Fig 7.

Benefit-harm trade-offs change substantially when subgroups are stratified by their risk of treatment related harms. (A) In the IRIS study, pioglitazone was shown to reduce the risk of recurrent events (stroke or MI) (RR=0.76) in patients with ischemic stroke and insulin resistance, but with an increase in the risk of fracture. At five years, the incremental risk of fracture was 4.9% (13.6% v 8.8%; HR 1.53). When patients were stratified by their risk of fracture using a simple risk score with eight variables, for each 100 patients at low risk of fracture treated with pioglitazone for five years, two to three had a pioglitazone related fracture, compared with six to seven in each 100 patients at high risk.¹⁰² During this same interval, in both risk groups three to four fewer patients treated with pioglitazone had a recurrent stroke or MI. Thus, the number of ischemic events prevented per fracture caused was two in the group at low risk of fracture and 0.5 in the high risk group. When only serious fractures were considered (those requiring hospital admission or surgery), pioglitazone prevented six ischemic events per serious fracture caused in those at low risk of fracture, but only about one event in those at high risk. These clinically important differences in benefit-harm trade-offs across strata emerged despite consistency of effects on the proportional scale for both the harm and benefit of treatment. (B) Similarly, when patients were stratified by their bleeding risk using a simple five variable risk score, prolonged DAPT (aspirin plus clopidogrel or ticagrelor) after percutaneous coronary intervention had a very favorable harm-benefit trade-off in patients at low risk of bleeding but not in those at high risk.¹⁰³ DAPT: dual antiplatelet therapy; HR: hazard ratio; IRIS: Insulin Resistance In Stroke; MI: myocardial infarction; RR: relative risk.