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. Author manuscript; available in PMC: 2013 Apr 1.
Published in final edited form as: Am J Med. 2012 Feb 7;125(4):399–410. doi: 10.1016/j.amjmed.2011.10.013

Renin-angiotensin inhibition in systolic heart failure and chronic kidney disease

Ali Ahmed 1,2, Gregg C Fonarow 3, Yan Zhang 1, Paul W Sanders 1,2, Richard M Allman 1,2, Donna K Arnett 1, Margaret A Feller 1, Thomas E Love 4, Inmaculada B Aban 1, Raynald Levesque 5, O James Ekundayo 3,6, Louis J Dell’Italia 1,2, George L Bakris 7, Michael W Rich 8
PMCID: PMC3324926  NIHMSID: NIHMS336294  PMID: 22321760

Abstract

Background

The role of renin-angiotensin inhibition in older systolic heart failure patients with chronic kidney disease remains unclear.

Methods

Of the 1665 patients, age ≥65 years, with systolic heart failure (ejection fraction <45%) and chronic kidney disease (estimated glomerular filtration rate <60 ml/min/1.73 m2), 1046 received angiotensin-converting enzyme inhibitors or angiotensin receptor blockers. Propensity scores for the receipts of these drugs, estimated for each of the 1665 patients, were used to assemble a matched cohort of 444 pairs of patients receiving and not receiving these drugs who were balanced on 56 baseline characteristics.

Results

During over 8 years of follow-up, all-cause mortality occurred in 75% and 79% of matched patients with chronic kidney disease receiving and not receiving angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, respectively (hazard ratio {HR}, 0.86; 95% confidence interval {CI}, 0.74–0.996; p=0.045). There was no significant association with heart failure hospitalization (HR, 0.86; 95% CI, 0.72–1.03; p=0.094). Similar mortality reduction (HR, 0.83; 95% CI, 0.70–1.00; p=0.046) occurred in a subgroup of matched patients with estimated glomerular filtration rate <45 ml/min/1.73 m2. Among 171 pairs of propensity-matched patients without chronic kidney disease, the use of these drugs was associated with significant reduction in all-cause mortality (HR, 0.72; 95% CI, 0.55–0.94; p=0.015) and heart failure hospitalization (HR, 0.71; 95% CI, 0.52–0.95; p=0.023).

Conclusions

Discharge prescription of angiotensin-converting enzyme inhibitors or angiotensin receptor blockers was associated with a significant modest reduction in all-cause mortality in older systolic heart failure patients with chronic kidney disease including those with more advanced chronic kidney disease.

Keywords: systolic heart failure, chronic kidney disease, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers

Inhibition of the renin-angiotensin system using angiotensin-converting enzyme inhibitors or angiotensin II type-1 receptor blockers improves outcomes in systolic heart failure.1,2 Chronic kidney disease is common in heart failure and is associated with poor outcomes.3,4 Although renin-angiotensin system suppression has been shown to improve outcomes in chronic kidney disease,5 systolic heart failure patients with chronic kidney disease are less likely to receive angiotensin-converting enzyme inhibitors or angiotensin receptor blockers.6 In addition to the elevation of serum creatinine after initiation of angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, a key reason for the underuse of these drugs is the apparent lack of randomized clinical trials evidence of their benefit in systolic heart failure patients with chronic kidney disease.7–9 Systolic heart failure patients with renal dysfunction were often excluded from randomized clinical trials of angiotensin-converting enzyme inhibitors or angiotensin receptor blockers and it is unlikely that the role of these drugs in these patients will be definitely resolved in randomized clinical trials due to ethical concerns of randomizing systolic heart failure patients, albeit with chronic kidney disease, to placebo, and lack of industry interests to sponsor such randomized clinical trials. However, when randomized clinical trials are unethical or impractical, propensity score matching can be used to design non-randomized studies to assemble balanced cohorts while remaining blinded to study outcomes.10–13 Therefore, the objective of the current study is to examine the association of angiotensin-converting enzyme inhibitor or angiotensin receptor blocker use with outcomes in a propensity-matched balanced cohort of systolic heart failure patients with chronic kidney disease.

Methods

Data source and study patients

We used the Alabama Heart Failure Project data for the current study, the details of which have been described previously.14 Briefly, medical records of fee-for-service Medicare beneficiaries discharged with a principle discharge diagnosis of heart failure from 106 Alabama hospitals between July 1, 1998 and October 31, 2001 were identified.14,15 A diagnosis of heart failure was based on the International Classification of Diseases, 9th Revision, Clinical Modification, codes for heart failure. Copies of the 9649 charts were abstracted by trained technicians who directly entered data into a computer database. The 9649 hospitalizations occurred in 8555 unique patients. For patients with multiple hospitalizations, charts from the first hospitalization were used.

Of the 8555 patients, 8049 were discharged alive, of whom 7058 (88%) were 65 years of age or older and of which, 2608 (37%) had left ventricular ejection fraction less than 45%. Of these, 2573 patients had data on baseline (admission, 2557 and in-hospital, 16) serum creatinine, of whom 1665 had chronic kidney disease, defined as estimated glomerular filtration rate <60 ml/min/1.73 m2 and 908 had no chronic kidney disease.16 Extensive data on baseline demographics, medical history including use of medications, hospital course, discharge disposition including medications, and physician specialty were collected.

