DENVER—In severe sepsis, coagulation abnormalities often develop following endothelial damage or organ dysfunction. Tissue factor pathway inhibitor (TFPI) is an endogenous anticoagulant secreted by endothelial cells. Three phase II trials investigating a recombinant form of TFPI, tifacogin, found it safe and effective in patients with severe sepsis. Recently, a large phase III trial suggested that tifacogin reduced mortality during the first nine months of study enrollment; however, this trend was reversed in the last seven months of the study in favor of the placebo.[1]

OPTIMIST

The Optimized Phase III Tifacogin in Multicenter International Sepsis Trial (OPTIMIST) was a randomized, double-blind, placebo-controlled trial study by Chiron and Pharmacia conducted at 245 centers in 17 countries. The trial had two stages: In the first stage, patients with severe sepsis and an international normalized ratio (INR) of 1.2 or greater were recruited between March 21, 2000, and September 27, 2001. Stage II, which ran from January 19, 2001, to September 27, 2001, continued recruitment of high-INR patients but also recruited patients having an INR below 1.2. All patients had severe sepsis with at least two signs of organ dysfunction and/or hypoperfusion.

A total of 1,955 patients were included (1,754 with high INRs, 201 with low INRs). Patients were randomly assigned to receive either 0.025 mg/kg/h of intravenous tifacogin for 96 hours or an equivalent volume of placebo infused for the same period. Blood samples for measuring TFPI concentrations were collected before infusion, twice on day 1, once on days 2 and 3, and at the end of dosing. The primary efficacy end point was death from any cause within 28 days of initiation of tifacogin in the high-INR group. The safety of tifacogin was evaluated in both the high-INR and low-INR groups.

REVERSAL OF TREATMENT BENEFIT

In the treatment group, mean concentrations of TFPI quickly increased to approximately twice the endogenous circulating TFPI levels of the placebo group. Increases in TFPI were the same in both INR groups and were maintained throughout the treatment period.

In patients with high INRs, there was no significant difference in 28-day all-cause mortality between the treatment (n = 880) and placebo (n = 874) groups (34.2% vs 33.9%, respectively). There was a trend toward improvement in the tifacogin group during the first nine months of enrollment, but this changed in favor of placebo for the last seven months.

Two hundred one patients with low INRs were randomized in stage II—118 received placebo and 83 received tifacogin. The 28-day mortality rate was 12% in the tifacogin group compared with 22.9% in the placebo group. After the research team adjusted for treatment, baseline APACHE II score, and log10 interleukin 6, a significant treatment benefit remained. However, because the patients with low INRs had been enrolled in the study only as part of the safety analysis, the clinical significance of this finding remains unclear.

Edward Abraham, MD, lead author of the study and Head of the Division of Pulmonary Sciences and Critical Care Medicine at the University of Colorado Health Sciences Center in Denver, observed that there is no specific reason why tifacogin had no effect in high-INR patients during the second part of the study. “We have previously seen negative phase III results after encouraging phase II clinical trials,” said Dr. Abraham. “It is always disappointing, but not necessarily surprising.”

In an accompanying editorial, Derek C. Angus, MD, MPH, and Mark A. Crowther, MD, MSc, examined the study’s results and concluded that “In the absence of a clear explanation for the change in the pattern of mortality, [it] appears to be due to the play of chance, as unlikely as this might seem.”[2]

HEPARIN EFFECT?

One factor that might have affected the study results was the administration of other anticoagulants, and thus the researchers compared mortality in the high- and low-INR groups according to heparin use. Among the patients in the high-INR group, mortality in the tifacogin recipients was about 34%, regardless of whether heparin was given. In the placebo cohort, however, mortality was 42.7% if heparin was given and 29.8% if it was not. The tifacogin recipients with low INRs also had a similar mortality, regardless of whether heparin was (12.3%) or was not (11.1%) given. In the placebo cohort, mortality was 19.8% when heparin was administered and 29.7% when it was not.

Interpretation of these findings is hampered by the fact that the patients who received heparin were not as severely ill as the patients not given heparin. In the high-INR group, the incidence of adverse events was similar in both the placebo and treatment groups, with 51% experiencing at least one serious adverse event. In the low-INR group, 36% of the tifacogin recipients and 43% of the placebo cohort experienced one or more serious adverse events.

Throughout the enrollment period there were no measurable changes in degree of disease severity among patients nor were there any changes in care that would have affected patient outcome. “Patients with severe sepsis are a very difficult and heterogeneous population,” explained Dr. Abraham, who is also the Roger Sherman Mitchell Professor of Pulmonary and Critical Care Medicine at the University of Colorado Health Sciences Center. He acknowledged that the use of heparin may have been a confounding factor but added that “since it was not prospectively controlled for, its effects are unknown.”

Three endogenous anticoagulants—antithrombin III, activated protein C, and TFPI—have been studied in severe sepsis. Of these, said Dr. Abraham, only activated protein C has been shown to reduce death rates in severely ill sepsis patients.

According to editorialists Drs. Angus and Crowther, there is still a strong rationale for the use of anticoagulants in patients with sepsis. “Heparin, the most widely available, least expensive, and most easily used anticoagulant, has not been rigorously tested for the treatment of sepsis,” they commented.

Dr. Abraham agreed, saying, “There are suggestive data from several studies indicating that heparin may be beneficial in sepsis. I would very much like to see a large study examine this issue.”

—Gale Jurasek

References
1. Abraham E, Reinhart K, Opal S, et al. Efficacy and safety of tifacogin (recombinant tissue factor pathway inhibitor) in severe sepsis: a randomized controlled trial. JAMA. 2003;290:238-247.
2. Angus DC, Crowther MA. Unraveling severe sepsis: why did OPTIMIST fail and what’s next? JAMA. 2003;290:256-258.

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