Neurology -- Correspondence for Morgenstern et al., 60 (1) 132-135

Correspondence published:

Reply to Letter to the Editor: Walter N. Kernan, Lawrence M. Brass, Joseph P. Broderick, Thomas Brott, Edward Feldmann, Lewis M. Morgenstern, and Catherine M. Viscoli (7 March 2003)

Use of Ephedra-containing products and risk for hemorrhagic stroke: Steven B Karch (7 March 2003)

Reply to Letter to the Editor 7 March 2003

Walter N. Kernan
Yale University School of Medicine New Haven CT,
Lawrence M. Brass, Joseph P. Broderick, Thomas Brott, Edward Feldmann, Lewis M. Morgenstern, and Catherine M. Viscoli
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Re: Reply to Letter to the Editor

walter.kernan{at}yale.edu Walter N. Kernan, et al.

The Hemorrhagic Stroke Project was a case-control study to measure the association between phenylpropanolamine and risk for hemorrhagic stroke. In a secondary analysis from this project published in Neurology, we examined the association between ephedra containing products and risk for hemorrhagic stroke. [1] To our knowledge, ours is the largest case control study to investigate the association between Ephedra alkaloids and specific adverse vascular effects. Our findings, which are not the focus of Dr. Karch's letter, did not indicate an association between use of Ephedra-containing products and risk for hemorrhagic stroke. A trend was observed for the dose over 32 mg per day, and we suggested further investigation was warranted. We presume that our suggestive findings for higher doses prompted Dr. Karch to address the issue of mechanism.
Dr. Karch is puzzled by our statement that hypertension has been discussed as a potential mechanism for observed and proposed associations between ephedra and vascular events. Among the papers referenced by Dr. Karch as evidence that Ephedra does not cause hypertension, one did not report blood pressure values [2] and another enrolled obese, normotensive persons in a trial that demonstrated unexplained imbalance in treatment assignment. [3] The risk of transitory systolic blood pressure changes in certain individuals in response to ingestion of ephedra cannot be excluded by clinical studies of average blood pressure responses observed after weeks or months of therapy. However, we agree with Dr. Karch that the papers we cite do not provide definitive evidence for a hypertensive effect of Ephedra. Our statement is correct, however, that Ephedra is commonly believed to be a potential cause of hypertension [4] and selected controlled data tend to support this belief. [5]
An important value of case control research is in detecting increased risk for rare adverse events when the mechanism may be unknown or involves idiosyncratic phenomena among susceptible individuals. It remains possible that our observation of an increased but not statistically significant association between doses of Ephedra over 32 mg/day and risk for hemorrhagic stroke represents an unusual phenomenon in susceptible individuals. While clinical trials in the past may have suggested this product's safety, more studies are needed to confirm that suggestion.
References
1.Morgenstern LB, Viscoli CM, Kernan WN, et al. Use of Ephedra- containing products and risk for hemorrhagic stroke. Neurology 2003; 60:132-135.
2.DeMatteis R, Arch JR, Petroni ML, Ferrari D, Cinti S, Stock MJ. Immunohistochemical identification of the beta(3)-adrenoceptor in intact human adipocytes and ventricular myocardium: effect of obesity and treatment with ephedrine and caffeine. International Journal of International Journal of Obesity and Related Metabilic Disorders 2002; 26:1442-1450.
3.Kalman D, Incledon TA, Gaunaurd I, Schwartz H, Krieger D. An acute clinical trial evaluating the cardiovascular effects of an herbal ephedra- caffeine weight loss product in healthy overweight adults. International Journal of Obesity and Related Metabilic Disorders 2002; 26:1363-1366.
4.Hoffman BB, Lelkowitz RJ. Catecholamines, sympathomimetic drugs, and adrenergic receptor antagonists. In: Hardman JG, Limbird LE, eds. Goodman & Gilman's The Pharmacological Basis of Therapeutics. New York: McGraw-Hill, 2001:237.
5.White LM, Gardner SF, Gurley BJ, Marx MA, Wang P-L, Estes M. Pharmacokinetics and cardiovascular effects of Ma-Huang (Ephedra sinca) in normotensive adults. Journal of Clinical Pharmacology 1997; 37:116-122.

