Evidence-based Medicine: A Narrative Review on the Evolving Opportunities and Challenges

BACKGROUND

Over the decades, how we approach medicine has come a long way, evolving from authority, to experience, to EBM.^[1,2] tHis transition can well be represented by the progression from “ipse dixit” (Latin), a modus operandi driven by dogmatic expression of opinion, to the practice increasingly moving toward inclusion of the knowledge gained from experience to the traditional teachings.^[2,3] Thereby, remarkable improvement in the field of medicine was witnessed as a result of self-reflection and internal audits, nonetheless lacking the requisite standardization with the practice being intricately linked to the skills of the practitioner.^[1,2]

Meanwhile, the initial marks of evidence-based practice can be traced to the mid-19^th century; it was only in 1996 when the late Prof Sackett et al. formally defined EBM as “the conscientious, explicit, and judicious use of current best evidence in making decisions about the care of individual patients.”^[1] In reference to the modern-day context, however, where a section of fraternity is engrossed in debating the implications of the evidence-based guideline protocols on physician autonomy,^[4] the conduct of EBM has recently been faced with other peculiar challenges that mandate comprehensive elaboration when staging a discussion in the relevant subject.

THE CANONICAL EBM PYRAMID OF PRIORITIES

EBM is envisaged as a hierarchical system that motivates us to seek the best available evidence and guides when classified in accordance with their weightage and subsequently fall back on the evidence in the absence of the higher [Figure 1]. ^[5] However, it provides a particularly useful teaching tool connoting the cornerstone of the EBM hierarchy. The former pictorial illustration, better known as the EBM pyramid, characteristically demands a methodical literature search and critical appraisal, thereby integrating the best-available evidence with practice, concurrently acknowledging the patient characteristics, and comprehending the context appropriateness of the evidence at hand.^[5-8] Looking closely through this pyramid, two important practical aspects emerge – the first one refers to the source of evidence that EBM practitioners can use, as epitomized by the 6S version of the pyramid, representing a hierarchy spanning from (S)tudies, (S)ynopses, (S)ynthesis, (S)ynopses of synthesis, and (S)ummaries to (S)ystems;^[9] whereas the second aspect pertains to the questions surrounding the traditional pyramid being over simplistic, at times. In the early 2000s, the Grading of Recommendations Assessment, Development and Evaluation (GRADE) Working Group devised a framework where the certainty of evidence was premised on a multitude of factors and not solely dictated by the study design.^[10] Meanwhile, the former framework by itself besets the conventional pyramid of priorities, a riveting perspective by Subbiah states that the EBM pyramid in its current form is merely the tip of the iceberg, offering shallow evidence for the care of a generic patient.^[6] They further emphasize the need for a deep synthesis and amalgamation of the natural history data to achieve the “next-gen(eration) EBM.” Herein, they anticipate that exploring the potential of multidimensional evidence procreation would be challenged by the extraction-collation mining of large datasets in addition to the genomics and other “omics” analysis (the discussion of the role of which follows) not without highlighting the lucrative opportunities in acquiring data offered by the innovations in wearables, sensor technology and the Internet of Medical tHings (IoMT) Architecture.^[6,8]

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Figure 1:

The basic construct of the evidence-based medicine pyramid, the tiers cemented by “critical appraisal.”

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EBM, IN THE ERA OF PRECISION MEDICINE (PM)

Of late, the undertone of PM in practice has steadily been rising to the forefront across all branches of medicine.^[4,8,11,12] PM tailors the diagnosis and treatment of diseases to the individual attributes premised on diverse facets of patient-centric characteristics, as outlined in [Table 1].^[11,12] Propounding the notion of administering the right treatment to the right patient at the right time, practice is transiting from a kitchen sink to a personalized approach, maximizing the value of specialized services in anesthesia and critical care.^[11-13] With the revolutionary trend of PM, translational research and novel domains like the “omics” [as outlined in Table 1] are actively transcending into perioperative medicine to feature as “Anesthesiomics.”^[11,12,14]

