 |
 |
 |
 |
 |
 |
 |
 |
 |
 |
 |
 |
 |
 |
 |
|
Prepared Witness Testimony The House Committee on Energy and Commerce
Issues Relating to Ephedra-containing Dietary Supplements.
Subcommittee on Oversight and Investigations
Dr. Douglas Zipes M.D.
I. Introduction I am a clinical cardiologist and scientist specializing in heart rhythm
disturbances. The findings and opinions that follow are based upon my education,
training and experience in medicine, cardiology, cardiovascular pharmacology,
cardiac electrophysiology, and review of the medical literature. Recent articles in the medical literature highlight the concern of medical
practitioners with the overall quality, safety, and efficacy of some herbal
products.1 In my opinion, the Dietary Supplement Health and Education Act (DSHE)
passed in 1994 has not provided a satisfactory framework to protect the public
health by allowing dietary supplements to be marketed without prior approval of
efficacy or safety by the FDA. Though DSHE limits certain health claims for
dietary supplements, these products are marketed in such a way that consumers
believe they are effective to cure or treat many of the conditions that afflict
the population, including obesity. Laboratory analysis of these products2 has
disclosed that there is considerable variation in the composition of herbal
supplements from one manufacturer to another and often from lot to lot from the
same manufacturer. Most of these herbal products have not been tested
rigorously, with the accepted norm of standardized, controlled, prospective,
randomized trials that we use to test medical drugs and devices. In
addition to lack of efficacy for the claimed use, some of these products produce
important side effects either directly or by interactions between the herbal
remedies and prescription drugs and over-the-counter (OTC) drugs. Due to
limitations in the reporting system, it is estimated that less than one percent
(1%) of the adverse effects caused by dietary supplements are reported to the
FDA.3 The current regulatory framework requires that, if a safety concern
arises, the burden of proof for safety lies not with the manufacturer but with
the FDA to prove that the product is unsafe. In particular, dietary
supplements containing ephedra and caffeine illustrate the health risks posed to
consumers from the current system and will be the focus of this report. II. Normal heart function The heart and blood vessels provide
oxygen and nourishment to every cell of the body and remove waste material by
circulating blood throughout the body. The heart contracts, pumping about
5 quarts (4.7 liters) of blood every minute, or 1800 gallons (6768 liters) of
blood every day. Oxygenated blood is pumped from the left ventricle to the
body to provide oxygen and nutrients, while returning (de-oxygenated) blood is
pumped through the lungs from the right ventricle to remove carbon dioxide and
become re-oxygenated. This continuous cycle of synchronized contractions
is driven by the heart's electrical system. A healthy heart beats steadily and rhythmically at a rate of about 60 to 100
beats per minute when at rest (normal sinus rhythm). During strenuous exercise,
the heart can increase the amount of blood it pumps fourfold. The normal
heart beats approximately 38 million times per year, or about 3 billion times in
a normal lifespan. The sinus node, a small group of specialized cells in
the top right portion of the heart's upper chamber (atrium), serves as the
pacemaker, initiating and orchestrating each heartbeat. Other tissues in
the heart wait for the arrival of each sinus-generated beat, almost like
electricity traveling over a wire, and fire in an orderly sequence, from the
atria to the ventricles, to produce each heartbeat. Multiple factors can influence the rate of discharge of the sinus node and
can cause other tissues in the heart to fire prematurely and usurp control of
the heartbeat. Among these factors, the autonomic nervous system is most
prominent. 4 Predominantly two groups of nerves make up the
autonomic nervous system: vagus nerves and sympathetic nerves. The
vagus nerves exert an inhibitory effect on heart function by release of a
substance called acetylcholine, slowing the heart rate, slowing conduction from
the atria to bottom chambers (ventricles), lessening the strength of heart
muscle contraction and dilating blood vessels. They oppose the action of
sympathetic nerves. Sympathetic nerves are stimulatory by release of
substances known collectively as catecholamines (adrenaline or epinephrine, and
noradrenaline or norepinephrine), causing an increase in the heart rate, a
quickening of conduction between the atria and ventricles, an increase in the
strength of heart muscle contraction, and, for the most part, a constriction of
the blood vessels. These actions result in an increase in blood pressure
and also can provoke spontaneous discharge of the heartbeat from areas other
than the sinus node. When heart tissue other than the sinus node initiates
a heartbeat, this results in arrhythmias, or disorders of the heartbeat.
