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J Am Coll Cardiol, 2003; 41:718-724, doi:10.1016/S0735-1097(02)02956-X
© 2003 by the American College of Cardiology Foundation
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CLINICAL STUDY: ACUTE CORONARY SYNDROME

Influence of concurrent renal dysfunction on outcomes of patients with acute coronary syndromes and implications of the use of glycoprotein IIb/IIIa inhibitors

Rosario V. Freeman, MD, MS*,*, Rajendra H. Mehta, MD, MS, FACC{dagger}, Wisam Al Badr, MD{dagger}, Jeanna V. Cooper, MS{dagger}, Eva Kline-Rogers, RN, MS{dagger} and Kim A. Eagle, MD, FACC{dagger}

* Division of Cardiology, University of Washington, Seattle, Washington, USA
{dagger} Division of Cardiology, University of Michigan, Ann Arbor, Michigan, USA

Manuscript received March 27, 2002; revised manuscript received August 14, 2002, accepted August 29, 2002.

* Reprint requests and correspondence: Dr. Rosario V. Freeman, University of Washington, Division of Cardiology, 1959 NE Pacific Street, Box 356422, Seattle, Washington 98195-6171, USA
rosariof{at}u.washington.edu


   Abstract
Top
 Abstract
Methods
 Results
 Discussion
 References
 
OBJECTIVES: The purpose of this study was to examine the in-hospital outcome and influence of glycoprotein (GP) IIb/IIIa antagonists on patients with acute coronary syndromes (ACS) across a range of renal function.

BACKGROUND: Recent studies demonstrate increasing cardiovascular risk with progressive renal dysfunction. Previous studies investigating GP IIb/IIIa antagonist use have excluded patients with renal dysfunction.

METHODS: Patients presenting with ACS between January 1999 and May 2000 were identified, and data on demographics, in-hospital management, and clinical events were collected using standardized definitions. Patients were stratified according to renal function assessed by calculated creatinine clearance (CrCl) at presentation. Primary outcome measures included in-hospital mortality and major bleeding events.

RESULTS: Renal insufficiency was present in 312 of 889 patients. There were 40 in-hospital deaths. In non-dialysis-dependent patients, as CrCl worsened, there was a decline in utilization of routine diagnostics and therapeutics, an increase in in-hospital mortality (p = 0.002), and an increase in major bleeding (p = 0.03). Although the use of GP IIb/IIIa antagonists was associated with an increase in major bleeding (p < 0.001), there was a protective effect on in-hospital mortality (p = 0.04) after controlling for CrCl.

CONCLUSIONS: Renal dysfunction is present in a substantial proportion of patients with ACS and is associated with increased in-hospital death. Although GP IIb/IIIa antagonist use in patients with ACS and renal insufficiency resulted in increased bleeding events, its administration was associated with a decreased risk of in-hospital mortality. These preliminary findings need to be confirmed in future randomized clinical trials.

Abbreviations and Acronyms
  ACC/AHA
  American College of Cardiology/American Heart Association
  ACS
  acute coronary syndrome
  CI
  confidence interval
  CrCl
  creatinine clearance
  GP
  glycoprotein
  MI
  myocardial infarction
  OR
  odds ratio
  PCI
  percutaneous coronary intervention

Cardiovascular disease represents the most important cause of death among patients with end-stage renal disease (1). Recent studies on patients with lesser degrees of renal dysfunction have also demonstrated increased cardiovascular risk (2–9), with predictive indices from large acute myocardial infarction (MI) registries showing renal insufficiency to be a risk factor for adverse outcome in patients admitted for acute MI (10). Despite this increased risk, clinical trials examining cardiovascular morbidity and mortality associated with renal dysfunction excluded patients with more severe degrees of renal dysfunction (11–13). Moreover, these studies preceded the era of recent therapeutic advances in the management of patients with acute coronary syndromes (ACS), including newer antithrombotic agents such as glycoprotein (GP) IIb/IIIa receptor antagonists, which have been shown to improve clinical outcome for the general population (14,15). Previous clinical trials investigating GP IIb/IIIa receptor antagonists have excluded patients with renal dysfunction or failure (16,17). Therefore, it is not clear if this patient subgroup derives the same therapeutic benefit from GP IIb/IIIa receptor antagonists as patients with normal renal function. Accordingly, we sought to examine the impact of the range of renal dysfunction on cardiovascular outcomes for all patients presenting with an ACS and determine the safety and efficacy of GP IIb/IIIa receptor antagonist use on the clinical outcomes of ACS patients with impaired renal function.