Angiotensin-converting enzyme inhibitor or angiotensin receptor blocker use

Of the 1665 systolic heart failure patients with chronic kidney disease, 1046 (63%) were prescribed angiotensin-converting enzyme inhibitors or angiotensin receptor blockers. Of these, 83% (866/1046) received angiotensin-converting enzyme inhibitors, and 23% (180/799) of those not receiving angiotensin-converting enzyme inhibitors, received angiotensin receptor blockers. Seventeen patients received both drugs. Of the 908 systolic heart failure patients without chronic kidney disease, 693 (76%) received angiotensin-converting enzyme inhibitors or angiotensin receptor blockers. Of these, 89% (619/693) received angiotensin-converting enzyme inhibitors, and 26% (74/289) of those not receiving angiotensin-converting enzyme inhibitors received angiotensin receptor blockers. Considering the benefit of higher doses of angiotensin-converting enzyme inhibitors in heart failure,17 we categorized patients into receiving below-target or (at or above) target doses of angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, using guideline recommendations based on doses used in large randomized clinical trials.18

Mortality and hospitalization

The primary outcome of the current analysis was all-cause mortality through to April 2, 2007. Secondary outcomes included all-cause and heart failure hospitalizations. Data on outcomes and time to events were obtained from the Centers for Medicare and Medicaid Services Denominator File, Medicare Provider Analysis and Review File and Inpatient Standard Analytical File.

Assembly of a balanced cohort

Because of the imbalances in baseline characteristics between patients receiving and not receiving angiotensin-converting enzyme inhibitors or angiotensin receptor blockers (Table 1 and Figure 1), we used propensity scores to assemble a cohort in which those receiving and not receiving angiotensin-converting enzyme inhibitors or angiotensin receptor blockers would be well-balanced on all measured baseline covariates.10–13 We began by estimating propensity scores or probability of receiving discharge prescription of angiotensin-converting enzyme inhibitors or angiotensin receptor blockers for each of the 1665 systolic heart failure patients with chronic kidney disease given that patient’s measured baseline characteristics.19 We used a non-parsimonious multivariable logistic regression model in which receipt of angiotensin-converting enzyme inhibitors or angiotensin receptor blockers was the dependent variable, and 56 baseline characteristics displayed in Figure 1 were used as covariates.20–22

Table 1.

Baseline patient characteristics of older systolic heart failure patients with chronic kidney disease by discharge prescription of angiotensin-converting enzyme inhibitor (ACEIs) or angiotensin receptor blockers (ARBs), before and after propensity score matching

