Thursday, June 21, 2007

Did Conflicts of Interest Affect a Review of Anti-Coagulants to Treat Blood Clots?

In an article published last week on Medscape [Cundiff DK. Evidence-based medicine and the Cochrane Collaboration on Trial. Medscape Gen Med 2007; 9(2):56, link here] are allegations that conflicts of interest affected the Cochrane Collaboration review of the use of anti-coagulants for pulmonary embolism and deep venous thrombosis. Here are the main points of the article:

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. Juliet Manyemba, a physician from England, and John Pezzullo, PhD, a retired biostatistician formally from Georgetown 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.

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.

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.

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).'

At the suggestion of Dr. [Kay] Dickersin [the Director of Cochrane's US Center for Clinical Trials], I issued a complaint to the Cochrane Collaboration publication arbitrator in September 2006.

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.

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.[Cundiff DK. Anticoagulation therapy for venous thromboembolism. MedGenMed. 2004;6(3):5. See link here.] 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, George 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?' [MedGenMed. September 9, 2004;6(3):36. See link here.]

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.

This article has received no attention in the press, as far as I can tell. Note that the main benefit of warfarin after DVT is supposed to be prevention of extension and new clots, not postponement of death. However, Cundiff is certainly correct that the use of warfarin entails the risk of major, sometimes disabling or fatal bleeding, so that mortality should be assessed in any trials of this drug.

Note further that the article did not disclose the identity of the reviewers with alleged conflicts of interest, nor the nature of their alleged conflicts. Nonetheless, add this to other cautionary tales about how financial entanglements can influence the design, execution, and in this case, dissemination and discussion of clinical research.

ADDENDUM (22 June, 2007) - This post on Notes from Dr RW reminds us that blog first posted about this story in 2005.

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