IMR Press / RCM / Volume 23 / Issue 3 / DOI: 10.31083/j.rcm2303102
Open Access Systematic Review
Hypertensive status is associated with renoprotection by remote ischemic conditioning for acute myocardial infarction—a meta-regression and trial sequential analysis of randomized clinical trials
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1 Department of Cardiology, State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Disease, Chinese Academy of Medical Sciences and Peking Union Medical College, 100037 Beijing, China
2 Department of Anesthesiology, State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Disease, Chinese Academy of Medical Sciences and Peking Union Medical College, 100037 Beijing, China
3 Department of Cardiology, The First Affiliated Hospital of Baotou Medical College, 014000 Baotou, Inner Mongolia, China
*Correspondence: chenghuizhou@yahoo.com (Chenghui Zhou); phjfyss@126.com (Hanjun Pei)
These authors contributed equally.
Academic Editor: Gianluca Campo
Rev. Cardiovasc. Med. 2022 , 23(3), 102; https://doi.org/10.31083/j.rcm2303102
Submitted: 15 November 2021 | Revised: 4 January 2022 | Accepted: 18 January 2022 | Published: 16 March 2022
(This article belongs to the Special Issue Myocardial infarction: unsolved issues and future options)
Copyright: © 2022 The Author(s). Published by IMR Press.
This is an open access article under the CC BY 4.0 license.
Abstract

The potential modifiable factors for remote ischemic conditioning (RIC) in reducing contrast-associated acute kidney injury (CA-AKI) in patients with acute myocardial infarction (AMI) have not been investigated. The aim of this meta-regression was to address these issues.We searched Pubmed, Embase and the Cochrane Library database for published randomized controlled trials (RCTs) with registration number CRD42020155532. Nine RCTs comprising of 1540 subjects were included in our meta-analysis. Compared with control group, RIC was associated with reduced incidence of CA-AKI [(9 studies, 1540 subjects, relative risk (RR) 0.51, 95% confidence intervals (CI) 0.35 to 0.76, p = 0.000, I2 = 52%, p for heterogeneity 0.04)] and major adverse cardiovascular events (MACE) (5 studies, 1078 subjects, RR 0.52, 95% CI 0.38 to 0.73, p = 0.000, I2 = 9%, p for heterogeneity 0.36) for AMI. In addition, both meta-regression and subgroup analyses have shown that RIC was more effective in the hypertensive patients in reducing CA-AKI for AMI (regression coefficient = –0.05, p = 0.021; for subgroup with more hypertensive patients: RR 0.36, 95% CI 0.25 to 0.52 vs the one with less hypertensive patients: RR 0.72, 95% CI (0.40 to 1.30, p for subgroup difference 0.008). Subsequent trial sequential analysis confirmed the effect of RIC in both CA-AKI and MACE. RIC is an effective strategy in reducing CA-AKI and MACE in patients with AMI, especially for patients with hypertension.

Keywords
RIC
AMI
CA-AKI
meta-analysis
1.Introduction

Acute myocardial infarction (AMI) is one of the leading causes of mortality and morbidity globally. Emergency percutaneous coronary intervention (PCI) was recommended as the standard therapy to perfuse the ischemic myocardium, especially for the ST-segment elevated myocardial infarction (STEMI) [1, 2]. However, reperfusion seems like as a double-edged sword, acting the role of rescuing but causing injury for the myocardium. The latter is also known as ischemia-reperfusion injury (IRI) [3]. IRI during emergency PCI not only directly causes damage to heart, but also inducing systematic inflammatory response potentiating the impairment of vital organs such as kidney [4, 5].

Contrast-associated acute kidney injury (CA-AKI), as defined by the increment of serum creatinine >44.2 mmoL/L or 25% above the baseline value within 48–72 h of contrast media exposure [6], is a common complication during cardiovascular intervention for reduced renal blood of renal medulla [7, 8]. What’s more, emergency PCI is more frequently associated with hemodynamic instability which could deteriorate the renal blood infusion. Moreover, patients breaking out with AMI are likely to possess other combined risk factors [9]. Many clinical studies have indicated that CA-AKI not only prolongs the hospitalization but also increases the mortality in long term [10]. Till now, many strategies such as use isotonic contrast agents, cysteine, statins have been tried but failed to show the effective results [11]. Remote ischemic conditioning (RIC), including pre-, per- and post-conditioning, a technique to apply the mild nonlethal ischemia and reperfusion in one organ and protect lethal IRI in other organs or tissues [12]. Accumulating experimental and clinical evidence have reported that RIC was effective in reducing infracted size, attenuating left ventricular remodeling and increasing myocardial salvage after AMI [13, 14, 15, 16]. Many studies have reported that RIC is helpful to reduce CA-AKI in patient with stable coronary artery diseases undergoing either elective coronary artery bypass graft (CABG) surgery or PCI [17, 18]. However, the effect of RIC on CA-AKI for AMI is still controversial. Some studies have indicated that RIC was helpful in reducing CA-AKI while others did not show the similar results [19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29]. Given the mixed background, we performed a meta-analysis of randomized controlled trials (RCTs) to explore the effect of RIC in reducing CA-AKI as well as to explore the potential factors affecting RIC in renoprotection for AMI.

