麻豆传媒

BARCELONA -- Angiotensin receptor blockers (ARBs) and beta-blockers both reduced expansion of the aortic root in patients with Marfan syndrome, according to a meta-analysis, suggesting a likely benefit from combination therapy.

Randomization to an ARB approximately halved the annual rate of increase in the aortic root Z score compared with controls (mean 0.07 vs 0.13, P=0.012) over a median 3 years of follow-up, reported Alex Pitcher, BMBCh, DPhil, of the University of Oxford in England, at the European Society of Cardiology Congress. The findings were also published in .

There was also no signal for difference in the effects of an ARB based on baseline beta-blocker use (heterogeneity P=0.54), and the reduction with ARB and beta-blocker therapy was statistically similar (absolute difference 0.03, 95% CI -0.05 to 0.10).

"Assuming additivity, combination therapy with both ARBs and beta-blockers from the time of diagnosis would provide even greater reductions in the rate of aortic enlargement than either treatment alone, which, if maintained over a number of years, would be expected to lead to a delay in the need for aortic surgery," the researchers concluded.

In fact, they calculated that the delay in time to surgery could average 10 years.

An by Christiane Pees, MD, of the University Children's Hospital in Vienna, praised the design of the meta-analysis for sussing out the impacts from the trials, which previously had been unable to show any clear effects.

"The trials that have emerged over the past decade have been confusing and difficult to interpret until we put them together in this meta-analysis," Pitcher agreed in an interview with 麻豆传媒. "We think the meta-analysis provides conclusive evidence that angiotensin receptor blockers are effective, and that has been uncertain until now."

The meta-analysis included seven randomized controlled trials with individual patient data on a total of 1,442 patients, and was re-evaluated according to a harmonized study protocol for patient inclusion, such as the requirement for no prior aortic root surgery.

"This method overcomes the problem of data heterogeneity of previous meta-analyses by allowing the exclusion of inconclusive patient data, recalculation of different study datasets, and an in-depth analysis of possible biasing heterogeneity in patients' baseline characteristics," Pees noted.

The mean age of patients was 29 years, 54% were women, and 75% were on beta-blockers at baseline, which were allowed to be continued by trial protocol.

One source of significant heterogeneity in ARB treatment effects was FBN1 pathogenic variants, identified in 83% of 630 genotyped patients. Other subgroups showed similar treatment effects, and the different methods of measuring aortic root size did not appear to impact the findings.

Across all the trials comparing an ARB versus any control, the rate of aortic dissection, aortic root surgery, or death during study follow-up was 8% in both groups (P=0.86). The three trials that compared ARBs against beta-blockers showed the same, with rates of 5% and 4%, respectively (P=0.23).

Pitcher's group also indirectly assessed the impact of beta-blockers by combining the results of the ARB versus control trials with the ARB versus beta-blocker trials. It showed a -0.09 difference in mean absolute annual change in the aortic root Z score with beta-blockers over controls, which the researchers said was "similar to the direct estimate when comparing ARB with control."

However, those two groups had patients within different age ranges, and progressive body growth as the therapy slowed aortic root enlargement would impact the Z score, Pees pointed out.

"The calculated beta-blocker effect is all the more uncertain because the patients in the ARB versus control subgroup were allowed to take additional beta-blockers, and 507 (75%) of all 676 participants did so, resulting in a true indirect control group for beta-blocker therapy of 81 (25%) of 323 patients in the control group," she added.

Future evaluations should consider the respective doses of both drugs, Pees suggested.

"Whether higher dosages of ARBs (e.g., up to 2 mg/kg per day losartan) do not produce better results than beta-blockers, or even than the combination therapy of both, cannot be conclusively clarified at present," she wrote. "Because losartan, as a prodrug, is subject to a genetically individual metabolism to its effective metabolite, a personalized dosing regimen could be useful here. This monotherapy would possibly improve patient compliance, and accumulated side effects such as hypotension could also be avoided."

But as Pitcher noted, "Angiotensin receptor blockers and beta-blockers are some of the most widely prescribed and used medications in the world. ... They are known to be well tolerated, they are very widely available, and they are very cheap. So we think those medications should certainly be considered."