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Original Investigation |

β-Blocker Use in Long-term Dialysis Patients:  Association With Hospitalized Heart Failure and Mortality FREE

Kevin C. Abbott, MC, USA; Fernando C. Trespalacios, MD; Lawrence Y. Agodoa, MD; Allen J. Taylor, MC, USA; George L. Bakris, MD
[+] Author Affiliations

Author Affiliations: Nephrology (Drs Abbott, Trespalacios, Agodoa, and Bakris) and Cardiology (Dr Taylor) Services, Walter Reed Army Medical Center, Washington, DC; Divisions of Nephrology (Dr Abbott) and Cardiology (Dr Taylor), Uniformed Services University of the Health Sciences, Bethesda, Md; Nephrology Service, Madigan Army Medical Center, Ft Lewis, Wash (Dr Trespalacios); National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda (Dr Agodoa); and Preventive Medicine Service, Rush Presbyterian Medical Center, Chicago, Ill (Dr Bakris).


Arch Intern Med. 2004;164(22):2465-2471. doi:10.1001/archinte.164.22.2465.
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Background  β-Blockers have been shown to be beneficial in the treatment and prevention of heart failure (HF) in the general population, but they have not been assessed for their association with nonfatal HF in a nationally representative population of long-term dialysis patients.

Methods  We conducted a retrospective cohort study of 2550 patients enrolled in the US Renal Data System (USRDS) Wave 2 who were Medicare eligible at the start of the study. Analysis was stratified by the presence or absence of a known diagnosis of HF, and patients followed up until December 31, 2000. Cox regression analysis, including propensity scores, was used to model adjusted hazard ratios for β-blocker use (assessed separately by cardioselective activity and lipid solubility) with time to the first Medicare institutional claim for HF, cardiovascular-related death, or death from any cause.

Results  In patients without a previous history of HF, β-blocker use was significantly associated with a lower adjusted risk of HF (adjusted hazard ratio, 0.69; 95% confidence interval, 0.52-0.91; P=.008), with a similar reduction in risk of cardiac-related and all-cause death. β-Blocker use had no statistically significant associations with outcomes in patients with previous HF.

Conclusions  In dialysis patients without a previous documented history of HF, β-blocker use was associated with a lower risk of new HF, cardiovascular death, and death from any cause. No such associations were seen for dialysis patients with a previous history of HF. These results are hypothesis generating only and should be confirmed in randomized trials.

Figures in this Article

In patients with severe (stage 5) chronic kidney disease, including those receiving long-term dialysis1,2 and those who have received kidney transplants,3,4 heart failure (HF) is more common and at least as lethal as ischemic coronary heart disease (CHD). It is also increasingly recognized that HF has substantial differences in epidemiologic features, pathogenesis, and therapy compared with CHD. Volume control (ie, preload reduction) and blood pressure (BP) control (which has substantial overlap with volume control) are necessary, but not sufficient, therapies for HF,5,6 regardless of the degree of kidney disease. In addition to control of volume and BP, neurohormonal blockade with β-blockers710 and angiotensin-converting enzyme (ACE) inhibitors11,12 is also essential for the prevention and treatment of HF. Given the overactivity of the sympathetic nervous system in renal parenchymal disease, β-blockers would seem to be ideal antihypertensive agents for treating dialysis patients.13

Results of recent studies14 have indicated that use of β-blockers, including carvedilol therapy in dialysis patients with established cardiomyopathy, has beneficial effects on survival. β-Blocker use has had beneficial effects on left ventricular function15 and all-cause mortality16 in long-term dialysis patients. The effect of β-blocker use on the risk of incident nonfatal HF or cause-specific mortality in certain at-risk subgroups in the long-term dialysis population is not known. Furthermore, given the unique pharmacologic considerations of long-term dialysis patients, analysis of β-blockers by class (cardioselective vs noncardioselective and degree of lipid solubility) would also be useful. Therefore, we undertook a retrospective cohort analysis of the US Renal Data System (USRDS) Dialysis Morbidity and Mortality Study (DMMS) Wave 2, which contains information on many important comorbid conditions and risk factors for HF. Our study objective is to determine whether use of β-blockers, alone or in combination with other medications or factors, is associated with a reduced risk of HF in this population.

