Without evidence of benefit, an intervention should not be presumed to be beneficial or safe.

- Rogue Medic

Publication Bias – The Lit Whisperers

ResearchBlogging.org
 

The Lit Whisperers raise an important point about publication bias and the validity of published drug company studies that show benefit of treatments that still have patent exclusivity.[1]

There are many problems with science. Science will never be perfect, but only people who do not understand science claim that it should be perfect.

One of the problems with science is publication bias. A paper that has a positive results about a brand name drug is twice as likely to be published than a paper with neutral results or with negative results.

The drug company has no incentive to publish a paper that does not make their drug look good. If you think that this is conspiracy talk, ask the drug companies for the results of the studies that have not been published.

Dr. Joe Lex states that we should take the published positive results for any drug and cut the claimed benefit in half, because the first published studies are often the most positive results that we will ever see.

Positive results may be seen as the best case scenario.

Look at the way that the antiarrhythmic amiodarone (Cordarone by Wyeth Pharmaceuticals Company, a subsidiary of Pfizer Inc.) became the ACLS (Advanced Cardiac Life Support) standard of care for VF/Pulseless VT (Ventricular Fibrillation/Pulseless Ventricular Tachycardia). One study showed that we had more ROSC (Return Of Spontaneous Circulation) with amiodarone than with lidocaine (Xylocaine by Astra Apotekarnes Kem Fab [SE], now AstraZeneca LP, originally patented in 1948 as a local anesthetic, but probably no longer patent protected as an antiarrhythmic at the time of the studies).

In the 2000 ACLS guidelines, we were told that we should treat every VF/Pulseless VT patient with amiodarone.

Why?

A single study compared ROSC among patients treated with 300 mg amiodarone or an equal volume of Polysorbate 80. Polysorbate 80 is a diluent in amiodarone that appears to cause bradycardia and hypotension, so it is not appropriate as a placebo.[2]
 


 

Wow! That’s Effective!

There was a statistically significant difference in ROSC. 44 percent (108 of 246) of the amiodarone group and 34 percent (89 of 258) in the placebo group had ROSC for a p value of 0.03.

There was not a statistically significant difference in survival to discharge – 13.4 percent (33 of 246) of the amiodarone group and 13.2 percent (34 of 258) of the Polysorbate 80 placebo group.

Yawn. That’s NOT Effective.
 

Of the 504 study patients, 67 (13 percent) were discharged alive from the hospital. Of the remaining 130 patients who were admitted to the hospital, 13 patients awakened, and 117 (90 percent) never regained consciousness.[3]

 

Since the best outcome for 90% of these patients was a short-term coma, followed by death, was this result of a single study appropriate to change the standard of care?

More patients had ROSC, but none of them survived to discharge.

ROSC is the wrong goal.

The standard of care was changed based on this single study that did not show any improvement that mattered.

Wyeth stated that they were studying the effect of amiodarone on survival to discharge, but after becoming the standard of care, Wyeth had no reason to publish a study that did not show improved outcomes with
 

Brandon Oto mentions this 13 1/2 minute presentation by Dr. Ben Goldacre at Ted Talks, which is very good to watch.

Ben Goldacre: What doctors don’t know about the drugs they prescribe
 

A better, much more informative 1 1/2 hour presentation by Dr. Goldacre is available at CSPAN –
 

Go watch the discussion of Bad Pharma.
 
 
Listen to Dr. Joe Lex’s A Skeptic’s Guide to the Medical Literature.
 

Footnotes:

[1] Publication Bias
June 5, 2013
by Brandon Oto
The Lit Whisperers
Article

[2] Amiodarone
2010 American Heart Association Guidelines for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care Science
Part 8: Adult Advanced Cardiovascular Life Support
Part 8.2: Management of Cardiac Arrest
Medications for Arrest Rhythms
Antiarrhythmics
Free Full Text from Circulation.
 

The adverse hemodynamic effects of the IV formulation of amiodarone are attributed to vasoactive solvents (polysorbate 80 and benzyl alcohol).

 

[3] Amiodarone for resuscitation after out-of-hospital cardiac arrest due to ventricular fibrillation.
Kudenchuk PJ, Cobb LA, Copass MK, Cummins RO, Doherty AM, Fahrenbruch CE, Hallstrom AP, Murray WA, Olsufka M, Walsh T.
N Engl J Med. 1999 Sep 16;341(12):871-8.
PMID: 10486418 [PubMed – indexed for MEDLINE]

Free Full Text from New England Journal of Medicine.

Kudenchuk, P., Cobb, L., Copass, M., Cummins, R., Doherty, A., Fahrenbruch, C., Hallstrom, A., Murray, W., Olsufka, M., & Walsh, T. (1999). Amiodarone for Resuscitation after Out-of-Hospital Cardiac Arrest Due to Ventricular Fibrillation New England Journal of Medicine, 341 (12), 871-878 DOI: 10.1056/NEJM199909163411203

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Comments

  1. My rule is that almost any clever new intervention you study will probably show a positive effect, and then the sobering effects of time will gradually take it away. (Whether there’s anything left in the end determines whether it’s real.) Even if the initial studies aren’t linked with industry, it’s still the pet hypothesis of some researcher who wants to be right, which means inherent bias.

    (Nobody really has a negative pet hypothesis until the positive effect is already out there and someone sets out to prove it wrong. So pretty much any ridiculous treatment will have its day in the sun.)

    That’s why the history of medical research looks like a capnogram waveform — a series of sudden peaks that gradually return to baseline.

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