Kidney Function and Mortality among Patients with Left Ventricular Systolic Dysfunction
Nadia A. Khan*,
Irene Ma*,
Christopher R. Thompson,
Karin Humphries,
Deeb N. Salem,
Mark J. Sarnak and
Adeera Levin||
* Internal Medicine; Cardiology; || Nephrology, University of British Columbia, Vancouver, British Columbia, Canada; and Divisions of; Cardiology; and Nephrology, Tufts-New England Medical Center, Boston, Massachusetts
Address correspondence to: Dr. Nadia A. Khan, University of British Columbia, Department of Medicine, 620-B, 1081 Burrard Street, Vancouver, BC, Canada, V6Z 1Y6. Phone: 604-266-0961; Fax: 604-266-0962 nakhan{at}shaw.ca
Received for publication March 10, 2005.
Accepted for publication September 28, 2005.
Kidney disease has emerged as a risk factor for mortality inheart failure populations. The objective of this study was todetermine the impact of different stages of kidney dysfunction(defined using the Kidney Disease Outcomes Quality Initiative[K/DOQI] classification system) and changes in kidney functionon mortality in a cohort of patients with heart failure. A retrospectiveanalysis was conducted of data from the randomized controlledtrials Studies of Left Ventricular Dysfunction. A total of 6640participants with asymptomatic and symptomatic heart failurewere studied. Estimated GFR (eGFR) were calculated and thencategorized according to the K/DOQI classification system intothe following categories: 90, 60 to 89, 30 to 59, and 15 to29 ml/min per 1.73 m2. Reduction in eGFR from baseline was calculatedand subsequently categorized according to rate of decline (<5,5 to 10, 11 to 15, and >15 ml/min per 1.73 m2 per year).Independent of baseline differences, lower levels of eGFR wereassociated with a higher total mortality compared with thosewith eGFR 90 ml/min (30 to 59 ml/min per 1.73 m2: hazard ratio[HR] 1.32, 95% confidence interval [CI] 1.10 to 1.59, P = 0.004;15 to 29 ml/min per 1.73 m2: HR 2.54, 95% CI 1.54 to 4.19, P< 0.001). eGFR deteriorated rapidly (>15 ml/min per 1.73m2 per year) in 12% of participants. This decline was associatedwith a significant increase in mortality compared with slowerdecline (<5 ml/min per 1.73 m2 per year), despite adjustmentsfor baseline kidney function, baseline heart failure, or changein heart failure (HR 5.63; 95% CI 4.90 to 6.46; P < 0.0001).The levels of eGFR from the K/DOQI classification system areassociated with mortality in a well-characterized heart failurepopulation. Rate of decline in kidney function is a strong predictorof increased mortality in this population, independent of worseningheart failure and baseline kidney function.
The presence of chronic kidney disease (CKD) is associated withworse outcomes among those with acute coronary syndromes (1–4)and chronic heart failure (5–7). The classification ofkidney disease recently established by the National Kidney Foundation(Kidney Disease Outcomes Quality Initiative [K/DOQI]) has becomethe new standard for staging severity of CKD (8). The utilityof this staging system to predict outcomes in patients withheart failure is unknown despite the recognition that patientswith heart failure often have kidney disease. In addition, therate of decline in kidney function at each of the K/DOQI stagesof kidney disease is unknown. Although slow rates of declinein kidney function can occur in normally aging populations,small studies have shown that acute worsening of kidney functionis associated with increased mortality in hospitalized patientswith decompensated heart failure (7,9–12). Therefore,we hypothesized that progressive kidney dysfunction would beindependently associated with mortality in a large ambulatoryheart failure population.
We sought to assess the value of the K/DOQI staging system usingestimates of baseline GFR (eGFR) (13) by examining the prevalenceof abnormalities associated with CKD at each eGFR level andthe associated mortality rates at each of these levels of eGFR.We studied the rate of decline in kidney function accordingto these baseline levels of eGFR, factors associated with rapiddecline in kidney function, and the impact of this decline onmortality. In addition, we determined the effect of angiotensin-convertingenzyme (ACE) inhibition on rate of decline in kidney functionand mortality according to severity of baseline renal function.To study these objectives, we used data from two randomized,controlled trials (the Studies of Left Ventricular Dysfunction[SOLVD]) that contain serial serum creatinine levels for a largecohort of patients who had ambulatory heart failure and werefollowed over a long period of time.
