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. 2024 Nov;55(11):2632-2640.
doi: 10.1161/STROKEAHA.123.046894. Epub 2024 Sep 25.

Prediction of Severe Baseline Asymptomatic Carotid Stenosis and Subsequent Risk of Stroke and Cardiovascular Disease

Michiel H F Poorthuis  1 , Steven H J Hageman  2 , Aernoud T L Fiolet  3 , L Jaap Kappelle  1 , Michiel L Bots  4 , Ph Gabriel Steg  5   6 , Frank L J Visseren  2 , Deepak L Bhatt  7 , Gert J de Borst  8
Affiliations

Prediction of Severe Baseline Asymptomatic Carotid Stenosis and Subsequent Risk of Stroke and Cardiovascular Disease

Michiel H F Poorthuis et al. Stroke. 2024 Nov.

Abstract

Background: Risk models to identify patients at high risk of asymptomatic carotid artery stenosis (ACAS) can help in selecting patients for screening, but long-term outcomes in these patients are unknown. We assessed the diagnostic and prognostic value of the previously published Prevalence of ACAS (PACAS) risk model to detect ACAS at baseline and to predict subsequent risk of stroke and cardiovascular disease (CVD) during follow-up.

Methods: We validated the discrimination and calibration of the PACAS risk model to detect severe (≥70% narrowing) ACAS with patients from the Reduction of Atherothrombosis for Continued Health registry. We subsequently calculated the incidence rates of stroke and CVD (fatal and nonfatal stroke or myocardial infarction or vascular death) during follow-up in 4 risk groups (low, medium, high, and very high, corresponding to sum scores of ≤9, 10-13, 14-17, and ≥18, respectively).

Results: Among 26 384 patients, aged between 45 and 80 years, without prior carotid procedures, 1662 (6.3%) had severe baseline ACAS. During ≈70 000 patient-years of follow-up, 1124 strokes and 2484 CVD events occurred. Discrimination of the PACAS model was 0.67 (95% CI, 0.65-0.68), and calibration showed adequate concordance between predicted and observed risks of severe baseline ACAS after recalibration. Significantly higher incidence rates of stroke (Ptrend<0.011) and CVD (Ptrend<0.0001) during follow-up were found with increasing PACAS risk groups. Among patients with high PACAS sum score of ≥14 (corresponding to 27.7% of all patients), severe baseline ACAS prevalence was 11.4%. In addition, 56.6% of incident strokes and 64.9% of incident CVD events occurred in this group.

Conclusions: The PACAS risk model can reliably identify patients at high risk of severe baseline ACAS. Incidence rates of stroke and CVD during follow-up were significantly higher in patients with high PACAS sum scores. Selective screening of patients with high PACAS sum scores may help to prevent future stroke or CVD.

Keywords: asymptomatic diseases; cardiovascular diseases; carotid stenosis; epidemiologic methods; mass screening; risk assessment; stroke.

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Conflict of interest statement

