Top

Intensive Care Medicine

Published in:

01-10-2008 | Original

How many patients with severe sepsis are needed to confirm the efficacy of drotrecogin alfa activated? A Bayesian design

Authors: Andre C. Kalil, Junfeng Sun

Published in: Intensive Care Medicine | Issue 10/2008

Abstract

Objectives

Controversies concerning the pivotal trial and negative results from other Drotrecogin alfa activated (DAA) trials have raised questions about its efficacy in severe sepsis patients. Based on all available evidence, our study aimed to respond to: (1) What is the current probability that DAA is not better than the control? If the current probability is not small, e.g. greater than 0.05, then (2) How many patients will be needed for the DAA confirmatory trial?

Design

We applied the Bayesian methodology to all randomized trials which tested anti-thrombotic therapies for severe sepsis. Prior distributions were defined as severe skeptic (all anti-thrombotic trials or DAA trials); moderate skeptic (anti-thrombotic trials with high risk of death); mild skeptic (DAA trials only); enthusiastic (DAA trials with high risk of death).

Results

The total study sample includes 7,683 patients: DAA (N = 3,143); Anti-thrombin-III (N = 2,581); tissue factor pathway inhibitor (N = 1,959). Answer 1: All current probabilities that DAA is not better than the control (except for the enthusiastic analysis) range from 0.14 to 0.48, which strongly suggest the need for a confirmatory trial. Answer 2: The number of patients necessary for the DAA confirmatory trial ranges up to 8,350 for the severe skeptic; 730–810 for moderate skeptic; 550–685 for mild skeptic; and zero for enthusiastic analysis.

Conclusions

A confirmatory trial with approximately 600 patients with severe sepsis and high risk of death can provide a convincing answer for both the mild and moderate skeptic physicians concerning the efficacy of DAA in severe sepsis.

Available only for authorised users

Deans KJ, Minneci PC, Cui X, Banks SM, Natanson C, Eichacker PQ (2005) Mechanical ventilation in ARDS: one size does not fit all. Crit Care Med 33:1141–1143PubMedCrossRef

Friedrich JO, Adhikari NK, Meade MO (2006) Drotrecogin alfa (activated): down and not out, but not really in either. Crit Care 10:420PubMedCrossRef

Wiedermann CJ (2006) When a single pivotal trial should not be enough-the case of drotrecogin-alfa (activated). Intens Care Med 32:604CrossRef

Mackenzie AF (2005) Activated protein C: do more survive? Intens Care Med 31:1624–1626CrossRef

Eichacker PQ, Danner RL, Suffredini AF, Cui X, Natanson C (2005) Reassessing recombinant human activated protein C for sepsis: time for a new randomized controlled trial. Crit Care Med 33:2426–2428PubMedCrossRef

Schultz MJ, Wolthuis EK, Moeniralam HS, Levi M (2005) Struggle for implementation of new strategies in intensive care medicine: anticoagulation, insulin, and lower tidal volumes. J Crit Care 20:199–204PubMedCrossRef

Warren HS, Suffredini AF, Eichacker PQ, Munford RS (2002) Risks and benefits of activated protein C treatment for severe sepsis. N Engl J Med 347:1027–1030PubMedCrossRef

Bernard GR, Vincent JL, Laterre PF, LaRosa SP, Dhainaut JF, Lopez-Rodriguez A, Steingrub JS, Garber GE, Helterbrand JD, Ely EW, Fisher CJ Jr (2001) Efficacy and safety of recombinant human activated protein C for severe sepsis. N Engl J Med 344:699–709PubMedCrossRef

Cook DJ, Russell JA (2001) Recombinant human activated protein C reduced all-cause mortality in patients with severe sepsis. ACP J Club 135:81

10.

Barkun J, Christou NV (2003) Canadian Association of General Surgeons Evidence Based Reviews in Surgery. 8. Efficacy and safety of recombinant human activated protein C for severe sepsis. Can J Surg 46:468–470PubMed

11.

Matthay MA (2001) Severe sepsis–a new treatment with both anticoagulant and antiinflammatory properties. N Engl J Med 344:759–762PubMedCrossRef

12.

Davidson BL, Geerts WH, Lensing AW (2002) Low-dose heparin for severe sepsis. N Engl J Med 347:1036–1037PubMedCrossRef

13.

