Antipsychotics May Influence Patients' Risk for Heart Disease

Daumit and colleagues used the Framingham Heart Study formula to calculate 10-year CHD risk for five medications prescribed to patients enrolled in the CATIE study; change in 10-year risk was calculated as an absolute percentage change from baseline to the end of the treatment phase.

Inputs to the formula included age, total and HDL cholesterol, blood-pressure stage, presence of diabetes mellitus, and presence of smoking.

The formula reports the average risk of developing CHD over a 10-year period as a percentage, controlling for baseline age so that changes in CHD risk reflect factors other than aging. Secondary outcomes were changes in diabetes, smoking status, hypertension, total cholesterol, and HDL by antipsychotic treatment.

The CATIE study was conducted between January 2001 and December 2004 at 57 U.S. sites. A total of 1,460 patients were randomly assigned to take one of the second-generation antipsychotics olanzapine, quetiapine, risperidone, and ziprasidone or the first-generation antipsychotic perphenazine and were followed under double-blind conditions for up to 18 months or until initial treatment discontinuation; of these, 10-year CHD risk was calculable at baseline and the end of phase 1 for 1,125 patients.

The researchers found significant differences in the change in 10-year risk for CHD across treatment groups. The estimates of risk change were highest for olanzapine, followed by quetiapine; and lowest for risperidone and ziprasidone, followed by perphenazine. Individual comparisons between treatment groups revealed that the difference in the change in risk between the olanzapine- and the risperidone-treated groups was statistically significant.

The most important single risk factor for CHD across treatment groups appeared to be cholesterol measurements, with decreases in total cholesterol and increases in HDL cholesterol being statistically different across certain treatment groups.

Lowering of total cholesterol in patients treated with risperidone and ziprasidone, for instance, largely contributed to overall differences in CHD risk between treatments. But also contributing to the difference was an unexpected racial differentiation in HDL cholesterol changes: white patients who took perphenazine and nonwhite patients who took ziprasidone showed elevated levels of HDL cholesterol.

“If replicated, identification of physiologic or molecular mechanisms underlying race differences in antipsychotic effects on HDL will be of considerable interest,” the researchers stated.

The change in 10-year cardiac risk was significantly different across the five treatment arms for participants with a baseline CHD risk of 10 percent or greater. In this subgroup, the risk for risperidone-treated patients remained lower than that for the olanzapine-treated patients, although not statistically significant. For participants with less than a 10 percent baseline CHD risk, the change in risk did not differ across treatment groups.

Psychiatrist John Newcomer, M.D., who has been a leader in raising awareness about cardiometabolic risks in patients with schizophrenia, told Psychiatric News that the study builds on a growing body of evidence about the role of antipsychotics in what has been called an“ epidemic” among severely mentally ill individuals. He is the Gregory B. Couch Professor of Psychiatry, Psychology, and Medicine at Washington University School of Medicine and medical director of the Center for Clinical Studies.

“Given the U.S. Public Health Service focus on overweight and obesity as leading modifiable contributors to cardiovascular and diabetes risk, it is not surprising that there is growing interest in those medications—not just antipsychotics—that can significantly increase body weight or produce other effects that increase cardiometabolic risk,” Newcomer said.

He said CATIE produced a critical body of data for analyzing the five antipsychotics' public health effect on CHD risk, but he cautioned that the prestudy treatment history of patients in CATIE is important to understand the results of the new analysis.

“It is less clear how much of the change in risk, especially the risk reductions observed in some groups, was due to intrinsic effects of those treatments versus the effect of switching from whatever treatment subjects were on before to the treatment condition under analysis,” Newcomer said.

For example, a switch from a treatment associated with greater mean adverse effects on weight and lipids to one associated with fewer adverse effects has been reported to be associated with weight loss and lipid improvements. But at the same time, treatment of first-episode patients with such lower-risk agents is routinely reported to produce some degree of weight gain. Therefore, the cardiovascular risk “benefit” of switching treatment to lower-risk agents might be available only to those patients currently treated with higher-risk medications.

“Patients on perphenazine and ziprasidone looked like they improved, but that is very likely an epiphenomenon,” Newcomer said, arising from the fact that they were previously taking a medication that worsened their risk and then were switched to something that is better, so that their numbers appeared to improve.

“Certainly, there is no evidence that any of the antipsychotics are lipid-lowering agents.”

Newcomer also pointed out that the Framingham Heart Study formula was designed for measuring risk in a general population and may not fully capture the specific factors influencing CHD risk in the subsample of psychiatric patients taking antipsychotic medication. So, for instance, the finding that cholesterol was the most important factor in increasing risk is likely a function of the measurement tool, he said.

He explained that the Framingham formula is heavily weighted toward measuring and predicting risk associated with LDL cholesterol, but is not specifically focused on measuring the change in risk associated with changes in adiposity, insulin resistance, and triglyceride levels—those factors most affected by antipsychotic medication.

“The key thing is that increases in triglycerides and changes in body weight are far and away the biggest signal in antipsychotic treatment,” he said. “The blood pressure and cholesterol changes are more subtle.”

That's a caveat that Daumit and colleagues acknowledge themselves.“ The rapid and large weight change associated with some antipsychotics substantially differs from typical weight change patterns in the general population from which the risk equation was derived,” they wrote.“ Because weight is not a variable in the Framingham equation, it is possible that the long-term impact on cardiac health of rapid antipsychotic-induced weight gain may not be sufficiently captured.

“Moreover, although triglycerides are part of total cholesterol, which is in the Framingham equation, the model does not specifically incorporate risk for triglycerides, which are increasing in acceptance as an independent risk factor for coronary disease.” ▪