|Year : 2022 | Volume
| Issue : 2 | Page : 74-79
The association of serum uric acid and 1-year major adverse cardiovascular events in patients undergoing percutaneous coronary intervention
Anjum Naim, Ashish Jha, Amresh Kumar Singh, Bhuwan Chandra Tiwari, Sudarshan K Vijay, Naveen Jamwal
Department of Cardiology, Dr. RMLIMS, Lucknow, Uttar Pradesh, India
|Date of Submission||26-Feb-2022|
|Date of Decision||02-Mar-2022|
|Date of Acceptance||22-Apr-2022|
|Date of Web Publication||12-Aug-2022|
Dr. Bhuwan Chandra Tiwari
Department of Cardiology, Dr. RMLIMS, Vibhuti Khand, Gomti Nagar, Lucknow - 226 010, Uttar Pradesh
Source of Support: None, Conflict of Interest: None
Context: Elevated uric acid (UA) is seen in several vascular diseases. Its significance as a prognostic marker in patients undergoing percutaneous coronary intervention (PCI) is unknown.
Aims: The aim of this study was to evaluate the association between elevated UA and major adverse cardiovascular events (MACE) at 1 year in patients undergoing PCI.
Settings and Design: This was a prospective, observational, single-center study.
Subjects and Methods: Patients undergoing PCI were categorized into hyperuricemic (HU, UA >6.0 mg/dl in women and >7.0 mg/dl in men) and normouricemic (NU) groups and were observed for 1 year. The endpoint was difference in MACE (composite of deaths, nonfatal myocardial infarction, stroke, and target vessel revascularization) at 1 year between the two groups. The secondary endpoints were the difference in Killip class at presentation, angiographic severity of coronary artery disease (CAD), cardiac arrhythmias, and congestive heart failure (CHF) between the two groups.
Results: A total of 215 patients (107 in HU arm and 108 in NU arm) were recruited. Patients in the HU arm were older, had higher frequency of multivessel CAD (93.5% vs. 79.6%, P < 0.05) and complex coronary lesions (98.1% vs. 91.7%, P < 0.05). MACE at 1 year were more frequent in the HU arm compared to the NU arm (21.5% vs. 6.5%, P < 0.05). New-onset atrial fibrillation (AF) (11.2% vs. 3.7%, P < 0.05) and CHF (13.1% vs. 4.6%, P < 0.05) were also more frequent in the HU arm versus the NU arm.
Conclusions: Elevated serum UA level in patients undergoing PCI was associated with angiographically more severe and multivessel CAD, a higher frequency of MACE, CHF, new-onset AF, and a higher mortality than those having normal UA levels.
Keywords: Angiographic severity of coronary artery disease, congestive heart failure, hyperuricemia, major adverse cardiovascular events, new-onset atrial fibrillation
|How to cite this article:|
Naim A, Jha A, Singh AK, Tiwari BC, Vijay SK, Jamwal N. The association of serum uric acid and 1-year major adverse cardiovascular events in patients undergoing percutaneous coronary intervention. Heart India 2022;10:74-9
|How to cite this URL:|
Naim A, Jha A, Singh AK, Tiwari BC, Vijay SK, Jamwal N. The association of serum uric acid and 1-year major adverse cardiovascular events in patients undergoing percutaneous coronary intervention. Heart India [serial online] 2022 [cited 2022 Sep 29];10:74-9. Available from: https://www.heartindia.net/text.asp?2022/10/2/74/353729
| Introduction|| |
Coronary artery disease (CAD) is the leading cause of death and disability globally. There are several traditional and novel risk factors and risk markers for CAD. Elevated uric acid (UA) is a marker, which has been observed to be associated with several vascular diseases such as hypertension (HT), CAD, cerebrovascular disease, vascular dementia, preeclampsia, and chronic kidney disease., Production of reactive oxygen species during the synthesis of UA by xanthine oxidase pathway has been shown to damage cell membrane and exert pro-inflammatory effects on vasculature leading to endothelial dysfunction and decreased nitric oxide production., Elevated serum UA levels have been shown to be associated with worse outcomes in patients with HT and various presentations of CAD.,,
However, there is an insufficient information on prognostic value of UA levels in patients undergoing percutaneous coronary intervention (PCI). The present study was undertaken to evaluate the association between serum UA level and the risk of major adverse cardiovascular events (MACE) at 1 year in CAD patients undergoing PCI.
| Subjects and methods|| |
This was a prospective study, done at a tertiary care, teaching hospital in North India. The study was approved by the institutional ethics committee. Written informed consent was obtained from the study participants. Follow-up was done for all patients upto 1 year from PCI.