Abraham E, Laterre PF, Garg R, Levy H, Talwar D, Trzaskoma BL, Francois B, Guy JS, Bruckmann M, Rea-Neto A, Rossaint R, Perrotin D, Sablotzki A, Arkins N, Utterback BG, Macias WL (2005) Drotrecogin alfa (activated) for adults with severe sepsis and a low risk of death. N Engl J Med 353:1332–1341PubMedCrossRef

14.

Carlet J (2006) Drotrecogin-alpha (activated) did not reduce death and increased bleeding in patients with severe sepsis and low risk for death. ACP J Club 144:43PubMed

15.

Gupta S, Milbrandt EB, Chelluri L (2006) Drotrecogin alfa (activated) should not be used in patients with severe sepsis and low risk for death. Crit Care 10:316PubMedCrossRef

16.

Parrillo JE (2005) Severe sepsis and therapy with activated protein C. N Engl J Med 353:1398–1400PubMedCrossRef

17.

LaRosa SP (2006) Drotrecogin alfa (activated) in severe sepsis. N Engl J Med 354:94–96 author reply 94–96PubMedCrossRef

18.

Friedrich JO (2006) Drotrecogin alfa (activated) in severe sepsis. N Engl J Med 354:94–96 author reply 94–96PubMedCrossRef

19.

Baillie JK, Murray G (2006) Drotrecogin alfa (activated) in severe sepsis. N Engl J Med 354:94–96 author reply 94–96PubMedCrossRef

20.

Minneci PC, Deans KJ, Cui X, Banks SM, Natanson C, Eichacker PQ (2006) Antithrombotic therapies for sepsis: a need for more studies. Crit Care Med 34:538–541PubMedCrossRef

21.

Abraham E, Reinhart K, Opal S, Demeyer I, Doig C, Rodriguez AL, Beale R, Svoboda P, Laterre PF, Simon S, Light B, Spapen H, Stone J, Seibert A, Peckelsen C, De Deyne C, Postier R, Pettila V, Artigas A, Percell SR, Shu V, Zwingelstein C, Tobias J, Poole L, Stolzenbach JC, Creasey AA (2003) Efficacy and safety of tifacogin (recombinant tissue factor pathway inhibitor) in severe sepsis: a randomized controlled trial. JAMA 290:238–247PubMedCrossRef

22.

Warren BL, Eid A, Singer P, Pillay SS, Carl P, Novak I, Chalupa P, Atherstone A, Penzes I, Kubler A, Knaub S, Keinecke HO, Heinrichs H, Schindel F, Juers M, Bone RC, Opal SM (2001) Caring for the critically ill patient. High-dose antithrombin III in severe sepsis: a randomized controlled trial. JAMA 286:1869–1878PubMedCrossRef

23.

Burton PR, Gurrin LC, Campbell MJ (1998) Clinical significance not statistical significance: a simple Bayesian alternative to p values. J Epidemiol Community Health 52:318–323PubMedCrossRef

24.

Sterne JA, Davey Smith G (2001) Sifting the evidence-what’s wrong with significance tests? BMJ 322:226–231PubMedCrossRef

25.

Gill CJ, Sabin L, Schmid CH (2005) Why clinicians are natural bayesians. BMJ 330:1080–1083PubMedCrossRef

26.

Diamond GA, Kaul S (2004) Prior convictions: Bayesian approaches to the analysis and interpretation of clinical megatrials. J Am Coll Cardiol 43:1929–1939PubMedCrossRef

27.

Berry DA (2006) Bayesian clinical trials. Nat Rev Drug Discov 5:27–36PubMedCrossRef

28.

Harrell FE Jr, Shih YC (2001) Using full probability models to compute probabilities of actual interest to decision makers. Int J Technol Assess Health Care 17:17–26PubMedCrossRef

29.

Spiegelhalter DJ, Myles JP, Jones DR, Abrams KR (2000) Bayesian methods in health technology assessment: a review. Health Technol Assess 4:1–130PubMed

30.

Goodman SN (2005) Introduction to Bayesian methods. I: measuring the strength of evidence. Clin Trials 2:282–290 discussion 301–284, 364–278PubMedCrossRef

31.

Browner WS, Newman TB (1987) Are all significant P values created equal? The analogy between diagnostic tests and clinical research. JAMA 257:2459–2463PubMedCrossRef

32.

Davidoff F (1999) Standing statistics right side up. Ann Intern Med 130:1019–1021PubMed

33.

(2001) FDA label : Xigris Drotrecogin alfa (activated). In:FDA

34.

