Circulating microRNAs as biomarkers of cardiovascular disease: A systematic review

Table 1 Characteristics of the included studies

Ref.	Design/setting (country)	Sample size	miRNAs	Source	Sample timing	Cases	Controls	Function of miRNA	Main findings	Diagnostic/prognostic values
Cardiomyopathy
Klenke et al[15], 2018	PCS (Germany)	91	1 miRNA (hsa-miR-192-5p)	Serum	During routine heart failure clinic check-ups	Patients diagnosed with HF due to ICM (59.3%)	Patients with HF due to non-ICM (40.7%)	Prognosis (p53-responsive prognostic marker involved in cardiomyocyte apoptosis)	High expression of miR-192 was associated with worse survival in ICM (P = 0.003)	Independent prognostic marker (P = 0.014) for survival in ICM; high expression resulted in a 17-year lower median age at death (67 years vs 84 years)
Heart failure
Shah et al[16], 2018	PCS (United States)	2763	3 miRNAs (miR-106b-5p, miR-17-5p, miR-20a-5p)	Plasma	Baseline plasma from the eighth Framingham Offspring Cohort examination	Patients without HF	No controls	Prediction of incident HF	Higher circulating levels of miR-17, miR-20a, and miR-106b were associated with a lower risk of incident HF	Among 2681 participants, 116 developed HF during a median follow-up of 7.7 years. MiR-20a: HR = 0.86, P = 0.047; miR-17: HR = 0.84, P = 0.03; miR-106b: HR = 0.85, P = 0.04
Acute coronary syndrome
Shen et al[18], 2021	Prospective nested case-control study (China)	1190	14 miRNAs (miR-4286 significant for ACS)	Plasma	Baseline blood samples were collected in 2013, with a median follow-up of 1.8 years	Incident ACS cases during follow-up	Matched controls free of CVD and cancer at the time of the case event	Prediction of incident ACS risk	Upregulation of miR-4286 was associated with increased risk of incident ACS	Highest tertile vs lowest tertile: OR = 1.80 (95%CI: 1.28-2.53); per IQR increase: OR = 1.26 (95%CI: 1.07-1.48)
Pilbrow et al[17], 2014	PCS (New Zealand)	300	5 miRNAs (miR-323-3p, miR-652, miR-27b, miR-103, and miR-208a)	Plasma	Baseline (approximately 30 days post-ACS), 4 months, and 12 months post-ACS	Patients with recent ACS	Healthy controls matched according to age and gender, where possible	Diagnosis and prognosis	MiR-323-3p, miR-652, and miR-27b were elevated in ACS patients. miR-652 in the lowest tertile was associated with heart failure readmission	MiR-652: AUC = 0.861; miR-323-3p: AUC = 0.806; miR-27b: AUC = 0.799 for ACS discrimination; low baseline miR-652 was associated with HF readmission (log-rank P < 0.001)
Biener et al[19], 2022	PCS (Germany)	1042	11 miRNAs (miR-134-5p, miR-21-5p, miR-191-3p, miR-29a-3p, miR-22-3p, miR-92a-3p, miR-126-3p, miR-122-5p, miR-132-3p, miR-133a-3p, and miR-423-5p)	Plasma	At presentation to the emergency department	Patients presenting with suspected ACS	NR	Prognosis	Higher expression of miR-133a-3p was observed in patients with higher troponin levels at baseline. Higher miR-21-5p and lower miR-122-5p were observed in patients who died during follow-up; higher miR-126-3p was observed in patients with the composite endpoint of all-cause mortality, AMI, and stroke	MiR-21-5p: AUC = 0.659 (95%CI: 0.596-0.723); miR-122-5p: AUC = 0.605 (95%CI: 0.526-0.685) for all-cause mortality; ROC-optimized miR-21-5p cutoff predicted all-cause mortality with HR = 3.3 (P25-P75: 1.2-9.4)
Acute myocardial infarction (STEMI and NSTEMI)
Eyyupkoca et al[20], 2022	PCS (Turkey)	10 (all male)	8 miRNAs (miR-26b-5p, miR-301a-3p, miR-23b-3p, miR-374a-5p, miR-199a-5p, miR-483-5p, miR-423-5p, and miR-652-3p)	Plasma	Baseline (1 day), 2 weeks, and 6 weeks after AMI	STEMI patients with ALVR	STEMI patients with reverse left ventricular remodeling	Prediction of ALVR	At day 1 after AMI, miR-199a-5p, miR-23b-3p, and miR-483-5p were downregulated, whereas miR-26b-5p and miR-652-3p were upregulated in ALVR; at 2 weeks, miR-374a-5p was downregulated; at 6 weeks, miR-301a-3p and miR-374a-5p were downregulated, whereas miR-423-5p was upregulated in ALVR	ALVR was defined as a ≥ 13% increase in LVEDV and LVESV at 6 months after AMI
