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[Fred A. Baughman Jr., MD:
This was published in the San Diego Union-Tribune as a letter to the
editor Sat. July 27, 2002. See also the important article by Moore,
regarding the fact that there are few, truly long-term trials/studies in
medicine (virtually none more than weeks to a few months in duration in
psychiatry) meaning that long term side effects await post-marketing
observations in persons using them, never having had assurances of
long-term studies. Fred A. Baughman Jr., MD July 30, 2002.]


Editor 7/23/02
San Diego Union-Tribune

Prempro, Premarin: Risk vs. benefit analysis; informed consent.


Fred A. Baughman Jr., MD
1303 Hidden Mountain Drive
El Cajon, CA 92019
Phone: 619 440 8236

Cheryl Clark writes [San Diego Union-Tribune, 7/21/02, A1] "Many doctors
in San Diego County are skeptical, confused--and in some cases
defiant--in the aftermath of an alarming national study linking hormone
replacement ( estrogen and progestin) drugs to higher risk of heart
disease, breast cancer, blood clots and strokes." "Should women
immediately stop taking hormones or taper off gradually? Could lower
doses just as effectively solve the problems of night sweats,
depression, mood swings and insomnia?"

Oral contraceptives contain either a mix of estrogen and progestin or
progestin alone, although in substantially higher doses than in Prempro
(also estrogen plus progestin) or Premarin (estrogen alone). However,
throughout our years of experience with these drugs, it has been clear
that they put the young, reproductive-aged, women at an increased risk
of venous blood clots (thrombo-embolism) heart attack and strokes. As a
neurologist, I saw the occasional, but striking and tragic, case of
stroke in previously healthy, young, women. While the risk of such
complications clearly lessens with lessening doses of the active agents
in these preparations, there is no dose at which the risk disappears.
The Physician's Desk Reference, under Premarin, warns, " estrogens
should be discontinued at least four weeks before surgery of the type
associated with an increased risk of thromboembolism." Under "Adverse
Reactions," it lists "Venous thromboembolism, Pulmonary thromboembolism,
Myocardial infarction and Stroke."

In risk/benefit analysis essential to informed consent, the physician
and patient, together, weigh the risks and benefits of treatment against
the risks and benefits of taking nothing. What has been lost in the
discussions of this study is the fact that the objects of treatment
listed above "night sweats, depression, mood swings and insomnia..." are
symptoms--(and, therefore, subjective) of menopause--aging, none of them
abnormalities/diseases, as are many of the adverse reactions to these
drugs which include, not only the cardiovascular diseases, listed above,
but certain types cancers as well. While present-day "biological"
psychiatry contends that depression and all thing emotional/behavioral
are diseases, that claim is the lynch-pin of psychiatric-pharmaceutical
marketing and is devoid of science and fact--something always to be born
in mind before opting to take psychiatric drugs.

A year ago my wife had transient paralysis of the right side--a
thrombotic stroke. We were forced, for the first time, to look
critically at why she was taking Premarin and whether or not to continue
it (deciding not to).

Doctors have a duty to dis-passionately, objectively, weigh the risks
and benefits of any treatment situation with their patient so as to
allow the patient to give or withhold what is truly informed consent. It
is paternalistic and inappropriate for the physician to decide alone
whether or not to defy facts in evidence about this treatment or that.


Comments of Fred A. Baughman Jr., MD, 7/25/02, on:

An Op-ed in The Boston Globe by Thomas J. Moore, a respected health
policy analyst at George Washington University Medical Center in
Washington, warns that the current system under which the safety and
efficacy of medical treatments are being tested is not designed to
detect long-term effects or a drug's multiple effects. Yet, today's
complex, multi-action drugs--many of which are taken for long periods of
time--have multiple effects on people

[Fred A. Baughman Jr., MD:
almost no psychiatric drug,
all of them given to previously, medically, physically normal persons,
undergo trials of longer than weeks to 2 or 3 months; not long enough to
detect any of what would be called long-term side effects]

narrow focus of clinical trials conducted by scientists contracted by
drug companies, focus on demonstrating a desired marketable

[Fred A. Baughman Jr., MD:
in psychiatry, feeling better on the short-term, or
improved behavior in the eyes of the beholder; teachers, jailers, foster
parents, parents not able to cope with their child]

--not to look
for undesirable effects which may be lurking beneath the surface. When a
clinical trial fails to demonstrate a significant (desired) effect, the
methodology rather than the product tends to be blamed: "Scientists can
find just as many technicalities to debate as a skilled lawyer with a
guilty client."