The extent of the heartbeat disorder can range from a single premature beat,
often felt as a "thump" in the chest or palpitation, to a lethal heart
rhythm called ventricular fibrillation. The latter arrhythmia is the major
cause of sudden cardiac death. It is a disorganized, rapid (400-600 times
per minute) heart rhythm originating in the bottom chambers (ventricles) and
preventing blood flow to the brain, which causes death in 3-5 minutes unless
reversed. 5,6 III. Action of ephedra and caffeine on the heart and blood vessels A. Ephedra/ephedrine The ephedra products under discussion are marketed as dietary supplements for
weight loss and to boost energy. These preparations stimulate both the
heart and blood vessels, and the brain. They are chemically related to
methamphetamine. 7 Most of these ephedra substances contain extracts of
the ma huang plant, which is referred to as ephedra. Ephedra contains
primarily ephedrine, which is a sympathomimetic amine. That means its
actions mimic those actions produced by stimulation of the sympathetic nerves,
noted above. Ephedra does this by both a direct effect on stimulating
alpha and beta 1 and beta 2-adrenergic receptors, as the body's own
catecholamines do, and indirectly by stimulating the release of the body's
store of catecholamines and another compound called dopamine (20-30% increase).
Ephedra can be chemically synthesized as ephedrine, rather than extracted from a
plant, and has the same actions. B. Caffeine Most of these ephedra products also contain caffeine, typically extracts from
guarana seed. Caffeine causes an anti-vagal effect by antagonizing the
actions of adenosine, and can therefore promote vasoconstriction (blood pressure
elevation) and increase the release of epinephrine, norepinephrine and dopamine. Importantly, an exercising individual normally activates the autonomic
nervous system to decrease vagal, and increase sympathetic, activity.
These changes summate with the actions of ephedra and caffeine. C. Physiologic effects The result of the actions of ephedra and caffeine noted above is to: 1) Elevate the blood pressure 2) Elevate the heart rate 3) Put more stress on the heart (needs more oxygen) 4) Reduce the potassium level
in the blood These responses to ephedra/caffeine compounds can cause abnormal heart
rhythms ranging from single premature beats to ventricular fibrillation and
sudden death IV. What evidence exists to show that ephedra compounds can cause
cardiovascular harm? Many animal and clinical studies have established the physiologic actions on
the heart and blood vessels of the vagus and sympathetic nerves, catecholamines,
and sympathomimetic amines like ephedra and ephedrine, as well as the actions of
caffeine. No controversy exists about the physiologic actions of these
drugs. The major issue under discussion is whether these ephedra/caffeine
combinations have pathophysiologic actions, that is, can they cause bodily harm.
Information to support the latter comes mostly from adverse event reports (AERs)
and case reports, which are not as "robust" as clinical studies.