2. Methods
2.1 Literature search

We reported this meta-analysis following the guidance of PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-analysis)statement [30]. We searched Pubmed (Medline), Embase and the Cochrane Library database (http://www.cochrane.org) (up to June 2020) with registration number CRD42020155532. We also manually searched reference lists of the retrieved articles. The key words used in search were (ischemic post-conditioning or post-conditioning or ischemic pre-conditioning or pre-conditioning or remote ischemic conditioning) paired with (myocardial infarction or myocardial injury or percutaneous coronary intervention or acute kidney injury or contrast induced nephropathy).

2.2 Study outcomes and selection

The primary endpoint was CA-AKI, which was diagnosed by increment of serum creatinine >44.2 mmoL/L or above the base value of 25% with 48–72 h exposure of contrast without other obvious factors. The secondary outcome was long-term major adverse cardiovascular events (MACE). The definitions of MACE used by each study and included all cause death, cardiac death, heart failure, revascularization or myocardial infarction.The third outcome was the net change in creatinine or estimate glomerular filtration (eGFR) due to RIC.

Inclusion criteria for the retrieved studies were as follows: (1) prospective RCT design; (2) performed in the patients with AMI (including STEMI and non-STEMI (NSTEMI)); (3) inclusion of outcomes of CA-AKI; (4) inclusion of multivariable-adjusted or unadjusted relative risk (RR)/hazard ratio (HR) and their corresponding 95% confidence intervals (CI); or provided the number of events and total population in each group;

2.3 Quality assessment

Two authors (Yuehua Li and Ying Lou) assessed the quality of the RCTs by the Cochrane criteria including adequacy of random sequence generation, allocation concealment, blinding of participants and personnel, blinding of outcome assessment, incomplete outcome data, intention-to-treat analysis and other bias [31]. Trials scored one point for each item addressed. If 3 quality criteria were not met, the study was classified as having high risk of bias; others were classified as having moderate (3–5 points) or low (5 points) risk of bias.

2.4 Data extraction

Data were extracted by two independent authors (Yuehua Li and Ying Lou). Discrepancies were resolved by group discussion. The extracted data included source of study (author, publication year, country), population characteristics [protocol, conditioning, patients number, mean age, male proportion, percentage of smoking, diabetes mellitus (DM), hypertension, hyperlipidemia, multi-vessel disease, left anterior descending (LAD)branch involving, use of angiotensin-converting enzyme inhibitor(ACEI)/angiotension receptor blocker (ARB), beta-blocker (BB) and statin, follow-up period], the clinical endpoints, RRs or HRs and their corresponding 95% CI.

2.5 Statistical analysis

We considered the HRs as RRs in the prospective studies. We calculated the RR by the number of events and total population in the RIC and control group. The random-effect model was also used in the pooled analysis for the potential clinical heterogeneity [32]. The heterogeneity was assessed by Q statistic, I2 and p value (I2> 50%, p < 0.05 was considered to be statistically significant). If there is no significant heterogeneity, we would use the fixed-effect model. Univariable meta-regression analyses (including age, percentage of male, smoking, DM, hypertension, hyperlipidemia, multi-vessel disease, LAD inclusion, use of ACEI/ARB, BB and statin, protocol time, study quality, area) were conducted to explore the potential sources of heterogeneity [33]. Subgroup analyses we real so conducted to explore the potential sources of heterogeneity by specified study characteristics including area (China or other countries), study quality [high risk (quality score <3 points) or moderate/low risk (quality score 3 points)], protocol (conditioning time 15 min or <15 min), conditioning (by pre-conditioning or post-conditioning), AMI type (STEMI or NSTEMI) and the mean of the mentioned factor such as age, proportion of smoking, DM, hypertension, hyperlipidemia, multi-vessel disease, LAD occlusion, use of ACEI/ARB, BB and statin [33].

Publication bias was assessed by Begg’s test and Egger’s test [34]. We performed the trial sequential analyses (TSA) of CA-AKI or MACE following AMI based on the data from our pooled analysis (RR and incidence of CA-AKI and MACE) to calculate the required sample size for the statistical power (Two sided: Type-I error = 0.05; λ = 2.0; Power = 80%). Two sided p value < 0.05 was considered to be significant. All data analyses were performed by STATA software (10.0 version, StataCorporation, TX, USA), REVMAN software (version 5.0; Cochrane Collaboration, Oxford, United Kingdom) and Trail Sequential Analysis (Copenhagen Trial Unit, Copenhagen, Denmark).

3. Results
3.1 Search results

We initially identified 9223studies by database and manual searching. After exclusion of duplicates and non-relevant studies, 29 potential articles were selected for detailed evaluation. We further excluded 20 articles as shown in Fig. 1. Finally, nine studies were included. Among them, all have reported the impact of RIC on CA-AKI and five about the endpoint of long-term MACE [19, 21, 22, 23, 29].