[Fred A. Baughman Jr., MD:
Top academic psychiatrists, such as Biederman
of Harvard, appear to have as their number one duty, the defense of
drugs whose safety is being questioned. He has defended desipramine and
clonidine both when they were causing fatalities. He rushed to the
defense of Ritalin when it was declared the case of the heart death of
Matthew Smith, 13, of Clawson, Michigan]

Without systemic change there will be other preventable medical
disasters. Only long-term clinical studies conducted by independent
federal scientist are capable of providing "a conclusive, balanced
perspective on all the risks and benefits."

[Fred A. Baughman Jr., MD:
Every psychiatric patient is devoid of organic, physical
disease, meaning their is no such thing as "treatment," only "drugging",
"poisoniong," meaning their is no scientific rationale for the use of
any drugs, such as is the use of anitbiotics for demonstrated




In short drug tests, fatal flaws
A narrow focus on effectiveness is a prescription for harm
By Thomas J. Moore, 7/14/2002
It is a major medical debacle when hormone replacement therapy - a drug
treatment that doctors recommended to millions of women - is discovered
to be harmful despite 60 years of widespread use. Yet because of
weaknesses in the entire system that tests and promotes drugs for
long-term use, this major surprise surely will not to be the last.
The Women's Health Initiative trial provides an object lesson about how
easily some inadequately-tested drug treatments can cause harm. These
findings speak with unusual authority because they come from one of the
largest, longest, and best-designed clinical trials reported in many years.
So what was the magnitude of the hormone replacement debacle? Estrogen
and progestin significantly harmed about 1 percent of the women tested
over the 5.2 years they took the hormones, but caused no additional
deaths. The harmful events included breast cancer, stroke, heart attack,
or blood clots in the lungs. In addition, about a third of treated women
had gynecological symptoms requiring a doctor's care.
How could this happen with one of the most extensively researched,
high-visibility treatments in all of medicine? It occurred, and will
happen again, for three reasons. First, our society settles for
short-term studies about drugs taken for long-term effects. Second, the
health professionals tend to see drugs with tunnel vision, focusing
narrowly on a particular benefit while forgetting that drugs have many
effects. Finally, many popular long-term treatments provide very small
benefits to people with an already low risk of death or serious injury.
In such circumstances, only a small, unintended effect tips the balance
from good to harm.
To get new drugs more quickly, drug testing worldwide is often
extensive, but lasts only for short periods. Antidepressants are usually
tested for six weeks, new blood pressure drugs for a matter of months,
and drugs for adult-onset diabetes from six months to a year. To limit
development costs, an individual trial for Food and Drug Administration
approval seldom has more than a few hundred participants.
The harm of hormone replacement therapy was detected only because
taxpayers paid for a much larger, longer trial with 16,608 participants
who were going to be observed for 81/2 years.
This is hardly the first time that long-term trials conducted at
government expense have produced findings of harm. A heart drug called
Tambocor, effective in the short term in suppressing mild irregular
heartbeats, was discovered in a longer government trial to cause people
to drop dead with cardiac arrest. Cardura, a blood pressure drug, was
found inferior to other drugs in another large, long-term study
conducted by the National Institutes of Health. In other long studies,
two cholesterol-lowering drugs were found to be harmful overall, even
though they lowered cholesterol.
However, no system is in place to ensure that drugs intended for
long-term treatment ever receive long-term testing. The legal structure
of our drug-approval laws has been built around simpler drugs such as
painkillers and antibiotics - which are taken for short periods of time
with effects that are more immediately apparent.
As a result, we know little about the long-term effects of many
important drugs. For example, millions of schoolchildren take Ritalin
and other powerful stimulants for years without long-term trials to
establish safety, and despite evidence they cause brain damage in some
children. The long-term benefits of some best-selling drugs to lower
cholesterol or blood pressure are similarly unknown. Although many
popular drugs caused cancer in animals, few have been tested for the
five years or longer needed to document excess cancer risks in humans.
Until the hormone trial results were published, the scientific case for
estrogen replacement therapy seemed persuasive, so long as focus was
limited to just part of the evidence. Estrogen does preserve bone
density, and the Women's Health Initiative confirmed its ability to
reduce bone fractures. Estrogen also lowered ''bad'' (or low-density)
cholesterol, so it seemed reasonable to presume it would prevent heart
But drugs have many effects, and these were only two. Estrogen is also a
