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

Abstract: Objectives. The purpose of this study was to assess the effect of remote ischemic precondition (RIPC) on the incidence of myocardial and renal injury in patients undergoing cardiovascular interventions as measured by biomarkers. Clinical data were pooled to evaluate the usefulness of RIPC to benefit clinical outcomes. Background. Debate exists regarding the merit of using RIPC for patients undergoing cardiovascular interventions. Methods. Systematic review and meta-analysis of prospective randomized clinical trials of patients undergoing cardiovascular interventions who received RIPC versus control were performed. Two independent reviewers selected articles from MEDLINE, EMBASE, SCOPUS, Cochrane, ISI Web of Science, and BIREME, and through hand search of relevant reviews and meeting abstracts upon agreement. Surrogate markers of myocardial (troponin T or I and CK-MB) and renal (serum creatinine) injury for primary outcomes were abstracted. Results. Final pooled analysis from 17 clinical trials showed significant heterogeneity of results and no relevant publication bias. 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%). A lower incidence of perioperative myocardial infarction (7.9% RIPC vs 13.9% placebo; RR, 0.56; 95% CI, 0.37-0.84; P=.005; I2 = 0%) was also noted. In patients undergoing abdominal aortic aneurysm repair, RIPC when compared to control also decreased renal injury (SMD, 0.28; 95% CI, -0.49 to -0.08; P=.007; I2 = 51%). Conclusions. RIPC appears to be associated with a favorable effect on serological markers of myocardial and renal injury during cardiovascular interventions. Larger trials should be conducted to substantiate this initial impression.

J INVASIVE CARDIOL 2012;24:42-48

Key words: abdominal aortic aneurysm repair, coronary artery bypass grafting, percutaneous coronary intervention, remote ischemic preconditioning

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Perioperative myocardial ischemia is known to occur with cardiac and vascular interventions — coronary artery bypass grafting (CABG),^1,2 percutaneous coronary intervention (PCI),³ abdominal aortic aneurysm (AAA) repair,⁴ and carotid endarterectomy.⁵ Various studies have demonstrated the prognostic significance of postoperative troponin release in relation to both short- and long-term clinical outcomes.^1,3,4,6-8 Similarly, renal injury, a consequence of hemodynamic changes after application of the aortic cross clamp and ischemia-reperfusion injury after its release, is a common cause of morbidity and mortality. Acute renal failure develops in nearly 10% of patients after elective open AAA repair and is an independent predictor of death.⁹

Ischemic preconditioning has been shown to provide myocardial protection, especially in patients undergoing cardiac surgery;¹⁰ however, this method remains invasive and impractical as it causes ischemia to the vital organs. Oxman et al¹¹ used the non-invasive technique of applying a hind-limb tourniquet for 10 minutes to reduce reperfusion arrhythmias in a rat heart following a sustained ischemic insult. Since then, different investigators have successfully demonstrated the beneficial effects of remote ischemic preconditioning (RIPC) on the heart by applying remote ischemia to the intestine,^12-21 kidneys,^22-28 aorta,^29,30 extremities,^31-34 carotid35 and femoral^36,37 vessels in rats,^{11,12,14-22,26-30,32,34,36,38} pigs,³³ mice,^35,37 and rabbits.^13,23-25,31 These benefits have ranged from reduction in myocardial infarct size by 40-50% and reduction in reperfusion arrhythmias to improvement in left ventricular ejection fraction. MacAllister and co-workers^39-41 pioneered this technique of transient ischemia and reperfusion in humans by 3 repetitive cycles of alternating inflation and deflation of a blood pressure cuff placed on the upper arm to 200 mm Hg for 5 minutes each. This evolved to be the most common protocol used as of now, though minor variations by different investigators have included up to 6 cycles in place of the commonly used 3 cycles (Table 1). Potential mechanistic pathways underlying remote ischemic preconditioning involve neural (adenosine,²² bradykinin,¹⁴ or calcitonin gene-related peptide¹³), humoral (adenosine,²⁴ bradykinin,¹⁷ opioids,^18,29 endocannabinoids,²⁰ or angiotensin I²⁶) or systemic pathways (inflammation/apoptosis^37,38). Activation of mitogen-activated protein kinases, p38, Erk1/2, and JNK²¹ within the remote organ also have been implicated in RIPC-induced cardioprotection.

Human randomized clinical trials evaluating the role of RIPC as a protective strategy have been conducted in patients undergoing CABG, PCI (both elective and emergent), AAA repair, and carotid endarterectomy. Although initial trials evaluating the role of RIPC in patients undergoing CABG yielded positive results, recent trials show no benefits.^42,43 Mixed results have also been obtained when RIPC was used in patients undergoing PCI.^44-46 Besides that, the trials published thus far have been only powered to detect differences in biomarkers of myocardial and renal injury and not clinical endpoints, such as death, myocardial infarction, or arrhythmias. We conducted a meta-analysis with an aim to assess the effect of RIPC on myocardial and renal injury in patients undergoing cardiovascular interventions as measured by biomarkers. We also pooled the available clinical data to evaluate the effects of RIPC on clinical outcomes.

