Association of glomerular filtration rate on presentation with subsequent mortality in non-ST-segment elevation acute coronary syndrome; observations in 13307 patients in five TIMI trials
C. Michael Gibson*,
Raphaelle L. Dumaine,
Eli V. Gelfand,
Sabina A. Murphy,
David A. Morrow,
Stephen D. Wiviott,
Robert P. Giugliano,
Christopher P. Cannon,
Elliott M. Antman and
Eugene Braunwald For the TIMI Study Group
From the TIMI Study Group, Cardiovascular Division, Brigham & Women's Hospital and the Department of Medicine, Harvard Medical School, 350 Longwood Avenue, Boston, MA 02115, USA
Received April 2, 2004;
revised August 13, 2004;
accepted August 19, 2004
* Corresponding author. Tel.: +1 617 525 6884; fax: +1 888 249 5261 (E-mail: mgibson{at}timi.org).
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Abstract
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AIMS: To determine the association of glomerular filtration rate (GFR) with clinical outcomes in the setting of non-ST-segment elevation acute coronary syndromes (NSTE-ACS).
METHODS AND RESULTS: Data were pooled from five NSTE-ACS TIMI trials (TIMI 11A and B, TIMI 12, OPUS-TIMI 16 and TACTICS-TIMI 18) and were available in 13 307 patients. GFR was assessed as a continuous and a categorical variable (normal: ⩾90 mL/min/1.73 m2, n=4952; mildly decreased: 60-89 mL/min/1.73 m2, n=6262; and moderately to severely decreased GFR: <60 mL/min/1.73 m2, n=2093). There was an independent association between decreasing GFR and mortality at 30 days (OR 1.19, 95% CI 1.121.27, p<0.001) and at 6 months (OR 1.16, 95% CI 1.111.22, p<0.001). The combination of TIMI risk score (TRS) and decreasing GFR provided further mortality risk stratification with highest 30-day and 6-month mortality rates among patients with the lowest GFR who also had a TRS⩾5 (9.1% and 15.4%, respectively). Decreasing GFR was also independently associated with stroke and recurrent ischaemia at 30-days as well as with major bleeding (p<0.001).
CONCLUSION: In the setting of NSTE-ACS, impaired GFR is associated with higher mortality as well as higher rates of thrombotic and major bleeding events, independent of TRS.
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Introduction
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Similar to diabetes, renal dysfunction (RD) continues to emerge as a major risk factor in the development of coronary artery disease.1
Prior studies have focussed on the epidemiology of coronary artery disease (CAD) among patients with RD or on the effectiveness of revascularization strategies among patients with RD.25 More recently, outcomes have been observed to be worse among patients with RD than among patients with normal renal function in the setting of ST-segment elevation myocardial infarction (STEMI).6,7 In the setting of non-ST-segment elevation acute coronary syndromes (NSTE-ACS), in-hospital outcomes8 and mid to long-term mortality9,10 are worse among patients with RD. These observations have led some to advocate that renal function be included as a risk indicator in the assessment of prognosis at the time of presentation with ACS.11
The aim of this study was to evaluate the prognostic value of glomerular filtration rate (GFR) and its association with clinical outcomes after adjustment for clinical and biological confounders in a large cohort of NSTE-ACS patients drawn from international multi-centre trials, and to evaluate its relative importance in risk stratification.
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Methods
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Study population and clinical endpoints
Clinical data were pooled from the TIMI 11A/B,12,13 TIMI 12,14 OPUS-TIMI 1615 and TACTICS-TIMI 1816 trials (n=13,307). All patients presented with NSTE-ACS, and the major treatment assessed was low molecular weight heparin (TIMI 11A/B), oral GP IIb/IIIa inhibitors (TIMI 12, OPUS-TIMI 16) or invasive versus conservative management strategies (TACTICS-TIMI 18). Notably, TIMI 11A/B excluded patients with creatinine above 2 mg/dl (177 μmol/l), TIMI 12 excluded patients with creatinine above 1.5 mg/dl (133 μmol/l), OPUS-TIMI 16 excluded patients with creatinine above 1.6 mg/dl (141 μmol/l) or a calculated creatinine clearance of less than 40 mL/min and TACTICS-TIMI 18 excluded patients with creatinine above 2.5 mg/dl (221 μmol/l).