Fig. 1.

Flow Chart of the Trial Selection Process. AMI, acute myocardial infarction; CA-AKI, contrast-associated acute kidney injury; RIC, remote ischemic conditioning.

3.2 Study characteristics and data quality

Tables 1,2 (Ref. [19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29]) showed the main characteristics of the data extracted from the included studies. All included studies were randomized and prospective.Three study scored low risk of bias [19, 20, 21], three with moderate [23, 26, 29] and three with high risk of bias [22, 24, 25] (Supplementary Fig. 1).

Table 1.Characteristics of included randomized clinical trials.
Study Country MItype Protocol Algorithm Conditioning Patients No. (RIC vs control) Age Male (%) Diabetes (%) Hypertension (%) Smoking (%)
Deftereos et al. 2013 [19] Greece NSTEMI 4 × 1 min at lesion site post-conditioning 113 vs 112 68 64 36 65 29
Crimi et al. 2014 [20] Italy STEMI 3 × 5 min/5 min at lower limb (200 mmHg) post-conditioning 47 vs 48 58.5 87.5 12 53.5 53.5
Yamanaka et al. 2015 [21] Japan STEMI 3 × 5 min/5 min at upper limb (200 mmHg) pre-conditioning 47 vs 47 67 74.5 33 63.8 55.3
Wang et al. 2016 [22] China STEMI 3 × 2 min at infarct-related artery post-conditioning 123 vs 128 62.6 77.7 26.7 65.3 66.9
Cao et al. 2018 [24] China STEMI 4 × 5 min/5 min at upper limb (200 mmHg) post-conditioning 36 vs 44 59 86.2 18.8 66.3 NA
Caoet al. 2018 [25] China STEMI 4 × 5 min/5 min at upper limb (200 mmHg) post-conditioning 29 vs 35 59.2 87.5 18.8 65.6 71.9
Gaspar et al. 2018 [26] Portugal STEMI 3 × 5 min/5 min at upper limb (200 mmHg) pre-conditioning 231 vs 217 60 80.1 27.9 50 58.9
Moretti et al. 2018 [27] Italy NSTEMI 4 × 5 min/5 min at upper limb (200 mmHg) pre-conditioning 107 vs 116 72.3 67.2 38.4 89.2 16.7
Zhou et al. 2018 [28] China ACS 4 × 5 min/5 min at upper limb (200 mmHg) pre-conditioning 50 vs 57 69.3 60.7 47.7 56.1 20.6
Elbadawi et al. 2018 [23] USA STEMI 3 × 5 min/5 min at upper limb (200 mmHg) pre-conditioning 30 vs 30 51.5 83 41 32.4 70.4
Guo et al. 2019 [29] China NSTEMI 3 × 5 min/5 min at upper limb (200 mmHg) pre-conditioning 110 vs 110 71.3 59.1 44 NA NA
Table 2.Coronary involvement, risk factors, medication, and endpoints of included trials.
Study Dyslipidemia (%) Muti-vessel disease (%) LAD occlusion (%) ACEI/ARB (%) β-blocker (%) Statins (%) CA-AKI (RIC vs control) MACE
Deftereos et al. 2013 [19] 59 55.1 54.2 NA 17 36 14/113 vs 33/112 14/113 vs 25/112
Crimi et al. 2014 [20] 31.5 35 100 NA 100 100 7/47 vs 6/48 NA
Yamanaka et al. 2015 [21] 55.3 NA 42.6 95.7 5.32 16 5/47 vs 17/47 2/47 vs 7/47
Wang et al. 2016 [22] NA 78.9 NA NA NA NA 7/123 vs 18 /128 9/123 vs 20 /128
Cao et al. 2018 [24] 12.5 18.8 46.3 33.8 68.8 100 4/36 vs 18 /47 NA
Cao et al. 2018 [25] 20.3 12.5 48.4 42.2 85.9 100 3/29 vs 11/35 NA
Gaspar et al. 2018 [26] 50 11.6 44 35.9 15.2 29.2 45/231 vs 45/217 19/231 vs 28/217
Moretti et al. 2018 [27] 67.4 NA NA NA NA NA 10/57 vs 15/54 NA
Zhou et al. 2018 [28] 25.2 NA NA 67.3 72.9 95.3 5/50 vs 15/57 2/50 vs 3/57
Elbadawi et al. 2018 [23] 76.7 10 NA NA NA NA 1/30 vs 5/30 4/30 vs 2/30
Guo et al. 2019 [29] NA 35 NA 86.4 75.9 94.5 12/110 vs 18/110 NA
NOTE: ACEI, angiotensin-converting enzyme inhibitor; ACS, acute coronary syndrome; AMI, acute myocardial infarction; ARB, angiotensin receptor blocker; CA-AKI, contrast-induced nephropathy; LAD, left anterior descending; MACE, major adverse cardiovascular events; MI, myocardial infarction; NA, not available; RIC, remote ischemic conditioning.
3.3 Effect of RIC in reducing CA-AKI, MACE, serum creatinine and eGFRin AMI

