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Published ahead of print on June 7, 2007, doi:10.1164/rccm.200612-1803OC
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American Journal of Respiratory and Critical Care Medicine Vol 176. pp. 483-490, (2007)
© 2007 American Thoracic Society
doi: 10.1164/rccm.200612-1803OC

Original Article

Prophylactic Heparin in Patients with Severe Sepsis Treated with Drotrecogin Alfa (Activated)

Marcel Levi1, Mitchell Levy2, Mark D. Williams3, Ivor Douglas4, Antonio Artigas5, Massimo Antonelli6, Duncan Wyncoll7, Jonathan Janes3, Frank V. Booth3, Dazhe Wang3, David P. Sundin3, William L. Macias3 and for the Xigris and Prophylactic HepaRin Evaluation in Severe Sepsis (XPRESS) Study Group*

1 Departments of Vascular Medicine and Internal Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands; 2 Rhode Island Hospital and Brown University Medical School, Providence, Rhode Island; 3 Lilly Research Laboratories, Eli Lilly, Indianapolis, Indiana; 4 Division of Pulmonary Sciences and Critical Care Medicine, Denver Health and University of Colorado Health Sciences Center, Denver, Colorado; 5 Critical Care Center, Sabadell Hospital, Red GIRA G03/063, University Institute Parc Tauli, Autonomous University of Barcelona, Sabadell, Spain; 6 Policlinico Universitario A. Gemelli Università Cattolica del Sacro Cuore, Rome, Italy; and 7 Guy's and St. Thomas' National Health Service Foundation Trust, London, United Kingdom

Correspondence and requests for reprints should be addressed to Marcel Levi, M.D., Chairman, Department of Medicine Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands. E-mail: m.m.levi{at}amc.uva.nl


   ABSTRACT
TOP
 ABSTRACT
AT A GLANCE COMMENTARY
 METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Rationale: Patients with severe sepsis frequently receive prophylactic heparin during drotrecogin alfa (activated) (DrotAA) treatment due to risk of venous thromboembolic events (VTEs). Biological plausibility exists for heparin to reduce DrotAA efficacy and/or increase bleeding.

Objectives: Primary: demonstrate in adult patients with severe sepsis receiving DrotAA treatment that 28-day mortality was equivalent for patients treated with concomitant prophylactic heparin compared with placebo; secondary: safety and VTE incidence.

Methods: International, randomized, double-blind, phase 4, equivalence-design trial (n = 1994). Patients were eligible if indicated for and receiving DrotAA treatment under the country's approved label. Study drug (low molecular weight/unfractionated heparin) or placebo (saline) was administered every 12 hours during DrotAA infusion (24 ug/kg/hr for 96 hr). In patients on baseline heparin and randomized to placebo, heparin was stopped.

Measurements and Main Results: Twenty-eight–day mortality was not equivalent between treatment groups. Heparin mortality was numerically lower (28.3 vs. 31.9%; p = 0.08). In the prospectively defined subgroup of patients exposed to heparin at baseline, patients receiving placebo experienced higher mortality (35.6 vs. 26.9%; p = 0.005). For safety, significant differences were observed during Days 0–6 for any bleeding event (placebo, n = 78; heparin, n = 105; p = 0.049) and ischemic stroke during Days 0–6 (placebo, n = 12; heparin, n = 3; p = 0.02) and Days 0–28 (placebo, n = 17; heparin, n = 5; p = 0.009). The VTE rate was low, with no statistical difference between groups (0–6 d, p = 0.60; 0–28 d, p = 0.26).

Conclusions: Compared with placebo, concomitant prophylactic heparin was not equivalent, did not increase 28-day mortality, and had an acceptable safety profile in patients with severe sepsis receiving DrotAA. Heparin discontinuation should be carefully weighed in patients considered for DrotAA treatment.

XPRESS clinical trial registered with www.clinicaltrials.gov (NCT 00049777). The study ID numbers are 6743; F1K-MC-EVBR.

Key Words: critical care • recombinant human activated protein C • XPRESS • clinical trial



   AT A GLANCE COMMENTARY
TOP
 ABSTRACT
 AT A GLANCE COMMENTARY
METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Scientific Knowledge on the Subject
The efficacy and safety of heparin in patients with severe sepsis who are treated with recombinant human activated protein C (rh-APC) is not known.

What This Study Adds to the Field
Heparin has an acceptable safety profile during treatment with rh-APC and showed a trend toward a lower 28-day mortality compared with placebo, which was mainly caused by an adverse outcome in patients who stopped heparin during treatment with rh-APC.

 
Despite recent therapeutic advances for severe sepsis (1), the attributable mortality remains high (2–5). Drotrecogin alfa (activated) (DrotAA), a recombinant form of activated protein C (APC) has demonstrated efficacy in reducing sepsis-related mortality and morbidity, and is approved for use in patients with severe sepsis at high risk of death (6).

Sepsis is associated with systemic activation of coagulation and frequently results in disseminated intravascular coagulation (DIC) (7). Patients with severe sepsis are at high risk of venous thromboembolic events (VTEs) due to one or more risk factors, including advanced age, chronic cardiopulmonary disease, recent surgery, immobilization, in-dwelling vascular catheters, and previous VTE history (8). Indeed, VTE prophylaxis using unfractionated heparin (UFH), low molecular weight heparin (LMWH), and/or mechanical methods has become standard of care in most institutions (9). Despite modest prophylactic efficacy (10), it has been suggested that heparins may have direct therapeutic effects in severe sepsis and DIC, independent of their role in thromboprophylaxis (11–19).