The SOLVD studies included two large, double-blind, randomizedtrials that evaluated the effect of the ACE inhibitor enalaprilversus placebo among patients with left ventricular ejectionfractions of 0.35 or less. Patients were included when theyhad asymptomatic heart failure (in the prevention trial) orsymptomatic heart failure (in the treatment trial). Patientswere excluded from entering the study if they had recognizablekidney disease (i.e., a serum creatinine >2.5 mg/dl [177mmol/L]). For study participants, serum creatinine was obtainedat baseline and during regularly scheduled follow-up every 4mo. The primary end point of the SOLVD trials and this analysiswas death from any cause. The details of the rationale, design,and methods have been described previously (14).
Patients with incomplete creatinine data (157 patients, or 2%of SOLVD participants) were excluded from this analysis. Thefollowing variables were treated as continuous: age, left ventricularejection fraction, pulse pressure, serum creatinine level, andserum hematocrit. Dichotomous variables based on their presenceor absence included current smoking, previous myocardial infarction,left ventricular hypertrophy, history of angina, previous strokeor transient ischemic attack (cerebrovascular accident), ischemic(versus nonischemic) origin of left ventricular dysfunction,history of hypertension, and history of diabetes. Categoricalvariables included ethnicity (black, white, Hispanic, or other)and New York Heart Association (NYHA) functional class (I, II,III, or IV). Change in NYHA functional class was defined asany increase by one or more functional class. GFR were estimatedusing a validated prediction formula (15): eGFR (ml/min per1.73 m2) = 186 x (serum creatinine)–1.154 x (age in years)–0.203x (0.742 if female) x (1.210 if black). eGFR then was categorizedaccording to the K/DOQI classification of CKD established bythe National Kidney Foundation (8) into the following five categories:90, 60 to 89, 30 to 59, 15 to 29, or <15 ml/min per 1.73m2. According to the K/DOQI guideline, patients with decreasedeGFR between 60 and 89 ml/min per 1.73 m2 can be consideredas having CKD only when they also have albuminuria or abnormalitieson kidney biopsy or imaging studies. However, as there was apaucity of data on albuminuria, we studied the effects of theeGFR cut points as per the K/DOQI guideline and used 60 ml/minper 1.73 m2 to describe conservatively "normal" kidney function.eGFR loss per year was calculated using the difference betweenthe last reported eGFR and the baseline eGFR per year of follow-up.Reduction in eGFR from baseline was categorized as <5, 5to 10, 11 to 15, and >15 ml/min per 1.73 m2 per year. BecauseeGFR may normally decline 1 to 2 ml/min per 1.73 m2 per yearin aging populations (16), we conservatively estimated <5ml/min per 1.73 m2 per year as normal loss. To account furtherfor variations in eGFR as a function of time (i.e., length offollow-up), we analyzed change in each measurement of eGFR frombaseline as a time-dependent covariate.
Statistical Analyses
We used ANOVA or Kruskal-Wallis test to compare continuous dataamong the different eGFR categories and the 2 statistic to comparedichotomous data. Rates of overall survival were estimated accordingto the Kaplan-Meier method, and differences between groups wereassessed by means of the log-rank statistic. We used logisticregression to assess the univariate and multivariate associationof independent variables with development of rapid decline inkidney function (defined as >15 ml/min per 1.73 m2 per year)and Cox proportional hazard models for the outcome of totalmortality. Variables that were significantly associated withmortality from the univariate analyses (P < 0.10) were includedin multivariate models. Proportionality of hazards over timefor eGFR categories was assessed with no violations of assumptiondetected. We also tested separate models for the presence ofstatistical interaction between level of eGFR and either thepresence of diabetes or assignment to enalapril versus placebo.To account for differing number of eGFR measurements over time,we also used a time-varying covariate to describe the changein eGFR from baseline in the multivariate Cox proportional hazardmodel. The hazard ratios (HR) are reported with 95% confidenceintervals (CI). A two-sided P 0.05 was considered to indicatestatistical significance. Statistical analyses were conductedwith the Statistical Analysis System software, version 8.02(SAS Institute, Cary, NC).