Albeit gaining wide recognition in disease prevention treatment, the scope of precision perioperative medicine remains far from fully explored. To name a few; hemodynamic optimization, circulatory assistance, anesthesia-critical care pharmacological regimens, coagulation-bleeding management, blood and blood-product transfusion, mechanical ventilation, analgesic therapy, prediction of end-organ complications, and contextual protective strategies serve as pertinent contextual examples for the application of PM in perioperative medicine.^[8,11] As an exemplar, Shah et al. categorize the post-cardiac surgery cohort with vasoplegia as poor responders, responders, sustainers, and rebounders while studying their response to hydroxocobalamin.^[15] With more such research experiences accruing in the literature on the role of patient-centered care (PCC), PM is captivating enhanced attention in anesthesia and critical care.^[16]

Simultaneously, an argument regarding the programs, guidelines, and protocols being the antithesis of PM has gained recent impetus, as elucidated in an editorial by Columb and Hopkins.^[17] Guidelines can be peculiarly rigid in nature, targeted to an average patient for the mentioned situation; nonetheless, every patient is unique and may or may not fall in that average. tHus, much against the “one-size-fits-all” regime, proponents of PM propose that such standardized therapies fail to cater to the widely prevalent heterogeneity in patient characteristics and the patient-related response to therapy in practice.^[8,11] To that end, another interesting editorial on the implications of practice variability by Sessler, questions the basis for assigning a free pass to clinical pathways, buttressing the need for robust context-sensitive evidence.^[18]

That being said, sackett et al., during their very first writing on ebm, emphasized that it is all about integrating individual clinical expertise with the best external evidence.^[1] therefore, it becomes equally worthwhile to appreciate that EBM is not a “cookbook” medicine and a personalized approach can well be appreciated within its’ realms, and apart from conceptualizing PM as a paradigm shift and seeking the dichotomy (if at all, there exists one), a middle ground can be chosen to harmonize PM and EBM as “evidence-based precision medicine” with the noble objective of improving the patient outcomes, at large.^[1,4,19]

THE GLOBAL PANDEMIC, NOT WITHOUT ITS’ DISTINCT IMPACT ON EBM

The coronavirus disease 2019 (COVID-19) potentially challenged the EBM in principle, which had been taught to us for long. The pandemic had thrown into relief the pivotal differences between the evidence-based practice and the traditional form of care that lacked a strong evidentiary background, likely owing to a considerably perturbed demand-supply equilibrium of the scientific evidence required to battle the unfamiliar viral enemy.^[20,21]

The fundamentals of EBM, i.e., curtailing the use of non-documentary knowledge for clinical decision-making, stood defeated during the pandemic. Journal houses were necessitated to furnish early publications, having had to hasten their peer review, which further heightened the prevailing dilemma regarding the requisite evidence for clinical decision-making in COVID-19. To add to it, considering the hyperdynamic and volatile nature of the existing research, the pandemic spawned too many uninformative or, at times, misleading clinical trials and reviews, which were again detrimental to the overall quality of the available evidence.^[21,22] As an exemplar, the age-old, well-reputed journal, “The Lancet” had to retract an online published research article on chloroquine therapy for COVID-19 due to concerns raised with respect to the veracity of the research data, with the Journal lamenting having collaborated to contribute in good faith, during the unprecedented times of great need presented by the global viral pandemic.^[23]

Talking further on the massive increase in research across the board during the pandemic, “publication hyperinflation” is another epiphenomenon that deserves mention. Tsutsumi et al. Recently evaluated the publications in intensive care medicine in a meta-epidemiological study spanning more than three decades.^[24] they outlined a hyperinflation in the number of randomized controlled trials (rcts), increasing from 66 in 1990 to 309 in 2021, which equated to as much as 26 rcts per month. Of note, their analysis also delineated the number of systematic reviews (srs) to be escalating at an even higher pace – which from 2 in 1990, increased to 327 in 2016 and reached 519 in 2021, implying the ratio of srs/rcts >1, i.e., 1.68 srs for every RCT in 2021 (519/309, as elucidated above).^[24] this heralds the growing wave of srs and meta-analysis (mas), which might/might not be reasonable but certainly no substitutes for well-conducted multicentric large rcts, which would be subsequently discussed in the article.^[25]

Specific to the pandemic though, the media and the political interference had their own peculiar impact, which can simultaneously not be undermined. Anecdotal shreds of evidence were being circulated on social media, propagating a “viral infodemic” which was by no means an easy battle for the scientific community. The pandemic having encouraged preprints, the researchers posted their findings online, which, albeit lacking external scrutiny, were widely shared on social media and disseminated at an even accelerated pace in the current age of liking and retweeting.^[21,22]

Meanwhile, some may argue that medical practice is often dogged by dogma in several practical areas of management; the COVID-19 pandemic, in addition, might have exposed some of the pre-existing shortcomings of our practice of EBM.^[20-22,26] However, on a more positive note, there is always light at the end of the tunnel and the silver lining is indeed offered by the valuable research lessons learned from the pandemic, particularly on how to balance the hope and the hype when reeling under a perpetual scanner.

