Evidence-Based Medicine and the Cochrane Collaboration on Trial

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Commentaries

Evidence-Based Medicine and the Cochrane Collaboration on Trial

http://www.medscape.com/viewarticle/557263

Posted 06/12/2007

K. Cundiff, MD

Author Information

The Cochrane Collaboration was founded in 1993 and was named for the

British epidemiologist Archie Cochrane, MD (1908-1988). At the

initiation of the National Health Service in the 1940s in the United

Kingdom, Dr. Cochrane suggested that the free care in the National

Health Service should be limited to interventions supported by evidence

of their effectiveness. This was a very innovative thought in the 1940s.

Dr. Ian Chalmers, the driving force behind the Cochrane Collaboration,

was strongly influenced by the writings of Archie Cochrane.

Most physicians perceive that " evidence-based medicine " means practicing

medicine by using tests and treatments that have been vetted by

randomized controlled clinical trials (RCTs) to prove that they work.

Although the Cochrane Collaboration focuses mainly on systematic reviews

of RCTs, it also addresses issues specific to reviewing other types of

evidence when relevant.[1]

Bernadine Healy, MD, former Director of the National Institutes of

Health, wrote an essay entitled " Who Says What's Best? " ; the piece,

critical of evidence-based medicine, appeared on September 11, 2006 in

US News and World Report.[2] Kay Dickersin, PhD, the Director of

Cochrane's US Center for Clinical Trials, asked me and other Cochrane

Collaboration evidence-based medicine reviewers to respond by sending

op-ed pieces to the media.

I agree with many of the points made by Dr. Healy. She writes that the

rigid adherence to RCTs as the only valid form of scientific evidence

about medical tests and treatments unfairly excludes other ways of

determining what medical interventions will best serve an individual

patient with a particular health problem. Dr. Healy put it succinctly:

" The autonomy and authority of the doctor, and the subsequent

variability in care, are the problems that evidence-based medicine wants

to cure. "

While I concur with Dr. Healy that relying solely on evidence-based

medicine to determine medical guidelines better suits the needs of

governments and insurance companies for cost control than the needs of

patients for optimal medical treatment, I agree for a different reason.

While evidence-based medicine is absolutely essential to comprehensive

healthcare reform, it has been profoundly corrupted by money.

In 2001, I volunteered to help conduct a review for the Cochrane

Collaboration of the evidence base for the use of anticoagulants

(warfarin [Coumadin] and heparins) for blood clots in the lungs

(pulmonary emboli, or PE) and legs (deep venous thromboses, or DVT), as

recently affected Vice President Dick Cheney. Dr. t Manyemba, a

physician from England, and Pezzullo, PhD, a retired

biostatistician formally from town University School of Medicine,

were my coauthors. I disclosed to the Cochrane editor that my research

interest in anticoagulants for DVT and PE originated because of a

malpractice case against me concerning a DVT patient that resulted in

the loss of my medical license.

Warfarin, heparin, and other anticoagulant drugs have been used to treat

blood clots since the 1940s based on unscientific anecdotal evidence and

observational studies with historical controls. Subsequently, countless

RCTs involving blood thinners for venous thromboembolism (VTE) patients

have included no un-anticoagulated control subjects. According to

anticoagulation researchers contracted or employed by drug companies,

the rationale is that it would be " unethical " not to give anticoagulants

to clinical research subjects with blood clots in their legs or lungs.

After reading over 1000 studies on the topic, I found 1 randomized and

properly controlled trial of DVT patients. Patients in the study

received either standard treatment (warfarin and heparin) or

phenylbutazone (an anti-inflammatory drug like aspirin). From this

single well-designed study of anticoagulants came a startling result:

The anticoagulants did not prevent deaths.[3,4]

Cochrane archivists turned up 2 other RCTs of anticoagulation therapy in

DVT patients. Neither trial found any benefit due to anticoagulants.

Summing the results of the 3 trials, 66 DVT patients received

anticoagulants and 6 of them died; 60 DVT patients did not receive

anticoagulants, and 1 of them died. None of the 3 trials had been

referenced in any journal articles or reviews of anticoagulant therapy

that I read.

Although these 3 trials show a trend suggesting that warfarin and

heparin do harm, there were too few patients to show with statistical

significance that anticoagulants increase deaths. But they contain

enough subjects to show that anticoagulants do not reduce mortality.

Based on the complication rate of anticoagulation for DVT or PE in much

larger observational studies, anticoagulants kill 1000-4000 Americans

with VTE each year due to internal bleeding, mostly in the brain.[5-7]

According to a recent population-based study of anticoagulation-related

intracerebral bleeding (AAICB) rates in the greater Cincinnati area,

AAICB occurred in 2000-2500 VTE American patients in 2004 (5.1-6.5 AAICB

cases per 100,000 population; 12.9% of AAICB cases were related to

anticoagulation of VTE patients). About 60% of AAICB patients die within

1 year.[8] Most of the surviving 40% remain permanently disabled.

Warfarin distribution in the United States quadrupled on a per-capita

basis between 1988 and 1999. In Cincinnati, cases of AAICB rose 5.5-fold

from 1988 to 1999.[9]

The Cochrane peer reviewers (at least 4 out of 7 of which had

undisclosed financial ties to the drug companies that make

anticoagulants) delayed four years over releasing this review for

publication. When the only 3 RCTs discovered showed no benefit and

possible harm from anticoagulants, the editor and peer reviewers

directed us to include 8 additional lines of evidence supporting

anticoagulation from about 50 other studies in the medical literature.