Still, more than 1200 serious reactions related to ephedra have been reported to
the FDA, and it is suspected that the actual number of events is undoubtedly far
greater due to the under-reporting noted earlier. 7 These include strokes,
arrhythmias, myocardial infarction, psychosis, and death. 8,9 Apparently,
13,000 complaints have been registered with the manufacturer of Metabolife 356,
including several hundred patients who required hospitalization and 80 incidents
of serious injury or death. 10 Canadian authorities have requested the voluntary recall of health
products containing ephedra, noting its enhanced toxicity when combined with
caffeine. 11 The reason for relying on AER and case report data is due to the relative infrequency of the adverse events. If a drug causes an adverse effect in only 1 of 1000 treated patients, then many patients have to be treated before a statistically significant result is noted. Such studies can be impossibly expensive to perform. And while information from AERs is less acceptable as proof of an effect, criteria can be applied to help establish validity. These include the following six criteria: 1) Temporal relation between taking the drug and the adverse response 2) Appropriate dose taken to have an effect 3) No other cause recognized to have produced the effect 4) Biologic plausibility, that is, the known action of the drug is consistent with the adverse response 5) De-and re-challenge, that is, stopping the drug eliminates further adverse responses, or re-starting the drug produces the same adverse response 6) Similar supportive data in
published medical literature Most of the reports on ephedra/caffeine compounds meet all six of these
criteria. Some examples follow. The report by Haller and Benowitz applied reasoning similar to the above 6
criteria in evaluating 140 AER reports submitted to the FDA between June 1997
and March 19998 and considered that 31% were definitely related to supplements
containing ephedra and 31% possibly related. Ten events resulted in death
and 13 produced a disability, representing 26% of the definite/probable and
possible cases. Palpitations or tachycardia (rapid heart beat) occurred in
13. Samenuk et al9 analyzed 37 patients from 926 cases of possible ma huang
toxicity reported to the FDA between 1995 and 1997 and found that the compound
was temporally related to stroke, heart attack, and sudden death at the normally
taken doses in 36 of 37 people. Gardner et al12 treated 10 healthy men with 2 Metabolife 356 caplets (12
ephedra and 40mg caffeine in each) 3 times daily for 2 weeks and found that at
day 3, all subjects reported adverse effects, most commonly dry mouth, shakiness
and insomnia. Two men reported chest pain, two had large numbers of
premature atrial beats and one had a 3 beat run of ventricular tachycardia. AERs were noted in an 8 week controlled prospective weight loss study of 72
mg/day ephedrine and 240 mg/day caffeine. 13 Boozer et al noted systolic
pressure (4mm Hg) and heart rate (7 bpm) were higher in the ephedra group.
One of thirty-five subjects left the study early due to elevated blood pressure
and four due to palpitations with (1) or without (3) chest pain. Four
additional subjects left the study after week 2 due to increased blood pressure,
palpitations or extreme irritability. None left the study in the placebo
group because of side effects. In a later 6-month study, Boozer14 found
treated patients had increases in heart rate (4 bpm), blood pressure (3-5 mm
Hg), dry mouth, insomnia, and heartburn. An important recent review of the relative safety of ephedra products
analyzed the number of adverse reactions adjudicated by poison control centers
in the US in 2001 to be attributable to several commonly used herbal products.
They found that products containing ephedra alone or combined with other herbs
or substances accounted for 64% of all adverse reactions, yet these products
represented only 0.82% of herbal sales. The relative risks for adverse reactions
among ephedra users were 100-fold greater than the risk among users of other
herbal products. 15 A comprehensive literature review of 59 articles that corresponded to 52
controlled clinical trials of ephedrine or herbal ephedra for weight loss or
athletic performance found that short term use was associated with approximately
2 pounds weight loss per month compared with placebo. There was a modest
effect on very short-term athletic performance. However, there was a two
to three times increase in the risk of nausea, vomiting, psychiatric symptoms,
autonomic hyperactivity, and palpitations. The number of individuals
studied were insufficient to evaluate events with a risk of less than 1.0 per
thousand. 16 V. Supporting information Supporting information about the potential harm of catecholamines and
sympathomimetic agents can be found in multiple sources. For example,
plasma norepinephrine concentration is independently related to the subsequent
risk of mortality. 17 Patients who have sustained ventricular
arrhythmias have a selective increase in cardiac sympathetic activity. 18,19
In addition, use of sympathomimetic drugs leads to increased risk of
hospitalization for arrhythmias in patients with congestive heart failure. 20
Plasma norepinephrine predicts survival and cardiovascular events in
patients with end-stage renal disease. 21 Large stores of
noradrenaline in the heart have been related to sudden death. 22 VI. What can account for the apparent unpredictable sporadic events? The following can explain the above individual reactions to recommended doses of ephedra/caffeine compounds: 1) Variable absorption occurs, so that the amount of drug in the body can vary from one person to the next. 2) Variability in active drug content of botanical, as shown by Gurley et al. 2 3) Presence or absence of underlying disease or drugs. It is possible that patients with pre-existing conditions such as coronary disease or high blood pressure, or who are taking other drugs that may interact with the ephedra/caffeine compounds, are at increased risk for an adverse response. 4) Variability in electrolytes, particularly potassium that can predispose to the development of arrhythmias. 5) Herbal products may contain undeclared pharmaceuticals or heavy metals. 6) Genetic influences.
