Evidence-Based Medicine

Ashley Shreves, Kavita Bhanot, David Newman

The formal definition of evidence-based medicine (EBM) is “the conscientious, explicit and judicious use of current best evidence in making decisions about the care of individual patients.”¹ This definition is useful but leaves ambiguities. What does “explicit” mean? How might we define “judicious”? What constitutes “evidence”? And perhaps most important, who is “making decisions,” the doctor or the patient?

Broadly introduced to medical culture in 1992, EBM has exploded in the past 2 decades.² The term has become ubiquitous and is often co-opted by working groups, professional societies, and individual authors who neither systematically adhere to core EBM principles nor complete the fundamental tasks that define EBM. In addition, the most important principle underlying medical practice and the Hippocratic Oath—that the physician’s goals should be aligned with the patient’s goals—has not been routinely integrated into these applications of EBM.

The methodologic superstructure of EBM can be summarized by the four A’s: ask, acquire, appraise, and apply. In the text that follows we use this structure to answer clinical questions and offer a potential road map for the true, focused application of EBM. We will use two distinct, frequently encountered, high-stakes emergency department (ED) clinical scenarios—evaluation of a patient with an acute headache and evaluation of a patient with chest pain—to illustrate how physicians might use EBM to enhance their practice and knowledge and best inform and achieve their patient’s goals. Because a fully detailed demonstration of the EBM process is neither feasible nor digestible in the space provided, we will emphasize concept over detail and in many cases will be summarizing. Although we use clinical scenarios to demonstrate the EBM process, in most cases, formulation of a proper question, literature search for that question, and appraisal of the literature to help answer the question will all be done over a period of hours to days and will not be possible contemporaneously. The greatest utility of the EBM process is often in being prepared for the next encounter.

Clinical Scenarios

Acute Headache in the Emergency Department

Ms. Mason, a previously healthy 40-year-old woman, arrived at the ED 4 hours after the onset of a severe headache. It has an “acute” quality (i.e., it reached maximum intensity within minutes of onset), and she has no history of significant headaches. She appears well but is uncomfortable, with normal vital signs, a Glasgow Coma Scale (GCS) score of 15, and normal findings on neurologic examination.

Emergency physicians will immediately consider subarachnoid hemorrhage (SAH), among the most dangerous possible diagnoses, and will want to make an estimate of the probability of this disease. Had her clinical manifestations been extreme, the next step in her management would be more straightforward. For instance, consider a 50-year-old woman with a known cerebral aneurysm who goes to the ED after a sudden-onset, severe headache associated with loss of consciousness. On arrival she is vomiting and minimally responsive and has papilledema. Alternatively, consider a 25-year-old neurologically normal female with her typical migraine headache. If the primary disease that concerns us is SAH, the first patient seems very likely to have it and will be managed accordingly. The second patient, although she may have SAH, is at low-enough risk that most physicians would feel comfortable forgoing any formal diagnostic testing for the disease.

Ask

In contrast to the latter two cases described, Ms. Mason’s case represents true diagnostic uncertainty. She has a pretest probability (actual risk of having SAH at the moment of our encounter) that is neither immediately intuitive nor easily estimated based on clinical experience. It is in such scenarios that the medical literature is particularly useful. However, before seeking answers, we must be explicit in defining our question. We could start with a broad inquiry such as “What is the chance that she has SAH?” Formulating plus refining this question is a difficult and fundamental skill of EBM. It is an important endeavor that often has the greatest bearing on the value of the answer generated by the EBM process. Accordingly, considerable time and thought should be allocated to careful deliberation over what it is that we actually want to know. In this case, because we are primarily concerned with prognosis and diagnosis, we will focus most of our energy on defining the population most relevant to our patient.

The prevalence of SAH varies considerably across practice settings and research cohorts, which is often a reflection of biases such as spectrum bias, or enrollment of an overly narrow or broad spectrum of patients, and referral bias, which is one type of spectrum bias and typically occurs when a study enrolls only a referred patient cohort. A recent publication of patients referred to a neurosurgical department for headache suspicious of SAH found a remarkable prevalence of 59%.³ In contrast, in a large retrospective study of nearly all patients with headache encountered in an ED, only 1% were found to have SAH.⁴ In the second example, a broad cohort with limited inclusion or exclusion criteria related to headache quality was evaluated, and very few had the disease of interest. Conversely, when only a highly selected population of patients with headache referred to a neurosurgeon were studied, the majority had significant pathology. Ideally, any study that we use to generate a risk estimate for Ms. Mason should be from the ED setting and should enroll those with a similarly “acute” headache.

