Marfan syndrome

Losartan, atenolol demonstrate similar efficacy, safety in Marfan syndrome

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Children and young adults with Marfan syndrome had a similar rate of aortic root dilation during 3 years after treatment with losartan or atenolol.

Ronald V. Lacro, MD, from the department of cardiology at Boston Children’s Hospital, and fellow researchers with the Pediatric Heart Network evaluated 608 patients aged 6 months to 25 years (mean age, 11.2 years, 60% male) with Marfan syndrome. The patients were treated at 21 clinical sites between 2007 and 2011.

Ronald V. Lacro, MD

Ronald V. Lacro

Patients were randomly assigned to receive losartan (Cozaar, Merck) up-titrated to a maximum dose of 1.4 mg/kg per day (n=305) or atenolol up-titrated to a maximum dose of 4 mg/kg per day (n=303). The researchers conducted follow-up visits at 6, 12, 24 and 36 months. The primary endpoint was the rate of enlargement of the aortic root, as indicated by change in body surface area-adjusted maximum aortic root dimension z score (ARz).

At baseline, the mean aortic-root diameter was 3.4 cm and the median ARz score was 4.0. At follow-up, the researchers observed no significant difference in the rate of ARz change following treatment, with a decrease of –0.139 ± 0.013 SD units per year in the atenolol group compared with –0.107 ± 0.013 SD units per year in the losartan group (P=.08). Absolute diameter increased at a similar rate between the treatment groups: 0.069 ± 0.004 cm per year with atenolol vs. 0.075 ± 0.004 cm per year with losartan (P=.2).

Subgroup analyses indicated no significant differences according to patient age, ARz score at baseline, prior beta-blocker use or gender. However, Lacro said, both treatments appeared more effective in younger patients, with a greater annual decrease in ARz score observed in younger recipients of both atenolol (P<.001) and losartan (P=.002).

Adverse events were also similar between the two treatment groups, for all events (P=.1) and serious events (P=.31). Lacro noted that the rate of adverse events considered possibly or probably related to treatment was significantly higher in patients assigned atenolol (P=.03), but this was not observed when only serious events were considered (P=.25). Patients in both treatment groups also had similar rates of freedom from dissection, surgery and death (P=.1).

“We found no significant difference in the rate of aortic root dilation between the two treatment groups over 3 years,” Lacro concluded. “Both drugs were well tolerated, giving patients and providers options for treatment.”

Given the observed increase in effectiveness in younger patients for both losartan and atenolol, “treatment at an earlier stage may be beneficial,” he said. – by Adam Taliercio

For more information:

Lacro RV. Abstract #16361. Presented at: American Heart Association Scientific Sessions; Nov. 15-19, 2014; Chicago.

Lacro RV. N Engl J Med. 2014;doi:10.10156/NEJMoa1404731.

PERSPECTIVE

 Robert H. Beekman III, MD)

Robert H. Beekman III, MD

Currently, the concern with Marfan syndrome, from a CV perspective, is the aortic root dilation that can be progressive and lethal if it dissects. The current standard therapy is beta-blockers, with the thought being that they will decrease the wall stress in the aorta and hopefully decrease the rate of progression of aortic root dilation in these patients. However, we know that standard beta-blocker therapy isn’t perfect, as patients still experience progressive aortic root dilation, dissection and death, so there is a need for improved therapy.

The Pediatric Heart Network is to be congratulated for accomplishing this randomized trial, which is an enormous feat, because rare diseases in childhood are very difficult to study in a randomized trial. The findings, at first glance, are somewhat disappointing, but I think this study does not close the door on the likelihood that losartan and angiotensin receptor blockers may benefit the aorta in patients with Marfan syndrome.

One needs to look at the limitations of the trial presented: The researchers only studied patients whose aortas were already dilated significantly at baseline. The study then compared how those aortas changed over the next 3 years and found no difference between patients randomized to losartan or beta-blocker. This does not mean, however, that losartan would have no effect if given earlier in the course of disease progression. That is one possible direction for future studies.

Also, consider that this is a lifetime disease that begins in early childhood. The aorta dilates and progresses throughout life, and perhaps a beneficial ARB effect may be identified if patients were followed for a longer period of time. The challenge, of course, is to conduct a study longer than 3 years in a population of children with a relatively rare disease.