Biomarker data were drawn from OPUS-TIMI 1615 and TACTICS-TIMI 1816 for B-type natriuretic peptide (BNP) (3293 data available), from TIMI 11A12, OPUS-TIMI 1615 and TACTICS-TIMI 1816 for high-sensitivity C-reactive protein (hs-CRP) (4484 data available), from TIMI 11B13, OPUS-TIMI 1615 and TACTICS-TIMI 1816 for troponin I (cTn I) (4042 data available) and from TIMI 11A,12 TIMI 1214 OPUS-TIMI 1615 and TACTICS-TIMI 1816 for white blood cell count (8240 data available). In TIMI 11B and TACTICS-TIMI 18, cTnI was measured using the ACS 180 Immunoassay (Bayer Diagnostics, USA), and a threshold of 0.1 ng/mL was used. In OPUS-TIMI 16, cTnI was measured using an assay from Biosite Inc (USA), with a cut-off point of 1.5 ng/mL. Hs-CRP was measured with the BN II Nephelometer (Dade-Behring, USA), and a threshold of 1.5 mg/dL was used. BNP was measured using an established immunoassay (Biosite Inc, USA), and a decision limit of 80 pg/mL was used.
All-cause mortality was assessed from randomization through 6-month follow-up. The 6-month mortality data were not available among patients of the TIMI 12 trial (325 patients). The incidence of minor, major bleeding and intracranial haemorrhage during hospitalization were assessed as previously described.17 Stroke, recurrent myocardial infarction (MI) and recurrent ischaemia were assessed from randomization through 30 days of follow-up. The distribution of the TIMI Risk Score (TRS) for NSTE-ACS, as previously reported,18 was used to assess the association of GFR with mortality in low risk (TRS 02), intermediate risk (TRS 34) and high risk (TRS⩾5) patients.
Renal function assessment
The abbreviated Modification of Diet in Renal Disease Study Group equation19 was used to calculate GFR:
GFR (mL/min/1.73 m2)=186x(SCr)1.154x(Age)0.203x(0.742 if female)x(1.210 if African American), where SCr is serum creatinine concentration in mg/dL, and age is in years. Patients were grouped as follows: normal (
90 mL/min/1.73 m2), mildly impaired (6089 mL/min/1.73 m2), and moderately to severely impaired GFR (<60 mL/min/1.73 m2), as defined by the Kidney Disease Outcome Quality Initiative.20
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Angiographic analysis methods
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Angiographic data were available in 536 patients enrolled in the TACTICS-TIMI 18 trial. Angiographic outcomes were assessed by a single observer (CMG) blinded to clinical outcomes and treatment strategy assignment. The TIMI flow grade,21 corrected TIMI frame count2224 and TIMI myocardial perfusion grade25 were assessed as previously defined.
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Statistical analysis
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All analyses were performed using Stata version 7.0 (College Station, Texas, USA). All continuous variables are reported as the mean±standard deviation (SD). GFR was assessed both as a continuous variable and a categorical variable. The
2 test and t-test were used for the analysis of categorical and continuous variables, respectively. All tests were two-sided. The t-test for trend across ordered groups was performed for the three GFR groups. p-values ⩽0.05 were considered significant. Multivariable logistic regression was used for the analysis of clinical endpoints, adjusting for clinical differences in baseline characteristics: GFR (per 10 units decrease), weight, smoking habit, prior myocardial infarction, systolic and diastolic blood pressure at the time of admission (per 10 units increase), heart rate (per 10 units increase), diabetes, history of hypertension, history of hypercholesterolaemia, history of congestive heart failure, history of percutaneous coronary intervention, history of coronary artery bypass grafting (CABG), ST-segment deviation. As age, gender and race were already taken into account in the GFR formula, these parameters were not adjusted for in the multivariable analysis. Furthermore, in order to optimise the power of the multivariable model, biomarker data were not adjusted for as they were available only in a subgroup of the population studied. Instead, the independent contribution of renal function in addition to biomarkers or age was assessed through stratification of GFR groups by biomarkers levels and age.
