In this presentation, Dr. Ridker explores three questions: Can we rely on surrogate outcomes in clinical trials? Can we rely on surrogate endpoints in clinical trials?..And if not, is there any use for biomarkers such as C-reactive protein (CRP) in the phase III clinical trial process?

The federal definition of biomarkers states that “A surrogate end point, or ‘biomarker’, is a laboratory measure or physical sign that is used in therapeutic trials as a substitute for a clinically meaningful end point that is a direct measure of how a patient feels, functions, or survives and is expected to predict the effect of the therapy” (1). There are no surrogate outcomes, only surrogate endpoints, and a classic paper published by Fleming and DeMets, published in Ann Int Med in 1996, described the setting that provides the greatest potential for the surrogate end point to be valid, and reasons for failure of surrogate endpoints (2). Dr. Ridker reviews several bodies of evidence illustrating why it's not certain that surrogate endpoints can be relied upon in clinical trials.

Is there any use then for biomarkers? Apparently yes, for the purpose of defining clinical trial populations where the risk-to-benefit ratio might be improved. As far as hs-CRP levels are concerned, data from ten major cohort studies worldwide have shown that levels <1 mg/L, between 1-3mg/L and >3 mg/L predict the future risk of cardiovascular events after adjustment for the Framingham risk score. A recently reported U.S. cohort study in women further showed that inclusion of hs-CRP in a global risk prediction model improved cardiovascular risk classification, particularly among those with a 10-year risk of 5% to 20%. These data also suggest that hs-CRP enters global risk prediction models before total, HDL and LDL cholesterol (3).

Is there evidence to support a role for hs-CRP in targeting statin therapy for primary prevention of coronary events? In the AFCAPS/TexCAPS trial, not only subjects with high LDL cholesterol at baseline but also those with relatively low LDL cholesterol and elevated CRP levels had reduced event rates with statin therapy (4). This led to the design of the ongoing JUPITER trial, which is looking at primary prevention of cardiovascular events with rosuvastatin in individuals with low LDL cholesterol and elevated CRP levels. Dr. Ridker also discusses evidence from the PROVE IT-TIMI 22 and A to Z trials, showing relationships between achieved LDL cholesterol and hs-CRP values following statin therapy and the risk of adverse outcomes.

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After viewing this presentation the participant will be able to discuss:

- What is a surrogate endpoint?
- How reliable are surrogate endpoints in cardiovascular clinical trials?
- How biomarkers may be used in the phase III clinical trial process

1. 57 Federal Register 1992;13234-13242.

2. Fleming TR, DeMets DL.Surrogate End Points in Clinical Trials: Are We Being Misled? Ann Intern Med. 1996 Oct 1;125(7):605-13.

3. Cook NR, Buring JE, Ridker PM.The Effect of Including C-Reactive Protein in Cardiovascular Risk Prediction Models for Women Ann Intern Med. 2006 Jul 4;145(1):21-9.

4. Ridker PM, Rifai N, Clearfield M, Downs JR, Weis SE, Miles JS, Gotto AM Jr; Air
Force/Texas Coronary Atherosclerosis Prevention Study Investigators.Measurement of C-Reactive Protein for the Targeting of Statin Therapy in the Primary Prevention of Acute Coronary Events N Engl J Med. 2001 Jun 28;344(26):1959-65.