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Randomized Controlled Trial
. 2024 Apr;29(2):143-152.
doi: 10.1177/1358863X241228542. Epub 2024 Mar 17.

Methods, design, and initial results of an angiographic core lab from VOYAGER-PAD

R Kevin Rogers  1   2 , Joerg Herold  3 , Nicholas Govsyeyev  1   2 , Roberto Iezzi  4 , Justin Morrison  1 , Shea E Hogan  1   2 , Mark Nehler  1   2 , Rory Bricker  1 , Brice Andring  5 , Brian Bergmark  6 , Matt Cavender  7 , Emily Malgor  1 , Donald Jacobs  1 , Michael N Young  8 , Warren Capell  1   2 , Joseph W Yčas  2 , Sonia S Anand  9 , Scott D Berkowitz  1   2 , E Sebastian Debus  2 , Lloyd P Haskell  10 , Eva Muehlhofer  11 , Manesh R Patel  12 , Connie N Hess  1   2 , Rupert M Bauersachs  13 , Victoria Anderson  2 , Marc P Bonaca  1   2
Affiliations
Randomized Controlled Trial

Methods, design, and initial results of an angiographic core lab from VOYAGER-PAD

R Kevin Rogers et al. Vasc Med. 2024 Apr.

Abstract

Background: Anatomy is critical in risk stratification and therapeutic decision making in coronary disease. The relationship between anatomy and outcomes is not well described in PAD. We sought to develop an angiographic core lab within the VOYAGER-PAD trial. The current report describes the methods of creating this core lab, its study population, and baseline anatomic variables. Methods: Patients undergoing lower-extremity revascularization for symptomatic PAD were randomized in VOYAGER-PAD. The median follow up was 2.25 years. Events were adjudicated by a blinded Clinical Endpoint Committee. Angiograms were collected from study participants; those with available angiograms formed this core lab cohort. Angiograms were scored for anatomic and flow characteristics by trained reviewers blinded to treatment. Ten percent of angiograms were evaluated independently by two reviewers; inter-rater agreement was assessed. Clinical characteristics and the treatment effect of rivaroxaban were compared between the core lab cohort and noncore lab participants. Anatomic data by segment were analyzed. Results: Of 6564 participants randomized in VOYAGER-PAD, catheter-based angiograms from 1666 patients were obtained for this core lab. Anatomic and flow characteristics were collected across 16 anatomic segments by 15 reviewers. Concordance between reviewers for anatomic and flow variables across segments was 90.5% (24,417/26,968). Clinical characteristics were similar between patients in the core lab and those not included. The effect of rivaroxaban on the primary efficacy and safety outcomes was also similar. Conclusions: The VOYAGER-PAD angiographic core lab provides an opportunity to correlate PAD anatomy with independently adjudicated outcomes and provide insights into therapy for PAD. (ClinicalTrials.gov Identifier: NCT02504216).

Keywords: angiography; clinical trial design, vascular imaging/diagnostics; peripheral artery disease (PAD).

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Conflict of interest statement