A total of 6640 participants were available for this analysisand followed for an average (± SD) of 34.2 ± 14mo in the prevention trial and 32.3 ± 15 mo in the treatmenttrial. Of these, 86% were male, and the mean age was 60 ±10 yr. Despite the exclusion of patients into the original trialswith serum creatinine of >2.5 mg/dl (177 mmol/L), the majority(86%) of participants in the cohort had an eGFR <90 ml/minper 1.73 m2, and 33% would be classified as having CKD (eGFR<60 ml/min per 1.73 m2), according to current guidelines.It is difficult to comment conclusively on the group of patientswith eGFR between 60 and 89 ml/min per 1.73 m2, as there wasa lack of albuminuria or other data to confirm the diagnosisof CKD.
Baseline Characteristics Tables 1 and 2 describe the baseline demographics, heart function,and comorbid conditions as a function of eGFR level. The prevalenceof cardiovascular risk factors and comorbid conditions increasedwith worsening level of eGFR. Patients with lower eGFR wereolder and more often white and female. The prevalence of diabetes,stroke, hypertension, and angina was higher among those withlower levels of eGFR, and the mean pulse pressure, a surrogatemarker for arterial stiffness, was higher in those with lowereGFR. Lower levels of eGFR were also associated with lower hematocritlevels.
Table 2. Baseline characteristics according to eGFR (n = 6440): Baseline cardiac function and risk factorsa
Mortality According to Baseline Kidney Function
There were a total of 1566 deaths during follow-up. Among thosewith baseline eGFR 90 ml/min per 1.73 m2, 18% who died, 20%in 60 to 89 ml/min per 1.73 m2, 31% in 30 to 59 ml/min per 1.73m2, and 50% in the 15 to 29 ml/min per 1.73 m2 groups. The Kaplan-Meiersurvival curves in Figure 1 show that survival decreased sharplyonce eGFR levels fell below 60 ml/min per 1.73 m2. There wasno difference in total mortality between those with mildly depressedeGFR (60 to 89 ml/min per 1.73 m2) and those with normal-rangeeGFR (90 ml/min per 1.73 m2). Further subdivision of the GFRlevel 30 to 59 ml/min per 1.73 m2 to 45 to 59 and 30 to 44 ml/minper 1.73 m2 yielded similar risks for increased mortality. Table 3demonstrates the adjusted mortality rates for each level ofeGFR. Both moderate and severe reductions in baseline eGFR wereindependently associated with increased mortality when comparedwith eGFR 90 ml/min per 1.73 m2, even after adjustment for age,race, ejection fraction, baseline NYHA functional class, historyof diabetes, history of hypertension, prevention versus treatmenttrial, and enalapril assignment.
Table 3. Adjusted HR for total mortality according to baseline eGFRa
Effect of Enalapril and Diabetes on Outcomes after Adjustment for eGFR
Two subgroup analyses were performed to determine whether theeffect of eGFR on mortality was modified by randomization toenalapril or diabetic status. Although there was no statisticalinteraction between eGFR level and randomization to enalapril,lower levels of eGFR and increased mortality were more pronouncedamong those with diabetes (P = 0.02 for interaction). Randomizationto enalapril (versus placebo) was independently associated withdecreased mortality (HR 0.86; 95% CI 0.78 to 0.95; P < 0.01),even after adjustment for level of eGFR (Table 3).
Worsening Kidney Function
Serial eGFR measurements were available for 98% (6535 of 6640)of patients. Loss in eGFR was common, as demonstrated in Figure 2.Of the participants, 30% had no decline in renal function,34% had a decline of <5 ml/min per 1.73 m2 per year, 19%had a decline of 5 to 10 ml/min per 1.73 m2 per year, 5% hada decline of 11 to 15 ml/min per 1.73 m2 per year, and 12% hada decline of >15 ml/min per 1.73 m2 per year. The significantdecline in kidney function was evident across the baseline levelsof eGFR. Even when analyzed as a percentage decrease, 22% ofthe cohort had a reduction in eGFR of at least 20% from baseline(1453 of 6535), and this percentage reduction was seen acrossall levels of baseline eGFR (data not shown).
Figure 2. Rate of decline in kidney function per year according to baseline eGFR.
Factors Associated with Decline in eGFR
Factors that were independently associated with developmentof a rapid decline in kidney function (i.e., >15 ml/min per1.73 m2 decline per year) included age, female gender, nonwhiterace, lower ejection fraction, poor NYHA functional class (IIIor IV versus I or II), and lower hematocrit. As discerned frommultivariable analysis in Table 4, diuretic and antiplateletuse was not associated with rapid decline in renal function.Enalapril assignment was also not associated with rapid declinein renal function regardless of baseline eGFR level (P >0.05for interaction).
