The Potential of Prognostic Biomarkers of Uric Acid Levels in Coronary Heart Disease Among Aged Population: A Scoping Systematic Review of the Latest Cohort Evidence

Figures & data

Figure 1 PRISMA flow diagram.

Note: Adapted from Liberati A, Altman D, Tetzlaff J, et al. The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration. Journal of Clinical Epidemiology. 2009;62(10)e1–e34¹⁹

Table 1 Characteristics of Study

Study	Country	Age (Mean)	Participant	Follow-Up (Years)	Critical Appraisal
(Sinan Deveci et al., 2010)^Citation40	Turkey	59.4 ± 10.24	1012 patients with symptoms of CAD	N/I	7/11
(Duran et al., 2012)^Citation30	Turkey	59 ± 12	520 patients with ACS	N/I	6/11
(Teng et al., 2012)^Citation32	Singapura	45 ± 74	52.322 CHD patients	8.1	10/11
(Eisen et al., 2013)^Citation34	Israel	45-74	3122 stabile CAD	8	11/11
(Lin et al., 2013)^Citation26	Taiwan	Male (M)= 64.8 Female (F)= 66.9	1054 Angiographic confirmed CAD patients with >50% stenosis	3.1	11/11
(Ndrepepa et al., 2013)^Citation22	Germany	M= mean: 65.6-67.1 F= mean: 69.8-74.3	13.273 CAD patients	N/I	7/11
(Li et al., 2013)^Citation21	Taiwan	BMI> 25 group 64.0 ± 10.3 (SUA< 6.6) 64.5 ± 10.9 (SUA≥ 6.6) MI< 25 group 66.5 ± 10.5 (SUA< 6.6) 67.6 ± 10.7 (SUA≥ 6.6)	1,202 Angiography-confirmed CAD patients	5.4	9/11
(Berezin & Kremzer, 2013)^Citation33	Ukraine	58.34 ± 9.60	126 asymptomatic CAD patients	N/I	6/11
(Calvo et al., 2014)^Citation38	USA	White: 64.6 Filipino: 59.3	202 white women and 166 postmenopausal Filipino women (N= 368)	4.6	10/11
(Yu et al., 2014)^Citation31	China	Low: 61.8 ± 11.6 Moderate: 64.6 ± 10.2 High: 64.6 ± 10.2	347 patients	1.10	9/11
(Liu et al., 2014)^Citation25	Taiwan	Gout group: 61.08 ± 13.69 Control group: 60.72 ± 12.90	444 patients with STEMI	49 ± 28 month	8/11
(Baumann et al., 2016)^Citation20	Germany	62.5 ± 13.4	803 STEMI patients undergoing primary PCI	N/I	8/11
(Ando et al., 2016)^Citation23	Japan	69.1 ± 10.9	385 patients undergoing PCI	N/I	8/11
(Kawabe et al., 2016)^Citation36	Japan	M= 64.5 ± 11.7 F= 72.1 ± 10.6	1380 patients with ACS	1.2 (437 days)	8/11
(Ranjith et al., 2017)^Citation35	South Africa	51.7 ± 11.5	2683 patients with AMI	N/I	7/11
(Larsen et al., 2018)^Citation29	Denmark	59.4	1039 patients with suspected or definite AMI		9/11
(Liu et al., 2017)^Citation24	Taiwan	57	951 STEMI patients undergoing PCI	N/I	6/11
(Lopez-Pineda et al., 2018)^Citation28	Spain	68 ± 13	1119 patients with ACS	3	10/11
(Gaubert et al., 2018)^Citation37	France	67.8 ± 9.4	80 patients with first episode of non-ST segment ACS	N/I	7/11
(Joo et al., 2018)^Citation27	Korea	Normal uric acid = 64.6 ± 9.9 High uric acid = 65.3 ± 10.3	317 restenotice patients undergoing repeated PCI	1088 days (3)	10/11
(Karabağ et al., 2019)^Citation39	Turkey	62.2 ± 10.96	331 patients with stable angina pectoris	505 ± 13 days	10/11

