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(Circulation. 2002;106:974.)
© 2002 American Heart Association, Inc.

Clinical Investigation and Reports

Prognostic Implications of Abnormalities in Renal Function in Patients With Acute Coronary Syndromes

Jassim Al Suwaidi, MB, ChB; Donal N. Reddan, MB, MRCPI; Kathryn Williams, MS; Karen S. Pieper, MSc; Robert A. Harrington, MD; Robert M. Califf, MD; Christopher B. Granger, MD; E. Magnus Ohman, MD; David R. Holmes, Jr, MD, for the GUSTO-IIb, GUSTO-III, PURSUIT, and PARAGON-A Investigators

From the Mayo Clinic and Foundation (J.A.S., D.R.H.), Rochester, Minn, and Duke University Medical Center, Durham, NC.

Correspondence to David R. Holmes, Jr, MD, Cardiovascular Diseases and Internal Medicine, Mayo Clinic, 200 First St SW, Rochester, Minn 55905. E-mail holmes.david{at}mayo.edu

	Abstract

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Background— Outcomes in patients with mild to moderate renal function (RF) abnormalities presenting with acute coronary syndromes (ACS) are not well defined.

Methods and Results— A convenience sample of 4 ACS trial databases including all enrolled patients was assessed to determine 30- and 180-day outcomes. The 4 trials were Global Use of Strategies to Open Occluded Coronary Arteries (GUSTO) IIb, GUSTO-III, Platelet Glycoprotein IIb/IIIa in Unstable Angina: Receptor Suppression Using Integrilin Therapy (PURSUIT), and Platelet IIb/IIIa Antagonism for the Reduction of Acute coronary syndrome events in a Global Organization Network (PARAGON-A). Patients were stratified into ST-segment elevation (STE) and non–ST-segment elevation (NSE) groups and by the presence or absence of abnormal RF (creatinine clearance <70 mL/min). In the STE group, 7670 of 18 621 patients (41%) had abnormal RF. In the NSE group, 8152 of 19 304 (42%) had abnormal RF. Patients with abnormal RF were older, more often female, and more likely to have adverse baseline characteristics. They had higher mortality and higher mortality/nonfatal myocardial infarction (MI) at both 30 and 180 days, regardless of ST-segment status. Creatinine clearance was independently associated with risk of mortality (hazard ratio 0.79 in the STE group and 0.81 in the NSE group) and with risk of mortality/MI (hazard ratio 0.93) in the NSE group at 180 days.

Conclusions— Patients presenting with ACS frequently have abnormal RF. Abnormal RF is a marker of adverse baseline clinical characteristics and is independently associated with increased risk of death and death/MI.

Key Words: myocardial infarction • mortality • prognosis • coronary disease • kidney

	Introduction

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Cardiovascular disease is common in patients with chronic renal failure, particularly end-stage renal disease (ESRD). In 1997, 1-year mortality for patients with ESRD was 21.6%, and approximately half of the deaths were cardiac in origin; 35% of dialysis patients had congestive heart failure (CHF), 25% had coronary artery disease, and 9% had prior infarction (MI).¹ Patients with ESRD who suffer MI have a 59.3% mortality rate during the subsequent year.^2,3 Those who undergo percutaneous angioplasty may have more restenosis,⁴ and survival for patients undergoing coronary artery bypass surgery (CABG) is lower than those without ESRD.² The development of atherosclerotic cardiovascular disease probably begins during early renal insufficiency.⁵

There are few studies of patients with mild to moderate abnormalities of renal function (RF) who have coronary artery disease, although this population is quite large.^6,7 The third National Health And Nutrition Examination Survey (NHANES)⁶ found creatinine levels 1.5 mg/dL (132.6 µmol/L) in 9.74% of men and 1.78% of women. McCullough et al⁸ reported a graded association of renal function with mortality in 9500 patients admitted to a coronary care unit. To optimize the care of such patients, we must gain greater appreciation of their outcomes when they present with acute coronary syndromes (ACS).