n (%) or mean (±SD) Before propensity score matching Use of ACEIs or ARBs After propensity score matching Use of ACEIs or ARBs
No (n=619) Yes (n=1046) P value No (n=444) Yes (n=444) P value
Age (years) 78 (±7) 78 (±7) 0.610 78 (±8) 78 (±7) 0.509
Female 283 (46) 565 (54) 0.001 221 (50) 229 (52) 0.639
African American 142 (23) 202 (19) 0.077 99 (22) 91 (21) 0.565
Current smoker 58 (9) 82 (8) 0.277 37 (8) 36 (8) 1.000
Nursing home residents 34 (6) 53 (5) 0.706 30 (7) 27 (6) 0.791
Left ventricular ejection fraction (%) 29 (±9) 28 (±9) 0.367 29 (±9) 29 (±9) 0.985
Past medical history
 Prior heart failure 513 (83) 809 (77) 0.007 356 (80) 353 (80) 0.868
 Hypertension 416 (67) 764 (73) 0.011 301 (68) 314 (71) 0.375
 Coronary artery disease 431 (70) 706 (68) 0.366 306 (69) 302 (68) 0.835
 Myocardial infarction 215 (35) 343 (33) 0.417 150 (34) 153 (35) 0.889
 Angina pectoris 103 (17) 145 (14) 0.124 68 (15) 70 (16) 0.925
 Percutaneous coronary intervention 98 (16) 167 (16) 0.943 73 (16) 64 (14) 0.460
 Coronary artery bypass graft 201 (33) 370 (35) 0.228 149 (34) 141 (32) 0.629
 Left bundle branch block 138 (22) 240 (23) 0.759 96 (22) 97 (22) 1.000
 Diabetes mellitus 286 (46) 446 (43) 0.157 192 (43) 196 (44) 0.831
 Atrial fibrillation 173 (28) 305 (29) 0.598 129 (29) 121 (27) 0.602
 Stroke 145 (23) 211 (20) 0.118 103 (23) 101 (23) 0.937
 Chronic obstructive pulmonary disease 220 (36) 326 (31) 0.066 148 (33) 155 (35) 0.661
 Dementia 68 (11) 88 (8) 0.082 52 (12) 48 (11) 0.744
 Cancer 10 (2) 36 (3) 0.028 10 (2) 8 (2) 0.815
Clinical findings
 Pulse (beats per minute) 92 (±24) 91 (±23) 0.902 92 (±25) 93 (±23) 0.628
 Systolic blood pressure (mmHg) 142 (±34) 145 (±31) 0.152 143 (±34) 145 (±32) 0.551
 Diastolic blood pressure (mmHg) 78 (±20) 79 (±18) 0.067 79 (±20) 79 (±18) 0.762
 Respiration (breaths per minute) 24 (±6) 24 (±7) 0.239 24 (±6) 24 (±6) 0.938
 Peripheral edema 429 (69) 702 (67) 0.354 297 (67) 307 (69) 0.523
 Pulmonary edema by chest x-ray 452 (73) 751 (72) 0.590 320 (72) 311 (70) 0.554
Tests and procedures
 Serum sodium (mEq/L) 138 (±5) 139 (±5) 0.185 138 (±5) 139 (±5) 0.423
 Serum potassium (mEq/L) 4.4 (±0.7) 4.4 (±0.7) 0.136 4.4 (±0.7) 4.4 (±0.7) 0.702
 Serum creatinine (mEq/L) 2.3 (±1.4) 1.7 (±1.0) <0.001 2.0 (±1.1) 2.0 (±1.3) 0.652
 Estimated glomerular filtration rate (ml/min/1.73m2) 35 (±14) 42 (±12) <0.001 38 (±13) 37 (±13) 0.800
 Blood urea nitrogen (mg/dL) 40 (±22) 31 (±16) <0.001 36 (±19) 36 (±20) 0.631
 Serum glucose (mg/dL) 153 (±70) 156 (±72) 0.394 153 (±72) 151 (±68) 0.546
 Hematocrit (%) 36 (±6) 37 (±6) <0.001 37 (±6) 37 (±6) 0.647
 White blood cell (103/μL) 10 (±8) 9 (±6) 0.321 9 (±5) 9 (±7) 0.739
Hospital and care characteristics
 Pneumonia 196 (32) 261 (25) 0.003 119 (27) 124 (28) 0.765
 Acute myocardial infarction 44 (7) 55 (5) 0.123 29 (7) 27 (6) 0.888
 Pressures ulcer 66 (11) 92 (9) 0.209 44 (10) 46 (10) 0.911
 Rural hospital 143 (23) 231 (22) 0.631 106 (24) 110 (25) 0.818
 Cardiology consult 424 (69) 712 (68) 0.856 302 (68) 286 (64) 0.291
 Intensive care unit 44 (7) 37 (4) 0.001 24 (5) 26 (6) 0.883
 Length of stay (days) 8 (±5) 7 (±6) <0.001 7.5 (±4.5) 7.4 (±7.0) 0.864
Discharge medications
 Beta blockers (heart failure) 148 (24) 302 (29) 0.028 110 (25) 109 (25) 1.000
 Loop diuretics 483 (78) 929 (89) <0.001 368 (83) 359 (81) 0.444
 Potassium-sparing diuretics 87 (14) 213 (20) 0.001 67 (15) 62 (14) 0.696
 Digoxin 275 (44) 621 (59) <0.001 226 (51) 222 (50) 0.833
 Calcium channel blockers 126 (20) 168 (16) 0.026 90 (20) 91 (21) 1.000
 Potassium supplements 240 (39) 478 (46) 0.006 186 (42) 191 (43) 0.780
 Nitrates and hydralazine 95 (15) 24 (2) <0.001 26 (6) 22 (5) 0.572
 Anti-arrhythmic drugs 130 (21) 184 (18) 0.086 85 (19) 78 (18) 0.603
 Anti-coagulants 150 (24) 305 (29) 0.029 117 (26) 110 (25) 0.639
 Anti-platelet drugs 64 (10) 124 (12) 0.345 54 (12) 55 (12) 1.000
 Aspirin 223 (36) 481 (46) <0.001 169 (38) 167 (38) 0.944
 Insulin 94 (15) 156 (15) 0.881 70 (16) 68 (15) 0.923
 Statins 86 (14) 187 (18) 0.034 67 (15) 66 (15) 1.000
 Anti-depressants 122 (20) 221 (21) 0.489 94 (21) 99 (22) 0.750
 Non-steroidal anti-inflammatory drugs 30 (5) 94 (9) 0.002 25 (6) 27 (6) 0.883
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Figure 1.

Figure 1

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Absolute standardized differences comparing 56 baseline characteristics between older systolic heart failure patients with chronic kidney disease receiving and not receiving discharge prescription of angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, before and after propensity score matching

Using a greedy matching protocol, we were able to match 444 or 72% of the 619 patients not receiving angiotensin-converting enzyme inhibitors or angiotensin receptor blockers with 444 patients receiving these drugs who had similar propensity scores.23–25 We then estimated absolute standardized differences of the 56 measured covariates for those receiving and not receiving angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, and presented the percentages of pooled standard deviations as Love plots. 26–29 An absolute standardized difference of 0% indicates no residual bias and differences <10% are considered inconsequential.

We repeated the above process on 908 systolic heart failure patients without chronic kidney disease, matching 171 or 80% of the 215 patients not receiving angiotensin-converting enzyme inhibitors or angiotensin receptor blockers with 171 patients receiving these drugs who had similar propensity scores, thus assembling a balanced cohort of 171 pairs of systolic heart failure patients without chronic kidney disease.