   Methods
Top
 Abstract
 Methods
Results
 Discussion
 References
 
Study population.   Patients with an ACS enrolled in the database of the Michigan Cardiovascular Outcomes Research and Reporting Program (MCORRP) between January 1999 and May 2000 were included in this study. The objective of this program is to collect clinical information for various cardiovascular diseases, utilize this information to estimate risk-adjusted outcomes, and provide confidential feedback to physicians regarding their individual performance measures. This is done with an ultimate goal of improving outcomes of all patients with cardiovascular disease admitted to the University of Michigan Medical Center with ACS. Patients were identified prospectively, whereas data on more than 30 variables including patient demographics, history, in-hospital management, and clinical events were collected retrospectively using standardized data definitions. Entry criteria for the database included patients over the age of 18 years and a presenting event not precipitated or accompanied by a significant comorbidity. Additionally, patients fulfilled criteria for unstable angina or acute MI utilizing the American College of Cardiology/American Heart Association (ACC/AHA) criteria for data definition (18). Following institutional review, informed consent was waived, as there were no experimental interventions and patient confidentiality was guaranteed by the study protocol. In order to guarantee rigorous data quality, each submitted data record was reviewed for completeness and face validity. All in-hospital deaths were directly audited.

Definitions.   Standard ACC/AHA criteria were utilized for data definition (18). Baseline creatinine clearance (CrCl) was calculated for all patients according to the Cockcroft-Gault formula (19): CrCl = [140 – age] · weight (kg)/[serum creatinine (mg/dl) · 72].

Female gender adjustment was calculated by multiplying the result by 0.85. Renal insufficiency was defined as a calculated CrCl <60 cc/min at the time of presentation, according to guidelines established by the National Kidney Foundation (20). Creatinine clearance was used to categorize patients into five strata: 1) ≥90 cc/min; 2) 60 to 89 cc/min; 3) 30 to 59 cc/min; 4) <30 cc/min, but not dialysis requiring; and 5) dialysis requiring. Major bleeding events were defined according to criteria developed by the Global Use of Strategies To Open occluded arteries (GUSTO) study group and included intracranial bleeding, substantial hemodynamic compromise requiring treatment, or need for blood transfusion (21). Death from any cause was recorded as an in-hospital mortality.

Statistical analysis.   Continuous data are expressed as mean ± SD and categorical data as frequencies and percentages. Student t test was used to compare continuous variables and chi-squared analysis was used to compare categorical and dichotomous variables. Odds ratios (ORs) are given with 95% confidence intervals (CIs) and p values. P values <0.05 were considered significant. Tests for associative trends with increasing severity of renal insufficiency were performed using the Mantel-Haenszel chi-squared test. Predictors for in-hospital mortality were identified using univariate analysis. In addition, variables previously reported as risk factors for 30-day mortality after acute MI based on prior studies were identified (10). A multivariate logistic regression prediction model was developed utilizing both the variables found to show marginal association in univariate analysis (p < 0.20) and groups of previously known predictor variables. Interactions were checked for in the final model and none were found. The predictive accuracy of the multivariate logistic regression model was assessed by using the area under the receiver operating characteristic curve analysis (22). Statistical analysis was performed using SAS software version 8.2 (SAS Institute, Cary, North Carolina).


   Results
Top
 Abstract
 Methods
 Results
Discussion
 References
 
Demographics and missing data.   A total of 925 patients were admitted with a diagnosis of an ACS. Data on patient weight, necessary for calculation of CrCl, were missing on 36 patients, leaving 889 patients for the analysis. Of the 36 patients with missing weight data, there were 3 in-hospital deaths; 2 of the 3 patients who died in this group had a serum creatinine >1.5 mg/dl (2.1 and 2.8 mg/dl). Of the 889 patients with complete data, 178 patients suffered a Q-wave MI, 293 patients had a non–Q-wave MI, and those remaining had unstable angina. Renal insufficiency was present in 310 of 889 patients (34.9%). Patients with renal insufficiency were older, with a greater prevalence of hypertension, congestive heart failure, previous MI, peripheral vascular disease, and lower left ventricular ejection fractions compared with those without renal insufficiency (Table 1).