We analyzed prospectively collected data from the following trials: Global Use of Strategies to Open Occluded Coronary Arteries (GUSTO) IIb, GUSTO-III, Platelet Glycoprotein IIb/IIIa in Unstable Angina: Receptor Suppression Using Integrilin Therapy (PURSUIT), and Platelet IIb/IIIa Antagonism for the Reduction of Acute coronary syndrome events in a Global Organization Network (PARAGON-A). The objectives were to compare baseline characteristics of patients with and without abnormal RF and to evaluate the association between baseline creatinine clearance (CrCl) and long-term outcome among these patients.

	Methods

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GUSTO-IIb, GUSTO-III, PURSUIT, and PARAGON-A were large, randomized controlled trials of patients with ACS treated with glycoprotein IIb/IIIa inhibitors and direct thrombin inhibitors.^9–12 The Institutional Review Boards at hospitals involved in each trial approved the protocols. Briefly, GUSTO-IIb investigators randomly assigned 12 142 patients with ACS to a minimum of 72 hours of heparin (5000-unit bolus followed by a continuous infusion of 1000 U/h) or hirudin (0.1 mg/kg bolus followed by 0.1 mg/kg per h) (desirudin, Ciba-Geigy).⁹ Entry criteria included chest pain compatible with myocardial ischemia within 12 hours associated with either transient or persistent ST-segment elevation (STE), ST-segment depression >0.5 mm, or persistent T-wave inversion >1 mm. Patients with left bundle-branch block and typical symptoms were eligible. Patients were prospectively stratified into 2 groups: STE (4131 patients) and non–ST-segment elevation (NSE) (8011 patients). STE patients not eligible for accelerated tissue plasminogen activator or streptokinase were excluded.

In GUSTO-III,¹⁰ 15 059 patients who presented within 6 hours of onset of symptoms with STE or bundle-branch block were randomly assigned in a 2:1 ratio to receive reteplase (Boehringer Mannheim) in 2-bolus doses of 10 MU each 30 minutes apart or alteplase (Genentech and Boehringer Ingelheim) in an accelerated infusion of up to 100 mg over 90 minutes.

PURSUIT investigators evaluated 10 948 patients with NSE ACS.¹¹ Eligible patients who had ischemic chest pain within 24 hours and met prespecified electrocardiographic or cardiac enzyme requirements were randomly assigned in a double-blind manner to receive a bolus and infusion of either eptifibatide (Cor Therapeutics) or placebo, in addition to standard therapy, for up to 72 hours (up to 96 hours if coronary intervention was performed near the end of the 72-hour period).

PARAGON-A investigators enrolled 2282 patients with chest discomfort within the previous 12 hours associated with transient or persistent ST-segment depression (0.5 mm) or T-wave inversion or transient (30 minutes) STE (0.5 mm).¹² These patients were randomly assigned in a 3x2 factorial design to lamifiban (Hoffmann-La Roche) (low-dose [1 µg/min] with or without heparin, high-dose [5 µg/min] with or without heparin) or to standard therapy (placebo with or without heparin).

For our analysis, 1019 patients were excluded because CrCl concentrations were unavailable (GUSTO-IIb NSE [n=216], GUSTO-IIb STE [n=105], GUSTO-III [n=464], PURSUIT [n=194], PARAGON-A [n=40]). Thirty-one patients with CrCl >150 mL/min or creatinine <0.4 mg/dL were also excluded (GUSTO-IIb NSE [n=5], GUSTO-IIb STE [n=1], GUSTO-III [n=13], PURSUIT [n=9], PARAGON-A [n=3]). In PURSUIT, 1487 patients who received low-dose eptifibatide were excluded from the primary analysis (and from this analysis), because it was prespecified in the protocol to stop the lower-dose group after the higher dose demonstrated acceptable safety. Thus, we excluded a total of 2537 patients of the original 40 431 (6%).

Case report forms captured demographic and clinical characteristics at enrollment and during hospitalization. Data on patients who were transferred from one hospital to another were collected from the second hospital. Deaths and repeat MI follow-up data were ascertained from patients’ families, through telephone contact, or via registered mail; 30-day follow-up was available in all studies. Follow-up information at 6 months was obtained in GUSTO-IIb, PURSUIT, and PARAGON-A and 1-year data in GUSTO-III and PARAGON-A.

