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Logo of nihpaAbout Author manuscriptsSubmit a manuscriptHHS Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
 
Int J Cardiol. Author manuscript; available in PMC 2010 May 29.
Published in final edited form as:
PMCID: PMC2720313
NIHMSID: NIHMS119899

Effects of Diabetes Mellitus in Patients with Heart Failure and Chronic Kidney Disease: A Propensity-Matched Study of Multimorbidity in Chronic Heart Failure

Christine Ritchie, MD, MSPH,a,b Maureen Muchimba, MPH,a O. James Ekundayo, MBChB, DrPH,a Ruth C. Campbell, MD,a Stuart J Frank, MD,a,b Bo Liu, MPH,a Inmaculada B. Aban, PhD,a and Ali Ahmed, MD, MPHa,b,*

Abstract

Background

Chronic kidney disease (CKD) and diabetes mellitus (DM) are common comorbidities in heart failure (HF) and each is associated with poor outcomes. However, the effects of multimorbidity related to having both CKD and DM compared to CKD alone have not been well studied in a propensity-matched population of chronic HF patients.

Methods

Of the 7788 ambulatory chronic HF patients in the Digitalis Investigation Group trial, 3527 had CKD, of whom 1095 had DM. Based on the absence or presence of DM, patients were categorized into CKD-only and CKD-DM. Propensity scores for CKD-DM were calculated for each patient and were used to match 987 pairs of CKD-only and CKD-DM patients. Hazard ratios (HR) and 95% confidence intervals (CI) comparing CKD-DM patients with CKD-only patients were estimated using matched Cox regression models.

Results

All-cause mortality occurred in 47.0% (rate, 1783/10000 person-years) of CKD-DM patients and 39.6% (rate, 1414/10000 person-years of follow-up) of CKD-only patients (HR when CKD-DM is compared with CKD-only, 1.25; 95% CI, 1.07–1.46; p=0.006). All-cause hospitalization occurred in 75.4% (rate, 5710/10000 person-years) and 67.8% (rate, 4213/10000 person-years) of CKD-DM and CKD-only patients respectively (HR, 1.32; 95% CI, 1.15–1.52; p<0.0001). Respective HR and 95% CI for other outcomes were: cardiovascular mortality (1.27; 1.06–1.52; p=0.009), HF mortality (1.34; 1.04–1.72; p=0.025); cardiovascular hospitalization (1.29; 1.12–1.49; p=0.001) and HF hospitalization (1.37; 1.16–1.63; p<0.0001).

Conclusions

Compared with comorbidity due to CKD alone, multimorbidity with CKD and DM was associated with poor outcomes in chronic HF patients.

Keywords: heart failure, chronic kidney disease, diabetes mellitus, mortality

1. Introduction

Multimorbidity is common in patients with heart failure (HF) [1]. Chronic kidney disease (CKD) and diabetes mellitus (DM) are common comorbidities in HF and are individually associated with poor outcomes [2, 3]. However, the association of multimorbidity and outcomes in chronic HF has not been well studied. The objective of this study was to test the hypothesis that in patients with chronic HF, compared with the comorbidity due to CKD alone, multimorbidity due to both CKD and DM is associated with increased mortality and hospitalization.

2. Materials and Methods

2.1 Study design and patients

This is a secondary analysis of the Digitalis Investigation Group (DIG) trial, which was a randomized, double-blind placebo-controlled trial of digoxin in chronic HF conducted in the United States (186 centers) and Canada (116 centers) during 1991 to 1995. The design and the results of the DIG are well described in the literature [46].

2.2 Patients

All 7788 DIG participants were in normal sinus rhythm, 6800 had left ventricular ejection fraction ≤45%, and over 90% were receiving angiotensin-converting enzyme (ACE) inhibitors. Data on beta-blocker use were not collected. We focused our analysis to 3527 patients who had CKD. We categorized these patients into CKD-DM (n=1095) and CKD-only (n=2432) groups by the presence or absence of DM. CKD was defined as an estimated baseline glomerular filtration rate of <60 ml/min/1.73 m2 body surface area [7, 8]. DM was defined as a history or diagnosis of DM at baseline.