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Results
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Baseline characteristics
A total of 13,307 patients were included in the analysis. Normal renal function (GFR
90 mL/min/1.73 m2) was present in 4952 patients (37.2%), mildly impaired GFR (GFR=60 to 90 mL/min/1.73 m2) was present in 6262 patients (47.1%), moderately to severely impaired renal function (GFR<60 mL/min/1.73 m2) was present in 2093 patients (15.7%). Within this last group of patients, severely impaired renal function (GFR<30 mL/min/1.73 m2) was present in only 89 (0.67%) patients. There was a stepwise increase in the number of co-morbidities and in the proportion of patients with higher TIMI risk scores among patients with normal, mildly impaired and severely impaired renal function (Table 1). Lower GFRs were associated with older age, female gender, non-white race, non-smoking status, lower body weight as well as a higher frequency of prior MI, diabetes, congestive heart failure, hypertension, and prior CABG (p<0.001 for all). Patients with impaired renal function had significantly higher systolic blood pressure and heart rate at presentation (p<0.001). Lower GFRs were associated with higher TIMI risk scores and a greater incidence of ST-segment deviation on admission (p<0.001 for both).
There was a stepwise increase in the incidence of positive cTnI on admission as GFR decreased (Table 1). BNP levels increased as GFR declined. However, there was no statistical difference in either hs-CRP (by both categorical and continuous variable analyses) or in white blood cell count among the three GFR groups (Table 1).
Angiographic characteristics
GFR was significantly lower among patients with three-vessel disease than among patients without (75.04±2.12 vs 82.55±1.15 mL/min/1.73 m2, p=0.002). There was a stepwise increase in the proportion of three-vessel disease with worsening GFR (Fig. 1). However, other angiographic findings (TIMI flow grade, TIMI frame count, TIMI myocardial perfusion, percent diameter stenosis, presence of thrombus) were not associated with GFR (data not shown).

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Fig. 1 Proportion of triple vessel disease on angiography according to baseline glomerular filtration rate (GFR) groups. The number of patients within each GFR groups is displayed at the bottom of each bar.
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30-Day and 6-month mortality
A significant and graded association between short-term (30 days) and mid-term (6 months) mortality and reduced GFR was observed (p for trend ⩽0.001, Figs. 2 and 3(a)). GFR was significantly lower among patients who died at 30 days (71.05±26.04 vs 85.27±27.67 mL/min/1.73 m2, p<0.001) and 6 month follow-up (71.65±26.79 vs 85.61±27.64 mL/min/1.73 m2, p<0.001).

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Fig. 2 Mortality at 30 days according to baseline glomerular filtration rate (GFR) (a), and stratified by GFR and TIMI Risk Score (TRS) (b). The number of patients within each GFR group is displayed at the bottom of each bar in part A. All p-values are for trend.
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Within each TRS category (02, 34,
5) there was a stepwise increase in mortality among patients with normal, mildly and severely impaired renal function. A 9-fold gradient in 30-day and 6-month mortality was observed between the patients with lowest TRS and highest GFR, and patients with highest TRS and lowest GFR (Figs. 2 and 3(b)).
When patients were stratified by age, a similar stepwise increase was observed in short- and mid-term mortality when GFR decreased: among patients over 65 years old, mortality at 30 days was 2.5%, 3.1%, and 6.0% among patients with GFR
90, 6089 and <60 mL/min/1.73 m2, respectively (p for trend <0.001, data not shown), and mortality at 6 months was 4.7%, 5.3%, and 11.2% GFR
90, 6089 and <60 mL/min/1.73 m2, respectively (p for trend <0.001, data not shown).
In multivariable analysis, GFR remained independently associated with 30-day and 6-month mortality after adjustment for differences in baseline characteristics and the trials used for the analysis (Fig. 5). There was a 19% increase in the risk of mortality at 30 days, and a 16% increase in the risk of mortality at 6 months for each decrease of 10 mL/min/1.73 m2 in GFR (p<0.001, Fig. 5).

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Fig. 5 Association between glomerular filtration rate (GFR) per 10 units decrease and adverse outcomes following an acute coronary syndrome without ST-segment elevation. The clinical characteristics adjusted for in the multivariable logistic regression model include, in addition to GFR per 10 units decrease: weight, smoking habit, prior myocardial infarction, systolic and diastolic blood pressure at the time of admission (per 10 units increase), heart rate (per 10 units increase), diabetes, history of hypertension, history of hypercholesterolaemia, history of congestive heart failure, history of percutaneous coronary intervention, history of coronary artery bypass grafting, ST-segment deviation. In addition, the different trials used for the analysis were also adjusted for.
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Other clinical endpoints
The GFR was significantly lower among patients who experienced recurrent MI (78.82±38.93 vs 85.17±27.09 mL/min/1.73 m2, p<0.001), recurrent ischaemia (78.27±25.43 vs 85.82±27.82 mL/min/1.73 m2, p<0.001), or stroke (72.74±22.01 vs 85.36±27.86 mL/min/1.73 m2, p<0.001), as compared to patients who did not experience the event.