Determination of Renal Function
Baseline creatinine data were collected for patients enrolled in all 4 trials. Per protocol, patients with creatinine >2 mg/dL (177 µmol/L) were excluded from GUSTO-IIb, PURSUIT, and PARAGON-A.^9,11,12 Renal insufficiency was not an exclusion criterion in GUSTO-III.¹⁰

We assessed renal function using both serum creatinine and CrCl (mL/min). The latter was calculated using the Cockroft and Gault formula: CrCl=(140-age)xweight (kg)/(serum creatininex72[x0.85 for women]).¹³ A new dichotomous variable was defined for the presence and absence of abnormal RF, before the data analysis, using the arbitrary cutoff of 70 mL/min as the lower limit for normal RF.

Outcomes
The primary outcomes of our study were all-cause 30- and 180-day mortality. Death and reinfarction at 30 and 180 days were secondary end points. The reinfarction status at 30 days was based on a clinical events committee’s review in GUSTO-IIb, PURSUIT, and PARAGON-A; other end points were defined by the investigators. For GUSTO-III, reinfarctions were reported only in-hospital; thus, death/MI at follow-up could not be included for GUSTO-III.

Statistical Methods
The binary variable, abnormal RF, was used for illustrative purposes. No statistical tests were calculated with this variable. Instead, a continuous measure of CrCl was used in all formal outcome tests. Baseline characteristics were described by abnormal RF within each study. Continuous baseline variables were shown as medians with 25th and 75th percentiles and categorical variables as counts and frequencies. With the continuous measure of CrCl, Wilcoxon rank-sum tests were used for discrete variables and Spearman correlation tests for continuous variables. Unadjusted outcome rates were also described using Kaplan-Meier rates for those with and without abnormal RF and for tertiles of the continuous CrCl measures.

Cox proportional hazards modeling was used to evaluate the prognostic effect of CrCl at 30 and 180 days. HRs for an incremental increase in CrCl of 10 mL/min with 95% confidence intervals (CIs) were used to describe the association of CrCl with outcomes. One assumption made using a Cox proportional hazards model is that the log of the hazard ratio [HR] changes in a linear fashion with increasing values of continuous predictors. CrCl was found to be nonlinear. The risk of having an event decreased as CrCl increased up to 90 mL/min. Beyond 90 mL/min, the decrease in risk was much less. Therefore, a linear spline was used for this factor with a knot at 90 mL/min.

Models have been developed and validated for death and death/MI in both the STE^14,15 and NSE populations.¹⁶ The association of CrCl with outcomes was evaluated univariably after adjusting for previously determined baseline covariates. The STE models were applied to GUSTO-IIb STE and GUSTO-III patients. The NSE models were applied to the GUSTO-IIb NSE, PURSUIT, and PARAGON-A patients. History of CHF and concomitant medications at baseline were considered and exist in the models if they remained statistically significant. Left ventricular function or coronary anatomy was not considered.

Because CrCl was defined using age, weight, and sex, we recognized that adding CrCl to a model containing these factors might result in a problem of multicollinearity. We generated models of (1) baseline factors only, (2) baseline factors excluding age, sex, and weight but including CrCl, and (3) baseline factors plus CrCl. We compared the coefficients and Wald ² of (1) with (2) and (2) with (3) to help eliminate the problem of multicollinearity.

For this analysis, a convenience sample of available databases was used. This was not a meta-analysis in that all available trials of ACS were not included. Nevertheless, we used meta-analytical methods to estimate the weighted mean HRs for outcomes of the STE and NSE groups. This methodology used an empirical Bayes estimator in a random effects model. The variation between studies was included in the computation of the total uncertainty used to compute weights for each estimate.^17–19

	Results

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In the STE group, 10 951 patients (59%) had normal RF and 7670 (41%) had renal insufficiency. In the NSE group, 11 152 patients (58%) had normal RF and 8152 (42%) had renal insufficiency.

Baseline Characteristics
In each trial, patients with renal insufficiency (CrCl <70 mL/min) were older, more often female, and more likely to have adverse baseline characteristics, regardless of STE status (Table 1). They were less likely to be smokers. Table 2 describes procedures within 7 days of randomization by renal function. Patients with impaired renal function underwent fewer procedures in all 4 trials.

