Robert R. Fenichel
The CATHEDRAL Trial — Children and Adults Toward the High End of Risk from Altered Lipids
The question. Some middle-aged adults are at higher risk of atherosclerotic events than others. A few of these high-risk patients suffer from the extreme derangements of major familial hyperlipidemias, but the others have only high-normal blood pressure, high-normal total serum cholesterol, high-normal LDL/HDL ratio, nicotine addiction, diabetes, or some combination of these factors. Multiple hard-outcome trials have demonstrated that in these high-risk middle-aged adults, the risk of new atherosclerotic events is reduced by use of lipid-lowering therapy with HMG-coA-reductase inhibitors (“statins”).
Can this therapeutic recommendation be extended to younger patients? We know that adults with high cholesterol levels tend to have had high levels as children, and that fatty streaks are found within the aorta as early as late adolescence. Should younger adults with lipid levels similar to those of the middle-aged subjects in the hard-outcome trials receive statins? Should even children receive such therapy?
The case for extending the results of the hard-outcome trials to these younger groups cannot yet be made. In the middle-aged population, lipid-lowering therapy has prevented events during the course of each several-year trial. In younger adults, and especially in children, atherosclerotic events are vanishingly rare; there are no events to avert. Even assuming that a high-normal lipid level seen in childhood is likely to persist throughout life, there are simply no data to support use of anti-lipid therapy in (say) an eight-year-old child. Perhaps the consequences of hyperlipidemia are mediated by simple integrals of lipid levels over time, but perhaps the connections are more complex, so that nothing would be lost in deferring treatment of the child for (say) five or ten years.
Also, hyperlipidemia and lipid-lowering therapy may have pediatric effects that could not be anticipated on the basis of experience in adults. If the mildly hyperlipidemic eight-year-old child is treated with statins for the next five years, is he/she likely to enter adolescence a little shorter or a little taller? Is he/she likely to be a little smarter or a little stupider? Are the myotoxic and hepatotoxic effects of statins more or less frequent in children than in adults?
The trial. I here propose a trial to help determine at what age it becomes appropriate to institute lipid-lowering therapy in persons with only moderate degrees of hyperlipidemia.
This will be a randomized, double-blind, parallel-group, placebo-controlled trial. The blinded Treatment Period will be five years, but this period will be followed by a much longer Observation Period during which the blind will be maintained. The duration of recruitment remains to be determined.
A subject will be eligible for randomization if he or she would have been too young, but otherwise would have been qualified for randomization in one or another of the recent hard-outcome statin trials. That is, the recruited population will be persons whose risk factors (mainly, lipid levels) would qualify them for statin treatment if they were middle-aged adults. No a priori lower age limit will be set, but a practical lower limit of seven or eight years may arise from drug-formulation issues.
For the duration of the Treatment Period, each subject will be randomized to receive either placebo or a conventional regimen of statin therapy. During the Observation Period, subjects (still blinded to the treatment received during the Treatment Period) will be free to use antilipidemic therapy or not, in whatever regimens their physicians prefer. The primary endpoints sought during the Observation Period will be deaths and nonfatal vascular events. Because such events are rare in young patients, the Observation Period is likely to extend for about 40 years [sic].
Analysis of the trial will be stratified by age at randomization, probably grouped into strata defined by five-year brackets. At intervals to be determined, a Data Safety Monitoring Board will review the accumulated data to decide for each stratum whether the two treatments during the Treatment Period have been shown to have different outcomes.
Some results of interim analyses might lead to discontinuation of recruitment into one or another stratum, but subjects already recruited could still be followed to determine later-developing differences between the treatments. For example, suppose that five years of active treatment were associated with a 10-point reduction in the IQ of pre-adolescents. Recruitment of pre-adolescents might well then be stopped, but during the ensuing Observation Period it might be learned that active treatment reduced (or did not reduce) the incidence of primary endpoints. As this example illustrates, some combinations of early and late findings might lead to difficult ethical problems in future recommendations for therapy, but no more so than current ignorance.
Thinking about very long trials. Observational trials such as the Framingham Study have lasted for several decades, but the CATHEDRAL trial would be the longest intervention trial ever executed, probably the first one to predictably outlast all of its original investigators. Its name is meant to bring to mind the history of human efforts whose durations have exceeded those of any individual’s involvement.
In considering a trial of this duration, one must acknowledge that there is a greater-than-average risk that the trial will be overtaken by events. For example, new lipid-lowering therapies might relegate the statins to second-line therapy. Under some circumstances, the CATHEDRAL investigators would have perverse incentives to continue therapy that they had come to regard as suboptimal. On the other hand, because the Treatment Period will be relatively short, the risk of this situation is not substantially greater than that found in customary trials.
A greater risk is that some of the possible findings of the study might come to be of limited interest. If the statins were superseded by radically different anti-lipid therapy, then the CATHEDRAL results might come to be no more interesting than a hypothetical discovery of a hypertensive population in whom reserpine did not provide clinical benefit.
The questions addressed by CATHEDRAL would remain relevant, and one must contemplate the possibility that before the expiration of the Observation Period, the active treatment used during the Treatment Period would, on the basis of external evidence, be changed from a statin regimen to something else.
Page revised: 11/29/2010 21:43