Medical/Drug Studies Create Confusion
The way in which risk factors are modified really does matter
Large scale medical studies reveal levels of uncertainly, even confusion,
that that were not anticipated by physicians who rely on their results. Efforts
to prevent vascular disease, for example, focused on using drugs to lower “risk
factors” such as low-density lipoprotein (LDL) cholesterol, systolic blood
pressure, and glycated hemoglobin. The clinician attempts to reduce risk factors
below specific levels using drugs.
Krumholz and Lee stated: “This approach, however, neglects the
importance of which specific strategies are used to modify these factors. A
clinical trial is ultimately a test of a strategy, and we should not be
surprised that different strategies may have different effects on patients
beyond their effect on risk-factor levels. Awareness of this issue increased in
2006 when Pfizer stopped the study named ILLUMINATE and all other trials
involving torcetrapib, which until then had been seen as a promising agent that
lowered LDL cholesterol levels and raised high-density lipoprotein (HDL)
cholesterol levels. ILLUMINATE was halted because patients receiving torcetrapib
plus atorvastatin had a higher mortality rate than those receiving atorvastatin
alone — despite 72% increases in HDL levels and 25% decreases in LDL levels.
More studies have raised questions about patient management that prioritizes
target levels of risk factors over attention to the way in which those levels
are achieved.
They continued with other examples of studies that relied on surrogate
markers of disease that produced negative outcomes for patients. For
example, the Women's Health Initiative revealed that hormone-replacement
therapy, which reduces LDL cholesterol levels, increased the risk of
cardiovascular disease. Rosiglitazone improves glucose control, but can increase
cardiovascular risk. Adding an angiotensin-receptor blocker to an
angiotensin-converting–enzyme inhibitor is more effective reducing blood
pressure, but increases the risk of adverse events. What seemed to be a
reasonable hypothesis that more effecting lowering of blood glucose with
multiple medications would improve outcomes in Diabetics did not reduce the risk
of macrovascular complications and, in the ACCORD study, increased the risk of
death.
They stated: “Thus, the risk–benefit ratio of interventions designed to
modify risk factors can vary depending on the type and number of medications and
other approaches that are concurrently incorporated. In particular, some
medications may have beneficial or harmful effects beyond their effect on a risk
factor. Moreover, the strength of the evidence supporting particular strategies
varies. Some strategies are known to improve patient outcomes, whereas others
are known to affect only risk-factor levels or other intermediate outcomes. We
are now beginning to appreciate that a strategy's effect on a risk factor may
not predict its effect on patient outcomes.
Clearly, the way in which risk factors are modified really does matter.
Lifestyle interventions may have few risks, but we cannot assume the same for
drugs — and drug-related risks are not always known or appreciated. ACCORD,
ADVANCE, and other studies reminded us that practice is complex and that
ultimately we need to understand a strategy's effects on people, not just on
surrogate end points. “
Harlan M. Krumholz, M.D., and Thomas H. Lee, M.D. Redefining Quality —
Implications of Recent Clinical Trials. NEJM Volume 358:2537-2539 June 12,
2008 Number 24