Statistical analysis

For descriptive analyses, we used Pearson Chi square and Wilcoxon rank-sum tests for the pre-match, and McNemar’s test and paired sample t-test for post-match comparisons, as appropriate. Kaplan-Meier plots and Cox regression analyses were used to determine the associations of angiotensin-converting enzyme inhibitor or angiotensin receptor blocker use with outcomes during over 8 years of follow-up. To quantify the degree of a hidden bias that would be required to explain away a significant association among matched patients we conducted a formal sensitivity analysis. Subgroup analyses were conducted to determine the homogeneity of association. We then examined the associations of below-target and target doses of angiotensin-converting enzyme inhibitors or angiotensin receptor blockers with outcomes using patients not receiving these drugs as reference. Finally, we examined the associations of angiotensin-converting enzyme inhibitors or angiotensin receptor blockers with outcomes in those with chronic kidney disease Stage ≥3B (estimated glomerular filtration rate <45 ml/min/1.73 m2). All statistical tests were two-tailed with a p-value <0.05 considered significant. Statistical analyses were performed using SPSS-18 for Windows (SPSS, Inc., 2009, Chicago, IL).

Results

Baseline characteristics

Matched systolic heart failure patients with chronic kidney disease (n=888) had a mean age (±SD) of 78 (±7) years, 51% were women, and 21% were African American. Pre-match imbalances in the distribution of gender, comorbidities and treatment between patients receiving and not receiving angiotensin-converting enzyme inhibitors or angiotensin receptor blockers were well-balanced after matching (Table 1 and Figure 1). Of the 888 matched patients, 591 had chronic kidney disease stage ≥3B. These patients had a mean age (±SD) of 78 (±7) years, 51% were women, and 24% were African American. Matched systolic heart failure patients without chronic kidney disease (n=342) had a mean age (±SD) of 77 (±8) years, 45% were women, and 26% were African American. Pre-match imbalances in various baseline characteristics in these patients were also well balanced after matching (Table 2).

Table 2.

Baseline patient characteristics of older systolic heart failure patients without chronic kidney disease by discharge prescription of angiotensin-converting enzyme inhibitor (ACEIs) or angiotensin receptor blockers (ARBs), before and after propensity score matching

