Objective: A previous trial of the serotonin-norepinephrine reuptake inhibitor desvenlafaxine (administered as desvenlafaxine succinate) raised concerns on potential serious cardiovascular and hepatic events. The current study was designed to estimate these events in desvenlafaxine versus placebo in a larger population followed for 1 year.
Methods: Healthy postmenopausal women seeking treatment of vasomotor symptoms were randomized to placebo or desvenlafaxine 100 mg/day in a 1-year, multicenter, double-blind study. Safety was monitored throughout. Potential ischemic cardiovascular events (coronary heart disease–related death, new-onset myocardial infarction or unstable angina requiring hospitalization, and unscheduled revascularization procedures) and cerebrovascular events (definite stroke or probable stroke) identified by investigator reports and periodic adverse event review based on Standardized Medical Dictionary for Regulatory Activities Query were reviewed by blinded adjudication boards. Hepatic events (aspartate aminotransferase or alanine aminotransferase >5 times the upper limit of normal) were evaluated.
Results: A total of 2,118 participants (1,066 desvenlafaxine, 1,052 placebo) took one or more doses of study medication (mean, 280 d). There was one cardiovascular event; a placebo-treated participant was adjudicated to have had a myocardial infarction. One desvenlafaxine-treated participant was adjudicated to have had a probable stroke. Two participants in each treatment group had hepatic events. The excess risk (90% CI) of desvenlafaxine over placebo per 1,000 woman-years was −1.07 (−2.86 to 0.72) for cardiovascular events, 1.11 (−0.68 to 2.9) for cerebrovascular events, and 0.08 (−3.51 to 3.67) for hepatic events.
Conclusions: There is no evidence for an increased risk of cardiovascular, cerebrovascular, or hepatic events associated with desvenlafaxine 100 mg/day compared with placebo for the treatment of menopausal vasomotor symptoms.
From the 1Clinical Research Center, Eastern Virginia Medical School, Norfolk, VA; 2University of Virginia Health System, Charlottesville, VA; and 3Pfizer Inc., Collegeville, PA.
Received May 31, 2012; revised and accepted September 13, 2012.
ClinicalTrials.gov number NCT00683800.
Disclaimer: In September 2011, Pfizer received a Complete Response Letter from the US Food and Drug Administration on its application for approval to market desvenlafaxine for the treatment of moderate to severe vasomotor symptoms associated with menopause. The Complete Response Letter states that the data included in the application are not sufficient to establish an acceptable risk/benefit profile for the treatment of vasomotor symptoms in the general population of postmenopausal women and, therefore, that desvenlafaxine is not approved for the treatment of vasomotor symptoms in the United States at this time. This decision does not impact the approval of desvenlafaxine for the treatment of major depressive disorder in adults.
Funding/support: This study was sponsored by Wyeth, which was acquired by Pfizer Inc. in October 2009. Medical writing support was provided by Kathleen Dorries, PhD, formerly of Embryon (a division of Advanced Health Media LLC) and currently of Peloton Advantage LLC. Medical editing support was provided by Traci Stuve, MA, of Embryon (a division of Advanced Health Media LLC) and funded by Pfizer.
Financial disclosure/conflicts of interest: C.J.G.-P., E.H., and R.J.C. are Pfizer employees. D.F.A. has received for his institution grant for this study, grants from outside studies, and payment for the development of educational presentations. He has also received consulting fees for this study. In the past 12 months, J.V.P. has served as consultant (fees to the University of Virginia) to Pfizer Inc., Noven Pharmaceuticals, and Novogyne Pharmaceuticals; received grants/research support (fees to the University of Virginia) from DepoMed, Bionova, and Endoceutics; and received travel funds from Pfizer Inc., Noven Pharmaceuticals, and Novogyne Pharmaceuticals.
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Address correspondence to: David F. Archer, MD, Eastern Virginia Medical School, 601 Colley Avenue, Norfolk, VA 23507. E-mail: email@example.com