Prognostic impact of uric acid in patients with stable coronary artery disease

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1 Prognostic impact of uric acid in patients with stable coronary artery disease Gjin Ndrepepa, Siegmund Braun, Martin Hadamitzky, Massimiliano Fusaro, Hans-Ullrich Haase, Kathrin A. Birkmeier, Albert Schomig, Adnan Kastrati Deutsches Herzzentrum München and 1. Medizinische Klinik, Klinikum rechts der ISAR, Techniche Universität München, Munich, Germany

2 ABSTRACT Background: The association between uric acid and cardiovascular disease is poorly studied. We undertook this study to assess whether uric acid level predicts clinical outcome in patients with stable coronary artery disease (CAD) treated with percutaneous coronary intervention (PCI). Methods: This study included 8149 patients with stable CAD who underwent PCI. Uric acid was measured in all patients before angiography. The primary end point was 1-year mortality. Results: Quartiles of quartiles of uric acid were: 1.49 to <5.49 mg/dl (1st quartile; n=2032 patients), 5.49 to <6.40 mg/dl (2nd quartile; n=1981 patients), 6.40 to <7.50 mg/dl (3rd quartile; n=2093 patients) and 7.50 to mg/dl (4th quartile; n=2043 patients). There were 196 deaths during the 1-year follow-up. The numbers of deaths (Kaplan-Meier estimates) according to uric acid quartiles were: 35 deaths (1.8%) in the 1st quartile, 30 deaths (1.6%) in the 2nd quartile, 45 deaths (2.2%) in the 3rd quartile and 86 deaths (4.3%) in the 4th quartile (unadjusted hazard ratio [HR]=1.60, 95% confidence interval [CI] , P for each standard deviation [SD] increase in the logarithmic scale). Calculated for 1 mg/dl increase in the uric acid level, the unadjusted HR was 1.31 [ ]; P, indicating a 31% increase in the unadjusted risk of 1-year mortality with each 1 mg/dl increase in the uric acid level. After adjustment for traditional cardiovascular risk factors, renal function and inflammatory status, the association between uric acid and 1-year mortality remained significant (adjusted HR=1.26, 95% CI ; P=0.005 for each standard deviation SD increase in the logarithmic scale). Calculated for 1 mg/dl increase in the uric acid level, the adjusted HR was 1.15 [ ]; P=0.001, demonstrating a 15% increase in the adjusted risk for 1-year mortality for every 1 mg/dl increase in the uric acid level. Uric acid improved predictivity of the multivariable model regarding mortality (P=0.040). Conclusions: In patients with stable CAD treated wth PCI, elevated uric acid level predicts the increased risk of death independently from cardiovascular risk factors, status of renal function or inflammatory burden. Thus uric acid, a readily available test, has the potential to risk stratify the large group of patients with stable CAD in terms of mortality prediction.

3 BACKGROUND The association between uric acid and cardiovascular disease remains debatable Prior studies have shown that elevated uric acid level predicts an increased risk of all-cause mortality in the general population as well as in patients with hypertension, congestive heart failure, myocardial infarction, angiographically confirmed CAD and diabetes Few studies have addressed the association of uric acid with prognosis of patients with stable CAD and their findings remain controversial OBJECTIVES OF THE STUDY To investigate whether uric acid level predicts clinical outcome in a large series of patients with stable CAD

4 Patients METHODS I Source sample comprised consecutive patients with coronary artery disease (CAD) treated with percutaneous coronary intervention (PCI) between March 2000 and December Patients a clinical diagnosis of stable angina pectoris and angiographic confirmation of significant CAD were eligible for the study (n=8149) Exclusions: Patients with renal disease (creatinine level 2 mg/dl; n=312) Acute infections (n=130) No uric acid value available (n=832) Acute coronary syndromes (n=5124) Known malignancies with life expectancy <1 year (n=166) Coronary stents were implanted in 7222 patients (89%) The study was carried out in accordance with the Declaration of Helsinki and was approved by the institutional ethics committee.

5 METHODS II Uric acid measurements Blood samples were obtained before angiography Blood was collected into tubes containing lithium-heparin as anticoagulant (S-Monovette 4.9ml, Sarstedt, Nümbrecht, Germany) and samples were immediately transported to the laboratory, centrifuged and analyzed (median turn-around-time minutes, 98% of results within 90 minutes) The uric acid in plasma was determined using an enzymatic colorimetric test on a Cobas Integra 800 analyzer (Roche Diagnostics, Mannheim, Germany) The measuring range in plasma is mg/dl ( μmol/l) The reference range for males: mg/dl ( μmol/l) and for females mg/dl ( μmol/l)

6 METHODS III Outcome measurements The primary outcome analysis: Secondary outcome analyses: All-cause 1-year mortality. Cardiac mortality Non-fatal myocardial infarction Stroke Target lesion revascularization Follow-up A telephone interview at one month after the procedure, a visit at six months and a telephone interview at 12 months

7 RESULTS I Patients: 8149 patients with stable CAD Uric acid quartiles: 1st quartile (1.49 to <5.49 mg/dl); n= nd quartile (5.49 to <6.40 mg/dl); n=1981 3rd quartile (6.40 to <7.50 mg/dl); n=2093 4th quartile (7.50 to mg/dl); n=2043