2.3 Outcomes

The primary outcomes were all-cause mortality and all-cause hospitalization during a mean follow up of 32.6 months. Secondary outcomes studied were mortality and hospitalizations due to cardiovascular causes and worsening HF. Data on vital status were 99% complete [9].

2.4 Calculation of propensity scores

To assemble a cohort in which CKD-only and CKD-DM patients would be well-balanced on all measured baseline covariates, we calculated propensity scores for CKD-DM for each of the 3527 patients using a non-parsimonious multivariable logistic regression model [10, 11]. The propensity score for CKD-DM is the conditional probability of a patient having CKD-DM given that patient's measured covariates. In the model for propensity score, CKD-DM was the dependent variables and all baseline patient characteristics displayed in Figure 1 were used as covariates. We then used propensity scores to match 987 pairs of CKD-only and CKD-DM patients [2, 12].

Figure 1
Love plot displaying absolute standardized differences for covariates between chronic heart failure patients with comorbidity due to chronic kidney disease alone and those with multimorbidity due to both chronic kidney disease and diabetes mellitus, before ...

2.5. Assessment of bias reduction: absolute standardized differences

We assessed post-match covariate balance between the two groups by estimating absolute standardized differences and presented those results as Love plots [12]. Absolute standardized differences of <10% are taken to indicate inconsequential bias ([1214].

2.6. Statistical analysis

For descriptive analyses, we used Pearson Chi square and Wilcoxon rank-sum tests for the prematch, and McNemar's test and paired sample t-test for the post-match comparisons, as appropriate. Kaplan-Meier and matched Cox regression analyses were used to estimate associations of CKD-DM with various outcomes. We confirmed the assumption of proportional hazards by a visual examination of the log (minus log) curves. Homogeneity of the association between CKD-DM and all-cause mortality was further investigated in various subgroups of patients.

Although excellent balance was achieved in our post-match cohort in all measured covariates between the two groups, it is possible that there was bias due to imbalances in unmeasured covariates. Therefore, we conducted a formal sensitivity analysis to quantify the degree of a hidden bias that would need to be present to invalidate our main conclusions. All statistical tests were done using SPSS-15 for Windows [15].

3. Results

3.1 Patient Characteristics

Baseline characteristics for both groups before and after matching are displayed in Table 1 and Figure 1. Values of absolute standardized differences for all covariates were <5% after matching, suggesting substantial bias reduction (Figure 1).

Table 1
Baseline patient characteristics, before and after propensity score matching

3.2 CKD-DM and mortality

Overall, 855 (43.3%) patients died from all causes. All-cause mortality occurred in 47.0% (rate, 1783/10000 person-years) of CKD-DM patients, and 39.6% (rate, 1414/10000 person-years) of patients with CKD (matched hazard ratio {HR} when CKD-DM was compared with CKD-only, 1.25; 95% confidence interval {CI}, 1.07–1.46; p=0.006; Figure 2a and Table 2). In the absence of a hidden bias, a sign-score test for matched data with censoring provides strong evidence (p=0.005) that CKD-only patients outlived those with CKD-DM. A hidden covariate that is near-perfect predictor of mortality would need to increase the odds of having CKD-DM by 7.08% to potentially explain away this association. The association between CKD-DM and all-cause mortality was homogenous across different subgroups (Figure 3). Associations of CKD-DM with cardiovascular and HF mortality are displayed in Table 2.

Figure 2
Kaplan-Meier plots for (a) all-cause mortality, and (b) all-cause hospitalization (CI=confidence interval; CKD=chronic kidney disease; DM=diabetes mellitus; HR=hazard ratio)
Figure 3
Association of multimorbidity due to chronic kidney disease (CKD) and diabetes mellitus (DM) with all-cause mortality in subgroups of propensity-matched chronic heart failure patients (ACE=angiotensin-converting enzyme; CI=confidence interval; HR=hazard ...
Table 2
Association of multimorbidity due to both by chronic kidney disease (CKD) and diabetes mellitus (DM) relative to CKD alone, with mortality and hospitalization

3.4 CKD-DM and hospitalization

Overall 1413 (71.6%) patients were hospitalized for all causes. All-cause hospitalization occurred in 75.4% (rate, 5710/10000 person-years) and 67.8% (rate, 4213/10000 person-years) of CKD-DM and CKD-only patients, respectively (matched HR when CKD-DM was compared with CKD-only, 1.32; 95% CI, 1.15–1.52; p<0.0001; Figure 2b and Table 2). A sign-score test for matched data with censoring provides strong evidence (p<0.0001) that CKD-only patients had fewer hospitalizations than those with CKD-DM. A hidden covariate would need to increase the odds of hospitalization by 16.00% to potentially explain away this association. Associations of CKD-DM with cardiovascular and HF hospitalization are displayed in Table 2.

