Biologically implausible carotid intima–media thickness measurement values: effects on rate of change over time

Abstract

Objective:

Carotid intima–media thickness (CIMT) is a marker of atherosclerosis that is commonly used to assess the effect of therapeutic interventions. It is currently unclear to what extent biologically implausible values affect treatment effects. We evaluated the impact of biologically implausible CIMT values on the estimated rate of change in CIMT.

Methods:

Data were used from the METEOR (Measuring Effects on Intima–media Thickness: an Evaluation of Rosuvastatin) trial. METEOR was a randomized, placebo-controlled trial showing that rosuvastatin reduced the 2-year change in CIMT among low-risk individuals with subclinical atherosclerosis. In the main METEOR analysis, the data were analyzed without exclusion of biologically implausible data. In this post-hoc analysis, we constructed twelve definitions to define mildly or extremely biologically implausible values using distance from the interquartile range, median or mean. We evaluated the effect of removing implausible values on the estimated rate of change in CIMT.

Results:

The percentage of biologically implausible CIMT values ranged from 0.6% to 9.7%, depending on the definition used. Across all definitions, removal of biologically implausible CIMT values marginally reduced standard errors and did not change the primary outcome (i.e., a nonsignificant change in the rosuvastatin group, significant progression in the placebo group, and a statistically significant difference between treatment groups).

Limitation:

This study was focussed on the impact of implausible values in the analytical part of a CIMT study. Ultrasound images were not re-examined to determine whether an implausible measurement was due to measurement error or temporal morphological thickening,

Conclusion:

Removal of biologically implausible CIMT values marginally decreased the variability of the estimated rate of change in CIMT without having a large impact on the estimated rate of change.

Keywords::

• Biologically implausible values
• Carotid intima
• media thickness
• Methodology
• Outliers
• Study design

Transparency

Declaration of funding

The METEOR study was funded by AstraZeneca. The sponsor participated in discussions regarding the design and conduct of the study, and provided logistical support during the trial. The manuscript was prepared by the author group. The sponsor was permitted to review the manuscript and suggest changes, but the final approval of content was exclusively retained by the authors.

CMRO peer reviewers may have received honoraria for their review work. The peer reviewers on this manuscript have disclosed that they have no relevant financial relationships.

Declaration of financial/other relationships

S.A.E.P. is supported by an unrestricted grant from AstraZeneca. H.M.d.R. has disclosed that she has no significant relationships with or financial interests in any commercial companies related to this study or article. M.K.P. is a former employee of AstraZeneca and is a consultant for Boehringer-Ingelheim and AstraZeneca. D.E.G. has received grant or salary support from and delivered lectures for Pfizer, AstraZeneca, Organon, Servier and Merck. J.R.C. has received grant or salary support from Merck, Merck-Schering Plough, Pfizer, AstraZeneca and Kos Pharmaceuticals. He has delivered lectures for Merck, Merck-Schering Plough, Pfizer, AstraZeneca, Abbott and Kos Pharmaceuticals. D.H.O’L. serves on data safety and monitoring boards for Pfizer and AstraZeneca. He serves as a consultant to Pfizer, Sankyo Pharma, Sanofi-Aventis, GlaxoSmithKline, Eli Lilly, Schering-Plough, Esperion Therapeutics and Merck. He is an equity partner in Imagepace, LLC. G.W.E. has received grant support and honoraria from AstraZeneca, Organon and Pfizer, and has served as a consultant for AstraZeneca and Pfizer. J.S.R. is an employee of AstraZeneca. M.L.B. has received study grants for studies on CIMT and/or honoraria for professional input on CIMT issues from AstraZeneca, Boehringer-Ingelheim, Organon, Pfizer, Servier and Unilever.

Acknowledgments

Trial registration: Clinicaltrials.gov identifier: NCT00225589.

The authors would like thank all the METEOR investigators and the individuals involved in this study:

Belgium: Marcelo Goldstein, Anderlecht; Jan Staessen, Leuven; Guy Marchal, Leuven.

