Safety of remimazolam in comparison with midazolam for colonoscopy: A systematic review and meta-analysis

Introduction

Colonoscopy is one of the most widely performed diagnostic procedures. It has advanced surgical oncology due to its role in earlier cancer detection. Although relatively less time-intensive and invasive, patients often require the administration of opiates, sedatives, and hypnotics to help ameliorate post-procedural pain.¹ Benzodiazepines (a class of sedatives approved by the FDA) have resulted in their ubiquitous use due to their multiple therapeutic benefits as anti-anxiolytic and antiseizure and their established sedating and analgesic properties.² Moreover, various drugs can be employed for different populations and procedures due to their diverse potency and efficacy. Midazolam is currently employed for colonoscopy due to its high safety profile and ultra-short-acting properties. It is classically preferred over agents with a narrow therapeutic index, such as diazepam.^3,4 However, midazolam, with a relatively longer mean half-life (three hrs; 1.8–6.4 hr), is associated with a slow return of cognition and carries a risk of systemic accumulation; therefore, limiting its use in patients with chronic kidney disease.^2,5 Hence, alternative agents such as remimazolam with a similar biochemical structure and efficacy have been recently explored for their safety profile owing to their shorter recovery time.^6,7 Unlike midazolam, this has been attributed to its earlier inactivation, hence decreasing the systemic effects.⁵ As an ultra-short-acting, ester-based drug, remimazolam can be administered intravenously to achieve sedation within 3–3.5 minutes.⁸ Rendering its quicker induction and recovery, as seen across trials, including bronchoscopy and colonoscopy, remimazolam was approved for use in the US as an anesthetic.^7,9

This systematic review aims to evaluate the adequacy of remimazolam in replacing midazolam in colonoscopic procedures. Our review specifically looks at the randomized control trials comparing the safety of remimazolam and midazolam in patients undergoing colonoscopies to determine if the clinical effectiveness of remimazolam can be safely determined and whether this emerging drug could successfully replace midazolam in the future or not.

Methods

The Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA 2020) standards and PRISMA checklist were used to conduct this meta-analysis.^10,11 The literature search, quality assessment, data extraction, and statistical analysis were all accomplished by two independent reviewers (MA Khalid, M Sadiq). A third reviewer (MJ Siddiqui) was consulted in case of conflict for screening procedures. The report did not need ethics committee approval because raw data of human beings were not involved. The ultimate selection of studies for inclusion was determined through unanimous agreement among all authors. Additionally, we examined the reference lists of original papers, published reviews, systematic reviews, and meta-analyses to identify any trials that were not initially part of the database. Our search strategy was designed to encompass every randomized controlled trial (RCT) examining the efficacy of remimazolam in procedural sedation during colonoscopy.

Results

Literature search results

A preliminary search of the three electronic databases yielded thirteen potential studies. Four articles were selected based on the comparison of remimazolam and midazolam. After exclusions were done based on the similarity of the intervention and control group with no combination agents, three studies were left for analysis. The PRISMA flowchart (Figure 1, Extended data: File 2) summarizes the results of our literature search.¹²

Figure 1. Prisma flow chart.

From: Moher D, Liberati A, Tetzlaff J, Altman DG, The PRISMA Group (2009). Preferred Reporting Items for Systematic Reviews and Meta Analyses: The PRISMA Statement. PLoS Med 6(6): e1000097. doi: 10.1371/journal.pmed1000097.

The PRISMA flowchart was used in our systematic review and meta-analysis to shortlist articles. The articles were included based on similar PICO and underwent specific exclusion and inclusion criteria to form the final list.