n (%) or mean (±SD) Before propensity score matching Use of ACEIs or ARBs After propensity score matching Use of ACEIs or ARBs
No (n=215) Yes (n=693) P value No (n=171) Yes (n=171) P value
Age (years) 77 (±7) 76 (±7) 0.227 77 (±7) 77 (±8) 0.962
Female 91 (42) 319 (46) 0.340 73 (43) 82 (48) 0.412
African American 51 (24) 200 (29) 0.141 43 (25) 46 (27) 0.795
Current smoker 26 (12) 101 (15) 0.359 19 (11) 20 (12) 1.000
Nursing home residents 8 (4) 24 (4) 0.858 5 (3) 10 (6) 0.302
Left ventricular ejection fraction (%) 29 (±9) 28 (±9) 0.043 30 (±9) 29 (±9) 0.600
Past medical history
 Prior heart failure 136 (63) 457 (66) 0.469 110 (64) 105 (61) 0.630
 Hypertension 131 (61) 467 (67) 0.081 105 (61) 109 (64) 0.741
 Coronary artery disease 134 (62) 386 (56) 0.086 100 (59) 84 (49) 0.085
 Myocardial infarction 57 (27) 193 (73) 0.701 46 (27) 39 (23) 0.419
 Angina pectoris 38 (18) 110 (16) 0.532 30 (18) 25 (15) 0.551
 Percutaneous coronary intervention 29 (14) 107 (15) 0.484 23 (14) 18 (11) 0.487
 Coronary artery bypass graft 74 (34) 176 (25) 0.010 50 (29) 45 (26) 0.644
 Left bundle branch block 46 (21) 159 (23) 0.635 37 (22) 41 (24) 0.704
 Diabetes mellitus 67 (31) 300 (43) 0.002 54 (32) 59 (35) 0.620
 Atrial fibrillation 62 (29) 190 (27) 0.685 50 (29) 48 (28) 0.909
 Stroke 41 (19) 112 (16) 0.320 31 (18) 28 (16) 0.775
 Chronic obstructive pulmonary disease 85 (40) 242 (35) 0.218 68 (40) 61 (36) 0.505
 Dementia 15 (7) 49 (7) 0.962 10 (6) 12 (7) 0.832
 Cancer 9 (4) 22 (3) 0.476 7 (4) 5 (3) 0.774
Clinical findings
 Pulse (beats per minute) 95 (±24) 93 (±22) 0.346 94 (±22) 94 (±24) 0.726
 Systolic blood pressure (mmHg) 144 (±28) 150 (±29) 0.017 146 (±27) 145 (±30) 0.388
 Diastolic blood pressure (mmHg) 80 (±17) 83 (±17) 0.021 79 (±17) 80 (±18) 0.431
 Respiration (breaths per minute) 24 (±7) 24 (±6) 0.538 24 (±6) 24 (±6) 0.813
 Peripheral edema 140 (65) 450 (65) 0.961 110 (64) 115 (67) 0.672
 Pulmonary edema by chest x-ray 151 (70) 488 (70) 0.958 118 (69) 119 (70) 1.000
Tests and procedures
 Serum sodium (mEq/L) 138 (±5) 138 (±5) 0.911 139 (±5) 138 (±5) 0.092
 Serum potassium (mEq/L) 4.1 (±0.5) 4.2 (±0.6) 0.497 4.1 (±0.6) 4.2 (±0.5) 0.831
 Serum creatinine (mEq/L) 1.0 (±0.2) 1.0 (±0.2) 0.955 1.0 (±0.2) 1.0 (±0.2) 0.239
 Estimated glomerular filtration rate (ml/min/1.73m2) 77 (±15) 77 (±15) 0.838 77 (±15) 77 (±15) 0.227
 Blood urea nitrogen (mg/dL) 19 (±7) 18 (±7) 0.022 18 (±7) 19 (±7) 0.909
 Serum glucose (mg/dL) 147 (±67) 153 (±69) 0.237 146 (±56) 146 (±66) 0.727
 Hematocrit (%) 38 (±5) 38 (±5) 0.527 37 (±6) 38 (±5) 0.675
 White blood cell (103/μL) 9 (±4) 9 (±5) 0.380 9 (±7) 9 (±4) 0.740
Hospital and care characteristics
 Pneumonia 58 (27) 163 (24) 0.302 49 (29) 46 (27) 0.810
 Acute myocardial infarction 17 (8) 33 (5) 0.077 8 (5) 12 (7) 0.503
 Pressures ulcer 20 (9) 50 (7) 0.316 15 (9) 19 (11) 0.608
 Rural hospital 44 (21) 166 (24) 0.289 36 (21) 41 (24) 0.620
 Cardiology consult 145 (67) 484 (70) 0.505 116 (68) 114 (67) 0.908
 Intensive care unit 9 (4) 28 (4) 0.925 6 (4) 7 (4) 1.000
 Length of stay (days) 8 (±6) 6 (±4) <0.001 7.2 (±4.7) 6.8 (±4.6) 0.052
Discharge medications
 Beta blockers (heart failure) 33 (15) 203 (29) 0.000 31 (18) 31 (18) 1.000
 Loop diuretics 164 (76) 636 (92) <0.001 145 (85) 138 (81) 0.337
 Potassium-sparing diuretics 23 (11) 171 (25) 0.000 21 (12) 28 (16) 0.311
 Digoxin 92 (43) 444 (64) <0.001 85 (50) 88 (52) 0.813
 Calcium channel blockers 37 (17) 104 (15) 0.436 27 (16) 33 (19) 0.497
 Potassium supplements 96 (45) 350 (51) 0.134 86 (50) 81 (47) 0.734
 Nitrates and hydralazine 4 (2) 3 (0) 0.037 1 (1) 2 (1) 1.000
 Anti-arrhythmic drugs 34(16) 93 (13) 0.377 28 (16) 28 (16) 1.000
 Anti-coagulants 60 (28) 202 (29) 0.726 47 (28) 43 (25) 0.699
 Anti-platelet drugs 18 (8) 69 (10) 0.490 14 (8) 19 (11) 0.487
 Aspirin 64 (30) 314 (45) <0.001 58 (34) 56 (33) 0.901
 Insulin 15 (7) 97 (14) 0.006 15 (9) 15 (9) 1.000
 Statins 24 (11) 120 (17) 0.031 20 (12) 19 (11) 1.000
 Anti-depressants 44 (21) 107 (15) 0.084 32 (19) 36 (21) 0.678
 Non-steroidal anti-inflammatory drugs 21 (10) 57 (8) 0.481 16 (9) 18 (11) 0.860
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All-cause mortality in systolic heart failure patients with chronic kidney disease

All-cause mortality occurred in 75% and 79% of matched systolic heart failure patients with chronic kidney disease receiving and not receiving discharge prescriptions for angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, respectively, during 8 years of follow-up (hazard ratio {HR} when the use of angiotensin-converting enzyme inhibitors or angiotensin receptor blockers was compared with their non-use, 0.86; 95% confidence interval {CI}, 0.74–0.996; p=0.045; Table 3 and Figure 2). A hidden covariate that is a near-perfect predictor of all-cause mortality may potentially explain away this association if it would increase the odds of discharge prescription of these drugs by about 2%. This association was homogeneous across various subgroups of patients except for that by left ventricular ejection fraction (p for interaction, 0.004; Figure 3). Similar risk-adjusted associations were also observed among the 1665 pre-match patients with chronic kidney disease (Table 3).

Table 3.

