Gingerly, Kathleen Thoren's family gathered around her
in the intensive care unit, unable to speak to their beloved
sister, daughter, wife, or even stroke her hands. The
slightest stimulation might create a fatal amount of pressure
on the 25-year-old woman's swollen brain, warned the doctors.
"We were horrified, but we tried to just quietly be with
her," said her sister Erika Klein. "In the end, it didn't
help."
The mother of three died last fall, just after Thanksgiving,
after days of agonizing headaches that the coroner's report
said were brought on by hormones released into her system
by Ortho Evra, a birth control patch she had started using
a few weeks earlier.
She was among about a dozen women, most in their late
teens and early 20s, who died last year from blood clots
believed to be related to the birth control patch. Dozens
more survived strokes and other clot-related problems,
according to federal drug safety reports obtained by The
Associated Press under a Freedom of Information Act request.
Several lawsuits have already been filed by families of
women who died or suffered blood clots while using the
patch, and lawyers said more are planned.
Risk three times higher
Though the Food and Drug Administration and patch-maker
Ortho McNeil saw warning signs of possible problems with
the patch well before it reached the market, both maintain
that the patch is as safe as the pill.
However, the reports obtained by the AP appear to indicate
that in 2004 - when 800,000 women were on the patch -
the risk of dying or suffering a survivable blood clot
while using the device was about three times higher than
while using birth control pills.
The women who died were young and apparently at low risk
for clots - women like Zakiya Kennedy, an 18-year-old
Manhattan fashion student who collapsed and died in a
New York subway station last April. Or Sasha Webber, a
25-year-old mother of two from Baychester, N.Y., who died
of a heart attack after six weeks on the patch last March.
Some doctors, reviewing the Food and Drug Administration
reports at the request of The AP, were alarmed. "I was
shocked," said Dr. Alan DeCherney, editor-in-chief of
Fertility and Sterility and a UCLA professor of obstetrics
and gynecology.
But other doctors said they would have expected some deaths
and no investigation is warranted. They point to more
than 4 million women who have safely used the patch and
note that the FDA reports are called in voluntarily, rather
than gathered scientifically.
"It doesn't jump out at me to say, 'Let's look at this
any further,"' agreed Dr. Steven J. Sondheimer, professor
of obstetrics and gynecology at the University of Pennsylvania.
"I don't feel that these need to be looked at in any detail."
No cause for alarm?
Ortho McNeil, a subsidiary of Johnson & Johnson, says
none of the deaths can be directly attributed to the patch.
"Although we are investigating each and every one of the
reports that we get, we have not drawn any causal relationships
to the medication," said Dr. Katherine LaGuardia, Ortho
McNeil's director of women's health care.
Not one? "Right," she said. "It's difficult to reach a
definitive answer, and privacy laws prevent us from investigating
as thoroughly as we wish."
Blood clots are an accepted risk from hormonal birth control
because estrogen promotes blood coagulation.
But how many clots are too many?
The AP found that before the patch was approved, the FDA
had already noticed nonfatal blood clots from the patch
were three times that of the pill. The AP then examined
what has actually happened since the patch came on the
market and found that deaths also appear to be at least
three times as high.
If you are a woman taking the pill who doesn't smoke and
is under 35, the chance that you are going to have a blood
clot that doesn't kill you is between 1 and 3 in 10,000.
Your risk of dying from a blood clot while using the pill
is about 1 in 200,000.
By contrast, with the patch, the rate of nonfatal blood
clots was about 12 out of 10,000 users during the clinical
trials, while the rate of deaths appears to be 3 out of
200,000.
Clots usually form in the legs, and become serious problems
if they travel to a woman's heart, lungs or brain.
Early warning signs
In 2000, doctors at the FDA reviewing clinical trials
of the wafer-thin, plastic patch warned that blood clots
could be a problem if it was approved.
In those trials, two of the 3,300 women using the patch
were treated for blood clots that traveled to their lungs.
Ortho McNeil says one of those women shouldn't be counted
because she had undergone surgery. But an FDA reviewer,
using capital letters and underscoring his comments, took
issue with Ortho McNeil.
"THE REVIEWER DOES NOT AGREE WITH THE SPONSOR'S ABOVE
CONCLUSIONS. The two cases of pulmonary embolus, a serious
and potentially fatal condition, must be counted as two
cases ...," said the report. "The incidence rates quoted
by the sponsor may be misleading."