Table 2 Summary of Finding

Study	Measurement	Measurement Methods	Findings
(Sinan Deveci et al., 2010)^Citation40	The severity with clinical vessel score indicator	Angiography	Uric acid has a significant relationship with severity prognosis (p< 0.001). Improved severity prognosis associated with increased uric acid based on quartile increase in uric acid, p=0.015
(Duran et al., 2012)^Citation30	Coronary Collateral Vessel (CCV) with Rentrop classification	Angiography	The presence of CCV was associated with lower serum uric acid levels (p<0.001) CCV development was associated with lower uric acid levels (p= 0.003)
(Teng et al., 2012)^Citation32	Mortality	International Classification of Diseases (ICD)-10	Patients with gout have a higher risk of mortality from CHD than non-gout (HR 1.38, 95 CI 1.10-1.73)
(Eisen et al., 2013)^Citation34	Heart failure	New York Heart Association (NYHA) Classification	Uric acid levels are associated with heart failure with HR adjusted for age (HR 1.16; 95% CI 0.94-1.45) and (HR 1,28; 95% CI 1.04-1.59) in tertiles 2 and 3. Meanwhile, HR adjusted for several confounders (HR 1.18; 95% CI 0.95-1.47) dan (HR 1.25 95% CI 1.00-1.56) in tertile 2 and 3.
(Lin et al., 2013)^Citation26	Mortality	Death certificate	Elevated uric acid causes a 2.08-fold independent mortality risk mortality (HR 2.08; 95% CI 1.19-3.65; p= 0.01) viewed from the highest quartile.
(Ndrepepa et al., 2013)^Citation22	1-year mortality	Hospital records and death certificates	Uric acid is an independent predictor of 1-year mortality (HR 1.17; 95% CI 1.03-1.31; p= 0.012; male) dan (HR 1.25; 95% CI 1.06-1.48; p=0.007; Female)
(Li et al., 2013)^Citation21	Mortality	The death certificate and database	Independently, higher uric acid levels cause higher mortality in obese CHD patients (HR 1.79; 95% CI 1.14-2.82; P= 0.023), but obesity is not a predictor (HR 0.91; 95% CI 0.62-1.32)
(Berezin & Kremzer, 2013)^Citation33	Calcification with Agatston score index	Contrast-enhanced spiral Computed Tomography (CT) angiography	The uric acid level is an independent predictor of CHD (HR 1.12; 95% CI 1.01-1.52; p< 0.001)
(Calvo et al., 2014)^Citation38	Severity and progression Coronary Artery Calcium (CAC) with Agatston index score	Electron Beam Computed Tomography (EBCT)	Uric acid levels independently caused CAC severity in the Filipino group (OR 1.34; 95% CI 1.05-1.71) and not for the white group (OR 0.94; 95% CI 0.71-1.25) Uric acid levels independently led to CAC development in both groups (OR 1.26; 95% CI 1.02 – 1.56).
(Yu et al., 2014)^Citation31	Severity, Major Advance Cardiac Events (MACE), Mortality	Angiography and SYNergy between PCI with TAXUSTM and Cardiac Surgery (SYNTAX) score	Uric acid levels were independently correlated with high SYNTAX scores (B= 0.33, 95% CI 0.023-0.042, p<0.001). Comparison with normal uric acid levels, high uric acid levels tend to increase SYNTAX scores (p<0.0001) Uric acid levels are positively correlated with MACE (p<0.001) Kaplan-Meier analysis showed that event-free survival was higher in the high uric acid group (p< 0.001)
(Liu et al., 2014)^Citation25	Adverse non-fatal cardiac event (Unstable angina, symptomatic arrhythmias, repeated revascularization, recurrent infarction, rehospitalization due to heart failure)	Electrocardiography (ECG), cardiac enzyme checks, hospital documentation	Gout is independently associated with short and long term adverse non-fatal cardiac events (HR 1,88, 95% CI 1.09-3.24, p= 0.024; HR 1.82. 95% CI)
(Baumann et al., 2016)^Citation20	Major Adverse Cardiac Events (MACE)	Coronary angiography, echocardiography	Uric acid was not a significant predictor of MACE (AUC: 0.59; 95% CI 0.51-0.65; p= 0.83)