Table 4. Adjusted OR for development of rapid decline in kidney function (>15 ml/min per 1.73 m2 per year)a
Rate of Decline in Kidney Function and Mortality Table 5 shows that rate of decline in kidney function was associatedwith mortality. Among those with rapid decline, >15 ml/minper 1.73 m2 per year, mortality rates were considerably elevatedcompared with those with slower decline, <5 ml/min per 1.73m2 per year (369 of 756 [49%] versus 879 of 4475 [20%]; P <0.001). Given the above predictors of decline in eGFR, we adjustedfor baseline kidney function, baseline heart function, worseningheart function (any increase in NYHA functional class), andother cardiovascular risk predictors. Table 5 demonstrates thatrapid decline in renal function was independently associatedwith a substantially increased mortality. When change in eGFRwas analyzed as a continuous and time-varying covariate, reductionin eGFR from baseline remained independently associated witha higher rate of death (P < 0.0001). The survival curvesin Figures 3 and 4 demonstrate that rapid decline in kidneyfunction are associated with increased mortality even amongthose with relatively preserved baseline eGFR (60 ml/min per1.73 m2). In those with less residual kidney function at baseline(<60 ml/min per 1.73 m2), however, mortality begins to increaseat slower rates of decline (>5 ml/min per 1.73 m2 per year).Furthermore as shown in Table 5, enalapril conferred a survivalbenefit independent of these other factors as well.
Figure 3. Kaplan-Meier survival curve for participants with baseline eGFR 60 ml/min per 1.73 m2, according to rate of decline in eGFR (by log rank test, P < 0.0001).
Figure 4. Kaplan-Meier survival curve for participants with baseline eGFR <60 ml/min per 1.73 m2, according to rate of decline in eGFR (by log rank test, P < 0.0001).
There are several important findings in this study. There isa high prevalence (32%) of CKD (eGFR <60 ml/min per 1.73m2) in this group of patients with heart failure, originallyselected for lack of "severe" kidney disease. This finding isconsistent with studies of hospitalized patients and outpatientswith heart failure (5–11) and in this cohort of patientsin an earlier publication by Al Ahmed et al. (17). This studyextends the findings of Al Ahmed et al. (17) by using the morerefined K/DOQI classification system, instead of analyzing thecohort into tertiles. In conjunction with previous studies,this analysis highlights the lack of sensitivity of serum creatininealone to identify impaired kidney function and the potentialimportance of estimating eGFR to detect more accurately impairedkidney function.
The K/DOQI classification system, developed using general populationdata from the Third National Health and Nutrition ExaminationSurvey, is the new standard for staging severity of CKD. Theutility of this staging system to predict outcomes has not beenvalidated in an independent, high-risk patient population, despitethe recognition that patients with heart failure commonly havekidney dysfunction. Our analysis demonstrated an increasingprevalence of comorbid conditions by level of eGFR in a cohortof patients with systolic dysfunction. Our analysis supportsand extends the findings from the earlier general populationstudy, showing similar stepwise increases in the prevalenceof comorbid conditions such as anemia and hypertension as wellas other cardiovascular risk factors with decline in level ofeGFR but in an independent, high- risk heart failure population(18–20).
The use of eGFR and subsequent classification of kidney functionusing the K/DOQI system may provide a reasonable graded riskpredictor for total mortality in heart failure populations.This study determined that eGFR values below a threshold of60 ml/min per 1.73 m2 defined an increasing risk for death.Few studies have examined the impact of mild reductions of eGFRon mortality despite the high prevalence of patients with eGFRbetween 60 and 89 ml/min per 1.73 m2. We found no differencein mortality between those with mild reductions in baselineeGFR (60 to 89 ml/min per 1.73 m2) and those with normal eGFR(90 ml/min per 1.73 m2). These findings suggest a J-shaped curvefor mortality risk starting at a level <60 ml/min per 1.73m2.