Coadministration of some form of prophylactic heparin during DrotAA treatment is common. Exploratory, post hoc, nonrandomized analyses of a previous trial, the Recombinant Human APC Worldwide Evaluation in Severe Sepsis (PROWESS) trial, identified coadministration in 75% of the patients, with little or no evidence of increased bleeding risk (20, 21). However, DrotAA also has known antithrombotic and profibrinolytic properties (6), and might provide adequate VTE prophylaxis itself, potentially eliminating the need for prophylactic heparin.

Secondary analyses from the PROWESS study suggested higher 28-day mortality in DrotAA patients receiving baseline usual-care prophylactic heparin than if they were not (21). In addition, previous in vitro studies have indicated that high doses of heparin may increase the rate of inhibition of APC by protein C inhibitor (22–24), a plasma protease inhibitor, which could lead to increased clearance of DrotAA. Stimulated by these post hoc observations and as a condition of U.S. Food and Drug Administration approval, the Xigris and Prophylactic HepaRin Evaluation in Severe Sepsis (XPRESS) trial was designed to evaluate whether heparin interfered with the efficacy of DrotAA in adult patients with severe sepsis at a high risk of death.

The primary objective was to demonstrate that, in adult patients with severe sepsis receiving DrotAA treatment, concomitant treatment with prophylactic heparin was equivalent to treatment with placebo, as determined by 28-day all-cause mortality. Secondary objectives included safety and the incidence of VTE.


   METHODS
TOP
 ABSTRACT
 AT A GLANCE COMMENTARY
 METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
XPRESS was designed and conducted according to applicable laws and regulations, good clinical practices, and ethical principles originating in the Declaration of Helsinki and codified in the International Conference on Harmonization. All institutional/ethical review boards approved the study protocol and informed consent documents before the XPRESS trial was initiated at any site.

Study Design
XPRESS was an international, multicenter, randomized, double-blind, parallel, placebo-controlled, phase 4, equivalence-designed trial (see Figure E1 in Appendix 2 of the online supplement).

Patient Inclusion/Exclusion Criteria
Enrollment criteria were consistent with the U.S. Food and Drug Administration–approved package insert for DrotAA (see Appendix E3 for details). Enrollment criteria are briefly described in the following sections.

Inclusion criteria

  1. Aged 18 years or older
  2. Receiving inpatient treatment for severe sepsis
  3. Indicated for DrotAA treatment under an approved label in the country in which the patient enrolled, defined as one or both of the following: multiple organ dysfunction (MOD) (European Union label) or patients at higher risk of death (e.g., as defined by Acute Physiology Age and Chronic Health Evaluation [APACHE] II scores >= 25; U.S. label)

Exclusion criteria

  1. Contraindicated for treatment with prophylactic LMWH or UFH
  2. Required a higher dose of heparin than specified in protocol or concurrent need for other anticoagulant medication
  3. Acute or chronic renal failure with estimated creatinine clearance less than 30 ml/minute
  4. Moribund or not expected to survive 28 days
  5. Patient or family not committed to aggressive management of severe sepsis

Patient Evaluations
All randomly assigned patients who received study drug (heparin or placebo) for any length of time were followed to 28 days and were included in the intention-to-treat (ITT) 28-day mortality and safety evaluations. Baseline characteristics were assessed and APACHE II scores (25) were calculated from the most deviant variables assessed in the 24-hour period before randomization. A lower-extremity bilateral compression ultrasound was performed for the presence or absence of deep vein thrombosis (DVT) at the end of study drug infusion (i.e., Study Days 4–6). Patients experiencing an objectively confirmed symptomatic DVT before Study Day 4 did not have this procedure performed.

Interventions
All patients received DrotAA (Xigris; Eli Lilly & Co., Indianapolis, IN) at 24 µg/kg per hour for 96 hours, according to local hospital guidelines.

Study drug was either UFH (5,000 U subcutaneously twice per day), LMWH (enoxaparin, 40 mg subcutaneously once per day), or placebo (0.9% sodium chloride), administered using a 1:1:2 randomization scheme (see Figure 1).


Figure 1
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  		Figure 1. Patient disposition: 1,994 patients were enrolled, of which 1,961 received drotrecogin alfa (activated) (DrotAA); 1,935 patients received study drug (heparin or placebo); 1,927 patients completed the protocol.

 
Study drug was administered by subcutaneous injection every 12 hours during the planned 96-hour infusion of DrotAA. Patients randomized to receive LMWH had placebo for their second daily injection to maintain blinding. The first study drug injection was given as soon as possible after starting DrotAA infusion, but no more than 12 hours later. If DrotAA infusion continued beyond Day 4 because of interruptions, study drug injections were continued every 12 hours until the infusion was completed. If the 12-hour time point for study drug administration occurred within 2 hours after completion of DrotAA infusion, the final study drug injection was administered then. All other patient care was at the discretion of the investigator, including use of commercial heparin (commercial heparin use during Days 0–6 refers to use in the 1–2 d after DrotAA and study drug administration). There were no statistically significant differences in use of commercial heparin between treatment arms (data not shown). Patients, investigators, and all other study personnel remained blinded to treatment assignments for the duration of the study.

Efficacy
The primary analysis was performed on the randomly assigned ITT population. The objective was to compare the 28-day all-cause mortality rates observed between the placebo and combined heparin groups. Patients with unknown mortality status at the 28-day time point were excluded. The primary cause of death was determined by the investigator's opinion and was not defined by blinded experts.

