NEWER ANTIEPILEPTIC DRUGS ARE SAFER

Newer Antiepileptic Drugs Cause Less Cardiovascular Risk Than Older Agents

March 19, 2009 — Switching patients with epilepsy from older antiepileptic drugs that induce cytochrome P450 to 1 of the newer drugs that do not affect this enzyme system can dramatically reduce cardiovascular risk.

Investigators at Thomas Jefferson University, in Philadelphia, Pennsylvania, report these findings online March 18 in the Annals of Neurology in 34 epilepsy patients switched from phenytoin or carbamazepine to either lamotrigine (Lamictal, GlaxoSmithKline) or levetiracetam (Keppra, UCB).

Within 6 weeks of the switch, patients had significant decreases in total cholesterol, non–high-density-lipoprotein (atherogenic) cholesterol, triglycerides, and C-reactive protein (CRP). All 4 markers are associated with elevated risk for atherosclerosis, cardiovascular disease, and stroke.

"The most important point that clinicians should take from this study is that carbamazepine and phenytoin cause a panoply of serologic changes that would be expected to increase myocardial infarction and stroke risk significantly.

"In the epilepsy field, that means that it is highly questionable whether or not these drugs should be first-line agents. In psychiatry, this has to be balanced against the potential risks and benefits of alternative treatments," principal investigator Scott Mintzer, MD, told Medscape Psychiatry.

Unexpected Reduction in Lipoprotein(a)

This repeated-measures, within-patient study is also notable because it is 1 of the few vascular risk studies done in adults with epilepsy. Most previous studies are either conducted in children or are cross-sectional.

After changing to lamotrigine or levetiracetam, subjects had average declines of 24.8 mg/dL in total cholesterol, 19.9 mg/dL in atherogenic cholesterol, and 47.1 mg/dL in triglycerides (all P < .0001). Average CRP levels fell by 31.4% (P = .027).

One unexpected finding was that patients who stopped taking carbamazepine also had a 31.2% decline in lipoprotein(a) (Lp[a]) levels (P = .0004), while those who stopped phenytoin had a 1.7 mmol/L decrease in homocysteine (P = .005).

"Many of the findings were expected, but 2 findings surprised me — first, that carbamazepine and phenytoin appear to have such sharply different effects on Lp(a); and second, that CRP appears to be markedly affected by these drugs. No one has ever examined CRP in epilepsy patients or in any patients who take these drugs, to my knowledge," said Dr. Mintzer.

More data are needed to establish that patients who were seizure-free on the older drugs will remain seizure-free on the newer drugs. However, said Dr. Mintzer, in his opinion, all epilepsy patients are potential candidates for this switch.

Reduction in Health Costs?

Cost questions typically arise when clinicians begin pressing for switching from older, usually cheaper agents, to newer, usually more expensive, drugs. Dr. Mintzer's data are expected to be helpful to clinicians arguing this point with third-party payers, national health agencies, or formulary committees.

He predicts that changing patients to the newer drugs will actually save healthcare dollars by reducing the current high rate of cardiovascular problems in these patients. “In any case, most of the newer drugs have just come off patent, so their prices will drop substantially in the not-too-distant future,” he added.

John O. Elliott, clinical research data manager at Ohio State University, in Columbus, told Medscape Psychiatry that the study design "was the correct one to use, and this paper certain adds much to the literature."

However, Mr. Elliott noted, there is still some question about whether cardiovascular disease is more prevalent in people with epilepsy.

"Based on my own research, I believe that poorer health habits (lack of exercise, smoking, and poor diet) in people with epilepsy put them at greater risk for comorbid conditions. Patients with chronic epilepsy also have significant economic challenges (unemployment and lower education) that are significantly related to poorer health outcomes.

"In a recent project that will be coming out in the journal Epilepsy Research we examine the effects that social determinants of health, including poverty, have on people with epilepsy. Practitioners recognize the effect that these factors have on treatment and health outcomes. However, there are also no quick and easy solutions to such social problems," Mr. Elliott said.