All studies have reported the endpoint of CA-AKI and five reported the risk of MACE. Compared with the control group, the group with RIC was associated with reduced risk of CA-AKI (9 studies, 1540 subjects, RR 0.51, 95% CI 0.35 to 0.76, p = 0.007, I2 = 52%, p for heterogeneity 0.04) (Fig. 2A) and MACE (5 studies, 1078 subjects, RR 0.52, 95% CI 0.38 to 0.73, p = 0.0001, I2 = 9%, p for heterogeneity 0.36) (Fig. 2B) for patients with AMI. The net change in serum creatinine and eGFR were 0.52 (95% CI 0.38 to 0.53) and 17.96 (95% CI 14.92 to 21.00), respectively (Supplementary Figs. 2,3). Given the study by Crimiet al. [20] is a post-hoc analysis, we performed sensitivity analysis by excluding this study and found that the group with RIC was also associated with reduced risk of CA-AKI (8 studies, 1445 subjects, RR 0.47, 95% CI 0.32 to 0.71, p = 0.0003, I2 = 52%, p for heterogeneity 0.04).

Fig. 2.

Funnel plot of RIC in Reducing CA-AKI (2A) and MACE (2B) in AMI. Meta-analysis of the effect of RIC in reducing CA-AKI (A) and risk of MACE (B) in the condition of AMI. AMI, acute myocardial infarction; CI, confidence intervals; CA-AKI, contrast-associated acute kidney injury; MACE, major adverse cardiovascular events; RIC, remote ischemic conditioning.

3.4 Meta-regression and subgroup analysis

For the main endpoint of CA-AKI, we performed both meta-regression and subgroup analyses by specific study characteristics which was mentioned above. In univariable meta-regression, the percentage of hypertension at baseline was negatively related to risk of CA-AKI (regression coefficient = –0.05, p = 0.021) (Table 2, Fig. 3). This factor was further confirmed by subgroup analysis [for subgroup with hypertensive patients over 58% (mean): RR 0.36, 95% CI 0.25 to 0.52 vsless than 58% (mean): RR 0.72, 95% CI 0.40 to 1.30, p for subgroup difference 0.008] (Table 3). The subgroup analysis also has indicated that the proportion of age, male, DM, conditioning, quality score might be possible modifiable factors, however these factors were not verified by meta-regression analyses (Tables 3,4).

Fig. 3.

Meta-regression plot on the incidence of CA-AKI against proportion of hypertension. Meta-regression analysis of the percentage of hypertension as a modifiable factor for CA-AKI. CA-AKI, contrast-associated acute kidney injury; RR, risk ratio.

