Elevated uric acid (UA) levels have been associated with cardiovascular disease in epidemiologic studies. The relation between UA levels and long-term outcomes in patients with ST-segment elevation myocardial infarction who undergo primary percutaneous coronary intervention is not known. Data from 2,249 consecutive patients with ST-segment elevation myocardial infarction who underwent primary percutaneous coronary intervention were evaluated. Patients were divided into 2 groups with high or low UA using upper limits of normal of 6 mg/dl for women and 7 mg/dl for men. There were 1,643 patients in the low-UA group (mean age 55.9 ± 11.6 years, 85% men) and 606 patients in the high-UA group (mean age 60.5 ± 12.6 years, 76% men). Serum UA levels were 8.0 ± 1.5 mg/dl in the high-UA group and 5.2 ± 1.0 mg/dl in the low-UA group (p <0.001). The in-hospital mortality rate was significantly higher in patients with high UA levels (9% vs 2%, p <0.001), as was the rate of adverse outcomes in patients with high UA. The mean follow-up time was 24.3 months. Cardiovascular mortality, reinfarction, target vessel revascularization, heart failure, and major adverse cardiac events were all significantly higher in the high-UA group. In a multivariate analyses, high plasma UA levels were an independent predictor of major adverse cardiac events in the hospital (odds ratio 2.03, 95% confidence interval 1.25 to 3.75, p = 0.006) and during long-term follow-up (odds ratio 1.64, 95% confidence interval 1.05 to 2.56, p = 0.03). In conclusion, high UA levels on admission are independently associated with in-hospital and long-term adverse outcomes in patients with ST-segment elevation myocardial infarction who undergo primary percutaneous coronary intervention.
Uric acid (UA) is the final oxidation product of purine metabolism in the circulation. UA is an independent risk factor for the development of coronary heart disease. Serum UA levels have been correlated with all major forms of death from cardiovascular disease, including acute, subacute, and chronic forms of coronary artery disease, heart failure, and stroke. Although there is an association between UA and cardiovascular disease, the underlying pathophysiology remains poorly understood.
Although the association of elevated UA levels with early adverse outcomes in acute myocardial infarction has been documented, the relation between UA levels and long-term outcomes in patients with ST-segment elevation myocardial infarction (STEMI) treated with primary percutaneous coronary intervention (PCI) has not been evaluated. It was hypothesized that elevated UA levels would be associated with in-hospital and long-term adverse outcomes after primary PCI for STEMI.
Methods
A total of 2,568 consecutive STEMI patients who underwent primary PCI from October 2003 to January 2009 were included in this study. Three hundred nineteen patients were excluded because of a lack of compliance with the defined inclusion criteria: PCI was not performed (n = 91), UA values were missing or unavailable (n = 142), or no follow-up was documented after primary PCI (n = 86). After these exclusions were accounted for, the final study population consisted of 2,249 patients. Patients were divided into normal and elevated groups on the basis of upper limits of normal for UA of 6 mg/dl in women and 7 mg/dl in men.
Cardiovascular risk factors were ascertained on the basis of review of medical records. Angina-to-reperfusion time and door-to-balloon time were also documented during each patient’s hospital stay. Electrocardiography was performed and complete blood counts and other serum values were determined on admission before catheterization procedures. Glomerular filtration rates were estimated using the simplified Modification of Diet in Renal Disease (MDRD) equation. Transthoracic echocardiography was performed using a System V machine (GE Vingmed Ultrasound AS, Horten, Norway) with a 2.5-MHz phased-array transducer. Recordings were taken with patients positioned in the left lateral decubitus position. The left ventricular ejection fraction was measured using modified Simpson’s rule.
All patients received chewable aspirin 300 mg (unless contraindicated) and a 300-mg loading dose of clopidogrel before they underwent coronary angiography. The infarct-related artery was then graded according to the Thrombolysis In Myocardial Infarction (TIMI) classification. Heparin (10,000 U) was administered once the coronary anatomy had been ascertained. Primary PCI was performed only in the infarct artery. Successful primary PCI was defined as a residual stenosis <50% and TIMI grade 3 flow after the procedure.
Follow-up data were obtained from hospital records or by interviewing (in person or by telephone) patients, family members, or primary care physicians. Cardiogenic shock was defined as marked and persistent (>30 minutes) hypotension with systolic arterial pressure <80 mm Hg and signs of hypoperfusion due to left ventricular dysfunction, right ventricular infarction, or mechanical complications. Patients were also evaluated according to Killip clinical examination classification. Advanced heart failure was defined as New York Heart Association functional classification ≥III. Multivessel disease was defined as stenosis >50% in >1 of the major coronary arteries. Acute stent thrombosis was defined as an abrupt onset of cardiac symptoms (i.e., acute coronary syndromes), elevations in biomarker levels, or electrocardiographic evidence of myocardial injury after stent deployment in the first 24 hours and angiographic evidence of a flow-limiting thrombus near a previously placed stent. Cardiovascular mortality was defined as unexplained sudden death, death due to acute myocardial infarction, heart failure, and/or arrhythmia. Reinfarction was defined as serum creatine kinase-MB enzyme levels twice the upper limit of normal and new ST-segment elevations. Major adverse cardiac events (MACEs) were defined as cardiovascular mortality, reinfarction, repeat target vessel revascularization (percutaneous or surgical), or acute stent thrombosis.
