LDL-cholesterol differences predicted survival benefit in statin trials by the surrogate threshold effect (STE).
OBJECTIVE
We describe a new statistical method called the surrogate threshold effect (STE) that estimates the threshold level of a surrogate needed in a clinical trial to predict a benefit in the target clinical outcome. In this article, we apply this method to the LDL-cholesterol biomarker surrogate and survival benefit-target outcome in statin trials.


METHODS
We identified randomized trials comparing statin treatment to placebo treatment or no treatment and reporting all-cause and cardiovascular mortality. Trials with fewer than five all-cause deaths in at least one arm were excluded. Multiple regression modeled the reduction in all-cause and cardiovascular mortality as a function of LDL-cholesterol difference. The 95% confidence and 95% prediction bands were calculated and graphed to determine the minimum LDL-cholesterol difference (the surrogate threshold) below which there would be no predicted survival benefit.


RESULTS
In 16 qualifying trials, regression analysis yielded an all-cause mortality model whose prediction bands demonstrated no overall survival gain with LDL-cholesterol difference values below 1.5 mmol/L. The cardiovascular mortality model yielded prediction bands that demonstrated no cardiovascular survival benefit with LDL-cholesterol difference values below 1.4 mmol/L.


CONCLUSIONS
In a multitrial setting, the STE approach is a promising yet straightforward statistical method for evaluating the surrogate validity of biomarkers.
Department of Clinical Pharmacology, University of Newcastle, Mater Hospital, Waratah NSW 2298, Australia. kent.johnson@newcastle.edu.au
Kent R
KR
Johnson
Nick
N
Freemantle
Danielle M
DM
Anthony
Marissa N D
MN
Lassere
D015415:Biomarkers / Q000097:blood; D002318:Cardiovascular Diseases / Q000188:drug therapy / Q000401:mortality*; D002423:Cause of Death; D008078:Cholesterol, LDL / Q000097:blood*; D005260:Female; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000627:therapeutic use*; D008297:Male; D010919:Placebos; D011237:Predictive Value of Tests; D016032:Randomized Controlled Trials as Topic; D012307:Risk Factors; D016019:Survival Analysis; D016896:Treatment Outcome
D015415:Biomarkers; D008078:Cholesterol, LDL; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D010919:Placebos