Derivation of an Outcome-Driven Threshold for Aortic Pulse Wave Velocity: An Individual-Participant Meta-Analysis

BACKGROUND: Aortic pulse wave velocity (PWV) predicts cardiovascular events (CVE) and total mortality (TM), but previous studies proposing actionable PWV thresholds have limited generalizability. This individual-participant meta-analysis is aimed at defining, testing calibration, and validating an outcome-driven threshold for PWV, using two populations studies, respectively, for derivation (IDCARS) and replication (MONICA).
METHODS: A risk-carrying PWV threshold for CVE and TM was defined by multivariable Cox regression, using stepwise increasing PWV thresholds and by determining the threshold yielding a 5-year risk equivalent with systolic blood pressure of 140 mmHg. The predictive performance of the PWV threshold was assessed by computing the integrated discrimination improvement (IDI) and the net reclassification improvement (NRI).
RESULTS: In well-calibrated models in IDCARS, the risk-carrying PWV thresholds converged at 9 m/s (10 m/s considering the anatomical pulse wave travel distance). With full adjustments applied, the threshold predicted CVE (HR [CI]: 1.68 [1.15-2.45]) and TM (1.61 [1.01-2.55]) in IDCARS and in MONICA (1.40 [1.09-1.79] and 1.55 [1.23-1.95]). In IDCARS and MONICA, the predictive accuracy of the threshold for both endpoints was ~0.75. IDI was significant for TM in IDCARS and for both TM and CVE in MONICA, whereas NRI was not for any outcome.
CONCLUSIONS: PWV integrates multiple risk factors into a single variable and might replace a large panel of traditional risk factors. Exceeding the outcome-driven PWV threshold should motivate clinicians to stringent management of risk factors, in particular hypertension, which over a persons lifetime causes stiffening of the elastic arteries as waypoint to CVE and death. ### Competing Interest Statement The authors have declared no competing interest. ### Clinical Trial N/A ### Funding Statement The Non-Profit Research Association Alliance for the Promotion of Preventive Medicine, Mechelen, Belgium (www.appremed.org) received a nonbinding grant from OMRON Healthcare Co. Ltd., Kyoto, Japan, which supports the scholarships of D. W.A, B.C., and Y.-L.Y. The grants which supported the cohort studies are listed by country. Argentina: The Internal Medicine Service, Hospital Italiano de Buenos Aires, Buenos Aires, Argentina; Belgium: European Union (HEALTH-F7-305507 HOMAGE), European Research Council (Advanced Researcher Grant 2011-294713-EPLORE and Proof-of-Concept Grant 713601-uPROPHET), European Research Area Net for Cardiovascular Diseases (JTC2017-046-PROACT), and Research Foundation Flanders, Ministry of the Flemish Community, Brussels, Belgium (G.0881.13); China: The National Natural Science Foundation of China (grants 82270469, 82070432 and 82070435), the Ministry of Science and Technology (2018YFC1704902), Beijing, China, and by Shanghai Municipal Health Commission (2022LJ022 and 2017BR025); Czech Republic: European Union (grants LSHM-CT-2006-037093 and HEALTH-F4-2007-201550) and Charles University Research program ?Cooperatio - Cardiovascular Science". Denmark: 01-2-9-9A-22914 from the Danish Heart Foundation and R32-A2740 from the Lundbeck Fonden. Finland: Academy of Finland (grant 321351), Emil Aaltonen Foundation, the Paavo Nurmi Foundation, the Urmas Pekkala Foundation, and the Hospital District of South-Western Finland; Italy: European Union (grants LSHM-CT-2006-037093 and HEALTH-F4-2007-201550); Poland (Gda?sk): European Union (grants LSHM-CT-2006-037093 and HEALTH-F4-2007-201550); Poland (Kraków): European Union (grants LSHM-CT-2006-037093 and HEALTH-F4-2007-201550) and Foundation for Polish Science. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Not Applicable The details of the IRB/oversight body that provided approval or exemption for the research described are given below: All studies complied with the Helsinki Declaration on research in humans34 and were approved by the competent Institutional Review Boards. Participants provided informed written consent. Before transfer to the coordinating office in Leuven, Belgium, the data were stripped from all personal identifiers, and if required by national legislations, additional ethical clearances were obtained. For a detailed description, see https://doi.org/10.1093/ajh/hpab139 and reference articles. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Not Applicable I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Not Applicable I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Not Applicable All available data are shown within the article and the online-only Data Supplement. Anonymized data are available from the corresponding author upon request, on condition that an analysis plan is accompanying the request and that the principal investigators of all cohorts approve data sharing.