Further refining our question, we note that Ms. Mason is awake and alert with normal findings on neurologic examination. One review has suggested that 15% of patients seen in the ED with a thunderclap headache have SAH, but the two studies in this review did not distinguish between neurologically compromised and normal patients.^5,⁶ In both studies, one in five patients enrolled was noted to have either lethargy or altered mental status. Not surprisingly, another prospective study in which fewer patients with abnormal neurologic findings were enrolled found a much lower prevalence of disease⁷ (Table 1).

Table 1 Prospective Studies Including Patients with Severe, Acute Headaches, Including Patients with Abnormal Findings on Neurologic Examination

Incorporating this background research into our question, we decide that the following variables are critically important when considering her risk for SAH: she has no comorbid conditions, is seen in the ED setting, and has a headache of acute onset. She has normal mental status and neurologic findings.

The outcome of interest is SAH. There are effectively two “gold standard” tests available for identifying this disease. The presence of subarachnoid blood on unenhanced computed tomography (CT) is the most common means by which this diagnosis is made. Alternatively, the presence of blood or xanthochromia in cerebrospinal fluid, acquired via lumbar puncture (LP), in the presence of an aneurysm or arteriovenous malformation on cerebral angiography is considered diagnostic. In some studies in which patients are being evaluated for SAH, not all undergo these conventional tests, and clinical follow-up is used as a surrogate measure. In these cases, the assumption is that those with SAH, missed at the index visit, would experience significant neurologic decline or death during the follow-up period.

Thus, we generate a question using terminology that will assist in the next step of the EBM process. In neurologically normal patients seen in the ED with an acute headache, what is the risk (or prevalence) of SAH?

When the diagnosis of SAH is being pursued, the current recommended approach includes a CT scan, followed by LP when imaging is negative.¹⁰ Based on study design and disease prevalence, the sensitivity of CT has varied widely across research populations, between 82% and 100%, and this has been judged inadequate in the context of the disease.⁸ Although a recent investigation of CT for SAH reported a sensitivity approaching 100%, spectrum bias was evident because all the subjects were referred to a neurosurgical center for evaluation.³

Moving back to our appraisal step, we perform a more in-depth analysis of the study results of Perry et al. In the cohort there were 1999 subjects, and SAH was diagnosed in 130 of them. One hundred twenty-one of the 130 SAH cases were detected by CT, thus generating a sensitivity of 93%, whereas the remaining 9 cases were detected by LP. A potential limitation exists in that only 80% of the patients enrolled underwent CT and only 45% had LP performed, the criterion standard for SAH, but nearly all had extensive clinical follow-up. Because it is presumed that dangerous SAH would result in a deleterious neurologic event at some point, we decide that clinical follow-up is a good surrogate outcome (an outcome that can act as a valid replacement for the criterion or gold standard). All CT positives were considered true-positives, so we presume a specificity of 100% for the test. With this information available, we can calculate the negative likelihood ratio (LR) for a normal CT scan. The LR is a simple tool that calculates the probability of the disease based on the sensitivity and specificity of the test and the test result. In this case, with a negative CT result and 93% sensitivity and 100% specificity of CT, the calculation is 1 − sensitivity/specificity, or (1 − 0.93)/1. The negative LR in this case is therefore 0.07 (95% confidence interval, 0.04 to 0.13).

We decide to presume a worst-case scenario for the imaging test and choose an LR of 0.13, which represents the upper boundary of the confidence interval. Plotting a pretest probability of 6.5% on a Fagan nomogram and using an LR of 0.13, we generate a posttest probability of just under 1% (Fig. 1). You explain to the patient that a less than 1 in 100 chance (1 in 118 to be exact) persists that she has SAH detectable by LP. She carefully considers these numbers and asks another question: “How much lower would her risk be if LP were performed and determined to be normal?” In the EBM style of practice, one question often begets another. We return to the acquire and appraise steps.