OBJECTIVES: A Cochrane review concluded that PCSK9 inhibitors reduce cholesterol levels and cardiovascular events but do not decrease mortality, however, the largest study (FOURIER) included participants with low baseline LDL-cholesterol. We generated a synthetic population to model the likely impact of PCSK9 inhibitors (PCSK9i) in a higher risk population with LDL-C levels typical of the 4S study.

METHODS: Population characteristics were taken from the 4S study placebo group and used to generate the synthetic population of 2,222 people. The sample was matched on binary variables (gender ratio, age, smoking status, diabetes) and on continuous factors (BMI, systolic BP, total cholesterol: HDL cholesterol ratio, cigarettes and alcohol consumption). A stochastic Markov model was created in R using the Framingham points-based system for CVD events and calibrated to match the event outcomes in the 4S placebo group. Reduction in cholesterol with the PCSK9i evolocumab was taken from the FOURIER study, in which patients were already being treated with simvastatin. We modelled 1,000 simulations for each of three treatment arms: simvastatin 20-40 mg daily, evolocumab 420 mg every 4 weeks, or placebo, over 5.4 years.

RESULTS: Myocardial infarctions (MI), ischaemic strokes (IS) and CVD deaths were all lower in the PCSK9i group compared with the statin and placebo groups. With reference to the placebo group outcomes, there was a 28% reduction in MI mortality in the statin group, RR = 0.72 (0.66-0.78) and 49% in the PCSK9i group, RR=0.51 (0.46-0.56) For IS mortality there was a 45% reduction in the statin group, RR=0.55 (0.34-0.76) and 70% in the PCSK9i group, RR=0.3 (0.14-0.45). There were no differences in non-CVD-related deaths.

CONCLUSIONS: Our model suggests that adding PCSK9is to statins in a higher risk population could reduce CVD mortality compared with statins alone. The simulated sample is a rapid and low-cost approach to estimating treatment effects.