Table 3 Examples of Clinically Important Risk-based Heterogeneity of Treatment Effect

Symptomatic carotid stenosis

Carotid endarterectomy (CEA)

While overall results showed CEA to reduce stroke risk in patients with severe stenosis, risk-benefit stratification demonstrated that benefit is limited to those with high risk features, but without risks factors for perioperative complications[21].

Non-valvular atrial fibrillation (AF)

Anticoagulation for primary prevention of stroke

While warfarin prevents stroke in patients with AF compared to aspirin, patients without risk factors for stroke do not benefit incrementally[49, 50].

Coronary artery disease (CAD)

Coronary artery bypass grafting (CABG)

Early coronary artery bypass grafting reduces total mortality compared to medical therapy in medium and high risk patients, while low risk patients have a non-significant trend toward increased mortality[64].

Primary prevention of coronary artery disease

Lipid lowering

Statin therapy reduced risk of myocardial infarction or death, but low risk patients are highly unlikely to benefit despite hyperlipidemia[65].

Acute coronary syndromes (ACS)

Early invasive (versus conservative) strategy

Enoxaparin (versus unfractionated heparin)

Tirofiban (versus placebo)

These therapies reduce the risk of myocardial infarction or death in high risk but not in low risk patients[46–48, 66, 67]. The risks of bleeding with intensive antithrombotic regimens outweigh benefits in low risk patient. Risk stratification has become central to the management of ACS[68].

ST-Elevation acute myocardial infarction

tPA (versus streptokinase)

Percutaneous coronary intervention [PCI] (versus thrombolytic therapy)

tPA improves mortality in high risk patients compared to streptokinase, but not in low risk patients. When low risk patients have an excess of risk factors for bleeding, risks of therapy may outweigh benefits[17, 55].

Mortality benefits of PCI are limited to only a relatively limited high risk subgroup [69, 70].

Severe sepsis

Drotrecogin alfa (activated protein C)

While the pivotal phase III trial demonstrated a significant mortality reduction overall, this was found to be limited only to the half of patients with a high baseline mortality risk. Lower risk patients were exposed to bleeding risks, without a mortality benefit [68, 71, 72].