Randomized trial evaluating serial protein C levels in severe sepsis patients treated with variable doses of drotrecogin alfa (activated)

Andrew F Shorr, Jonathan M Janes, Antonio Artigas, Jyrki Tenhunen, Duncan L A Wyncoll, Emmanuelle Mercier, Bruno Francois, Jean-Louis Vincent, Burkhard Vangerow, Darell Heiselman, Amy G Leishman, Yajun E Zhu, Konrad Reinhart, RESPOND investigators, R Bellomo, P-F Laterre, J-L Vincent, H Spapen, J Decruyenaere, R Fowler, R Hall, L McIntyre, O Lesur, R B Light, C Martin, J Russell, V Pettilä, M Varpula, J Tenhunen, E Ruokonen, T Ala-Kokko, D Perrotin, B Francois, J Reignier, R Robert, A Desachy, C Rolfes, M Lebender, A Sablotzki, K Reinhart, U Kaisers, M Antonelli, G Iapichino, W Rodriguez-Cintro, A Artigas, R Ferrer, A Esteban de la Torre, S Bennett, G Raghuraman, D Wyncoll, A Kapila, M Blunt, S Drage, A Gordon, K Krell, T Lo, C Naum, R Riker, J Southard, C Beechler, P Sanchez, J Siever, R Lakshmanan, P Wright, K Van Gundy, J Reyno, S Awad, M Saad, Andrew F Shorr, Jonathan M Janes, Antonio Artigas, Jyrki Tenhunen, Duncan L A Wyncoll, Emmanuelle Mercier, Bruno Francois, Jean-Louis Vincent, Burkhard Vangerow, Darell Heiselman, Amy G Leishman, Yajun E Zhu, Konrad Reinhart, RESPOND investigators, R Bellomo, P-F Laterre, J-L Vincent, H Spapen, J Decruyenaere, R Fowler, R Hall, L McIntyre, O Lesur, R B Light, C Martin, J Russell, V Pettilä, M Varpula, J Tenhunen, E Ruokonen, T Ala-Kokko, D Perrotin, B Francois, J Reignier, R Robert, A Desachy, C Rolfes, M Lebender, A Sablotzki, K Reinhart, U Kaisers, M Antonelli, G Iapichino, W Rodriguez-Cintro, A Artigas, R Ferrer, A Esteban de la Torre, S Bennett, G Raghuraman, D Wyncoll, A Kapila, M Blunt, S Drage, A Gordon, K Krell, T Lo, C Naum, R Riker, J Southard, C Beechler, P Sanchez, J Siever, R Lakshmanan, P Wright, K Van Gundy, J Reyno, S Awad, M Saad

Abstract

Introduction: Serial alterations in protein C levels appear to correlate with disease severity in patients with severe sepsis, and it may be possible to tailor severe sepsis therapy with the use of this biomarker. The purpose of this study was to evaluate the dose and duration of drotrecogin alfa (activated) treatment using serial measurements of protein C compared to standard therapy in patients with severe sepsis.

Methods: This was a phase 2 multicenter, randomized, double-blind, controlled study. Adult patients with two or more sepsis-induced organ dysfunctions were enrolled. Protein C deficient patients were randomized to standard therapy (24 μg/kg/hr infusion for 96 hours) or alternative therapy (higher dose and/or variable duration; 24/30/36 μg/kg/hr for 48 to 168 hours). The primary outcome was a change in protein C level in the alternative therapy group, between study Day 1 and Day 7, compared to standard therapy.

Results: Of 557 patients enrolled, 433 patients received randomized therapy; 206 alternative, and 227 standard. Baseline characteristics of the groups were largely similar. The difference in absolute change in protein C from Day 1 to Day 7 between the two therapy groups was 7% (P = 0.011). Higher doses and longer infusions were associated with a more pronounced increase in protein C level, with no serious bleeding events. The same doses and longer infusions were associated with a larger increase in protein C level; higher rates of serious bleeding when groups received the same treatment; but no clear increased risk of bleeding during the longer infusion. This group also experienced a higher mortality rate; however, there was no clear link to infusion duration.

