Author Affiliations: Chicago College of Osteopathic Medicine, Chicago College of Pharmacy Midwestern University, Downers Grove, Illinois (Drs Phillips, Sullivan, Snyder, and Allegretti); and Marcella Niehoff School of Nursing and Stritch School of Medicine, Loyola University Chicago (Dr McBride).
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Dietary supplements represent a distinct class of biologically active compounds which, unlike prescription and over-the-counter products, have been available to the public without regulatory oversight for nearly 15 years and are responsible for more than 13 000 adverse events annually.1,2 Like many dietary supplements, Enzyte (Vianda, Cincinnati, Ohio)—a dietary supplement marketed for “male enhancement,” a euphemism for erectile dysfunction—is a multicomponent preparation marketed to consumers without stringent regulatory oversight or premarketing evaluation of pharmacokinetics, pharmacodynamic, or drug interaction studies, including thorough QT and corrected QT (QTc) studies to assess proarrhythmic risk. Considering this information, we conducted a randomized, double-blind, double-dummy, placebo-controlled, dose-ranging, crossover study of the effects of Enzyte on the electrocardiographic (ECG) parameters including the QTc interval.
Consenting healthy male volunteers were randomized using a double-blind, double-dummy (ie, masking the difference in shape, appearance, and dosing schedule of the active and placebo preparations), placebo-controlled, dose-ranging, crossover study design approved by the institutional review board at Midwestern University, Downers Grove, Illinois. Active capsules contained the contents of one-half of a pulverized Enzyte immediate-release tablet. Lactose-containing placebo capsules were prepared in the pharmaceutics laboratory at Midwestern University. Because interlot variability has been reported with preparations of various dietary supplements and could impact results, we limited the study of Enzyte to tablets purchased from a single lot. Exclusion criteria included the following: risk factors for torsades de pointes,3 concurrent use of potentially interacting drugs (anticoagulants, monoamine oxidase inhibitors, over-the-counter medications containing pseudoephedrine, or any dietary supplements), female sex, or unwillingness to sign informed consent.
The primary ECG end point was the maximum postdosing QTc interval attained at 1, 3, and 5 hours between the placebo and each of the dosing periods. Maximum postdosing QTc interval was prospectively defined as the longest QTc interval from all evaluable leads in each of the 3 postdosing ECGs. The maximum postdosing QTc interval was assessed because the time to maximal absorption of the compounds in the dietary supplements have not been established. The QTc interval was calculated using the Bazett formula [QTc = QT/(R-R)1/2] for the primary analysis, since it is the most commonly used clinically. The hazard ratio was calculated based on the mean R-R interval using the following formula: 60/(R-R interval/1000).
Interperiod analysis of continuous data was performed using a repeated measures analysis of variance with post hoc Bonferroni correction. The study was conducted using a power analysis under the assumption that an interperiod difference in the QTc interval by 6 ±3 milliseconds (ms) would be significant.
Fifty subjects were approached for recruitment. Thirty-seven subjects declined enrollment, and 4 met study exclusion criteria. Nine male subjects (2 Asian and 7 white; mean [SD] age, 28.7 [11.3] years; and mean [SD] body mass index, 26.8 [4.4] [calculated as weight in kilograms divided by height in meters squared]) were randomized and completed the entire study protocol.
At baseline, there were no interperiod differences in the QTc interval. Following ingestion, the QTc interval increased at all dosages (Table). When subjects received the single-tablet dose (as is indicated on the product labeling), the QTc increased by 8.4% (95% CI, 8.01%-60.01%) or 32 ms (P < .05) at 3 hours after dosing and 11% (95% CI, 10.31%-69.70%) or 37 ms at 5 hours after dosing (P < .05). The results were of the same magnitude and direction when the Framingham Linear Corrected Formula was used. Aside from QT and QTc intervals, there were no changes in any other electrocardiographic end point during the study (data not shown). There were no cases of atrial or ventricular arrhythmias. Of the 9 subjects enrolled, 4 (44%) developed profound cutaneous flushing consistent with the effect of niacin, which is found in the preparation. Subjects reported no other adverse effects including prolonged erection.
Although guidelines for the clinical measurement of the QT interval are not yet adopted in the United States, procedures used for the assessment of QT prolongation in clinical trials indicate that changes in QTc from baseline greater than 30 or 60 ms signify an increased risk for the development of the polymorphic ventricular tachycardia, torsades de pointes.3 Indeed, the US Food and Drug Administration has exhibited a stricter policy germane to drug-induced QTc prolongation with the removal of cisapride and terfenadine from the market after increased reports of drug-induced sudden death despite mean increases in the QTc interval of 13 and 17 ms, respectively.4,5 Despite the presence of risk factors leading to exaggerated drug-induced QT prolongation (ie, bradycardia, heart disease, hypomagnesemia, hypokalemia), the risk of drug-induced torsades des pointes is imprecise and remains highly stochastic even among patients with the same risk profile and equivalent QT intervals.6 Because most male patients are embarrassed to report erectile dysfunction, the use of QTc prolonging supplements, such as Enzyte, are likely to be underreported to health care providers. This creates a relatively anonymous patient population at an elevated risk for drug-induced sudden death.
This study has some important limitations primarily due to safety precautions. The majority of subjects enrolled in this study were young healthy male volunteers, which lowered the mean QTc interval observed at baseline. Since patients with erectile dysfunction are older than our study subjects and may have some form of underlying cardiovascular disease (eg, atherosclerosis, hypertension), their baseline QTc intervals, and thus proarrhythmic risk, may be higher. Although prolonged QTc intervals are a risk factor for sudden cardiac death, we did not study the effect of Enzyte on all-cause or cardiovascular mortality. Finally, our assessment of noncardiac adverse effects is limited by the lack of case reports. Clearly, more studies are needed to establish the safety of Enzyte in the population to which it is marketed. Clinicians should advise patients to refrain from using Enzyte until more information is known.
Correspondence: Dr McBride, Marcella Niehoff School of Nursing, Loyola University Chicago, 2160 S First Ave, Bldg 102, Room 4602, Maywood, IL 60153 (Bf.firstname.lastname@example.org).
Author Contributions:Study concept and design: Sullivan, Allegretti, and McBride. Acquisition of data: Phillips, Sullivan, Snyder, and McBride. Analysis and interpretation of data: Phillips and McBride. Drafting of the manuscript: Phillips, Sullivan, Snyder, Allegretti, and McBride. Critical revision of the manuscript for important intellectual content: Phillips and McBride. Statistical analysis: Phillips and McBride. Obtained funding: McBride. Administrative, technical, and material support: Sullivan, Snyder, Allegretti, and McBride. Study supervision: Allegretti and McBride.
Financial Disclosure: None reported.
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