Safety
The safety profile was assessed from (1) serious adverse events, including serious bleeding events; (2) nonserious bleeding events that occurred during the infusion period (Study Days 0–6) that led to or contributed to the need for transfusion of packed red blood cells; (3) study drug–related nonserious adverse events; (4) adverse events that led to permanent discontinuation of the study drug infusion; (5) VTE, defined as objectively confirmed nonfatal or fatal pulmonary embolism (PE), asymptomatic lower-extremity DVT, detected by bilateral compression ultrasonography performed at the end of study drug administration (Study Days 4–6), symptomatic lower extremity DVT confirmed by objective means (ultrasound or other accepted diagnostic modalities), and symptomatic central vein thrombosis, confirmed by objective means (see above); (6) heparin-induced thrombocytopenia; and (7) ischemic stroke.

Definitions of Serious and Nonserious Bleeding Events
Serious bleeding events
Fatal bleeding (overt bleeds considered the primary cause of death) and/or nonfatal serious bleeding (defined as intracranial hemorrhage confirmed by brain imaging or autopsy or bleeding at a critical location [e.g., retinal hemorrhage, major hemarthrosis, or spinal hemorrhage]), and/or an otherwise life-threatening bleed that did not meet other criteria.

Nonserious bleeding events
Bleeding events reported as nonserious adverse events that occurred during infusion (Days 0–6) and led or contributed to the need for transfusion of packed red blood cells.

Statistical Analyses and Sample Size Calculation
All analyses were performed on the ITT population. The ITT population was defined as and included all randomly assigned patients who received any amount of study drug for any length of time. Patients lost to follow up were not included in efficacy analyses. Statements of statistical significance were based on a two-tailed test with an {alpha} level of 0.05 unless otherwise stated. Continuous variables were analyzed using ranked analysis of variance for between-treatment comparisons. Categorical variables and treatment groups were compared using the chi-square test. Breslow-Day tests for homogeneity of odds ratios across strata were performed. For subgroups with significant Breslow-Day p values, baseline imbalances between treatment groups were assessed. Twenty-eight–day all-cause mortality was compared between treatment groups using a log-rank test. Baseline characteristics of ITT patients were summarized for the combined and individual heparin groups and the placebo group. Two-sided p values from chi-square and ranked analysis of variance tests were used to summarize the comparability of treatment groups with respect to these factors. However, significance testing for baseline imbalance was not the purpose of these analyses.

The study was designed as an equivalence study to show that concomitant prophylactic heparin administration was equivalent to placebo in patients with severe sepsis receiving DrotAA. The projected XPRESS sample size was 2,000 patients (LMWH, ~ 500 patients; UFH, ~ 500 patients; placebo, ~ 1,000 patients). A relative risk equivalence boundary from 0.8 to 1.2 was used. The equivalence margin was set at ±6.2%, based on a predicted 28-day all-cause mortality rate of 31% for both treatment groups (data from PROWESS DrotAA patients with baseline APACHE II scores >=25). Power calculations were based on a two-sided 90% confidence intervals approach for differences in proportions using nQuery Advisor (Statistical Solutions, Saugas, MA). The projected 2,000-patient sample size yielded 85% power to demonstrate equivalence between the combined heparin and placebo treatment groups. Assuming no difference in mortality between treatment groups, there was an 85% chance that the 90% two-sided confidence limits for the observed difference would fall entirely within ±6.2%. Using these assumptions, it was estimated that the observed absolute risk difference between the two groups needed to be less than 2.8% to conclude equivalence.

Similar analyses were performed for VTEs occurring over the first 6 days and the entire 28-day study period. Given recent studies estimating VTE rates of 5–25% in patients in the intensive care unit (ICU) (8, 26–30), a predicted rate of VTE was projected to be 12% for XPRESS. The equivalence margin for this endpoint was set at ±2.5%. Because the power to establish equivalence between heparin and placebo was expected to be small, overall conclusions were also based on individual case reviews.


   RESULTS
TOP
 ABSTRACT
 AT A GLANCE COMMENTARY
 METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
The XPRESS trial was conducted from December 2002 to August 2005 at 224 sites in 20 countries. Patient disposition is displayed in Figure 1. The Data Monitoring Committee recommended continuation at each of two interim analyses (conducted after ~ 670 and ~ 1,340 patients were enrolled). A total of 2,002 patients were enrolled; however, 8 were removed from the reporting database due to informed consent issues. Of the 1,994 patients who met criteria, provided appropriate informed consent, and were enrolled (included in reporting database), study drug (i.e., heparin or placebo) was received by 1,935 patients (defined as the ITT population). Of the 59 patients not receiving study drug, 35 died before receiving study drug; 10 had a surgical procedure and deteriorated or eventually met an exclusion criteria; 4 improved to the point where inclusion criteria were no longer met; 3 were excluded due to physician decision; 3 received wrong, expired, or prohibited study drug; 1 was excluded due to family decision; 1 was excluded due to a positive antiheparin antibody test; 1 was excluded due to a positive pregnancy test; and 1 was excluded due to unknown cause. A total of 8 patients had unknown 28-day survival status and were not included in efficacy analyses.

Patient Characteristics
Table 1 displays baseline characteristics of each treatment group. In general, the combined heparin and placebo treatment groups were well balanced. Lung was the most common site of infection in both groups (heparin, 50.0%; placebo, 50.8%; see Table E1 in the online supplement) and approximately one-half of patients in both groups (heparin, 48.3%; placebo, 50.2%) had not been exposed to any anticoagulant (LMWH and UFH, vitamin K antagonist, or any antiplatelet agent) at baseline.


