[Ip-health] The Evidence Gap,The Minimal Impact of a Big Hypertension Study

[Riaz K Tayob]

The New York Times
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November 28, 2008
The Evidence Gap
The Minimal Impact of a Big Hypertension Study
By ANDREW POLLACK

The surprising news made headlines in December 2002. Generic pills for
high blood pressure, which had been in use since the 1950s and cost only
pennies a day, worked better than newer drugs that were up to 20 times
as expensive.

The findings, from one of the biggest clinical trials ever organized by
the federal government, promised to save the nation billions of dollars
in treating the tens of millions of Americans with hypertension =97 even
if the conclusions did seem to threaten pharmaceutical giants like
Pfizer that were making big money on blockbuster hypertension drugs.

Six years later, though, the use of the inexpensive pills, called
diuretics, is far smaller than some of the trial's organizers had hoped.

"It should have more than doubled," said Dr. Curt D. Furberg, a public
health sciences professor at Wake Forest University who was the first
chairman of the steering committee for the study, which was known by the
acronym Allhat. "The impact was disappointing."

The percentage of hypertension patients receiving a diuretic rose to
around 40 percent in the year after the Allhat results were announced,
up from 30 to 35 percent beforehand, according to some studies. But use
of diuretics has since stayed at that plateau. And over all, use of
newer hypertension drugs has grown faster than the use of diuretics
since 2002, according to Medco Health Solutions, a pharmacy benefits
manager.

The Allhat experience is worth remembering now, as some policy experts
and government officials call for more such studies to directly compare
drugs or other treatments, as a way to stem runaway medical costs and
improve care.

The aftereffects of the study show how hard it is to change medical
practice, even after a government-sanctioned trial costing $130 million
produced what appeared to be solid evidence.

A confluence of factors blunted Allhat's impact. One was the simple
difficulty of persuading doctors to change their habits. Another was
scientific disagreement, as many academic medical experts criticized the
trial's design and the government's interpretation of the results.

Moreover, pharmaceutical companies responded by heavily marketing their
own expensive hypertension drugs and, in some cases, paying speakers to
publicly interpret the Allhat results in ways that made their products
look better.

"The pharmaceutical industry ganged up and attacked, discredited the
findings," Dr. Furberg said. He eventually resigned in frustration as
chairman of the study's steering committee, the expert group that
continues to oversee analysis of data from the trial. One member of that
committee received more than $200,000 from Pfizer, largely in speaking
fees, the year after the Allhat results were released.

There was another factor: medicine moves on. Even before Allhat was
finished, and certainly since then, new drugs appeared. Others,
meanwhile, became available as generics, reducing the cost advantage of
the diuretics. And many doctors have shifted to using two or more drugs
together, helped by pharmaceutical companies that offer combination
pills containing two medicines.

So Allhat's main query =97 which drug to use first =97 became "an outdated
question that doesn't have huge relevance to the majority of people's
clinical practices," said Dr. John M. Flack, the chairman of medicine at
Wayne State University, who was not involved in the study and has
consulted for some drug makers.

Dr. Sean Tunis, a former chief medical officer for Medicare, remains an
advocate for comparative-effectiveness studies. But, as Allhat showed,
"they are hard to do, expensive to do and provoke a lot of political
pushback," said Dr. Tunis, who now runs the nonprofit Center for Medical
Technology Policy, which tries to arrange such trials.

"There's a lot of magical thinking," he said, "that it will all be
science and won't be politics."

Expensive Pills

Promising better ways to treat high blood pressure, drug companies in
the 1980s introduced a variety of medications, including ones known as
calcium channel blockers and ACE inhibitors.

Although there was no real evidence the newer pills were better,
diuretics fell to 27 percent of hypertension prescriptions in 1992, from
56 percent in 1982. Use of the more expensive pills added an estimated
$3.1 billion to the nation's medical bill over that period.

So the National Heart, Lung and Blood Institute, part of the federal
National Institutes of Health, decided to compare the various drugs'
ability to prevent heart attacks, strokes and other cardiovascular
problems. "This was a big-bucks issue," said Dr. Jeffrey Cutler, the
Heart, Lung and Blood Institute's project director for the study.

Allhat =97 short for the Antihypertensive and Lipid-Lowering Treatment to
Prevent Heart Attack Trial =97 began enrolling patients with high blood
pressure, age 55 and older, in 1994, with more than 42,000 people
eventually participating. Patients were randomly assigned one of four
drugs: a diuretic called chlorthalidone; an ACE inhibitor called
lisinopril, which AstraZeneca sold as Zestril; a calcium channel
blocker, amlodipine, sold by Pfizer as Norvasc; and an alpha blocker,
doxazosin, which Pfizer sold as Cardura.

Cardura was added only after Pfizer, which had already agreed to
contribute $20 million to the trial's costs, increased that to $40
million, Dr. Cutler said.