Table 3.Univariable meta-regression of baseline characteristics for RIC in reducing CA-AKI for AMI.
Baseline characteristics Number of trials Risk of CA-AKI
Coefficient 95% CI I2 (%) p
Age 10 –0.012 (–0.095 to 0.072) 47.54 0.75
Male proportion 10 0.004 (–0.037 to 0.045) 50.57 0.82
Diabetes proportion 10 –0.010 (–0.051 to 0.031) 50.94 0.59
Hypertension proportion 9 –0.050 (–0.090 to –0.010) 9.01 0.02
Smoking proportion 8 0.003 (–0.029 to 0.034) 55.61 0.83
Dyslipidemia proportion 8 0.002 (–0.030 to 0.034) 62.34 0.88
Multi-vessel disease proportion 8 –0.006 (–0.007 to 0.027) 39.23 0.49
LAD branch occlusion 6 0.016 (–0.023 to 0.056) 71.29 0.31
ACEI/ARB use proportion 6 –0.005 (–0.033 to 0.024) 56.72 0.68
Beta-blocker use proportion 8 0.002 (–0.014 to 0.017) 60.73 0.82
Statin use proportion 8 –0.0004 (–0.015 to 0.014) 59.22 0.95
Protocol 11 0.003 (–0.025 to 0.032) 45.91 0.79
Area 11 –0.366 (–1.082 to 0.349) 36.36 0.28
Conditioning time 11 0.358 (–0.322 to 1.038) 30.92 0.26
Qulity score 11 0.102 (–0.109 to 0.313) 42.71 0.30
ACEI, angiotensin-converting enzyme inhibitor; AMI, acute myocardial infarction; ARB, angiotensin receptor blocker; CI, confidence interval; CA-AKI, contrast-associated acute kidney injury; LAD, left anterior descending; RIC, remote ischemic conditioning.
Table 4.Subgroup analysis by specific study characteristics for RIC in reducing CA-AKI for AMI.
Characteristic Risk of CA-AKI
Data points, No Pooled RR (95% CI) pa pb
All studies 11 0.52 (0.38 to 0.72) 0.07
age
<63 6 0.55 (0.31 to 0.95) 0.491 0.049
63 4 0.45 (0.31to 0.64) 0.048
Male proportion
<76% 4 0.45 (0.31to 0.64) 0. 048 0.049
76% 6 0.55 (0.31 to 0.95) 0.491
Percentage of hypertension
<58% 4 0.72 (0.40 to 1.30) 0.156 0.000
58% 5 0.36 (0.25 to 0.52) 0.942
Percentage of diabetes
<31% 4 0.58 (0.33 to 1.02) 0.042 0.031
31% 5 0.44 (0.311 to 0.62) 0.573
Percentage of multi-vessel diseases
<32% 4 0.46 (0.20 to 1.05) 0.041 0.215
32% 4 0.55 (0.36 to 0.85) 0.262
Percentage of LAD occlusion 0.205
<56% 5 0.45 (0.25 to 0.89) 0.012
56% 1 1.19 (0.43to 3.29) 0
Percentage of dyslipidemia
<41% 4 0.46 (0.24 to 0.87) 0.197 0.230
41% 4 0.49 (0.25 to 0.96) 0.016
Percentage of smoking
<53% 2 0.41 (0.25 to 0.66) 0.857 0.062
53 6 0.54 (0.31 to 0.94) 0.039
Percentage of ACEI/ARB use
<60% 3 0.50 (0.21 to 1.22) 0.032 0.094
60% 3 0.46 (0.27 to 0.76) 0.310
Percentage of beta-blocker use
<55% 3 0.52 (0.26 to 1.07) 0.01 0.343
55% 5 0.52 (0.32 to 0.84) 0.244
Percentage of statin use
<71% 3 0.52 (0.26 to 1.07) 0.010 0.343
71% 5 0.52 (0.32 to 0.84) 0.244
Study quality
High risk 6 0.42 (0.29 to 0.63) 0.697 0.044
Moderate/low risk 5 0.62 (0.39 to 1.00) 0.034
By protocol time
<15 min 2 0.41 (0.26 to 0.66) 0.923 0.086
15 min 9 0.55 (0.38 to 0.80) 0.069
By conditioning
Pre-conditioning 5 0.61 (0.40 to 0.92) 0.395 0.035
Post-conditioning 6 0.43 (0.30 to 0.63) 0.097
By type of myocardial infarction 0.348
STEMI 7 0.49 (0.29 to 0.83)
NSTEMI 2 0.51 (0.33 to 0.80)
By area 0.067
China 5 0.44 (0.30 to 0.65)
others 6 0.59 (0.37 to 0.95)
ACEI, angiotensin-converting enzyme inhibitor; AMI, acute myocardial infarction; ARB, angiotension receptor blocker; CI, confidence interval; CA-AKI, contrast-associated acute kidney injury; LAD, left anterior descending; NSTEMI, non-STEMI; RIC, remote ischemic conditioning; STEMI, ST-segment elevated myocardial infarction. a: p for heterogeneity; b: p for subgroup analysis analysis.
3.5 Trial sequential analysis

To confirmed the pooled effect sizes of CA-AKI or MACE as true estimated effect, the required sample sizes for the CA-AKI is 959 (RR reduction = 50.0%, incidence of Control arm = 22.0%), and MACE (RR reduction = 50.0%, incidence of Control arm = 17.0%) is 561. However, the same size of CA-AKI (1540 vs 959) or MACE (1078 vs 561) is enough for the estimated effect (Supplementary Figs. 4,5).

3.6 Publication bias

The publication bias of CA-AKI was not observed by Begg’s adjusted rank correlation test (p = 0.35) and Egger’s test (p = 0.06) (Supplementary Fig. 6).

4.Discussion

In this meta-analysis of nine RCTs including 1540 subjects, we found that RIC was an effective strategy in reducing the incidence of CA-AKI in patients with AMI, with a profound protection associated with a 0.51-fold lower risk. What’s more, our meta-regression showed that the effect of RIC seemed to be more beneficial for the hypertensive patients. In addition, RIC was also showed long-term protective effect with a reduce risk of MACE for long term (RR 0.52). To our knowledge, this is the first meta-regression analysis focusing on the modifiable factors for renoprotection of RIC in AMI patient.

The effect of RIC from previous studies in reducing CA-AKI in patients with AMI was inconsistent. We combined all available RCTs and found that RIC was an effective strategy in preventing RIC. Our study was in line with previous two meta-analyses which have showed that RIC was beneficial for prevention of acute kidney injury in patients with PCI, coronary artery bypass grafting and other cardiac surgeries [35, 36]. However, these two meta-analyses did not discriminate the effect of RIC in different conditions separately. Our study has found that RIC was not only effective in reducing the incidence of CA-AKI in AMI, but also associated with an improved long-term prognosis. The current meta-analysis has extended previous finding that that RIC was effective in reducing CA-AKI in elective PCI [37, 38]. In addition, our meta-analysis has indicated that RIC also showed a long-term cardiac protection in reducing MACE. This result was consistent with recent studies which have reported that RIC was an benefit for AMI patents in reducing MACE, heart failure as well as myocardial edema levels, myocardial salvage index [26]. Moreover, the TSA results showed that, assuming future trials record the same event rates as the published trials, they did not need additional participants to provide future meta-analysis with the power to confirm the benefit for CA-AKI and MACE. This meaningful and intriguing finding indicates that RIC is probably an effective renoprotection strategy in the condition of AMI.