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  		Table 1 Baseline Demographics

 
Outcomes in patients with renal insufficiency.   Overall, there were 40 in-hospital deaths, predominantly due to arrhythmic causes (n = 21) and cardiogenic shock (n = 13) (Fig. 1). Patients with renal insufficiency tended to have a longer hospital length of stay, with a higher incidence of non–Q-wave MI, and were less likely to receive percutaneous coronary intervention (PCI). In-hospital mortality was significantly higher in patients with renal insufficiency compared to those without (8.1% vs. 2.6%, p < 0.001) (Table 2). Utilization of both diagnostic coronary angiography (p < 0.001, chi-square = 25.0) and PCI (p < 0.001, chi-square = 24.5) decreased significantly with worsening CrCl stratum, with the exception of the group of patients that were dialysis requiring. Utilization of coronary artery bypass grafting surgery was unchanged across CrCl stratum (p = 0.94, chi-square = 0.01) (Fig. 2).



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  		Figure 1 In-hospital deaths (n = 40 patients).

 

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  		Table 2 In-Hospital Outcomes

 


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  		Figure 2 Utilization of cardiovascular diagnostic tests and therapeutics across creatinine clearance stratum. Numbers at the top of each bar are the total number of patients within each creatinine clearance stratum, and the percentages represented by each bar are the respective portion of that total number. Black bars = catheterization; white bars = glycoprotein IIb/IIIa antagonist; hatched bars = percutaneous coronary intervention; striped bars = coronary artery bypass graft surgery.

 
Multivariate predictors and model.   Multivariate predictors of in-hospital mortality are presented in Table 3. Beside other predictors, worsening creatinine clearance stratum was an important predictor of in-hospital mortality (adjusted OR = 1.74, 95% CI 1.23 to 2.46, p = 0.002). The adjusted OR associated with CrCl stratum did not change when controlling for coronary revascularization procedures, including percutaneous intervention and coronary artery bypass surgery. There was an increase in in-hospital mortality after adjustment for the other covariates in the model (Fig. 3). The predictive accuracy of the model was adequate with an area under the receiver operating characteristic curve of 0.86 ± 0.03.


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  		Table 3 Multivariate Logistic Regression Model

 


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  		Figure 3 Unadjusted and adjusted odds ratios for mortality stratified by creatinine clearance. Black bars = unadjusted; hatched bars = adjusted.

 
GP IIb/IIIa receptor antagonists.   There were 312 of 889 patients (35.1%) that received GP IIb/IIIa receptor antagonists. The use of GP IIb/IIIa receptor antagonists decreased from 39.3% usage in stratum 1 (≥90 cc/min) to 12.7% in stratum 4 (<30 cc/min) (p < 0.001, chi-square = 13.8) (Fig. 2). There was an increase in use of GP IIb/IIIa receptor antagonists if patients required dialysis. Adjusting for the use of GP IIb/IIIa receptor antagonists in the multivariate logistic regression model did not significantly change the increased risk of in-hospital mortality associated with worsening CrCl stratum: with GP IIb/IIIa receptor antagonist use added as a covariate in the model (adjusted OR = 1.67, 95% CI 1.18 to 2.37, p = 0.004), and without GP IIb/IIIa receptor antagonist use as a covariate in the model (adjusted OR = 1.74, 95% CI 1.23 to 2.46, p = 0.002). Moreover, when controlling for CrCl stratum and other covariates, there was a significant protective effect on in-hospital mortality associated with the use of GP IIb/IIIa receptor antagonists compared to not (adjusted OR = 0.34, 95% CI 0.12 to 0.98, p = 0.04).

Bleeding events.   With worsening CrCl stratum in non-dialysis-requiring patients, there was an increase in major bleeding events (p = 0.03, chi-square = 4.6) (Fig. 4). When controlling for CrCl stratum, there was a twofold increase in the odds of a major bleeding event with use of GP IIb/IIIa receptor antagonists compared to not (adjusted OR = 2.13, 95% CI 1.39 to 3.27, p < 0.001).



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  		Figure 4 Absolute major bleeding event rate and creatinine clearance stratum. The lighter portion of each bar represents the relative proportion that received glycoprotein IIb/IIIa antagonists during hospitalization. Numbers at the top of each bar are the total number of patients within each creatinine clearance stratum, and the percentages represented by each bar are the respective portion of that total number. Hatched bars = did not receive glycoprotein IIb/IIIa antagonists; black bars = received glycoprotein IIb/IIIa antagonists.

 

   Discussion
Top
 Abstract
 Methods
 Results
 Discussion
References
 
This study demonstrates that varying degrees of renal dysfunction are not uncommon among patients presenting with ACS, and shows that patients with renal dysfunction have a greater in-hospital mortality risk approaching that observed in patients with end-stage renal disease (1). Importantly, this relationship is linear and inverse such that in-hospital mortality increases as CrCl worsens. The increased mortality risk seen in patients with renal insufficiency persists after adjustment for baseline differences in clinical characteristics, suggesting that associated comorbid conditions explain only a part of the mortality risk with renal insufficiency and that it is a strong independent predictor of adverse in-hospital events.

