Effects of Ischemic Preconditioning on Abdominal Aortic Aneurysm Repair: A Systematic Review and Meta-analysis

Abstract

Background

Ischemic preconditioning is an innate mechanism of cytoprotection against ischemia, with potential for end-organ protection. The primary goal of this study was to systematically review the literature to determine the effect of ischemic preconditioning on outcomes after open and endovascular abdominal aortic aneurysm (AAA) repair.

Methods

The methodology followed the Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines. We included randomized clinical trials that evaluated the effect of remote ischemic preconditioning (RIPC) in reducing morbidity and mortality in patients undergoing open or endovascular AAA repair surgery. The primary outcomes were death, myocardial infarction, and renal impairment. Outcomes were addressed separately for open AAA repair and endovascular AAA repair (EVAR). Data were collected on patient characteristics, methodology, and preconditioning protocol for each trial.

Results

Nine trials of ischemic preconditioning in aortic aneurysm surgery were included with a total of 599 patients; 336 patients were included in the open AAA repair meta-analysis, and 263 patients were included in the EVAR meta-analysis. For both open and endovascular repairs, ischemic preconditioning did not have a significant effect on death, myocardial infarction, or renal impairment requiring dialysis.

Conclusions

The randomized clinical trials investigating the effect of ischemic preconditioning on outcomes after open and endovascular AAA repair that have been completed to date have not been adequately powered to evaluate improvements in patient-important outcomes. The evidence is insufficient to support the use of ischemic preconditioning for AAA repair in clinical practice. The variability in treatment effect across studies may be explained by clinical and methodological heterogeneity.

Introduction

Remote ischemic preconditioning (RIPC) refers to interventions that expose tissues to brief periods of ischemia in anticipation of a longer-lasting ischemic insult.¹ This innate mechanism of cytoprotection was first discovered through the intermittent occlusion of a single coronary artery.² It is now understood that preconditioning of almost any vascular bed renders multiorgan protection against sustained ischemia. Numerous potential end-organ benefits have been suggested for RIPC but there remains uncertainty with respect to outcomes in randomized trials.³ Although two recent trials of preconditioning in cardiac surgery showed no benefit, these results cannot be extrapolated to patients undergoing abdominal aortic aneurysm (AAA) surgery.4, 5

Despite advances in perioperative care, AAA repair carries significant morbidity and mortality.6, 7 Endovascular AAA repair (EVAR) is associated with decreased 30-day mortality when compared with open AAA repair (OAR), but long-term survival is similar for both approaches.⁸ For both open and endovascular AAA surgery, adverse cardiac events determine mortality.⁸ During OAR, the predominant mechanism of myocardial infarction (MI) is an oxygen supply–demand imbalance or a type II MI.⁹ This occurs in patients with significant but stable coronary artery disease. Attempts to reduce perioperative MI through prophylactic coronary revascularization and beta-adrenergic blockade have not been successful.10, 11 Data from randomized trials estimate that the risk of MI is approximately 7% after elective OAR; this risk may be as high as 25% in higher risk groups.¹² Interventions to reduce MI after vascular surgery are therefore highly desirable.

Elevations in cardiac troponins without electrocardiographic changes are far more common than perioperative MI. This phenomenon, termed myocardial injury after noncardiac surgery, is evident in up to one-fifth of patients after major vascular surgery.¹³ Many prospective studies have shown that myocardial injury after noncardiac surgery strongly predicts mortality.14, 15, 16 The ability of RIPC to attenuate this postoperative rise in cardiac biomarkers is evident in the setting of cardiac surgery.¹⁷ However, this concept has not been ascertained in vascular surgery. As with cardiac outcomes, renal protection has been appraised based on changes in biochemical markers of renal function rather than hard endpoints, such as the need for hemodialysis. Overall, the translation of surrogate markers into patient-relevant outcomes has been challenging across the breadth of ischemic preconditioning randomized trials.

One major shortfall of the trials in vascular surgery is the heterogeneity of ischemic insults experienced by patients during surgery. Endovascular and OARs are accompanied by vastly different changes in perioperative hemodynamics such as severity of hypotension, duration of tachycardia, and extent of blood loss—all of which are important determinants of MI.⁹ Similarly, the mechanisms of renal impairment imposed by open and endovascular surgery vary considerably. To mitigate these limitations, we formed a collaborative group in which preconditioning trialists provided patient-level data about the results of RIPC specific to the type of AAA repair performed. Pooling results of the available data from existing randomized controlled trials on RIPC will generate an overall estimate of effect size and, more importantly, help clinicians to delineate variability in treatment effect between groups.

The primary objective of this study was to assess the effect of RIPC on mortality, MI, and renal impairment in patients undergoing AAA repair. Second, we aimed to determine whether the treatment effect of ischemic preconditioning differs for EVAR versus OAR.