Discussion

Our meta-analysis comprising three RCTs with a total study population of 697 aims to evaluate the safety profile of remimazolam as an alternative sedative in patients undergoing colonoscopy. In accordance with the results, it is indicated that remimazolam is an overall safe sedative that can be considered for use as a replacement for midazolam in patients undergoing colonoscopy. Unlike the previous meta-analysis “Efficacy of Remimazolam for Procedural Sedation in American Society of Anesthesiologists (ASA) I to IV Patients Undergoing Colonoscopy”, this systematic review and meta-analysis maintain a strict focus on the safety aspect of remimazolam. The primary outcome highlights all the treatment-emergent adverse effects, not the procedural success predictors such as completion of endoscopy, need for rescue sedative, and additional need for top-up dosages.¹⁹

In the three RCTs to draw a comparison between remimazolam and midazolam, remimazolam was found to have a similar safety profile when compared to midazolam. However, pooled effects revealed remimazolam to be associated with increased treatment-emergent adverse effects. The mean terminal elimination half-life of remimazolam was estimated at 0.75 hours, and that of midazolam was 4.3 hours. Remimazolam was found to have a shorter half-life, early bioavailability, and early return of the patient to conscious levels.¹⁸ The early recovery is also explained by the ultra-short-acting nature of the drug, as discussed earlier.²⁰ Another possible explanation for this early recovery with remimazolam compared with midazolam is the difference in nature of the metabolites of the two drugs. Midazolam has an active metabolite, a-hydroxy-midazolam, which has the potential risk of repeat sedation when the active metabolite becomes bioavailable, whereas no metabolites of remimazolam have been reported to cause repeat sedation.²¹ Additionally, remimazolam has a lesser degree of drug interaction in comparison to midazolam and uneventful use in a patient with myotonic dystrophy endorses its safety profile.^22,23

These findings are in contrast to a previous meta-analysis evaluating the safety and efficacy of remimazolam in various endoscopic procedures.²⁴ Remimazolam was linked with fewer cases of hypotension in comparison to midazolam. Additionally, both groups carried an equal risk of undergoing postoperative hemodynamic and respiratory derangements. The discrepancy could be attributed to the absence of subgroup analysis on patients undergoing colonoscopy, a larger sample size (1996 vs. 697), and a more diverse patient population than ours. Moreover, in order to achieve a similar anesthesia effect, often larger doses of remimazolam need to be administered, which could explain the increased incidence of TEAEs.²⁵ Isolated incidences of anaphylaxis and failure of flumazenil to fully reverse the sedative effects of the drug have raised suspicions regarding the reported exceedingly safe nature of the drug.^26–28 Meanwhile, bradycardia, hypotension, and injection site pain occurred less often in the remimazolam group.^29,30 Furthermore, the drug may become less popular with patients due to its inability to decrease postoperative nausea and vomiting.³¹

Although many important characteristics highlighting the effectiveness and potential of remimazolam as an alternative sedative are available, the high failure rate of the drug in inducing sedation in 11/44 patients in one clinical trial cannot be ignored. This is coupled with the fact that one patient was seen to have an adverse event (hypotension and oxygen desaturation).³² Thus, it is evident that the use of remimazolam is subject to a higher risk of TEAEs.

The review had some limitations, including statistical heterogeneity in some meta-analyses, reliance on observational data, and potential bias in included studies. Fentanyl dose may have contributed to inconsistent results in the Pambianco and Rex Phase III study. Future reviews may consider pooling results from studies with the same dose for the same procedure. This review focused on randomized controlled trials. This meta-analysis incorporated only three trials, which implies that the conclusion may lack decisiveness. However, the results indicated that several outcomes had a sufficient sample size and statistical significance.

Conclusions

The studies included in the meta-analysis showed that both the drugs under observation had multiple TEAEs, with remimazolam having a higher frequency of adverse effects compared to midazolam. Nonetheless, patients administered with midazolam were at a higher risk of repeat sedation.

In conclusion, despite a significant difference in the safety profile, the data indicates that more research and, specifically, more RCTs must be performed to find the most effective sedative agent with the least possible treatment-emergent side effects. Furthermore, other aspects of safety, such as depth of sedation and further intra-procedural and post-procedural outcomes, need to be assessed in future studies.