There exist some patients with genetic changes in the autonomic nervous system
that make them susceptible to large outpouring of catecholamines which could put
them at risk of developing an arrhythmia, heart attack or stroke. 23,24
Also, some patients have inherited electrical abnormalities that do
not become manifest until triggered by an external source like a drug. 25
This drug could have totally benign actions in all other individuals without the
inherited abnormality. VII. Ephedra/Caffeine and Exercise Many ephedra products are marketed for sports nutrition or for weight loss.
The directions for use suggest that they should be taken before exercise. During
exercise, the oxygen requirements of the heart increase dramatically. If the
oxygen supply falls behind the demands of the heart, such a response can trigger
abnormal heart rhythms. Oxygen consumption of the heart is directly related to
wall stress and heart rate, both of which increase during exercise. The effects
of the ephedra/caffeine drugs exacerbate these responses. Serious arrhythmias
can develop because of this constellation of events. As physicians, we
know that humans are biologic organisms that are imperfect. Humans do not
run with absolute precision like a Swiss watch. Slight variations in blood
pressure, heart rate, and conduction of the heart's impulse can make a
difference between having an arrhythmia that produces sudden death and not
having one. These responses are often unpredictable. Numerous sport
organizations, including the NCAA, NFL, and International Olympic Committee,
prohibit the use of ephedra-containing products. 15 VIII. RECOMMENDATIONS: Because of our inability to predict who might have an adverse response to
these drugs, because of their minimal (if any) therapeutic effect and because of
the potential for major adverse responses, I would recommend the following: 1) Recognize that ephedra and
ephedrine are drugs, not dietary supplements 2)
Recognize that they are capable of provoking harm, including ventricular
fibrillation and sudden death 3) Eliminate over-the-counter
use based on minor proven benefit and potential for major harm 4) Regulate their use by
applying FDA criteria to distribution of ephedra/caffeine compounds as is done
for all other drugs Respectfully submitted, Douglas P. Zipes, MD References: 1. DeSmet TAGM. Herbal Remedies. N Engl J Med. 2002;347:246-256. 2. Gurley DJ, Gardner SF, Hubbard MA. Content versus Label Claims in
Ephedra-containing Dietary Supplements. Am J Health Syst Pharm.
2000;57:963-969. 3. Adverse Event Reporting for Dietary Supplements: An Inadequate Safety
Valve. Washington, DC: Office of Inspector General, April 2001. (report
#OEI-01-00-00-180). 4. Schwartz PJ, Zipes DP. Autonomic Modulation of Cardiac
Arrhythmias. In: Cardiac Electrophysiology. From Cell to
Bedside. Edition 3. Ed. Zipes DP, Jalife J, W.B. Saunders, Orlando. pp 300-314,
2000. 5. Zipes DP, Wellens HJJ. Sudden Cardiac Death.
Circulation. 1998;98:2334-2351. 6. Priori SG, Aliot E,
Blomstrom-Lundqvist C, Bossaert L, Breithardt G, Brugada P, Camm AJ, Cappato R,
Cobbe SM, DiMario C, Maron BJ, McKenna WJ, Pedersen AK, Ravens U, Schwartz PJ,
Trusz-Gluza M, Vardas P. Wellens HJ, Zipes DP. Task Force on Sudden
Cardiac Death of the European Society of Cardiology. Eur Heart J.
2001;22(16):1374-1450. 7.
Marcus DM, Grollman, AP. Botanical Medicines - the Need for New
Regulations. New England Journal of Medicine. 2002;347:2073-2076. 8.