When my critique of those 8 lines of evidence showed that they were all

faulty, the peer reviewers did not rebut a single point. Instead, the

editor demanded that we delete the additional lines of evidence from the

review, because they were not from RCTs. The Cochrane editor also would

not allow publication of the estimate of major and fatal bleeding from

anticoagulants for VTE, because I derived those figures from large

retrospective observational studies and not RCTs.

When the author of one of the randomized trials discovered by the

Cochrane archivists refused to cooperate and clarify to us his method of

randomizing patients in his study, the Cochrane editor and/or peer

reviewers invented a reason to disqualify the trial from inclusion in

our review. The editor told us to accept the edits or the review

wouldn't be published. The " authors' conclusions, " written into our

article by the Cochrane editor and peer reviewers, were these: " The

limited evidence from randomized controlled trials of anticoagulants

versus nonsteroidal anti-inflammatory drugs or placebo is inconclusive

regarding the efficacy and safety of anticoagulants in venous

thromboembolism (DVT and PE) treatment. The use of anticoagulants is

widely accepted in clinical practice, so a further randomized trial

comparing anticoagulants to placebo could not ethically be carried out. "

In our final draft of the review, we authors said that a

placebo-controlled trial would be impractical and suggested a

" noninferiority trial " with anticoagulants vs a nonsteroidal

anti-inflammatory drug. One of the peer reviewers, with no conflict of

interest that I could find, commented, " Note that it is ethically

possible to conduct a study to determine if anticoagulation therapy is

harmful. If nothing else, dose reduction studies could determine if

lower doses or weaker therapies (aspirin or NSAIDS?) are equally

effective " (ie, a noninferiority trial).

Finally, in January 2006, The Cochrane Database of Systematic Reviews

published our review -- completely altered by the peer reviewers and

editor -- entitled, " Anticoagulants or Non-steroidal Anti-inflammatories

or Placebo for Treatment of Venous Thromboembolism. " [10] At the

suggestion of Dr. Dickersin, I issued a complaint to the Cochrane

Collaboration publication arbitrator in September 2006. In the 7 months

since I submitted the complaint, 580-2300 American VTE patients have

bled to death from anticoagulants as estimated from observational

studies.[5-7] This estimate is consistent with 1160-1450 deaths based on

the above mentioned Cincinnati population-based AAICB study.[8]

Worldwide, at least twice as many have died.

Dr. Dickersin recently told me that she cannot estimate when the

Cochrane investigation will be completed. A recent similar investigation

took 2 years. The publication arbitrator has resigned, and she has no

guarantee of finding a replacement anytime soon. Options that they are

considering include withdrawing the review from the Cochrane Database of

Systematic Reviews and having new peer reviewers critique the review

(except that she doesn't know when she can find new peer reviewers with

expertise in anticoagulation). Options that are not under consideration

include printing the review as we authors wrote it, having the Cochrane

peer reviewers reply to my analysis of their 8 lines of evidence

supposedly supporting anticoagulation, and asking the FDA Office of

Surveillance and Epidemiology (formerly Office of Drug Safety) to

examine the evidence and issue a report, as I suggested 7 months ago.

Medscape General Medicine published my entire review, including the

evidence from the 8 lines other than the 3 RCTs included in our Cochrane

VTE review.[11-13] The Medscape VTE review concluded, " Anticoagulants

have not been shown to be efficacious in reducing morbidity or mortality

or safe in venous thromboembolism treatment. " Medscape Chief Editor,

Lundberg, MD (former Chief Editor of JAMA), wrote the

accompanying editorial, entitled " Is the Current Standard of Medical

Practice for Treating Venous Thromboembolism Simply Wrong? " [14] I sent

the link to the review to several anticoagulation experts at the Food

and Drug Administration. Warren Rumble, Ombudsman - FDA, Center for Drug

Evaluation and Research, replied for them: " Thank you for asking FDA to

provide an official response to your published article in Medscape

General Medicine. I have consulted with officials in our Center for Drug

Evaluation and Research regarding your request, and we will not have a

response to your publication. We appreciate that you provided access to

your article, and the chance to comment on it. "

Since anticoagulation researchers and FDA scientists chose not to rebut

any of the data or conclusions of either review, the media was not

interested, few physicians read the reviews, and no debate ensued.

Researchers continue receiving lucrative contracts from drug companies

for more anticoagulant trials. The medical establishment (drug

companies, doctors, hospitals) keeps making money from the diagnosis and

treatment of DVT and PE with anticoagulants (estimated total cost in

2007 will be $13 billion-$48 billion in the United States[15]), and

medical journals keep publishing more anticoagulation trials without

proper controls, which are dutifully covered by a compliant media, while

thousands of DVT and PE patients keep bleeding to death.

To have a fair resolution concerning the interpretation of the

scientific evidence about the efficacy and safety of anticoagulants for

the treatment of VTE, I suggest that the reader call for the FDA Office

of Surveillance and Epidemiology to investigate the issue and decide

which of the 2 reviews of this topic published under my name[11,10] is

valid (Office of Surveillance and Epidemiology Director Gerald Dal Pan,

MD, gerald.dalpan@... ; Ph: ; or go to

http://www.fda.gov/cder/comment.htm).

Readers are encouraged to respond to the author at

dkcundiff3@... or to Blumenthal, MD, Deputy Editor of

MedGenMed, for the editor's eyes only or for possible publication via

email: pblumen@...

--

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