Aims: Clinical guidelines often recommend treating individuals based on their cardiovascular risk. We revisit this paradigm and quantify the efficacy of three treatment strategies: (i) overall prescription, i.e. treatment to all individuals sharing the eligibility criteria of a trial; (ii) risk-stratified prescription, i.e. treatment only to those at an elevated outcome risk; and (iii) prescription based on predicted treatment responsiveness.

Methods and results: We reanalysed the PROSPER randomized controlled trial, which included individuals aged 70–82 years with a history of, or risk factors for, vascular diseases. We conducted the derivation and internal–external validation of a model predicting treatment responsiveness. We compared with placebo (n = 2913): (i) pravastatin (n = 2891); (ii) pravastatin in the presence of previous vascular diseases and placebo in the absence thereof (n = 2925); and (iii) pravastatin in the presence of a favourable prediction of treatment response and placebo in the absence thereof (n = 2890). We found an absolute difference in primary outcome events composed of coronary death, non-fatal myocardial infarction, and fatal or non-fatal stroke, per 10 000 person-years equal to: −78 events (95% CI, −144 to −12) when prescribing pravastatin to all participants; −66 events (95% CI, −114 to −18) when treating only individuals with an elevated vascular risk; and −103 events (95% CI, −162 to −44) when restricting pravastatin to individuals with a favourable prediction of treatment response.

Conclusion: Pravastatin prescription based on predicted responsiveness may have an encouraging potential for cardiovascular prevention. Further external validation of our results and clinical experiments are needed.