PATIENTS

A historical cohort study of the USRDS DMMS Wave 2 was performed; details of the studies performed by the USRDS are described elsewhere.17 Briefly, the USRDS collects demographic and clinical data on patients who have survived more than 90 days on dialysis. The DMMS Wave 2 was a prospective cohort study that included all eligible patients who initiated peritoneal dialysis and a 20% random sample of patients who initiated hemodialysis in 1996 and early 1997. Because only a fraction of the patients from 1997 were available, the present analysis includes only patients whose initial date of end-stage renal disease was in 1996. Other details of the demographics and extraction of DMMS Wave 2 have been described in other studies.2

DATA COLLECTION

As part of the USRDS cohort study, dialysis unit personnel performed medical chart reviews to obtain baseline and follow-up patient data. Selected data for each patient at the start of the study, stratified by prevalent HF status (missing for 3.8% of the study cohort), are listed in Table 1. In addition, a maximum of 15 medications prescribed to each patient at the study start date (day 60 of dialysis) were recorded in the DMMS Wave 2 database. From this list, use of ACE inhibitors, β-blockers, calcium antagonists, 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, aspirin, calcium supplements, and vitamin D supplements was determined. Carvedilol was approved for use by the US Food and Drug Administration in 1997 and, therefore, despite its excellent record in patients with established HF,18 was not assessed. Use of angiotensin II receptor blockers and aluminum-containing binders was rare in the study population. β-Blockers were further subdivided into those with cardioselective properties (atenolol, acebutolol, betaxolol hydrochloride, bisoprolol, and metoprolol) and those with noncardioselective properties (nadolol, propranolol hydrochloride, labetalol hydrochloride, timolol, carteolol hydrochloride, penbutolol sulfate, and pindolol) and by lipid solubility (see the last footnote in Table 1). Blood pressures before and after dialysis and intradialytic weight gains (hemodialysis patients only) were averaged for 3 values determined after the start of the study.

Table Graphic Jump LocationTable 1. Selected Factors Assessed in Patients With ESRD Who Had Medicare as the Primary Payer at Day 60, DMMS Wave 2, 1996
OUTCOME MEASUREMENTS

Because Medicare claims were used as the primary outcome, analysis was restricted to patients for whom Medicare eligibility could be confirmed at the start of the study (ie, 60 days after the start of dialysis). Medicare institutional claims data (ie, primarily hospitalization claims) for HF (International Classification of Diseases, Ninth Revision, code 428.x) were linked to the DMMS Wave 2 data from the file, using only the first claim for HF for a given patient occurring during the study. In addition, de novo and recurrent HF were analyzed separately, as per previous investigators.1 De novo HF was defined as HF occurring in patients without a previous history of HF, and recurrent HF was defined as HF occurring in patients with a previous or preexisting history of HF as determined by the study questionnaire. Survival status was linked to the DMMS Wave 2 data from the 2000 USRDS Patients Standard Analysis File via unique patient identifiers assigned by the USRDS. The date and cause of death listed in a patient's Standard Analysis File were obtained from a form submitted to the USRDS by the patient’s nephrologist (formerly Health Care Finance Authority, HCFA 2746). The most recent Medicare claims date was December 31, 2000. Patient survival status was complete through September 30, 2001.

Time to claims for HF was calculated as the time from 60 days after the date of the first end-stage renal disease treatment until the date of the first Medicare claim for HF during the study, censored for death, date of renal transplantation, or the end of the study.

STATISTICAL ANALYSIS

Univariate analysis was performed using the χ2 test for categorical variables and the 2-tailed t test for continuous variables. Continuous variables that did not have a normal distribution (serum parathyroid hormone levels) were analyzed using the Mann-Whitney test. Missing values for continuous variables were set to the mean of the variable, and missing values for categorical variables were presumed to be absent, as in previous investigations by the USRDS.19 For validation purposes, analysis was also performed without interpolation of missing values for continuous variables. Analysis was also performed without censoring for the date of renal transplantation.