Association of discharge prescription of angiotensin-converting enzyme inhibitor (ACEIs) or angiotensin receptor blockers (ARBs) with all-cause mortality in older systolic heart failure patients with and without chronic kidney disease

All-cause mortality % (total events/total patients) Use of ACEIs or ARBs Absolute risk difference* (%) Hazard ratio† (95% confidence interval) P value
No Yes
Chronic kidney disease
 Pre-match unadjusted 81% (503/619) 72% (753/1046) −9 0.71 (0.64–0.80) <0.001
 Pre-match multivariable-adjusted --- --- --- 0.85 (0.75–0.97) 0.016
 Pre-match propensity-adjusted --- --- --- 0.88 (0.78–1.00) 0.050
 Post-match 79% (352/444) 75% (331/444) −4 0.86 (0.74–0.996) 0.045
No chronic kidney disease
 Pre-match unadjusted 70% (151/215) 58% (399/693) −12 0.69 (0.58–0.84) <0.001
 Pre-match multivariable-adjusted --- --- --- 0.73 (0.59–0.91) 0.005
 Pre-match propensity-adjusted --- --- --- 0.76 (0.62–0.95) 0.013
 Post-match 70% (119/171) 56% (96/171) −14 0.72 (0.55–0.94) 0.015
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*

Absolute risk differences were calculated by subtracting percent events in patients not receiving angiotensin-converting enzyme inhibitors or angiotensin receptor blockers with from those receiving those drugs

†

Hazard ratios comparing patients receiving angiotensin-converting enzyme inhibitors or angiotensin receptor blockers with those not receiving those drugs

Figure 2.

Figure 2

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Kaplan-Meier plots for all-cause mortality in a propensity-matched cohort of older systolic heart failure patients with chronic kidney disease receiving and not receiving discharge prescription of angiotensin-converting enzyme inhibitors or angiotensin receptor blockers (CI=confidence interval)

Figure 3.

Figure 3

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Association of discharge prescription of angiotensin-converting enzyme inhibitors or angiotensin receptor blockers with all-cause mortality in subgroups of propensity-matched older systolic heart failure patients with chronic kidney disease

Among the 487 matched patients without pre-admission use of angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, all-cause mortality occurred in 77% and 78% of those receiving and not receiving a new discharge prescription for angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, respectively (HR, 0.97; 95% CI, 0.78–1.21; p=0.780). In contrast, among the 401 matched patients receiving pre-admission angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, all-cause mortality occurred in 73% and 83% of those receiving and not receiving continuation therapy with angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, respectively (HR, 0.73; 95% CI, 0.56–0.94; p=0.013).

Of the 444 matched patients receiving angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, data on dosages were available for 324 (73%) patients. Of these, 107 (24%) patients received at or above target doses and 217 (49%) received below-target doses of these drugs. Compared with matched patients not receiving angiotensin-converting enzyme inhibitors or angiotensin receptor blockers (79% mortality, reference), 75% of those receiving below-target doses (HR, 0.90; 95% CI, 0.74–1.08; p=0.248) and 67% of those receiving target doses (HR, 0.69; 95% CI, 0.53–0.89; p=0.004) died. Among pre-match patients, multivariable-adjusted HRs associated with below-target and target doses of angiotensin-converting enzyme inhibitors or angiotensin receptor blockers were 0.88 (95% CI, 0.75–1.02; p=0.077) and 0.77 (95% CI, 0.63–0.94; p=0.012), respectively.

Hospitalization in systolic heart failure patients with chronic kidney disease

Among matched systolic heart failure patients with chronic kidney disease, discharge prescription of angiotensin-converting enzyme inhibitors or angiotensin receptor blockers had no significant association with heart failure hospitalization (HR, 0.86; 95% CI, 0.72–1.03; p=0.094) or all-cause hospitalization (HR, 0.89; 95% CI, 0.77–1.02; p=0.101; Tables 4 and 5). HRs for heart failure hospitalization associated with below-target and target doses of angiotensin-converting enzyme inhibitors or angiotensin receptor blockers were 0.76 (95% CI, 0.61–0.95; p=0.017) and 0.74 (95% CI, 0.55–0.92; p=0.037), respectively.

Table 4.

Association of discharge prescription of angiotensin-converting enzyme inhibitor (ACEIs) or angiotensin receptor blockers (ARBs) with heart failure hospitalization in older systolic heart failure patients with and without chronic kidney disease

Heart failure hospitalization % (total events/total patients) Use of ACEIs or ARBs Absolute risk difference* (%) Hazard ratio† (95% confidence interval) P value
No Yes
Chronic kidney disease
 Pre-match unadjusted 57% (354/619) 58% (601/1046) +1 0.76 (0.67–0.87) <0.001
 Pre-match multivariable-adjusted --- --- --- 0.82 (0.71–0.95) 0.009
 Pre-match propensity-adjusted --- --- --- 0.85 (0.74–0.99) 0.032
 Post-match 57% (253/444) 55% (245/444) −2 0.86 (0.72–1.03) 0.094
No chronic kidney disease
 Pre-match unadjusted 55% (118/215) 54% (372/693) −1 0.76 (0.62–0.94) 0.010
 Pre-match multivariable-adjusted --- --- --- 0.79 (0.62–1.00) 0.052
 Pre-match propensity-adjusted --- --- --- 0.77 (0.61–0.97) 0.029
 Post-match 55% (94/171) 46% (79/171) −9 0.71 (0.52–0.95) 0.023
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*

Absolute risk differences were calculated by subtracting percent events in patients not receiving angiotensin-converting enzyme inhibitors or angiotensin receptor blockers with from those receiving those drugs

†

Hazard ratios comparing patients receiving angiotensin-converting enzyme inhibitors or angiotensin receptor blockers with those not receiving those drugs

Table 5.