Cai et al[21], 2024	Observational study (China)	100	1 miRNA (miR-133)	Plasma	At diagnosis and 24 hours after diagnosis	Patients with AMI	Healthy subjects and unstable angina patients	Diagnosis	MiR-133 levels were upregulated in AMI patients	MiR-133 showed high diagnostic accuracy for AMI (AUC = 0.956; sensitivity = 87.6%; specificity = 94.7%)
Grabmaier et al[22], 2017	CCS (Germany)	62	4 miRNAs (miR-1, miR-21, miR-29b, and miR-92a)	Plasma	Day 4, day 9, and 6 months after AMI	Patients with AMI in the SITAGRAMI trial	Age-, sex- and risk factor-matched controls	Diagnosis and prognosis	MiR-1, miR-21, and miR-29b were increased after AMI; miR-1 and miR-29b were inversely correlated with infarct volume changes, and miR-29b at day 9 inversely correlated with changes in LVEDV at 6 months	MiR-1 and miR-29b inversely correlated with change in infarct volume (P < 0.05), and miR-29b inversely correlated with change in LVEDV (P < 0.05)
Wang et al[23], 2011	CCS (China)	79	2 miRNAs (miR-133 and miR-328)	Plasma	Within 24 hours and at 7 days after AMI	Patients with AMI	Control subjects (CAD excluded by coronary angiography)	Diagnosis	Plasma miR-133 and miR-328 levels were increased in AMI patients (10.9-fold in plasma and 16.1-fold in whole blood) and returned to control levels by 7 days	MiR-133 plasma AUC = 0.890 (95%CI: 0.772-0.965); miR-328 plasma AUC = 0.810 (95%CI: 0.705-0.916)
Devaux et al[24], 2015	Prospective observational study (multicenter)	1155	6 miRNAs (miR-133a, miR-208b, miR-223, miR-320a, miR-451, and miR-499)	Plasma	At presentation with acute chest pain	Patients with AMI	Patients with final diagnoses other than AMI	Diagnosis and prognosis	Levels of miR-208b, miR-499, and miR-320a were higher in AMI; miR-208b levels were higher in patients who died within 30 days	MiR-208b showed the highest diagnostic accuracy for AMI (AUC = 0.76, 95%CI: 0.72-0.80); miR-208b for predicting 30-day mortality (AUC = 0.67, 95%CI: 0.52-0.81)
Jakob et al[25], 2017	Nested case-control study (multicenter)	189	14 miRNAs (miR-26b-5p, miR-320a, and miR-660-5p)	Plasma	At presentation with STEMI	Patients with STEMI who experienced MACE	Patients without MACE during 1-year follow-up	Prognosis	MiR-26b-5p was decreased, whereas miR-320a and miR-660-5p were increased in patients with MACE	MiR-26b-5p AUC = 0.707; miR-660-5p AUC = 0.683; miR-320a AUC = 0.672; combined AUC = 0.718
Matsumoto et al[26], 2013	CCS (Japan)	86	3 p53-responsive miRNAs (miR-192, miR-194, and miR-34a)	Serum	Median 18 days after AMI onset	Post-AMI patients who developed HF within 1 year	Matched controls without subsequent cardiovascular events	Prognosis	Serum miR-192, miR-194, and miR-34a were upregulated in patients who developed ischemic HF after AMI	MiR-194 and miR-34a correlated with larger left ventricular diastolic dimension at 1 year (r = 0.33, P = 0.01; r = 0.38, P = 0.003)
Cortez-Dias et al[27], 2016	Prospective observational study (Portugal)	160	6 miRNAs (miR-1-3p, miR-122-5p, miR-133a-3p, miR-133b, miR-208b-3p, and miR-499a-5p)	Serum	At the time of cardiac catheterization; additional sampling at 8 hours, 16 hours, 24 hours, 48 hours, and 72 hours in a subset	Patients with STEMI undergoing primary PCI	Healthy controls and non-STEMI controls	Prognosis	A higher miR-122-5p/miR-133b ratio was associated with increased risk of death or recurrent MI and with adverse cardiovascular events after STEMI	HR = 1.49 (95%CI: 1.09-2.03), P = 0.012; patients in the highest tertile of the miR-122-5p/133b ratio had an almost 9-fold higher risk of death or recurrent MI and a 4-fold higher risk of MACE. Multivariable model (miR ratio and LVEF) for all causes mortality: AUC = 0.81 (95%CI: 0.64-0.99)