Although CKD accompanies traditional cardiac risk factors aswell as kidney-associated comorbid conditions, we adjusted forthese factors to determine the independent effect of level ofGFR on mortality. Previous analyses that demonstrated associationsbetween increased mortality and kidney function in heart failurepopulations (5,17) were limited by using data-dependent tertileor dichotomous divisions rather than using predetermined cutpoints for eGFR and by controlling for a number of other variablesthat affect outcome, such as change in kidney function overtime. The findings of an independent, graded association betweenreduced eGFR and risk for death is concordant with findingsfrom large community-based cohorts and other cardiovascularpopulations, such as patients after myocardial infarction (17,21–23).
Enalapril assignment was associated with a reduced risk forall-cause mortality, even at moderate and severely depressedlevels of baseline eGFR, and did not seem to have an adverseimpact on kidney function. This finding is important for clinicians,as there may be a tendency not to initiate ACE inhibitors (6,24–26)because of potential for worsening renal function. The mortalitybenefit of enalapril remains regardless of degree of baselinekidney dysfunction or change in kidney function. These findingsare corroborated by earlier studies that demonstrate that ACEinhibitors reduce risk for cardiovascular disease and delaythe progression of CKD (6,27–35).
The natural course of kidney disease in patients with heartfailure was largely unknown, as most studies were cross-sectionalor limited in follow up data. In this ambulatory heart failurepopulation, kidney function deteriorated significantly in morethan one third of all patients and occurred across all levelsof baseline eGFR. Rapid decline in kidney function was associatedwith a significant increase in mortality compared with slowerdecline (<5 ml/min per 1.73 m2 per year), despite adjustmentsfor baseline kidney function, baseline heart failure, or changein heart failure (HR 5.63; 95% CI 4.90 to 6.46; P < 0.0001).As discerned from Figures 3 and 4, mortality increased withrapid decline in renal function for those with CKD and amongthose with preserved renal function (60 ml/min per 1.73 m2).Previous studies that evaluated change in kidney function werelimited by evaluating only in-hospital patients who were followedfor short periods of time (9,11) or used proxies for decliningkidney function, such as change in serum creatinine, which areless sensitive than eGFR (29). This study provides novel informationon the "natural" course of kidney disease in a large ambulatorypopulation who had systolic dysfunction and were followed fora mean of 2.6 yr. These findings suggest that rate of changein kidney function may provide a new powerful tool for riskstratifying patients with heart failure beyond baseline kidneyfunction.
Given the strong association with rapid deterioration in eGFRand mortality, understanding the reasons for this high prevalenceof deterioration is important. In heart failure, low cardiacoutput, neurohumoral stimulation, aggressive diuresis, and ACEinhibitor use may contribute to a higher rate of decline ineGFR (5,29,36–38). Prolonged renal vasoconstriction mediatedby both anemia and heart failure may also contribute to rapiddecline in kidney function (39). Several recent studies identifiedthat anemia can worsen kidney function and cause a more rapidprogression to dialysis compared with those without anemia (40,41).Our study demonstrated that poor heart function and anemia wereassociated with development of rapid decline in kidney function.Anemia is a modifiable risk factor that is currently being studiedin a number of populations with and without heart disease. Possibleexplanations for the association between higher mortality andrapid deterioration in kidney function include that deteriorationin kidney function merely reflects severity of baseline heartdisease or worsening heart failure, i.e., kidney function declineswith overly aggressive diuresis or low cardiac output. Consistentwith this, Dries et al. (5) also found that moderate reductionsin eGFR (<60 ml/min per 1.73 m2) were associated with increasedhospitalization for heart failure and death as a result of pumpfailure. However, kidney disease itself is associated with othernovel factors that may increase mortality: proinflammatory markers,arterial stiffness, dyslipidemia, hyperhomocysteinemia, andanemia (17,23,42–46). We attempted to understand better,using multivariate modeling, whether worsening kidney functionwas a reflection of heart failure or due to other mechanisms.We adjusted for baseline heart failure severity and declinein NYHA functional class (defined as any increase in functionalclass level), and despite these adjustments and adjustmentsfor traditional cardiac risk factors, rapid decline in kidneyfunction remained independently associated with a marked increasein all-cause mortality. These data support the hypothesis thatother mechanisms beyond worsening heart failure should be exploredas contributing to higher mortality.