There was a stepwise increase in the incidence of stroke, recurrent MI and recurrent ischaemia with worsening GFR (Fig. 4).

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Fig. 4 Incidence of adverse event by glomerular filtration rate (GFR) groups: stroke, in-hospital TIMI major bleeding, recurrent myocardial infarction (MI), and recurrent ischaemia at 30 days. The number of patients within each subgroup is displayed at the bottom of each bar. GFR is expressed in mL/min/1.73 m2.
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In multivariable analysis, the impairment of renal function was independently associated with stroke and recurrent ischaemia (Fig. 5). There was a trend toward an increase in the risk of myocardial infarction at 30 days with the decrease of renal function in multivariable analysis, but this association did not reach significance (Fig. 5).
Bleeding events
Patients who experienced an episode of major bleeding or intracranial haemorrhage had lower levels of GFR than patients who did not (70.01±23.95 vs 77.74±26.11 mL/min/1.73 m2, p<0.001; and 66.10±22.23 vs 85.03±27.75 mL/min/1.73 m2, p<0.001, respectively). The risk of TIMI major bleeding rose as GFR decreased (Fig. 4). There was no difference in the risk of TIMI minor bleeding among the three groups (6.3% vs. 5.1% vs. 6.3% in GFR
90, 6089 and <60 mL/min/1.73 m2, respectively, p for trend 0.921). In multivariable analysis, there was a 12% increase in the risk of major bleeding for each 10 mL/min/1.73 m2 decrease in GFR (p<0.001, Fig. 5).
Similarly, intracranial haemorrhage frequency increased among the three groups (0.04%, 0.05%, and 0.29% in GFR
90, 6089 and <60 mL/min per 1.73 m2, respectively, p for trend <0.001). The number of events was too small to perform a multivariable analysis.
Renal function and biomarkers
Within each GFR category, high levels of biomarkers were associated with a significant increase in mortality as compared with normal levels of biomarkers (Fig. 6(a)(c)). There was a significant stepwise increase in 6-month mortality with the decrease of renal function regardless of hs-CRP (Fig. 6(a)). This increase was also maintained among patients with positive cTnI. Among patients with negative cTnI, the trend was not significant because there was no difference in mortality between patients with normal and mildly impaired renal function (Fig. 6(b)). When the data were stratified using a BNP cut-off point of 80 pg/mL, similar directionality in trends were observed, but these observations did not reach statistical significance (Fig. 6(c)).

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Fig. 6 6-Month Mortality, stratified by glomerular filtration rate (GFR) and biomarkers levels. (a) Stratification by high-sensitivity C-reactive protein (hs-CRP) levels. (b) Stratification by Troponin I (cTnI) levels. (c) Stratification by B-type natriuretic peptide (BNP) levels. The number of patients within each subgroup is displayed at the bottom of each bar.
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Discussion
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Among 13307 NSTE-ACS patients, impaired renal function was associated with an increased risk of mortality at 30 days and 6 months. This increased risk of short- and mid-term mortality is consistent with observations from prior studies of patients undergoing percutaneous coronary intervention,5 community patients,26 STEMI patients6,7,27 and ACS patients from randomized trials9,28 or hospital-based registries.8,29 This study extends prior work to demonstrate the prognostic value of GFR when added to a clinical risk stratification tool such as the TIMI Risk Score in the setting of NSTE-ACS.18
This study also highlights the independent association of moderate to severe renal impairment with major bleeding as well as thrombotic events such as stroke, and recurrent ischaemia at 30-days following an ACS event.