Dr Bhatt discloses the following relationships: advisory board: Angiowave, Bayer, Boehringer Ingelheim, CellProthera, Cereno Scientific, Elsevier Practice Update Cardiology, High Enroll, Janssen, Level Ex, McKinsey, Medscape Cardiology, Merck, MyoKardia, NirvaMed, Novo Nordisk, PhaseBio, PLx Pharma, and Stasys; board of directors: American Heart Association New York City, Angiowave (stock options), Bristol Myers Squibb (stock), DRS.LINQ (stock options), and High Enroll (stock); consultant: Broadview Ventures, Hims, SFJ, and Youngene; data monitoring committees: Acesion Pharma, Assistance Publique-Hôpitaux de Paris, Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute, for the PORTICO trial [Portopulmonary Hypertension Treatment With Macitentan: A Randomized Clinical Trial], funded by St. Jude Medical, now Abbott), Boston Scientific (chair: the PEITHO trial [Pulmonary Embolism Thrombolysis]), Cleveland Clinic, Contego Medical (chair: PERFORMANCE 2 [Protection Against Emboli During Carotid Artery Stenting Using the Neuroguard IEP System]), Duke Clinical Research Institute, Mayo Clinic, Mount Sinai School of Medicine (for the ENVISAGE trial, funded by Daiichi Sankyo; for the ABILITY-DM trial, funded by Concept Medical; for ALLAY-HF [Safety and Efficacy of the Alleviant System for No-Implant Interatrial Shunt Creation in Patients With Chronic Heart Failure], funded by Alleviant Medical), Novartis, Population Health Research Institute, and Rutgers University (for the National Institutes of Health-funded MINT trial [Myocardial Ischemia and Transfusion]); honoraria: American College of Cardiology (senior associate editor: Clinical Trials and News, ACC.org; chair: ACC Accreditation Oversight Committee), Arnold and Porter law firm (work related to Sanofi/Bristol Myers Squibb clopidogrel litigation), Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute; the RE-DUAL PCI [Evaluation of Dual Therapy With Dabigatran vs Triple Therapy With Warfarin in Patients With AF That Undergo a PCI With Stenting] Clinical Trial Steering Committee funded by Boehringer Ingelheim; AEGIS-II [Study to Investigate CSL112 in Subjects With Acute Coronary Syndrome] Executive Committee funded by CSL Behring), Belvoir Publications (editor-in-chief: Harvard Heart Letter), Canadian Medical and Surgical Knowledge Translation Research Group (clinical trial steering committees), CSL Behring (AHA lecture), Cowen and Company, Duke Clinical Research Institute (clinical trial steering committees, including for the PRONOUNCE trial [A Trial Comparing Cardiovascular Safety of Degarelix Versus Leuprolide in Patients With Advanced Prostate Cancer and Cardiovascular Disease], funded by Ferring Pharmaceuticals), HMP Global (editor-in-chief: Journal of Invasive Cardiology), Journal of the American College of Cardiology (guest editor, associate editor), K2P (co-chair: interdisciplinary curriculum), Level Ex, Medtelligence/ReachMD (Continuing Medical Education [CME] steering committees), MJH Life Sciences, Oakstone CME (course director: Comprehensive Review of Interventional Cardiology), Piper Sandler, Population Health Research Institute (for the COMPASS [Cardiovascular Outcomes for People Using Anticoagulation Strategies] Operations Committee, Publications Committee, Steering Committee, and USA national coleader, funded by Bayer), WebMD (CME steering committees), and Wiley (steering committee); other: Clinical Cardiology (deputy editor); patent: Sotagliflozin (named on a patent for sotagliflozin assigned to Brigham and Women’s Hospital that assigned to Lexicon; neither he nor Brigham and Women’s Hospital receive any income from this patent); research funding: Abbott, Acesion Pharma, Afimmune, Aker Biomarine, Alnylam, Amarin, Amgen, AstraZeneca, Bayer, Beren, Boehringer Ingelheim, Boston Scientific, Bristol Myers Squibb, Cardax, CellProthera, Cereno Scientific, Chiesi, CinCor, Cleerly, CSL Behring, Eisai, Ethicon, Faraday Pharmaceuticals, Ferring Pharmaceuticals, Forest Laboratories, Fractyl, Garmin, HLS Therapeutics, Idorsia, Ironwood, Ischemix, Janssen, Javelin, Lexicon, Lilly, Medtronic, Merck, Moderna, MyoKardia, NirvaMed, Novartis, Novo Nordisk, Otsuka, Owkin, Pfizer, PhaseBio, PLx Pharma, Recardio, Regeneron, Reid Hoffman Foundation, Roche, Sanofi, Stasys, Synaptic, The Medicines Company, Youngene, and 89Bio; royalties: Elsevier (editor: Braunwald’s Heart Disease); site coinvestigator: Abbott, Biotronik, Boston Scientific, CSI, Endotronix, St. Jude Medical (now Abbott), Philips, SpectraWAVE, Svelte, and Vascular Solutions; trustee: American College of Cardiology; and unfunded research: FlowCo. Dr Steg discloses the following relationships: employment: Assistance Publique-Hôpitaux de Paris and Université Paris-Cité; research grants: Bayer; consulting: Amarin, Amgen, AstraZeneca, Bayer, Bristol Myers Squibb, Boehringer Ingelheim, Janssen, Pfizer, PhaseBio, Novartis, NovoNordisk, Regeneron, Sanofi, and Servier; and patent issued as coinventor of use of alirocumab to reduce cardiovascular risk (patent assigned to Sanofi). The other authors report no conflicts.

Figures

Figure 1.
Figure 1.
Calibration plot of external validation of prevalence of asymptomatic carotid artery stenosis (PACAS) in the REACH registry (Reduction of Atherothrombosis for Continued Health). The calibration plot showing the mean predicted risk against the observed risk of severe baseline asymptomatic carotid artery stenosis (ACAS) across deciles of predicted risk. The boxes represent the mean predicted risk for each decile, and the vertical lines represent the 95% CIs. The dotted diagonal line indicates perfect calibration. Boxes above the diagonal line indicate underestimation of risk and boxes below the diagonal line, overestimation of risk. The mean calibration (calibration in the large) was 0, indicating adequate overall predictions, and the calibration slope was 0.618, suggesting that estimated risks are too extreme, that is, too high for patients who are at high risk and too low for patients who are at low risk.
Figure 2.
Figure 2.
Incidence rates and hazard ratios (HRs) of stroke during follow-up, by prevalence of asymptomatic carotid artery stenosis (PACAS) sum score. The bar chart (left) shows the annual incidence rate of stroke (per 100 patient-years [PYs]) in patients with and without severe baseline asymptomatic carotid artery stenosis (ACAS) for each PACAS risk group. The figure (right) shows the HRs of stroke in patients with severe baseline ACAS. The vertical bars represent the 95% CIs in both figures. *We calculated the HRs of stroke in patients with severe baseline ACAS using group-specific CIs.
Figure 3.
Figure 3.
Incidence rates and hazard ratios (HRs) of cardiovascular disease (CVD) during follow-up, by prevalence of asymptomatic carotid artery stenosis (PACAS) sum score. The bar chart (left) shows the annual incidence rate of CVD (per 100 patient-years [PYs]) in patients with and without severe baseline asymptomatic carotid artery stenosis (ACAS) for each PACAS risk group. The figure (right) shows the HRs of CVD in patients with severe baseline ACAS. The vertical bars represent the 95% CIs in both figures. *We calculated the HRs of CVD in patients with severe baseline ACAS using group-specific CIs.
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