Abstract:
There is no clear consensus on the safety of renin–angiotensin–aldosterone system inhibitors in patients with contrast media exposure. We aimed to assess the safety of renin–angiotensin–aldosterone system inhibitors in patients exposed to contrast media at 1-year follow-up. Patients treated with angiotensin-converting enzyme inhibitor/angiotensin receptor blocker (ACEI/ARB) were recruited and randomly divided into 2 groups (1:1 ratio): with ACEI/ARB group (ACEI/ARB continued throughout the study period) and without ACEI/ARB group (ACEI/ARB stopped 24 hours before and continued 48 hours after the procedure). The primary endpoint was contrast-induced acute kidney injury (CI-AKI) and secondary endpoints were major adverse cardiovascular events (MACEs), and the need for renal replacement therapy during hospitalization and at 1-year follow-up. The occurrence rates of CI-AKI were not comparable in the ACEI/ARB group and the without ACEI/ARB group (2.92% and 2.62%, respectively; P = 0.866). No significant between-group differences were found with respect to the frequency of MACEs or renal replacement therapy during hospitalization and at 1-year follow-up. On subgroup analysis, among patients with estimated glomerular filtration rate (eGFR) < 45 mL/min, the incidence of CI-AKI was significantly higher in the ACEI/ARB group [17.95% (14/78) vs. 6.02% (5/83), P = 0.029]. Among patients with eGFR ≥ 45 mL/min, the incidence of CI-AKI was comparable in the 2 groups [0.87% (5/572) vs. 2.12% (12/567), P = 0.094]. The incidence of MACEs and renal replacement therapy was not comparable in the 2 groups, during hospitalization and at 1-year follow-up. ACEI or ARB treatment can safely be continued after exposure to contrast media, but not in patients with eGFR < 45 mL/min.
Key Words: angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, renin–angiotensin–aldosterone system, contrast-induced acute kidney injury
INTRODUCTION
With the increasing use of contrast media in clinical investigations, contrast-induced acute kidney injury (CI-AKI) is a key concern, particularly for patients with coronary artery disease (CAD).1,2 CI-AKI occurs in 2%–30% of patients exposed to contrast media, leading to an increased risk of severe adverse events such as renal failure, cardiovascular events, stroke, and death.3 Despite the advances in medicine, CI-AKI has been reported to be the third biggest cause of hospital-acquired acute renal failure in the United States and European countries.4
Renin–angiotensin–aldosterone system (RAAS) inhibitors, including angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs), are deemed to be effective against cardiovascular disease and kidney disease.5,6 However, there is no clear consensus on the effect of ACEIs/ARBs on the occurrence of CI-AKI. Wolak et al7 found that ACEIs and ARBs can safely be continued after coronary angiography in patients with estimated glomerular filtration rate (eGFR) ≥ 60 mL/min. On the contrary, Ma et al8 found that the incidence of CI-AKI postcoronary artery angiography (CAG)/percutaneous coronary intervention (PCI) in the ACEI/ARB group was significantly higher than that in the no-ACEI/ARB group (26.6% vs. 16.2%, P < 0.001). Peng et al9 also found that ARBs increased the risk of CI-AKI [odds ratio (OR) = 3.31, P < 0.0005], but not to be observed for ACEI (OR = 0.86, 95% CI = 0.43–1.72; P = 0.664). However, these were single-center studies with a limited sample size. In addition, hydration therapy is now a standard protocol for patients receiving intravenous contrast to reduce the risk of CI-AKI. This may have affected the occurrence of CI-AKI in these patients.
Therefore, we conducted a randomized controlled study to evaluate the effect of ACEI/ARB treatment on the incidence of CI-AKI in patients with contrast media exposure at 1-year follow-up.
