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

Abstract

Background: Aortic pulse wave velocity (PWV) predicts cardiovascular events (CVEs) 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 2 populations studies, respectively, for derivation IDCARS (International Database of Central Arterial Properties for Risk Stratification) and replication MONICA (Monitoring of Trends and Determinants in Cardiovascular Disease Health Survey - Copenhagen).

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 mm Hg. The predictive performance of the PWV threshold was assessed by computing the integrated discrimination improvement and the net reclassification improvement.

Results: In well-calibrated models in IDCARS, the risk-carrying PWV thresholds converged at 9 m/s (10 m/s considering the anatomic pulse wave travel distance). With full adjustments applied, the threshold predicted CVE (hazard ratio [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 end points was ≈0.75. Integrated discrimination improvement was significant for TM in IDCARS and for both TM and CVE in MONICA, whereas net reclassification improvement 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 person's lifetime causes stiffening of the elastic arteries as waypoint to CVE and death.

Keywords: cardiovascular diseases; diabetes mellitus; hypertension; metabolic syndrome; pulse wave analysis.

Figure 1.

Threshold and calibration of pulse wave velocity (PWV) in 3378 IDCARS (International Database of Central Arterial Properties for Risk Stratification) participants. Hazard ratios (HRs) express the risk at each PWV level relative to the average risk in the whole study population for composite cardiovascular (CV) end point (A) and total mortality (B) with PWV at 8.7 and 8.8 m/s signifying increased risk by crossing unity (dotted line). PWV levels yielding equivalent 5-year risks compared with systolic blood pressure categories for composite cardiovascular end point (C) and total mortality (D) with bars indicating 5-year risks and point and line for PWV thresholds. PWV levels at 8.5 and 8.2 m/s indicate equivalent risk as a systolic blood pressure of 140 mm Hg. Model calibration for the composite cardiovascular end point (E) and total mortality (F), showing the predicted risk against overoptimism-corrected Kaplan-Meier estimates in PWV quintiles. All analyses were multivariable adjusted for cohort, sex, age, mean arterial pressure (excluding C and D), heart rate, the total-to-high-density lipoprotein serum cholesterol ratio, smoking and drinking, use of antihypertensive drugs, diabetes, and history of cardiovascular disease.

Figure 2.

Rescaling the outcome-driven pulse wave threshold for the anatomical pulse wave travel distance path. In the analysis of the IDCARS (International Database of Central Arterial Properties for Risk Stratification) and the Copenhagen MONICA (Monitoring of Trends and Determinants in Cardiovascular Disease Health Survey – Copenhagen) data, the pulse wave travel distance was standardized to the subtraction method, as applied in IDCARS. To keep consistency with the current guidelines and clinical practice, the 9-m/s threshold derived in IDCARS and replicated in MONICA was rescaled to account for the difference between the measured and anatomic pulse wave travel path, using the formula published in references.^, With this adjustment applied the 9-m/s threshold corresponded with 10 m/s. The gray line represents the line of identity. PWV indicates pulse wave velocity.