Variables with P<.10 in univariate analysis for a relationship with development of a first Medicare claim for HF were entered into multivariate analysis as covariates. An exception was made for factors thought to have a clinical reason to be associated with HF, in accordance with established epidemiologic principles.20 These factors included ACE inhibitor use, calcium antagonist use, β-blocker use, body mass index, race, sex, CHD, hematocrit value, and end-stage renal disease network (to assess for regional differences).

Cox proportional hazards regression analysis was used to assess the association between baseline factors and time to HF, independent of other predictors. Formal and graphic methods were used to verify the existence of proportional hazards. Because of the nonrandomized nature of medication use, a propensity score for use of β-blockers, calcium antagonists, and ACE inhibitors was developed from logistic regression analysis of factors associated with each medication. This score (in quartiles) was entered into the Cox regression model. In addition, because of possible survival bias due to the use of death as a censoring point for time to HF, a composite outcome of Medicare claims for HF and death due to cardiovascular causes was also assessed in Cox regression. Because BP is an independent risk factor for the development of HF in the general population and in dialysis patients, and because antihypertensive and other medications are underused among long-term dialysis patients, the use of specific agents was also analyzed, limited to patients taking β-blockers, ACE inhibitors, or calcium channel blockers.21

Of 4065 patients included in the DMMS Wave 2 cohort, 3621 had valid dates for starting dialysis in 1996. From this cohort, 3374 patients had sufficient information to calculate follow-up times, and of these, 2550 had confirmed Medicare eligibility 60 days after the start of dialysis. Table 1 gives the characteristics of the study population, stratified by patients with and without a documented history of HF within 10 years of the start of the study.

In unadjusted analysis of factors associated with de novo HF, aspirin was the only medication significantly associated with HF. Other factors significant in unadjusted analysis were older age, diabetes mellitus, history of CHD, presence of left ventricular hypertrophy (on either chest radiographs or electrocardiograms), elevated systolic BP and pulse pressure, and hemodialysis (vs peritoneal dialysis). The only 2 factors associated with recurrent HF were hemodialysis and use of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors.

Logistic regression analysis of factors independently associated with medications for the development of a propensity score revealed that the following factors were independently associated with use of β-blockers: previous CHD, peritoneal dialysis (vs hemodialysis), higher systolic BP, aspirin use, and lower use in patients with diabetes mellitus. Previous HF was not significantly associated with use of β-blockers (20.1% β-blocker use in patients with known HF vs 18.9% in patients without known HF; P = .47 by χ2 test), and the adjusted odds ratio for β-blocker use in patients with known HF was 0.95 (95% confidence interval, 0.68-1.32; P = .76 by logistic regression). Only 2 factors were significantly associated with ACE inhibitor use: older age (P<.001) and diabetes mellitus (P = .001). Use of calcium channel blockers was independently associated with peritoneal dialysis, smoking, higher serum albumin levels, African American race, and higher systolic BPs.

Use of β-blockers was independently associated with a lower risk of de novo HF; among subtypes of β-blockers, cardioselective β-blockers were statistically significant and noncardioselective β-blockers (which were also used much less frequently) were not; use of β-blockers and aspirin together, however, was associated with an increased risk of HF (Table 2). Other factors significantly associated with de novo HF in adjusted analysis were older age, diabetes mellitus, hemodialysis (vs peritoneal dialysis), and lower serum albumin levels. The decreased risk of HF associated with β-blocker use was proportional over time (as assessed by formal and graphical methods), although by visual inspection there was some disparity in unadjusted risk of HF in the first year by β-blocker use, after which the risk of HF was similar (Figure 1).

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Figure 1.

Kaplan-Meier plot of unadjusted time to Medicare institutional claims for de novo heart failure (HF) (International Classification of Diseases, Ninth Revision, code 428.x) by use or nonuse of β-blockers 60 days or more after the start of dialysis in patients with Medicare as the primary payer at day 60, United States Renal Data System Morbidity and Mortality Study Wave 2 cohort, excluding patients with a known diagnosis of HF. Time to de novo chronic heart failure was significantly longer for use of β-blockers, P = .007 by the log rank test.