The effect of RIC in reducing CA-AKI for AMI may be influenced by some modifiable factors. Our meta-regression has showed that hypertension status was negatively associated with the reduced risk of CA-AKI. What’s more, our subgroup analyses have showed that the group with more percentage of hypertensive patients was benefit more (RR 0.36 vs 0.72) from RIC treatment under the condition of AMI. Our results were in lined with previous studies which have reported that RIC was effective in reducing systolic blood pressure about 5 mmHg [39, 40]. In addition, hypertension is a well-known risk factor for AMI and our results have also suggested that RIC might be more effective for some high-risk patients. Our study was consistent with previous trials which have also suggested that RIC was more effective in kidney protection for high-risk patients undergoing PCI or cardiac surgery [41, 42]. Nevertheless, the influential effect of hypertension in RIC-induced renoprotection needs more large sample-size and high-quality clinical trials to verify in future.

Results from our meta-analysis indicated that RIC was an effective strategy in reducing CA-AKI and MACE for AMI. This meaningful and intriguing finding indicates that RIC is probably an effective renoprotection strategy in AMI. Hence, routine performance of RIC would be helpful for renal protection under the condition of acute ischemic events. Future experimental studies are needed to explore the mechanism about the RIC for kidney protection. In addition, large randomized controlled trials are necessary to extend the investigation of the effect of RIC for renal protection in both cardiac and non-cardiac conditions.

5. Limitation

Our meta-analysis has some limitations. First, we did not use the multivariable adjusted RR for the effect size, resulting inpotential residual confounders. Second, the excluded studies which performed in patients with acute coronary syndrome might influence on the effect size. Third, five included studies were from China. Although our subgroup analyses have indicated that area was not a modifiable factor, it needs further investigation for RIC in reducing CA-AKI for AMI. Finally, our meta-analysis used pooled data, rather than individual data, which restricted detailed analysis for the potential confounding factors.

6. Conclusions

Our meta-analysis of nine RCTs comprising 1540 patients has demonstrated that RIC remains an effective strategy in reducing CA-AKI for AMI, especially for the hypertensive group. Routine RIC in AMI should be recommended for renal protection.

Author contributions

Conceptualization, CZ and HP; methodology, YLi; software, YLi; validation, YLi, YLo, HP, and CZ; formal analysis, YLi; investigation, YLo; resources, YLo; data curation, YLo; writing—original draft preparation, YLi; writing—review and editing, YLo, HP, and CZ; visualization, CZ; supervision, CZ; project administration, HP; funding acquisition, HP, and CZ. All authors have read and agreed to the published version of the manuscript.

Ethics approval and consent to participate

Not applicable.

Acknowledgment

Not applicable.

Funding

This work was supported by the Clinical Research Foundation of Fuwai Hospital (No. 2016-ZX033), and the National Natural Science Foundation of China (No. 81970290 and 81760096).

Conflict of interest

The authors declare no conflicts of interest.