Association of discharge prescription of angiotensin-converting enzyme inhibitor (ACEIs) or angiotensin receptor blockers (ARBs) with all-cause hospitalization in older systolic heart failure patients with and without chronic kidney disease

All-cause hospitalization % (total events/total patients) Use of ACEIs or ARBs Absolute risk difference* (%) Hazard ratio† (95% confidence interval) P value
No Yes
Chronic kidney disease
 Pre-match unadjusted 83% (503/619) 85% (753/1046) +2 0.79 (0.70–0.88) <0.001
 Pre-match multivariable-adjusted --- --- --- 0.88 (0.78–0.99) 0.040
 Pre-match propensity-adjusted --- --- --- 0.89 (0.79–1.01) 0.061
 Post-match 85% (376/444) 83% (369/444) −2 0.89 (0.77–1.02) 0.101
No chronic kidney disease
 Pre-match unadjusted 84% (181/215) 85% (592/693) +1 0.79 (0.67–0.93) 0.006
 Pre-match multivariable-adjusted --- --- --- 0.78 (0.64–0.94) 0.010
 Pre-match propensity-adjusted --- --- --- 0.82 (0.68–0.99) 0.039
 Post-match 83% (141/171) 85% (145/171) +2 0.94 (0.75–1.19) 0.603
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*

Absolute risk differences were calculated by subtracting percent events in patients not receiving angiotensin-converting enzyme inhibitors or angiotensin receptor blockers with from those receiving those drugs

†

Hazard ratios comparing patients receiving angiotensin-converting enzyme inhibitors or angiotensin receptor blockers with those not receiving those drugs

Outcomes in systolic heart failure patients with chronic kidney disease stage ≥3B

Among the subset of 591 matched systolic heart failure patients with chronic kidney disease stage ≥3B, all-cause mortality occurred in 80% and 83% of those receiving and not receiving angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, respectively (HR, 0.83; 95% CI, 0.70–1.00; p=0.046). Relative to non-use of these drugs, HRs for all-cause mortality associated with their use in below-target and target doses were 0.90 (95% CI, 0.72–1.12; p=0.326) and 0.67 (95% CI, 0.49–0.91; p=0.011), respectively. Respective HRs for heart failure hospitalization associated with below-target and target doses were 0.75 (95% CI, 0.57–0.98; p=0.038) and 0.60 (95% CI, 0.40–0.88; p=0.009), respectively.

Outcomes in systolic heart failure patients without chronic kidney disease

All-cause mortality occurred in 56% and 70% of matched systolic heart failure patients without chronic kidney disease receiving and not receiving angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, respectively (HR, 0.72; 95% CI, 0.55–0.94; p=0.015; Table 3). Heart failure hospitalization occurred in 46% and 55% of these patients receiving and not receiving angiotensin-converting enzyme inhibitors or angiotensin receptor blockers (HR, 0.71; 95% CI, 0.52–0.95; p=0.023; Table 4).

Discussion

Summary and relevance of the key findings

Findings of the current analysis demonstrate that in a propensity-matched balanced cohort of older systolic heart failure patients with chronic kidney disease, discharge prescriptions of angiotensin-converting enzyme inhibitors or angiotensin receptor blockers were associated with a modest but significant reduction in all-cause mortality, and that these associations were stronger for those receiving target doses of these drugs. We also observed that these associations persisted in those with more advanced chronic kidney disease. However, angiotensin-converting enzyme inhibitors or angiotensin receptor blockers had no significant associations with heart failure hospitalizations in systolic heart failure patients with chronic kidney disease. In contrast, in systolic heart failure patients without chronic kidney disease, the use of angiotensin-converting enzyme inhibitors or angiotensin receptor blockers was associated with a significant and robust reduction in both all-cause mortality and heart failure hospitalization. These findings based on rigorous propensity matching designs provide further evidence that despite concerns for worsening kidney function in systolic heart failure patients with chronic kidney disease receiving angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, discharge prescription of these drugs may be safe and associated with improved outcomes.

Potential explanation and mechanism of the key findings

A large body of evidence from randomized clinical trials supports an intrinsic beneficial effect of renin-angiotensin system inhibition in systolic heart failure.30 Angiotensin-converting enzyme inhibitors or angiotensin receptor blockers reduce ventricular preload and after load, attenuate myocardial fibrosis and maladaptive remodeling, and improve left ventricular ejection fraction and functional capacity.31,32 Renin-angiotensin system inhibition also delay disease progression and improve clinical outcomes in patients with chronic kidney disease,5,33 and improve renal function in systolic heart failure patients with advanced chronic kidney disease.34 Therefore, it is possible that angiotensin-converting enzyme inhibitors or angiotensin receptor blockers improved outcomes in those with both systolic heart failure and chronic kidney disease by improving both cardiac and renal function. Although residual bias is possible but unlikely as propensity-matched patients in our study were well-balanced on key baseline confounders.