Declaration of conflicting interestsThe authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Drs Rogers, Hogan, Nehler, Capell, Berkowitz, Hess, Yčas, and Bonaca receive salary support from CPC, a nonprofit academic research organization affiliated with the University of Colorado that receives or has received research grant/consulting funding between February 2021 and June 2023 from the following organizations: Abbott Laboratories, Adamis Pharmaceuticals Corporation, Agios Pharmaceuticals, Inc., Alexion Pharma, Alnylam Pharmaceuticals, Inc., Amgen Inc., Angionetics, Inc., ARCA Biopharma, Inc., Array BioPharma, Inc., AstraZeneca and Affiliates, Atentiv LLC, Audentes Therapeutics, Inc., Bayer and Affiliates, Beth Israel Deaconess Medical Center, Better Therapeutics, Inc., BIDMC, Boston Clinical Research Institute, Bristol-Meyers Squibb Company, Cambrian Biopharma, Inc., Cardiol Therapeutics Inc., CellResearch Corp., Cook Medical Incorporated, Covance, CSL Behring LLC, Eidos Therapeutics, Inc., EP Trading Co. Ltd, EPG Communication Holdings Ltd, Epizon Pharma, Inc., Esperion Therapeutics, Inc., Everly Well, Inc., Exicon Consulting Pvt Ltd, Faraday Pharm-aceuticals, Inc., Foresee Pharmaceuticals Co. Ltd, Fortress Biotech, Inc., HDL Therapeutics Inc., HeartFlow Inc., Hummingbird Bioscience, Insmed Inc., Ionis Pharmaceuticals, IQVIA Inc., JanOne Biotech Holdings Inc., Janssen and Affiliates, Kaneka, Kowa Research Institute, Inc., Kyushu University, Lexicon Pharm-aceuticals, Inc., LSG Kyushu University, Medimmune Ltd, Medpace, Merck & Affiliates, Novartis Pharmaceuticals Corp., Novate Medical, Ltd, Novo Nordisk, Inc., Pan Industry Group, Pfizer Inc., PhaseBio Pharmaceuticals, Inc., PPD Development, LP, Prairie Education and Research Cooperative, Prothena Biosciences Limited, Regeneron Pharmaceuticals, Inc., Regio Biosciences, Inc., Rexgenero, Sanifit Therapeutics S.A., Sanofi-Aventis Groupe, Silence Therapeutics PLC, Smith & Nephew plc, Stealth Bio-Therapeutics Inc., State of Colorado CCPD Grant, The Brigham & Women’s Hospital, Inc., The Feinstein Institutes for Medical Research, Thrombosis Research Institute, University of Colorado, University of Pittsburgh, VarmX, Virta Health Corporation, WCT Atlas, Worldwide Clinical Trials Inc., WraSer, LLC, and Yale Cardiovascular Research Group. Dr Bonaca receives support from the AHA SFRN under award numbers 18SFRN3390085 (BWH-DH SFRN Center) and 18SFRN-33960262 (BWH-DH Clinical Project). Dr Bonaca also reports stock in Medtronic and Pfizer.

Figures

Figure 1.
Figure 1.
Overall schema of the VOYAGER-PAD angiographic core lab. ABI, ankle–brachial index; CKD, chronic kidney disease; CLTI, chronic limb-threatening ischemia; MACE, major adverse cardiovascular events; MALE, major adverse limb events; PAD, peripheral artery disease; PROs, patient-reported outcomes.
Figure 2.
Figure 2.
Example of angiogram and scoring for VOYAGER-PAD angiographic core lab for the segments: common femoral, profunda femoral, superficial femoral, and popliteal. For the purposes of this sample table, anatomic segments are numbered according to the angiogram on the left. The severity of stenosis is qualitatively determined by the core lab reader. The length of stenosis is determined quantitatively if an internal ruler is present. Otherwise, it is qualitatively determined by the core lab reader. The presence of calcification is qualitatively determined by the core lab reader. In this case, subtraction images preclude easy identification of calcification. The presence of prior stents or bypass grafts are recorded. The presence of thrombus is subjectively ascertained by the core lab reader. The presence of an aneurysm is assessed based on the catheter-based angiogram. If angiographic images include a revascularization procedure, characteristics of the result of the procedure are recorded (such as residual stenosis, placement of new stent, new bypass graft, dissection). *the segment PFA CFA, common femoral artery; PFA, profunda femoral artery; SFA, superficial femoral artery.
Figure 3.
Figure 3.
Consort diagram of the VOYAGER-PAD study population, showing subset with available catheter-based angiographic images, subgroups, and planned analyses. ABI, ankle–brachial index; WIQ, Walking Impairment Questionnaire
Figure 4.
Figure 4.
Forest plots of (A) efficacy results for the angiographic core lab cohort compared to those not in the angiographic core lab, and (B) safety results for the angiographic core lab cohort compared to those not in the angiographic core lab. There were 1667 participants in the angiographic core lab cohort. Of these, 855 patients were in the rivaroxaban group and 812 were in the placebo group. There were 4897 participants in the nonangiographic core lab group. The primary efficacy outcome included acute limb ischemia, major amputation for vascular causes, myocardial infarction, ischemic stroke, or death from cardiovascular causes. ALI, acute limb ischemia; CV, cardiovascular; ICH, intracranial hemorrhage; MACE, major adverse cardiovascular events; MALE, major adverse limb events; MI, myocardial infarction; TIMI, thrombolysis in myocardial infarction.
Figure 5.
Figure 5.
Across anatomic segments: (A) distribution of stenosis severity, (B) presence of calcification, and (C) length of disease. Numbers in bars correspond to frequencies within respective categories.
See this image and copyright information in PMC

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