Practical Management of Drotrecogin Alfa (Activated) Therapy in Patients with Severe Sepsis

More than 5,000 critical care intensivists, critical care nurses, critical care pharmacists and pharmacologists, respiratory therapists, and other healthcare professionals gathered at the 31st Critical Care Congress of the Society of Critical Care Medicine, held in San Diego, California, on January 26–30, 2002, to take part in a full complement of basic science and clinical updates designed to appeal to a wide range of critical care clinicians and researchers. One of the topics given major consideration was the problem of severe sepsis, a disorder so complex that a treatment that specifically attacks the syndrome has remained elusive for decades.

Recently, results from a major Phase III clinical trial, the PROWESS (Recombinant Human Activated Protein C Worldwide Evaluation in Severe Sepsis) trial, pointed out that treatment with drotrecogin alfa (activated) (Xigris™, Eli Lilly & Co.) significantly reduces the risk of all-cause mortality in adult patients with severe sepsis, stated Gordon Bernard, M.D., Professor of Medicine and Associate Director of the Division of Allergy, Pulmonary, and Critical Care Medicine at the Vanderbilt University School of Medicine in Nashville, Tennes­see. These findings led to US Food and Drug Administration (FDA) approval of the drug for the reduction of mortality in adult patients with severe sepsis. With this approval comes the serious consid­eration of taking the findings from a closely supervised clinical trial with its strict criteria and translating this data into a practical way to manage patients with severe sepsis using drotrecogin alfa (activated).

Reviewing the PROWESS Trial

“The key to treating severe sepsis today is managing the practical aspects of actually administering drotrecogin alfa (activated) in routine kinds of intensive care unit (ICU) settings that have to be dealt with in everyday practice,” Dr. Gordon pointed out. “Recommendations pre­sented here are based not only on the study outcome vari­ables that have been published, those that have been pre­sented at meetings but are not yet published, and other information that comes from supervising the management of the Phase II and Phase III clinical trials, as well as the compassionate use program and the open-label studies.”

To briefly review, the PROWESS trial was a blinded, placebo-controlled, randomized study in which 1,690 patients with severe sepsis (infection plus three or more signs of systemic inflammation and at least one sepsis-induced organ failure present for not more than 24 hours) were randomly assigned to drotrecogin alfa (activated) as a 96 hour continuous infusion or placebo. The enrollment window was a maximum of 48 hours because the patients had another 24 hours to receive drugs if necessary after they met inclusion criteria. As noted, the infusion was a full 96 hours, unless there was some intervening event that prevented this. If the infusion was discontinued for a period of time, it was restarted so that patients received a total of 96 hours of treatment and then were followed for 28 days. The sites of infection, as in many sepsis trials, were predomi­nantly lung, but 25% were abdominal, along with some other types. Blood cultures were positive about a third of the time, again consistent with other studies.

It should be noted that drotrecogin alfa (activated) is a recombinant form of activated protein C, an anticoagulant that inhibits Factor Va and Factor VIIIa as well as formation of thrombin. It is profibrinolytic, allowing the activity of tissue plasminogen activator to do its job of dissolving existing clots, and it is anti-inflammatory, reducing interl­eukin-6 and other pro-inflammatory cytokines.

The conclusions from the PROWESS trial were that drotrecogin alfa (activated) increased 28-day survival by about 6.1%. This represented a relative risk reduction in the risk of death of 19.4%. Furthermore, treatment with drotrecogin alfa (activat­ed) shortened the duration of cardiovascular and respiratory dysfunction times. The treatment did not increase the duration of intensive care stay and did not increase the duration or intensity of care in the hospital. There may, however, be an associated increase in bleeding risk.

Common Management Considerations

Some common patient management issues that must be dealt with include determining treatment eligi­bility (who actually should receive this treatment and who to exclude), what to think about timing, whether steroids can be used simulta­neously, and what is the role of severity of illness in decisions to treat? At Vanderbilt, a number of general considerations have been arrived at on how to approach this situation. First, to be considered for this treatment, the patient should be in the ICU, with all life support measures being undertaken. Secondly, exclusive of sepsis, is there a reasonable expectation of survival? If the patient is likely to die of the underlying disease, it makes little sense to give additional treatment. Also, is the underlying infection being aggressively treated? Most importantly, is an appropriate physician involved in the treatment decision? While this latter factor may be somewhat controversial, it is important to realize that some level of specialization is needed to understand what severe sepsis is; to recognize it in a timely way; and to know what drotrecogin alfa (activat­ed) is, how to use it, how long to use it, and what its risks and benefits are. This is not the sort of infection where one just prescribes a third-generation cephalosporin for pneumonia.

What Are the Criteria?