Quantitative variables are expressed as mean ± SD and qualitative variables as percentages. Comparison of the parametric values between the 2 groups (high and low blood levels of UA) was performed using 2-tailed Student’s t tests. Categorical variables were compared using likelihood ratio chi-square tests. Backward elimination multivariate logistic regression analysis including variables with p values <0.10 was performed to identify independent risk factors of MACEs during in-hospital and long-term follow-up. The cumulative survival curve for long-term cardiovascular mortality was constructed using the Kaplan-Meier method, with differences assessed with log-rank tests. A p value <0.05 was considered statistically significant. All statistical studies were carried out using SPSS version 15.0 (SPSS, Inc., Chicago, Illinois).
Results
There were 1,643 patients in the normal-UA group (mean age 55.9 ± 11.6 years, and 85% men) and 606 patients (mean age 60.5 ± 12.6 years, 76% men) in the elevated-UA group. Baseline characteristics are listed in Table 1 . Patients with elevated UA tended to be older and more commonly had histories of hypertension and diabetes and had elevated Killip classes. Smoking was more prevalent in patients with normal levels of UA ( Table 1 ).
| Variable | Low UA Level | High UA Level | p Value |
|---|---|---|---|
| (n = 1,643) | (n = 606) | ||
| Age (years) | 55.9 ± 11.6 | 60.5 ± 12.6 | <0.001 |
| Men | 1,393 (85%) | 460 (76%) | <0.001 |
| Anterior myocardial infarction | 754 (46%) | 327 (54%) | 0.001 |
| Hypertension | 585 (36%) | 308 (51%) | <0.001 |
| Hypercholesterolemia | 539 (33%) | 200 (33%) | 0.587 |
| Diabetes mellitus | 370 (23%) | 172 (28%) | 0.002 |
| Current smoker | 960 (58%) | 306 (51%) | <0.001 |
| Previous coronary bypass | 43 (3%) | 15 (3%) | 0.065 |
| Previous PCI | 134 (8%) | 54 (9%) | 0.655 |
| Previous myocardial infarction | 163 (10%) | 72 (12%) | 0.196 |
| Admission cardiogenic shock | 74 (5%) | 36 (6%) | 0.009 |
| Killip class >1 | 64 (4%) | 63 (10%) | <0.001 |
| Reperfusion time (hours) | 3.2 ± 2.3 | 3.4 ± 2.5 | 0.07 |
| Door-to-balloon time (minutes) | 34 ± 23 | 30 ± 21 | 0.56 |
Serum UA levels were 5.2 ± 1.0 mg/dl in the normal-UA group and 8.0 ± 1.5 in the high-UA group (p <0.001). Baseline serum creatinine was higher and glomerular filtration rates were lower in the elevated-UA group (p <0.001 for each; Table 2 ).
| Variable | Low UA Level | High UA Level | p Value |
|---|---|---|---|
| (n = 1,643) | (n = 606) | ||
| Creatinine concentration at admission (mg/dl) | 0.94 ± 0.35 | 1.2 ± 0.54 | <0.001 |
| Admission glomerular filtration rate (ml/min/1.73 m 2 ) | 91.9 ± 22.6 | 74.8 ± 23.3 | <0.001 |
| Hemoglobin (g/dl) | 13.7 ± 1.7 | 13.5 ± 1.9 | 0.03 |
| Peak creatine kinase-MB (U/L) | 210.2 ± 170.2 | 249.9 ± 207.6 | <0.001 |
| Total cholesterol (mg/dl) | 186.1 ± 43.8 | 191.2 ± 41 | 0.026 |
| Low-density lipoprotein (mg/dl) | 117.9 ± 36.8 | 119.2 ± 34.5 | 0.499 |
| High-density lipoprotein (mg/dl) | 40.4 ± 11.1 | 40.6 ± 12.4 | 0.737 |
| Triglycerides (mg/dl) | 140.9 ± 34.2 | 152.3 ± 41.6 | 0.035 |
| Admission blood glucose concentration (mg/dl) | 156 ± 74.8 | 158 ± 74.7 | 0.574 |
| UA (mg/dl) | 5.2 ± 1.0 | 8.0 ± 1.5 | <0.001 |
| Mean platelet volume (fl) | 8.4 ± 1.0 | 8.6 ± 1.0 | 0.001 |
The mean left ventricular ejection fraction on admission was lower in the high-UA group (p <0.001). There was no statistically significant difference in the number of diseased vessels across groups. The culprit lesion was more often observed in the left anterior coronary descending artery in patients with elevated UA ( Table 3 ). TIMI grade 3 flow was less frequently restored after primary PCI in patients with elevated UA. The percentage of stents deployed and stent diameters were similar between the groups (p = 0.154 and p = 0.570, respectively), but in the high-UA group, implanted stent length was significantly longer than in the low-UA group (p = 0.006). With respect to stent type, there was no statistically significant difference between groups (p = 0.358).