4. Discussion

4.1 Key study findings

In the current analysis, we demonstrate that in patients with chronic HF, the risk of adverse outcomes associated with CKD is further increased by the presence of additional comorbidity due to DM. These findings are important as HF is common among older adults who also suffer from multimorbidity. To the best of our knowledge, this is the first report of a propensity-matched study of associations of multimorbidity associated with DM with outcomes in chronic HF patients with CKD.

4.2 Mechanistic insights to study findings

All patients in our study had chronic HF and CKD and thus had a high baseline risk for poor outcomes [2]. The additional risk associated with the presence of DM may be a direct intrinsic effect of DM, a confounding effect by one or more measured covariates, and/or a confounding effect by one or more unmeasured covariates. DM is associated with activation of neurohormonal systems and the direct metabolic effects of DM and hyperglycemia are well known [16, 17]. Patients with DM are at increased risk of developing diabetic cardiomyopathy and diabetic nephropathy, which may indicate poor control or long duration of DM. Therefore, DM in the presence of CKD may be a marker of advanced DM and concomitant vascular disease from oxidative stress, inflammation, and advanced glycation endproducts [18]. The association between multimorbidity and poor outcomes may also be explained by the disease burden. With each additional comorbidity, the overall disease burden is increased, which in turn may increase the risk of disease-disease and disease-treatment interaction, and poor outcomes.

The findings of our study are unlikely to be explained by differences in baseline characteristics, as our matched cohort was well-balanced at baseline on all measured covariates. Results of our sensitivity analysis suggest that our findings may be relatively insensitive to a hidden bias. However, sensitivity analysis cannot determine if such a hidden bias exists or not. More importantly, for an imaginary hidden bias to explain away our findings it should be a near-perfect predictor of mortality and hospitalization, and also should not be strongly correlated with any of the covariates used in our propensity score model.

4.3 Comparison with prior studies

In patients with acute myocardial infarction, the rate of all-cause mortality has been shown to be significantly higher in those with CKD and DM than those with CKD only (40% versus 27%; p <0.001) [19]. However, to the best of our knowledge this is the first report of a propensity-matched study of the association between multimorbidity involving DM and CKD in patients with chronic HF.

4.4 Study limitations

Several limitations of this study need to be acknowledged. Patients in the DIG trial were relatively young, predominantly white and mostly men, with normal sinus rhythm from the pre-beta-blocker era of HF therapy, which may limit generalizability. We also had no data on duration, severity and treatment of DM at baseline or during follow up. Patients without DM at baseline may have developed DM during follow up. This phenomenon, called regression dilution, may have underestimated the true associations observed in our study [20].

4.5 Conclusions

In conclusion, in this propensity-matched study of chronic HF patients with CKD, in which patients with and without DM were well-balanced on all measured baseline characteristics, the presence of DM was associated with significant increases in mortality and hospitalization. These findings highlight the importance of multimorbidity associated with DM and CKD on outcomes relative comorbidity due to CKD in patients with chronic HF. Future studies need to prospectively test preventive and therapeutic interventions to prevent multimorbidity and to reduce multimorbidity-associated poor outcomes in chronic HF.

Acknowledgement

“The Digitalis Investigation Group (DIG) study was conducted and supported by the NHLBI in collaboration with the DIG Investigators. This Manuscript was prepared using a limited access dataset obtained by the NHLBI and does not necessarily reflect the opinions or views of the DIG Study or the NHLBI.”

Funding/Support: Dr. Ahmed is supported by the National Institutes of Health through grants from the National Heart, Lung, and Blood Institute (5-R01-HL085561-02 and P50-HL077100), and a generous gift from Ms. Jean B. Morris of Birmingham, Alabama

Footnotes

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Conflict of Interest Disclosures: None

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