(Ando et al., 2016)^Citation23	Coronary plaque components	Integrated Backscatter Intravascular Ultrasound (IB-IVUS)	Uric acid levels were correlated with the percentage of lipid volume (r= 0.371, p < 0.001) and inversely with fiber volume (r = -0.347, p < 0.001). Uric acid levels were independently correlated with lipid-rich plaque (OR 2.43; 95% CI 1.75-3.47).
(Kawabe et al., 2016)^Citation36	Major Adverse Cardiac Events (MACE): mortality, heart failure, infarction, and stroke	Computed Tomography (CT)/Magnetic Resinance Imaging (MRI)	Uric acid level was an independent predictor of MACE in women (HR 2.84; 95% CI 1.19-6.77; p= 0.018), but not significant in men (HR 1.32; 95% CI 0.66-2.64; p= 0.422)
(Ranjith et al., 2017)^Citation35	Major Adverse Cardiac Events (MACE): heart failure, mortality, AF, complete heart block, cardiogenic shock, ventricular arrhythmias, recurrence of infarction and angina, and cerebrovascular events	N/I	Hyperuricemia significantly and independently caused mortality risk (OR 1.7; 95% CI 1.0-2.8; p= 0.042) High above-normal uric acid levels in tertiles correlated with a significant increase in MACE (p<0.001), especially for heart failure (p<0.001) and mortality (p=0.006).
Larsen et al., 2018)^Citation29	Severity of CAC	Non-contrast CT Scan	There is no relationship between uric acid and CAC severity.
(Liu et al., 2017)^Citation24	Death on Killip class	Records of patients who come to the ED	In Killip class I, hyperuricemia was associated with mortality at one year (HR 5.176; 95% CI 1.488-18007; p= 0.01) and for 30 days (HR 11.204; 95% CI 1.123-111.8; p= 0.047), but had no association. on Killip class II-IV
(Lopez-Pineda et al., 2018)^Citation28	Mid-term and long-term clinical outcomes and results after addition to the GRACE score	Cardiology notes, echocardiography	Independently, hyperuricemia was associated with cardiovascular death (HR 1.91; 95% CI 1.32-2.28; p < 0.01), all disease mortality (HR 1.59; 95% CI 1.18-2.15; p < 0.01), major cardiovascular events (HR 1.36; 95% CI 1.11-1.67; p<0.01). Addition of hyperuricemia to GRACE increased the risk of 38% of the total participants.
(Gaubert et al., 2018)^Citation37	Endothelial dysfunction with reactive hyperemia (RH) and severity of atherosclerosis	Non-invasive peripheral arterial tonometry (PAT) and angiography	The uric acid level had a significant relationship with Reactive Hyperemia Index/RHI (β= -0.17, p<0.001), and the uric acid level was associated with the Gensini score and SYNTAX score (p<0.001)
(Joo et al., 2018)^Citation27	Major adverse event (MAE): the cause of all mortality, non-fatal myocardial infarction, and revascularization.	Angiography	Uric acid was not an independent predictor of MAE (HR 1.110; 95% CI 0.980-1.257; p= 0.100)
(Karabağ et al., 2019)^Citation39	SYNTAX score II (SII) and long-term mortality	Angiography	Uric acid and SYNTAX independent predictors of long-term mortality (HR 1.24, 95% CI 1.046-1.482, p= 0.014; HR 1.042, 95% CI 1.007-1.079, p= 0.018)

Figure 2 Risk of bias.

Table 3 Cut off Uric Acid as a Predictor of Poor Prognosis

Study	Type of Prognosis	Value	Sensitivity	specificity
(Sinan Deveci et al., 2010)^Citation40	Clinical vessel score	6.86 mg/dl	-	-
(Duran et al., 2012)^Citation30	CCV	5.8 mg/dl	-	-
(Ndrepepa et al., 2013)^Citation22	Mortality	Male= 6.8 mg/dl female= 6.2 mg/dl	Male= 59% Female= 61%	Male= 59% female= 62%
(Berezin & Kremzer, 2013)^Citation33	Arterial calcification	35.9 mmol/dl	80.0%	59.2%
(Karabağ et al., 2019)^Citation39	SYNTAX score II (SSII)	>4.45	82%	35%

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