Methods

Search strategy and data extraction. The meta-analysis was conducted in accordance with the QUOROM guidelines.⁴⁷ A comprehensive and systematic search of PUBMED (1950-2010), Cochrane Library, Scielo, EMBASE, SCOPUS, and ISI Web of Science databases was performed using the following search terms: “remote ischemic preconditioning” OR “remote ischaemic preconditioning” OR “RIPC” OR “ischemic preconditioning” OR “ischaemic preconditioning” AND “heart surgery” OR “cardio protective surgery” OR “myocardial surgery” OR “heart infarction protection surgery” AND “human” OR “patient” OR “individual” OR “subject” OR “men” OR “man” OR “women” OR “woman.” Two authors independently selected studies based on their titles and abstracts. In the second evaluation, both authors reviewed the complete versions of all articles and included or excluded them after a common consensus. Finally, we sought cross references from relevant articles and tried to contact corresponding authors in order to obtain unpublished data.

Studies that were included met the following criteria: prospective randomized controlled trials of patients undergoing cardiac surgery for coronary artery disease or valve replacement surgery, PCI (elective or primary), or AAA repair that had at least one arm randomized to remote ischemic preconditioning and another to placebo. Other interventions were only accepted if they were equally distributed to all arms of the study. Studies were excluded if they were duplicate publications or reported no data on rate of myocardial infarction, levels of CK-MB, troponin T, troponin I, or creatinine. There was no restriction on language. Data were abstracted from the studies not only for the cardiac and renal biomarkers, but also for clinical outcomes, including the incidence of myocardial infarction, stroke/cerebrovascular accident, atrial fibrillation, ventricular arrhythmias, congestive heart failure, inotropic use, need for urgent hemodialysis, and mortality. The clinical outcomes were determined by preset criteria for original studies.

Statistical analysis. Since 24-hour postoperative troponin levels are strongly related to short- and long-term outcomes in patients undergoing cardiovascular interventions,^1,2,3,48 we used this time interval for our analysis. When this information was not readily available, we contacted the authors; if we did not receive a response, CK-MB/troponin levels at 24 hours, peak levels, or area under the curve over 72 hours were used for the analysis.

Different markers of myocardial necrosis and creatinine levels had to be corrected to standard mean differences (SMD) to allow for comparison between different studies.¹⁹ As a general rule, a pooled SMD lower than 0.4 is considered small and greater than 0.7 is considered large. For the articles that reported medians and interquartile ranges, means and SMDs were estimated using the algorithm proposed by Hozo et al.⁴⁹

The definition of clinical endpoints, such as “myocardial infarction,” was predetermined by the authors of original studies. For creatinine levels, the highest value in the first 72 hours after surgery was used. Myocardial infarction was reported as rate of events and summarized as a risk ratio. Heterogeneity was evaluated using the I2 test. If results were considered homogenous, a fixed effects model was used for data synthesis; if not, a random effects model was used. Publication bias was evaluated by visual analysis of the funnel plot. Alpha was set at P<.05. Data analysis was done using Review Manager 5 Software (2010, The Cochrane Collaboration).

The following subgroup analyses were planned: type of surgery, type of ischemic stimulus, use of beta-blockers, diabetes, and use of sevoflurane or desflurane. Sensitivity analysis was conducted in all comparisons with significant heterogeneity, by systematic elimination of each study from the analysis, until results were as homogenous as possible.

Results

Our search strategy identified 23 eligible studies (Figure 1). Three articles were excluded from final analysis as they did not report relevant data on cardiac biomarkers, incidence of myocardial infarction, or creatinine.^50-52 Two meeting abstracts were eliminated due to incomplete data.^53,54 The final meta-analysis included 1371 patients, with 689 randomized to RIPC and 682 to placebo.

Table 1 summarizes the characteristics of included studies. The most common settings were CABG for chronic coronary artery disease^42,43,55-60 and open AAA repair.^61-63 CABG studies induced RIPC using a pressure cuff around the arm, which was inflated for 5 minutes, than deflated for another 5 minutes, 2-4 times. Aortic aneurysm repair studies used a protocol of 10-minute clamping and release of each iliac artery.

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 repair^61-63 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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From ¹Baystate Medical Center, Tufts University School of Medicine and ²the Department of Internal Medicine, Hospital das Clinicas da Universidade de Sao Paulo, Sao Paulo, Brazil.
Disclosure: The authors have completed and returned the ICMJE Form for Disclosure of Potential Conflicts of Interest. The authors report no conflicts of interest regarding the content herein.
Manuscript submitted June 3, 2011, provisional acceptance given August 10, 2011, final version accepted October 24, 2011.
Address for correspondence: Gaurav Alreja, MD, Baystate Medical Center, Tufts University School of Medicine, Internal Medicine, 759 Chestnut Street, Springfield, MA 01089. Email: galreja@yahoo.com