Evidence Gap in Current Medical Rx Practices

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ALLIANCE FOR HUMAN RESEARCH PROTECTION

Promoting Openness, Full Disclosure, and Accountability

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FYI

The New York Times revisits the story of how Pfizer scuttled the

government-sponsored $130 million (ALLHAT, " antihypertensive and lipid

lowering to prevent heart attack trial " ) study findings published in the 18

December issue of JAMA (2002;288;2981-97).

The study compared incidence of heart attacks, strokes and other

cardiovascular problems in 42,000 patients randomized into 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.

The study was conducted by the National Heart, Lung and Blood Institute

(NHLBI), after it was noticed that there was no real evidence that the

newer, expensive, drugs were better than the old, cheap diuretics. Use of

the more expensive pills added an estimated $3.1 billion to the nation’s

medical bill over that period.

Cardura was added only after Pfizer, which had already agreed to contribute

$20 million to the trial’s costs, increased that to $40 million. However,

Pfizer’s bet on Cardura proved a big mistake. The ALLHAT data showed that

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. The finding lead the NHLBI to

suspend the Cardura part of the trial in 2000.

What happened next provides insight into just how Big Pharma companies

embark on aggressive marketing and large cash payments to key opinion

leaders (KOLs) and authoritative professional associations--in this case,

the American College of Cardiology--to drown out negative scientific

findings that would diminish prescriptions.

The saga was reported by Jeanne Lenzer in the BMJ (British Medical Journal)

in 2003 [1]

" Pfizer was not alone in blunting the response to ALLHAT results. The

American College of Cardiology (ACC) issued an alert in March 2000 urging

doctors to " discontinue use " of Cardura. However, another Pfizer memo dated

28 March 2000 and stamped " confidential " says that Pfizer was " successful in

getting the ACC to agree to a clarification " of the ACC press release. The

" clarification " that the ACC agreed upon replaced its initial press release

on the ACC website within just hours of the original posting and changed the

recommendation that Cardura be discontinued to a much milder recommendation

that doctors " reassess " its use. It may have added to Pfizer's standing with

the ACC that Pfizer has contributed more than $500 000 (£312 000; 474 000)

annually to the college in recent years. " http://tinyurl.com/6j6tbw

The Times reports (below):

" 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. "

" 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. "

" Dr. H. Grimm Jr. of the University of Minnesota, had led an effort

to remove Dr. Furberg from his position on the grounds that he had not been

impartial.

Dr. Grimm 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. "

" 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. "

" 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,â€

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!â€

The Food and Drug Administration waited a year before convening a meeting of

outside experts to discuss Cardura’s safety. And when the FDA got around to

doing so, there was sharp disagreement about the ALLHAT study conclusions.

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. 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. Pfizer’s decision to stop promoting Cardura

in late 2000--after the drug lost patent protection--was the most likely

primary factor resulting in the drug's sales decline. Drug comanies pull the

purse strings and doctors happily march in log step: they hardly act like

the " learned intermediaries " they were supposed to be.

Reference:

Lrenzer J. Spin doctors soft pedal data on antihypertensives, BMJ

2003;326:170 ( 18 January )

Contact: Vera Hassner Sharav

veracare@...

212-595-8974

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 — 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.â€

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 — which drug to use first — became “an outdated

question that doesn’t have huge relevance to the majority of people’s

clinical practices,†said Dr. 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. 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,â€

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.â€

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. Cutler, the Heart, Lung and Blood

Institute’s project director for the study.

Allhat — short for the Antihypertensive and Lipid-Lowering Treatment to

Prevent Heart Attack Trial — 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,â€

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!â€

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. 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.â€

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 — the prevention of heart attacks

— 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. 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.â€

Critics said the rules of the trial had favored the diuretics. If the first

drug did not adequately lower blood pressure — as happened in more than 60

percent of cases — 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,â€

he said, “was no longer as clear to physicians.â€

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.â€

Dr. 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.â€

Pfizer defends its actions. Dr. 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. 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 — 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.â€

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. 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. 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.â€

Copyright 2008 The New York Times Company

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