Bernard GR, Ely EW, Wright TJ, Fraiz J, Stasek JE Jr, Russell JA, Mayers I, Rosenfeld BA, Morris PE, Yan SB, Helterbrand JD (2001) Safety and dose relationship of recombinant human activated protein C for coagulopathy in severe sepsis. Crit Care Med 29:2051–2059PubMedCrossRef

35.

Barton P, Kalil AC, Nadel S, Goldstein B, Okhuysen-Cawley R, Brilli RJ, Takano JS, Martin LD, Quint P, Yeh TS, Dalton HJ, Gessouron MR, Brown KE, Betts H, Levin M, Macias WL, Small DS, Wyss VL, Bates BM, Utterback BG, Giroir BP (2004) Safety, pharmacokinetics, and pharmacodynamics of drotrecogin alfa (activated) in children with severe sepsis. Pediatrics 113:7–17PubMedCrossRef

36.

Balk RA, Bedrosian C et al (1995) Prospective, double-blind, placebo-controlled, trial of ATIII substitution in sepsis. Intens Care Med 21:S17

37.

Schuster HP, Eisele B, Lamy M, Thijs LG et al (1997) S-ATIII study: antithrombin III in patients with sepis. Intens Care Med S23:S76

38.

Fourrier F, Chopin C, Huart JJ, Runge I, Caron C, Goudemand J (1993) Double-blind, placebo-controlled trial of antithrombin III concentrates in septic shock with disseminated intravascular coagulation. Chest 104:882–888PubMedCrossRef

39.

Inthorn D, Hoffmann JN, Hartl WH, Muhlbayer D, Jochum M (1997) Antithrombin III supplementation in severe sepsis: beneficial effects on organ dysfunction. Shock 8:328–334PubMedCrossRef

40.

Eisele B, Lamy M, Thijs LG, Keinecke HO, Schuster HP, Matthias FR, Fourrier F, Heinrichs H, Delvos U (1998) Antithrombin III in patients with severe sepsis. A randomized, placebo-controlled, double-blind multicenter trial plus a meta-analysis on all randomized, placebo-controlled, double-blind trials with antithrombin III in severe sepsis. Intens Care Med 24:663–672CrossRef

41.

Abraham E, Reinhart K, Svoboda P, Seibert A, Olthoff D, Dal Nogare A, Postier R, Hempelmann G, Butler T, Martin E, Zwingelstein C, Percell S, Shu V, Leighton A, Creasey AA (2001) Assessment of the safety of recombinant tissue factor pathway inhibitor in patients with severe sepsis: a multicenter, randomized, placebo-controlled, single-blind, dose escalation study. Crit Care Med 29:2081–2089PubMedCrossRef

42.

Macias WL, Vallet B, Bernard GR, Vincent JL, Laterre PF, Nelson DR, Derchak PA, Dhainaut JF (2004) Sources of variability on the estimate of treatment effect in the PROWESS trial: implications for the design and conduct of future studies in severe sepsis. Crit Care Med 32:2385–2391PubMedCrossRef

43.

Spiegelhalter DJ, Abrams KR, Myles JP (2004) Bayesian approaches to clinical trials and health care evaluation. Wiley, Chichester, Hoboken

44.

Rosner B (2006) Fundamentals of biostatistics. Thomson-Brooks/Cole, Belmont

Title: How many patients with severe sepsis are needed to confirm the efficacy of drotrecogin alfa activated? A Bayesian design
Authors: Andre C. Kalil
Junfeng Sun
Publication date: 01-10-2008
Publisher: Springer-Verlag
Published in: Intensive Care Medicine / Issue 10/2008
Print ISSN: 0342-4642
Electronic ISSN: 1432-1238
DOI: https://doi.org/10.1007/s00134-008-1159-8

Keynote webinar | Spotlight on medication adherence

Springer Medicine

How many patients with severe sepsis are needed to confirm the efficacy of drotrecogin alfa activated? A Bayesian design

Abstract

Objectives

Design

Results

Conclusions

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Objectives

Design

Results

Conclusions

Please log in to get access to this content

Other articles of this Issue 10/2008

Airway pressure release ventilation and biphasic positive airway pressure: a systematic review of definitional criteria

Comment on “Clinical impact of vasopressin infusion on hemodynamics, liver and renal function in pediatric patients”

Protein C concentrate in adult septic patients

The elusive microcirculation

Weaning: can the computer help?

Nasal continuous positive airway pressure decreases respiratory muscles overload in young infants with severe acute viral bronchiolitis