He et al[28], 2014	CCS (China)	389	2 miRNAs (miR-328, and miR-134)	Plasma	Median 6 hours after symptom onset (range 2-10 hours)	Patients with AMI	Healthy controls	Diagnosis and prognosis	Plasma miR-328 (12.04-fold) and miR-134 (6.32-fold) were elevated in AMI patients; higher levels were associated with increased risk of cardiogenic death or HF within 6 months	Diagnostic AUC: MiR-328, 0.887; miR-134, 0.818. Prognostic OR for cardiogenic death or heart failure within 6 months: MiR-328, 7.35, P = 0.004; miR-134, 2.28, P = 0.013
Bauters et al[29], 2013	PCS (France)	246	2 miRNAs (miR-423-5p and miR-133a)	Plasma	Days 3-7 after AMI, then at 1 month, 3 month, and 12 months	Patients with first anterior wall Q-wave AMI	NR	Prognosis	Circulating miR-133a increased at 12 months, and miR-423-5p increased at 1 month, 3 months, and 12 months after MI	Neither miRNA was associated with LV function, LV remodeling, or BNP during 1-year follow-up
Hromádka et al[30], 2019	Retrospective cohort study (Czech Republic)	122	3 miRNAs (miR-1, miR-133a, and miR-499)	Plasma	24 hours after admission	AMI patients who died in 1 year	AMI patients who survived for 1 year	Prognosis	MiR-1, miR-133a, and miR-499 positively correlated with hsTnT, NT-proBNP, and negatively with LVEF; levels were higher in nonsurvivors, but differences were not statistically significant	All nonsurvivors had miR-499 > 0.088 and NT-proBNP > 891.5 ng/L (vs 28.4% of survivors, P = 0.001)
Angina
Zeller et al[31], 2014	CCS (Germany and Switzerland)	246	8 miRNAs (miR-19a, miR-19b, miR-132, miR-140-3p, miR-142-5p, miR-150, miR-186, miR-210)	Serum	At admission and 6 hours later	Patients with UA	Non-coronary chest pain patients and healthy controls	Diagnosis	Lower levels of 8 circulating miRNAs were significantly associated with UA; a 3-miRNA panel of miR-132, miR-150, and miR-186 showed the best discriminatory performance	3-miRNA panel (miR-132, miR-150, miR-186): AUC = 0.91 (95%CI: 0.84-0.98)
Simionescu et al[32], 2016	Cross sectional observational (Romania)	137	6 miRNAs (miR-146a, miR-125a, miR-92a, miR-486, miR-223, and miR-122)	Serum and HDL	Fasting serum samples at enrollment	Patients with stable angina and ACS	Healthy controls	Diagnosis	MiR-223, miR-92a, miR-486, miR-122, miR-125a, and miR-146a were increased in CAD patients; in hyperglycemic ACS, levels were higher than in normoglycemic ACS, especially for miR-223, miR-92a, and miR-486 in HDL	MiR-223, miR-486, and miR-92a discriminated ACS from stable angina
Wang et al[33], 2017	Observational study (various countries)	199	5 miRNAs (hsa-miR-126-5p, hsa-miR-3135b, hsa-miR-28-3p, hsa-miR-142-5p, hsa-miR-144-5p)	Whole blood	Baseline	Patients with non-STEMI and angina	Matched controls without any CVD event	Prognosis	Lower miR-3135b, miR-126-5p, miR-142-5p, and miR-144-5p were associated with HF; higher GRACE risk score was associated with lower miR-3135b and higher miR-28-3p	MiR-126-5p: Fold change 0718, P = 0.003; miR-142-5p: Fold change 0762, P = 0.044; miR-144-5p: Fold change 0816, P = 0.044; miR-3135b: Fold change 0769 with chronic HF (P = 0.044) and 0.994 per 1-SD increase in GRACE score (P = 0.013); miR-28-3p: Fold change 1004 per 1-SD increase in GRACE score (P = 0.019)
