this drug was already approved and in wide use for hypertension.

Dr Widmer: You gave us very promising animal data. Before the trial from Lacro and colleagues, had we looked at ARBs in humans?

Dr Bowen: There have been 10 trials worldwide, and two trials were reported last year.[3,4] One was a small trial[3] in only 28 children, and it was a positive trial showing the benefit of losartan when compared with the combination of losartan plus a beta-blocker. A larger trial[4] of 233 adult patients (the COMPARE trial) also demonstrated the benefit of losartan, and about 75% of losartan-treated patients were also treated with beta-blockers.

Dr Widmer: What did the Lacro and colleagues' trial investigators find when they compared losartan with atenolol by itself over a 3-year period?

Dr Bowen: This was a much-anticipated trial, because this is the largest trial to date with more than 600 patients. This trial compared losartan with a beta-blocker, without a placebo group, so it was a direct comparison. Most people expected that this trial would show a definite benefit of losartan in the rate of aortic dilatation; however, it did not. It did not show that losartan had any advantage compared with the beta-blocker.

Dr Widmer: Why do you think losartan was not shown to be superior to atenolol in this trial?

Dr Bowen: There are several possible reasons. In the other trials, the combination of beta-blocker and losartan was shown to be superior to beta-blocker alone. It is possible that in this trial the beta-blocker was more effective than anticipated. High doses of atenolol were used in this trial. It's also possible that treating patients who are more mildly affected might be more effective. These patients were severely affected, with aortic Z-scores > 3. The age range was 6 months to 25 years, so it is possible that treating patients who are less severely affected might prove more effective.

Dr Widmer: How will these results change your practice, and what you will tell your colleagues about treating patients with Marfan's syndrome?

Dr Bowen: In our clinic, we consider beta-blockade to be the primary therapy. We know that losartan shows efficacy. For example, in the Lacro trial, both losartan and beta-blocker reduced the Z-score, so they were both effective. It's just that losartan was not more effective. So we think that there is evidence for effectiveness of both, just not evidence for superiority of losartan. We will continue to use beta-blockers as primary therapy. In patients who are intolerant of beta-blockers, we will use losartan, and in selected patients, we will use the combination.

Dr Widmer: When does surgical therapy come in? Does medical treatment obviate the need for surgical treatment in these patients?

Dr Bowen: It is important to understand that medical treatment with beta-blockers is directed at hemodynamics and doesn't change the pathophysiology of the disease. The great appeal of TGF-beta-dysregulation–directed treatment is that it has the potential for actually changing the pathophysiology of the disease. We would hope that if this therapy were found to be effective, not only the cardiovascular manifestations would be attenuated, but other problems, as well. These patients, as they live longer, experience quality-of-life problems related to their vision, musculoskeletal pain, and disability. So right now, neither beta-blockade nor ARB therapy can prevent the need for aortic surgery, but they probably delay aortic surgery. And when patients undergo aortic surgery, it doesn't fix their cardiovascular problem for life. They will require lifelong monitoring, and there remains a risk for dissection, particularly involving the descending aorta, and all of the noncardiovascular issues. So, these patients require medical therapy, perhaps well-timed surgical therapy, and lifelong monitoring, and that is why the dream of a translational medicine approach that would really change the natural history of the disease remains an important goal.

Dr Widmer: It's certainly an elusive goal, and I see that the multimodality treatment will be important in these patients.

Dr Bowen: Yes, it will.

Dr Widmer: Thanks, Juan, for these great comments on this exciting trial that is coming out in the New England Journal of Medicine. We are looking forward to reading your editorial with Dr Connolly.[5] Thanks to our readers. We hope that you will continue to check out future content on Mayo Clinic's page at theheart.org on Medscape. Thank you.

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