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  		TABLE 1. XPRESS BASELINE CHARACTERISTICS

 
Efficacy
All patients received essentially the same total duration of DrotAA therapy (DrotAA + heparin, 84.5 h; DrotAA + placebo, 84.8 h). In the prospectively defined primary analysis (Figure 2A), the combined heparin and placebo groups were not equivalent for 28-day mortality (90% absolute risk difference confidence interval not within the 6.2% equivalence margin). An absolute 3.6%-lower 28-day mortality was observed in the heparin group compared with placebo (28.3 vs. 31.9%, respectively), but this was not statistically significant (p|=|0.08). Similar outcomes were observed in the individual heparin treatment groups, and equivalence was not concluded in either the analysis of LMWH or UFH versus placebo. Kaplan-Meier survival curves are illustrated in Figure 3.


Figure 2
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  		Figure 2. XPRESS (Xigris and Prophylactic HepaRin Evaluation in Severe Sepsis) equivalence (28-d mortality) and heparin subgroup (absolute risk reduction) analyses. (A) Twenty-eight–day mortality equivalence analysis. The 90% absolute risk difference confidence intervals of all three heparin groups lie outside the ±6.2% equivalence margin, so are not equivalent to placebo. (B) There was a significant treatment-by-subgroup interaction in the prospectively defined subgroup of patients exposed to heparin at baseline (Breslow-Day, p = 0.03). Patients on usual-care heparin at baseline, who were randomized to placebo, had higher mortality than those randomized to heparin. Patients not on usual-care heparin at baseline, who were randomized to placebo, had similar mortality. AD = absolute difference; DrotAA = drotrecogin alfa (activated); LMWH = low molecular weight heparin; UFH = unfractionated heparin.

 

Figure 3
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  		Figure 3. XPRESS (Xigris and Prophylactic HepaRin Evaluation in Severe Sepsis) Kaplan-Meier survival curves: combined and individual low molecular weight and unfractionated heparin (LMWH and UFH, respectively). (A) Kaplan-Meier survival curves for the combined heparin and placebo groups. Although the combined heparin group had increased survival compared with placebo, the difference was not statistically significant (log-rank p = 0.09). There was overlap of both curves through Study Day 5. The curves separate at Study Day 5 and remain separate through Study Day 28. Heparin = low molecular weight heparin or unfractionated heparin. (B). Kaplan-Meier survival curves for the LMWH, UFH, and placebo groups. There was no difference in survival between the three treatment groups (log rank p = 0.20). There was overlap of the three curves through Study Day 6. The LMWH and UFH curves separate from the placebo curve at Study Day 6, but never separate from each other over the 28-day study period. DrotAA = drotrecogin alfa (activated).

 
In the secondary analyses of VTE incidence, the heparin and placebo groups were equivalent during Study Days 0–6, but were not equivalent during Study Days 0–28. The use of prophylactic heparin or mechanical methods between Study Days 7 and 28 was very similar in both groups. The rate of VTE was low, and no statistical difference was noted between the two groups during Study Days 0–6 and 0–28 (p = 0.60 and p = 0.26, respectively; Table 2). During both time periods, asymptomatic (confirmed by bilateral compression ultrasound) and symptomatic lower-extremity DVT were clearly the most common VTEs. PE and symptomatic central venous thrombosis were relatively infrequent events. The incidence of ischemic stroke was significantly greater in the placebo group during Study Days 0–6 (p = 0.02) and 0–28 (p = 0.009).


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  		TABLE 2. XPRESS SAFETY ANALYSES

 
Subgroups
An important treatment-by-subgroup interaction was noted in the prospectively defined subgroup of patients exposed to heparin at baseline (Breslow-Day, p = 0.03; Figure 2B). Patients receiving heparin and those receiving placebo not exposed to heparin at baseline had similar mortality, whereas patients receiving placebo exposed to heparin at baseline had higher mortality than patients receiving heparin. In patients receiving baseline heparin who were subsequently randomized to receive study drug (i.e., heparin or placebo), it was determined that these patients were evenly matched by age, disease severity (APACHE II, number of organ failures, etc.) and comorbidities. Multiple subgroup analyses of 28-day mortality for patients not exposed to heparin at baseline showed no consistent benefit of heparin coadministered with DrotAA (data not shown). No significant difference was noted in the cause of death between the two treatment groups, although a greater percentage of patients receiving placebo died of non–sepsis-related causes compared with patients receiving heparin (19.4 and 12.2%, respectively). A greater number of patients receiving placebo died of cardiac events (11 vs. 4), cerebral events (5 vs. 2), bleeding events (5 vs. 2), and respiratory events (4 vs. 1) compared with patients receiving heparin.

There were no significant treatment-by-subgroup interactions in the APACHE II subgroups (< 25, >= 25) for efficacy (28-d mortality and VTE; data not shown), which suggested that efficacy signals were comparable. Results for the organ dysfunction subgroups (<=1 and >= 2) were somewhat different. Although sample sizes for the "<= 1 organ dysfunction" group were small (n = 76) compared with the ">= 2 organ dysfunction" group (n >= 876), for 28-day mortality, there was a significant treatment-by-subgroup interaction (Breslow-Day, p < 0.05; relative risk [RR] [95% confidence intervals (CI)], <=1, 0.45 [0.23–0.89]; >=2, 0.92 [0.80–1.06]), which suggested that patients with <=1 organ dysfunction may have received more benefit. Finally, there were no significant treatment-by-subgroup interactions for VTE in the <=1 and >=2 organ dysfunction subgroups.