MAINTAINING “TOP-NOTCH” STANDARDS AT THE “TOP TIER” OF EBM

Ever since the first description of EBM by Sackett et al., EBM has evolved.^[1] It is thus imperative to reflect upon the concerns that have evolved alongside as well. EBM (what we aim to practice) frequently presents us with questions and nuances, especially relevant for RCTs and MAs, which feature at the top-tier level of evidence where maintaining top-notch standards is the holy grail.^[5] tHis segment is discussed under the subheadings covering the specific research concerns to some generalized issues pertinent to the present times, to finally summarize the elements limiting confidence in medical research.

Other general issues of the modern-day

The phenomenon of “spin” in the present-day rcts (characterized by the manipulation of language to mislead the readers from the likely truth of the research results), clearly speaks of the rhetorical techniques being employed in conveying medical science.^[30,39] In an analysis of 162 articles published in high-impact anesthesia journals, Demarquette et al. Discovered that as much as 40% of the statistically negative trials potentially misled the readers through the inclusion of “spin”ning tricks.^[30] Such reporting strategies to suggest a benefit of an experimental intervention despite a statistically non-significant difference in the primary outcome is an evolving plague to scientific research. Concerted efforts must be directed toward the detection and reduction of spin in rcts to safeguard our “research-evidence translational continuum.”^[39]

At the same time, the researchers need to be particularly mindful of employing the retracted literature base while formulating their research projects and/or drafting the manuscripts for publication. Herein, citation of retracted literature is an additional menace, with the problem compounding further when the former has methodological implications on the primary investigation.^[40] Even in the second-order analysis of analyses, retracted literature can significantly distort the findings of the top-tier evidence.^[41]

Furthermore, any discussion on EBM in today’s age is incomplete without deliberating on the intriguing influences of artificial intelligence (AI) on scientific research. [Figure 2] illustrates the pros and cons of AI in research and analysis, leaving the question open to debate whether open AI is a boon or a bane to the scientific community.^[6,42-44]

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Figure 2:

The pros and cons of artificial intelligence in research and analysis.

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FUTURE DIRECTIONS

The quintessential altercation in the subject regarding the peak of the pyramid continues to intensify with some arguing in favor of well-conducted RCTs mimicking real-world situations better than any other study design, thus minimizing the likelihood of confounding. The usual counterargument is that the best evidence is provided by SRMAs, given the integration of all the relevant evidence, purportedly offering more reliable answers than a well-conducted single study, often mistaking an augmented external validity achieved by pooling of data, which, on the contrary, presents a sizeable risk of systematic error.^[32,46] Beyond this debate, the future is rather about refining our evidence to include patient-reported outcome and experience measures, shared decision-making, and seeking viable solutions to cultivate an increasing trust in the anesthesiologists’ endeavors in providing PCC while practicing the best-available evidence.^[16,47] However, the best evidence at hand is unlikely to always follow the hierarchy propounded by the EBM pyramid. Notably, dependent researchers put forth the need for upending the epic pyramid for certain clinical situations.^[48] To that end, it is hoped that the future awaits a better pyramid, given there exist no shortcuts to the truth – whatever the clinical evidence looks like and wherever it features on this pyramid.^[46] We believe the “3Es” would be instrumental in achieving this pinnacle, i.e., adequately backed by robust (E)vidence, physician (E)xperience, and meeting the patient (E)xpectations.

CONCLUSION

EBM is no less than a dynamic goal post wherein every opportunity be avidly sought to build a thorough, reproducible, and pragmatic basis for promoting good clinical practice. Acknowledging the complex, multifactorial, and deeply situational nature of our practice, today, there is an equally (if, not more) challenging need to meticulously interpret the ever-growing research repository to figure out what truly classifies as practice-changing evidence. Meanwhile, it remains to be seen in the future how PCC integrates with EBM in the upcoming age of AI; it would only be opportune to emphasize that our “param kartavya” of “primum non nocere” should unfailingly be observed, throughout the not so predictable evolving process.