Abstract
Objective: We describe anew 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.
Study Design and Setting: 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. (C) 2008 Elsevier Inc. All fights reserved.
Original language | English |
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Pages (from-to) | 328-336 |
Number of pages | 9 |
Journal | Journal of Clinical Epidemiology |
Volume | 62 |
Issue number | 3 |
DOIs | |
Publication status | Published - 1 Mar 2009 |
Keywords
- Surrogate
- Statins
- LDL-cholesterol
- Levels of evidence
- Forecasting
- Biomarker