Drotrecogin alfa (activated) in clinical practice and current evidences: reply

LETTER TO THE EDITOR

Drotrecogin alfa (activated) in clinical practice and current evidences

Márcio Soares^I; Fernando Osni Machado^II; Viviane Bogado Leite Torres^III; Jorge Ibrain Figueira Salluh^IV; André Carlos Kajdacsy-Balla Amaral^V

^IPhD, Physician from the Intensive Care Center of Instituto Nacional de Câncer- INCA, Rio de Janeiro (RJ), Brazil

^IIPhD, Associate Professor from the Universidade Federal de Santa Catarina - UFSC, Florianópolis (SC), Brazil

^IIIIntensive Care Fellow from the Instituto Nacional de Câncer- INCA, Rio de Janeiro (RJ), Brazil

^IVMaster, Physician from the Intensive Care Center and Critical Care Clinical Research Center from the Instituto Nacional de Câncer - INCA, Rio de Janeiro (RJ), Brazil

^VScientific Consultant from the Intensive Care Unit from Hospital Brasília - Rede ESHO, Brasília (DF), Brazil

Address for correspondence

Reply to the comments of Doctors Büchele and Janiszewski

Re: We thank Doctors Büchele and Janiszewski for their interest and comments on our article.¹ Every "non-systematic" review, above all, portrays the authors' position in relation to a specific subject in view of current knowledge and often, because of the limitations imposed by the journal's format, it is impossible to address all actual studies. In our opinion, results of the three studies pointed out do not significantly change our conclusions. To affirm that use of drotrecogin alfa activated (DrotAA) must be considered, as stated in our conclusion cannot be understood as a recommendation to suspend use of the drug in the treatment of sepsis, but must be interpreted as a need for readjustment. After the great euphoria in the early years of 2000, with publications of studies demonstrating the benefit of some interventions for the treatments of patients with sepsis and related complications, DrotAA is only one among the other interventions (such as low- dose corticosteroids, strict glycemic control and early-goal directed therapy) whose efficacy and safety have also been questioned.

We emphasize that every observational study is subject to problems and difficulties in the statistical analysis and interpretation of results, liable to bias of the effect assessment in an unpredictable manner.² In the observational studies about utilization of DrotAA, some additional methodological concerns arise: observations are subject to selection bias because the opinion of intensivists on risk of death is more accurate than the predictive scores³ which invalidate a posteriori comparisons, especially when the economic factor may affect decision making.^4,5 Stated in another way, the physician's opinion on risk of death, as well as on the patients' life prognosis, with or without treatment, bears a direct influence on the choice or not of using an intervention, especially if this has a significant economic impact. That is why, there is a natural tendency (and beneficial!) in the selection of patients with a better prognosis, for utilization of DrotAA, which cannot possibly be subjected to statistical treatment.

Another serious issue in observational studies is the tendency to group interventions in patients that are being treated by the same team⁶ whose statistical treatment rests upon a methodology not used in the cited studies.⁷ It is easy to understand that there are performance differences between the various units and if there is a variation in the use of an intervention by the same units, the effects observed cannot be the outcome of practice, but of better performance among units.⁸

Our comment is aligned with growing concerns of the international scientific and medical communities regarding the merit of the efficacy and safety of DrotAA, basically to identify subgroups of patients who have a real potential to benefit from the drug.^9-12 DrotAA presents an interesting physiopathological rationale for clinical use, but as with any intervention cannot be considered a panacea for all patients with sepsis, a syndrome that encompasses severe forms of infectious diseases, many with a distinct clinical and biological behavior.¹³ All these factors are further corroborated, even in the review of the Surviving Sepsis Campaign guidelines, recently published, in which recommendation for use of DrotAA was reviewed as a "weak recommendation for use" according to the GRADE System.¹⁴ The need for a set of new evidences to guide the use of DrotAA, brought about a request by FDA and by the European Union regulatory agencies for new studies, such as RESPOND (Phase II) and PROWESS SCHOCK (Phase III) that are now at patient recruitment stage.¹⁵ It is hoped that such studies may aid in the definition of the true role of drotrecogin alfa activated in the treatment of patients with severe sepsis and septic shock.

