Chronic kidney disease continues to be a major limiting factor for long-term survival of heart transplant recipients. Little is known about the early use of renin–angiotensin system (RAS) blocking agents and their impact on renal function and hemodynamics in heart transplant recipients. In this cohort study all eligible recipients of orthotopic heart transplants at the UTAH cardiac transplantation program from 2001 through 2007 were divided into 2 groups—patients who were started on angiotensin-converting enzyme inhibitors or angiotensin receptor blockers within the first 4 weeks of transplantation and continued on these for ≥4 weeks during the first 3 months (RAS blockade group, n = 75) and those who were not (non-RAS blockade group, n = 52). All patients were followed for 1 year after transplantation. There were no significant differences at baseline between the 2 groups. Estimated glomerular filtration rate at 12 months was significantly higher in the RAS blockade group compared to the non-RAS blockade group (mean ± SD, 56.3 ± 22.4 vs 47.3 ± 18.1 ml/min/1.73 m 2 , p = 0.036). At 12 months pulmonary artery systolic pressure was significantly lower in the RAS blockade group compared to the non-RAS blockade group (30.2 ± 7.4 vs 32.9 ± 9.3 mm Hg, p = 0.023). Left ventricular ejection fraction and pulmonary capillary wedge pressure were similar between the 2 groups. In conclusion, early RAS blockade after heart transplantation is safe, well tolerated, and associated with better renal function and hemodynamic profile at 1 year after transplantation.
Renin–angiotensin system (RAS) blocking agents such as angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) have been shown to add renal protection in various clinical settings. Little is known about the early use of RAS blockade agents in patients after heart transplantation and their impact on renal function, hemodynamic and clinical parameters during the first year after transplantation. We hypothesized that early use of RAS blockers in patients after heart transplantation may improve their outcomes by favorably preserving renal function and hemodynamics.
Methods
From 2001 through 2007, 219 patients underwent transplantation at our Utah cardiac transplantation program. We divided these patients into 2 groups. The RAS blockade group (n = 75) consisted of patients who were started on an antihypertensive regimen including an ACE inhibitor or an ARB within the first 4 weeks after transplantation and continued for ≥4 weeks during the first 3 months after transplantation. The non-RAS blockade group (n = 52) included patients who were not started on ACE inhibitor or ARB within the first year after transplantation. Patients who were started on ACE inhibitors or ARBs beyond the first 4 weeks of transplantation but within the first year were excluded (n = 92). Our institutional protocol for immunosuppression (combination of calcineurin inhibitors, cell-cycle inhibitors, and steroids) was used for most patients.
Data were collected from review of medical records and included baseline demographics, etiology of heart failure (ischemic vs nonischemic), allograft ischemic time, laboratory values, recipient history of hypertension or diabetes mellitus, vital signs, hemodynamic and echocardiographic parameters. The Modification of Diet in Renal Disease formula was used for the estimated glomerular filtration rate (eGFR). This study was approved by the institutional review board.
Data are presented as mean ± SD for normally distributed continuous variables. Multivariable linear regression was used for controlling for confounders, specifically for 12-month outcomes including serum creatinine, eGFR, and pulmonary artery (PA) pressures. All known and potential confounders were considered for inclusion in multivariable analysis in stepwise fashion. Baseline outcome measurement was included as a covariate in analysis of covariance fashion. The analysis of covariance approach is known to be a more powerful test than a group comparison of baseline to postintervention change. Another advantage is that analysis of covariance is not distorted by regression toward the mean bias, whereas a change analysis is subject to that bias. A t test or chi-square test was used for categorical data as appropriate. A 2-tailed p value ≤0.05 was considered statistically significant. Statistical analyses were performed using STATA 11.2 (STATA Corp., College Station, Texas).
Results
Study inclusion criteria were met in 127 patients who were included in the study and final analysis. Comparison was made between those who received RAS blockade (75 patients) for ≥4 weeks after heart transplantation versus those who did not (52 patients). There were no differences at baseline between the 2 groups in etiology of heart failure (p = 0.30), allograft ischemic time (p = 0.48), recipient history of hypertension (p = 0.70), or diabetes mellitus (p = 0.70). Baseline characteristics of the 2 groups are presented in Table 1 .
