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Abstract:
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Randomized controlled trials (RCTs) are used to estimate the causal effect of a treatment on an outcome in a patient population. The “treatment” in an RCT is sometimes a target, such as a goal biomarker measurement, that the patient's physician attempts to reach using available therapies. Large RCTs of targets are common in clinical research, and trials have been conducted to compare targets in the management of hypertension and other chronic diseases. However, different RCTs intended to evaluate the same targets have produced conflicting recommendations, and meta-analyses of these trials have been inconclusive. In this paper, we describe four key threats to the validity of trials of targets: 1) intention-to-treat analysis that masks the absence of well-defined interventions; 2) incomparability in results across trials of targets due to different distributions of trials features; 3) use of time-varying adaptive treatment strategies vulnerable to time-varying confounding; and 4) Goodhart's law, “when a measure becomes a target, it ceases to be a good measure.” We illustrate these findings using evidence from nine RCTs of blood pressure targets for management of hypertension.
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