Recombinant human activated protein C or dotrecogin alfa — better known as Xigris, by Eli Lilly — seemed a godsend when it was first approved for treatment of severe sepsis in 2001. Xigris’ FDA approval (despite an evenly split 10-10 vote) was based solely on the Eli Lilly-funded PROWESS study, a phase 3 randomized trial that was stopped early because Xigris’ results seemed so amazing: an absolute mortality reduction of 6% – an impressive number that implied Xigris could save thousands of lives every year (number needed to treat to save a life of about 17).
However, Xigris’ sales never really took off: only about $100 million per year worldwide, far short of the billion-dollar blockbuster it was forecasted to be. That’s about when Lilly funded the Surviving Sepsis Campaign in order to ensure Xigris’ inclusion in its guidelines, and created a task force on “Values, Ethics and Rationing in Critical Care” to paint Xigris-withholding physicians as unethical, according to perturbed NIH doctors in a 2006 NEJM editorial and press coverage.
Additional trials requested by FDA (1, 2) did not show a benefit of Xigris, either in critically ill severe sepsis patients (the subgroup believed most likely to benefit) or in less-ill patients, and were terminated early for futility. Numerous commentators pointed out irregularities in the original PROWESS design and implementation: patients were only followed for 28 days; the trial was stopped according to Lilly-prespecified endpoints of efficacy, and the protocol was changed during recruitment, after which reduced mortality was observed in the Xigris arm as compared to before the change. Another large trial was “requested” by the European Medicines Agency (like the FDA), and Eli Lilly’s PROWESS-SHOCK was born. On May 31, 2012, results were published in the New England Journal of Medicine.
What They Did
Randomized 1697 patients with septic shock requiring vasopressors and with clinical evidence of hypoperfusion (renal failure, acidosis, etc) to receive either Xigris or placebo. Patients were very sick (APACHE 25, 84% with 3 or more organs failing). Based on a subgroup analysis from the original PROWESS trial, Xigris was believed to be most efficacious in these very ill patients with severe sepsis.
Primary outcome: death at 28 days.
What They Found
Xigris didn’t work:
- Mortality at 28 days: 26% in Xigris group vs. 24% in placebo.
- Mortality at 90 days: 34% in Xigris group vs. 33% in placebo.
More “nonserious” bleeding occurred on Xigris (9% vs. 5%), but major bleeding (1% vs. 1%) was minimal and equivalent between groups.
What It Means
Xigris was removed from the worldwide market in October 2011 after PROWESS-SHOCK’s preliminary results were published, so this is all moot of course. If you’re looking for a souvenir, there may still be some street vendors in Szechuan with a vial or two for sale (not recommended), and of course you can always buy drugs, including “Xigris,” over the Internet from “Canada” (DO NOT DO THIS!!).
The moral of the story is … too complicated for me to even try to sum up here. Doctoral theses in public policy could (and hopefully will) be written about this saga, capturing as it does the complex interdependency of industry, academic institutions, ”thought leader” guideline-writing physicians of the expertocracy, and rank-and-file prescribing physicians forming the true market for a drug. Not to mention the sensitivity of trial findings to study design, a craft at which drug makers’ increasing control, secrecy and sophistication long ago outran most physicians’ ability to critically evaluate trial results.
It is truly interesting that multiple observational studies (1, 2, 3) purporting to control for patient-level differences (with propensity scores and other suchlike statistical black magic) observed benefits of Xigris “similar to PROWESS.”
Clinical Takeaway: For all of us, in a word? Humility. Okay, two words: and skepticism.
Ranieri VM et al (PROWESS SHOCK Study Group). Drotrecogin Alfa (Activated) in Adults with Septic Shock. NEJM 2012;366:2055-2064.