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J Am Coll Cardiol, 2006; 47:1987-1996, doi:10.1016/j.jacc.2005.11.084
(Published online 21 April 2006). © 2006 by the American College of Cardiology Foundation |
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,#,*
* Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut
Department of Epidemiology and Public Health, Yale University School of Medicine, New Haven, Connecticut
Robert Wood Johnson Clinical Scholars Program, Yale University School of Medicine, New Haven, Connecticut
General Internal Medicine Section, Medical Service, San Francisco Veterans Affairs Medical Center, San Francisco, California
|| Department of Medicine, University of California, San Francisco, California
¶ Department of General Internal Medicine, Cleveland Clinic Foundation, Cleveland, Ohio
# Center for Outcomes Research and Evaluation, Yale-New Haven Hospital, New Haven, Connecticut
Manuscript received July 26, 2005; revised manuscript received November 18, 2005, accepted November 21, 2005.
* Reprint requests and correspondence: Dr. Harlan M. Krumholz, Robert Wood Johnson Clinical Scholars Program, Yale University School of Medicine, Sterling Hall of Medicine (SHM), I-Wing, Suite 456, 333 Cedar Street, New Haven, Connecticut 06520. (Email: harlan.krumholz{at}yale.edu).
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Abstract |
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BACKGROUND: Renal impairment in HF patients is associated with excess mortality, although precise risk estimates are unclear.
METHODS: A systematic search of MEDLINE (through May 2005) identified 16 studies characterizing the association between renal impairment and mortality in 80,098 hospitalized and non-hospitalized HF patients. All-cause mortality risks associated with any renal impairment (creatinine >1.0 mg/dl, creatinine clearance [CrCl] or estimated glomerular filtration rate [eGFR] <90 ml/min, or cystatin-C >1.03 mg/dl) and moderate to severe impairment (creatinine 
1.5, CrCl or eGFR <53, or cystatin-C 1.56) were estimated using fixed-effects meta-analysis.
RESULTS: A total of 63% of patients had any renal impairment, and 29% had moderate to severe impairment. After follow-up 1 year, 38% of patients with any renal impairment and 51% with moderate to severe impairment died versus 24% without impairment. Adjusted all-cause mortality was increased for patients with any impairment (hazard ratio [HR] = 1.56; 95% confidence interval [CI] 1.53 to 1.60, p < 0.001) and moderate to severe impairment (HR = 2.31; 95% CI 2.18 to 2.44, p < 0.001). Mortality worsened incrementally across the range of renal function, with 15% (95% CI 14% to 17%) increased risk for every 0.5 mg/dl increase in creatinine and 7% (95% CI 4% to 10%) increased risk for every 10 ml/min decrease in eGFR.
CONCLUSIONS: Renal impairment is common among HF patients and confers excess mortality. Renal function should be considered in risk stratification and evaluation of therapeutic strategies for HF patients.
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We performed a systematic review and meta-analysis of published literature to characterize the prevalence of renal impairment in community-based, clinical trial, and hospitalized HF patients. Additionally, we sought to estimate the all-cause mortality risks associated with renal impairment, as determined by serum creatinine, cystatin-C, calculated creatinine clearance (CrCl), or estimated glomerular filtration rate (eGFR). Furthermore, we evaluated the association between renal impairment and other adverse outcomes such as early mortality (
6 months), cardiovascular mortality, hospital admissions, and functional status. Finally, we explored whether published studies have identified higher risk subgroups (according to demographic or clinical characteristics) that may have particularly high mortality risks.
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Methods |
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Study selection.
We included cohort studies and retrospective secondary analyses of randomized controlled trials whose primary objective was to analyze the association between renal impairment and mortality in HF patients. Titles and abstracts of all articles identified by the search strategy were evaluated and rejected on initial screen if they: 1) included subjects other than HF patients; 2) did not define HF using a combination of symptoms and signs (dyspnea, peripheral edema, third heart sound, jugular venous distention, limited exercise tolerance, or documented New York Heart Association [NYHA] functional class), imaging (documented pulmonary congestion or impaired ejection fraction), or medical record diagnosis by International Classification of Diseases-9; 3) had no evaluation of renal function; 4) did not include all-cause mortality as a primary outcome; 5) were published only in abstract form, because validity and quality of methods could not be adequately assessed and scored; or 6) included patients 18 years old. A Quality of Reporting of Meta-analyses (9) flow diagram illustrates the study selection process (Fig. 1). Excluded were studies with <6 months follow-up (10,11) and a study that defined renal impairment using International Classification of Diseases-9 code but no direct serum measures (12).
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1 criterion.
Renal function.