Finally, this study also did not have a control placebo group. It may be that losartan has a beneficial effect that is approximately equal to beta-blockers and that it is substantially better than no treatment at all, but we don’t know the latter because they didn’t have a control group.

Therefore, the fact that the researchers were not able to identify a significant difference in the rate of aortic root dilation between the two treatment groups, I think, does not mean that there is no benefit to this drug; they just weren’t able to prove that there is one in the study as designed.

Robert H. Beekman III, MD

Professor of Pediatric Cardiology

Children’s Hospital Medical Center, Cincinnati

Chair, Adult Congenital and Pediatric Cardiovascular Section

American College of Cardiology

Why losartan is effective in Marfan Syndrome?

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Another Treatment Option for Marfan Syndrome?

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An angiotensin-receptor blocker wasn’t better than standard beta-blockers for slowing the aortic-root enlargement that often leads to dissection and death in Marfan syndrome, a trial showed.

Aortic root size standardized for body surface area and adjusted for baseline improved similarly with treatment in both groups, Ronald V. Lacro, MD, of Boston Children’s Hospital, and colleagues found.

The z-score slopes were negative with both losartan (Cozaar) and atenolol (Tenormin, -0.107 versus -0.139 standard-deviation units per year, P=0.08), they reported here at the American Heart Association meeting.

“The 3-year rates of aortic-root surgery, aortic dissection, death, and a composite of these events did not differ significantly between the two treatment groups,” they wrote in a simultaneous publication online in the New England Journal of Medicine.

A press release from the National Heart, Lung and Blood Institute, which largely funded the study as part of its Pediatric Heart Network research, enthusiastically heralded the study as having found another good treatment option for the connective tissue disease.

“These study results are very valuable for clinical practice,” NHLBI director Gary H. Gibbons, MD, said in the statement. “Both drugs were well-tolerated by study participants, and losartan may be another treatment option for patients with Marfan syndrome.”

However, it’s just as likely that the trial found another equally ineffective treatment, study discussant John A. Elefteriades, MD, of director of the Aortic Institute at Yale, said at a press conference.

The trial included no placebo arm.

The evidence for a positive effect of beta-blockers on aortic root aneurysms is weak, he explained, citing limitations of the classic study and equivocal findings, at best, from other subsequent studies.

“If [the trial] was really comparing against a ‘straw man’ placebo, then the thrust of the trial is that losartan is of no benefit at all,” he said.

The answer may be “wait and see,” Juan M. Bowen, MD, and Heidi M. Connolly, MD, both of the Mayo Clinic in Rochester, Minn., suggested in an editorial accompanying the NEJMpaper.

Meanwhile, “clinicians should continue to consider beta-blockers to be the primary medical therapy for aortic protection in Marfan’s syndrome,” they wrote. “Losartan appears to be a reasonable treatment option, especially in patients who cannot take beta-blockers. The risk of harm from losartan appears to be very low, but its efficacy needs to be firmly established before it becomes a first-line therapy.”

There is hope, though, that other effective medications will be found, Elefteriades said. His group recently showed some benefit from statins.

Lacro’s group had carefully lined up over the years a molecular basis for why an ARB should be better in this population with animal models and small studies.

However, the negative findings were unlikely to be false negative because the trial was well-powered, of adequate duration, and generously dosed for losartan, Elefteriades noted.

The trial included 608 Marfan syndrome patients ages 6 months to 25 years with an aortic-root z score greater than 3.0 seen at 21 clinical centers.

They were randomized to atenolol at a maximum dose of 4 mg/kg per day, titrated to reduce heart rate by at least 20%, or to losartan at a maximum dose of 1.4 mg/kg per day for 3 years.

Other findings for atenolol versus losartan included:

  • No difference in estimated rate of change in aortic-root absolute diameter (0.069 versus 0.075,P=0.20)
  • No difference in dissection or surgery (P=0.10)
  • No difference in freedom from dissection, surgery, or death (P=0.10)

While there were no significant interactions by subgroup, the change in aortic-root diameter z-score from both treatments progressively declined across the age groups.

Adverse events and serious adverse events were similar between groups, although possibly or probably related mild or moderate events were significantly more common with atenolol (P=0.03).