Irbesartan slows aortic root dilatation in Marfan syndrome

MUNICH — Irbesartan in standard doses is linked to a significant decrease in the rate of aortic dilatation in patients with Marfan syndrome, according to data from the AIMS study presented at the European Society of Cardiology Congress.

In the AIMS trial, Michael Mullen, MBBS, MD, FRCP, from St. Bartholomew’s Hospital in London, and colleagues randomly assigned patients aged 6 to 40 years with Marfan syndrome at 22 centers in the United Kingdom to irbesartan or placebo. The researchers aimed to recruit 490 patients but only enrolled 192 patients.

After an initial run-in period during which all patients received irbesartan 75 mg, 104 patients were up-titrated to targets of 300 mg for patients weighing more than 50 kg and 150 mg for patients weighing less than 50 kg or placebo. Treatment with beta-blockers was not mandated but was encouraged because it is standard treatment, Mullen said.

Patients were followed for up to 5 years and underwent yearly echocardiograms, for which a core lab was used. The primary endpoint was annual change in aortic root diameter and secondary endpoints included annual change in z score and clinical events and requirement for surgery, including aortic dissection.

At baseline, there was a reasonable spread across various age groups, with approximately half of patients younger than 18 years and a good balance between male and female patients. Fifty-seven percent were also taking beta-blockers.

The overall study population was normotensive, and aortic root diameter was similar for the placebo (35.3 mm) and irbesartan groups (34.8 mm). The aortic z score was approximately 3 in both groups, “meaning that, compared with other trials, these patients were fairly early in pathogenesis of their disease,” Mullen said.

Key findings

The rate of aortic dilatation was slower in patients taking irbesartan vs. placebo, with a mean annual rate of change in aortic root diameter of 0.53 mm in the treatment group vs. 0.74 mm in the placebo group (difference, –0.22 mm; 95% CI, –0.41 to –0.02). Significant differences in the change in aortic root diameter were apparent at 1 year and continued out to 5 years, according to Mullen.

In terms of safety, irbesartan was well-tolerated, with four patients in both the placebo and irbesartan groups failing to tolerate medication. There was also no difference in the rate of adverse events between groups. Four patients in both groups underwent cardiac surgery, but the study was again not powered to detect differences in clinical outcomes, according to Mullen. No deaths occurred during the study.

Aortic z score, which adjusted the aortic diameter for patients’ body surface area and particularly any changes in body surface area, appeared to be fairly stable in the irbesartan group (annual rate of change, 0.05; 95% CI, –0.2 to 0.11) when compared with the placebo group (annual rate of change, 0.15; 95% CI, 0.08-0.22). The difference of –0.1 (95% CI, –0.19 to –0.01) was statistically significant, Mullen noted.

The researchers also evaluated the effect of treatment on BP, as irbesartan is a well-recognized antihypertensive treatment, he said. Results showed a significant reduction in systolic BP in patients taking irbesartan vs. placebo (–0.42 mm Hg vs. 1.27; mean difference, –1.69 mm Hg), which was maintained out to 5 years.

There was no difference in treatment effect of irbesartan in patients taking beta-blockers vs. those who were not, suggesting that there was no interaction or synergy between the two drugs. The annual rate of change in aortic diameter between study groups was also not significantly different when analyzed according to aortic z score. Additionally, no statistically significant difference was noted based on patient age, although the effect size appeared to be numerically larger in younger patients.

However, Mullen noted that the study was significantly underpowered to analyze subgroups and suggested interpreting the results with caution.

Interpretations, implications

The results of this study, according to Mullen, suggest that irbesartan may have potential benefits for patients with Marfan syndrome.

“The current treatment strategy is based around beta-blockade, based on small trials conducted many years ago, and monitoring aortic dimensions with timely surgical intervention. However, some patients will still experience aortic dissection prior to presentation or before reaching those thresholds for surgical intervention,” Mullen said. “If translated into clinical practice, long-term irbesartan treatment may impact favorably on clinical outcomes in patients with Marfan syndrome.”

During a discussion of the results, Artur Evangelista Masip, MD, PhD, from Hospital Universitari Vall d’Hebron in Barcelona, Spain, highlighted several issues that may affect these findings, including the study’s sample size.

Evangelista Masip also noted that the inclusion of children and adults in the same series complicates the ability to perform an accurate analysis of this study as well as other trials. The measurement of changes in aortic diameter in systole may also be affected by the reduction in systolic BP.

“It would be interesting to know their results measuring at end-diastole,” he said.

Additionally, Evangelista Masip said the difference in the rate of change in aortic root diameter between the irbesartan and placebo groups occurred mainly during the first year and was similar thereafter.

“This is an important study and I agree that long-term irbesartan treatment may impact favorably in the evolution of patients with Marfan syndrome,” he said. “However, we have to clarify some of the previous doubts and elucidate in future studies if the reduction or aortic enlargement is secondary to biological effect or related to the decrease of BP.” – by Melissa Foster

Reference:

Mullen M. Hot Line Session 5. Presented at: European Society of Cardiology Congress; Aug. 25-29, 2018; Munich.

Disclosures: Mullen and Evangelista Masip report no relevant financial disclosures.