Prognostic value of ultrasound carotid plaque length in patients with coronary artery disease

To the Editor: Coronary artery disease (CAD) remains a leading cause of morbidity and mortality worldwide.[1] Atherosclerosis is a slowly progressive process; therefore, effective secondary prevention is commonly recommended to halt or delay the progression of atherosclerosis toward subsequent cardiovascular events.[2] However, despite recent advances in medical and interventional therapies, patients with coronary atherosclerotic heart disease are still at high risk of cardiovascular events, resulting in an increasing global health expenditure. To date, there is a lack of reliable prognostic predictors for cardiovascular events in patients with CAD. The carotid artery is a commonly involved site of atherosclerosis and provides an indirect window into the coronary atherosclerosis process. Carotid plaque length (CPL) has a large dynamic range and seems more suitable to follow individual changes in the progression of coronary atherosclerosis. Nevertheless, the clinical importance of CPL has been often neglected by clinicians in the past. Recently, we reported that ultrasound maximal CPL had higher predictive value for the presence and severity of CAD than carotid plaque score and intima-media thickness (IMT).[3] However, until now, it has been uncertain whether max-CPL is capable of predicting future cardiovascular events. Herein, we performed this study to explore the efficacy and performance of max-CPL in risk prediction and stratification in patients with CAD confirmed by coronary angiography (CAG). This is a multicenter, observational cohort study (NCT05409209, https://clinicaltrials.gov) that was conducted at five Chinese cardiovascular centers. From January 2017 to December 2018, a total of 6270 consecutive patients without known CAD underwent first CAG for suspected CAD, and carotid ultrasound was performed during hospitalization. Overall, 3637 patients who had obstructive CAD (defined as ≥50% luminal stenosis) documented by CAG and who underwent carotid scanning were enrolled. The participant flow diagram of our study is shown in Supplementary Figure 1, https://links.lww.com/CM9/C433. The study protocol was approved by the Ethics Committee of Changhai Hospital (No. CHEC2021-041) and conducted in accordance with the principles established in the Declaration of Helsinki. All participants provided their informed consent prior to participation in this study. The mean IMT (mIMT), maximal carotid plaque length (max-CPL), and maximal carotid plaque thickness (max-CPT) were acquired through carotid ultrasound [Supplementary Figure 2, https://links.lww.com/CM9/C433]. The primary outcome was major adverse cardiovascular events (MACE), including cardiovascular death, myocardial infarction, ischemic stroke, and coronary revascularization. Details of study cohort and statistical analytic methods are provided in the Supplementary Material, https://links.lww.com/CM9/C433. During a median follow-up of 4.0 years (Q1–Q3: 3.8–4.3 years), there were a total of 603 MACE events (16.6%, 603/3637), including cardiovascular deaths (3.2%, 115/3637), myocardial infarction (2.1%, 76/3637), ischemic stroke (3.3%, 121/3637), and coronary revascularization (10.7%, 390/3637). The average age of enrolled patients was 66.0 [59.0–74.0] years, 67.2% (2443/3637) of whom were male. The baseline characteristics of the patients enrolled in this study are shown in Supplementary Table 1, https://links.lww.com/CM9/C433. First, we investigated the association between max-CPL, the number of obstructive vessels, and MACE. The proportion of patients with 3-vessel disease increased as max-CPL increased [Supplementary Figure 3A, https://links.lww.com/CM9/C433]. Moreover, the event rate per 1000 person-years according to tertiles of max-CPL and the number of vessels with obstructive CAD are described in Supplementary Figure 3B, https://links.lww.com/CM9/C433. Both high max-CPL and 3-vessel obstructive CAD were associated with a significant increase in event rate for MACE (P <0.001 for all). Of note, we found a significant increase in the risk of MACE when max-CPL was modeled as a continuous variable [Supplementary Figure 4, https://links.lww.com/CM9/C433]. The risk of MACE was relatively flat until around 5.0 mm and then started to increase rapidly afterwards. Moreover, in the progressively adjusted Cox proportional regression model, compared with low max-CPL or 1-vessel obstructive CAD, high max-CPL or 3-vessel obstructive CAD had higher risk of MACE, respectively (hazard ratio [HR] 5.01, 95% confidence interval [CI]: 3.91–6.42; P <0.001 and HR 2.91, 95% CI: 2.40–3.53; P <0.001, Supplementary Table 2, https://links.lww.com/CM9/C433). Associations remained significant when clinical factors were introduced as covariates into the partially adjusted multivariable models. In Model 3, every one standard deviation (SD) increment in max-CPL (6.6 mm) was associated with a 53% higher risk. Furthermore, these associations remained consistent in both stable and unstable CAD populations [Supplementary Table 3, https://links.lww.com/CM9/C433]. And, given that, there is a close correlation between max-CPL and max-CPT (rs = 0.791; P <0.001, Supplementary Figure 5A, https://links.lww.com/CM9/C433), as well as the number of obstructive vessels [Supplementary Figures 3A and 5B, https://links.lww.com/CM9/C433]. Subsequently, Model 4 was additionally adjusted for the number of obstructive vessels and max-CPT, and these associations remained unchanged. Risk of MACE events were assessed by max-CPL and the number of obstructive vessels. In Kaplan–Meier survival analysis, marked trends of higher MACE risk