Measures of renal function included serum-measured creatinine and cystatin-C or creatinine-based estimated CrCl using the Cockcroft-Gault equation (15) and eGFR using the Modification of Diet in Renal Disease equation (16). Renal impairment definitions were based on categorizations available in the published studies rather than on empiric re-categorization of raw data, which were not available for this analysis. Any (mild to severe) renal impairment was defined as all categories of renal function other than the baseline category (lowest tertile, quartile, and so on), which corresponded to creatinine >1.0 mg/dl, CrCl or eGFR <90 ml/min, or cystatin-C >1.03 mg/dl. Moderate to severe renal impairment was defined as the worst category of renal function (highest tertile, quartile, etc.), which corresponded to creatinine 1.5, CrCl or eGFR <53, or cystatin-C 1.56. The definitions based on eGFR are similar to categories proposed by the National Kidney Foundation for stage 2 or worse chronic kidney disease (eGFR <90) and stage 3 or worse disease (eGFR <60). National Kidney Foundation staging does not provide equivalent measures for creatinine and cystatin-C, and thus the "equivalent" definitions for our analysis were based on patient distributions (percentiles), as defined in the individual studies. Additionally, for our analysis, we evaluated worsening renal function in hospital and defined this as a change in creatinine 0.3 mg/dl.
Outcomes. The primary outcome was all-cause mortality, determined by individual study methods, including review of Medicare databases, death certificates, hospital records, or follow-up with proxy contacts. Secondary outcomes were also evaluated. Cardiovascular mortality (all cardiovascular mortality and HF or pump failure mortality) was determined according to individual study methods, including committee consensus regarding data from death certificates, hospital records, or follow-up with proxy contacts; hospital admissions/readmissions by review of Medicare databases, hospital administrative data, or by committee consensus regarding data from follow-up patient interviews and review of hospital records; hospital costs by review of Medicare databases or hospital administrative data; and functional decline by validated functional status scales such as NYHA functional class or activities of daily living assessment (17).
Statistical analysis. Fixed effects meta-analysis was conducted to estimate the magnitude of risk associated with renal impairment and all-cause mortality, as measured by combined crude mortality risks and unadjusted risk ratios (RR), and combined adjusted hazard ratios (HR) with 95% confidence intervals (CI). Adjusted risk estimates included those published in final multivariate models for each study, which considered confounding from sociodemographic and clinical covariates such as age, gender, race, comorbidities, medications, physical exam and symptoms, ejection fraction, electrocardiogram findings, laboratory values, and neurohormonal measures.
Inverse variance-weighted averages of logarithmic RRs and HRs were calculated for all-cause mortality and secondary outcomes. Meta-estimates reflected only the subset of studies reporting combinable risk estimates. Among-study heterogeneity of risk estimates was examined using a standard chi-square test for heterogeneity. A funnel plot based on the primary outcome evaluated for potential systematic bias in studies, including publication bias. Subgroup analyses stratifying by race, gender, etiology of HF, severity of HF symptoms (determined by NYHA functional class), and follow-up period (early mortality, defined as 1-year mortality or mean follow-up 1 year) were also conducted to identify highest risk patients.
All statistical tests assumed a two-tailed alpha level = 0.05. Studies using overlapping patient populations (multiple secondary analyses of randomized trial data) were included in calculations for combined risk estimates only once, with the study reporting outcomes for the greatest number of patients taking precedence. All analyses were conducted using Review Manager version 4.2 (Cochrane Collaboration) (18).
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Results |
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1 year (range 1 to 11.7 years) (2–5,19,21,26,28,30), 26% without impairment, 42% with any impairment, and 51% with moderate to severe impairment died. This translated into a combined unadjusted mortality risk of RR = 1.48, 95% CI 1.45 to 1.52, p < 0.001 in patients with any renal impairment and RR = 1.81, 95% CI 1.76 to 1.86, p < 0.001 in patients with moderate to severe impairment.
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Subgroup analyses. One prior study (23) found significantly higher mortality risk in whites versus blacks: severe renal impairment in whites was associated with HR = 2.61 (95% CI 2.44 to 2.80), but in blacks was HR = 1.99 (95% CI 1.62 to 2.45) (p < 0.001 for interaction). Though no prior study stratified the effects of renal impairment on mortality by gender, a single study reported results in a cohort limited to women (19) (HR = 2.40, 95% CI 1.60 to 3.62 for severe impairment). Finally, in an analysis stratified by HF etiology (23), significantly increased mortality risk was reported both for patients with non-ischemic HF and ischemic HF.
Level of baseline symptoms appeared to modify the effect of renal impairment. Asymptomatic patients (NYHA functional class I to II) (31,32) still had significantly increased mortality risk with moderate to severe renal impairment (HR = 1.41, 95% CI 1.15 to 1.73), whereas more symptomatic patients (NYHA functional class III to IV) (1) showed substantially higher mortality risk for any renal impairment (HR = 2.10, 95% CI 1.76 to 2.50) and severe renal impairment (HR = 3.23, 95% CI 2.42 to 4.31). In patients with follow-up for early mortality (<1 year), any renal impairment was associated with a higher adjusted mortality risk than the risk found for 1 year (HR = 1.84, 95% CI 1.62 to 2.09, p < 0.001), although the studies contributing to this risk estimate were relatively heterogeneous (Fig. 5).