There are several limitations to our analysis. Because thisis a post hoc re-analysis of a large, randomized, controlledtrial, there may be residual confounding by unmeasured factorsdespite adjustment for known risk factors with the multivariatemodeling. In particular, we were unable to account for adjustmentsin dosages of enalapril, early discontinuation of enalapril,and initiation of other cardiovascular medication during thestudy period. Given the uniform and standardized management,follow-up, and ascertainment of outcomes, this bias is lessened.Residual confounding is also less likely to explain the largeincreases in mortality associated with poor baseline kidneydysfunction or the rapid decline in kidney function. Also, becausewe did not have consistent measurements of urinalysis in allpatients with eGFR 60 ml/min per 1.73 m2, we are unable to predictthe true prevalence of impaired kidney function at higher levels,according to the K/DOQI definitions. In addition, change inNYHA functional class, as a marker of worsening heart failure,is limited as it describes only functional rather than structuralchanges and may be too insensitive to detect smaller or earlychanges in heart function. However, worsening NYHA functionalclass is a clinically relevant measure of change in heart function.
Clinical Implications
Kidney dysfunction is common among patients with heart failure.The K/DOQI classification system seems helpful for categorizingkidney impairment. This study corroborates the use of eGFR asa powerful predictor of mortality in an independent, high-riskpopulation. It seems that patients who have systolic dysfunctionand have eGFR <60 ml/min per 1.73 m2 are a particularly high-riskgroup but that ACE inhibition is associated with a significantreduction in mortality, even in those with relatively advancedkidney disease.
Because we demonstrate that rapid decline in eGFR both is commonand is associated with higher rates of death, independent ofbaseline kidney function, heart failure class, or progressionof heart failure, clinicians will need to recognize that serialmeasurement of eGFR are important in determining prognosis.Efforts should be made to identify factors that are responsiblefor the rapid decline in eGFR, and this study raises the importantquestion as to whether strategies that are aimed at preservingeGFR might lead to improved mortality in those with heart failure.
Kidney dysfunction that is classified according to the K/DOQIclassification system using eGFR is associated with increasedmortality among patients with asymptomatic and symptomatic leftventricular systolic dysfunction. A significant proportion ofpatients with systolic dysfunction will develop rapid declinein kidney function, regardless of baseline kidney function.This rapid decline in kidney function is associated with a markedincrease in mortality, independent of worsening heart failureand baseline kidney function. Rate of change in kidney functionmay provide a new powerful tool for risk stratifying patientswith heart failure beyond baseline kidney function. These findingsneed to be confirmed in large, prospective studies as understandingof the impact of renal impairment may lead to novel therapeuticstrategies in reducing mortality in patients with heart failure.
Acknowledgments
N.A.K. is supported by postdoctoral fellowship awards from theCanadian Institutes of Health and the Michael Smith Foundationfor Health Research (MSFHR); I.M. is supported from the ClinicalInvestigator Program and the Royal College of Physicians andSurgeons; K.H. is a MSFHR Scholar.
We acknowledge Dr. Min Gao, biostatistician, for assisting withthe analysis.
Footnotes
Published online ahead of print. Publication date availableat www.jasn.org.
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Abstract
Introduction
90, 60 to 89, 30 to 59, and 15 to 29 ml/min per 1.73 m2. Reduction in eGFR from baseline was calculated and subsequently categorized according to rate of decline (<5, 5 to 10, 11 to 15, and >15 ml/min per 1.73 m2 per year). Independent of baseline differences, lower levels of eGFR were associated with a higher total mortality compared with those with eGFR 
2 statistic to compare dichotomous data. Rates of overall survival were estimated according to the Kaplan-Meier method, and differences between groups were assessed by means of the log-rank statistic. We used logistic regression to assess the univariate and multivariate association of independent variables with development of rapid decline in kidney function (defined as >15 ml/min per 1.73 m2 per year) and Cox proportional hazard models for the outcome of total mortality. Variables that were significantly associated with mortality from the univariate analyses (P < 0.10) were included in multivariate models. Proportionality of hazards over time for eGFR categories was assessed with no violations of assumption detected. We also tested separate models for the presence of statistical interaction between level of eGFR and either the presence of diabetes or assignment to enalapril versus placebo. To account for differing number of eGFR measurements over time, we also used a time-varying covariate to describe the change in eGFR from baseline in the multivariate Cox proportional hazard model. The hazard ratios (HR) are reported with 95% confidence intervals (CI). A two-sided P 
0.05 was considered to indicate statistical significance. Statistical analyses were conducted with the Statistical Analysis System software, version 8.02 (SAS Institute, Cary, NC). 
