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Centre for Evidence-
Based Medicine

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?

We'd want to make sure that the exposure occurred before the outcome and that it wasn't just a marker that the outcome was already underway. With an RCT, the exposure clearly precedes the outcome as with the trial that we found. If it's a case control study, this question becomes more difficult to answer, and more important to ascertain.

Is there a dose-response gradient?

With larger doses of the agent, was there an increased risk of the outcome event? In the study we retrieved, this wasn't tested since the investigators looked at one dose of sotalol.

Is there positive evidence from a dechallenge-rechallenge study?

This occurs when the outcome event disappears (or decreases in intensity) when the putative agent is withdrawn and reappears when it is reinstituted. This couldn't be done in the RCT we found because the outcome was death.

Is the association consistent from study to study?

Or, is this the only study where the association has been identified? We would be happy to see that several studies have looked at this question and have come to the same conclusion (or even better, if there was a systematic review of the topic). Only 1 RCT has had sufficient power to look at the use of sotalol and the risk of death.

Does the association make biological sense?

If the association between outcome and exposure makes biological sense, a causal relationship is more plausible. The results of the sotalol RCT are consistent with findings from studies that have looked at other antiarrythmics (e.g. CAST).

If the study fails any of the above criteria, we need to decide if the flaw is significant and threatens the validity of the study. If this is the case, we'll need to look for another study. Returning to our clinical scenario, the paper we found satisfies all of the above criteria and we will proceed to assessing it for importance.

  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?