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Table Graphic Jump LocationTable 2. Cox Regression Analysis of Factors Associated With De Novo Heart Failure

Analysis of composite outcomes of HF and cardiovascular death produced similar findings, except that individual classes of β-blockers were not statistically significant (Table 3). Figure 2 shows the results of Cox regression analysis limited to specific subgroups. β-Blocker use was independently associated with a lower risk of de novo HF, a composite outcome of HF and cardiovascular death, and all-cause death, even in models limited to patients taking β-blockers, ACE inhibitors, or calcium channel blockers. β-Blocker use retained its statistical significance even in adjusted models limited to patients with or without diabetes mellitus, CHD, or hemodialysis/peritoneal dialysis, although the number of diabetic patients in whom noncardioselective β-blockers were used was insufficient to calculate hazard ratios. Use of ACE inhibitors was not associated with de novo HF, cardiovascular death, or all-cause death in dialysis patients who did not have known HF.

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Figure 2.

Graphic representations of the relative risks (RRs) (as determined in Cox regression analysis, including propensity score derived from logistic regression of factors associated with β-blocker [BB] use, age, race, sex, diabetes mellitus status, coronary heart disease [CHD] status, quartiles of serum albumin concentration, dialysis modality, pulse pressure, aspirin use, angiotensin-converting enzyme [ACE] inhibitor use, calcium channel blocker [CCB] use, and left ventricular hypertrophy by chest radiography) for de novo heart failure (HF) or composite outcomes by use of BBs: Medicare claims for HF for all patients without previous HF (left side of graph) and for patients without previous HF who took either BBs, ACE inhibitors, or CCBs (right side of graph) (A); for patients without previous HF with and without a previous history of diabetes (B); for patients without previous HF with and without a previous history of CHD (C); and patients without previous HF with and without both diabetes and CHD (D). Adjusted HRs for the composite outcome of HF and all-cause death, limited to patients without previous HF (E). CS indicates cardioselective; asterisk, P<.05 by Cox regression; dagger, insufficient numbers to calculate. Error bars represent 95% confidence intervals. For E, 1 indicates composite outcome of claims for de novo HF of cardiovascular death; 2, cardiovascular death only; and 3, all-cause death.

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Table Graphic Jump LocationTable 3. Cox Regression Analysis of Time to Either De Novo Heart Failure or Cardiac Death (Composite)

Factors independently associated with recurrent HF are given in Table 4. Aspirin use was associated with an increased risk of recurrent HF, whereas use of calcium channel blockers was associated with a reduced risk of recurrent HF. Other factors included older age and history of CHD. β-Blocker use was not statistically significantly associated with recurrent HF, composite HF and cardiovascular death, or all-cause death in this subgroup, including stratification by subgroups.

Table Graphic Jump LocationTable 4. Cox Regression Analysis of Factors Associated With Recurrent Heart Failure

In the present study, in long-term dialysis patients without a known previous history of HF, use of β-blockers was independently associated with a lower subsequent risk of de novo HF, combined HF and cardiac death, and all-cause death. β-Blockers were used by only 20% of patients in this cohort regardless of the presence of previous HF. Studies in the general population suggest that, at most, 70% of high-risk patients can tolerate β-blockers, even under optimal conditions.22 Therefore, the use of β-blockers in dialysis patients seems far lower than would seem appropriate. Furthermore, the association of β-blocker use with de novo HF and survival persisted even when limited to patients who were taking β-blockers, ACE inhibitors, or calcium channel blockers, independent of measures of BP control, which is suboptimally treated in this population.23 The association with outcomes was more pronounced in terms of statistical significance and reduction of risk for cardioselective β-blockers. Cardioselective β-blockers are also less prone to peripheral vasoconstriction7 and, perhaps most important, have a lower risk of hyperkalemia than noncardioselective β-blockers,7,24 which may partly explain why they were used more frequently than noncardioselective β-blockers.