Conclusions: The study met its primary objective of increased protein C levels in patients receiving alternative therapy demonstrating that variable doses and/or duration of drotrecogin alfa (activated) can improve protein C levels, and also provides valuable information for incorporation into potential future studies.

Trial registration: ClinicalTrials.gov identifier: NCT00386425.

Figures

Figure 1
Figure 1
Patient disposition and study flow diagram of patients. *Patients who signed informed consent, but did not proceed to randomization or the nondrug-interventional arm.
Figure 2
Figure 2
Absolute mean change in protein C levels. Change in mean protein C levels from study Day 1 up to study Day 7 for different therapy groups in the primary efficacy population. Alt, alternative; std, standard
Figure 3
Figure 3
Protein C level over time by therapy in the primary efficacy population. Alt, alternative; std, standard.
Figure 4
Figure 4
Comparison between studies of 28-day mortality by Day 4 protein C level. Twenty-eight-day mortality is shown based on Day 4 protein C levels by categories: normal (> 80%); moderately deficient (41 to 80%); and severely deficient (≤40%) for PROWESS [3], ENHANCE [17] (both reported by Vangerow et al. 2007 [14]), and RESPOND. The number (n) under each column is the total number of patients in each category. DAA, drotrecogin alfa (activated).

References

    1. Levy MM, Dellinger RP, Townsend SR, Linde-Zwirble WT, Marshall JC, Bion J, Schorr C, Artigas A, Ramsay G, Beale R, Parker MM, Gerlach H, Reinhart K, Silva E, Harvey M, Regan S, Angus DC. Surviving Sepsis Campaign. The Surviving Sepsis Campaign: results of an international guideline-based performance improvement program targeting severe sepsis. Crit Care Med. 2010;38:367–374. doi: 10.1097/CCM.0b013e3181cb0cdc.
    1. Sheth SB, Carvalho AC. Protein S and C alterations in acutely ill patients. Am J Hematol. 1991;36:14–19. doi: 10.1002/ajh.2830360104.
    1. Bernard GR, Vincent JL, Laterre PF, LaRosa SP, Dhainaut JF, Lopez-Rodriguez A, Steingrub JS, Garber GE, Helterbrand JD, Ely EW, Fisher CJ Jr. Recombinant human protein C Worldwide Evaluation in Severe Sepsis (PROWESS) study group. Efficacy and safety of recombinant activated protein C for severe sepsis. N Engl J Med. 2001;344:699–709. doi: 10.1056/NEJM200103083441001.
    1. Yan SB, Helterbrand JD, Hartman DL, Wright TJ, Bernard GD. Low levels of protein C are associated with poor outcome in severe sepsis. Chest. 2001;120:915–922. doi: 10.1378/chest.120.3.915.
    1. Kinasewitz GT, Yan SB, Basson B, Comp P, Russell JA, Cariou A, Um SL, Utterback B, Laterre P-F, Dhainaut J-F. for the PROWESS Sepsis Study Group. Universal changes in biomarkers of coagulation and inflammation occur in patients with severe sepsis, regardless of causative micro-organism. Crit Care. 2004;8:R82–R90. doi: 10.1186/cc2459.
    1. Fourrier F, Chopin C, Goudemand J, Hendrycx S, Caron C, Rime A, Marey A, Lestavel P. Septic shock, multiple organ failure, and disseminated intravascular coagulation: Compared patterns of antithrombin III, protein C and protein S deficiencies. Chest. 1992;101:816–823. doi: 10.1378/chest.101.3.816.
    1. Lorente JA, García-Frade LJ, Landín L, de Pablo R, Torrado C, Renez E, García-Avello A. Time course of hemostatic abnormalities in sepsis and its relation to outcome. Chest. 1993;103:1536–1542. doi: 10.1378/chest.103.5.1536.