8 RESULTS II Main Baseline Characteristics Characteristic Age (years) Women Arterial hypertension Hypercholesterolemia Diabetes Body mass index (kg/m 2 ) Current smoker Prior myocardial infarction Prior coronary artery bypass surgery NYHA class Number of coronary artery narrowed Multivessel disease Left ventricular ejection fraction (%) Glomerular filtration rate (ml/min) C-reactive protein (mg/l) 1st (n = 2032) 66.9 [60.1; 73.5] 729 (35.9) 1499 (73.8) 1478 (72.7) 596 (29.3) 26.0 [23.7; 28.6] 264 (13.0) 644 (31.7) 303 (14.9) 1232 (60.6) 686 (33.8) 110 (5.4) 4 (0.2) 392 (19.3) 596 (29.3) 1044 (51.4) 1640 (80.7) 60.0 [52.0; 64.0] 82.5 [65.1; 103.7] 1.5 [0.7; 3.8] Quartiles of uric acid 2nd (n = 1981) 66.7 [60.0; 73.5] 387 (19.5) 1427 (72.0) 1509 (76.2) 516 (26.0) 26.8 [24.6; 29.3] 229 (11.6) 705 (35.6) 298 (15.0) 1135 (57.3) 728 (36.7) 117 (5.9) 1 ( (15.5) 534 (27.0) 1140 (57.5) 1674 (84.5) 59.0 [52.0; 64.0] 85.4 [68.1; 106.6] 1.6 [0.8; 3.8] 3rd (n = 2093) 66.8 [59.1; 73.8] 315 (15.1) 1520 (72.6) 1601 (76.5) 529 (25.3) 27.4 [25.1; 29.8] 242 (11.6) 803 (38.4) 353 (16.9) 1197 (57.2) 760 (36.3) 128 (6.1) 8 (0.4) 279 (13.3) 546 (26.1) 1268 (60.6) 1814 (86.7) 59.0 [50.0; 63.0] 82.8 [64.1; 104.3] 1.9 [0.9; 4.6] 4th (n = 2043) 68.1 [60.5; 75.0] 310 (15.2) 1512 (74.0) 1502 (73.5) 633 (31.0) 27.8 [25.5; 30.9] 274 (13.4) 767 (37.5) 369 (18.1) 1005 (49.2) 819 (40.1) 206 (10.1) 13 (0.6) 300 (14.7) 488 (23.9) 1255 (61.4) 1743 (85.3) 56.0 [45.0; 62.0] 72.7 [54.4; 96.4] 2.9 [1.2; 6.8] P value

9 RESULTS III Independent Correlates of Uric Acid Level Variable Beta coefficient* P value Age (years) Female sex Body mass index (kg/m 2 ) Diabetes Smoking NYHA class (1 to 4 classes) Multivessel disease Left ventricular ejection fraction (%) C-reactive protein (mg/dl) Glomerular filtration rate (ml/min) For continuous variables, beta coefficients are calculated for 1 unit increase in the independent variable scale Uric acid was entered after logarithmic transformation.

10 RESULTS IV Clinical outcome: Univariable Correlates of One-year Mortality Variable Unadjusted hazard ratio [95% confidence interval] P value Uric acid (for 1 SD increase in the logarithmic scale)* 1.60 [ ] Age (for 10-year increase) 2.05 [ ] Diabetes 1.86 [ ] Body-mass index (for 5 kg/m 2 increase) 0.77 [ ] Hypercholesterolemia 0.60 [ ] NYHA class (for 1 class increase) 2.71 [ ] Glomerular filtration rate (for 30 ml/min decrease) 2.63 [ ] Baseline C-reactive protein (for 5 mg/l increase) 1.09 [ ] Uric acid was entered into the model as continuous variable after logarithmic transformation

11 Clinical outcome: Independent Correlates of One-year Mortality (Cox proportional hazards model) RESULTS V Variable Adjusted hazard ratio [95% confidence interval] P value Uric acid (for 1 SD increase in the logarithmic scale) 1.24 [ ] Age (for 10-year increase) 1.41 [ ] Body mass index (for 5 kg/m 2 increase) 0.72 [ ] Diabetes 1.80 [ ] NYHA class (for 1 class increase) 2.00 [ ] Glomerular filtration rate (for 30 ml/min decrease) 1.78 [ ] C-reactive protein (for 5 mg/l increase) 1.06 [ ] Uric acid was entered into the model as continuous variable after logarithmic transformation

12 RESULTS VI Kaplan-Meier Curves of All-Cause Mortality According to Uric Acid Quartiles Probability of mortality (%) Log-rank test P 4th quartile 3rd quartile 2nd quartile 1st quartile Patients at risk Months 4th quartile rd quartile nd quartile st quartile

13 RESULTS VII Kaplan-Meier Estimates of 1-year Mortality in Combined 1st to 3rd Uric Acid Quartiles Versus 4th Uric Acid Quartile Probability of mortality (%) % P 4.3% Uric acid combined 1st-3rd quartiles Uric acid 4rth quartile

14 CONCLUSIONS 1. In patients with stable CAD, elevated uric acid level predicts the increased risk of death independently from cardiovascular risk factors, status of renal function or inflammatory burden 2. Uric acid, a readily available test, has the potential to risk-stratify the large group of patients with stable CAD in terms of mortality prediction