| Early RAS Blockade Group | Non-RAS Blockade Group | p Value | |
|---|---|---|---|
| (n = 75) | (n = 52) | ||
| Age at transplantation (years), mean ± SD | 47.7 ± 12.9 | 47.6 ± 14.8 | 0.94 |
| Men | 63 (84%) | 37 (71%) | 0.08 |
| Etiology of Heart Failure | 0.30 | ||
| Ischemic | 31 (41%) | 19 (36%) | |
| Nonischemic | 44 (59%) | 33 (63%) | |
| Cold ischemic time (minutes), mean ± SD | 206 ± 64.8 | 197.6 ± 61.9 | 0.48 |
| Pretransplantation history of hypertension | 18 (24%) | 14 (27%) | 0.70 |
| Pretransplantation diabetes mellitus | 15 (20%) | 9 (17%) | 0.70 |
| Pretransplantation serum creatinine (mg/dl), mean ± SD | 1.2 ± 0.3 | 1.3 ± 0.5 | 0.06 |
| Patients on angiotensin-converting enzyme inhibitors after transplantation | 64 (85%) | 0 | — |
| Patients on angiotensin receptor blockers after transplantation | 11 (15%) | 0 | — |
| Patients on β blocker after transplantation | 10 (13%) | 13 (25%) | 0.93 |
| Patients on statins after transplantation | 61 (81%) | 34 (65%) | 0.04 |
| Immunosuppressive regimen | |||
| Mycophenolate mofetil | 47 (63%) | 38 (73%) | 0.22 |
| Azathioprine | 10 (13%) | 4 (8%) | 0.32 |
| Cyclosporine | 56 (75%) | 31 (60%) | 0.07 |
| Tacrolimus | 19 (25%) | 21 (40%) | 0.07 |
| Prednisone | 75 (100%) | 52 (100%) | 0.23 |
| Rapamycin | 4 (5%) | 2 (4%) | 0.70 |
At 3 months the average systolic/diastolic blood pressures in the early RAS blockade group was 127 ± 13/79.1 ± 11.9 versus 124 ± 21/76.6 ± 13.9 mm Hg (p = 0.31) for the non-RAS blockade group. Similarly, there was no significant difference in average systolic/diastolic blood pressures between the 2 groups at 12 months after transplantation (126 ± 15/79 ± 10 vs 128 ± 18/78 ± 12, p = 0.61). For renal function at 3 months there was a trend toward better renal function in the RAS blockade group compared to the non-RAS blockade group (unadjusted eGFR by univariable analysis was 62.3 ± 22.1 vs 55.3 ± 20.9 ml/min/1.73 m 2 , respectively, p = 0.07). Adjusted eGFR by multivariable analysis was not significant (p = 0.18). Serum creatinine at 3 months was 1.4 ± 0.4 for the RAS blockade group versus 1.6 ± 1.1 for the non-RAS blockade group (p = 0.19). PA systolic pressures were similar (31.5 ± 7.8 vs 30.7 ± 7.8, p = 0.55) for the RAS blockade group compared to the non-RAS blockade group, respectively.
At 12 months unadjusted eGFR was significantly better for the RAS blockade group compared to the non-RAS blockade group (56.3 ± 22.4 vs 47.3 ± 18.1 ml/min/1.73 m 2 , p = 0.027). The difference in eGFR for the 2 groups remained significant after adjusting for covariates and baseline eGFR in multivariable analysis (p = 0.036). In concordance with this finding serum creatinine at 12 months was significantly better for the RAS blockade group than for the non-RAS blockade group (1.6 ± 0.54 versus 1.9 ± 2.1, p = 0.025) after controlling for age, gender, ischemic time, cyclosporine and rapamycin use, and baseline serum creatinine ( Figure 1 ) . We further analyzed the effect of statin therapy when added to RAS blockade on renal function at 1 year after transplantation. Addition of statin to RAS blockade therapy did not seem to be of added advantage in preserving renal function in univariable and multivariable analyses. Serum creatinine was 1.6 ± 0.6 versus 1.5 ± 0.32 (p = 0.5) for the combined statin and RAS blockade group compared to patients treated with only ACE inhibitor/ARB.
Systolic PA pressure at 12 months on early RAS blockade therapy was 30.2 ± 7.4 versus 32.9 ± 9.3 mm Hg for the non-RAS blockade group (p = 0.023) after controlling for potential confounders such as age, gender, ejection fraction, pulmonary capillary wedge pressure, and baseline PA pressure. Diastolic PA pressures at 12 months did not differ (12.6 ± 5.1 vs 13.6 ± 5.4 mm Hg, p = 0.13) between the 2 groups. Various outcomes at 3 and 12 months are presented in Table 2 .
| Early RAS Blockade Group | Non-RAS Blockade Group | p Value | |
|---|---|---|---|
| (n = 75) | (n = 52) | ||
| Outcomes at 3 months | |||
| Estimated glomerular filtration rate (ml/min/1.73 m 2 ) ⁎ | 62.3 ± 22.1 | 55.3 ± 20.9 | 0.18 |
| Serum creatinine (mg/dl), mean ± SD | 1.4 ± 0.4 | 1.6 ± 1.1 | 0.19 |
| Systolic blood pressure (mm Hg) | 127 ± 13 | 124 ± 21 | 0.31 |
| Diastolic blood pressure (mm Hg) | 79.1 ± 11.9 | 76.6 ± 13.9 | 0.31 |
| Mean arterial pressure (mm Hg) | 95 ± 9.9 | 92.5 ± 15.2 | 0.24 |
| Pulmonary artery systolic pressure (mm Hg) | 31.5 ± 7.8 | 30.7 ± 7.8 | 0.55 |
| Outcomes at 12 months | |||
| Pulmonary artery systolic pressure (mm Hg) † | 30.2 ± 7.4 | 32.9 ± 9.3 | 0.02 |
| Pulmonary artery diastolic pressure (mm Hg) | 12.6 ± 5.1 | 13.6 ± 5.4 | 0.13 |
| Pulmonary capillary wedge pressure (mm Hg) | 11.3 ± 4.8 | 11.7 ± 5.2 | 0.58 |
| Systolic blood pressure (mm Hg) | 126 ± 15 | 128 ± 18 | 0.61 |
| Diastolic blood pressure (mm Hg) | 79 ± 10 | 78 ± 12 | 0.61 |
| Mean arterial pressure (mm Hg) | 94.9 ± 10.7 | 94.4 ± 13.1 | 0.97 |
| Left ventricular ejection fraction (%) | 59.4 ± 5.4 | 59.9 ± 5.4 | 0.60 |
| Serum creatinine (mg/dl), mean ± SD ‡ | 1.6 ± 0.5 | 1.9 ± 2.1 | 0.02 |
| Estimated glomerular filtration rate (ml/min/1.73 m 2 ) ⁎ | 56.3 ± 22.4 | 47.3 ± 18.1 | 0.036 |
| Serum potassium (mEq/L) | 4.4 ± 0.4 | 4.3 ± 0.5 | 0.35 |
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