Given the observational nature of this study, we cannot entirely exclude bias in indication for the use of β-blockers, namely, that β-blockers were withheld from patients perceived to be at the highest risk of HF or death, which could have yielded the same results. In logistic regression analysis of factors associated with β-blocker use, β-blockers were used more frequently in patients with known CHD but less frequently in patients with diabetes mellitus, although both are known risk factors for mortality. Diabetes mellitus was more common but not as strongly associated with mortality as CHD. We used multiple methods, including adjustment, stratification, propensity scores, and multiple outcomes, to account for baseline differences in patient characteristics, and the statistical significance of β-blockers was robust in all these analyses. From a clinical point of view, it is not clear why β-blocker use would be “reserved” for healthier or low-risk patients in this population, other than its relative avoidance in patients with diabetes mellitus; in fact, just the opposite is more likely, because β-blocker use is preferentially recommended for patients with known CHD,25 and use of β-blockers is often avoided in patients with high expectations of physical exercise or sexual function, usually markers of better health,26 which the present study could not measure. Of course, only randomized controlled trials could exclude the possibility of residual confounding.

In contrast to de novo HF, the lack of apparent benefit of β-blocker use in patients with established HF in the present study is rather striking. Studies27 in the general population have found that the survival benefit associated with β-blocker use was similar regardless of the degree of severity of HF. However, Foley et al28 reported in a prospective cohort study of dialysis patients that conventional risk factors (hypertension, anemia, serum albumin level, and mode of dialysis) corresponded with left ventricular enlargement during the first year of therapy but were no longer significant during the second through fourth years, suggesting that intervention after the first year of dialysis (or perhaps in patients with established cardiomyopathy) might be relatively less effective. In that cohort approximately one third of the patients were taking β-blockers, but no specific medication was associated with changes in cardiac enlargement over time. Theoretical disadvantages of β-blockers, such as effects on arterial compliance (which may, in part, be class specific),29 may thus be relatively more important in patients with established HF. Whether advantages reported for carvedilol compared with other β-blockers are independent of differences in dosing regimens is controversial.18,30,31 However, although β-blocker use in general may reduce cardiovascular risk in patients with stage 5 chronic kidney disease, carvedilol is the one thus far with data from a randomized trial14 documenting this relationship. Calcium channel blockers, in particular those of the dihydropyridine class, which do not have known beneficial effects on neurohormonal activity in HF, were associated with a reduced risk of recurrent HF, analogous to their association with all-cause and cardiovascular mortality reported previously.17

Aspirin use was associated with an increased risk of recurrent HF in dialysis patients, a finding that our group2 discussed previously. A recent randomized controlled trial32 indicated that use of aspirin was associated with higher risk of recurrent hospitalized HF in patients with prevalent HF, a risk that was independent of prevalent CHD. Results of recent preliminary studies33 indicate that this association may be related to adverse effects of aspirin on arterial stiffness, at least at dosages of 325 mg/d. To quote a recent review,34(p149)

COX inhibitors may therefore be deleterious in cardiovascular disease and/or counteract part of ACE inhibitor (ACE-I) efficacy. This has been clearly demonstrated with non-steroidal anti-inflammatory drugs (NSAIDs), including high-dose aspirin, in hypertension, coronary artery disease and chronic heart failure (CHF); most guidelines recommend avoiding their use in such patients.

An adverse effect of aspirin use on survival in patients with established HF has not been demonstrated.35 Although use of nonsteroidal anti-inflammatory agents is discouraged in patients with HF, most expert recommendations do not discourage the use of low-dose aspirin (<100 mg/d) in patients who also use ACE inhibitors.36 We are not aware of any reported interactions between β-blockers and aspirin in association with incident HF.

The limitations of the present analysis have been discussed in depth in a previous article,2 but, in addition, the use of medications in a retrospective cohort analysis is prone to potential bias. Despite using multiple methods to address this potential bias, we cannot exclude the possibility of residual confounding. We could not assess medication adverse effects or changes in medication use after the start of the study. Use of International Classification of Diseases, Ninth Revision, codes, in particular code 428.x, for outcomes may underestimate the true incidence of HF in this population. However, among dialysis patients, other codes, such as “volume overload,” may have different implications than in the general population and so were not used in this analysis. Misclassification of events is also possible because diagnoses could not be verified. The analysis of recurrent HF, in contrast to de novo HF, was, in essence, a cross-sectional study of survival of previous HF episodes, and the severity and recency of HF could not be assessed. Ideally, patients with HF would be followed up from the time of their first HF event, an approach not possible in this study. Use of quartiles for propensity scores could have resulted in residual confounding. In any case, retrospective, nonrandomized analyses cannot prove causation but can suggest hypotheses to be tested in prospective trials and can provide useful information on potential sample size requirements, effect size, and possible confounders.