Although treatment effect is generally more pronounced in those with more severe or advanced disease,35 it was modest in those patients with systolic heart failure and chronic kidney disease in our study. Considering that systolic heart failure patients with chronic kidney disease had more advanced disease, it is likely that pump failure was a more common cause of death than sudden death.36,37 Although angiotensin-converting enzyme inhibitors reduce both forms of death in heart failure,2 they may be less effective in reducing disease progression in those with chronic kidney disease. This notion is also supported by the lack of a significant reduction in heart failure hospitalization in those with chronic kidney disease, but not in those without chronic kidney disease. Another potential explanation for a more modest effect in those with chronic kidney disease is that more severe adverse effects (namely, renal insufficiency, hyperkalemia or hypotension) leading to a higher rate of drug discontinuation thus leading to an attenuated benefit. Although we had no data on medication use during follow-up, a post-hoc analysis demonstrated a higher admission-to-discharge discontinuation among those with chronic kidney disease stage ≥3B (24%) than with stage 3A (10%; p <0.001).

Comparison with findings from relevant published literature

In patients with coronary artery disease, systolic heart failure and chronic kidney disease, angiotensin-converting enzyme inhibitor use had no association with mortality.38 In post-acute myocardial infarction patients with reduced left ventricular ejection fraction, on the other hand, angiotensin-converting enzyme inhibitor use was associated with reduced mortality.39 Several small observational studies in systolic heart failure patients with chronic kidney disease have also suggested potential benefits of these drugs.40–42 However, the current study is distinguished from the prior studies by its larger sample size, longer follow-up, use of a more rigorous methodology, inclusion of both angiotensin-converting enzyme inhibitors and angiotensin receptor blockers, and the use of contemporary therapy for systolic heart failure. Cumulative findings from these studies, taken together with the evidence of their benefit in systolic heart failure as well as in chronic kidney disease, suggest that the use of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers should be expanded to include systolic heart failure patients with chronic kidney disease, including those with more advanced chronic kidney disease.

Clinical and public health importance

Nearly half of all systolic heart failure patients have chronic kidney disease, which is associated with poor outcomes and underuse of angiotensin-converting enzyme inhibitors or angiotensin receptor blockers. Physicians often attribute this to lack of evidence of benefit and concern for potential harmful effects.7–9 Findings from the current study should attenuate these concerns and lead to increased use of these drugs in older systolic heart failure patients with chronic kidney disease. We also observed that the benefit of these drugs was similar in those with more advanced chronic kidney disease. Nonetheless, these drugs should be prescribed with caution in those with low systolic blood pressure or high serum potassium. Because mild hypokalemia is common in heart failure patients with chronic kidney disease and is associated with poor outcomes,43 elevation of serum potassium during therapy with angiotensin-converting enzyme inhibitors or angiotensin receptor blockers may be beneficial in these patients. However, close monitoring of serum potassium is advisable, especially if serum potassium is above 5.5 mEq/L or concomitant aldosterone antagonists are prescribed.44

Potential limitations and future direction

Our study has several limitations. Despite balance in all measured baseline covariates, bias due to imbalances in unmeasured covariates is possible. Sensitivity analysis suggests that mortality reduction associated with angiotensin-converting enzyme inhibitor or angiotensin receptor blocker use in our study was rather sensitive to a potential unmeasured confounder. However, sensitivity analysis cannot determine if such an unmeasured confounder exists or not. Further, to act as a confounder, an unmeasured covariate that is a near-perfect predictor of mortality must also be associated with discharge prescription of angiotensin-converting enzyme inhibitors or angiotensin receptor blockers and not be strongly correlated with any of the 56 measured baseline covariates used in our study. Loss of data in the matching process may limit external validity but enhances internal validity. Further, over 72% of patients not receiving angiotensin-converting enzyme inhibitors or angiotensin receptor blockers (the smaller of the two groups) were matched. Patients discharged on angiotensin-converting enzyme inhibitors or angiotensin receptor blockers may have discontinued their use and vice versa. However, this is likely to be minimal,45 and the resultant regression dilution may have underestimated the observed associations.46 Findings of the current study based on a single state may limit generalizability but may have important implication for Alabama that has one of the highest heart failure mortality.47

Conclusions

A discharge prescription for angiotensin-converting enzyme inhibitors or angiotensin receptor blockers was associated with a significant but modest reduction in all-cause mortality in older systolic heart failure patients with chronic kidney disease including those with more advanced chronic kidney disease, and this association seemed stronger among those receiving these drugs at or above target doses. The use of angiotensin-converting enzyme inhibitors or angiotensin receptor blockers was also associated with a trend toward lower heart failure hospitalization in those with chronic kidney disease. These findings suggest that angiotensin-converting enzyme inhibitors or angiotensin receptor blockers are safe and beneficial in older systolic heart failure patients with chronic kidney disease.

Acknowledgments

Funding/Support: Dr. Ahmed is supported by the NIH through grants (R01-HL085561, R01-HL085561-S and R01-HL097047) from the NHLBI and a generous gift from Ms. Jean B. Morris of Birmingham, Alabama. Dr. Allman is supported by the NIH through grant (5UL1 RR025777). Dr. Sanders is supported by the NIH through grant (R01-DK46199) and by the Department of Veterans Affairs.

Footnotes

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