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. 9.
Samenuk D, Link MS, Homoud MK, et al. Adverse Cardiovascular Events
Temporally Associated with Ma Huang, an Herbal Source of Ephedrine. Mayo
Clinic Proceedings. 2002;77:12-16. 10.
Hilts PJ. US in Criminal Inquiry on Metabolife Product. New York
Times. August 16, 2002:C1. 11.
Health Canada Requests Recall of Certain Products Containing Ephedra/Ephedrine.
Ottawa, Ont: Health Canada, January 9, 2002 (accessed November 27, 2002 at
http//:www.hc-sc.gc.ca/English/protection/warnings/2002/2002_01E.htm). 12.
Gardner SF, Franks AM, Gurley DJ, et al. Effect of a Multicomplement,
Ephedra-containing Dietary Supplement (Metabolife 356) on Holter Monitoring and
Hemostatic Parameters in Healthy Volunteers. Am J of Cardiol
2003;91:1510-1513. 13.
Boozer C, Nasser J, Heymsfield S, et al. An Herbal Supplement Containing
Ma Huang-Guarana for Weight Loss: a Randomized Double Blind Trial. Int J
Obes Relat Metab Disord. 2001;25:316-324. 14.
Boozer CN, Daly PA, Homel P, et al. Herbal Ephedra/Caffeine for Weight
Loss: a Six Month Randomized Safety and Efficacy Trial. Int J Obes.
2002;26:593-604. 15.
Bent S, Tiedt TN, Odden MC, et al. The Relative Safetty of Ephedra
Compared with Other Herbal Products. Ann Int Med. 2003;138:468-471. 16.
Shekelle P, Hardy M, Morton SC, et al. Ephedra and Ephedrine for Weight
Loss and Athletic Performance Enhancement: Clinical Efficacy and Side Effects.
Prepared for Agency for Healthcare Research and Quality, U.S. Department of
Health and Human Services. (Contract No. 290-97-0001, Task Order No. 9) (AHRQ
Publication No. 03-E-022), 2003. 17.
Cohn JN, Levine TD, Olvarin T, et al. Plasma Norepinephrine as a Guide to
Prognosis in Patients with Chronic Congestive Heart Failure. N Engl J Med.
1984;311:819-823. 18.
Meredith IT, Broughton A, Jennings GL, et al. Evidence of a Selective
Increase in Cardiac Sympathetic Activity in Patients with Sustained Ventricular
Arrhythmias. N Engl J Med. 1991;325:618-624. 19.
Zipes DP. Sympathetic Stimulation and Arrhythmias. Editorial. N Engl
J Med. 1991;325:656-657. 20.
Bouvy ML, Heerdink ER, DeBruin ML, et al. Use of Sympathomimetic Drugs
Leads to Hospitalization for Arrhythmias in Patients with Congestive Heart
Failure. Arch Int Med. 2000;160:2477-2480. 21.
Zoccali C, Mallamaci F, Parlongo S. Plasma Norepinephrine Predicts
Survival and Incident Cardiovascular Events in Patients with End-stage Renal
Disease. Circulation. 2002;105:1354-1359. 22. Brunner-LaRocca HP, Esler MD,
Jennings GL. Effect of Cardiac Sympathetic Nervous Activity on Mode of
Death in Congestive Heart Failure. European Heart Journal.
2001;22:1069-1071. 23. Drede M, Wiesmann F, Jahns R.
Feedback Inhibition of Catecholamine Release by Two Different Alpha2 -
Adrenoceptor Subtypes Prevents Progression of Heart Failure. Circulation.
2002;106:2491-2496.) 24. Hein L, Altman JD, Kobilka, BK.
Two Functionally Distinct Alpha2-Adrenergic Receptors Regulate Sympathetic
Neurotransmission. Nature. 1999;402:181-184. 25. Yang P, Kanki H, Drolet B, et al. Allelic Variance in Long QT Disease Genes and Patients with Drug-associated Torsades de Pointes. Circulation. 2002;105:1943-1948.
|
|||||||||||
|