ACS and renal dysfunction.   Our data corroborate the findings of other previous investigations. In 3,837 post-MI patients from the Beta-blocker Heart Attack Trial (BHAT), patients with a serum creatinine >1.0 mg/dl had an increase in overall mortality (8). In a post-hoc analysis of 417 MI survivors from the Program on Surgical Control of Hyperlipidemias (POSCH) trial, each with 0.1 mg/dl increment in the baseline serum creatinine, the relative risk for overall mortality increased by 36% and the relative risk for atherosclerotic heart disease mortality increased by 47% (11). A recent single-center study of 1,724 patients with ST-segment elevation MI over an eight-year period demonstrated an early mortality hazard for patients with renal dysfunction not requiring dialysis compared with patients having normal renal function, with graded increases in mortality seen as renal function declined (7). In a substudy of the Heart Outcomes Prevention Evaluation (HOPE) trial, patients with a serum creatinine between 1.4 and 2.3 mg/dl were divided into quartiles of serum creatinine concentration. There was an incremental increase in the combined primary end point of cardiac mortality, acute MI, or stroke compared with patients having a serum creatinine <1.4 mg/dl. Patients with serum creatinine >2.3 mg/dl were excluded from entry into the HOPE trial (12).

Evidence from major risk prediction indices in acute MI mortality has also suggested the importance of renal insufficiency. Clinical surrogates for renal dysfunction have been previously identified in selected patients enrolled in large acute MI registries as a risk factor for adverse outcome. In a recent meta-analysis of acute MI mortality in patients over 65 years of age, Krumholz et al. (10) presented a risk model from 82,359 patients to predict 30-day mortality. Seven predictor variables were identified: 1) older age, 2) cardiac arrest, 3) anterior or lateral location of MI, 4) systolic blood pressure, 5) white blood cell count, 6) congestive heart failure, and 7) serum creatinine. Of these variables, serum creatinine (adjusted OR 2.06, 95% CI 1.98 to 2.14) was second only to presentation in cardiac arrest for the prediction of 30-day mortality. In the same paper, six other mortality risk prediction models were reviewed. A prior history of chronic renal failure, blood urea nitrogen level, or serum creatinine was included as a predictor in five of the six models (10). Our study differs from these other investigations in several aspects. Although most of these investigations were based on data from randomized clinical trials with obligatory patient exclusion criteria, the present study utilized data from consecutive patients and looked specifically at the influence of renal insufficiency in ACS.

Utilization of routine diagnostics and therapeutics in ACS.   Utilization of both diagnostic coronary angiography and PCI decreased significantly as renal function declined. Other studies have demonstrated similar findings (7), and are not surprising given that complications from these procedures are increased in the presence of renal dysfunction. Coronary angiography and percutaneous revascularization in the setting of renal dysfunction is a predictor for developing worsening nephropathy or need for dialysis support post-angiography and carries significantly increased in-hospital mortality risk (23–28). Despite this, there is a paucity of other therapeutic options for coronary revascularization; therefore, PCI may provide an advantageous risk-to-benefit ratio in patients with concurrent renal dysfunction despite patient comorbidities. Surgical revascularization has been associated with an increased risk for mortality over percutaneous revascularization in patients with renal dysfunction (29–31). The ACC/AHA guidelines for coronary artery bypass grafting surgery suggest that older patients with an elevated preoperative creatinine are at extreme risk of dialysis dependence and should be considered for alternative options such as PCI (32).

GP IIb/IIIa receptor antagonist use.   In this study, the use of GP IIb/IIIa receptor antagonists decreased as renal function declined, suggesting that physicians were more apprehensive for fear of causing increased bleeding. Importantly, although our findings support the concern for increased bleeding events, the in-hospital mortality rate was not adversely affected by the use of GP IIb/IIIa receptor antagonists. After controlling for the degree of renal dysfunction, the mortality-protective benefit of GP IIb/IIIa receptor antagonists was still present. Because of the increased risk burden of cardiovascular morbidity in this population, the incremental benefit of GP IIb/IIIa receptor antagonist use may outweigh potential adverse effects and may not support a reduced use of these agents with worsening renal function. Rather, a more clear understanding of the alteration of the therapeutic effect and optimal dosing is necessary to maximize clinical benefit.

