When the margin between benefits and adverse effects is narrow

Treatment is of modest or uncertain benefit, with an important possibility of adverse effects.

•   Aspirin for prevention of cardiovascular events in a healthy patient; increase in haemorrhage;

•  Antibiotics for acute otitis media in children; risk of rash and diarrhoea;

•  Urgent direct current cardioversion in patients with new atrial fibrillation who are cardiovascularly stable; risk of stroke from cardioversion.

Treatment is potentially highly beneficial, but there are major safety concerns.

• Aspirin for patient with a stroke, but who has a past history of gastrointestinal haemorrhage;

• Carotid endarterectomy in older patients with ischaemic heart disease who present with stroke.

Treatment is potentially beneficial in long term, or to community, but no immediate direct benefit to individual.

• Improving uptake of a vaccine to promote herd immunity, while trying to assuage fears about early serious neurological adverse effects.

When a number of efficacious treatments differ in their safety profiles

Treatments are of equivalent efficacy, but they have different safety profiles.

• Antiepileptic drugs for women of childbearing age with epilepsy;

• A new insulin injection device is thought to cause less pain than the existing device.

The balance of benefits and adverse effects differs substantially, e.g. the most efficacious intervention may have serious adverse effects, while the less effective intervention is potentially safer.

•  Disease-modifying drug in erosive rheumatoid arthritis, e.g. using hydroxychloroquine (relatively safe) or methotrexate (potentially more effective, but less safe);

• Polychemotherapy versus sequential single agent chemotherapy for metastatic breast cancer.

When adverse effects deter a patient from continuing on an efficacious treatment

Treatment is of considerable benefit but adverse effects threaten patients’ adherence, and evidence is needed to guide further management.

•  An effective intervention has well-recognized adverse effects, which can make it difficult for the patient to continue therapy. Evidence is needed on whether reducing the intensity of the intervention (e.g. lower dose or duration) will help avoid the adverse effects, or whether there is a treatment strategy that can prevent adverse effects (e.g. proton pump inhibitor for peptic ulcers caused by aspirin).