Development and Validation of a Risk Prediction Model for Ischemic Stroke in Acute Myocardial Infarction Without Comorbid Atrial Fibrillation
Conditions: Myocardial Infarction
Sponsor: First Affiliated Hospital of Ningbo University

Clinical Research Protocol 
(Version: V1.0, Date: August 1, 2025) 
I. Title: Risk Prediction Model for Ischemic Stroke in Patients with Acute Myocardial 
Infarction Without Atrial Fibrillation 
II. Background: 
Patients with acute myocardial infarction (AMI) who do not have atrial fibrillation (AF) 
still exhibit a significantly higher risk of ischemic stroke compared to the general 
population. A multicenter retrospective study by Ferreira et al. found that among 
patients with reduced left ventricular ejection fraction (LVEF ≤ 35%) following AMI, 
the incidence of stroke was 5.97% in those with AF and 2.9% in those without AF over 
a median follow-up of 1.9 years. However, this study had important limitations: it 
focused on a restricted population (only those with LVEF ≤ 35%), making its findings 
unsuitable for extrapolation to the full range of LVEF; it did not distinguish between 
ischemic stroke and cerebral hemorrhage (despite the latter accounting for less than 
10%); and it underestimated the annual stroke risk in non-AF patients, which remained 
as high as 1.5%, significantly higher than in healthy individuals. 
Ischemic stroke dramatically worsens the prognosis of AMI patients. Evidence from 
clinical studies shows that the in-hospital mortality rate among patients with 
concomitant stroke is as high as 46.2%, compared to 6.3% in those without stroke, with 
a hazard ratio of 7.3. Even when stroke does not lead to death, it significantly reduces 
quality of life and increases public health expenditures. 
The pathophysiology of ischemic stroke in non-AF AMI patients is complex and 
involves four major pathways: 

1. Cardiogenic embolism: Detachment of left ventricular mural thrombi or spontaneous 
echo contrast (SEC) in the left atrium; 
2. Arterio-arterial embolism: Thrombosis resulting from rupture of atherosclerotic 
plaques in cerebral arteries; 
3. Paradoxical embolism: Deep vein thrombosis in the lower extremities passing 
through a patent foramen ovale; 
4. Hypercoagulable state: Systemic inflammation leading to endothelial dysfunction. 
For patients with sinus rhythm (excluding AF), anticoagulation combined with 
antiplatelet therapy can also provide significant benefits. The COMPASS trial 
demonstrated that in patients with stable atherosclerosis (including 22% with a history 
of MI), rivaroxaban (2.5 mg twice daily) combined with aspirin significantly reduced 
the risk of the composite endpoint of cardiovascular death, MI, or ischemic stroke by 
24% (HR 0.76; 95% CI 0.66–0.86; P < 0.001), with a 40% reduction in the risk of 
ischemic stroke. However, this regimen also increased the risk of major bleeding by 
70%, highlighting the necessity of precise risk stratification. 
Current evidence indicates that advanced age, heart failure, left atrial enlargement, renal 
insufficiency, history of stroke, hypertension, and diabetes are independent predictors 
of stroke in non-AF AMI patients. However, current clinical practice faces a critical 
gap: although stroke prediction models for AF patients (such as CHA₂DS₂-VASc) are 
well established, there is no specific tool for predicting ischemic stroke in non-AF AMI 
patients. Non-AF AMI accounts for more than 85% of all AMI cases, and ischemic 
stroke in these patients constitutes more than 75% of all ischemic strokes in AMI 

patients. This lack leads to under-recognition of high-risk patients and challenges in 
decision-making regarding anticoagulant therapy, underscoring the need to develop a 
dedicated predictive model for precise intervention. 
Innovation and Rationale:   
Based on the "multiple pathways of thrombosis after MI," we propose to integrate the 
following novel predictive factors: 
Imaging features: Left atrial diameter 
Biomarkers: D-dimer, LP(a) 
Treatment parameters: Duration of dual antiplatelet therapy 
III. Study Objectives: 
To construct and validate a specialized risk prediction model for ischemic stroke in non-
AF AMI patients (CAMI-Stroke Score), with the following goals: 
1.  Screening for high-risk patients for in-hospital stroke (positive predictive value > 
85%) 
2.  Stratifying stroke risk at 3 months and 1 year post-discharge (C-index target > 0.80) 
IV. Study Content: 
A retrospective analysis of hospital records of AMI patients admitted between January 
1, 2014, and December 31, 2023, will be conducted. Cases meeting the diagnostic 
criteria for AMI will be identified, and those with AF will be excluded. Baseline data, 
clinical information, and follow-up data will be collected. After retrieving and verifying 
the original medical records, a total of 3,832 AMI patients with completed follow-up 
will be analyzed. 

Model Development: 
Predictive variables: Significant factors will be selected using LASSO regression, 
followed by multivariate Cox regression modeling. 
Validation methods: 70% of the sample will be used for training, and 30% for internal 
validation. Discrimination (AUC, C-index) and calibration (Hosmer-Lemeshow test) 
will be evaluated. Decision curve analysis (DCA) and clinical net benefit analysis will 
be performed. Key performance metrics will include uncertainty (e.g., confidence 
intervals). If public database data becomes available, external validation may be 
considered. The development of the model and feature selection must take into account 
the feasibility of clinical implementation and the availability of data. The impact of the 
model on patient outcomes (e.g., mortality, morbidity, quality of life) and healthcare 
costs in real-world clinical settings will be assessed. The goal is to establish a model 
development ecosystem that is data-driven, methodologically rigorous, clinically 
relevant, ethically sound, and continuously improved. 
V. Quality Control and Assurance: 
This study is a retrospective study. All patient identity information will be anonymized 
to protect privacy. To prevent the leakage of patient identity information, electronic 
medical records should be closed and screen protected when leaving the workstation. 
Medical records will be handled in accordance with the "Medical Records Management 
Regulations." When using patient imaging data, all patient identity information will be 
removed. During the model validation phase, the predictive performance across 
subgroups (e.g., age ≥ 75 years, eGFR < 60 ml/min) will be analyzed. Fairness 

