Beginning in the 1970s and 1980s, the emergence of randomized clinical trials and studies with large cohorts, associated with the development of the methodology for systematic reviews and meta-analyses, triggered a revolution in the way of thinking and performing healthcare practice. Evidence-based medicine (EBM), defined as the integration of the best research evidence with clinical experience and patient values, has become a new paradigm, orienting medical education and specialized publications. One of the principles of EBM was precisely the primacy of information obtained from randomized clinical trials and meta-analyses, which were placed at the top of an evidence hierarchy, valuing quantitative results more than clinical experience and expert opinion. Indeed, it has always been challenging for EBM to integrate empirical evidence with other types of medical knowledge, such as clinical expertise and pathophysiological rationale, or even with the preferences of individual patients.

The use of EBM in clinical practice also runs into the difficulty of finding robust evidence for all subgroups of clinical situations found in the real world, “gray areas” in which no reliable evidence can be obtained from the scientific literature to guide the physician in caring for his patient. Randomized clinical trials are expensive and generally require large study samples and long-term follow-up. There are several situations without evidence, or situations in which the evidence is inconsistent or of poor quality.

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The historical practice of medicine has evolved over centuries based on empirical knowledge derived from experience and observation rather than rigorous scientific data. Over the second half of the twentieth century, this form of medical knowledge progress was largely supplanted by rigorous scientific data collection, particularly in the realm of cardiovascular diseases, where virtually every new drug discovery has been thoroughly evaluated in randomized clinical trials (RCT). The impressive improvement in the quality of the information provided by such study design has led to the development of an entirely new field in the medical knowledge which became known as Evidence-Based Medicine (EBM).

EBM soughs to move away from empirical information by providing a structured grading of the epistemological strength of evidence available. It further requires the highest levels of evidence to give strong recommendations for or against the use of any particular therapy. By this approach, RCTs are considered among the highest quality study designs which support those stronger recommendations. Still, despite their capability to avoid confounding and other biases, RCTs conclusions can only be interpreted as an overall averaged benefit for the collective population included in the study. Although such information may suffice to document the effect of any given therapy at the population level, this does not necessarily apply to any individual patient. While some individuals may benefit considerably more than the average population included in the study, other might benefit significantly less, whereas no benefit or even significant harm may occur in some individuals.

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