Safety
Except for "any-bleeding-event" during Study Days 0–6 (p = 0.049) and ischemic stoke during Study Days 0–6 and 0–28 (p <= 0.02 for both), no statistically significant differences were observed between patients receiving heparin and those patients receiving placebo in the occurrence of serious adverse events, serious bleeding events, central nervous system bleeding events, fatal bleeds, VTE, and heparin-induced thrombocytopenia (HIT) during Study Days 0–6 and 0–28 (Table 2). More serious adverse events and fatal bleeding events occurred during Study Days 0–28 in the placebo versus heparin group, but the differences were not statistically significant. Patients already receiving baseline usual-care heparin who were subsequently randomized to placebo were particularly at risk for serious adverse events (Days 0–28: heparin, 11.6% vs. placebo, 18.0%; p = 0.06). The increased events included more cardiac, gastrointestinal, and thrombotic events. Finally, a statistically significant greater percentage of patients receiving heparin experienced a study drug–related, nonserious adverse event during Days 0–6 (10.0 vs. 7.2%; p = 0.03).

Subgroups
For safety, there were no significant treatment-by-subgroup interactions in the APACHE II subgroups (< 25 and >= 25). However, for the organ dysfunction subgroups (<=1 and >= 2), there was a significant treatment-by-subgroup interaction during infusion (0–6 d Breslow-Day, 0.01; RR [95% CI]: <=1, 0.10 [0.01–0.76]; >= 2, 0.87 [0.61–1.24]) and a strong trend during the 28-day time period (0–28 d Breslow-Day, < 0.06; RR [95% CI]: <= 1, 0.31 [0.11–0.90]; >= 2, 0.85 [0.67–1.08]).


   DISCUSSION
TOP
 ABSTRACT
 AT A GLANCE COMMENTARY
 METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
Results of the XPRESS trial indicate that there is no harmful interaction between DrotAA and heparin. Coadministration of heparin was not equivalent to coadministration of placebo in patients with severe sepsis receiving DrotAA. Indeed, in contrast to initial concerns from post hoc analyses of previous studies, heparin coadministration was associated with a nonsignificant reduction in 28-day mortality in patients randomized to treatment with heparin. In general, these data suggest that it would be inappropriate to forgo concomitant heparin prophylaxis in patients with severe sepsis receiving treatment with DrotAA.

It is important to note that rejection of equivalence does not necessarily demonstrate superiority of heparin over placebo. Rather, the data reject the original biologically plausible concern that heparin and DrotAA coadministration could reduce the efficacy of DrotAA. The important subgroup analysis of patients not receiving heparin before randomization (i.e., heparin naive) failed to show any significant benefit of heparin coadministration either for survival or VTE prophylaxis. Because all patients received DrotAA, no conclusions can be made regarding the efficacy of DrotAA; however, one can conclude that there was no negative interaction on mortality in patients treated with DrotAA and heparin. Of interest, no significant treatment-by-subgroup interaction was observed for efficacy in the APACHE II score < 25 or >= 25 subgroups, which suggests that results were comparable between these groups. Also, in the <= 1 and >= 2 organ dysfunction subgroups, there was a significant treatment-by-subgroup interaction, which suggests that the lower disease severity subgroup received greater benefit.

However, the subgroup of patients receiving usual-care heparin at baseline is particularly notable. In this subgroup, there was significantly higher mortality in patients randomized to receive placebo (i.e., heparin stopped). Based on this analysis, early discontinuation of prophylactic heparin may be harmful in patients with severe sepsis receiving DrotAA. Although no clear mechanism has been characterized, previous studies in patients with acute coronary syndromes have shown that abrupt termination of heparin leads to rebound thrombin generation, which is associated with thrombotic events (31–33). Similarly, in the XPRESS trial, there were more adverse events leading to death in patients who were on usual-care heparin at baseline and then subsequently randomized to placebo. Because markers of thrombin generation were not measured, it was not possible to confirm this hypothesis.

The XPRESS trial demonstrated a significant reduction (> threefold) in the incidence of ischemic stroke in patients receiving concomitant DrotAA plus heparin versus placebo. This may be an especially relevant finding, because ischemic stroke may contribute to death or sustained disability in patients with severe sepsis. Although the precise incidence of ischemic stroke in patients with severe sepsis remains unknown, many patients with severe infection suffer from acute arterial events, such as ischemic stroke and coronary events. However, any potential efficacy conclusion based on adverse event profiles should be made with caution pending further study.

We systematically studied all patients with ultrasound for the presence of VTE between Study Days 4 and 6. The observed incidence of VTE was relatively low (~ 5%) and not different between the heparin and placebo groups. Previous observational studies in mixed ICU populations with and without heparin prophylaxis documented higher incidence of VTE (26, 34, 35). Although there are no data to support the use of DrotAA for VTE prevention, the lower incidence of venous thrombosis in our study may be related to the anticoagulant effect of DrotAA. Direct comparison with previous studies is limited by the single VTE assessment between Study Days 4 and 6 in this study and the presence of multiple exclusion criteria. Previous reports were based on sequential ultrasound examinations throughout the entire ICU stay and had relatively few exclusion criteria. A baseline ultrasound assessment would have been useful in XPRESS. However, it was believed that the procedure would have made execution of the study more complex and, thus, was not included. This is a limitation of the XPRESS trial, and may cloud interpretation of the true incidence of VTE. Additionally, the XPRESS trial was limited to patients with severe sepsis, whereas previous studies included postoperative patients or patients with severe trauma at high risk of venous thrombosis.