Investigations on the therapeutic efficacy and clinical outcome after administration of GP IIb/IIIa receptor antagonists in patients with renal dysfunction are limited. Impaired function of the platelet GP IIb/IIIa receptor has been demonstrated in patients with end-stage renal disease, with some reversibility noted following dialysis treatment (33–36). It is not clear if patients with renal dysfunction but not yet end-stage renal disease manifest analogous impairment. Studies of the pharmacokinetics of GP IIb/IIIa receptor antagonists show that these agents are largely cleared by renal mechanisms (37–42). Although specific dosing recommendations reflect these findings, they are not uniform and vary. Clinical studies of eptifibatide have included only 15 patients with serum creatinine between 2 and 4 mg/dl and excluded patients with serum creatinine >4 mg/dl (16). Similarly, clinical studies of tirofiban have excluded patients with a serum creatinine >2.5 mg/dl (43,44) and 2.0 mg/dl (45). In a phase I study of lamifiban specifically addressing renal function, 20 patients were stratified by CrCl into three groups: 1) no renal impairment, 2) mild-to-moderate renal impairment, and 3)severe renal impairment). The mean plasma concentration necessary to inhibit platelet aggregation by 50% ex vivo was reduced only in the severe renal impairment group (CrCl <29 cc/min). In this group, platelet recovery time was prolonged fourfold compared with subjects with mild-to-moderate or no renal impairment (46). In the clinical setting, recent retrospective studies examining the usage of GP IIb/IIIa receptor antagonists in patients with renal dysfunction have demonstrated clinical benefit (47,48). However, as noted previously, the PRISM studies excluded patients with moderate-to-severe renal dysfunction. This suggests the need for further investigations and perhaps targeted clinical trials to assess the clinical benefit and optimal dosing of GP IIb/IIIa receptor antagonists in patients with renal insufficiency.

Clinical implications.   Although the mechanism of increased mortality risk for mortality after ACS in patients with renal insufficiency is not entirely clear, recognition of the increased mortality risk burden of patients with renal dysfunction is crucial. Coexisting conditions and comorbidities such as volume overload, diabetes mellitus, congestive heart failure (systolic and diastolic), hypoalbuminemia, anemia, and older age may contribute (49). In addition, studies in this population have indicated more unfavorable lipid profiles, chronic inflammatory conditions, elevated homocysteine, aggressive atherosclerosis, endothelial dysfunction, and altered cytokine levels (50–54). Abnormal drug pharmacokinetics in these patients may further contribute to increased risk. The specific contribution of each of the above factors to the greater morbidity and mortality risk needs to be addressed in future studies. Although investigations suggest that the benefit-to-risk ratio of various therapeutic interventions is increased for patients at highest risk of adverse events, this needs to be proven in future studies. Until such data are available, physicians should continue to use their best judgment in patient management while at the same time not depriving appropriate patients of newer treatment strategies, such as GP IIb/IIIa receptor antagonists, that may improve clinical outcome.

Study limitations.   The results from this study may not be applicable to patients at nonteaching, non-tertiary care facilities. This was an observational study and is prone to the limitations inherent in such evaluations. Renal insufficiency was defined utilizing the calculated CrCl at the time of presentation. Duration and etiology of renal insufficiency was not recorded; therefore acute changes in renal function just before admission or as a consequence of the acute event were not known. Although data on the administration of GP IIb/IIIa receptor antagonists were recorded, type, dosage, and the clinical setting administered under were not recorded. It is not evident how renal function impacted decisions on therapy with GP IIb/IIIa receptor antagonists and whether those that received GP IIb/IIIa receptor antagonists represent a different patient population compared with those who did not. Additionally, this study did not address other outcome measures such as functional status and quality of life.

Conclusions.   Renal dysfunction is present in a substantial proportion of patients with acute coronary syndromes, and, in non-dialysis-dependent patients with worsening renal dysfunction, there is an associated incremental increase in risk of in-hospital adverse outcomes. Recognition of the risk burden of renal dysfunction is essential for risk stratification and may assist in development of management strategies tailored to improve outcome, including appropriate utilization of cardiovascular diagnostic tests and therapeutics used in current cardiovascular care. In this study, GP IIb/IIIa receptor antagonist use was not associated with increased mortality risk in the setting of concurrent renal insufficiency. Additional investigations are necessary to assess optimal dosing of GP IIb/IIIa receptor antagonists for maximization of clinical benefit in this high-risk cohort.


   References
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 Abstract
 Methods
 Results
 Discussion
 References
 

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