powerful growth promoter, and it is also reasonable to assume it might
accelerate the growth of some cancers. It also increases blood clotting,
and therefore might cause heart attacks and dangerous blood clots in the
lungs and legs. These effects were well documented in scientific
literature, along with the benefits, but many doctors ignored them. Only
a large, long-term clinical trial such as the Women's Health Initiative
was capable of providing a conclusive, balanced perspective on all the
risks and benefits.
Examples abound of this medical tunnel vision. Many clinicians have
embraced two heavily marketed drugs for adult-onset diabetes called
Actos and Avandia. These drugs had a small effect in lowering blood
sugar (the benefit the doctors saw) but also increased stress on the
heart and induced weight gain (the drawbacks that get little attention).
Without a long-term trial of about 10 years, no one knows whether the
net effects on health are harmful or beneficial. Doctors and patients
alike embraced an arthritis drug called Vioxx, impressed by evidence
that people had fewer stomach ulcers of microscopic size compared to
ibuprofen and naproxen. But few noted that Vioxx lacked the
cardioprotective effects of naproxen until hard evidence emerged in
another large clinical trial. For many people, a greater risk of a heart
attack or stroke with Vioxx might outweigh any benefits from fewer
injuries to the digestive tract. In each of these cases, the lesson is
that drugs have many effects, not just the benefits used for marketing
and promotion.
The hormone replacement debacle also illustrates why relatively small
adverse effects can render a drug treatment harmful overall. The reason
is that the participants - two-thirds from 60 to 75 years old - were
remarkably healthy regardless of whether they took a placebo or the
hormone replacement therapy. Over five years only 52 of 8,102 older
women taking the placebo died of breast cancer, colorectal cancer, heart
attack, or stroke - less than 1 percent. Among people so healthy it is
extremely difficult for a drug to have a beneficial effect because there
is so little room for improvement.
That fact also doomed the most important benefit of hormone replacement
therapy - prevention of hip fractures. Despite an avalanche of medical
advertising about the dangers of osteoporosis, hip fractures were rare.
Just 62 hip fractures occurred in the placebo group, compared with 44
among those on hormone replacement. Helping just 18 women avoid a hip
fracture among more than 8,000 treated was a benefit so tiny it was
outstripped by very modest increases in strokes, breast cancer, and
heart disease.
How many drugs are so completely free of adverse effects that fewer than
1 person per 1,000 per year is injured? Yet an adverse effect of that
rarity nullifies the protection against hip fractures provided by
hormone replacement therapy. One has to wonder whether many drugs
targeted at a population with such an excellent health status are
destined to fail in a large clinical trial capable of detecting risks
and benefits that are this small. Yet the pharmaceutical industry loves
to market drugs to the healthiest people because there are so many of
them, and the largest market yields the most money.
It is also noteworthy that the important but unwelcome findings of the
Women's Health Initiative came in an NIH study conducted by medical
investigators without a financial stake in the outcome. What if this
study had been sponsored by a pharmaceutical company whose stock would
plummet, and if the investigators were bound by secrecy agreements not
to reveal the findings? Furthermore, the companies have no legal
obligation to make public such findings.
Every large complex clinical study raises questions capable of
triggering a technical debate over the validity of its findings.
Scientists can find just as many technicalities to debate as a skilled
lawyer with a guilty client. It does not even take the assumption that
companies would deliberately fudge the numbers - as so many large
corporations now stand accused of doing. A fat consulting fee to a
specialist with sterling credentials who is willing to advance one side
of a technically-arguable issue is all it would take to mire important
findings in an endless technical debate. For this reason, drug companies
with a financial stake in the outcome should not be allowed to control
these large, long-term studies.
We need new laws, a national scientific program, and money to assure
that every important drug intended for long-term use receives the same
long-term testing as was provided for hormone replacement therapy. The
funds should come from a new tax on the pharmaceutical companies that
profit from the sale of such drugs.
It now remains to be seen whether Congress and the Bush administration
will respond to this clear public need - or to the millions of dollars
spent on pharmaceutical lobbying. But the fact remains that drugs
intended for long-term use require long-term testing. And under our
present system they don't get it.
This story ran on page C1 of the Boston Globe on 7/14/2002.
© Copyright 2002 Globe Newspaper Company.

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