Small, uncontrolled, nonrandomized studies of heparin as a treatment for sepsis, especially in the presence of DIC, have suggested that heparin may be beneficial in controlling systemic activation of coagulation, but randomized, controlled trials with clinically relevant outcomes are lacking (11–19). Indeed, there are no adequate studies comparing heparin to DrotAA plus heparin, and any potential future trials would need to be closely monitored. The XPRESS study is the first randomized controlled trial of heparin versus placebo in patients with severe sepsis, albeit with DrotAA treatment in all patients. The numeric reduction of 28-day mortality in favor of heparin is interesting but not definitive evidence that heparin may modulate the pathogenesis and clinical course of severe sepsis. Indeed, the difference in mortality appeared to be driven by a higher mortality in patients who were on baseline heparin and subsequently randomized to placebo. Additional analyses focusing on subgroups of patients with severe sepsis complicated by DIC and future prospective studies may further characterize any potential benefit of administering heparin in severe sepsis. A potential supplemental trial of interest would be to directly demonstrate whether there is harm in abruptly stopping heparin in this fragile population.

DrotAA has anticoagulant properties, and the combination with heparin may increase the risk of bleeding. Indeed, in the XPRESS trial, the risk of any bleeding event increased from 8.1% in the placebo group to 10.8% in the heparin group during the initial study period (0–6 d). However, the risk of a serious, central nervous system, or fatal bleeding event was not different during either time period. Of clinical interest, there was a trend (p = 0.06) for more fatal bleeding in the placebo group during the 28-day period. It is reassuring that, with coadministration of heparin and DrotAA, the risk of bleeding requiring more than limited blood transfusions or associated with major complications was relatively low and consistent with previous randomized studies with DrotAA (6, 34).

In safety subgroup analyses, there was no treatment-by-subgroup interactions for the APACHE II subgroups (< 25 and >= 25), which suggests that the safety signals were comparable between these groups. In the organ dysfunction subgroups (<= 1 and >= 2), there was a significant treatment-by-subgroup interaction during the infusion period (0–6 d) and a strong trend (p < 0.06) during the 0- to 28-day period. This interaction suggests that the risk of bleeding was actually smaller for the <= 1 organ dysfunction group. These data again suggest that coadministration of DrotAA and heparin has an acceptable safety profile.

In conclusion, results of the XPRESS study indicate that concomitant prophylactic heparin does not cause an increase in 28-day mortality and has an acceptable safety profile in patients with severe sepsis receiving DrotAA treatment. There was a small increased risk of nonserious bleeding. Coadministration of prophylactic heparin and DrotAA was associated with a reduction in ischemic stroke incidence in patients with severe sepsis. Furthermore, the data suggest that, in patients with severe sepsis who are receiving or who are about to receive DrotAA treatment, prophylactic heparin should not be abruptly discontinued unless the potential risks of heparin outweigh the potential benefits.


   Acknowledgments
 
The authors acknowledge the efforts of all the investigators, study coordinators, and pharmacists involved in this clinical trial (see Appendix E1 for a list of primary investigators and sites). Without their efforts, this article would not have been possible. In addition, they acknowledge Nancy Correll for her detailed knowledge of the Xigris and Prophylactic HepaRin Evaluation in Severe Sepsis trial and informative discussions, and David R. Nelson, M.S., and Jin Xie, M.S., for additional statistical support.


   FOOTNOTES
 
Supported by Eli Lilly and Company.

* A complete list of primary investigators and investigator sites may be found in Appendix E1 in the online supplement. Back

This article has an online supplement, which is accessible from this issue's table of contents at www.atsjournals.org

Originally Published in Press as DOI: 10.1164/rccm.200612-1803OC on June 7, 2007

Conflict of Interest Statement: M. Levi has served as a paid consultant for Eli Lilly & Co. in 2003 and has participated in previous trials sponsored by Eli Lilly & Co.. M. Levy has served as a paid consultant for Eli Lilly & Co. and Edward Lifesciences, received grants from Eli Lilly & Co., Edwards Lifesciences, Philips Medical Systems, Novartis, and Biosite, and has participated in previous trials sponsored by Eli Lilly & Co. M.D.W. is an employee and stockholder of Eli Lilly & Co. I.D. received $66,000 in research grants between 2003 and 2005 for participating in multicenter clinical trials and $2,000 in 2004 for serving on an advisory board for Eli Lilly & Co., has served as a paid consultant for Eli Lilly & Co. A.A. received $4,500 from Eli Lilly & Co. as a consultant in August 2004 to perform an integrated review of retrospective SAEs from the INDEPTH database and has participated in previous trials sponsored by Eli Lilly & Co. M.A. received {euro}2,000 in 2004 for serving on an advisory board for Eli Lilly & Co., {euro}2,500 from MSD in 2006, {euro}1,500 from Glaxo in 2006, {euro}1,500 in 2005 and 2006 from Pfizer, {euro}1,500 from Tyco in 2005 and 2006 in lecture fees, a {euro}20,000 grant was given to M.A.'s institution from Eli Lilly & Co. for educational courses, and he has participated in previous trials sponsored by Eli Lilly & Co. D. Wyncoll received {euro}300 in 2004, {euro}1,000 in 2005, and {euro}2,600 in 2006 for serving as a consultant for Eli Lilly & Co., received {euro}8,148 in 2004, {euro}4,750 in 2005, and {euro}13,750 in 2006 for speaking at meetings sponsored by Eli Lilly & Co., and has participated in previous trials sponsored by Eli Lilly & Co. J.J. is an employee and stockholder of Eli Lilly & Co., the manufacturer of drotrecogin alfa (activated). F.V.B. was a full-time employee of Eli Lilly & Co. for the majority of the time during which this study was performed and analyzed. F.V.B is no longer employed by Eli Lilly & Co., but currently has 700 shares in Lilly stock. D. Wang is an employee and stockholder of Eli Lilly & Co. D.P.S. is an employee and stockholder of Eli Lilly & Co. W.L.M. is an employee and stockholder of Eli Lilly & Co. The XPRESS trial was designed by the sponsor, Eli Lilly & Co.