    1. Mesters RM, Helterbrand J, Utterback BG, Yan SB, Chao YB, Fernandez JA, Griffin JH, Hartman DL. Prognostic value of protein C concentrations in neutropenic patients at high risk of severe septic complications. Crit Care Med. 2000;28:2209–2216. doi: 10.1097/00003246-200007000-00005.
    1. Shorr AF, Nelson DR, Wyncoll DLA, Reinhart K, Brunkhorst F, Vail GM, Janes J. Protein C: a potential biomarker in severe sepsis and a possible tool for monitoring treatment with drotrecogin alfa (activated) Crit Care. 2008;12:R45. doi: 10.1186/cc6854.
    1. Macias WL, Nelson DR. Severe protein C deficiency predicts early death in severe sepsis. Crit Care Med. 2004;32:S223–S228. doi: 10.1097/.
    1. Shorr AF, Bernard GR, Dhainaut J-F, Russell JR, Macias WL, Nelson DR, Sundin DP. Protein C concentrations in severe sepsis: an early directional change in plasma levels predicts outcome. Crit Care. 2006;10:R92. doi: 10.1186/cc4946.
    1. Brunkhorst F, Sakr Y, Hagel S, Reinhart K. Protein C concentrations correlate with organ dysfunction and predict outcome independent of the presence of sepsis. Anesthesiology. 2007;107:15–23. doi: 10.1097/01.anes.0000267531.39410.d3.
    1. Dhainaut J-F, Laterre PF, Janes JM, Bernard GR, Artigas A, Bakker J, Riess H, Basson BR, Charpentier J, Utterback BG, Vincent J-L. Recombinant Human Activated Protein C Worldwide Evaluation in Severe 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.
    1. Vangerow R, Shorr AF, Wyncoll D, Janes J, Nelson DR, Reinhart K. The protein C pathway: implications for the design of the RESPOND study. Crit Care. 2007;11:S4. doi: 10.1186/cc6155.
    1. Lui KD, Matthay MA. Protein C as a surrogate end-point for clinical trials of sepsis. Crit Care. 2008;12:139. doi: 10.1186/cc6859.
    1. Rivers EP, Kruse JA, Jacobsen G, Shah K, Loomba M, Otero R, Childs EW. The influence of early hemodynamic optimization on biomarker patterns of severe sepsis and septic shock. Crit Care Med. 2007;35:2016–2024. doi: 10.1097/01.CCM.0000281637.08984.6E.
    1. Vincent JL, Bernard GR, Beale R, Doig C, Putensen C, Dhainaut J-F, Artigas A, Fumagalli R, Macias W, Wright T, Wong K, Sundin DP, Turlo MA, Janes J. for the ENHANCE Study Group. Drotrecogin alfa (activated) treatment in severe sepsis from the global open-label trial ENHANCE: Further evidence for survival and safety and implications for early treatment. Crit Care Med. 2005;33:2266–2277. doi: 10.1097/01.CCM.0000181729.46010.83.
    1. Ahishakiye D, Lorent S, De Backer D, Gottignies P, Vincent J-L. Drotrecogin alfa (activated) for severe sepsis: Could we consider a shorter treatment period in patients with a favorable course? J Crit Care. 2009;24:590–594. doi: 10.1016/j.jcrc.2009.03.009.
    1. Dravid T, Pawar B, Bhurke B, Akole P, Rajhans P, Jog S. Activated protein C: cost matters! Crit Care. 2010;14(Suppl 1):P405. doi: 10.1186/cc8637.
    1. Hochreiter M, Köhler T, Schweiger AM, Keck FS, Bein B, von Spiegel T, Schroeder S. Procalcitonin to guide duration of antibiotic therapy in intensive care patients: a randomized prospective controlled trial. Crit Care. 2009;13:R83. doi: 10.1186/cc7903.

Source: PubMed

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