Thursday, October 26, 2006

The Surviving Sepsis Guidelines: guilt by association?

The Surviving Sepsis Guidelines have been under fire for the role of Eli Lilly in their development and promotion. In a recent blog post I argued that much of the criticism of the guidelines is irresponsible because it ignores the evidence and relies solely on the fallacious argument of “guilt by association” or, as one of my commenters put it, “corruption.”

Two of my favorite bloggers who recently weighed in on the controversy took a somewhat more negative view of the guidelines than I. Dr. Roy Poses of Health Care Renewal cites the guidelines as the latest example of “stealth marketing” and concludes with “Maybe with increasing realization how pervasive conflicts of interest fuel deceptive marketing and promotion will come some increased skepticism and a will to address this problem.” I’m all for more skepticism, but what was it that was deceptive about Lilly’s promotion, exactly?

Retired Doc’s response was more scathing. (Retired Doc sees eye to eye with me on many issues, but we may have to agree to disagree on this one!). He’s concerned about how drug companies use EBM for promotional purposes and wonders whether their spin of evidence puts patients’ lives at risk. He cites the NEJM Perspective authors’ concerns that information on the risks of bleeding due to Xigris was suppressed, and feels the jury is still out concerning Xigris.

Let’s examine these questions. Did the guideline authors spin the evidence on Xigris? The guideline section on activated protein C is on page 863 of volume 32, issue 3 of Critical Care Medicine. Looks pretty straightforward to me. Right out of the PROWESS article. Where is the spin here?

Although the guideline authors appropriately emphasize that Xigris is to be used in patients assessed to be at high risk of death, some might criticize their failure to be more explicit in how the APACHE II score and the number of failing organs should determine candidacy for the drug. The results of ADDRESS later suggested restricting Xigris to patients with two or more failing organs or an APACHE II score above 25, but those results were not announced until 7 months following the guideline publication and were not published until 18 months after the guidelines. That fact didn’t stop the NEJM Perspective authors from trying to hold the guideline authors accountable. They state: “Although the results of the ADDRESS study were reported at the October 2004 ESICM meeting, no mention of the study was included in a supplement to the Surviving Sepsis Campaign Guidelines published the following month in Critical Care Medicine.”

But, digging deeper, the ESICM meeting in question was held October 10-13 2004. The November supplement to Critical Care Medicine was certainly already posted and printed during the month of October and probably in press by the time the ADDRESS results were announced. The Perspective authors left out those little details. Now who’s being deceptive?

Was the risk of bleeding suppressed? The body of the report mentions bleeding risk and refers the reader to an appendix which explicitly states this risk and cites product labeling containing the actual data on bleeding from clinical trials. I’m still looking for the smoking gun.

What about the evidence favoring activated protein C in severe sepsis? Critics of the guidelines talk around this issue but seem to come short of any direct criticism. Retired Doc correctly notes that the jury is still out. That’s often the case, to one degree or another, in clinical research, but at any given time we have to go by the best evidence we have. Is PROWESS so hopelessly flawed that we should throw it out? Nothing in the subsequent analysis or research on this topic suggests that we should. The NEJM Perspective authors acknowledge that the Surviving Sepsis Guidelines are supported by randomized controlled trials but make this astounding statement: “Although such trials represent the gold standard of medical evidence, overreliance on them in the construction of guidelines has a tendency to favor new drugs and devices, which typically undergo at least one such trial in order to obtain government approval.” Overreliance on randomized controlled trials? Do the authors want to turn evidence based medicine upside down?

I should mention the XPRESS study comparing outcomes in patients receiving Xigris with and without heparin in DVT prophylactic doses, showing a mortality rate comparable to the treatment arm of PROWESS. Although presented last January at the Society of Critical Care Medicine meeting the NEJM perspective authors did not mention it. The results indicate that DVT prophylaxis using low molecular weight or unfractionated heparin need not be withheld during treatment with activated protein C.

Most of the critics of drug company marketing, up until now, have complained that doctors are influenced to prescribe counter to the best evidence. The NEJM Perspective authors have taken the novel tack of complaining that a drug company promotes in line with evidence. The drug companies can’t seem to win for loosing!

1 comment:

Daniel Haszard said...

Big pharma should rebuild it's public image.Recent survey shows only about 9% of Americans trust them,this is the same rating as the tobacco companies.

Hey,they have an estimated 90,000 drug reps in the USA promoting to doctors.Enough is enough!
Eli Lilly has a rich humanitarian history,but if you do a blog search of "Eli Lilly and "zyprexa (their blockbuster) keywords you will find much negative blogging.

Some of it is from claimants of their Zyprexa settlement like myself who developed complications and are still awaiting promised resolution.
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Daniel Haszard Bangor Maine