Table 4 The application of the GRADE “Paradigmatic situations in which a strong recommendation may be warranted despite low or very low confidence in effect estimates” for T&CM^a

1. When low quality evidence suggests benefit in a life-threatening situation (evidence regarding harms can be low or high)

   e.g. Very low quality evidence for intravenous silibinin for life-threatening amatoxin mushroom poisoning [91, 92], or intravenous ascorbate for life-threatening viral infections [93, 94]. Recommend to use if there are no alternate proven interventions.

2. When low quality evidence suggests benefit and high quality evidence suggests harm or a very high cost

  e.g. Low quality evidence that intravenous ascorbate improves quality of life and reduces chemotherapy toxicity in cancer treatment, and high quality of evidence of very high costs compared to oral ascorbate [95].   If there are significant opportunity costs to the patient, recommend not to use intravenous.

3. When low quality evidence suggests equivalence of two alternatives, but high quality evidence of less harm for one of the competing alternatives

   e.g. Low quality evidence of equivalence of glucosamine and non-steroidal anti-inflammatory drugs (NSAIDS) for the long-term symptomatic management of osteoarthritis; but high quality evidence of increased gastrointestinal and cardiovascular risks for NSAIDs only [96, 97]. Recommend glucosamine as first-line treatment, especially for patients with a higher risk of complications from NSAIDs.

4. When high quality evidence suggests equivalence of two alternatives and low quality evidence suggests harm in one alternative

  e.g. High quality equivalence of certain proprietary extracts of St. John’s Wort and selective serotonin reuptake inhibitors (SSRIs) for depression; and low quality evidence of a higher risk of suicide with SSRIs [98–100]. If   these certain proprietary St. John’s Wort extracts are available and affordable, then recommend as first-line treatment before an SSRI.

5. When high quality evidence suggests modest benefits and low/very low quality evidence suggests the possibility of catastrophic harm

   e.g. High quality evidence of modest benefit from peri-operative use of fish oil for elective Coronary Artery Bypass Surgery; and low quality evidence for catastrophic haemorrhage [80–82]. Recommend not to cancel CAB surgery if the patient has taken fish oil pre-operatively.