METHODS
Study Population and Design
This multicenter randomized controlled study was conducted in 2 medical centers (Shenzhen People's Hospital and Guangdong Provincial People's Hospital) in China. A total of 1300 patients who required contrast media exposure for cardiac catheterization or coronary computed tomography angiography (CCTA) between October 2017 and December 2019 were randomized into 2 groups: with ACEI/ARB group (n = 650, ACE/ARB continued throughout the study period) and without ACEI/ARB group (n = 650, ACE/ARB stopped 24 hours before the procedure and continued 48 hours after) (Fig. 1). The sample size for each group (n ≥ 635) was calculated by Pearson χ2 test for comparison of 2 proportions with 1:1 sampling) using PASS 15 software.10 Written informed consent was obtained from all patients before their enrolment.
FIGURE 1.
Schematic illustration of the study design and patient-selection criteria.
All patients followed the standard protocol for the preparation for cardiac catheterization or CCTA including hydration treatment 12 hours before and at least 24 hours after, according to the guidelines. This study was approved by the ethics committee of the Shenzhen People's Hospital and registered in the Chinese Clinical trial Registry (ChiCTR1800015188).
Inclusion Criteria
The inclusion criteria were: Patients aged >18 years with suspected CAD undergoing cardiac catheterization (CAG or PCI) or CCTA; 2) chronic therapy with ACEI and/or ARB for at least one week.
Exclusion Criteria
Exclusion criteria were: (1) systolic blood pressure < 90 mm Hg; (2) patients using nonsteroidal anti-inflammatory drugs; (3) contrast media exposure ≤14 days; (4) allergic to contrast media; (5) patients on continuous renal replacement therapy or prior renal transplantation; (6) age >90 years. Patients with acute myocardial infarction (AMI) requiring primary PCI were also excluded.
Study Endpoints
The primary endpoint was CI-AKI defined as serum creatinine increase ≥ 25% from the baseline or 44 µmol/L ≤ 48 hours. eGFR was calculated by the 4-variable Modification of Diet in Renal Disease (MDRD).11 The secondary endpoints were major adverse cardiovascular events (MACEs) (defined as the composite of cardiac death, nonfatal myocardial infarction, unstable angina, and heart failure) and the need for renal replacement therapy during hospitalization and at 1-year follow-up. Follow-up data were collected by telephonic interview.
Statistical Analysis
SPSS 22.0 (SPSS, Inc., Chicago, IL) was used for statistical analysis. Continuous variables are expressed as mean ± SD and between-group differences assessed using Student's test for normally distributed variables and Kruskal–Wallis test or Mann–Whitney U test for abnormally distributed variables. Categorical variables are expressed as frequency (percentage) and between-group differences assessed using χ2 or Fisher Exact test. A repeated measures analysis adjusted for the baseline levels was performed to compare creatinine, urea, and eGFR measures before and 24 and 48 hours after catheterization or CCTA between the 2 groups.
RESULTS
Baseline Characteristics of the Two Groups
Between October 2017 and September 2019, a total of 1300 patients were included in this study. The baseline characteristics of patients in the ACEI/ARB group and without ACEI/ARB group are compared in Table 1. There was no significant between-group difference with respect to the mean age of patients (57.1 ± 13.9 years and 57.1 ± 12.7 years, respectively, P = 0.978), hypertension (580, 89.23% and 594, 91.38%, respectively, P = 0.874), or baseline creatinine levels (96.91 ± 41.85 and 97.27 ± 45.93 respectively, P = 0.883, Table 2). Similarly, there were no significant between-group differences with respect to other demographic characteristics, laboratory parameters, clinical manifestations, type of angiography, medical treatment, volume of contrast media, or daily fluid intake.
TABLE 1.
