Controversial heart drug to remain on market
Health Canada rejects calls to withdraw nifedipine

Saturday, July 5, 1997
By Laura Eggertson
Parliamentary Bureau

Health Canada has decided to keep the controversial heart drug nifedipine
on the Canadian market despite studies indicating that it can cause fatal
heart attacks and strokes in some patients.

In a decision that highlights the difficulty of approving powerful and
lucrative drugs without longterm safety studies, the department's
healthprotection branch has accepted an advisory committee's
recommendation that the medication is safe if used pro perly.

Shortacting nifedipine is a capsule that patients take three times a
day to relieve angina, or chest pain associated with heart trouble. Some
doctors also prescribe it for high blood pressure a use for which the
drug was never approved.

"When used in the right way, there's not a problem," said Ellen
Burgess of Calgary's Foothills Hospital, who chaired the committee.

But recent articles in medical journals have linked the drug to fatal
heart attacks, cancer and bleeding from the stomach and intestinal tract,
even when given for angina.

Several medical experts in Canada and the United States believe there is
an urgent need for regulators in both countries to err on the side of
caution by withdrawing the drug.

They are concerned both by the way doctors prescribe the drug and by the
lack of safety data on patients taking the medication for longer than a
year.

At least 11 people have died in the United States because of the negative
side effects of taking nifedipine, said Franz Messerli of Louisiana's
Tulane University.

Those deaths are only the ones he knows about, cautioned Dr. Messerli,
who is is among those who want the drug off the market and who reported
some of the deaths in an article in the Journal of American Medicine.

"You have to consider, though, that physicians do not like to report
that their treatment causes death," he said in an interview from New
Orleans. "I think this is the tip of the iceberg because you do not
want to report adverse outcomes in m edical journals."

In a 1995 editorial in Circulation, a journal of the American Heart
Association, Canadian cardiologist Salim Yusuf cautioned against using the
entire class of drugs, calcium channelblockers, to which nifedipine
belongs.

Dr. Yusuf based his decision on studies showing that patients taking the
channelblockers had a 63percent increase in the odds of adverse
outcomes, including heart attacks or strokes. In the same issue of the
magazine, other researchers linked growing numbers of deaths in patients
taking increasing doses of nifedipine.

"The preponderance of evidence is that shortacting nifedipine is
unlikely to save lives or heart attacks or strokes and in fact the data is
in the adverse direction," Dr. Yusuf said in an interview from
Hamilton.

"That's a very conservative statement."

The advisory committee was aware of Dr. Messerli's reports that the drug
was causing deaths and Dr. Yusuf's articles, Dr. Burgess said. But it is
difficult to prove that the deaths involved were a direct result of using
nifedipine appropriately for angi na, she said.

Shortacting nifedipine is sold in Canada and the United States by Bayer
Inc. under the trademark Adalat. It is also sold in the United States by
Pfizer Inc. as Procardia and is available in generic formulations.

In the United States, the FDA held a series of public hearings when
articles about shortacting nifedipine first appeared in the medical
literature. In response to those concerns, the U.S. regulators required
Bayer to change its labelling to reflect wa rnings in boldface type.

Those warnings advise doctors not to use Adalat for the acute reduction
of blood pressure, control of essential hypertension, or for patients at
risk of heart attack.

"Several welldocumented reports describe profound hypotension,
myocardial infarction and death when immediate release [shortacting]
nifedipine was used in this way," says the FDA wording on use of the
drug to reduce blood pressure.

Doctors say there are less expensive, more reliable choices for treating
angina and hypertension, preferably older classes of drugs known as
betablockers.

Michele Brill Edwards, a senior drug reviewer at Health Canada until she
quit last year to be able to speak publicly about her fear that
shortacting nifedipine is harming patients, said she does not think that
Health Canada needs proof of harmful effects to pull a drug off the market.

The government has a legal obligation under the Food and Drugs Act to
make sure a drug is safe before approving it for sale, Dr. Brill Edwards
said in an interview yesterday. "The burden of proof lies with the
manufacturer to demonstrate safety."