Inclusion and exclusion criteria
Patients undergoing PCI for stable CAD or acute coronary syndrome (ACS), who were older than 18 years, were eligible to participate in the study, provided they consented for participation and follow-up for 1 year.
The study excluded patients in whom coronary angiography (CAG) revealed normal coronary arteries or noncritical CAD. Patients who had a history of previous coronary revascularization (PCI or coronary artery bypass surgery) and those who were deemed unsuitable for PCI due to their coronary anatomy were also excluded from the study. Other exclusion criteria included pregnancy, active systemic inflammatory disorder or infection, end-stage renal disease or postkidney transplant, and heavy alcohol intake (defined as >15 drinks per week for men and >8 drinks per week for women; one standard drink equal to 14 g of pure alcohol).
The primary objective of the study was to determine the association between serum UA level and 1-year MACE (a composite of cardiovascular death, nonfatal myocardial infarction [MI], target vessel revascularization [TVR], and stroke). The secondary objectives were to study the association between serum UA and Killip class at presentation in ACS patients; the relationship between serum UA levels and angiographic severity of CAD; the association of serum UA and new-onset cardiac arrhythmia (atrial fibrillation [AF], supraventricular tachycardia, ventricular tachycardia [VT], and complete heart block requiring temporary pacing); and the association of serum UA and congestive heart failure (CHF).
Sample size calculation
Sample size calculation was done based on the observed MACE rates in CAD patients in relation to the serum UA using a study by Bae et al. (7.2% in NU group and 20.1% in HU group) as the reference. Assuming an alpha error of 0.05 and beta of 0.2 and power of 80%, the sample size was calculated to be 110 in each group. Post hoc analysis revealed the power of the study to be 89.2%.
A detailed assessment of history and physical examination was done on each patient. Killip class was noted in patients presenting with the diagnosis of ACS. Blood investigations included complete blood counts, kidney function tests, liver function tests, Random Blood Sugar (RBS), prothrombin time/international normalized ratio, viral markers, troponin I, and serum UA. Estimated glomerular filtration rate was calculated using the MDRD equation. The serum UA measurement was done by Uricase-Trinder method using Beckman Coulter AU480 chemistry analyzer. Two-dimensional transthoracic echocardiography was performed using Philips IE33 machine, and left ventricular ejection fraction (LVEF) was measured using modified Simpson's method.
All patients underwent CAG within 72 h of admission, using the radial route as the preferred approach. The coronary flow was graded according to the thrombolysis in MI (TIMI) classification. PCI was performed, after written informed consent, as per the standard clinical practice guidelines. Standard guideline-directed medical therapy was prescribed in study subjects.
Hyperuricemia (HU) was defined by serum UA >6.0 mg/dl in women and >7.0 mg/dl in men. Patients were categorized into HU and normouricemia (NU) groups. Their baseline characteristics were compared, and they were followed for a period of 1 year from the time of inclusion for the occurrence of MACE. MI was defined as per the fourth universal definition of MI.
Clinical follow-up was done on an outpatient basis at 3, 6, and 12 months. Patients with new or worsening symptoms, or any MACE, underwent clinical and laboratory evaluation, with inpatient evaluation as indicated. Mortality data were obtained from the hospital records or by telephonic inquiry/information from the family members or close relatives.
| Results|| |
Over the period of 1 year, 215 CAD patients undergoing PCI were included in the study. Out of these, 107 (49.8%) patients had HU and 108 (50.2%) patients had NU.
The baseline characteristics of the study participants are shown in [Table 1]. Patients in the HU group were older in comparison to the NU group. Patients with age ≥75 years were more frequent in the HU group as compared to the NU group (P < 0.05). Males outnumbered females in both groups but proportion of females was significantly greater in HU group (P<0.05).