Baseline Characteristics of Patients in the Two Groups
| Characteristics | With ACEI/ARB Group (n=650) | Without ACEI/ARB Group (n=650) | P |
| Age (y) | 57.12 ± 13.95 | 57.10 ± 12.79 | 0.978 |
| Male, n (%) | 516 (79.38) | 519 (79.85) | 0.891 |
| Body mass index, kg/m2 | 23.09 ± 3.42 | 24.45 ± 3.18 | 0.065 |
| SBP (mm Hg) | 132.60 ± 24.27 | 134.34 ± 23.07 | 0.187 |
| HR (bpm) | 81.72 ± 18.23 | 81.22 ± 17.15 | 0.128 |
| Hypertension, n (%) | 580 (89.23) | 594 (91.38) | 0.874 |
| Diabetes mellitus, n (%) | 161 (24.77) | 148 (22.77) | 0.790 |
| Insulin requiring, n (%) | 73 (45.34) | 70 (47.30) | 0.731 |
| Metformin, n (%) | 144 (89.44) | 134 (90.54) | 0.675 |
| Current smoking, n (%) | 330 (50.77) | 335 (51.54) | 0.811 |
| Previous MI, n (%) | 31 (4.77) | 33 (5.08) | 0.792 |
| Previous PCI, n (%) | 24 (3.69) | 26 (4.00) | 0.968 |
| Diagnosis, n (%) | |||
| STEMI, n (%) | 40 (6.15) | 34 (5.38) | 0.154 |
| NSTEMI, n (%) | 120 (18.46) | 116 (17.85) | 0.900 |
| Unstable angina, n (%) | 289 (44.46) | 294 (45.23) | 0.892 |
| Stable angina, n (%) | 70 (12.31) | 65 (10.0) | 0.676 |
| Without significant stenosis, n (%) | 131 (20.15) | 141 (21.69) | 0.889 |
| Hemoglobin (g/L) | 137.38 ± 22.79 | 139.09 ± 19.75 | 0.148 |
| Albumin (g/L) | 31.5 ± 9.3 | 30.4 ± 10.6 | 0.765 |
| LDL (mmol/L) | 2.83 ± 0.98 | 2.93 ± 0.98 | 0.076 |
| HbA1C, % | 6.56 ± 3.87 | 6.67 ± 4.51 | 0.016 |
| Na+ (mmol/L) | 138.12 ± 4.36 | 143.42 ± 6.54 | 0.125 |
| LVEF, % | 54.46 ± 10.72 | 54.80 ± 22.93 | 0.743 |
| Medical treatment | |||
| Aspirin, n (%) | 585 (90.00) | 584 (89.85) | 0.912 |
| Clopidgrel/ticadgrol | 545 (83.85) | 540 (83.08) | 0.930 |
| Statin, n (%) | 632(97.23) | 635 (97.69) | 0.939 |
| Beta-blocker, n (%) | 311 (47.85) | 300 (46.15) | 0.899 |
| Diuretics, n (%) | 90 (13.85) | 85 (13.77) | 0.896 |
| Ca channel blocker, n (%) | 125 (19.23) | 150 (23.08) | 0.565 |
| ACEI, n (%) | 281 (43.23) | 275 (42.31) | 0.776 |
| ARB, n (%) | 369 (56.77) | 375 (57.69) | 0.836 |
| Type of angiography | |||
| Cardiac catheterization, n (%) | 551(84.77) | 531(81.69) | 0.553 |
| CCTA, n (%) | 99 (15.23) | 119 (18.31) | 0.494 |
| No. of patients with PCI, n (%) | 335 (52.15) | 328 (50.46) | 0.757 |
| No. of stents/patient | 1.43 ± 0.90 | 1.40 ± 0.97 | 0.685 |
| Bleeding complications* | 1 (0.15) | 1 (0.15) | 1.0 |
| TRA/dTRA | 638 (98.15) | 641 (98.62) | 0.911 |
| Volume of contrast media (mL) | 92.67 ± 48.34 | 96.19 ± 42.43 | 0.165 |
| Hydration | |||
| Intravenous hydration, n (%) | 410 (63.08) | 405 (62.31) | 0.673 |
| Oral hydration, n (%) | 240 (39.92) | 245 (37.69) | 0.673 |
| Daily fluid intake, ml | |||
| 24h-post | 2242.86 ± 97.59 | 2295.49 ± 115.01 | 0.316 |
| 48h-post | 2554.29 ± 167.22 | 2687.27 ± 257.45 | 0.203 |
ACEI/ARB, angiotensin-converting enzyme inhibitor/angiotensin receptor blocker; dTRA, distal transradial approach; HR, heart rate; LVEF, left ventricular ejection fraction; MI, myocardial infarction; PCI, percutaneous coronary intervention; SBP, systolic blood pressure; TRA, transradial approach.