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Discussion |
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Though risk-stratification models in HF have increasingly included renal function for mortality risk prediction (33), evidence for therapeutic strategies to actually reduce mortality in HF patients with renal impairment is still lacking. Typically, HF patients with creatinine 2.5 have been systematically excluded from therapeutic trials, and thus optimal pharmacotherapy remains poorly defined, especially in patients with severe renal impairment (34). Evidence for therapeutic benefit from angiotensin-converting enzyme (ACE) inhibitors in HF patients with renal impairment is incomplete. One randomized trial of enalapril in patients with severe HF found a significant mortality benefit even with the inclusion of patients with moderate to severe renal impairment (6). An observational study by Masoudi et al. (1,35) recently showed similar or even increased relative survival benefit from ACE inhibitor treatment in HF patients with severe renal impairment compared with treatment in patients with moderate impairment or normal renal function. In contrast, Ezekowitz et al. (4) found no mortality benefit from ACE inhibitors in patients with CrCl <30 and ischemic HF, potentially because of interactions between combined aspirin and ACE inhibitor use. Interestingly, Ezekowitz et al. (4) noted a certain degree of "therapeutic nihilism" toward HF patients with renal impairment, as these patients had lower prescription rates of ACE inhibitors and beta-blockers. Certainly, caution is warranted, given evidence for risk of worsening renal function from spironolactone and nesiritide, as well as ACE inhibitors (5,26,29). The therapeutic dilemma concerning treatment of HF patients with renal impairment supports the need for randomized trials of therapeutic agents that specifically target HF patients with moderate to severe renal function. Indeed, though many of the studies in our meta-analysis adjusted for use of medical therapies, it is still possible that the excess mortality associated with renal impairment reflected, in part, a lack of efficacious treatment options available or possible underutilization of current therapies.
Results from our study also highlight the need to establish the best estimator of renal function and standardized definitions of renal impairment in HF patients. The studies reviewed in this analysis utilized a variety of directly measured serum markers as well as calculated estimates of GFR, but no study has empirically compared these estimators. Yet despite the varied definitions of renal impairment in the studies included in our meta-analysis, the association with mortality remained robust. However, future studies are still required to better define incremental mortality risk, and whether a linear and continuous characterization of the association between renal impairment and mortality is appropriate. Our study found conflicting results, with at least one study finding a threshold effect for eGFR >50, suggesting that excess risk was virtually null above this threshold (30). However, alternative studies suggested incremental risk even at the lowest levels of renal impairment (36). Notably, studies reporting incremental risks assumed a priori a linear relationship between eGFR or creatinine and mortality risk. Although both the categorical and continuous characterizations of renal function appeared to affirm the presence of a dose-response relationship, the validity of the linearity assumption could not be confirmed by our analysis and should be addressed in future studies. Finally, newer measures of renal function, including cystatin-C, may show promise for risk stratification and mortality risk prediction of HF patients although, to date, only one study had been published using cystatin-C to assess renal function in HF patients (37).
A causal pathway?. Our findings support the hypothesis that renal impairment could be a marker for worsening HF. However, some investigators have further postulated that renal impairment could be on the causal pathway to worsening HF. Our findings of the strength, consistency, and dose-response effect may help to support, although certainly not prove, causality. In particular, the temporal relationship between renal impairment and worsening HF could not be established in our study. However, other investigators have found that baseline renal impairment in healthy community subjects appears to increase the risk of developing HF, providing initial evidence to support a temporal relationship. Proposed biological mechanisms also support a potential causal pathway, as investigators have postulated that renal impairment could upregulate the renin-angiotensin-aldosterone system, enhance basal sympathetic nerve discharge, increase pro-inflammatory factors, and exacerbate underlying anemia, worsening left ventricular hypertrophy and myocyte contractility, leading to impaired volume handling, pump failure, and death. If renal impairment in HF is truly causal for mortality, cardio-renal pathophysiologic pathways could be an important target for preventing worsening HF, especially in those patients with the most severe levels of renal impairment.
Study limitations. For mortality risk estimates, our analysis could not rule out residual confounding from individual studies in adjusted analyses, although most studies did adjust for all known major confounders and yielded consistent estimates. However, this limitation emphasizes the inability of our analysis to establish a causal association. Second, sampling strategies varied for the different studies included in our analysis, so our results are not a nationally representative sample for prevalence. However, estimates for the prevalence of any renal impairment, despite the heterogeneity of definitions and populations, remained surprisingly consistent in both hospitalized and non-hospitalized patients. Thus, a conservative estimate of renal impairment in at least half of HF patients is likely valid (particularly given that clinical trial populations usually exclude patients with severe impairment).
Conclusions. Renal impairment confers a clinically significant risk for excess mortality in patients with HF, and the magnitude of this increased mortality risk is comparable to that associated with traditional prognostic indicators in HF, such as ejection fraction. Though more common in patients hospitalized for HF, at least some degree of renal impairment is still present in about half of stable HF outpatients. As renal function is a key independent prognostic factor in HF and relevant for developing optimal therapeutic strategies, a more refined understanding of the best method of estimating and characterizing renal impairment, particularly in the mild to moderately impaired range, is still required.
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Footnotes |
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