Establishing causality from case reports: was ephedra to blame?

Ephedra has a long history of being associated with severe cardiovascular events, often in young, healthy patients. The Food and Drug Administration (FDA), which officially banned the sale of ephedra products in April 2004, had issued warnings about it dating back to September 1994. (1) Numerous case reports have documented adverse events in persons taking ephedra, (2-5) including myocardial infarction, stroke, and death. In the largest published case series, Haller and Benowitz (2) reviewed 140 adverse event reports involving ephedra and found that 31% were definitely or probably related to the supplement and another 31% were possibly related. The report by Moawad et al (6) in this issue of the Southern Medical Journal is the first published report of an association between ephedra and posterior reversible encephalopathy syndrome (PRES), a neurologic event that is believed to be precipitated by a rapid rise in systemic blood pressure.

With so many published reports of associations between ephedra and severe cardiovascular events, why did it take 10 years for the FDA to ban this dangerous supplement? Part of the problem lies in the fact that most of the evidence regarding the danger of ephedra comes from case reports similar to the one published in this issue. The central question in these reports is, "How does one determine if ephedra, rather than some other patient characteristic or risk factor, caused the adverse event?" While many different formal systems are available for determining causality from case reports, most systems rely on five basic data elements: 1) the timing of the adverse event relative to ingestion of the drug (or herb); 2) the presence of other factors that might have caused the event; 3) the result of withdrawing the drug ("de-challenge"); 4) the result of reintroducing the drug ("re-challenge"); and 5) other supporting evidence, including similar cases and biologic plausibility. (7)

In the current case, the exact timing of the ingestion of ephedra is not stated, although the history notes that the patient recently initiated taking the supplement as part of a weight-loss program. The history and initial presentation suggest that the patient had no other known risk factors for an acute rise in blood pressure. Specifically, the patient was not taking any other prescription medications or supplements, had no known history of hypertension or other medical illness, and had a negative urine drug screen. As is often the case in published case reports, there is very little information about what happened to the patient after withdrawing the drug (his blood pressure and neurologic examination were normal at a two-week follow-up visit), and it would not be safe to attempt a reintroduction of ephedra (though in some cases, patients will restart ephedra even after severe medical events). Finally, the review of other evidence suggests that ephedra caused the adverse event in the current case. Ephedra, when combined with caffeine (a common combination in many weight loss products), has been shown to raise blood pressure in healthy volunteers (by an average of 11.5 mm Hg systolic and 7.3 mm Hg diastolic in one study). (8) Similarly, there have been many similar case reports where ephedra use has been temporally associated with severe cardiovascular adverse events that are believed to be at least partially due to the blood pressure effects of the herb. (2,3) The biologic plausibility is also strong, because ephedra is known to contain ephedrine and other sympathomimetic agents that increase heart rate, blood pressure, cardiac contractile force, and vasoconstriction. (9) The weight of the evidence, therefore, strongly suggests that ephedra, and not some other risk factor, was responsible for the adverse event in this patient.

Will there ever be more definitive evidence about the dangers of ephedra beyond case reports similar to the one published here? Probably not. More conclusive evidence about the potential risks of ephedra could come from case-control studies, cohort studies, or randomized controlled trials. One case-control study found that ephedra was associated with a nonsignificant trend of an increased risk of hemorrhagic stroke among users (OR 3.59, 95% CI: 0.70-18.35). (10) However, since ephedra is now banned, it would be difficult to enroll a sufficient number of patients to conduct another case-control study or a cohort study. Large randomized controlled trials of ephedra could theoretically be conducted to examine both the potential weight-loss benefits as well as cardiovascular risks. However, it would be unethical to enroll patients in a study of this herb, which has substantial risks and only minimal benefits. A prior systematic review of all randomized controlled trials of ephedra found that the herb is associated with a two-pound weight loss per month for up to 4 to 6 months. The same study found that ephedra was associated with a two- to three-fold increased risk of nausea, vomiting, psychiatric symptoms, autonomic hyperactivity, and palpitations. (11) Therefore, future decisions about the regulation and availability of ephedra will likely rely heavily on evidence from case reports. The current report adds to this body of evidence, and strongly suggests that ephedra causes severe cardiovascular effects in patients and should not be available to unsuspecting consumers like the young man described in this case.

References

1. U.S. Food and Drug Administration Center for Food Safety and Applied Nutrition. Dietary Supplements: Ephedrine Alkaloids. Available at http://www.cfsan.fda.gov/dms/ds-ephed.html. Accessed December 22, 2005.

2. Haller CA, Benowitz NL. Adverse cardiovascular and central nervous system events associated with dietary supplements containing ephedra alkaloids. N Engl J Med 2000;343:1833-1838.

3. Samenuk D, Link MS, Homoud MK, et al. Adverse cardiovascular events temporally associated with ma huang, an herbal source of ephedrine. Mayo Clin Proc 2002;77:12-16.

4. Theoharides TC. Sudden death of a healthy college student related to ephedrine toxicity from a ma huang-containing drink. J Clin Psychopharmacol 1997;17:437-439.

5. Zahn KA, Li RL, Purssell RA. Cardiovascular toxicity after ingestion of 'herbal ecstacy'. J Emerg Med 1999;17:289-291.

6. Moawad FJ, Hartzell JD, Biega TJ, et al. Transient blindness due to posterior reversible encephalopathy syndrome following ephedra overdose. South Med J 2006;99:511-514.

7. Jones JK. Determining causation from case reports. In: Strom BL, ed. Pharmacoepidemiology. West Sussex, England, John Wiley & Sons Ltd, 2000, pp 525-552.

8. Haller CA, Jacob P, Benowitz NL. Short-term metabolic and hemodynamic effects of ephedra and guarana combinations. Clin Pharmacol Ther 2005;77:560-571.

9. Hardman JG, Limbird LE, eds. In: Goodman & Gilman's the Pharmacological Basis of Therapeutics. 10th ed. New York, McGraw-Hill, 2001.

10. Morgenstern LB, Viscoli CM, Kernan WN, et al. Use of ephedra-containing products and risk for hemorrhagic stroke. Neurology 2003;60:132-135.

11. Shekelle P, Morton S, Maglione M, et al. Ephedra and ephedrine for weight loss and athletic performance enhancement: clinical efficacy and side effects. Evidence Report/Technology Assessment No. 76 (Prepared by Southern California Evidence-based Practice Center, RAND, under Contract No. 290-97-0001, Task Order No. 9). AHRQ Publication No. 03-E022. Rockville, MD, Agency for Healthcare Research and Quality, 2003.

If I had my life to live over ... I'd dare to make more mistakes next
time.
--Nadine Stair

Stephen Bent, MD

From the Osher Center for Integrative Medicine, San Francisco, CA.

Reprint requests to Stephen Bent, MD, Osher Center for Integrative Medicine, University of California San Francisco, 4150 Clement Street, 111-A1, San Francisco, CA 94121. Email: [e-mail]

Accepted January 25, 2006.