| NEW YORK, June 14
NEW YORK, June 14 For millions of heart
patients, a pair of new blood thinners have been heralded as the
first replacements in 60 years for warfarin, a pill whose
hardships and risks have deterred many from using the
But growing complaints of risks and deaths tied to the new
crop of drugs have made some t op U.S. cardiologists hesitant to
prescribe them. Some are proposing a more rigorous monitoring
regimen for when they are used.
Most concerns revolve around Pradaxa, a twice daily pill
from Boehringer Ingelheim that was approved by the U.S. Food and
Drug Administration in October 2010 to prevent strokes in
patients with an irregular heartbeat called atrial fibrillation.
It was the first new oral treatment for that use since warfarin
was introduced in the 1950s.
"The good news is you now have an alternative to warfarin,"
said Dr. Alan Jacobson, director of anti-coagulation services at
the Veterans Administration (VA) healthcare system in Loma
Linda, California. "The bad news is you can kill a patient as
easily with the new drug as you could with the old drug" if it
is not handled properly.
"The average patient doesn't understand anything about the
new drug, or what the risks are, or what other medicines he can
or can't take," said Jacobson, citing interactions with common
painkillers and other drugs that can alter Pradaxa blood levels.
Xarelto, a once daily pill that Johnson & Johnson
developed with Bayer AG, was approved last November
for atrial fibrillation. The condition affects about 3 million
Americans, causing blood to pool in a storage chamber of the
heart, where it can clot and travel to the brain.
Both new drugs were designed to sidestep risks of warfarin,
including brain hemorrhages and other dangerous bleeding, and
become mainstays of a new therapeutic market worth at least $10
billion a year. Patients taking warfarin require close
monitoring and regular blood tests as well as dietary and
Doctors have less data and familiarity with Xarelto, which
is still being rolled out.
But Jacobson and another dozen physicians interviewed by
Reuters expressed similar concerns about both Pradaxa and
They say that real world use of Pradaxa and Xarelto, which
do not require regular blood monitoring or frequent doctor
follow-up, raises concerns ab out t he risk of stroke, serious
bleeding and blood clots if not taken properly, particularly in
patients with poor kidney function.
The nonprofit Institute for Safe Medication Practices
estimated last month that 542 reports of deaths associated with
Pradaxa were reported to the FDA in 2011, topping all other
medicines, including warfarin, with 72 deaths. Adverse event
reports on Xarelto were not available.
A case study published in March raised alarm in
particular, showing an elderly Utah patient on Pradaxa developed
a massive brain hemorrhage and died after a minor fall.
European regulators have instructed Boehringer Ingelheim to
add warnings about the bleeding risk to Pradaxa's package
insert. Almost two dozen U.S. federal lawsuits have been filed
against Boehringer Ingelheim alleging harm from Pradaxa.
Boehringer declined to comment on the lawsuits. The German
company also declined to comment about the deaths, but said the
number of reports of bleeding with Pradaxa were within
Boehringer's expectations, given the incidence of bleeding seen
in the drug's largest study.
"Research has shown that the number of reported adverse
events for a drug peaks during its first few years on the
market," when doctors are most likely to file voluntary reports
to regulators and drugmakers, company spokeswoman Emily Baier
Dr. Robert Temple, a top official in the FDA's Center for
Drug Evaluation and Research, said few doctors notify the agency
about incidents from warfarin because its risks are already well
known. So the lopsided number of Pradaxa reports compared with
warfarin may not indicate an elevated risk, he said.
"We don't necessarily believe it is real," he said. "But
we're watching it. We can't help but notice it."
A SHIFT IN PRACTICE
The makers of Pradaxa and Xarelto say it takes time for
doctors to get up to speed on new types of treatments and how to
best administer them outside the controls of clinical trials.
"This is a shift in medical practice," said Dr. John
Smith, senior vice president for clinical development at
Boehringer. "Individual physicians have to determine what the
follow-up plan will be, to use common medical-sense judgment."
Dr. Peter Wildgoose, a senior director of clinical
development at J&J, said the company has not provided special
advice on follow-up care for patients on Xarelto.
"There's nothing more than for any other drug that people
regularly take," he said, adding that most atrial fibrillation
patients probably see their doctors on a regular basis. "These
drugs have been tested long term, for several years at a time,
with very good outcomes."
Boehringer Ingelheim and Johnson & Johnson officials
stressed there was far less evidence in trials of brain bleeding
- the most worrisome side effect of anti-coagulants - in
patients taking Pradaxa and Xarelto than those taking warfarin.
In the meantime, warfarin is holding its own, with 33
million U.S. prescriptions filled for atrial fibrillation and
other uses last year, according to IMS Health, a healthcare
information and services company. Some 2.2 million prescriptions
were filled for Pradaxa.