Czech Republic: Ales Linhart, Prague.

Finland: Jukka T Salonen, Kuopio.

France: Alain Simon, Paris Cedex; Patrick Audouy, Paris; Charles Baranes, Paris; Jean-Philippe Brugnaux, Paris; Eric Chabaud, Ivry sur Seine; Daniel Delbecq, Paris; Jean Claude Mouchet, Meudon; Andre Sebbah, Paris; Gilles Bertrand, Metz; Marcel Frohn, Moutiers; Jean-Luc Jacques, Mars la Tour; Dominique Richter, Jarney; Jean-Louis Doubet, Thionville; Philippe Martin, Yutz; Alain Prochasson, Metz; Eric De Ste Lorette, Paris; Jean-Claude Ingrand, Les Lilas; Denis Smila, Yerres; Genevieve Arcizet, Bangolet; Pascal Didi, Paris; Albert Cohen, Les Lilas; Mohamed Oulmekki, Drancy; Karima Allouache, Bangolet; Serge Kownator, Thionville.

Germany: Raimund Erbel, Essen; Clemens Von Shacky, Munich.

Norway: Leiv Ose, Oslo; Knut Risberg, Skedsmokorset; Andreas Tandberg, Bekkestua; Olyvind Aabo, Oslo; Jon Christensen, Oslo; Anne C Poole, Oslo; David Russell, Oslo.

The Netherlands: Annette Bak, Utrecht; Jan Jonker, Rotterdam.

USA: Thomas W Littlejohn, Winston-Salem, NC; David M Capuzzi, Philadelphia, PA; John Morgan, Philadelphia, PA; Robert Davidson, Los Angeles, CA; Michael Davidson, Chicago, IL; Alan Hirsch, Minneapolis, MN; Stephen Glasser, Minneapolis, MN; Leslie Miller, Minneapolis, MN; Daniel Duprez, Minneapolis, MN; Donald Hunninghake, Minneapolis, MN; Robert Knopp, Seattle, WA; Christie Ballantyne, Houston, TX; William Insull, Houston, TX; Daniel Edmundowicz, Pittsburgh, PA; Alan Gradman, Pittsburgh, PA; Neville Bittar, Madison, WI; Laurence Yellen, San Diego, CA; David Cameron, Kirkland, WA; Evan Stein, Cincinnati, OH; Eli Roth, Cincinnati, OH; Tasneem Z Naqvi, Los Angeles, CA; Cecil Farrington, Salisbury, NC; Bernard Mizok, Chicago, IL; Zane P Osborne, Chicago, IL; Monica Perlman, La Jolla, CA; Margaret Drehobl, San Diego, CA; Dean Kereiakes, Cincinnati, OH; Norman M Lunde, Brooklyn Center, MN; Stephen Pomeranz, Cincinnati, OH; Steven Feinstein, Chicago, IL; Charles McCollum, Houston, TX; James Stein, Madison, WI; Laurence Needleman, Philadelphia, PA; Kim Sutton-Tyrell, Pittsburgh, PA; Shirley Otis, La Jolla, CA; Kirk Beach, Seattle, WA.

CIMT core laboratory USA: Wake Forest University School of Medicine, Winston-Salem, USA. Gregory Evans, MA; Ward Riley, PhD (co-chairs).

CIMT core laboratory Europe: Vascular Imaging Center, Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, The Netherlands. Anne-Marie Bos; Michiel Bots, MD, PhD (co-chair); Corine van Everdingen; Marrij Geurtsen; Frank Leus; Corry Loffveld; Rudy Meijer MSc; Dicky Mooiweer-Bogaerdt; Karin Nijssen (co-chair) BSc; Hannie Noordzij; Anneke Rutgers; Els Stooker; Brigitte van der Vlist; Lucienne van der Vlist; Arthur Waterschoot; Elise Wineke.