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Pitcher A, Spata E, Emberson J, et al. Angiotensin receptor blockers and β blockers in Marfan syndrome: an individual patient data meta-analysis of randomised trials. Lancet. 2022;400(10355):822-831. PMID 36049495

One-paragraph summary

Collaborative (Marfan Treatment Trialists) IPD meta-analysis of randomized trials of ARBs and beta-blockers in Marfan syndrome: 7 eligible trials, 1,442 patients without prior aortic surgery, primary endpoint the annual rate of change in BSA-adjusted root z-score. ARB vs control (4 trials, n=676, median 3 yr): annual z-score increase 0.07 vs 0.13 SD/yr — ARBs roughly halve progression (absolute difference −0.07, 95% CI −0.12 to −0.01, p=0.012), with larger effects in pathogenic FBN1 variant carriers (heterogeneity p=0.005) and no interaction with background beta-blocker use. ARB vs beta-blocker (3 trials, n=766): no difference (0.03 SD/yr, p=0.48); by indirect comparison, beta-blocker vs control −0.09 SD/yr (p=0.042). Authors infer additive combination benefit and project delayed need for aortic surgery.

Key findings

  • Ends the 15-year losartan controversy with a class-level answer: both drug classes work, comparably, modestly.
  • Effect independence from concomitant beta-blockade supports combination therapy — the basis of the 2022 ACC/AHA 2a recommendation for dual therapy and the 1/A for either agent (PMID 36322642).
  • Genotype interaction (FBN1 pathogenic variants) echoes the COMPARE haploinsufficiency substudy (Franken 2015, PMID 25613431).

Limitations

  • Endpoint is a surrogate (z-score slope); no trial or the pooled data shows reduction in dissection, surgery, or death.
  • Median 3-year follow-up in a lifelong disease; projected surgery delay is modeled, not observed.
  • Heterogeneous trial designs (placebo-controlled, open control, active comparator) bridged by indirect comparison for the beta-blocker-vs-control estimate.

Why it matters

The definitive synthesis of Marfan medical therapy and the sole LOE A pillar under any TAA drug recommendation; it also exemplifies the mouse-to-human effect-size discount (prevention in Fbn1 mice → ~50% slowing of a slow surrogate in humans), a calibration lesson for every pipeline therapy in this knowledge base.

Cited by wiki pages

  • medical-therapy
  • guidelines