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What is wrong with What is said?


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Title: What is wrong with What is said?

What is wrong with What is said?
  • Hasan Yazici, MD
  • University of Istanbul

Vitamin-E in gout the Hypothesis
  • Several recent reports hint that vitamin E can
    lower serum uric acid levels (1-3).
  • These are either single case reports or
    uncontrolled, open studies in small groups of
  • Thus we tested the hypothesis to see whether
    vitamin E was effective treatment for gout in a 6
    month, double blind, placebo controlled study.

What is wrong?
  • A hypothesis should not be formulated as a

Methods - 1
  • The patients were randomized into the vitamin E
    (n 60) and placebo (n 60) groups.
  • After randomization each patient signed a written
    informed consent.
  • The patients were assessed monthly with serum
    uric acid, hematocrit, serum creatinine,
    cholesterol and testosterone levels.
  • The number of gout attacks were also noted.

What is wrong?
  • The randomization follows, not precedes, the
    informed consent.

Methods -2
  • 30 patients had to leave the study for various
  • 20 patients from the active drug group and 10
    from the placebo left the study before its
    completion (ns).
  • Thus the final analysis for drug efficiency was
    made among 90 patients.
  • Among the 20 patients who dropped out from the
    treatment group 3 moved to another city.
  • 15 complained of severe indigestion and no
    information was available for the remaining 2.
  • Dyspepsia was the reason for withdrawal in 7
    patients in the placebo group while headaches
    were the main reason for discontinuation of
    treatment in the remaining 3.

What is wrong?
  • The intention to treat principle is neglected.

Intention to treat another study
  • 90 patients were initially randomized into 30
    patients each of placebo, QXY 2mg qd and QXY 5mg
    qd groups.
  • One patient in the QXY 5mg group developed
    pneumonia and had to be hospitalized 10 days
    after treatment started.
  • The patient was withdrawn and, according to the
    protocol, another patient was recruited.
  • Thus, the intention to treat analysis brought the
    number analyzed to 31 in the QXY 5mg group and
    the total number to 91.

What is wrong?
  • How was randomization achieved in the newcomer?
  • The newcomer inflates the denominator when
    looking at harm.

  • The allocation of 60 patients to the active drug
    and the placeo arms ensured a 86 power to detect
    a difference rate of 25 in the uric acid levels
    between the 2 groups using a 2-sided Fishers
    exact test with a set at 0.05

What is wrong?
  • In a power calculation it is not enough to state
    the magnitude of change, the anticapated event
    rates should also be given.
  • Ensured 86 power?

Sample size calculations 4 components
  • I. Type I (alpha) error
  • II. Type II (beta) error
  • III. Event rate in the control group
  • IV. Event rate in the treatment group

Power calculations for efficacy and harm
  • The primary end point was the achievement of at
    least 25 improvement according to the ACR
    criteria (ACR20) at week 20.
  • The sample size of 180 patients per group was
    chosen to ensure an adequate safety evaluation.
  • The sample size also ensured that there was 90
    power to detect a significant difference in the
    proportion of ACR20 responders between the
    treatment groups using a significance level of
    0.05, assuming 20 and 42 of the patients in the
    control and the treatment groups respectively
    achieved ACR 20 responses.

What is wrong?
  • No basis for the assumptions related to harm
  • Post hoc power calculations

Powering for safety
  • A sample size of 300 patients each in the study
    drug and the control groups was determined to
    demonstrate a specific adverse event rate of 1
    or less with 95 confidence.

What is wrong?
  • The probability of an event not happening does
    not give us information about the likelihood of
    events happening in the different arms of the

The zero patient method
  • If one screens n individuals and does not find an
    attribute y among this group
  • Then one can conclude that the frequency of y is
    less than 1/0.33n among the n individuals
    surveyed, with 95 confidence.
  • This approximation is true for prevalances lt
    0.02 of the attribute surveyed.
  • H Yazici et al
    Rheumatology Oxford (2001)

Efficacy a subgroup analysis
  • The uric acid levels decreased to 5.2 1.5mg/dL
    from a baseline of 9.3 2.3 mg/dL in the
    treatment and from 9.7 1.9 mg/dL in the placebo
  • There were no differences in the lowering of uric
    acid between the 2 groups (pgt0.05).
  • There were also no differences in the number of
    gout attacks between the 2 groups of patients.
    However a subgroup analysis was also done.
  • Among those patients in the treatment group who
    gave a history of more than 5 gouty attacks per
    year, as compared to those who had less than 3,
    the uric acid levels were significantly lower
    after treatment (plt 0.05).

Reviewer comments
  • The findings in the subgroup analysis, conducted
    among a small number of patients, should be
    interpreted with caution.
  • Even though the authors found a statistically
    significant difference in efficacy the study was
    not primarily planned to assess this difference.
  • This lessens the external validity of these

What is wrong?
  • The main problem with this subgroup analysis
    is not that the subgroup is small. It is an
    effort in the direction of proving that the new
    drug at hand is effecacious.