About 130,000 U.S. prescriptions were written for Xarelto in
the first three months of 2012. Pradaxa and Xarelto each cost
about $3,000 a year, versus just $200 for generic warfarin.
Prominent U.S. heart doctors stress that neither new drug
has a known antidote for a bleeding emergency, as warfarin does.
They also say that patients using them should undergo
testing ahead of time to ensure good kidney function, be
carefully taught potential pitfalls of the drugs and be seen by
doctors periodically, especially after a switch is made.
"I have received a dozen phone calls from local colleagues
in the last couple of months about bleeding on Pradaxa and have
yet to find a single case where that bleeding was not related to
improper use of the drug," said Dr. Sanjay Kaul, a cardiologist
at Cedars-Sinai Medical Center in Los Angeles.
Kaul found that many of the doctors failed to test patient
kidney function before prescribing Pradaxa, though 80 percent of
the drug is excreted in that organ. Weak kidneys allow the
medicine to build to unsafe levels in the bloodstream. About two
thirds of Xarelto is eliminated by the kidneys. Other doctors
failed to ask patients whether they had a history of
gastrointestinal bleeding, which raises the risk for Pradaxa.
"What really compounds the matter is the lack of a specific
antidote to reverse life-threatening bleeding" from Pradaxa,
said Kaul, who served on independent panels that advised the FDA
on both new medications. Kaul said he had written only one
prescription for Pradaxa and none for Xarelto.
Boehringer Ingelheim said it is working on an antidote, but
declined to elaborate. Johnson & Johnson said it is not
developing an antidote, but is monitoring early efforts by other
drugmakers to come up with one. Bristol-Myers Squibb Co,
which is developing a blood clot drug called Eliquis that is
similar to Xarelto, declined to comment on the antidote issue.
HOPES FOR A THIRD NEW DRUG
Warfarin thins the blood by blocking Vitamin K, while
Pradaxa directly inhibits thrombin - a protein involved in
clotting. Xarelto and Eliquis - which Bristol-Myers is
developing with Pfizer Inc - interferes with a protein
called Factor Xa.
Richard Purkiss, an analyst with Atlantic Equities, sees the
new blood clot drugs reaching combined global annual sales of
$10 billion for stroke prevention and other uses, with Eliquis
commanding up to a 60 percent market share, based on data
showing it was more effective and safer than warfarin, including
less bleeding and risk of death from all causes.
Neither Pradaxa nor Xarelto were able to claim both
superiority and better safety than warfarin, or reduced risk of
Eliquis is eliminated mainly by the liver, which some
doctors say could make it more appropriate than Pradaxa or
Xarelto for older patients and those with kidney problems. The
FDA is expected to make a decision on Eliquis by June 28.
Michael Liss, portfolio manager at American Century
Investments, predicts Eliquis will overtake Pradaxa and Xarelto
within six months after it is introduced. He expects it to
capture peak annual sales of up to $4 billion, with Pradaxa and
Xarelto dividing up another $3 billion.
Dr. Kenneth Bauer, head of hematology for the Veterans
Administration health system in Boston, said the FDA should
never have approved Pradaxa and Xarelto for patients with severe
kidney dysfunction, since such patients were excluded from large
studies. Nor should the agency have approved an untested
75-milligram half dose of Pradaxa for such patients, he said.
"These are people whose kidneys are already damaged ... and
even at the smaller dose (of Pradaxa), you risk overdosing
yourself," Bauer said.
The FDA said it routinely approves adjusted doses of
medicines, and noted that patients with severe liver dysfunction
were included in smaller studies of Xarelto and Pradaxa.
Boehringer Ingelheim's Smith said the FDA cleared the lower
dose of Pradaxa after conducting its own analysis of how it
performs in the bloodstream.
FRAIL ELDERLY 'CANARY IN COAL MINE'
Almost 15 percent of Americans over the age of 80 are
believed to have atrial fibrillation and face a fivefold higher
risk of stroke if untreated.
Dr. Richard Besdine, director of the Center for Gerontology
at Brown University, said he had switched only two of his
approximately 100 elderly patients from warfarin. He is unlikely
to switch many others for at least a few years.
"If there's an adverse event lurking in the closet for a new
drug, it's most likely to come out in patients that are old and
frail and taking multiple medications. They're the canary in the
coal mine," he said.
Even so, Besdine - like many other doctors now on the
sidelines - believes the new drugs may eventually displace
warfarin as doctors become familiar with them.
Others note that warfarin's disadvantages have led as many
as 70 percent of prospective patients to refuse to take it,
leaving plenty of room for the new drugs.
Dr. Robert Califf, a Duke University cardiologist who headed
the largest study of Xarelto, noted warfarin is still one of the
biggest causes of U.S. emergency room fatalities.
"We shouldn't lose sight of what warfarin is like in the
real world," he said.