were observed with increasing max-CPL (Supplementary Figure 6, https://links.lww.com/CM9/C433, log rank P <0.001 for all), and the cut-off value of max-CPL for MACE was 9.1 mm using maximally selected rank statistics. Similar patterns were observed when stratified by the number of obstructive vessels or max-CPT; patients with 3-vessel obstructive CAD or high max-CPT had the highest risk of MACE events (Supplementary Figures 7 and 8, https://links.lww.com/CM9/C433, log rank P <0.001 for both). A multivariable clinical risk base model with Cox multivariable analysis was constructed [Supplementary Table 4, https://links.lww.com/CM9/C433]. Supplementary Table 5, https://links.lww.com/CM9/C433 shows the discriminative capacity and reclassification improvement of the prediction models. The impact on model performance of adding max-CPL, max-CPT, or mIMT to the base model was further evaluated. Additionally, adding max-CPL to the base model yielded the highest improvement in discrimination (C-statistic 0.742, P <0.001) and reclassification (net reclassification improvement [NRI] 0.43, and integrated discrimination improvement [IDI] 0.19, P <0.001 for both). Risk of MACE was assessed according to the different combination groups. Supplementary Figure 9A,B, https://links.lww.com/CM9/C433 depicts the four groups according to the max-CPL threshold (≥10.0 mm or <10.0 mm) and whether they had multi-vessel obstructive CAD. The group with a combination of high max-CPL and multi-vessel obstructive CAD had the highest MACE risk. Interestingly, a significantly higher risk was observed in the group with high max-CPL and 1-vessel disease (HR 3.15, 95% CI: 2.33–4.25, P <0.001) than that in the group with low max-CPL and multi-vessel disease (HR 1.92, 95% CI: 1.46–2.53; P <0.001). Moreover, the subgroup with a combination of max-CPL ≥10.0 mm and max-CPT <2.4 mm was associated with a greater risk of MACE than that with max-CPL <10.0 mm and max-CPT ≥2.4 mm (P <0.001, Supplementary Figure 10, https://links.lww.com/CM9/C433). The present study, based on a multi-center cohort of 3637 consecutive patients with obstructive CAD confirmed by CAG, provided novel findings that max-CPL is a powerful predictor of adverse events, independent of traditional risk factors (TRF), max-CPT, and number of obstructive vessels. Moreover, max-CPL enabled significant improvement in risk stratification over the number of obstructive vessels and/or TRF on the individual management of CAD patients [Figure 1 and Supplementary Table 5, https://links.lww.com/CM9/C433].Figure 1: (A) Restricted cubic spline for the hazard of MACE by carotid max-CPL. The red dotted line is the reference (HR = 1.0). (B) Kaplan–Meier curves for the cumulative incidence of MACE by max-CPL tertiles; (C) MACE risk classified by max-CPL and number of obstructive vessels; (D) Combination of high max-CPL and 1-vessel disease produced higher MACE risk than low max-CPL and multivessel disease. CAD: Coronary artery disease; CI: Confidence interval; MACE: Major adverse cardiovascular events; max-CPL: Maximal carotid plaque length.In general, patients with significant CAD account for more frequent cardiovascular events, which may be due to their high coronary atherosclerotic burden and vulnerable plaques. In view of the high mortality rate and disease burden, accurate risk assessment for CAD patients poses a major clinical challenge. The commonly used coronary imaging markers, that is, the degree of stenosis, the number of obstructive vessels, and coronary artery calcium, have been well proven to improve risk prediction.[4] Our study observed consistent results that patients with 3-vessel lesions had a 1.6-fold MACE risk, compared with those with 1-vessel lesions. However, the invasiveness, high cost, radiation, and renal toxicity of these markers must be considered. CPL may allow us to distinguish the differences in plaque progression more easily, as it grows faster along the vessel wall and has a large variation range.[3,5] As expected, we uncovered a pronounced positive association between max-CPL and adverse events in the CAD population. The risk of adverse events increased in a stepwise manner with increasing max-CPL. In multivariable analyses, after adjusting for well-known factors, every 1-SD (6.6 mm) increase in max-CPL was associated with a 40% increased MACE risk. As such, our results suggested that the prognostic value conferred by increased max-CPL may signify not only high coronary plaque burden but also plaque vulnerability. Further analysis demonstrated an interesting finding that the prognosis of CAD patients presenting with long and thin plaques was worse than that of patients presenting short and thick plaques. Therefore, the above findings stress a novel viewpoint that max-CPL should not be omitted, considering its good prognostic value and clinical practicability. The major limitation of this study is that our study included patients with both stable and unstable CAD, thereby increasing the heterogeneity of the analyzed cohort. However, our results were robust even after excluding patients with unstable CAD from the analysis [Supplementary Table 3, https://links.lww.com/CM9/C433]. Second, although we adjusted for baseline characteristics in Cox multivariable analyses, residual uncontrolled confounders such as medication adherence or lifestyle factors (e.g., diet, physical activity) may affect our findings. Funding This work was supported in part by grants from the Chinese Natural Science Foundation (Nos. N82170275 and 82000420), Health Care Science Foundation (No. 21BJZ06), Strengthening Foundation Plan (No. 23M3001) and Shanghai Talent Development Fund (No. 2021064). Conflicts of interest None.