References
[1]
Ibanez B, James S, Agewall S, Antunes MJ, Bucciarelli-Ducci C, Bueno H, et al. 2017 ESC Guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation: the Task Force for the management of acute myocardial infarction in patients presenting with ST-segment elevation of the European Society of Cardiology (ESC). European Heart Journal. 2018; 39: 119–177.
[2]
Danchin N, Popovic B, Puymirat E, Goldstein P, Belle L, Cayla G, et al. Five-year outcomes following timely primary percutaneous intervention, late primary percutaneous intervention, or a pharmaco-invasive strategy in ST-segment elevation myocardial infarction: the FAST-MI programme. European Heart Journal. 2020; 41: 858–866.
[3]
Yellon DM, Hausenloy DJ. Myocardial Reperfusion Injury. New England Journal of Medicine. 2007; 357: 1121–1135.
[4]
Heusch G, Libby P, Gersh B, Yellon D, Böhm M, Lopaschuk G, et al. Cardiovascular remodelling in coronary artery disease and heart failure. The Lancet. 2014; 383: 1933–1943.
[5]
Candilio L, Malik A, Hausenloy DJ. Protection of organs other than the heart by remote ischemic conditioning. Journal of Cardiovascular Medicine. 2013; 14: 193–205.
[6]
Mehran R, Dangas GD, Weisbord SD. Contrast-Associated Acute Kidney Injury. The New England Journal of Medicine. 2019; 380: 2146–2155.
[7]
Vlachopanos G, Schizas D, Hasemaki N, Georgalis A. Pathophysiology of Contrast-Induced Acute Kidney Injury (CIAKI). Current Pharmaceutical Design. 2019; 25: 4642–4647.
[8]
Faucon A, Bobrie G, Clément O. Nephrotoxicity of iodinated contrast media: from pathophysiology to prevention strategies. European Journal of Radiology. 2019; 116: 231–241.
[9]
McCullough PA, Choi JP, Feghali GA, Schussler JM, Stoler RM, Vallabahn RC, et al. Contrast-Induced Acute Kidney Injury. Journal of the American College of Cardiology. 2016; 68: 1465–1473.
[10]
Rihal CS, Textor SC, Grill DE, Berger PB, Ting HH, Best PJ, et al. Incidence and prognostic importance of acute renal failure after percutaneous coronary intervention. Circulation. 2002; 105: 2259–2264.
[11]
Almendarez M, Gurm HS, Mariani J, Montorfano M, Brilakis ES, Mehran R, et al. Procedural Strategies to Reduce the Incidence of Contrast-Induced Acute Kidney Injury during Percutaneous Coronary Intervention. JACC: Cardiovascular Interventions. 2019; 12: 1877–1888.
[12]
Heusch G. Cardioprotection: chances and challenges of its translation to the clinic. The Lancet. 2013; 381: 166–175.
[13]
Yamaguchi T, Izumi Y, Nakamura Y, Yamazaki T, Shiota M, Sano S, et al. Repeated remote ischemic conditioning attenuates left ventricular remodeling via exosome-mediated intercellular communication on chronic heart failure after myocardial infarction. International Journal of Cardiology. 2015; 178: 239–246.
[14]
Bøtker HE, Kharbanda R, Schmidt MR, Bøttcher M, Kaltoft AK, Terkelsen CJ, et al. Remote ischaemic conditioning before hospital admission, as a complement to angioplasty, and effect on myocardial salvage in patients with acute myocardial infarction: a randomised trial. The Lancet. 2010; 375: 727–734.
[15]
Wei M, Xin P, Li S, Tao J, Li Y, Li J, et al. Repeated remote ischemic postconditioning protects against adverse left ventricular remodeling and improves survival in a rat model of myocardial infarction. Circulation Research. 2011; 108: 1220–1225.
[16]
Honda T, He Q, Wang F, Redington AN. Acute and chronic remote ischemic conditioning attenuate septic cardiomyopathy, improve cardiac output, protect systemic organs, and improve mortality in a lipopolysaccharide-induced sepsis model. Basic Research in Cardiology. 2019; 114: 15.
[17]
Zhou C, Jeon Y, Meybohm P, Zarbock A, Young PJ, Li L, et al. Renoprotection by remote ischemic conditioning during elective coronary revascularization: a systematic review and meta-analysis of randomized controlled trials. International Journal of Cardiology. 2016; 222: 295–302.
[18]
Bei W, Duan C, Chen J, Wang K, Liu Y, Liu Y, et al. Remote Ischemic Conditioning for Preventing Contrast-Induced Acute Kidney Injury in Patients Undergoing Percutaneous Coronary Interventions/Coronary Angiography: a Meta-Analysis of Randomized Controlled Trials. Journal of Cardiovascular Pharmacology and Therapeutics. 2016; 21: 53–63.
[19]
Deftereos S, Giannopoulos G, Tzalamouras V, Raisakis K, Kossyvakis C, Kaoukis A, et al. Renoprotective effect of remote ischemic post-conditioning by intermittent balloon inflations in patients undergoing percutaneous coronary intervention. Journal of the American College of Cardiology. 2013; 61: 1949–1955.
[20]
Crimi G, Ferlini M, Gallo F, Sormani MP, Raineri C, Bramucci E, et al. Remote ischemic postconditioning as a strategy to reduce acute kidney injury during primary PCI: a post-hoc analysis of a randomized trial. International Journal of Cardiology. 2014; 177: 500–502.
[21]
Yamanaka T, Kawai Y, Miyoshi T, Mima T, Takagaki K, Tsukuda S, et al. Remote ischemic preconditioning reduces contrast-induced acute kidney injury in patients with ST-elevation myocardial infarction: a randomized controlled trial. International Journal of Cardiology. 2015; 178: 136–141.
