How Changes In Surrogate Markers Predict Clinical Outcomes

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To avoid large and lengthy clinical trials, investigators and trial sponsors often resort to surrogate markers in the testing of an intervention. The blood pressure lowering effect of a new antihypertensive agent can be documented in a placebo controlled trial of 50-100 hypertensive subjects treated for 8-12 weeks. A stroke prevention trial of the same agent would require 4-5000 subjects treated for 4-5 years. Thus, small, short term trials with surrogate markers offer obvious advantages. Other examples of common surrogates in the cardiovascular field include low density and high density lipoprotein (LDL and HDL) cholesterol, HbAIC, premature ventricular depolarisations, ejection fraction, other haemodynamic measures, and angiographic changes.

A valid surrogate marker is one whose response to an intervention closely mimics that of the real (clinical) outcome it is supposed to represent. Unfortunately, this requirement is seldom met. The Veterans Affairs high density lipoprotein intervention trial6 reported that gemfibrozil reduced the risk of major coronary events in coronary patients with normal LDL cholesterol, but low HDL cholesterol. The assumption was that benefit was mediated through gemfibrozil induced increases in HDL cholesterol. When the investigators analysed the trial data to determine how much of the health benefit could be explained by individual changes in the surrogate marker (HDL cholesterol), they came up with the surprising finding that only 22% of the benefit could be attributed to gemfibrozil induced increases in HDL cholesterol. Similar observations have been reported for raised blood pressure (CD Furberg, unpublished data).

By contrast, sometimes drugs have favourable effects on surrogates, but actually cause harm. The cardiac arrhythmia suppression trial7 reported that even though encainide and flecainide notably reduced the number of premature ventricular depolarisations (a surrogate for sudden death), these drugs increased the risk of sudden death. A handful of inotropic agents have been shown to improve haemodynamic parameters in patients with congestive heart failure, but they were later shown to increase mortality.

The magnitude of the "improvement" of a surrogate marker cannot be assumed to predict, with high precision, the magnitude of a health benefit in individual patients. The expectation

that common surrogates are clinically useful and predictive rests on the assumptions that drugs have only one mechanism of action (that of the surrogate) and that the development of clinical complications evolves through a single mechanism (mediated through the surrogate). All antihypertensive drugs lower raised blood pressure, but they differ greatly in their blood pressure independent actions. Hypertension is not just high blood pressure. Thus, there are good scientific reasons to expect that different classes of antihypertensive agents differ in how they reduce risk.8

It is important to remember that clinical trials investigate and report results for groups of subjects, not individual subjects. When we interpret trials, we assume that the group data apply equally to all individuals. Two recent articles910 highlight the issues of interpreting and applying research findings to individuals. Caution is advised in inferring that a large change in a surrogate marker in an individual automatically translates to a greater clinical benefit than a small marker change. Subjects with small changes may also stand to benefit clinically.

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Blood Pressure Health

Blood Pressure Health

Your heart pumps blood throughout your body using a network of tubing called arteries and capillaries which return the blood back to your heart via your veins. Blood pressure is the force of the blood pushing against the walls of your arteries as your heart beats.Learn more...

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