Tuesday, March 23, 2010

ACC--Biomarkers, future clinical endpoint in heart failure trials

A biomarker is in general a substance used as an indicator of a biological state. In clinical trials, the candidate markers include dyspnea, weight change, blood pressure, natriuretic peptides, markers for left ventricular (LV) and gene expression and so on. For example, COMPANION biomarker is a well established endpoint for morbidity in clinical trials, while SCD-HeFT is used for mortality.

In recent heart failure clinical trials, the biomarkers are also being widely used as primary and secondary indications. The primary biomarkers are dyspnea, weight loss, LV size and composite. The secondary biomarkers are LV size and function-ACE-I, BB trials, BNP-Val-HeFT, NYHA class-ACTION-HF.

However, these common biomarkers are not relevant endpoints in heart failure trials as a result of lacking better fidelity, cleaner signal to noise ratio, convincing evidence of meaningful clinical benefit and ideal surrogacy. Cardiologists keep looking for the ideal biomarkers which can better address these questions and become the clinical endpoints in heart failure trials in future.

They have even already written down the scenarios for the future of biomarkers not so far away.
Scenario I: clinical trial XXX tests the ability of treatment YYY to reduce the likelihood of developing heart failure; a biomarker assay is used as the endpoint that biomarker ZZZ is used as a surrogate for heart failure.

Scenario II: clinical trial XX hypothesizes that intervention YYY will improve outcomes in patients with established heart failure; rather than follow longitudinal events, a biomarker assay is used as a surrogate for prognosis.

Scenario III: because an elevated biomarker corresponds with a poor prognosis company AAA develops a “biomarker blocker”; clinical XXX is then done with drug YYY, endpoint combined morbidity/mortality.

Scenario IV: a new antihypertensive purportedly works in part via unregulation of natriuretic peptide production.

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