Safety of Digestive Endoscopy following Acute Coronary Syndrome: A Systematic Review

Background. The safety of endoscopy after an acute coronary syndrome (ACS) is poorly characterized. We thus performed a systematic review assessing the safety of endoscopy following ACS. Methods. Searches in EMBASE, Medline, and Web of Science identified articles for inclusion. Data abstraction was completed by two independent reviewers. Results. Fourteen retrospective studies yielded 1178 patients (mean 71.3 years, 59.0% male) having suffered an ACS before endoscopy. Patients underwent 1188 endoscopies primarily to investigate suspected gastrointestinal bleeding (81.2%). Overall, 810 EGDs (68.2%), 191 colonoscopies (16.1%), 100 sigmoidoscopies (8.4%), 64 PEGs (5.4%), and 22 ERCPs (1.9%) were performed 9.0 ± 5.2 days after ACS, showing principally ulcer disease (25.1%; 95% CI 22.2–28.3%) and normal findings (22.9%; 95% CI 20.1–26.0%). Overall, 108 peri- and postprocedural complications occurred (9.1%; 95% CI 7.6–10.9%), with hypotension (24.1%; 95% CI 17.0–32.9%), arrhythmias (8.1%; 95% CI 4.5–18.1%), and repeat ACS (6.5%; 95% CI 3.1–12.8%) as the most frequent. All-cause mortality was 8.1% (95% CI 6.3–10.4%), with 4 deaths attributed to endoscopy (<24 hours after ACS, 3.7% of all complications; 95% CI 1.5–9.1%). Conclusion. A significant proportion of possibly endoscopy-related negative outcomes occur following ACS. Further studies are required to better characterize indications, patient selection, and appropriate timing of endoscopy in this cohort.


Introduction
Performing endoscopic procedures in the setting of an acute coronary syndrome (ACS) can prove challenging. These patients are at increased risk of arrhythmias, heart failure, further ischemic events, and death [1,2]. The stress of undergoing endoscopic procedures with the utilization of procedural sedation can theoretically precipitate cardiac complications and increase procedural risk.
As a result of these concerns, physicians may be hesitant to perform endoscopy following an ACS. Currently, there exists no consensus regarding the optimal timing of an urgent endoscopy following an ACS. We present a systematic review of the literature on the safety, efficacy, and complications of luminal endoscopy in this setting.

Review of the Literature.
A comprehensive computerized medical literature search was performed using MEDLINE, EMBASE, Cochrane library, and the ISI Web of Knowledge from 1990 to April 2014. A highly sensitive search strategy was used to identify all observational studies (case-control, cohort, or case series) with a combination of controlled vocabulary (MeSH) and text words related to (1) upper or lower gastrointestinal endoscopy or ERCP and (2) myocardial infarction or acute coronary syndrome (in the appendix).
All adult human studies in English were included as well as published abstracts from scientific meetings only if the data were not duplicated in subsequent publications. Recursive searches and cross-referencing were also carried out using  a "similar articles" function; hand searches of articles were identified after an initial search.

Study Inclusion and Patient Population.
Two authors independently reviewed all abstracts for potential inclusion. Relevant abstracts were then further reviewed based on manuscript content, with a third independent reviewer resolving any disagreements.
Case reports were excluded, and case series with a sample size of <5 were also excluded. Papers published by the same author(s) were screened for duplication of results. In order to be included, publications had to have assessed patients undergoing endoscopy within 60 days of suffering an ACS. ACS was defined as unstable angina, non-ST elevation myocardial infarction (NSTEMI), ST elevation myocardial infarction (STEMI), or ACS not specified. All forms of endoscopic diagnostic or therapeutic procedures involving the gastrointestinal tract were considered for inclusion into the study.

Data Collection and Statistical Analysis.
Information from all relevant papers, including demographic information, type of endoscopy, indications, complication rates, and ACS subtypes, was compiled. Complications were defined based on initial descriptions provided in the papers being reviewed. Complications were subsequently classified according to general categories. Two authors independently classified complication events as major or minor. For every study, we determined weighted data for timing of endoscopy and rates of endoscopic complications and all-cause mortality. Descriptive statistics included categorical variables expressed as proportions and 95% confidence intervals and continuous variables as means ± standard deviation or medians and ranges. All statistical analyses were performed using SAS 9.2, SAS Institute Inc., Cary, NC, USA.