Bleeding complications were defined as those requiring blood transfusion or causing a decrease in hemoglobin of >3.0g/dL within 72 h after PCI.
TABLE 2.
Comparison of Renal Function Indices in the Two Groups
| With ACEI/ARB Group (n=650) | Without ACEI/ARB Group (n=650) | P | |
| Before contact with contrast | |||
| Creatinine, µmol/L | 96.91 ± 41.85 | 97.27 ± 45.93 | 0.883 |
| Urea, mmol/L | 7.65 ± 9.73 | 8.15 ± 1.03 | 0.434 |
| eGFR* (mL/min) | 77.74 ± 27.49 | 77.64 ± 24.24 | 0.945 |
| cystatin C, mg/L | 2.54 ± 1.54 | 2.44 ± 1.64 | 0.665 |
| Hs-CRP, mg/L | 4.54 ± 3.84 | 4.34 ± 2.96 | 0.543 |
| 24-post contact with contrast | |||
| Creatinine, µmol/L | 94.66 ± 42.96 | 94.09 ± 56.79 | 0.839 |
| Urea, mmol/L | 8.95 ± 10.01 | 9.65 ± 10.33 | 0.771 |
| eGFR* (mL/min) | 80.49 ± 28.75 | 83.10 ± 27.64 | 0.100 |
| cystatin C, mg/L | 3.24 ± 1.31 | 2.945 ± 1.53 | 0.766 |
| Hs-CRP, mg/L | 5.04 ± 3.13 | 4.99 ± 2.82 | 0.675 |
| 48-post contact with contrast | |||
| Creatinine, µmol/L | 97.82 ± 48.07 | 97.31 ± 52.40 | 0.855 |
| Urea, mmol/L | 8.55 ± 11.54 | 8.95 ± 13.21 | 0.454 |
| eGFR* (mL/min) | 79.78 ± 40.64 | 80.63 ± 31.65 | 0.675 |
| cystatin C, mg/L | 3.99 ± 2.11 | 3.44 ± 2.54 | 0.449 |
| Hs-CRP, mg/L | 5.44 ± 4.52 | 5.35 ± 4.44 | 0.531 |
Data presented as mean ± SD.
*eGFR was calculated by the four-variable Modification of Diet in Renal Disease (MDRD).
Primary and Secondary Endpoints In-Hospital
The occurrence rates of CI-AKI (primary endpoint) in the ACEI/ARB group and the without ACEI/ARB group were 2.92% and 2.62% (P = 0.866; Table 3 and Fig. 2), whereas the occurrence rates of MACEs and renal replacement therapy during hospitalization were 8.62% versus 8.92% (P = 0.837) and 0% versus 0%, respectively. At one-year follow-up, there were no significant between-group differences with respect to the frequency of MACEs (19.54% vs. 18.92%, P = 0.872) or renal replacement therapy (0.31% vs. 0.15%, P = 0.795), respectively (Table 3).
TABLE 3.
Comparison of Primary and Secondary Outcomes Between the Two Groups
| With ACEI/ARB Group (n = 650) | Without ACEI/ARB Group (n = 650) | P | |
| In-hospital | |||
| CI-AKI, n (%) | 19 (2.92) | 17 (2.62) | 0.866 |
| ACEI | 9/281 (3.20) | 8/275 (2.91) | 0.821 |
| ARB | 10/369 (2.71) | 9/375 (2.40) | 0.874 |
| MACE, n (%) | 56 (8.62) | 58 (8.92) | 0.837 |
| Cardiac death, n (%) | 0 (0) | 0 (0) | 1.0 |
| Nonfatal MI, n (%) | 19 (2.92) | 18 (2.77) | 0.834 |
| Unstable angina, n (%) | 22 (3.38) | 26 (2.4) | 0.787 |
| Heart failure, n (%) | 15 (2.31) | 14 (2.15) | 0.833 |
| Renal replacement therapy | 0 (0) | 0 (0) | 1.0 |
| 1-year follow-up | |||
| MACE, n (%) | 127 (19.54) | 123 (18.92) | 0.872 |
| Cardiac death, n (%) | 1 (0.15) | 0 (0) | 0.657 |
| Nonfatal MI, n (%) | 34 (5.23) | 31 (4.77) | 0.821 |
| Unstable angina, n (%) | 44 (6.77) | 42 (6.46) | 0.910 |
| Heart failure to hospitalization, n (%) | 46 (7.08) | 49 (7.54) | 0.901 |
| Renal replacement therapy, n (%) | 2 (0.31) | 1 (0.15) | 0.795 |
MI, myocardial infarction.