In summary, the present retrospective analysis demonstrates that use of β-blockers was independently associated with a reduced risk of incident HF and cardiovascular-related and all-cause death in long-term dialysis patients who did not have a known diagnosis of HF at the time of dialysis initiation. Together with the findings of previous studies21 in this same cohort, the results of the present study also suggest that different medications may have different associations with outcomes based on a previous diagnosis of heart disease, with implications for research and clinical practice. Because of the potential limitations of this analysis, it would be premature for clinicians to withhold β-blockers from patients with end-stage renal disease and a history of HF.

Correspondence: LTC(P) Kevin C. Abbott, MC, USA, Nephrology Service, Walter Reed Army Medical Center, Washington, DC 20307-5001 (kevin.abbott@na.amedd.army.mil).

Accepted for Publication: July 28, 2004.

Disclaimer: The opinions are solely those of the authors and do not represent an endorsement by the Department of Defense or the National Institutes of Health. This is a US government work. There are no restrictions on its use.

Financial Disclosure: Dr Bakris is a consultant and speaker for Astra Zeneca, Abbott, Amersham, Alteon, Biovail, Boerhinger-Ingelheim, Bristol-Myers/Squibb, Forest, GlaxoSmithKline, Merck, Novartis, Sanofi, Sankyo, and Solvay and has received grants from the National Institute of Diabetes and Digestive and Kidney Diseases/National Heart, Lung, and Blood Institute, National Institutes of Health; AstraZeneca; Abbott; Amersham; Alteon; Boerhinger-Ingelheim; Forest; GlaxoSmithKline; Merck; Novartis; Sankyo; and Solvay.

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Figures

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Figure 1.

Kaplan-Meier plot of unadjusted time to Medicare institutional claims for de novo heart failure (HF) (International Classification of Diseases, Ninth Revision, code 428.x) by use or nonuse of β-blockers 60 days or more after the start of dialysis in patients with Medicare as the primary payer at day 60, United States Renal Data System Morbidity and Mortality Study Wave 2 cohort, excluding patients with a known diagnosis of HF. Time to de novo chronic heart failure was significantly longer for use of β-blockers, P = .007 by the log rank test.

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Place holder to copy figure label and caption
Figure 2.

Graphic representations of the relative risks (RRs) (as determined in Cox regression analysis, including propensity score derived from logistic regression of factors associated with β-blocker [BB] use, age, race, sex, diabetes mellitus status, coronary heart disease [CHD] status, quartiles of serum albumin concentration, dialysis modality, pulse pressure, aspirin use, angiotensin-converting enzyme [ACE] inhibitor use, calcium channel blocker [CCB] use, and left ventricular hypertrophy by chest radiography) for de novo heart failure (HF) or composite outcomes by use of BBs: Medicare claims for HF for all patients without previous HF (left side of graph) and for patients without previous HF who took either BBs, ACE inhibitors, or CCBs (right side of graph) (A); for patients without previous HF with and without a previous history of diabetes (B); for patients without previous HF with and without a previous history of CHD (C); and patients without previous HF with and without both diabetes and CHD (D). Adjusted HRs for the composite outcome of HF and all-cause death, limited to patients without previous HF (E). CS indicates cardioselective; asterisk, P<.05 by Cox regression; dagger, insufficient numbers to calculate. Error bars represent 95% confidence intervals. For E, 1 indicates composite outcome of claims for de novo HF of cardiovascular death; 2, cardiovascular death only; and 3, all-cause death.

Graphic Jump Location

Tables

Table Graphic Jump LocationTable 1. Selected Factors Assessed in Patients With ESRD Who Had Medicare as the Primary Payer at Day 60, DMMS Wave 2, 1996
Table Graphic Jump LocationTable 2. Cox Regression Analysis of Factors Associated With De Novo Heart Failure
Table Graphic Jump LocationTable 3. Cox Regression Analysis of Time to Either De Novo Heart Failure or Cardiac Death (Composite)
Table Graphic Jump LocationTable 4. Cox Regression Analysis of Factors Associated With Recurrent Heart Failure

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