HT was significantly more prevalent in the HU group than the NU group (52.3% [n = 56] vs. 35.2% [n = 38] [P < 0.05]). Distribution of other risk factors was similar between the two groups [Table 1]. Patients with ACS outnumbered stable CAD in both the arms. Although the proportion of stable CAD was numerically higher in the NU arm than the HU arm, the difference was not statistically significant. Killip class ≥II was significantly more common in the HU-ACS patients as compared to NU-ACS (42.1% vs. 22.4% [P < 0.05]). Patients in the HU group had a lower LVEF on transthoracic echo as compared to the NU group (46% vs. 50%, P < 0.001). UA level (mg/dL) was 7.5 (7.1–7.9) and 6.0 (5.2–6.4) in the HU and NU groups, respectively [Table 1].
CAG revealed a higher proportion of single-vessel disease in the NU group and multivessel disease in the HU group [Table 2]. Triple-vessel CAD was seen in 57% of patients in the HU arm versus 32.4% in the NU arm (P < 0.001). Coronary artery lesions were more severe in the HU group, with 98.1% of patients having Type B1 or more severe lesions as compared to 91.7% in the NU group (P < 0.05). Preprocedure and postprocedure TIMI flow and the number of stents implanted were similar between the two groups [Table 2].
The primary endpoint (MACE at 1 year) occurred significantly more frequently in the HU group as compared to the NU group (21.5% vs. 6.5%, P < 0.05) [Table 3]. This observed difference was predominantly because of a higher frequency of deaths and nonfatal MI in the HU group than the NU group [Figure 1] and [Table 3].
|Figure 1: MACE at 1 year in HU and NU groups. MACE: Major adverse cardiac events, HU: Hyperuricemic group, NU: Normouricemic group, MI: Myocardial infarction, TVR: Target vessel revascularization|
Click here to view
The potential predictors for MACE were identified on univariate analysis, and multivariate logistic regression analysis was performed for the primary endpoint [Table 4], which showed that HU was an independent predictor of 1-year MACE (adjusting for age, gender, HT, diabetes mellitus, hypercholesterolemia, smoking, prior MI, CHF, and number of diseased vessels) with an adjusted (odds ratio [OR] = 2.93, 95% confidence interval [CI] = 1.07–7.99 [P < 0.05]). Besides HU, age (adjusted OR = 1.08, 95% CI = 1.03–1.13, P < 0.05), diabetes mellitus (adjusted OR = 3.56, 95% CI = 1.36–9.33), and CHF (adjusted OR = 4.35, 95% CI = 1.37–13.85, P < 0.05) was also independent predictors of the MACE at 1 year [Table 4] and [Figure 2].
|Table 4: Multivariate analysis of predictors for 1-year major adverse cardiac event|
Click here to view
|Figure 2: Multivariate predictors of a year MACE. MACE: Major adverse cardiac events, CHF: Congestive heart failure, MI: Myocardial infarction|
Click here to view
The frequency of TVR and stroke was similar between the two groups. Arrhythmias were more frequent in the HU group than the NU group, predominantly due to more frequent AF in the HU group [Table 3]. CHF during follow-up occurred more frequently in the HU group as compared to the NU arm (13.1% vs. 4.6%, P < 0.05) [Table 3].
| Discussion|| |
The present study included 215 CAD patients undergoing PCI. The mean age was 57.9 ± 10.4 years, and the majority of the patients (81.5%) were aged 45–75 years. Patients with HU were older than NU patients (mean age of 60.8 ± 9.4 years vs. 55.0 ± 10.6 years [P < 0.001]). Overall, 80% of the patients were male and 20% were female. Patients with HU had a higher proportion of females than the NU patients (26.2% vs. 13.9%, P < 0.05). Similar to the present study, a study by Spoon et al., involving 1916 patients undergoing coronary angioplasty, reported a higher mean age and a greater proportion of females among HU as compared to NU patients (45% vs. 18%, P < 0.001). Yu et al., in a similar study on 1005 AMI patients, reported a higher proportion of patients aged ≥75 years in HU as compared to the NU group (24.8 vs. 14.2, P < 0.001).
