Caution when starting statins in high-risk patients

Effects on cerebrovascular disease not clear

Research at the University of Mississippi Medical Center indicating that statin therapy reduces risk of developing all cerebrovascular events (CVE) and ischemic stroke, but is associated with a nonsignificant increase in risk of hemorrhagic stroke, is not likely to cause a major change in medical practice. Lead researcher Daniel Riche, PharmD, tells Drug Formulary Review the major takeaway from his meta-analysis is that not everyone should be started on statins. "They're not meant to be in the water," he says. "When starting a patient on statins, you should think about who you're starting it in."

Riche and his colleagues went through 56 full-text reports of clinical trials and three abstracts. They found 27 trials that met their study inclusion criteria: 1) controlled clinical trial vs. placebo; 2) well-described protocol; and 3) data reported on incidence of all CVEs, ischemic stroke, or hemorrhagic stroke. Trials that used cerivastatin (Bayer's Baycol®) as the active treatment were excluded because the studies were ended before they were completed when the drug was pulled from the market. The majority of patients were white males with a history of high cholesterol. Most studies were a mixture of primary and secondary cardiovascular disease prevention trials with a placebo run-in period. Some 21% of the overall population were current smokers.

A total of 26 trials reported data on all CVEs. The meta-analysis showed that statin therapy significantly reduced the risk of all CVEs (17%). Six trials were included in the analysis of the effect of statin therapy on ischemic stroke. Under meta-analysis, statin therapy was shown to significantly reduce the risk of ischemic stroke (21%). Nine trials reported data on hemorrhagic stroke and in them, statin therapy was shown to nonsignificantly increase the risk of hemorrhagic stroke (11%).

"There is ample epidemiologic and experimental data suggesting that high cholesterol is a risk factor for coronary artery disease that can be modified through use of statins," Riche says. "But the effect of statins on cerebrovascular disease is less clear."

Evidence from randomized controlled trials suggests that reducing cholesterol, particularly LDL-cholesterol, by giving statins to patients at high risk for cardiovascular disease reduces the incidence of ischemic stroke. Paradoxically, however, data from large epidemiologic observational studies suggest an inverse relationship between risk of hemorrhagic stroke and serum cholesterol levels.

Problem seen in several trials

"Although the increased risk of hemorrhagic stroke seen in this meta-analysis was driven predominantly by results of the SPARCL trial, the LIPID, CARDS, and MEGA trials each contributed a nonsignificant increase in incidence of hemorrhagic stroke to the totality of data," Riche says. "Whether increased risk of hemorrhagic stroke is a direct class effect of statins or is dependent on the degree of cholesterol reduction remains unknown."

Riche tells Drug Formulary Review he was motivated to conduct this study after the SPARCL trial results showed the risk of hemorrhagic stroke increased with statin therapy. "We wanted to look at all the data," he explains. "When you find something in the future, you always want to look at the past. We found the trend toward hemorrhagic stroke was not driven by a single study and no subgroup analysis showed a difference. This all tells us not to stop using statins, but to be aware of the potential."

The problem, he says, may be related to starting statins at already low LDLs. Physicians shouldn't start high statin use in people who have just had an ischemic stroke if their LDL-cholesterol is already low, he says.

[Editor's note: For more information contact Dr. Riche at driche@sop.umsmed.edu or telephone (601) 984-2640.]