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Efficacy and Safety of Ephedra and Ephedrine for Weight Loss and Athletic Performance A metaanalysis

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Monthly rates of weight loss (based on 2, 3, 4 month data separately) Monthly weight loss effect sizes using a random-effects model ... Weight loss trials ... – PowerPoint PPT presentation

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Title: Efficacy and Safety of Ephedra and Ephedrine for Weight Loss and Athletic Performance A metaanalysis


1
Efficacy and Safety of Ephedra and Ephedrine for
Weight Loss and Athletic PerformanceA
meta-analysis
  • Department of Family Community Medicine
  • Journal Club Presentation
  • August 20, 2003
  • Brian Swan, M.D.

2
Why is this an important topic?
  • In the United States, dietary supplements are
    used by millions of people every day.
  • Dietary supplements are not required to have FDA
    approval or to be registered with the FDA before
    they are produced and marketed to consumers.
  • Currently, there are no FDA regulations to ensure
    the identity, purity, quality, composition or
    strength of dietary supplements.
  • These products are widely promoted by the
    producers, often with unsubstantiated claims of
    benefit and rarely any mention of potential
    hazards.
  • Ephedra and ephedrine are among the most
    controversial dietary supplements available, with
    reports of toxicity linked to the use of these
    compounds accumulating at an alarming rate.

3
Objective of the Present Study?
  • To assess the efficacy and safety of ephedra and
    ephedrine, when it is used for weight loss and/or
    enhancing athletic performance

4
How was this objective approached?
  • Reviewers searched 9 electronic databases for
    published controlled trials and case reports
  • They also searched for unpublished or gray
    literature
  • Posted announcements in the Journals,
    Phytomedicine and Herbalgram
  • Wrote to several regulatory officials and herbal
    experts in other countries seeking unpublished
    evidence

5
Then what did they do?
  • 2 independent reviewers conducted a meta-analysis
    of the literature
  • Eligible studies were controlled trials studying
    the efficacy and safety of ephedra and ephedrine
    on weight loss or athletic performance
  • Eligible case reports involved adverse events
    associated with the use of ephedra or ephedrine

6
What variables were assessed in the studies?
  • Variables assessed in controlled trials
  • Efficacy in weight loss
  • Adverse events / Safety
  • Athletic performance
  • Variables assessed in case reports
  • Adverse events

7
Methods How was the data synthesized for the
controlled trials?Weight loss trials
  • First, they statistically pooled the outcomes by
  • Clinically similar trials
  • Monthly rates of weight loss (based on 2, 3, 4
    month data separately)
  • Monthly weight loss effect sizes using a
    random-effects model
  • Percentage weight loss from baseline (for
    comparison with other weight loss products)

8
Methods How was the data synthesized for the
controlled trials?Adverse effects / Safety trials
  • They estimated the pooled-odds ratios (OR) for
    clinically-related groups of symptoms

9
Methods How was the data synthesized for the
controlled trials?Athletic performance trials
  • Trials assessing athletic performance were too
    heterogeneous to support statistical pooling.
  • They were reviewed individually.

10
Methods How was the next piece of data
synthesized in the controlled trials?Weight loss
trials
  • Next, they tested the outcomes for a dose effect
    using a meta-regression model, defining the doses
    as
  • Ephedrine low dose 10-20 mg/d
  • Ephedrine medium dose 40-90 mg/d
  • Ephedrine high dose 100-150 mg/d

11
Methods How was the next piece of data
synthesized for the controlled trials?Adverse
events / safety trials
  • For this variable, the outcomes for dose response
    were then assessed by stratified analysis
  • with the dose strata defined as for the efficacy
    analysis

12
What other methods were employed to assess the
controlled trials?All trials
  • Conducted sensitivity analyses
  • Dropped trials by attrition rate 20
  • Dropped trials that presented in abstract forms
  • Dropped trials scoring 2 or less on the Jadad
    scale of quality
  • Dropped trials that included other medications
    with ephedrine (like ASA, synephrine)

13
Methods Case reports
  • Adverse events needed to be categorized
  • Documented report that an adverse event occurred
  • Documented report that the subject had consumed
    ephedra or ephedrine within 24 hours prior to the
    adverse event or a tox screen (blood or urine)
    was found positive for either product
  • An adequate investigation by an expert clinician
    excluded other potential causes

14
Methods Case reports
  • Adverse events were then labeled
  • Sentinel event cases that met all 3 criteria
  • Possible sentinel event cases that met the
    first 2 criteria, but had other possible causes
    in which to attribute the event

15
ResultsEfficacy Weight Loss
  • The comparisons of 20 controlled trials were
    classified into 6 categories
  • Ephedrine vs. Placebo
  • Ephedrine Caffeine vs. Placebo
  • Ephedrine Caffeine vs. Ephedrine
  • Ephedrine vs. Other weight loss product
  • Ephedra vs. Placebo
  • Ephedra with herbs (containing caffeine) vs.
    Placebo

16
ResultsEfficacy Weight LossEphedrine vs.
Placebo
  • 5 randomized, placebo controlled trials, with
    results reported at 3-4 months duration of
    treatment assessed
  • Rate of weight loss above placebo was 0.6 kg/mth
    (95 CI 0.2-1.0)
  • Average percentage weight loss in the treatment
    groups (compared to pre-treatment weight) was 11
    at 4 months
  • In dose analysis, only high doses of ephedrine
    produced a weight loss statistically
    significantly.