In the index study, HT was more frequent in the HU group than the NU group (52.3% vs. 35.2%, P < 0.05). Other major CAD risk factors, including diabetes mellitus, hypercholesterolemia, smoking, obesity, history of prior MI, and family history of CAD, were similarly distributed between the two groups. The study by Kaya et al., involving 2249 ST-elevation myocardial infarction (STEMI) patients undergoing coronary angioplasty, similarly reported a higher prevalence of HT (51% vs. 36%, P < 0.001) in HU patients as compared to NU. There were no differences in the other major CV risk factors, except for smoking which was more commonly seen in the NU group.
Among the 143 ACS patients in the present study, the HU group had a higher frequency of Killip ≥II than the NU group (42.1% vs. 22.4%, P < 0.05). A study by Timóteo et al., involving 683 ACS patients, similarly reported a significantly higher percentage of Killip class ≥II in the HU group than in the NU group (33.5% vs. 15.1%, P < 0.001).
In the present study, multivessel CAD was more frequently seen in the HU group than NU (P < 0.05), mainly due to more frequent triple vessel disease in them (P < 0.001). Worst coronary lesion Type ≥ B1 was more prevalent in the HU than the NU patients (P < 0.05). No differences were observed in the preprocedural TIMI flow grades. A study by Yu et al., involving 347 CAD patients undergoing PCI, similarly reported a greater percentage of multivessel CAD in association with HU patients than NU (88.5% vs. 72.5%, P < 0.001). In a study by Spoon et al., no differences were reported in the preprocedural TIMI flow grades based on the levels of UA.
The present study showed that HU patients had a more frequent new-onset AF than the NU patients (11.2% vs. 3.7% [P < 0.05]). In a study by Karataş et al. of 621 STEMI patients undergoing primary PCI, serum UA was reported as a significant predictor of new-onset AF post PCI (adjusted OR = 1.29 [1.02–1.62], P < 0.05). Kaya et al. also reported a more frequent new-onset AF in patients with HU than with NU (2% vs. 1%, P < 0.05), however, VT was the most common arrhythmia in their study.
In the present study, patients with HU had significantly worse LV function than patients NU (P < 0.001) (median interquartile range LVEF (%): 45 [40–50] vs. 50 [45–55]). CHF during follow-up was also more frequent among HU patients than NU (14.1% vs. 4.6% [P < 0.05]). Kaya et al. also reported more frequent CHF in the HU than NU patients (12% vs. 6%, P < 0.001).
In the present study, there was a significantly higher occurrence of the primary outcome, i.e., composite MACE at 1 year, in the patients with HU as compared to NU (21.5% vs. 6.5% [P < 0.05]), as a result of the significantly higher rates of death and nonfatal MI (11.2% vs. 2.8% and 8.4% vs. 1.9%, respectively [P < 0.05]). Multivariate analysis revealed that UA was a strong independent predictor of 1-year MACE (OR: 3.24; P = 0.032). Age, diabetes, and CHF were also significant predictors of 1-year MACE. TVR and stroke both occurred with a similar frequency of 0.9% in both the groups. The result of the present study is similar to a study by Kaya et al., who reported a strong association of HU with composite MACE (41% vs. 26% in patients with HU vs. NU, P < 0.001). They also reported a significantly higher cardiovascular mortality and nonfatal MI in the HU group than the NU group (10% vs. 4%, P < 0.001). Tscharre et al. also reported a strong association between HU and the composite MACE in their study (HR = 1.750 [1.388–2.207], P < 0.001).
A few limitations of the present study need mentioning. Index study was done in the times of COVID pandemic, which limited the number of patients who could be enrolled in the study. It was a single-center, hospital-based study; thus, the results may not be generalizable to other populations. Measurement of UA was done only once at the time of inclusion into the study; thus, the cumulative duration of exposure to elevated UA level is unknown. UA level can be altered by a number of comorbid conditions, medications, and dietary factors. Thus, it could have been difficult to rule out all confounding factors in the study. Despite these limitations, the study clearly showed an association of UA levels with MACE in patients undergoing PCI.
| Conclusions|| |
This prospective, observational study evaluated the utility of serum UA as a prognostic marker in patients undergoing PCI. Overall, the patients with HU were older than NU. Patients in the HU arm had a worse Killip class at presentation and had a higher frequency of multivessel CAD and more complex coronary lesions than the NU arm. The primary composite endpoint of MACE at 1 year was more frequent in patients with HU. New-onset AF and CHF were also more frequent in HU patients. Larger studies with serial measurement of UA and assessment for effect of UA lowering medications on MACE in patients undergoing PCI may provide us further insights into this relationship.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
All procedures followed were in accordance with the ethical standards of institutional ethics committee and with the Helsinki Declaration of 1964 and later versions. Informed consent was obtained from all patients participating in the study.