FIGURE 2.
Occurrence of CI-AKI in the 2 groups (2.92% vs. 2.62%, P = 0.866).
We further performed subgroup analysis based on eGFR levels. Among patients with eGFR < 45 mL/min, the occurrence rate of CI-AKI in the ACEI/ARB group [17.95% (14/78)] was significantly higher than that in the without ACEI/ARB group [6.02% (5/83), P = 0.029]. However, among patients with eGFR ≥ 45 mL/min, there was no significant difference in the occurrence rate of CI-AKI [0.87% (5/572) versus 2.12% (12/567), P = 0.094], respectively (Fig. 3).
FIGURE 3.
Influence of RAAS inhibitors on CI-AKI after coronary angiography in patients with different eGFR grade during hospitalization. A, Patients with eGFR < 45 mL/min: the incidence of CI-AKI was significantly higher in the with ACEI/ARB group [17.95% (14/78) versus 6.02% (5/83); P = 0.029]. B, Patients with eGFR ≥ 45 mL/min: the incidence of CI-AKI in the with and without ACEI/ARB groups was 0.87% (5/572) versus 2.12% (12/567), respectively; P = 0.094).
We also further performed subgroup analysis based on AMI or with PCI. The incidences of CI-AKI were similar between groups in patients with AMI [9.38% (15/160) versus 8.00% (12/150); P = 0.691] or with PCI [5.07% (17/335) versus 4.57% (15/328); P = 0.857], respectively (Fig. 4).
FIGURE 4.
Influence of RAAS inhibitors on CI-AKI after coronary angiography in patients with AMI or with PCI during hospitalization. A, Patients with AMI: The incidence of CI-AKI was no difference between groups [9.38% (15/160) versus 8.00% (12/150); P = 0.691]. B, Patients without PCI: The incidence of CI-AKI was no difference between groups [5.07% (17/335) vs. 4.57% (15/328); P = 0.857].
DISCUSSION
The multicenter randomized controlled study was conducted to evaluate the safety of ACEI/ARB in patients with contrast exposure at 1-year follow-up. The major findings were as follows: (1) ACEI/ARB use was not associated with increased incidence of CI-AKI, composite frequency of MACE, or the requirement for renal replacement therapy. (2) ACEI/ARB should be avoided in patients with eGFR < 45 mL/min.
ACEI/ARBs are commonly used in patients with cardiovascular diseases such as hypertension, diabetes mellitus, heart failure, or chronic kidney disease to prevent end organ damage, unless contraindicated.12,13 These drugs have been shown to improve the long-term prognosis of patients with cardiovascular and renal diseases. However, the effect of ACEI/ARBs on CI-AKI is not clear. In the study by Rim et al,14 64% of patients undergoing coronary angiography were treated with ACEI/ARB, which significantly increased the incidence of CI-AKI after propensity score matching (11.4% vs. 6.3%, P < 0.001). Bainey et al15 randomly divided 208 patients with renal insufficiency requiring contrast media into 2 groups: continuing ACEI/ARB or stopping ACEI/ARB 24 hours before surgery. The incidence of CI-AKI (18.5% vs. 10.9%) and renal replacement therapy (3.9% vs. 0%) was obviously higher in the continuing ACEI/ARB group. RAAS inhibitors cause a decrease in eGFR and an increase in SCr, promoting CI-AKI.16 However, Wolak et al7 and Kevin et al15 found no significant difference between ACEI/ARB use and contrast contact in patients with eGFR ≥ 60 mL/min or moderate renal insufficiency. Similar conclusions were drawn by a meta-analysis of RCTs (pooled OR = 1.22, P = 0.63) in patients with normal or mild-to-moderate renal insufficiency.17 Our results also suggest that ACEIs and ARBs can be safely continued after angiography in patients exposed to contrast media with suspected CAD. The following factors may explain these results. First, these studies included patients with normal or mild-to-moderate renal dysfunction. In our RCT, patients with eGFR < 45 mL/min accounted for only 10.08% of all patients. Second, each included patient received rigorous standardized hydration treatment. The increasing awareness of hydration treatment and the improvement in surgical techniques of PCI, have caused a dramatic decline in the occurrence of CI-AKI.