View this table: [in this window] [in a new window]   Table 1. Baseline Characteristics of the Study Groups

View this table: [in this window] [in a new window]   Table 2. Procedures Within 7 Days of Randomization by Abnormal and Normal Renal Function*

Baseline systolic blood pressures were significantly higher in patients with RF abnormalities for the NSE study groups. Baseline heart rate was significantly higher in patients with abnormal RF in PURSUIT and the GUSTO-IIb NSE group (Table 1).

Outcomes at 30 and 180 Days
Patients with abnormal RF had higher mortality and combined mortality/MI at 30 days regardless of ST-segment status. The 180-day death and death/MI outcomes were inversely related to tertiles of CrCl; as CrCl increased, death and death/MI decreased in each trial (Tables 3 and 4). HRs for 180-day unadjusted combined death/MI are displayed in Figure 1. Figure 2 demonstrates an adjusted mortality curve for a representative STE (GUSTO-III) trial.

View this table: [in this window] [in a new window]   Table 3. All-Cause Mortality at 180 Days

View larger version (13K): [in this window] [in a new window]   Figure 1. HRs for 180-day unadjusted mortality in the 3 NSE trials and both STE trials.

View larger version (14K): [in this window] [in a new window]   Figure 2. Adjusted survival curve for patients with normal and abnormal renal function in GUSTO-III, a trial of patients with STE.

View this table: [in this window] [in a new window]   Table 4. Combined All-Cause Mortality and Reinfarction at 180 Days*

Adjusted Clinical Events
After adjusting for baseline differences in comorbidities and case-mix variables, CrCl remained independently associated with increased all-cause mortality at 30 and 180 days in all trials except PARAGON-A (30 days, HR 1.01 [95% CI, 0.98 to 1.03]; 180 days, HR 0.98 [95% CI, 0.93 to 1.03]). Similarly, CrCl remained independently associated with increased risk of combined all-cause mortality/MI in all trials except PARAGON-A at 180 days (HR 1.0 [95% CI, 0.99 to 1.01]) and PURSUIT (HR 0.96 [95% CI, 0.92 to 1.01]) and the GUSTO-IIb NSE group at 30 days (0.98 [95% CI, 0.91 to 1.05]) (Tables 3 and 4). Table 5 describes the relative contribution of various variables, including CrCl, to the GUSTO-III 30-day death model; this model was used to generate the adjusted survival curve in Figure 2.

View this table: [in this window] [in a new window]   Table 5. GUSTO-III 30-Day Death Model

Results Across Studies
The significant prognostic effect of CrCl persisted after analysis of the STE and NSE groups for all 4 trials combined. Stratification by STE and NSE status did not significantly affect this prognostic effect in combined all-cause mortality at 30 days (HR 0.80 [95% CI, 0.76 to 0.85]; HR 0.88 [95% CI, 0.83 to 0.95], respectively) and 180 days (HR 0.79 [95% CI, 0.76 to 0.82]; HR 0.81 [95% CI, 0.70 to 0.92], respectively). CrCl was also an independent predictor of combined death/MI at 180 days in the NSE group (HR 0.93 [95% CI, 0.90 to 0.96]) (Table 6).

View this table: [in this window] [in a new window]   Table 6. Adjusted Outcomes for Each 10-mL/min Increment in Creatinine Clearance*

	Discussion

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Our study demonstrates that a significant proportion of patients who present with ACS have abnormal RF. Compared with patients with normal RF, those with abnormal RF also have more adverse baseline clinical characteristics. Most importantly, abnormal RF is an independent predictor of adverse outcome.

Recent observations in a coronary care unit population^6,20 and from the Heart Outcomes Prevention Evaluation study (HOPE)²¹ have highlighted the increased risk of adverse outcomes in patients with chronic kidney disease not yet receiving renal replacement therapy. However, most studies of renal insufficiency and coronary artery disease have focused on patients on long-term dialysis.^{2–4,22–27} Herzog et al³ observed a dismal prognosis for patients with ESRD on long-term dialysis after MI; only 41% survived for 1 year and 27% for 2 years. Poor survival remained an issue when only patients treated in the reperfusion era were considered. Despite significant improvements in the management of patients with ACS with thrombolytic agents, glycoprotein IIb/IIIa inhibitors, and mechanical reperfusion therapy,^28–30 the benefits are unclear in patients with ESRD, who are typically excluded from clinical trials.

