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Is Aortic Z-score an Appropriate Index of Beneficial Drug Effect in Clinical Trials in Aortic Aneurysm Disease?

Elkinany, Sherif ; Weismann, Constance G. LU orcid ; Curtis, Alexander ; Smith, Tanya ; Zafar, Mohammad A. ; Breen, Thomas ; Li, Yupeng ; Tranquilli, Maryann ; Rizzo, John A. and Mukherjee, Sandip K. , et al. (2021) In American Journal of Cardiology 143.
Abstract

Aortic Z-score (Z-score) is utilized in clinical trials to monitor the effect of medications on aortic dilation rate in Marfan (MFS) patients. Z-scores are reported in relation to body surface area and therefore are a function of height and weight. However, an information void exists regarding natural, non-pharmacological changes in Z-scores as children age. We had concerns that Z-score decrease attributed to “therapeutic” effects of investigational drugs for Marfan disease connective tissue diseases might simply reflect normal changes (“filling out” of body contour) as children age. This investigation studies natural changes with age in Z-score in normal and untreated MFS children, teasing out normal effects that might erroneously be... (More)

Aortic Z-score (Z-score) is utilized in clinical trials to monitor the effect of medications on aortic dilation rate in Marfan (MFS) patients. Z-scores are reported in relation to body surface area and therefore are a function of height and weight. However, an information void exists regarding natural, non-pharmacological changes in Z-scores as children age. We had concerns that Z-score decrease attributed to “therapeutic” effects of investigational drugs for Marfan disease connective tissue diseases might simply reflect normal changes (“filling out” of body contour) as children age. This investigation studies natural changes with age in Z-score in normal and untreated MFS children, teasing out normal effects that might erroneously be attributed to drug benefit. (1) We first compared body mass index (BMI) and Z-scores (Boston Children's Hospital calculator) in 361 children with “normal” single echo exams in four age ranges (0 to 1, 5 to 7, 10 to 12, 15 to 18 years). Regression analysis revealed that aging itself decreases ascending Z-score, but not root Z-score, and that increase in BMI with aging underlies the decreased Z-scores. (2) Next, we examined Z-score findings in both “normal” and Marfan children (all pharmacologically untreated) as determined on sequential echo exams over time. Of 27 children without aortic disease with sequential echos, 19 (70%) showed a natural decrease in root Z-score and 24 (89%) showed a natural decrease in ascending Z- score, over time. Of 25 untreated MFS children with sequential echos, 12 (40%) showed a natural decrease in root Z-score and 10 (33%) showed a natural decrease in ascending Z-score. Thus, Z-score is over time affected by natural factors even in the absence of any aneurysmal pathology or medical intervention. Specifically, Z-score decreases spontaneously as a natural phenomenon as children age and with fill out their BMI. Untreated Marfan patients often showed a spontaneous decrease in Z-score. In clinical drug trials in aneurysm disease, decreasing Z-score has been interpreted as a sign of beneficial drug effect. These data put such conclusions into doubt.

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publication status
published
subject
in
American Journal of Cardiology
volume
143
publisher
Excerpta Medica
external identifiers
  • scopus:85099168349
  • pmid:33352210
ISSN
0002-9149
DOI
10.1016/j.amjcard.2020.12.025
language
English
LU publication?
yes
id
1fec15b5-3a2f-42d3-b596-51f042a29679
date added to LUP
2021-01-21 09:25:33
date last changed
2024-06-13 05:55:43
@article{1fec15b5-3a2f-42d3-b596-51f042a29679,
  abstract     = {{<p>Aortic Z-score (Z-score) is utilized in clinical trials to monitor the effect of medications on aortic dilation rate in Marfan (MFS) patients. Z-scores are reported in relation to body surface area and therefore are a function of height and weight. However, an information void exists regarding natural, non-pharmacological changes in Z-scores as children age. We had concerns that Z-score decrease attributed to “therapeutic” effects of investigational drugs for Marfan disease connective tissue diseases might simply reflect normal changes (“filling out” of body contour) as children age. This investigation studies natural changes with age in Z-score in normal and untreated MFS children, teasing out normal effects that might erroneously be attributed to drug benefit. (1) We first compared body mass index (BMI) and Z-scores (Boston Children's Hospital calculator) in 361 children with “normal” single echo exams in four age ranges (0 to 1, 5 to 7, 10 to 12, 15 to 18 years). Regression analysis revealed that aging itself decreases ascending Z-score, but not root Z-score, and that increase in BMI with aging underlies the decreased Z-scores. (2) Next, we examined Z-score findings in both “normal” and Marfan children (all pharmacologically untreated) as determined on sequential echo exams over time. Of 27 children without aortic disease with sequential echos, 19 (70%) showed a natural decrease in root Z-score and 24 (89%) showed a natural decrease in ascending Z- score, over time. Of 25 untreated MFS children with sequential echos, 12 (40%) showed a natural decrease in root Z-score and 10 (33%) showed a natural decrease in ascending Z-score. Thus, Z-score is over time affected by natural factors even in the absence of any aneurysmal pathology or medical intervention. Specifically, Z-score decreases spontaneously as a natural phenomenon as children age and with fill out their BMI. Untreated Marfan patients often showed a spontaneous decrease in Z-score. In clinical drug trials in aneurysm disease, decreasing Z-score has been interpreted as a sign of beneficial drug effect. These data put such conclusions into doubt.</p>}},
  author       = {{Elkinany, Sherif and Weismann, Constance G. and Curtis, Alexander and Smith, Tanya and Zafar, Mohammad A. and Breen, Thomas and Li, Yupeng and Tranquilli, Maryann and Rizzo, John A. and Mukherjee, Sandip K. and Ziganshin, Bulat A. and Elefteriades, John A.}},
  issn         = {{0002-9149}},
  language     = {{eng}},
  publisher    = {{Excerpta Medica}},
  series       = {{American Journal of Cardiology}},
  title        = {{Is Aortic Z-score an Appropriate Index of Beneficial Drug Effect in Clinical Trials in Aortic Aneurysm Disease?}},
  url          = {{http://dx.doi.org/10.1016/j.amjcard.2020.12.025}},
  doi          = {{10.1016/j.amjcard.2020.12.025}},
  volume       = {{143}},
  year         = {{2021}},
}