Early Trouble Signs

Pfizer's bet on Cardura proved a big mistake. As the Allhat data came
in, patients taking Cardura were nearly twice as likely as those
receiving the diuretic to require hospitalization for heart failure, a
condition in which the heart cannot pump blood adequately. Concerned,
the Heart, Lung and Blood Institute announced in March 2000 that it had
stopped the Cardura part of the trial.

What happened next provided the first signs that the Allhat evidence
might not be universally embraced.

Rather than warn doctors that Cardura might not be suited for
hypertension, Pfizer circulated a memo to its sales representatives
suggesting scripted responses they could use to reassure doctors that
Cardura was safe, according to documents released from a patients'
lawsuit against the company.

And in an e-mail message unearthed in those same court documents, a
Pfizer sales executive boasted to colleagues that company employees had
diverted some European doctors attending an American cardiology
conference from hearing a presentation on the Allhat results and
Cardura. "The good news," the message said, "is that they were quite
brilliant in sending their key physicians to sightsee rather than hear
Curt Furberg slam Pfizer once again!"

Pfizer declined to comment on the messages.

The Food and Drug Administration waited a year before convening a
meeting of outside experts to discuss Cardura's safety. At that session,
some of the experts sharply challenged the conclusions of the Allhat
organizers. They argued that the heart failure cases might have been
false readings and that an inadequate dose of Cardura had been used in
the trial.

By the end of the daylong meeting, Dr. Robert J. Temple, a senior F.D.A.
official, was clearly exasperated by the experts' varying
interpretations of a supposedly definitive trial.

"This is the largest and best attempt to compare outcomes we are ever
going to see," he said. "And people are extremely doubtful about whether
it has shown anything at all."

The committee decided that there was no need to issue an urgent warning
to doctors and patients about Cardura.

Cardura sales held up in 2000. But the next year, worldwide sales fell
to $552 million, from $795 million. Prescriptions for all alpha blockers
fell 22 percent from 1999 to 2002 after having risen before then,
according to one study.

Pfizer's decision to stop promoting Cardura in late 2000, after the drug
lost patent protection, was a factor in the decline. But Allhat clearly
was, too.

Cost-Benefit Analysis

The main Allhat results were announced in December 2002 at a news
conference in Washington and published in The Journal of the American
Medical Association.

In the primary target outcome of the trial =97 the prevention of heart
attacks =97 the three remaining drugs were proved equal. But patients
receiving the Norvasc calcium channel blocker from Pfizer had a 38
percent greater incidence of heart failure than those on the diuretic.
And those receiving the ACE inhibitor from AstraZeneca had a 15 percent
higher risk of strokes and a 19 percent higher risk of heart failure.

Moreover, the diuretic cost only about $25 a year, compared with $250
for an ACE inhibitor and $500 for a calcium channel blocker. So the
diuretic was declared the winner.

But some hypertension experts accused the government of overstating the
case for the diuretics, as a way to cut medical spending.

"There was a feeling there was a political and economic agenda as much
as a scientific agenda," said Dr. Michael Weber, a professor of medicine
at the Health Science Center at Brooklyn, part of the State University
of New York, who had been an investigator in the study but afterward
became one of its leading critics. "They pushed beyond what the data
allowed them to say."

Critics said the rules of the trial had favored the diuretics. If the
first drug did not adequately lower blood pressure =97 as happened in more
than 60 percent of cases =97 a second drug could be added. But that second
drug was usually a type that worked better with diuretics than with ACE
inhibitors.

There were also more new cases of diabetes among the patients who took
diuretics, although experts argued over how meaningful that finding was.

Adding fuel to the debate, an Australian study released two months after
Allhat found an ACE inhibitor superior to a diuretic. The proper lesson
to draw from Allhat, some critics contended, was that what matters most
is how much blood pressure is lowered, not which drug is used to do it.
For these and other reasons, European hypertension experts discounted
Allhat.

Allhat's proponents discounted the Australian study as less
authoritative, and they dismissed the other criticisms.

Still, the arguments "muddied the waters," said Dr. Randall S. Stafford
of Stanford, who studied the effect of Allhat on prescriptions. "The
message," he said, "was no longer as clear to physicians."

Science Moves On

By the time the Allhat results were released, lisinopril, the ACE
inhibitor, had become generic. That meant AstraZeneca and Merck, which
sold a version of the compound as Prinivil, had less interest in
defending their drugs.

Not so Pfizer. Norvasc was the best-selling hypertension treatment in
the world, with sales of $3.8 billion in 2002, and Pfizer's
second-biggest drug behind the cholesterol medication Lipitor.

The company set out to accentuate the positive. In a news release after
the Allhat results were announced, it said that Norvasc was found to be
"comparable to the diuretic in fatal coronary heart disease, heart
attacks and stroke." And in a medical journal advertisement, it
proclaimed "ALL HATs off" to its drug.

Neither the news release nor the ad, however, included the 38 percent
greater risk of heart failure with Norvasc in the Allhat study.