Zhong et al[34], 2018	Observational study (China)	78	8 miRNAs with ROC curve for 4 miRNAs (miR-126-5p, miR-17-5p, miR-142-3p, and miR-340-3p)	Plasma	At enrollment	Patients with UA and STEMI	Controls with a normal coronary artery	Diagnosis	MiR-126-5p, miR-142-3p, miR-17-5p, and miR-340-3p were upregulated in UA and STEMI compared with controls	In UA patients, only miR-142-3p achieved a high ability to distinguish from the normal coronary artery patients (AUC = 0.80). In STEMI patients, miR-17-5p and miR-142-3p both had good discriminative ability compared with normal coronary artery patients, with AUCs of 0.84 and 0.85, respectively
Coronary artery disease
Polyakova et al[35], 2021	Cross-sectional study (Russia)	100	3 miRNAs (miR-27a, miR-133a, and miR-203)	Serum and atrial myocardium	Before elective cardiac surgery after 12-hour fasting	CAD patients undergoing elective CABG	Patients without CAD undergoing isolated valve surgery	Diagnosis/disease severity	MiR-27a, miR-133a, and miR-203 were higher in CAD than in controls (in serum and atrial myocardium); serum miR-203 correlated with CAD extent and was highest in multivessel disease	Serum miR-203 correlated with SYNTAX score I (r = 0.693, P < 0.001); serum miR-203 > 101 relative expression units predicted multivessel disease (OR = 5.90, 95%CI: 2.34-9.46, P < 0.001)
Karakas et al[36], 2017	PCS (Germany)	1112	8 miRNAs (miR-19a, miR-19b, miR-132, miR-140-3p, miR-142-5p, miR-150, miR-186, and miR-210)	Serum	Baseline, before angiography	Patients with documented CAD (ACS and stable angina)	None	Prognosis	Higher circulating levels of most candidate miRNAs were associated with cardiovascular death, particularly in ACS patients	In ACS patients, miR-132: HR = 2.85 per 1-SD increase, P = 0.022, AUC = 0.737; miR-140-3p: HR = 2.88, P = 0.022, AUC = 0.756; miR-210: HR = 3.10, P = 0.039, AUC = 0.754
de Gonzalo-Calvo et al[37], 2019	PCS (Spain)	237	10 miRNAs (let-7 g-5p, miR-15b-5p, miR-21-5p, miR-24-3p, miR-29b-3p, miR-130a-3p, miR-143-3p, miR-146a-5p, miR-222-3p, and miR-663a)	Plasma	At nonurgent CCTA evaluation	Patients with suspected stable CAD	None	Diagnosis/disease severity	Lower circulating levels of several miRNAs were associated with greater coronary atherosclerosis extension and severity; miR-143-3p was inversely associated with segment involvement score, and let-7 g-5p, miR-15b-5p, miR-21-5p, miR-24-3p, miR-130a-3p, miR-143-3p, miR-146a-5p, and miR-222-3p were inversely associated with segment stenosis score	Circulating miRNAs had poor discriminative ability for CAD indexes (AUC = 0.539-0.644)
Wang et al[38], 2014	CCS (China)	181	5 miRNAs (miR-487a, miR-29b, miR-502, miR-208, and miR-215)	Serum	After 12-hour overnight fast	Patients with atypical coronary artery disease	Age-matched healthy controls	Diagnosis	Serum miR-487a, miR-502, miR-208, and miR-215 were increased, whereas miR-29b was decreased in atypical coronary artery disease patients compared with controls	The 5 miRNAs were able to distinguish CAD patients from the controls with high discriminative ability. AUC = 0.850 (95%CI: 0.734-0.966) in the training set and 0.909 (95%CI: 0.858-0.960) in the validation set
Wang et al[39], 2020	PCS (China)	2812	5 miRNAs screened; miR-423-3p showed the best predictive performance	Serum	Baseline	General population participants without pre-existing CVD	None	Prediction of primary CAD events	Higher circulating miR-423-3p levels were associated with a lower risk of incident CAD events during 6-year follow-up	MiR-423-3p tertile 2 vs tertile 1 HR = 0.48 (95%CI: 0.27-0.84); tertile 3 vs tertile 1 HR = 0.28 (95%CI: 0.14-0.57); AUC improved from 0.782-0.806 after adding miR-423-3p to traditional risk factors; net reclassification improvement 19.18%