indicators (e.g., equal opportunity difference) will be used to assess bias, and the 
algorithm will be adjusted to reduce discrimination risk. 
Data Security Provisions: 
Storage location: Encrypted server within the hospital network (physically isolated area) 
Access control: Dual authentication (employee ID + dynamic password) + role-based 
access (researchers can only export aggregated data) 
Data transmission: Secure SSL-VPN transmission; prohibited to use WeChat or email 
to transfer data 
Device management: Data loss prevention (DLP) system installed on research-specific 
computers; USB ports disabled 
VI. Ethical Considerations: 
This study complies with Article 39 of the "Ethical Review Measures for Biomedical 
Research Involving Human Subjects" (2023):   
(1) The study uses existing medical records and cannot identify specific individuals;   
(2) The study does not involve the secondary use of sensitive personal information;   
(3) The study protocol has been approved by the Ethics Committee.   
The study only uses biochemical indicator concentrations and does not perform gene 
sequencing or genetic analysis, complying with Article 21 of the "Regulations on the 
Administration of Human Genetic Resources." The study protocol and related materials 
must be submitted to the Medical Ethics Committee for approval before the study 
begins. Researchers must submit annual reports to the Ethics Committee. Upon 
completion or termination of the study, researchers must notify the Ethics Committee 

in writing. Any changes during the study must be reported to the Ethics Committee, and 
such changes cannot be implemented without prior approval, unless they are necessary 
to eliminate an obvious and direct risk to participants, in which case the Ethics 
Committee must be notified immediately. 
VII. Conflict of Interest Statement: 
The researchers declare no commercial conflicts of interest. This study has no funding 
support. 
VIII. Additional Clauses: 
This model is intended solely as a research tool and is not to be used for clinical 
decision-making. If the model is applied in clinical practice in the future, prospective 
validation and the development of informed consent procedures for patients and 
physicians will be required. 
IX. Study Timeline: 
August 1, 2025 – December 31, 2025 
X. References: 
1.  Ferreira JP, Girerd N, Gregson J, Latar I, Sharma A, Pfeffer MA, McMurray JJV, 
Abdul-Rahim AH, Pitt B, Dickstein K, Rossignol P, Zannad F; High-Risk Myocardial 
Infarction Database Initiative. Stroke Risk in Patients With Reduced Ejection Fraction 
After Myocardial Infarction Without Atrial Fibrillation. _J Am Coll Cardiol_. 2018 Feb 
20;71(7):727-735. doi: 10.1016/j.jacc.2017.12.011. PMID: 29447733. 
2.  Murakami T, Sakakura K, Jinnouchi H, Taniguchi Y, Tsukui T, Watanabe Y, 
Yamamoto K, Seguchi M, Wada H, Fujita H. Acute Ischemic Stroke and Transient 

Ischemic Attack in ST-Segment Elevation Myocardial Infarction Patients Who 
Underwent Primary Percutaneous Coronary Intervention. _J Clin Med_. 2023 Jan 
20;12(3):840. doi: 10.3390/jcm12030840. PMID: 36769488; PMCID: PMC9917385. 
3.  Carella MC, Carulli E, Loizzi F, Quarta S, Freda A, Basile P, Amati F, Dicorato 
MM, Latorre MD, Naccarati ML, Lenoci CD, Cicco S, Pontone G, Forleo C, Guaricci 
AI, Ciccone MM, Santobuono VE. Intersections and Challenges in the Management of 
Acute Coronary Syndrome and Stroke: Pathophysiology, Treatment Dilemmas, and 
Integrated Prevention Strategies. _J Clin Med_. 2025 Mar 29;14(7):2354. doi: 
10.3390/jcm14072354. PMID: 40217803; PMCID: PMC11989927. 
4.  Eikelboom JW, Connolly SJ, Bosch J, Dagenais GR, Hart RG, Shestakovska O, 
Diaz R, Alings M, Lonn EM, Anand SS, Widimsky P, Hori M, Avezum A, Piegas LS, 
Branch KRH, Probstfield J, Bhatt DL, Zhu J, Liang Y, Maggioni AP, Lopez-Jaramillo 
P, O'Donnell M, Kakkar AK, Fox KAA, Parkhomenko AN, Ertl G, Störk S, Keltai M, 
Ryden L, Pogosova N, Dans AL, Lanas F, Commerford PJ, Torp-Pedersen C, Guzik TJ, 
Verhamme PB, Vinereanu D, Kim JH, Tonkin AM, Lewis BS, Felix C, Yusoff K, Steg 
PG, Metsarinne KP, Cook Bruns N, Misselwitz F, Chen E, Leong D, Yusuf S; 
COMPASS Investigators. Rivaroxaban with or without Aspirin in Stable 
Cardiovascular Disease. _N Engl J Med_. 2017 Oct 5;377(14):1319-1330. doi: 
10.1056/NEJMoa1709118. Epub 2017 Aug 27. PMID: 28844192. 
5.  Sampson UK, Pfeffer MA, McMurray JJ, Lokhnygina Y, White HD, Solomon SD; 
VALIANT Trial Investigators. Predictors of stroke in high-risk patients after acute 
myocardial infarction: insights from the VALIANT Trial. _Eur Heart J_. 2007 

Mar;28(6):685-91. doi: 10.1093/eurheartj/ehl197. Epub 2006 Sep 19. PMID: 16984929.