ACEI/ARBs should be avoided in patients with eGFR < 45 mL/min because the incidence of CI-AKI was significantly higher in this subgroup [17.95% vs. 6.02%; P = 0.029). It is generally believed that abnormal hemodynamics is the main pathological basis of CI-AKI caused by ACEI/ARBs. Their stronger effect of selectively expanding glomerular outlet arterioles leads to lower renal perfusion and lower glomerular filtration rate. Accordingly, CI-AKI is more likely to occur after exposure to contrast agents.18 In addition, recent studies have also indicated the existence of an angiotensin-converting enzyme-angiotensin II-angiotensin II receptor 1 axis in the RAAS system.19 Angiotensin II induces the formation of transforming growth factor-beta 1 to promote regeneration and repair after renal injury and the inhibition of angiotensin II activity by ACEI/ARB may be involved in the occurrence and development of CI-AKI.20,21 Therefore, the continued use of ACEI/ARB after contrast agent exposure aggravates the occurrence of CI-AKI and worsens the prognosis of patients with severe renal insufficiency. Several studies have confirmed the harmful effects of angiotensin II blockade on patients exposed to contrast agents, mostly in patients with impaired renal function and the elderly.22
Some limitations of our study should be acknowledged. First, since most RAAS inhibitors have a half-life of more than 24 hours, ACEI/ARBs should be stopped at least 48 hours before contrast media exposure. Second, a larger sample of patients with severe renal dysfunction should be included in next study. In addition, future RCT studies should separately assess the effect of ACEIs and ARBs on CI-AKI.
CONCLUSIONS
Our results suggest that ACEIs and ARBs can safely be continued after contrast media exposure during CAG/PCI or CCTA in patients with suspected CAD, but not in patients with eGFR < 45 mL/min.
ACKNOWLEDGMENTS
The authors would like to express their gratitude to all those who helped them during the writing of this manuscript. Thanks to all the peer reviewers for their opinions and suggestions.
Footnotes
Supported by Shenzhen Foundation (SZLY2017025 and JCY 20210324113614038), Shenzhen Key Medical Discipline Construction Fund (No. SZXK003) and Sanming Project of Medicine in Shenzhen (No. SZSM201412012).
The authors report no conflicts of interest.
Y. W. Lin, H. D. Liu, and D. Q. Yu designed, collected, analyzed and wrote this manuscript. Y. H. Liu, S. H. Dong, J. Yuan, Y. S. Wang and X. Sun assisted in the conduct of study. Y. H. Liu, S. H. Dong, J. Yuan, and X. Sun performed the research. Y. W. Lin, H. D. Liu, and D. Q. Yu was the principal investigator.
Ethics approval and consent to participate: The study was conducted in accordance with the Declaration of Helsinki. The protocol was approved by the Ethics Committee of Shenzhen People's Hospital (approval number: SZLY2017025). All participants provided informed consent prior to participation in the study.
Contributor Information
Shaohong Dong, Email: xnkdsh@yeah.net.
Yuanhui Liu, Email: xnliuqiyun@yeah.net.
Yongshun Wang, Email: xnkwangyongshun@yeah.net.
Xin Sun, Email: xnksunxin@yeah.net.
Jie Yuan, Email: xnkyuanjie@yeah.net.
Danqing Yu, Email: gdyudanqing@126.com.
Huadong Liu, Email: gdliuhuadong@yeah.net.
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