Yuan et al[40], 2018	CCS (China)	120	1 miRNA (miR-18a)	Serum and circulating endothelial cells	At sample collection	Patients with CAD	Healthy controls	Diagnosis/mechanistic association	Levels of miR-18a were upregulated in female CAD patients than in the controls. No significant difference was observed in the levels among male CAD patients. Higher miR-18a was associated with lower HDL-C and estradiol and higher LDL-C, total cholesterol, and triglycerides	In female patients, miR-18a was overexpressed vs controls (P < 0.01); correlations: HDL-C r = -0.772, P < 0.001; LDL-C r = 0.570, P = 0.0075; estradiol r = -0.481, P = 0.001; total cholesterol r = 0.526, P = 0.003; triglycerides r = 0.513, P = 0.004
Opstad et al[41], 2017	Cross sectional observational (Norway)	200	1 miRNA (miR-21)	Plasma	At study entry in fasting state	Patients with stable CAD who smoke	Patients with stable CAD without a history of smoking	Association	Current smoking was associated with lower circulating miR-21 expression and lower IL-12p35 mRNA expression in stable CAD patients	Adjusted P < 0.05 for lower miR-21 expression in current smokers
Iusupova et al[42], 2024	Cross-sectional observational study (Russia)	157	3 miRNAs (miR-145, miR-34a, and miR-222)	Plasma	At study evaluation	Patients with CAD (obstructive or non-obstructive) presenting with complaints of chest pain and dyspnea	Healthy controls	Diagnosis	MiR-34a and miR-222 were significantly upregulated in CAD patients than in the healthy controls	MiR-145 was an independent predictor of ischemia/angina with non-obstructive coronary artery disease: OR = 2.512 (95%CI: 1.294-4.875, P = 0.006)
Stroke
Mayer et al[43], 2019	Prospective cohort study (Czech Republic)	826	5 miRNAs (miR-1, miR-19a, miR-126, miR-133a, and miR-223)	Plasma	Baseline visit, 6-36 months after qualifying vascular event	Patients with stable vascular disease (CAD or post-ischemic stroke)	None	Prognosis	Low expression of miR-1, miR-19a, miR-126, miR-133a, and miR-223 was associated with increased 5-year mortality; low miR-19a remained the strongest independent predictor, particularly in CAD patients	Low miR-19a: HR = 2.27 (95%CI: 1.59-3.23) for 5-year all-cause mortality; in CAD patients, HR = 3.00 (95%CI: 1.77-5.08)
Mick et al[44], 2017	PCS (United States)	2763	6 miRNAs (hsa-miR-877-5p, hsa-miR-124-3p, hsa-miR-320d, hsa-miR-656-3p, hsa-miR-3615, and hsa-miR-941)	Plasma	At exam 8 baseline	Patients with prevalent or incident stroke	None	Diagnosis/prediction	Prevalent stroke was associated with lower expression of hsa-miR-877-5p, hsa-miR-124-3p, and hsa-miR-320d. For incident stroke, hsa-miR-656-3p and hsa-miR-3615 were associated with reduced risk, whereas hsa-miR-941 was associated with increased risk	Prevalent stroke: MiR-877-5p OR = 0.10 (95%CI: 0.05-0.21), miR-124-3p OR = 0.14 (95%CI: 0.05-0.35), miR-320d OR = 0.14 (95%CI: 0.05-0.39); Incident stroke: MiR-656-3p HR = 0.26 (95%CI: 0.13-0.52), miR-3615 HR = 0.36 (95%CI: 0.21-0.62), miR-941 HR = 3.06 (95%CI: 1.65-5.67)
Hypertension
Yildirim et al[46], 2019	Cross sectional study (Turkey)	64	1 miRNA (miR-21)	Plasma	At study evaluation after 12-hour fasting	Patients diagnosed with stage 1 HTN	Healthy controls	Diagnosis/association with asymptomatic organ damage	Plasma miR-21 was increased in hypertensive patients and was higher in those with asymptomatic organ damage; miR-21 correlated positively with blood pressure, microalbuminuria, carotid intima-media thickness, and CRP	For asymptomatic organ damage: AUC = 0.898; sensitivity 81.3%; specificity 81.2%, cut-off 44.6 (P < 0.001)