| Variable | Low UA Level | High UA Level | p Value |
|---|---|---|---|
| (n = 1,643) | (n = 606) | ||
| Culprit lesion | 0.016 | ||
| Left main | 2 (0.1%) | 1 (0.2%) | |
| Left anterior descending | 759 (46%) | 328 (54%) | |
| Circumflex | 226 (14%) | 60 (10%) | |
| Right | 644 (39%) | 215 (36%) | |
| Bypass graft | 10 (1%) | 2 (0.3%) | |
| Intermediate | 2 (0.1%) | 0 | |
| Number of narrowed coronary vessels | 0.135 | ||
| 1 | 693 (42%) | 226 (37%) | |
| 2 | 515 (31%) | 209 (35%) | |
| 3 | 433 (26%) | 171 (28%) | |
| Preprocedural TIMI grade | 0.045 | ||
| 0/1 | 1,429 (87%) | 541 (89%) | |
| 2 | 136 (8%) | 35 (6%) | |
| 3 | 78 (5%) | 30 (5%) | |
| Postprocedural TIMI grade | 0.004 | ||
| 0/1 | 140 (9%) | 8 (1%) | |
| 2 | 84 (5%) | 39 (6%) | |
| 3 | 1,419 (86%) | 487 (80%) | |
| Stenting | |||
| Stent use | 1,331 (81%) | 502 (83%) | 0.154 |
| Length (mm) | 18.9 ± 6.5 | 20.0 ± 7.0 | 0.006 |
| Diameter (mm) | 3.1 ± 0.4 | 3.1 ± 0.4 | 0.570 |
| Type | 0.358 | ||
| Bare metal | 1,304 (98%) | 487 (97%) | |
| Paclitaxel eluting | 13 (1%) | 7 (1%) | |
| Sirolimus eluting | 14 (1%) | 8 (2%) | |
| Proximal location of the lesion | 761 (46%) | 294 (49%) | 0.006 |
| Left ventricular ejection fraction (%) | 47.8 ± 10.3 | 45.4 ± 11.2 | <0.001 |
The in-hospital mortality rate was significantly higher in patients with elevated UA than in those with low UA (9% vs 2%, p <0.001), MACEs were more frequent (16% vs 7%, p <0.001), and the length of hospital stay was significantly longer (8.0 vs 6.9 days, p <0.001) ( Table 4 ).
| Variable | Low UA Level | High UA Level | p Value |
|---|---|---|---|
| (n = 1,643) | (n = 606) | ||
| In-hospital mortality | 39 (2%) | 52 (9%) | <0.001 |
| Reinfarction | 35 (2%) | 25 (4%) | 0.009 |
| Target vessel revascularization | 71 (4%) | 37 (6%) | 0.004 |
| Acute stent thrombosis | 15 (1%) | 9 (2%) | 0.241 |
| MACEs | 121 (7%) | 99 (16%) | <0.001 |
| Stroke | 8 (1%) | 7 (1%) | 0.004 |
| Serious ventricular arrhythmia | 61 (4%) | 47 (8%) | <0.001 |
| Cardiopulmonary resuscitation | 42 (3%) | 38 (6%) | <0.001 |
| Advanced heart failure | 93 (6%) | 76 (13%) | <0.001 |
| Intra-aortic balloon pump | 41 (3%) | 39 (6%) | <0.001 |
| Renal failure requiring dialysis | 1 (0.1%) | 12 (2%) | <0.001 |
| New atrial fibrillation | 21 (1%) | 11 (2%) | 0.017 |
| Complete atrioventricular block requiring transient pacemaker | 52 (3%) | 23 (4%) | 0.02 |
| Major bleeding requiring blood transfusion | 63 (4%) | 33 (6%) | 0.021 |
| Time of hospital stay (days) | 6.9 ± 4.4 | 8.0 ± 5.3 | <0.001 |
The mean follow-up time was 24.3 months. The Kaplan-Meier survival plot for cardiovascular death is presented in Figure 1 . Cardiovascular mortality (p <0.001), reinfarction (p = 0.004), target vessel revascularization (p <0.001), severe heart failure (p <0.001), and MACEs (p <0.001) were all higher in the elevated-UA group ( Table 5 ).
| Variable | Low UA Level | High UA Level | p Value |
|---|---|---|---|
| (n = 1,643) | (n = 606) | ||
| Cardiovascular mortality | 73 (4%) | 63 (10%) | <0.001 |
| Reinfarction | 151 (9%) | 81 (13%) | 0.004 |
| Target vessel revascularization | 286 (17%) | 185 (31%) | <0.001 |
| Advanced heart failure | 91 (6%) | 72 (12%) | <0.001 |
| MACEs | 424 (26%) | 251 (41%) | <0.001 |
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