Effect of Remote Ischemic Preconditioning on Myocardial and Renal Injury: Meta-Analysis of Randomized Controlled Trials

Author(s): 

Gaurav Alreja, MD1, Diogo Bugano, MD2, Amir Lotfi, MD1

Patients receiving RIPC had lower levels of markers of myocardial injury in the first few days after surgery (standardized mean difference [SMD], 0.54; 95% confidence interval [CI], -1.01 to -0.08; P=.01) with highly heterogeneous results (I2 = 93%) (Figure 2) and no serious signs of publication bias (Figure 3). They also had a lower incidence of perioperative myocardial infarction (7.9% RIPC vs 13.9% placebo; relative risk [RR], 0.56; 95% CI, 0.37-0.84; P=.005; I2 = 0%) (Figure 4). The effect of RIPC on markers of myocardial injury seemed constant for all subgroups evaluated (Figure 2), especially patients undergoing cardiac surgery (Figure 5). The main source of heterogeneity identified was the study by Rahman et al.42 If we exclude it from the subgroup on-pump CABG, the effect size of this group rises to SMD of -0.65 (95% CI, -0.9 to -0.4), the heterogeneity though falls to I2 = 0%, and the results reach statistical significance (P<.001).

Attempts were made to run separate analyses for studies that reported values of troponin at 24 hours and area under the curve (AUC) troponin at 72 hours, but this resulted in small sample sizes and unreliable results (data not shown). An analysis for the interaction of RIPC and beta-blockers or sevoflurane/desflurane was also not possible, because no study reported outcomes stratified for the use of these drugs. Only 2 studies reported data on mortality, and thus the effect of RIPC could not be estimated.

The analysis of the impact of RIPC on creatinine levels included 3 studies with patients undergoing open AAA repair61-63 and 2 studies with patients undergoing on-pump CABG.42,58 Patients undergoing RIPC had a significant reduction in the levels of creatinine in the first few days after surgery (SMD, 0.28; 95% CI, -0.49 to -0.08; P=.007; I2 = 51%) (Figure 6).

Discussion

Overall, our meta-analysis suggests that RIPC is an effective cardiac and renal protective strategy across different interventions as measured by biomarkers. In addition, we demonstrate for the first time that it reduces the incidence of myocardial infarction in the perioperative period for patients undergoing cardiovascular interventions.

Although the results obtained are similar to a previously published meta-analysis by Takagi et al,64 the SMD obtained by our analysis is lower (SMD, -0.54; 95% CI, -1.01 to -0.08 for ours vs SMD, -0.81; 95% CI, -1.29 to -0.33 for Takagi’s study). Since our analysis included 2 recent large trials with negative results,42,43 we can argue that this lower SMD is associated with a truly stronger effect. Besides, their meta-analysis had a small sample size (4 studies with a total of 184 patients), unexpected lack of heterogeneity, poor comparison between different interventions, and inability to compare different types of ischemic stimulus,65 all limitations that we tried to avoid.

We made an effort to compare the effectiveness of RIPC across different interventions: cardiac surgery (ie, CABG and heart valve replacement surgery), PCI both during elective and ST-elevation myocardial infarction and AAA repair (open and endovascular). In adults undergoing cardiac surgery, RIPC reduces the chances of myocardial injury significantly (SMD, -0.68; 95% CI, -1.20 to -0.16) and further subgroup analysis suggests that this benefit is higher in on-pump CABG (SMD, -0.49; 95% CI, -1.20 to 0.22; P=.18). However, this impact was not confirmed in the largest study on RIPC for CABG so far, published by Rahman et al.42

One of the main reasons for this difference might have been the high proportion of smaller studies with strongly positive results in our analysis, which might have over-estimated the effect of RIPC. However, the patients included in the study by Rahman et al42 used more beta-blockers than in other studies, and even if isoflurane was avoided, many subjects received enflurane or sevoflurane, which are all known to prevent myocardial injury in cardiac surgery.66-68 Because of these issues, a reasonable conclusion cannot be drawn, yet we believe that a large multicenter trial is required to evaluate the effectiveness of RIPC for on-pump CABG after controlling the aforementioned factors. Based on the current available evidence, the role of RIPC on patients undergoing off-pump CABG cannot be determined due to an insufficient number of trials.43,57

We also tried to compare different protocols of RIPC. In theory, the larger the mass undergoing ischemia, the stronger the protection provided. Most of the trials used cuff inflation around the upper arm for 2-4 sequential periods of 5 minutes followed by a similar period of reperfusion, but in the subgroup of patients undergoing AAA repair, clamping of the iliac arteries was used. Only 1 study (Ali et al61) using iliac clamping reported data on cardiac biomarkers and excluding it during the sensitivity analysis did not change the conclusions. Similarly, when we ran our analysis for the estimation of serum creatinine after excluding trials that deployed iliac artery clamping,61-63 the results did not change significantly (data not shown). However, at this point, no conclusion can be made on the protocol for RIPC, because few patients have used clamping of the iliac artery and because no trial has compared both protocols directly.

The studies evaluating the role of RIPC were primarily powered to detect differences in cardiac and renal biomarkers. While some clinical outcomes were reported, this was done on a secondary basis. Our meta-analysis is the first to provide evidence for reducing the incidence of perioperative myocardial infarction. This is in contrast to prior studies that have failed to demonstrate any benefit on postoperative inotropic requirements,42,45,55 cardiac hemodynamics,42,51 and length of postoperative critical care stay67 (54.2 ± 40.7 hours for RIPC vs 39.5 ± 25.7 hours for control group; P=.3).50 These findings should be considered cautiously favorable, as it could be argued that it is inappropriate to pool the clinical outcomes reported by these proof-of-concept studies. However, these trials comprise the only available source of clinical outcome data from cohorts randomized to RIPC or standard interventions.

Study limitations. Despite our best efforts and even after contacting the authors of abstracts published, we could not retrieve the data from 5 studies that had to be excluded from the final analysis. Two of these trials (totalling 68 patients) were published as abstracts and studied patients undergoing CABG,54,57 measured postoperative troponin release, and showed no benefits of RIPC. This could have biased our outcome. The study is limited by the lack of standard outcomes. Although we made every effort to unify the clinical outcomes by trying to obtain the data from the authors of original studies, we must concede that we had to accept the definition of clinical outcomes that was used by individual studies. We even tried to redefine these clinical outcomes by a common definition, but were limited due to lack of all of the original data used by the original studies.

Conclusion

RIPC constitutes an attractive means of ameliorating the adverse consequences of perioperative ischemia reperfusion injury in a range of clinical settings. It is easily performed, requires little additional equipment and may be highly cost effective. Our meta-analysis has demonstrated that RIPC appears to be associated with a favorable effect on the serological markers of myocardial and renal injury during cardiovascular interventions and reduced the incidence of periprocedural myocardial infarction. However, in view of the size and quality of currently published studies, and the inherent limitations of meta-analysis extracted from these studies, larger trials should be conducted to substantiate and quantify this initial impression. In conclusion, RIPC has great potential to improve patient outcomes, but further study is required to evaluate clinical endpoints.


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