This drug, intended to treat severe sepsis, has been shown in the new PROWESS-SHOCK trial to be no better than placebo in reducing mortality.
In some way, this news is HUGE. On the other hand, it is no big shocker. I can honestly say that as an ID physician and previous fellow-in-training I have not been in a position to recommended its use. My mentors didn’t believe it made any difference. I have not stopped it either when I would come across it in rare circumstances in a patients medication list since it was appropriate by national guidelines.
But as an internal medicine resident in the intensive care unit I would have been amiss to not have considered and initiated it where indicated per guidelines. That PROWESS phase III study (NEJM 2001;344:699-709) was one that we read and re-read, dissected and put back together, as medicine folks are apt to do, only to come to the conclusion du jour that this, Xigris, was the Holy Grail of sepsis treatment. There was no other conclusion, especially when the director of critical care medicine is a founding member of the Surviving Sepsis Campaign. You might as well have quit residency than to admit several septic patients to the intensive care unit overnight, not give them Xigris as indicated, and face the attending the next morning whose guidelines you decided to ignore.
Sepsis is a pretty common illness. It is a potentially life-threatening complication of an infection, whatever that infection may be. In sepsis, the body’s normal response to infection (eg. fever) goes haywire into overdrive setting off a cascade that leads to widespread inflammation and clotting of blood. In severe sepsis, oxygen and nutrients cannot get to various organs as a result of this cascade leading to acute organ dysfunction such as difficulty breathing (lungs), low urine output (kidneys),or confusion and coma (brain). As the cardiovascular system (heart) also begins to fail the patient is said to be in septic shock.
Each year an estimated 750,000 Americans develop sepsis and about 500 die every day. Time is of the essence in diagnosing and treating sepsis as the cascade happens fast. Treatment not only includes antibiotics but also lots of fluids, and often mechanical ventilation (life support) and dialysis. Yet, it is often difficult to recognise sepsis in the early stages and as a result mortality remains high.
Research trials to better understand this entity of sepsis and to improve survival in sepsis are always underway. The PROWESS trial which begun in 1998 was huge for this very reason. It studied a new drug, activated drotrecogin alfa (Xigris) also known as recombinant human activated protein C (rhAPC). Activated protein C is one of the “clot-busters” that the body produces to try to counter-act the cascade response to infection. Previous studies had shown that the majority of patients with sepsis had low levels of it and the theory was if one provided it in the form of medicine patients may be better able to fight sepsis.
So in the PROWESS phase III trial a total of 1690 randomised patients with systemic inflammation and organ failure due to acute infection were treated with either Xigris or placebo (“sugar pill”). The mortality rate was 30.8% in the placebo group compared to 24.7% in the Xigris group. The trial demonstrated a relative risk reduction in mortality among high risk patients by 29%. It was halted early because it met its primary endpoint of a significant reduction in mortality and led to the approval of Xigris globally. This even with its major adverse reaction of increased bleeding (makes sense since it is a “clot-buster”) including intracranial haemorrhage (a form of stroke). This even though it costs about $7000 for the four-day course of treatment.
In the United States, the FDA approved Xigris almost immediately in 2001 for use in adult patients at risk for death from sepsis. Controversy brewed just as immediately as well. Physicians argued that though the data was encouraging it was not enough to make Xigris standard of care in the management of severe sepsis. There were attacks upon the trial itself and upon the FDA approval process. Hospitals balked at the cost. It was a medical battlefield as physicians on the wards were cautious of the medication and slow to prescribe it while Eli-Lilly and the FDA defended themselves against criticism.
Afterall had Xigris not been proven to be a lifesaving advance in medicine? Wouldn’t it be unethical to not give it just because some refuted the study? Yes, Eli-Lilly went as far as funding a task force of bio-ethicists, public relation specialists, and other physicians that concluded that withholding or rationing a life-saving medication ie. Xigris was tantamount to unethical behaviour on the part of bedside physicians and hospitals. From this battlefield arose the Surviving Sepsis Campaign, an international initiative to improve the management, diagnosis, and treatment of sepsis and to provide education that was supported in part (a large part actually) by Eli-Lilly. Their guidelines included the recommendation to consider rhAPC in adult patients with sepsis-induced organ dysfunction with clinical assessment of high risk of death (typically APACHE II ≥25 or multiple organ failure) if there are no contraindications.
So for the past 10 years or so we have used Xigris per national guidelines. Doubt over its efficacy and concern over its risk profile continued. Finally, a state of clinical equipoise in terms of the use of Xigris for sepsis was reached. In 2007, the European version of the FDA, the European Medicines Agency (EMA) called for more robust evidence. Eli-Lilly agreed to conduct a new study to confirm that Xigris’ benefits outweighed its risks. This new study, PROWESS-SHOCK, enrolled 1696 patients and failed to show a statistically significant difference in 28-day-all-cause mortality rate between Xigris and placebo. This was today’s announcement. SHOCKING! Oh what I wouldn’t give to be back in an academic institution for the discussion that will ensue.
Now Xigris is gone but the memories will linger. It offered low rates of success at an extremely high cost but I think it will be most memorable as a lesson in how a drug gets from the lab bench to the bedside and all the many ways things can (and do) go wrong. What bioethical fodder. What fuel for those who believe that pharmaceutical companies are just out to make money through any means necessary including deception.
Amazing story!
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