Data on the effect of mild renal insufficiency in patients with coronary artery disease are limited.^31–33 Zanardo et al³¹ reported higher morbidity and mortality rates after cardiac operations in patients with preexisting renal dysfunction (serum creatinine 1.5 mg/dL). Rao et al³² studied 38 patients with mild renal dysfunction (serum creatinine >1.7 mg/dL) not requiring dialysis who underwent CABG surgery. Although there was no significant difference in overall mortality, these patients had higher perioperative morbidity. A recent retrospective study of 3954 patients undergoing CABG surgery demonstrated mild renal insufficiency (serum creatinine 1.5 to 3.0 mg/dL) to be independently associated with higher 30-day mortality, postoperative bleeding, and ventilatory complications.³³ Complication rates were comparable to patients with severe renal insufficiency (serum creatinine >3.0 mg/dL). In the ESRD population, percutaneous revascularization may be associated with a high rate of restenosis.^24,25

Previous investigators have identified chronic RF as an important predictor of morbidity and mortality after MI.³ Our results extend the documented association with adverse outcome to include patients with ACS who may not necessarily have had MI. Our study also demonstrates adverse baseline characteristics, including older age, diabetes, hypertension, and history of CHF in patients with mild to moderate renal insufficiency undergoing cardiac operations.^31–33 In addition, our study illustrates that each 10 mL/min decrement in CrCl is independently associated with increased risk of death and MI.

The increased risk of coronary atherosclerosis and cardiac events in renal impairment may be explained by biological mechanisms linked to the development of clinical arteriosclerosis in prospective studies of populations free of renal disease,^34–37 including fibrinogen,³⁸ homocystine,³⁷ increased lipoprotein (a),³⁷ elevated intermediate-density lipoprotein lipase cholesterol, lower high-density lipoprotein cholesterol, increased oxidized low-density lipoprotein,^39–41 increased inflammatory mediators such as C-reactive protein, and hypoalbuminemia.^42,43 Finally, left ventricular hypertrophy is highly prevalent in patients starting renal replacement therapy.⁶ Treatment strategies directed at these risk factors might reduce this risk.

The influence of chronic kidney disease on outcomes could also be explained by the increase in comorbidity and mortality rates conferred by the development of acute renal failure in the postprocedural period, the potential toxicity of drugs that are renally cleared, and the inherent therapeutic nihilism associated with the management of patients with renal disease.⁶

Clinical Implications
Our data support future research to achieve a better understanding of the mechanisms of adverse cardiovascular outcomes and provide additional therapeutic options to reduce this risk.

Limitations
There were extensive differences in baseline clinical characteristics between the study groups; although these were adjusted for in the statistical models, some adverse outcomes in patients with renal function abnormalities may be secondary to these baseline characteristics. The consistency of our findings, however, adds to the credibility of our conclusions.

These data are presented as a convenience sample of 4 clinical trials. Although we used meta-analytical techniques, this is not a meta-analysis.

CrCl is a powerful predictor of adverse outcomes after both percutaneous coronary intervention^43,44 and CABG.^33,45 Because CrCl may influence the choice of an interventional procedure, however, we considered procedures in these studies as outcomes rather than as baseline covariates, and consequently we did not undertake analyses considering interactions of procedures with CrCl with respect to outcomes. Our analysis therefore did not address the issue of procedural-renal interactions.

The analysis also has several sources of potential bias. First, 3 of the 4 studies (GUSTO IIb, PURSUIT, and PARAGON-A) excluded patients with creatinine >2 mg/dL (177 µmol/L), and all 4 studies excluded patients with ESRD. This exclusion may have reduced the magnitude of observed risk associated with the presence of renal impairment. Second, CrCl measurements were based on baseline serum creatinine measurements that may not have been stable. Transient renal impairment secondary to hypoperfusion on study entry may be more representative of cardiovascular risk than a risk attributable solely to renal insufficiency.

Conclusions
Mild to moderate renal abnormality independently predicts death and myocardial infarction in patients with ACS at 30-day and 6-month follow-up. Our data support the development of more aggressive strategies for preventing and treating ACS in patients with renal insufficiency.

Received April 9, 2002; revision received June 5, 2002; accepted June 7, 2002.

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