Although Biochemically Counterintuitive, Combo Parkinson Drug May Increase Cardiovascular Risk
The FDA advises that a combination drug for Parkinson disease may increase the risk of cardiovascular events—like MI, stroke, or CV death. The drug, containing carbidopa, levodopa, and entacapone and marketed by Novartis as Stalevo, is the focus of a 15-trial meta-analysis conducted by the agency to further determine the associated CV risks of the drug, when compared with the foundational treatment of carbidopa/levodopa (aka Sinemet) alone.
Entacapone, a peripheral inhibitor of the enzyme COMT, is also sold separately by Novartis as Comtan.* The drug is intended to smooth out the fluctuating clinical responses or dyskinesias associated with Sinemet treatment. (For a comprehensive 2009 review of entacapone, go here). Entacapone's sole competitor is tolcapone (Tasmar; Valeant), the use of which is limited by significant hepatotoxicity.
The FDA's retrospective review is prompted by data from the STRIDE-PD trial (published in July), which showed an increased number of heart attacks with Stalevo. During the 134-week study, there were 7 MIs and 1 CV death in 373 Stalevo-treated patients and none in 372 Sinemet-treated patients. The FDA's meta-analysis revealed 27 CV events with Stalevo and 10 with Sinemet, for a relative risk of 2.46. But removal of the STRIDE-PD data reduced the relative risk to 1.67. Most of the trials (11) included in the meta-analysis were briefer than 6 months, which makes a solid assessment of CV risk difficult. Other confounding factors include the fact that the baseline CV risk in PD patients is relatively increased, primarily owing to age.
An elevated risk of CV events with entacapone is counterintuitive, at least from a biochemical perspective. Inhibition of COMT reduces, at least in theory, homocysteine synthesis. High homocysteine levels have been suggested to raise the risk of atherosclerosis, although the American Heart Association has not yet labeled homocysteinemia as an official risk factor for heart disease.
The STRIDE-PD data also prompted the FDA to evaluate the risk of prostate cancer in men given entacapone (rates, 3.7% vs 0.9% with Sinemet). (Why COMT inhibition would increase the risk of prostate cancer is also a mystery.)
The FDA estimates that 154,000 patients have received Stalevo since its approval in June 2003 (through October 2009).
COMT = catechol-O-methyl transferase, which degrades catecholamine neurotransmitters like dopamine; CV = cardiovascular; STRIDE-PD = Stalevo Reduction in Dyskinesia Evaluation-Parkinson's Disease.
* The drug, by itself, has no antiparkinsonian effect. It is intended to prolong the half-life of levodopa by inhibiting the peripheral action of the dopamine-degrading enzyme COMT.
Image of 1886 drawing of PD patient by neurologist Sir William Richard Gowers from Wikimedia Commons.