A confidential document obtained by The Globe and Mail indicates that
Health Canada reviewers called for longterm safety data when they were
first asked to approve shortacting nifedipine for sale in 1981.

They agreed to approve the drug only when public demand had risen because
manufacturers supplied it to doctors on an emergencyrelease basis.

Longterm safety data were never supplied. Those studies are only now
under way and some will not be completed before 2001.

That is exactly the data that might have warned doctors against using
this drug, particularly in patients who had already had heart attacks, Dr.
Brill Edwards said.

Dr. Burgess agrees that the longterm data are important.

The big lesson the medical community should have learned from this
controversy is that largescale studies that demonstrate incidence of
harmful effects and deaths should be done "early on, so we have a much
better idea of how we should be using thes e drugs," she said.

Despite the medical debate, a June 25 letter to doctors from Health
Canada tells doctors that they can keep using shortacting nifedipine and
other calcium channelblockers.

"Right now, there is no reason to remove these products or even raise
questions about these products in relation to the treatment of
angina," said Mary Carman, director of Health Canada's pharmaceutical
assessment bureau.

Ms. Carman also dismissed concern about the longeracting form of
nifedipine, which is used to treat hypertension.

"They are safe and effective if you use them in the right individual,
as are most drugs."

The medical journals that questioned the safety of shortacting
nifedipine and the entire class of drugs to which it belongs were based on
"weak statistical effects" from observations of side effects,
instead of controlled drug trials, says the l etter, signed by Joseph
Losos, an assistant deputy health minister.

Because of the limitations of the studies, "it is premature to make
decisions which may have serious repercussions on the availability of
these drugs for use in carefully selected patients for appropriate
indications," Dr. Losos wrote.

Despite what Health Canada contends, Dr. Yusuf said he based his warnings
against the drug on the results of random trials, not observation. The
trials were small, but when combined with the observational evidence
should be taken seriously, he said.

A spokesman for Bayer said the company was happy with the Health Canada
decision.

"It really confirms what we've maintained all along, that the
shortacting formulation is safe and effective," said Tim Shannon,
vicepresident of medical and scientific affairs for Bayer in Toronto.

Adalat constitutes less than 1 per cent of Bayer's sales in Canada, Dr.
Shannon said.

In addition to being reassured on the medical front, Bayer was also
likely comforted that its bottom line will not be affected by a
withdrawal. Analysts say whenever a drug is removed from sale, companies
should worry about the possibility of classacti on lawsuits from patients
alleging harm.

"It is a concern," said Robert Uhl, a market analyst at Salomon
Brothers Inc. in New York.

Bayer would not comment on speculation about potential for lawsuits, Dr.
Shannon said.

Last year, Procardia was worth more than $1billion in sales to Pfizer.
But already this year sales have declined by 25 per cent, in part because
the company is not marketing the drug aggressively but is instead
promoting the use of another of its calci um channelblockers, Mr. Uhl
said.

Critics were not reassured by Health Canada's letter or the findings of
the advisory committee.

"The department is trying to downplay the importance of the evidence
against nifedipine by creating the appearance that these data are only
observational and that observational data can be ignored," Dr. Brill
Edwards said. "In the absence of large randomizedcontrol trials, we
must the food and drug law states very clearly we must take into
consideration the evidence as it exists from small controlled trials and
observational data."

Because shortacting nifedipine works quickly, doctors often use it to
treat emergencies patients in danger of a stroke because of high blood
pressure.

That quick effect is what worries Dr. Yusuf because he believes lowering
blood pressure too quickly can lead to heart attacks and strokes.

The advisory committee considered recommending that shortacting
nifedipine be withdrawn from sale, but it felt that would disadvantage a
small number of patients who might not be able to use any of the other
drugs available to relieve angina, Dr. Burge ss said.

The doctors on the committee were not concerned about the potential
effect withdrawal might have on Bayer and Pfizer, she said.


Copyright © 1997, The Globe and Mail Company