Medical/Drug Studies Create Confusion

Large scale medical studies reveal levels of uncertainly, even confusion, that that were not anticipated by physicians who once relied 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 attempted 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 (Investigation of Lipid Level Management to Understand Its Impact in Atherosclerotic Events) 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 raised questions about patient management that prioritizes target levels of risk factors over attention to the way in which those levels are achieved.The Women's Health Initiative revealed that hormone-replacement therapy, which reduces LDL cholesterol levels, increased the risk of cardiovascular disease. ENHANCE (Effect of Combination Ezetimibe and High-Dose Simvastatin versus Simvastatin Alone), showed that ezetimibe did not reduce the progression of arteriosclerosis when combined with simvastatin, as compared with simvastatin alone, even though the combination did result in a greater reduction of LDL cholesterol. Rosiglitazone improves glucose control, but it may also be associated with increased cardiovascular risk. Adding an angiotensin-receptor blocker to an angiotensin-converting–enzyme inhibitor may produce a greater reduction in blood pressure, but it may not reduce cardiovascular risk and it increases the risk of other adverse events. Two studies of diabetes treatment raised more questions: ACCORD (Action to Control Cardiovascular Risk in Diabetes) and ADVANCE (Action in Diabetes and Vascular Disease). Thetow studies tested the hypothesis that  tight glucose control using of multiple medications would improve outcomes in patients with type 2 diabetes mellitus. The studies revealed that multiple medications did not reduce the risk of macrovascular complications. The ACCORD study's intensive control strategy was associated with a higher risk of death, which led to early discontinuation of this part of the study. The ADVANCE study's findings indicate that its strategy may reduce the risk of worsening renal function at the cost of an excess risk of hypoglycemic events.

“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 recent studies remind 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