Discussion
There is a paucity of data surrounding the safety of endoscopy following ACS. This stems from the unpredictable nature, varying indication, and low incidence of endoscopy after ACS. This systematic review was performed to summarize existing information to guide clinicians in future management of their patients. The primary outcome of this study revealed an overall complication rate for all endoscopic procedures to be 9.1% (95% CI 7.6-10.9%), suggesting that this group of patients is prone to adverse events related to endoscopy. Even in the absence of recent ACS, endoscopy has been documented to provoke silent ischemic changes in patients with underlying coronary artery disease [17][18][19]. When the indication for endoscopy is acute GI bleeding, those patients with coronary artery disease (CAD) are at increased risk for both silent ischemia and arrhythmias [20]. The adrenergic response to endoscopy is felt to act as a "stress test," provoking ischemia in a supply-demand fashion.
The close proximity of endoscopy to initial ACS (mean 9.0 ± 5.2 days) raises concerns about increased cardiopulmonary complications. The important issue of elapsed time between the ACS and endoscopy with regard to incidence of complications was only assessed in one study. Indeed, Spier et al. noted an inverse relationship between endoscopic complications from timing of ACS; in 135 patients, the only 2 complications occurred with endoscopy performed the same day as ACS, in contrast to no complications in procedures performed 24 hours or more after an ACS [8].
Sharma et al. recently looked at all GI endoscopies entered into the Clinical Outcomes Research Initiative database over a 5-year period to identify factors predictive of endoscopic complications [21]. Conscious sedation, the age of the patient, a higher American Society of Anaesthesiology (ASA) grade, inpatient status, trainee participation, and routine use of oxygen were all associated with unplanned cardiopulmonary adverse events during GI endoscopy [21]. Many of the patients with recent ACS share these characteristics, suggesting that the additive role of recent injury must infer higher risk of cardiopulmonary complications.
The results presented here are in contrast to previous reports of complications encountered during elective endoscopy. Existing data have shown complications of upper GI endoscopy ranging from 1 in 200 to 1 in 10,000 [22][23][24][25], with recent data on mortality showing a rate of 1 in 10,000 [21]. In a large, systematic review including 57,742 patients across 17 prospective studies, serious adverse advents during screening colonoscopy were reported to occur at a rate of 2.8 complications per 1000 procedures [26]. A Canadian study looked at complications rates of 97,091 patients undergoing outpatient colonoscopy, finding 1.64 per 1000 and 0.85 per 1000 events for perforation and bleeding, respectively [27].
In contrast, in the current ACS setting, the calculated complication rates were 11.5% (95% CI 9.2-14.4%) and 9.0% (95% CI 4.8-16.2%), for EGD and colonoscopy, respectively; because of the size of the sampling, these values were felt to be more generalizable than the observed complication rates for PEG (10.3%; 95% CI 3.6-26.4%) and ERCP (14.3%; 95% CI 5.0-34.6%) that were based on smaller number of procedures (PEG = 64, ERCP = 22). Despite this, the high rate of complications seen with ERCP can be explained by its technical difficulty and the concomitant disease processes, largely cholangitis or choledocholithiasis ( Table 2, appendix). Moreover, the increase in complications across all endoscopic procedures is attributable to the comorbid state of these patients. A third suffered from congestive heart failure and a fifth from arrhythmias in the immediate period after ACS (data on 310), and at the time of endoscopy 18.2% (95% CI 15.9-20.7%) were mechanically ventilated.
Preventative measures should be employed to decrease the need for endoscopy, including the appropriate use of gastroprotective agents for those on antiplatelet agents. The routine use proton pump inhibitors (PPI) are preferred over histamine-2 receptor antagonists (H2RA) [35]. Furthermore, concerns regarding interactions between PPI and antiplatelet agents have been deemed to be clinically invalid [36,37]. If preventative measures fail, endoscopists should look towards improving endoscopic outcomes. Clinicians may find the use of hemostatic powders, such as TC-325, beneficial to lessen the intraprocedural time [38]. Other possibilities for improving success include deferring diagnostic and nonurgent procedural endoscopy. Based on these data, we suggest that patients having suffered a recent ACS should have procedural electrocardiographic monitoring in addition to standard monitoring. The ASA currently recommends continuous electrocardiographic monitoring for patients with history of cardiovascular disease or arrhythmias [39]. Determining the need for more intensive monitoring should be done at the discretion of the digestive endoscopist in consultation with the cardiology team.
Methodological limitations include the poor quality of the data, precluding the ability to perform a formal metaanalysis. In addition, adjudication of outcomes is not feasible given the nature of the data, limiting attribution of specific complications directly to endoscopy. The data collected are heterogeneous; the changing definition of ACS over time and the variation in the definition of complication across the articles force one to interpret the data cautiously. This highlights, however, the need for prospective data on the safety of endoscopy after ACS. Currently, these data are the best that exist regarding this topic. Finally, one author was responsible for 7 of the 19 publications included in our review, raising the possibility of selection bias. As they were felt to be of higher quality, we kept these studies, but steps were taken to ensure that we excluded duplicate data among studies.
This systematic review nonetheless clearly quantifies an increased rate of negative outcomes in ACS patients undergoing digestive endoscopy. The clinical management of ACS patients must therefore include minimizing risks such as GI bleeding. While not validated in this systematic review, the temporal relationship between the ACS event and the procedure may contribute to exacerbating cardiopulmonary complications. The risks and benefits must therefore be carefully considered on a case-by-case basis, limiting urgent endoscopy to clinical scenarios where a therapeutic benefit is likely to alter the patient course.

Authors' Contribution
Substantial contributions to the conception or design of the work, or the acquisition, analysis, or interpretation of data for the work were done by Alastair Dorreen, Sarvee Moosavi, Myriam Martel, and Alan N. Barkun. Drafting the work or revising it critically for important intellectual content was carried out by Alastair Dorreen, Sarvee Moosavi, and Alan N. Barkun. Final approval of the version to be published was carried out by Alastair Dorreen, Sarvee Moosavi, Myriam Martel, and Alan N. Barkun. Alastair Dorreen, Sarvee Moosavi, Myriam Martel, and Alan N. Barkun are responsible agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.