All authors have contributed significantly to the planning, execution and publication of this study and guarantee the authenticity of the manuscript.
| References|| |
Cannon PJ, Stason WB, Demartini FE, Sommers SC, Laragh JH. Hyperuricemia in primary and renal hypertension. N Engl J Med 1966;275:457-64.
Tuttle KR, Short RA, Johnson RJ. Sex differences in uric acid and risk factors for coronary artery disease. Am J Cardiol 2001;87:1411-4.
Erdogan D, Gullu H, Caliskan M, Yildirim I, Ulus T, Bilgi M, et al
. Coronary flow reserve and coronary microvascular functions are strongly related to serum uric acid concentrations in healthy adults. Coron Artery Dis 2006;17:7-14.
Kaya EB, Yorgun H, Canpolat U, Hazırolan T, Sunman H, Ülgen A, et al
. Serum uric acid levels predict the severity and morphology of coronary atherosclerosis detected by multidetector computed tomography. Atherosclerosis 2010;213:178-83.
Bickel C, Rupprecht HJ, Blankenberg S, Rippin G, Hafner G, Daunhauer A, et al
. Serum uric acid as an independent predictor of mortality in patients with angiographically proven coronary artery disease. Am J Cardiol 2002;89:12-7.
Kojima S, Sakamoto T, Ishihara M, Kimura K, Miyazaki S, Yamagishi M, et al
. Prognostic usefulness of serum uric acid after acute myocardial infarction (the Japanese Acute Coronary Syndrome Study). Am J Cardiol 2005;96:489-95.
Lazzeri C, Valente S, Chiostri M, Picariello C, Gensini GF. Uric acid in the early risk stratification of ST-elevation myocardial infarction. Intern Emerg Med 2012;7:33-9.
Bae JH, Hyun DW, Kwon TG, Yoon HJ, Lerman A, Rihal CS. Serum uric acid is associated with cardiovascular events in patients with coronary artery disease. Korean Circ J 2007;37:161-6.
Feig DI, Kang DH, Johnson RJ. Uric acid and cardiovascular risk. N Engl J Med 2008;359:1811-21.
Thygesen K, Alpert JS, Jaffe AS, Chaitman BR, Bax JJ, Morrow DA, et al
. Fourth universal definition of myocardial infarction (2018). Circulation 2018;138:e618-51.
Spoon DB, Lerman A, Rule AD, Prasad A, Lennon RJ, Holmes DR, et al
. The association of serum uric acid levels with outcomes following percutaneous coronary intervention. J Interv Cardiol 2010;23:277-83.
Yu J, Han J, Mao J, Guo L, Gao W. Association between serum uric acid level and the severity of coronary artery disease in patients with obstructive coronary artery disease. Chin Med J (Engl) 2014;127:1039-45.
Timóteo AT, Lousinha A, Labandeiro J, Miranda F, Papoila AL, Oliveira JA, et al
. Serum uric acid: A forgotten prognostic marker in acute coronary syndromes? Eur Heart J Acute Cardiovasc Care 2013;2:44-52.
Karataş MB, Çanga Y, İpek G, Özcan KS, Güngör B, Durmuş G, et al
. Association of admission serum laboratory parameters with new-onset atrial fibrillation after a primary percutaneous coronary intervention. Coron Artery Dis 2016;27:128-34.
Tscharre M, Herman R, Rohla M, Hauser C, Farhan S, Freynhofer MK, et al
. Uric acid is associated with long-term adverse cardiovascular outcomes in patients with acute coronary syndrome undergoing percutaneous coronary intervention. Atherosclerosis 2018;270:173-9.
[Figure 1], [Figure 2]
[Table 1], [Table 2], [Table 3], [Table 4]