17
ResultsEfficacy Weight lossEphedrine
Caffeine vs. Placebo
  • 7 randomized, double-blind, placebo controlled
    trials, with results reported at 2 and 4 months
    duration of treatment assessed
  • Rate of weight loss was 1.0 kg/mth (95 CI
    0.7-1.3) above placebo
  • Average percentage of weight loss in the
    ephedrine caffeine treated patients (compared
    to pre-treatment weight) was 11 at 4 months
  • In dose analysis, no statistically significant
    differences found

18
ResultsEfficacy Weight lossEphedrine
Caffeine vs. Ephedrine
  • 3 controlled trials assessed
  • Rate of weight loss was 0.4 kg/mth (95 CI
    0.02-0.7) above Ephedrine alone
  • No dose analysis performed

19
ResultsEfficacy Weight lossEphedrine
Caffeine vs. Other weight loss product
  • 2 controlled trials assessed
  • No statistically significant differences in
    weight loss when compared to Dexfenfluramine or
    Diethylpropion (Tenuate)

20
ResultsEfficacy Weight lossEphedra with herbs
(containing caffeine) vs. Placebo
  • 4 randomized, placebo controlled trials assessed
  • Rate of weight loss was 1.0 kg/mth (95 CI
    0.6-1.3) above placebo alone
  • Average percentage weight loss in the ephedra
    treated patients (compared to pre-treatment
    weight) was 5.2 at 4 months
  • Only medium doses assessed, no dose analysis
    performed

21
ResultsEfficacy Athletic Performance
  • 7 controlled trials assessed (individually)
  • Combination of Ephedrine (1 mg/kg) Caffeine (5
    mg/kg) consistently demonstrated a 20-30
    increase in performance compared to placebo
  • Neither Ephedrine (up to doses of 1 mg/kg) nor
    Caffeine (up to doses of 5 mg/kg) alone had
    significant effects on exercise performance
  • Combination of Ephedrine Caffeine ( at above
    doses) resulted in increased incidences of
    side-effects, such as nausea / vomiting (compared
    to lower doses)

22
ResultsAdverse Events Controlled Trials
  • 50 randomized, placebo controlled trials assessed
  • Participants in active treatment had between 2.2
    and 3.6 increased odds for adverse events
    including psychiatric sx, autonomic
    hyperactivity, upper GI sx, and heart
    palpitations
  • In dose analysis, there was a trend toward higher
    risk of adverse events with higher doses of
    ephedrine, but this trend was not statistically
    significant
  • 1 trial of herbal ephedra (herbal caffeine free)
    reported a statistically significant 2-fold
    increase in gastrointestinal symptoms

23
ResultsAdverse Events Controlled Trials
24
ResultsAdverse Events Case Reports
  • 70 published case reports reviewed
  • 1,820 FDA Med-Watch Files screened
  • 15,951 cases reported to one manufacturer of
    ephedra-containing dietary supplements screened

25
ResultsAdverse Events Case Reports
  • Sentinel events (following consumption of
    ephedra-containing products)
  • 2 deaths
  • 3 myocardial infarctions
  • 9 cerebrovascular accidents
  • 3 seizures
  • 5 psychiatric events

26
ResultsAdverse Events Case Reports
  • Sentinel events (following consumption of
    ephedrine-containing products)
  • 3 deaths
  • 2 myocardial infarctions
  • 2 cerebrovascular accidents
  • 1 seizure
  • 5 psychiatric events

27
ResultsAdverse Events Case Reports
28
Conclusions
  • Analysis of the available literature provided
    sufficient evidence that short-term use of
    ephedrine at high doses promotes weight loss in
    selected patient populations.
  • Short-term use of ephedrine caffeine, or
    ephedra, or ephedra herbs containing caffeine
    promoted weight loss in these populations.

29
Other conclusions.
  • The overall effect of ephedra or ephedrine on
    athletic performance is still unknown.
  • The investigators were unable to identify any
    controlled trials of ephedra.
  • The few identified trials of ephedrine did not
    study it as it is used by the general population
    (that is, with repeated use)

30
Also.
  • Sufficient evidence was found to conclude that
    ephedra and ephedrine are associated with 2 to 3
    times the risk of psychiatric events/symptoms,
    autonomic symptoms, upper GI symptoms, and heart
    palpitations.

31
Study limitations
  • There were a few.
  • Some trials had method problems, but the
    sensitivity analyses conducted were able to
    support their main analysis with respect to
    ephedrine caffeine, and with respect to ephedra
  • Significant heterogeneity among the athletic
    performance trials prevented the completion of a
    formal meta-analysis on the variable

32
Further limitations
  • The generalizability of the results to the use of
    ephedra or ephedrine in a general population may
    not be valid.
  • The weight loss trials frequently involved
    medical screening to detect preexisting
    conditions that may predispose subjects to an
    increased risk of adverse events. Such patients
    were then excluded from the trials.

33
And
  • The weight loss trials as a group had limited
    duration of treatment times.
  • Therefore, complete conclusions about the
    association between ephedra and weight loss over
    longer and more clinically relevant intervals
    could not be made.

34
To Conclude
  • If you, or your patients are looking for the best
    way to lose a minimal amount of weight, while
    experiencing the enjoyment of psychotic episodes,
    anginal chest pain and severe acid reflux, you
    need look no further than your local supermarket
    or nutritional supplement store.
  • The End

35
Reference
  • Shekelle PG, Hardy ML, Morton SC, Maglione M,
    Mojica WA, Suttorp MJ, Rhodes CL, Jungviv L,
    Gagne J. Efficacy and Safety of Ephedra and
    Ephedrine for Weight Loss and Athletic
    Performance. JAMA 20032891537-45.
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