The reviewer said "the label should clearly reflect this
reviewer's safety concern about a potential increased
risk." It would be important to study users after the
patch came on the market for clot problems, he wrote.
But when the patch was approved in the U.S. in 2001, there
were no requirements for follow-up studies beyond routine
FDA reviews of reports called in by consumers, doctors
and manufacturers.
The label's safety warning says two different and seemingly
contradictory things: First, it says the patch is expected
to be associated with similar risks as the pill. Then,
it says it is unknown if the risk of blood clots from
the patch is different from the pill.
The AP reviewed what has happened since the patch came
on the market in 2002.
Hormones enter bloodstream directly
The FDA responded to a FOIA request by providing the AP
with a database that contained about 16,000 different
reports of adverse reactions associated with the patch.
These ranged from mild rashes to deaths, and there were
many duplicate reports. Within this collection of reports,
the AP found 23 different deaths associated with the patch.
The primary cause of death in those reports isn't always
clear - some mention suicide, others abortion. Doctors
who reviewed the 23 cases found about 17 that appeared
to be clot-related, including 12 from last year.
"That number of deaths certainly sounds suspicious," said
Dr. Pamela Berens, associate professor of obstetrics and
gynecology at the University of Texas Medical School at
Houston. "There may be something about the way the drug
is metabolized that could increase the risk for clots."
Although the estrogen levels are similar in the patch
and the pill, the hormones in a pill must be processed
through the intestinal tract before they enter the blood
stream. Hormones in the patch, on the other hand, go directly
into the bloodstream.
Dr. Sidney Wolfe, director of Public Citizen's Health
Research Group, a consumer advocacy organization founded
by Ralph Nader, said that the deaths and high rate of
clots are "worrisome" and should be investigated.
"These days, more often than not the problems with a drug
show up after they're approved," he said.
But Dr. Daniel Shames, the FDA's director of the Division
of Reproductive and Urological Drug Products, who approved
the agency's medical review, said he has reviewed cases
of women who died using the patch and saw no cause for
alarm.
"We think the death rate here is of concern, but it's
not different than what we expect," he said. "As of right
now we still believe there's nothing that would precipitate
our doing anything additional to follow up on these reports."
And other doctors who prescribe the patch warned that
women should not overreact to news of deaths. It is more
risky to remove the patch and become pregnant, several
pointed out.
'You can use a patch safely'
Dr. Philip Darney, a professor of obstetrics and gynecology
at the University of California, San Francisco, and a
leading contraceptive researcher, cautioned that the FDA's
adverse event reports tend to be inflated for newer products
like the patch.
Patients and doctors are more likely to contact the FDA
when they have a bad reaction to a new drug than for something
that has been on the market for a long time, he said.
In addition, women using the patch are likely to either
be new to hormonal birth control or have reacted poorly
to the pill and are looking for a change. The result is
that the pool of women using the patch are at higher risk
than birth control users at large.
He tells patients, "If you can use a pill safely, you
can use a patch safely, and we're going to know a lot
more later as more women use patches," he said.
Ortho McNeil recommended that the AP speak to two doctors,
Dr. Hilda Hutcherson, co-director of the NY Center for
Women's Sexual Health and a professor at Columbia University
Medical Center, and Dr. Vanessa Cullins, vice president
of medical affairs at Planned Parenthood Federation of
America. Both doctors have served in the past as paid
advisers to Ortho McNeil.
Hutcherson said the risks of blood clots from hormones
are well known, and that "what has happened with the patch
is consistent."
Cullins said she did her own comparison of data for the
pill and patch and found the patch is safer than expected.
"My research was to determine whether or not the expected
number of deaths from the pill was lower than what was
seen with the number of deaths reported with Ortho Evra.
I found the opposite," said Cullins, who has done research,
consulted for and been a speaker for Ortho McNeil and
other drug companies.
Cullins said she reviewed the deaths looking at "women
years" rather than current users. Women years is a measure
that takes into account that different people use a particular
contraceptive for different periods of time. For example,
if three women each used a patch for four months, that
would count as one woman year rather than three current
users.
Cullins reviewed patch users from 2002, when the patch
came on the market, until late 2003. For that period,
Cullins said she would have expected 22 deaths and found
only 6.
The AP reviewed the deaths looking at both women years
and current users, but used more recent data, focusing
on 2004 when the patch had been much more widely adopted.