[22]
Wang Y, Li T, Liu Y, Wang Y, Hu X, Gao W, et al. Ischemic Postconditioning before Percutaneous Coronary Intervention for Acute ST-Segment Elevation Myocardial Infarction Reduces Contrast-induced Nephropathy and Improves Long-term Prognosis. Archives of Medical Research. 2016; 47: 483–488.
[23]
Elbadawi A, Awad O, Raymond R, Badran H, Mostafa AE, Saad M. Impact of Remote Ischemic Postconditioning during Primary Percutaneous Coronary Intervention on Left Ventricular Remodeling after Anterior Wall ST-Segment Elevation Myocardial Infarction: a Single-Center Experience. The International Journal of Angiology. 2017; 26: 241–248.
[24]
Cao B, Wang H, Zhang C, Xia M, Yang X. Remote Ischemic Postconditioning (RIPC) of the Upper Arm Results in Protection from Cardiac Ischemia-Reperfusion Injury Following Primary Percutaneous Coronary Intervention (PCI) for Acute ST-Segment Elevation Myocardial Infarction (STEMI). Medical Science Monitor. 2018; 24: 1017–1026.
[25]
Cao B, Zhang C, Wang H, Xia M, Yang X. Renoprotective effect of remote ischemic postconditioning in patients with ST-elevation myocardial infarction undergoing primary percutaneous coronary intervention. Therapeutics and Clinical Risk Management. 2018; 14: 369–375.
[26]
Gaspar A, Lourenço AP, Pereira MÁ, Azevedo P, Roncon-Albuquerque R, Marques J, et al. Randomized controlled trial of remote ischaemic conditioning in ST-elevation myocardial infarction as adjuvant to primary angioplasty (RIC-STEMI). Basic Research in Cardiology. 2018; 113: 14.
[27]
Moretti C, Cerrato E, Cavallero E, Lin S, Rossi ML, Picchi A, et al. The EUROpean and Chinese cardiac and renal Remote Ischemic Preconditioning Study (EURO-CRIPS CardioGroupi): a randomized controlled trial. International Journal of Cardiology. 2018; 257: 1–6.
[28]
Zhou F, Song W, Wang Z, Yin L, Yang S, Yang F, et al. Effects of remote ischemic preconditioning on contrast induced nephropathy after percutaneous coronary intervention in patients with acute coronary syndrome. Medicine. 2018; 97: e9579.
[29]
Guo S, Jian L, Cheng D, Pan L, Liu S and Lu C. Early Renal-Protective Effects of Remote Ischemic Preconditioning in Elderly Patients with Non-ST-Elevation Myocardial Infarction (NSTEMI). Medical Science Monito.2019;25:8602-8609.
[30]
Moher D, Liberati A, Tetzlaff J and Altman DG. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement.British Medical Journal, 2009; 339: b2535.
[31]
Higgins JPT and Sally G. Cochrane Handbook for Systematic Reviews of Interventions. Version 5.0.2. London: The Cochrane Collaboration. 2009.
[32]
DerSimonian R, Laird N. Meta-analysis in clinical trials. Controlled Clinical Trials. 1986; 7: 177–188.
[33]
Higgins JPT, Thompson SG. Quantifying heterogeneity in a meta-analysis. Statistics in Medicine. 2002; 21: 1539–1558.
[34]
Egger M, Davey Smith G, Schneider M, Minder C. Bias in meta-analysis detected by a simple, graphical test. British Medical Journal. 1997; 315: 629–634.
[35]
Yang Y, Lang X, Zhang P, Lv R, Wang Y, Chen J. Remote ischemic preconditioning for prevention of acute kidney injury: a meta-analysis of randomized controlled trials. American Journal of Kidney Diseases. 2014; 64: 574–583.
[36]
Zhang L, Diao Y, Chen G, Tanaka A, Eastwood GM, Bellomo R. Remote ischemic conditioning for kidney protection: a meta-analysis. Journal of Critical Care. 2016; 33: 224–232.
[37]
Wang X, Kong N, Zhou C, Mungun D, Iyan Z, Guo Y, et al. Effect of Remote Ischemic Preconditioning on Perioperative Cardiac Events in Patients Undergoing Elective Percutaneous Coronary Intervention: a Meta-Analysis of 16 Randomized Trials. Cardiology Research and Practice. 2017; 2017: 1–14.
[38]
Pranata R, Tondas AE, Vania R, Toruan MPL, Lukito AA, Siswanto BB. Remote ischemic preconditioning reduces the incidence of contras-induced nephropathy in patients undergoing coronary angiography/intervention: Systematic review and meta-analysis of randomized controlled trials. Catheterization and Cardiovascular Interventions. 2020; 96: 1200–1212.
[39]
Madias JE, Koulouridis I. Effect of repeat twice daily sessions of remote ischemic conditioning over the course of one week on blood pressure of a normotensive/prehypertensive subject. International Journal of Cardiology. 2014; 176: 1076–1077.
[40]
Madias JE. Effect of serial arm ischemic preconditioning sessions on the systemic blood pressure of a normotensive subject. Medical Hypotheses. 2011; 76: 503–506.
[41]
Zarbock A, Kellum JA, Van Aken H, Schmidt C, Küllmar M, Rosenberger P, et al. Long-term Effects of Remote Ischemic Preconditioning on Kidney Function in High-risk Cardiac Surgery Patients: follow-up Results from the RenalRIP Trial. Anesthesiology. 2017; 126: 787–798.
[42]
Savaj S, Savoj J, Jebraili I and Sezavar SH. Remote ischemic preconditioning for prevention of contrast-induced acute kidney injury in diabetic patients.IranianJournal of Kidney Diseases. 2014; 8: 457-460.
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