Received in original form December 13, 2006; accepted in final form June 7, 2007


   REFERENCES
TOP
 ABSTRACT
 AT A GLANCE COMMENTARY
 METHODS
 RESULTS
 DISCUSSION
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  1. Dellinger RP, Carlet JM, Masur H, Gerlach H, Calandra T, Cohen J, Gea-Banacloche J, Keh D, Marshall JC, Parker MM, et al.; Surviving Sepsis Campaign Management Guidelines Committee. Surviving Sepsis Campaign guidelines for management of severe sepsis and septic shock. Crit Care Med 2004;32:858–873.[CrossRef][Medline]
  2. Alberti C, Brun-Buisson C, Burchardi H, Martin C, Goodman S, Artigas A, Sicignano A, Palazzo M, Moreno R, Boulme R, et al. Epidemiology of sepsis and infection in ICU patients from an international multicentre cohort study. Intensive Care Med 2002;28:108–121.[CrossRef][Medline]
  3. Angus DC, Linde-Zwirble WT, Lidicker J, Clermont G, Carcillo J, Pinsky MR. Epidemiology of severe sepsis in the United States: analysis of incidence, outcome, and associated costs of care. Crit Care Med 2001;29:1303–1310.[CrossRef][Medline]
  4. Martin GS, Mannino DM, Eaton S, Moss M. The epidemiology of sepsis in the United States from 1979 through 2000. N Engl J Med 2003;348:1546–1554.[Abstract/Free Full Text]
  5. Vincent JL, Sakr Y, Sprung CL, Ranieri VM, Reinhart K, Gerlach H, Moreno R, Carlet J, Le Gall JR, Payen D; Sepsis Occurrence in Acutely Ill Patients Investigators. Sepsis in European intensive care units: results of the SOAP study. Crit Care Med 2006;34:344–353.[CrossRef][Medline]
  6. Bernard GR, Vincent JL, Laterre PF, LaRosa SP, Dhainaut JF, Lopez-Rodriguez A, Steingrub JS, Garber GE, Helterbrand JD, Ely EW, et al. Recombinant human protein C Worldwide Evaluation in Severe Sepsis (PROWESS) study group: Efficacy and safety of recombinant human activated protein C for severe sepsis. N Engl J Med. 2001;344:699–709.[Abstract/Free Full Text]
  7. Dhainaut JF, Yan SB, Joyce DE, Pettila V, Basson B, Brandt JT, Sundin DP, Levi M. Treatment effects of drotrecogin alfa (activated) in patients with severe sepsis with or without overt disseminated intravascular coagulation. J Thromb Haemost 2004;2:1924–1933.[CrossRef][Medline]
  8. Cook DJ, Crowther MA, Meade MO, Douketis J, for the VTE in the ICU Workshop Participants. Prevalence, incidence, and risk factors for venous thromboembolism in medical-surgical intensive care unit patients. J Crit Care 2005;20:309–313.[CrossRef][Medline]
  9. Perez J, Dellinger RP, and International Sepsis Forum. Other supportive therapies in sepsis. Intensive Care Med 2001;27(Suppl 1):S116–S127.
  10. Patel R, Cook DJ, Meade MO, Griffith LE, Mehta G, Rocker GM, Marshall JC, Hodder R, Martin CM, Heyland DK, et al.; Burden of Illness in venous ThromboEmbolism in Critical care (BITEC) Study Investigators; Canadian Critical Care Trials Group. Burden of illness in venous thromboembolism in critical care: a multicenter observational study. J Crit Care 2005;20:341–347.[CrossRef][Medline]
  11. Corrigan JJ Jr. Heparin therapy in bacterial septicemia. J Pediatr 1977;91:695–700.[CrossRef][Medline]
  12. Davidson BL, Geerts WH, Lensing AW. Low-dose heparin for severe sepsis. N Engl J Med 2002;347:1036–1037.[Free Full Text]
  13. Feinstein DI. Diagnosis and management of disseminated intravascular coagulation: the role of heparin therapy. Blood 1982;60:284–287.[Abstract/Free Full Text]
  14. Levi M, Ten Cate H. Disseminated intravascular coagulation. N Engl J Med 1999;341:586–592.[Free Full Text]
  15. Boldt J, Papsdorf M, Piper SN, Rothe A, Hempelmann G. Continuous heparinization and circulating adhesion molecules in the critically ill. Shock 1999;11:13–18.[Medline]
  16. Derhaschnig U, Pernerstorfer T, Knechtelsdorfer M, Hollenstein U, Panzer S, Jilma B. Evaluation of antiinflammatory and antiadhesive effects of heparins in human endotoxemia. Crit Care Med 2003;31:1108–1112.[CrossRef][Medline]
  17. Meyer J, Cox CS, Herndon DN, Nakazawa H, Lentz CW, Traber LD, Traber DL. Heparin in experimental hyperdynamic sepsis. Crit Care Med 1993;21:84–89.[Medline]
  18. Pernerstorfer T, Hollenstein U, Hansen J, Knechtelsdorfer M, Stohlawetz P, Graninger W, Eichler HG, Speiser W, Jilma B. Heparin blunts endotoxin-induced coagulation activation. Circulation 1999;100:2485–2490.[Abstract/Free Full Text]
