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Centre for Evidence-
Based Medicine

Were there clearly defined groups of patients, similar in all important ways other than exposure to the treatment or other cause?

Consider the following table:

Adverse Event Totals
Present (Case) Absent (Control)
Exposure to treatment (RCT or cohort)

a

b

a + b

No exposure to treatment (RCT or cohort)

c

d

c + d

Totals

a + c

b + d

a + b + c + d

This first question is easy to answer if we've been able to find an RCT during our search. Randomisation should make the 2 groups of patients similar for all causes of the outcome that we are interested in. In an RCT, patients in the experimental treatment group would be in cells a or b in the table above and patients in the control group would be in cells c or d.

Returning to our clinical scenario, we have been fortunate in our search and have managed to find an RCT and are satisfied that patients are similar in all important ways other than exposure to sotalol.

However, there's not always an RCT available to answer our questions and indeed more frequently we find cohort or case control studies to answer our questions about harm and etiology. In a cohort study, 2 groups of patients are followed - one group with the exposure to the treatment (a+b in the table) and one group without the exposure (c+d) - for the development of the outcome of interest (either a or c ). Because the decision about who receives treatment is not randomised, exposed patients may differ from nonexposed patients for important determinants of the outcome (these determinants are called confounders). Investigators should document characteristics of patients and either show that they are similar or adjust for the confounders that they identify. This is limited by the fact that investigators can only adjust for confounders that are known and that have been measured.

In case control studies, people with the outcome of interest (cases = a+c) are identified along with those without it (controls = b+d). The proportion of each group who were exposed to the putative agent is assessed. Case control studies are susceptible to more bias than cohort studies because confounders that are transient or that lead to early death won't get measured. We also need to ensure when reading a case control study, that people in the control group had the same opportunity for exposure as people in the case group. For example, if we found a case control study looking at the association between sotalol and sudden cardiac death and its investigators assembled people with sudden cardiac death as the cases but excluded patients with atrial fibrillation from the control group, we'd be concerned that the association found between sotalol and sudden cardiac death could be spurious.

  1. Were there clearly defined groups of patients, similar in all important ways other than exposure to the treatment or other cause?
  2. Were treatments/exposures and clinical outcomes measured in the same ways in both groups? (Was the assessment of outcomes either objective or blinded to exposure?)
  3. Was the follow-up of the study patients sufficiently long (for the outcome to occur and complete)?
  4. Do the results of the harm study fulfil some of the diagnostic tests for causation?
    • Is it clear that the exposure preceded the onset of the outcome?
    • Is there a dose-response gradient?
    • Is there any positive evidence from a 'dechallenge-rechallenge' study?
    • Is the association consistent from study to study?
    • Does the association make biological sense?