Use of Ephedra-containing products and risk for hemorrhagic stroke 7 March 2003

Steven B Karch
City and County of San Francisco
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Re: Use of Ephedra-containing products and risk for hemorrhagic stroke

Skarch{at}sonic.net Steven B Karch

In their recent paper, Morganstern et al. state that the "favored pathophysiologic basis for an association between Ephedra and hemorrhagic stroke is enhanced catecholaminergic effects leading to sharp blood pressure spikes." [1] The statement presumes a connection that has never been established.
The authors provide only one reference: an uncontrolled, open label, pharamcokinetic study of eight volunteers given 20 mg of ephedra alkaloids and 200 mg of caffeine. On average, a 14-mm rise in systolic blood pressure occurred. [2] This study comes from a group that has previously recorded elevations of a similar magnitude when caffeine is administered without ephedrine. [3]
The author's reliance upon one uncontrolled study is puzzling, especially when nearly 60 placebo-controlled clinical trials have measured the effects of ephedrine, ephedrine in combination with caffeine/aminophylline, and herbal ephedra, alone and in combination [4, 5] (Letters to NEUROLOGY are only permitted five citations, so only the two most recent studies are cited). Nearly 2000 individuals, some with serious underlying heart and lung disease have been evaluated in these controlled clinical trials, some for as long as a year. None of these studies found any evidence to support any association between hypertension and ephedra, let alone ephedra and stroke.
Ephedrine causes catecholamine release and also directly acts on adrenorecptors, including beta-2-receptors. Stimulation of the later leads to dilation of blood vessels in peripheral muscle, decreasing peripheral resistance, and little or no change in systolic or diastolic pressure. The phenomenon, known as "diastolic runoff," is very well documented, and discussed in basic pharamacology texts. When ephedrine is given intravenously to hypotensive surgical patients, vagal responses are blunted, no diastolic runoff occurs, and blood pressure rises.
A recent editorial in CIRCULATION, discussing the current confusion over hormone replacement therapy (HRT) points out that observational studies may be sufficient for hypothesis generation, but they are no replacement for clinical trials. [6] Observational studies suggesting benefits of HRT have been clearly refuted by clinical trials showing harm (the HERS study).
It may be that the authors reviewed the earlier ephedra/ephedrine trials and found all 60 of them wanting. If that is the case, then in the interest of balanced discussion, the authors should at least provide their reasons for rejecting the controlled clinical trials, and for relying on one, unblinded, uncontrolled, observational study. [2]
References:
1. Morgenstern MD, Viscoli CM, Kernan WN et al. Use of Ephedra- containing products and risk or hemorrhagic stroke. Neurology 2003;60:132- 135.
2. Haller CA, Jacob P 3rd. Benowitz NL. Pharmacology of ephedra alkaloids and caffeine after single-dose dietary supplement use. Clin Pharmacol Ther 2002.
3. Arciero PJ, Gardner AW, Benowitz NL, Poehlman ET. Relationship of blood pressure, heart rate and behavioral mood state to norepinephrine kinetics in younger and older men following caffeine ingestion. Eur J Clin Nutr. 1998;52:805-812.
4. De Matteis R, Arch JR, Petroni ML, Ferrari D, Cinti S, Stock MJ. Immunohistochemical identification of the beta(3)-adrenoceptor in intact human adipocytes and ventricular myocardium: effect of obesity and treatment with ephedrine and caffeine. Int J Obes Relat Metab Disord. 20002;26:1442-1450.
5. Kalman D, Incledon TA, Gaunaurd I, Schwartz H, Krieger D. An acute clinical trial evaluating the cardiovascular effects of an herbal ephedra- caffeine weight loss product in healthy overweight adults. Int J Obes Relat Metab Disord. 2002;26:1363-1366.
6. Harrington DM. Hormone replacement therapy and heart disease. Replacing dogma with data. Circulation 2003;107:2-4.