  19. Tanaka T, Tsujinaka T, Kambayashi J, Higashiyama M, Yokota M, Sakon M, Mori T. The effect of heparin on multiple organ failure and disseminated intravascular coagulation in a sepsis model. Thromb Res 1990;60:321–330.[CrossRef][Medline]
  20. Dhainaut JF, Laterre PF, Janes JM, Bernard GR, Artigas A, Bakker J, Riess H, Basson BR, Charpentier J, Utterback BG, et al.; Recombinant Human Activated Protein C Worldwide Evaluation in Sepsis (PROWESS) Study Group. Drotrecogin alfa (activated) in the treatment of severe sepsis patients with multiple-organ dysfunction: data from the PROWESS trial. Intensive Care Med 2003;29:894–903.[Medline]
  21. Anti-Infective Advisory Committee. FDA briefing document: drotrecogin alfa (activated) [recombinant human activated protein C (rhAPC)] Xigris. BLA #125029/0. Rockville, MD: Food and Drug Administration, September 12, 2001. Available from: http://www.fda.gov/ohrms/dockets/ac/01/briefing/3797b1_02_FDAbriefing.pdf (accessed June 13, 2006).
  22. Aznar J, Espana F, Estelles A, Royo M. Heparin stimulation of the inhibition of activated protein C and other enzymes by human protein C inhibitor: influence of the molecular weight of heparin and ionic strength. Thromb Haemost 1996;76:983–988.[Medline]
  23. Friedrich U, Blom AM, Dahlback B, Villoutreix BO. Structural and energetic characteristics of the heparin-binding site in antithrombotic protein C. J Biol Chem 2001;276:24122–24128.[Abstract/Free Full Text]
  24. Pratt CW, Church FC. General features of the heparin-binding serpins antithrombin, heparin cofactor II and protein C inhibitor. Blood Coagul Fibrinolysis 1993;4:479–490.[Medline]
  25. Knaus WA, Draper EA, Wagner DP, Zimmerman JE. APACHE II: a severity of disease classification system. Crit Care Med 1985;13:818–829.[Medline]
  26. Cook D, Crowther M, Meade M, Rabbat C, Griffith L, Schiff D, Geerts W, Guyatt G. Deep venous thrombosis in medical-surgical critically ill patients: prevalence, incidence, and risk factors. Crit Care Med 2005;33:1565–1571.[CrossRef][Medline]
  27. Fraisse F, Holzapfel L, Couland JM, Simonneau G, Bedock B, Feissel M, Herbecq P, Pordes R, Poussel JF, Roux L. Nadroparin in the prevention of deep vein thrombosis in acute decompensated COPD. The Association of Non–University Affiliated Intensive Care Specialist Physicians of France. Am J Respir Crit Care Med 2000;161:1109–1114.[Abstract/Free Full Text]
  28. Ibrahim EH, Iregui M, Prentice D, Sherman G, Kollef MH, Shannon W. Deep vein thrombosis during prolonged mechanical ventilation despite prophylaxis. Crit Care Med 2002;30:771–774.[CrossRef][Medline]
  29. Marik PE, Andrews L, Maini B. The incidence of deep venous thrombosis in ICU patients. Chest 1997;111:661–664.[Medline]
  30. Samama MM, Cohen AT, Darmon JY, Desjardins L, Eldor A, Janbon C, Leizorovicz A, Nguyen H, Olsson CG, Turpie AG, et al. A comparison of enoxaparin with placebo for the prevention of venous thromboembolism in acutely ill medical patients. Prophylaxis in Medical Patients with Enoxaparin Study Group. N Engl J Med 1999;341:793–800.[Abstract/Free Full Text]
  31. Bahit MC, Topol EJ, Califf RM, Armstrong PW, Criger DA, Hasselblad V, Betriu A, Hirsh J, Ardissino D, Granger CB. Reactivation of ischemic events in acute coronary syndromes: results from GUSTO-IIb. Global Use of Strategies to Open Occluded Arteries in Acute Coronary Syndromes. J Am Coll Cardiol 2001;37:1001–1007.[Abstract/Free Full Text]
  32. Bijsterveld NR, Moons AH, Meijers JC, Tijssen JG, Buller HR, Levi M, Peters RJ. Rebound thrombin generation after heparin therapy in unstable angina: a randomized comparison between unfractionated and low-molecular-weight heparin. J Am Coll Cardiol 2002;39:811–817.[Abstract/Free Full Text]
  33. Theroux P, Waters D, Lam J, Juneau M, McCans J. Reactivation of unstable angina after the discontinuation of heparin. N Engl J Med 1992;327:141–145.[Abstract]
  34. Abraham E, Laterre PF, Garg R, Levy H, Talwar D, Trzaskoma BL, François B, Guy JS, Brückmann M, Rea-Neto A, et al.; Administration of Drotrecogin Alfa (Activated) in Early Stage Severe Sepsis (ADDRESS) Study Group. Drotrecogin alfa (activated) for adults with severe sepsis and a low risk of death. N Engl J Med 2005;353:1332–1341.[Abstract/Free Full Text]
  35. Hirsch DR, Ingenito EP, Goldhaber SZ. Prevalence of deep venous thrombosis among patients in medical intensive care. JAMA 1995;274:335–337.[Abstract/Free Full Text]



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