Harm another subgroup analysis
  • Table 3 gives the rate of observed adverse
    events. Indigestion was rather frequent in either
    group 15/45 patients in the treatment and 14/45
    in the placebo groups.
  • A subgroup analysis was also done after the
    patients who participated in the trial were
    questioned about a pre-trial history of
    indigestion. It turned out that 20/45 patients in
    the treatment and 18/45 in the placebo group had
    pre-trial indigestion.
  • A further analysis among these patients revealed
    that 14/20 in the treatment and 2/18 in the
    placebo group (plt 0.03) with a history of
    pre-trial indigeston also reported indigestion
    during the trial.

Reviewer comments
  • The findings in the subgroup analysis, conducted
    among a small number of patients, should be
    interpreted with caution.
  • Even though the authors found a statistically
    significant difference in harm the study was not
    primarily planned to assess this difference. This
    lessens the external validity of these results.

What is wrong?
  • Again the main issue is not the size of the
    subgroup. This subgroup analysis looks at the
    possibility that this new drug might not be all
    that harmless. Thus the exercise is in the
    direction of falsification and therefore is

Dr. Pincus study
  • Recently, in a placebo controlled withdrawal
    study, Dr. Pincus showed that small doses of
    prednisone (1- 4 mg/day) were significantly
    effective in the management of rheumatoid
  • The study was conducted among 31 patients

Reviewer comments
  • This beneficial effect of prednisone described
    among a small number of patients should be
    interpreted with extreme caution even if the
    authors found a statistically significant
    difference. The number of patients studied, thus
    the study power, was simply too small.

What is wrong?
  • The reviewer is partially right.
  • The issue of power applies only if we are missing
    a more important outcome that would have been
    more evident in a larger group.
  • External validity? The small number of patients
    might be quite different from the real life RA
  • However (!) this is not simply an issue of
    numbers but of patient selection.

The coxib study
  • 6000 patients with osteoarthritis of the knee
    were randomized to recieve either the new coxib
    (NCB) or the traditional (TCB).
  • 40 of the NCB and 35 of the TCB patients found
    total pain relief.
  • Hypertension was a problem in 2.5 of the NCB
    and 4.5 of the TCB patients.
  • It was concluded
  • a. NCB decreased pain by 13
  • b. There was 45 less hypertension with NCB

What is wrong?
  • Nothing. Needs more interpretation.
  • A NNT analysis will tell you that you have to
    treat 10 patients to see the superiority of NCB
    over TCB in 1 patient.
  • A NNH analysis will say that you have to treat 50
    patients with TCB to harm 1 more patient with
    hypertension as compared to using NCB.

  • Relative risk (RR) outcome ratio in the control
    group/ outcome ratio in the control group
  • Absolute risk reduction (ARR) difference in the
  • Relative risk reduction (RRR) ARR/outcome in the
    control group OR 1-RR
  • NNH 1/ARR (frequency of hypertension in the
    control group 0.045, frequency of hypertension in
    the study group 0.025, ARR 0.020 NNT 50.)

A withdrawal study
  • Two previous double blind studies of colchicine
    in BS had shown no superiroity of this agent over
    placebo in treating the oral ulcers in this
  • Recently a withdrawal study was done among those
    patients who claimed benefit from colchicine.
    They were randomized to contiune to receive the
    active drug or placebo.
  • After 3 months those who stopped taking
    colchicine had significantly more ulcers (sign
    test, p 0.02).

Reviewer comments
  • This study is interesting but is of limited use.
    A problem with all withdrawal trials, they
    seldom represent real life use.
  • The authors used the sign test to analyze the
    differences in oral ulcers between the 2 groups.
    Is this a new test? I suspect it is not quite
    powerful. Why not use the more powerful tests of
    significance to show the real differences, if

What is wrong? (I)
  • The main problem with withdrawal studies is that
    they are not done often enough.
  • They provide excellent information about possible
    a type II error in previous, traditional RCTs.
  • An important issue is that they do not give a
    fair picture of drug associated harm.

What is wrong? (II)
  • The sign test is a time honored, conservative
  • Significance in a conservative test gives more
    validity to the significant differences observed.

The mighty p
  • Among the 96 patients allocated to the new
    medication there were 3 cases of myocardial
    infarction while the same was true for 2/94
    patients allocated to placebo (p0.86).

What is wrong?
  • Better give it with the statistic used (sign
    test, p 0.02).
  • Do not use it to mesmerize the reader.

The Commandments
  • Hypothesis as an affirmative statement
  • Intention to treat
  • Components of the power calculation
  • Post hoc power analyses
  • Powering for harm, no short cuts
  • Justifications for subgroup analyses
  • Small but significant
  • Meaning of treatment effects
  • Withdrawal studies to be cherished
  • The mighty p

  • In a RCT, like in all scientific endeavor, all
    efforts aimed at proving the hypotheses are
  • The aim is falcification.

Vitamin-E in gout the Conclusion
  • Vitamin E is an innocuous agent and with the
    possible additional benefit of an
    antihypertensive effect, as was also
    serendipitously noted in this study, such studies
    are surely warranted. We are about to start a
    study along those lines at our institution.

What is wrong?
  • Do not preempt!
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