If major bleeding rarely occurs spontaneously in a general population of patients with impaired renal function,30 the risk is highly increased by the administration of anti-thrombotic therapies, which are mandatory following an ACS. Most specifically, it has been shown that a single dose of 100 mg/m2 of aspirin induces a greater prolongation of bleeding time one hour after administration among patients with impaired renal function than among healthy subjects.31 The mechanisms of the interaction between aspirin and renal function might be related to the platelet abnormalities observed with RD. These abnormalities involve all steps of primary haemostasis: reduced adhesiveness, reduced aggregation, and impaired secretion in response to thrombin. Reduction of platelet receptor GP Ib32 as well as qualitative dysfunction of receptor GP IIbIIIa33 participate to these haemostatic disorders. Uraemic circulating toxins, such as accumulated nitrogenous compounds, may also most likely play a role as dialysis corrects partially the bleeding tendency.30
Besides the increased risk of bleeding, RD is associated with an increased risk of thrombotic events. The present study demonstrates that among patients with NSTE-ACS, this association is independent of other risk factors often associated with RD such as prior coronary events, hypertension, hypercholesterolaemia, diabetes or smoking habit. The higher incidence of multivessel coronary disease and progressive increase in stroke incidence observed in the present study among patients with impaired renal function may reflect a greater atherosclerotic burden than in patients with normal renal function. While there was a higher prevalence of two- and three-vessel coronary artery disease among patients with impaired renal function, there was no reduction in either epicardial or myocardial perfusion that might explain the poorer clinical outcomes. A state of hypercoagulation has been observed among uremic patients, with high levels of von Willebrand factor,34 fibrinogen, factors VII, VIII and XIII and enhanced thrombin generation.30 This pro-thrombotic state is also associated with a relative decrease in fibrinolytic activity with an elevation of plasminogen activator inhibitor-type 1 (PAI-1) likely due to an increased secretion after stimulation by uraemic toxins.30
The present analysis also demonstrates that, similarly to the STEMI setting,6 the assessment of renal function participates to the risk stratification in addition to the TIMI risk score. Estimation of the GFR should thus be part of the evaluation of any patient presenting with an ACS. Other well-known prognostic biomarkers include troponin, CRP and BNP.3537 In the present study, the stepwise association between increased 6-month mortality and decreased GFR remained, regardless of hs-CRP levels, and was maintained among patients with positive cTnI as well. When the data were stratified by BNP < or
80 pg/mL, directionality similar to the results with hs-CRP and positive cTnI was observed, but the findings did not reach statistical significance. However, the power to detect a significant difference in mortality between the different BNP subgroups may have been limited by the small sample size of this analysis. Nonetheless, moderate to severe RD was associated with a rise in hs-CRP, cTnI as well as BNP (Table 1) and among patients with RD (mild as well as moderate to severe RD), high levels of hs-CRP, cTnI and BNP all remained associated with an increase in 6-month mortality. This is consistent with prior observations10,38,39 and indicates that inflammation, coronary distal microembolisms as well as an activation of the neurohormonal axis may play a role in adverse outcomes of patients with RD following NSTE-ACS.
Management of patients with RD, following an ACS, is complex due to the increased risk of both bleeding and thrombotic events. Reducing aspirin doses to 75 and 100 mg/day has been shown to significantly decrease the incidence of bleeding events, without decreasing its anti-thrombotic efficacy in association with clopidogrel.40 Also, adjusting the level of anticoagulation, especially when using low molecular weight heparin, might be well-tolerated in subgroups of patients at high-risk of bleeding such as RD patients.41 Adjunctive therapies of proven benefit such as beta-blockers and statins, which are unfortunately underused among RD patients with ACS27 should also be extensively prescribed to these patients.
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Limitations
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The number of patients with severely impaired function was limited by the exclusion criteria of the trials used in the present analysis. The graded increase in adverse outcomes with impaired renal function may have been further strengthened in a broader population of ACS patients which might include an even larger number of patients with more severely impaired GFRs. However, this hypothesis remains untested and the conclusions of the present analysis cannot be extended to the sole group of patients with severe renal dysfunction.
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Conclusion
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Impaired renal function is associated with short and mid-term mortality, extent of atherosclerosis, and the incidence of thrombotic events as well as major bleeding among patients with NSTE ACS. GFR adds to the risk stratification of the TIMI risk score.

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Fig. 3 Mortality at 6 months according to baseline glomerular filtration rate (GFR) (a), and stratified by GFR and TIMI Risk Score (TRS) (b). The number of patients within each GFR group is displayed at the bottom of each bar in part A. All p-values are for trend.
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Footnotes
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The trials used in this analysis were supported in part by a grant from Aventis Pharma, Antony, France (TIMI 11 A and B); Genentech, Inc., South San Francisco CA (TIMI 12); G.D Searle, Skokie, IL (OPUS-TIMI 16); and Merck and Co, West Point PA (TACTICS-TIMI 18). None of the sponsors were involved in any step of the publication process of the present manuscript. There is no conflict of interest in connection with the submitted article.
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