With regard to criteria, in the clinical trial, pa­tients had to meet at least three of the serious inclusion criteria to be entered into the trial. While serious criteria are rigid and nice to use in clinical trials because they objectively put numbers around the screening process, from the practical perspective what is really being talked about is disordered temperature regulation, tachycardia, respiratory distress or a need for a ventila­tor, or some alteration in white blood count. For example, in the clinical trial, cardiovascular and respiratory organ failures were part of the screening process. What is really being talked about cardiovascular-wise in a clinical sense is hypotension that is unresponsive to fluids alone. In respiratory failure, what is really being considered clinically is marked respiratory distress, hypoxemia, or a need for mechanical ventilation. This is lung failure, something that gets the attention of critical care specialists.

Is Treatment Timing Critical?

A key question that should be addressed is whether treatment delay eliminates effective­ness. While everyone believes that early mechanical venti­lation, antibiotics, fluid resuscitation and all of those things are better early rather than delayed, in the trial, data for time from organ failure to treatment with drotrecogin alfa (activated) was divided by quartiles (0–11 hours of onset of organ failure, 11–18 hours, 18–22 hours, and greater than 22 hours), and in every category there was an effect with drotrecogin alfa (activated). It would appear, therefore, that the time to initiation of treatment, while it should be as soon as is reasonably possible, is not absolutely critical, distin­guishing it from agents like tPA in the treatment of myocar­dial infarction or stroke, where hours and maybe even minutes make a difference. Overall, patients should be addressed as they are found and, if they look like they could be treated, one should not be too bothered by whether it is one hour or 22 hours from the onset of their organ failure.

Selecting Patients at High Risk of Death

This is a highly controversial issue, resulting in considerable discussion at the advisory committee of the FDA. In the clinical trial, the APACHE-2 scoring system was used, with a score based on 12 physiological variables comprising the Acute Physiological Score, as well as age and previous health status. Scores range from 0 to 71. In the trial, the worst value in 24 hours after ICU admission was the standard APACHE score, with no adjustment for clinical course. This makes the APACHE a moving target, being one number in the first day of the ICU, with another number 12 hours later, and another number 12 hours after that. This works fine in a clinical trial, but if one is a clinician sitting and trying to evaluate a patient, a number that can go up or down in a very short period of time is not of considerable value. So the APACHE score is a very difficult tool to use in this situation.

In the trial, APACHE quartiles consisted of 3–19, 20–24, 25–29, and 30–53. In the lowest quartile, there was a slightly higher survival rate in the placebo-treated patients compared to those on drotrecogin alfa (activated). As the APACHE quartile increased, however, the treatment effect became greater at the more severe end of the spec­trum. As the severity of illness worsened, there was a greater treatment effect seen and this effect was seen in all treated patient groups. Age is another component of APACHE scoring and patients in the older age groups actually had a better response to drotrecogin alfa (activated).

Who Should and Should Not Be Treated?

As to a proposed algorithm or treatment guidelines, patients should be treated who have known or suspected infection, have altered vital signs, have a leukocyte count on the basis of this suspected infection, and have respira­tory or cardiovascular failure on the basis of this particu­lar infection. Patients should be excluded who have signif­icant active bleeding at any site. Recent surgery or trauma where homeostasis is uncertain also should probably be excluded. If, for example, a patient has had hepatic surgery and the surgeon seems very nervous about bleeding, that’s a situation with uncertain homeostasis.

Risk and benefit must be weighed in these patients. If the patient looks like he or she could benefit from drotrec­ogin alfa (activated), a GI bleed last week should not stop them from getting the treatment. On the other hand, because there is so little data on patients with closed head injury, intracranial and spinal surgery, or stroke within the past two months, these people should not be treated. Also, patients should be avoided who have had bone marrow trans­plantation or other aggressive chemotherapy, where their bone marrow has been wiped out, or who are not responding to platelet transfusions. In patients who have thrombocytope­nia due to sepsis and the platelet transfusion sort of sticks, drotrecogin alfa (activated) treatment is a viable o­ption. Other uncertain options include cirrhosis with portal hypertension, known bleeding disorders like hemophil­ia, and pregnancy. These are uncertain because they have never been studied. On the other hand, individuals who exhibit a number of conditions excluded from the trial, such as those patients under 18 years of age, patients over 135 kilograms, patients on chronic hemodialysis, lactating women, and patients who have under­gone bone marrow or solid organ transplants and recovered, would probably benefit the same as every­one else, provided their bleeding risks are taken into consider­ation.

Final Remarks

“In conclusion, clinical use should generally follow the inclusion criteria used in the PROWESS trial,” Dr. Bernard declared. “I’ve operationalized those of the exclusion criteria for everyday clinical use. I think you should be treating as early as possible, but delayed treatment is still effective and, if it takes a few hours to figure out whether somebody has a bleeding risk or not, like getting a CT scan, that might be worth doing if the patient has a higher risk of having a lesion there. Concomitant steroid use certainly seems to appear acceptable and, lastly, I think optimal use depends on dedicated physi­cians experienced in dealing with patients with severe sepsis. A lot of people out there will be faced with these problems that don’t have such experience with regard to either sepsis or drotrecogin alfa (activated).”

This article was written by Larry M. Prescott, PhD, (May 15, 2002) a frequent contributor to D&MD Newsletter.

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