Nor did Hank McKinnell, then Pfizer's chief executive, mention heart
failure in lauding the results during his quarterly earnings conference
call with analysts a few weeks after the Allhat report was released.
"Contrary to what you might have read in the press," Mr. McKinnell said,
"Allhat is extremely positive for Norvasc. It will be our job to explain
that to the medical community."

Dr. Paul K. Whelton, president of Loyola University Health System and
the current chairman of the Allhat steering committee, said that Pfizer
and other drug companies "took what was in their best interest and ran
with those, and conveniently didn't mention other things."

Pfizer defends its actions. Dr. Michael Berelowitz, the head of Pfizer's
global medical organization, said that in the trial's design, heart
failure was merely one component of a broader measure of various
cardiovascular problems. And in that broader measure, Dr. Berelowitz
said, there was no difference between Norvasc and the diuretic. Also, he
said, the label for Norvasc already contained a precaution about heart
failure.

"Further action regarding the heart failure finding was therefore not
considered necessary," he said in a statement in response to questions.

Pfizer was not the only company promoting its drugs. The drug giant
Novartis, for example, was spending heavily to market Diovan, a leader
among a class of hypertension drugs called angiotensin receptor
blockers, which were too new to have been included in Allhat. Diovan,
which had more than $5 billion in sales last year, sells for $1.88 to
$3.20 a pill on drugstore.com, compared with 8 to 31 cents for a diuretic.

No company, though, was spending money to promote generic diuretics. So
the federal Heart, Lung and Blood Institute recruited Allhat
investigators, provided them with training and sent them to proselytize
fellow physicians. In all, 147 investigators gave nearly 1,700 talks and
reached more than 18,000 doctors and other health care providers.

But it was a coffee-and-doughnuts operation compared with the sumptuous
dinners that pharmaceutical companies used to market to doctors.
Moreover, the steering committee's outreach program did not get under
way until about three years after the results were published.

Dr. Stafford of Stanford said the outreach seemed to have had a slight
effect on increasing the use of diuretics.

The results of Pfizer's efforts are easier to quantify. Norvasc sales
continued to grow to $4.9 billion in 2006, falling only after the drug
lost patent protection in the United States in 2007.

Tangles and Strife

Tensions about industry influence reached even the study's own steering
committee. Dr. Furberg, the chairman, bluntly accused some members of
the committee of being agents of the industry.

One member, Dr. Richard H. Grimm Jr. of the University of Minnesota, had
been receiving tens of thousands of dollars a year from Pfizer since at
least 1997, according to reports that pharmaceutical companies file in
that state.

In 2003, the year after the Allhat results were published, Dr. Grimm's
payments from Pfizer soared to more than $200,000 =97 an increase that The
New York Times reported in 2007.

Dr. Grimm said in a recent interview that about half those fees in 2003
came from giving about 100 Pfizer-sponsored talks to doctors about
Allhat. Dr. Grimm said he gave mainly the standard Allhat-sanctioned
talk. But instead of saying diuretics were outright better than the
other drugs, he said they were as good or better.

Meanwhile, Dr. Grimm had led an effort to remove Dr. Furberg from his
position on the grounds that he had not been impartial.

"He had a vendetta against the calcium channel blockers," Dr. Grimm
said. Dr. Furberg had been publicly questioning the safety of those
drugs based on some studies he did in the 1990s. The effort to oust Dr.
Furberg failed in 2001. But in August 2004, Dr. Furberg resigned as
chairman, contending that there had not been enough effort to
disseminate the Allhat message.

Dr. Whelton, who took over as chairman, said that the study's message
was never compromised by industry ties on the steering committee.

"Curt is a wonderful guy who is a crusader," said Dr. Whelton, who did
not have industry ties and was not involved in the effort to unseat Dr.
Furberg. "He has certainly rubbed a lot of people, even good friends,
the wrong way."

Changing Practice

Experts see several lessons to be learned from Allhat.

One is that "all trials have flaws" that leave the results open to
interpretation, said Dr. Robert M. Califf, a cardiologist at Duke who
served on the safety monitoring committee of Allhat.

Another is that providing doctors information is "necessary, but not
sufficient" to urge them to change their practices, said Dr. Carolyn M.
Clancy, director of the federal Agency for Healthcare Research and
Quality, which itself conducts studies comparing different medical
treatments.

And while insurers can influence practice through reimbursement
policies, they did not seem to have pushed strongly for diuretics after
Allhat, in part because some of the other drugs had become generic.

Even the cost-conscious medical system at the Department of Veterans
Affairs did not require diuretics, because too many doctors would
probably have requested exceptions, said Dr. William C. Cushman, chief
of preventive medicine at the department's medical center in Memphis.

Dr. Cushman, a member of the Allhat steering committee, said diuretic
use in the system was still "much lower" than he thought it should be.

Dr. Clancy said that her agency was now mainly using insurance records
to judge how treatments perform. While clinical trials are the gold
standard, she said, they are costly and time-consuming.

And, she added, "You might be answering a question that by the time you
are done, no longer feels quite as relevant."


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