Kara et al[47], 2021	CCS (Turkey)	82	2 miRNAs (miR-21, and miR-155)	Serum	8-12 hours (at study evaluation)	Patients with resistant hypertension or newly diagnosed hypertension	Healthy controls	Diagnosis/association with resistant hypertension	MiR-21 and aldosterone levels were significantly higher in resistant hypertension, whereas miR-155 did not differ between groups	MiR-21 predicted resistant hypertension at a cut-off of 9.6 copies/μL with 95% sensitivity and 71% specificity (AUC = 0.823, 95%CI: 0.72-0.92)
Cardiogenic shock
Jäntti et al[10], 2019	Prospective multinational observational study	179	1 miRNA (miR-423-5p)	Plasma	Baseline	Patients diagnosed with CS	None	Prognosis	Higher baseline miR-423-5p levels were associated with 90-day non-survival and with markers of hypoperfusion, including higher lactate and ALT and lower cardiac index and eGFR	MiR-423-5p above median independently predicted 90-day all-cause mortality: Adjusted HR = 1.9 (95%CI: 1.2-3.2), P = 0.01
Mäntylä et al[45], 2025	Prospective multicenter observational study	165	10 miRNAs studied; miR-20b-5p showed prognostic significance	Plasma	Baseline	Patients with cardiogenic shock	None	Prognosis	Higher baseline miR-20b-5p levels were associated with in-hospital and 90-day survival; patients with higher miR-20b-5p also had lower lactate, NT-proBNP, and growth differentiation factor-15	Highest quartile of miR-20b-5p independently predicted 90-day survival: Adjusted HR = 2.47 (95%CI: 1.16-5.28), P = 0.019

PCS: Prospective cohort study; miRNA: MicroRNA; ICM: Ischemic cardiomyopathy; HF: Heart failure; ACS: Acute coronary syndrome; CVD: Cardiovascular disease; NR: Not reported; ROC: Receiver operating characteristic; AUC: Area under the curve; STEMI: ST-segment elevation myocardial infarction; NSTEMI: Non-ST-segment elevation myocardial infarction; LVEDV: Left ventricular end-diastolic volume; LVESV: Left ventricular end-systolic volume; CCS: Case-control study; CAD: Coronary artery disease; MACE: Major adverse cardiovascular events; PCI: Percutaneous coronary intervention; LV: Left ventricle; BNP: B-type natriuretic peptide; LVEF: Left ventricular ejection fraction; UA: Unstable angina; HDL: High-density lipoprotein; CABG: Coronary artery bypass grafting; CCTA: Coronary computed tomography angiography; HDL-C: High density lipoprotein cholesterol; LDL-C: Low-density lipoprotein cholesterol; HTN: Hypertension; CRP: C-reactive protein; CS: Cardiogenic shock; ALT: Alanine aminotransferase; eGFR: Estimated glomerular filtration rate; ALVR: Adverse left ventricular remodeling.

Table 2 A Newcastle Ottawa scale summarizing the methodological quality of the included studies

Ref.	Selection	Comparability	Reporting	AHRQ standard
Klenke et al[15], 2018	3	2	3	Good
Shah et al[16], 2018	3	2	3	Good
Pilbrow et al[17], 2014	3	2	3	Good
Shen et al[18], 2021	3	2	3	Good
Biener et al[19], 2022	3	2	3	Good
Eyyupkoca et al[20], 2022	2	1	2	Fair
Cai et al[21], 2024	3	2	3	Good
Grabmaier et al[22], 2017	3	2	3	Good
Wang et al[23], 2011	3	2	3	Good
Devaux et al[24], 2015	3	2	3	Good
Jakob et al[25], 2017	3	2	3	Good
Matsumoto et al[26], 2013	3	2	3	Good
Cortez-Dias et al[27], 2016	2	2	3	Fair
He et al[28], 2014	3	2	3	Good
Bauters et al[29], 2013	3	2	3	Good
Hromádka et al[30], 2019	3	2	3	Good
Zeller et al[31], 2014	3	2	3	Good
Simionescu et al[32], 2016	3	2	3	Good
Wang et al[33], 2017	3	2	3	Good
Zhong et al[34], 2018	3	2	3	Good
Polyakova et al[35], 2021	3	2	3	Good
Karakas et al[36], 2017	3	2	3	Good
de Gonzalo-Calvo et al[37], 2019	3	2	3	Good
Wang et al[38], 2014	3	2	3	Good
Wang et al[39], 2020	3	2	3	Good
Yuan et al[40], 2018	3	2	3	Good
Opstad et al[41], 2017	3	2	3	Good
Iusupova et al[42], 2024	3	2	3	Good
Mayer et al[43], 2019	3	2	3	Good
Mick et al[44], 2017	3	2	3	Good
Mäntylä et al[45], 2025	3	2	3	Good
Yildirim et al[46], 2019	3	2	3	Good
Kara et al[47], 2021	3	2	3	Good
Jäntti et al[10], 2019	3	2	3	Good

AHRQ: Agency for Healthcare Research and Quality.