REFERENCES

• 01. Soares M, Machado FO, Torres VBL, Salluh JIF, Amaral ACKB. O uso da drotrecogina alfa ativada na prática clínica e as atuais evidências. Rev Bras Ter Intensiva. 2008;20(2):173-7.
• 02. Kunz R, Oxman AD. The unpredictability paradox: review of empirical comparisons of randomised and non-randomised clinical trials. BMJ. 1998;317(7167):1185-90.
• 03. Sinuff T, Adhikari NK, Cook DJ, Schünemann HJ, Griffith LE, Rocker G, Walter SD. Mortality predictions in the intensive care unit: comparing physicians with scoring systems. Crit Care Med. 2006;34(3):878-85. Comment in: Crit Care Med. 2006;34(3):932-3.
• 04. Brody B, Wray N, Bame S, Ashton C, Petersen N, Harward M. The impact of economic considerations on clinical decisionmaking: the case of thrombolytic therapy. Med Care. 1991;29(9):899-910.
• 05. Camidge DR, Oliver JJ, Skinner C, Attwood B, Nussey F, Jodrell D, Webb DJ. The impact of prognosis without treatment on doctors' and patients' resource allocation decisions and its relevance to new drug recommendation processes. Br J Clin Pharmacol. 2008;65(2):224-9.
• 06. Treggiari MM, Martin DP, Yanez ND, Caldwell E, Hudson LD, Rubenfeld GD. Effect of intensive care unit organizational model and structure on outcomes in patients with acute lung injury. Am J Respir Crit Care Med. 2007;176(7):685-90.
• 07. Reed JF 3rd. Adjusted chi-square statistics: application to clustered binary data in primary vare. Ann Fam Med. 2004;2(3):201-3.
• 08. Kahn JM, Goss CH, Heagerty PJ, Kramer AA, O'Brien CR, Rubenfeld GD. Hospital volume and the outcomes of mechanical ventilation. N Engl J Med. 2006;355(1):41-50. Comment in: N Engl J Med. 2006;355(15):1617; author reply 1617-9. N Engl J Med. 2006;355(15):1617; author reply 1617-9.
• 09. Friedrich JO, Adhikari NK, Meade MO. Drotrecogin alfa (activated): does current evidence support treatment for any patients with severe sepsis? Crit Care. 2006;10(3):145. Comment in: Crit Care. 2006;10(4):416. Crit Care. 2006;10(5):422. Crit Care. 2006;10(5):424.
• 10. Eichacker PQ, Natanson C. Increasing evidence that the risks of rhAPC may outweigh its benefits. Intensive Care Med. 2007;33(3):396-9.
• 11. Carlet J. Prescribing indications based on successful clinical trials in sepsis: a difficult exercise. Crit Care Med. 2006;34(2):525-9. Comment in: Crit Care Med. 2006;34(2):530-1.
• 12. Opal SM. Can we RESOLVE the treatment of sepsis? Lancet. 2007;369(9564):803-4. Comment on: Lancet. 2007;369(9564):836-43.
• 13. Levy MM, Fink MP, Marshall JC, Abraham E, Angus D, Cook D, Cohen J, Opal SM, Vincent JL, Ramsay G; SCCM/ESICM/ACCP/ATS/SIS. 2001 SCCM/ESICM/ ACCP/ATS/SIS International Sepsis Definitions Conference. Crit Care Med. 2003;31(4):1250-6. Comment in: Crit Care. 2007;11(2):411.
• 14. Dellinger RP, Levy MM, Carlet JM, Bion J, Parker MM, Jaeschke R, Reinhart K, Angus DC, Brun-Buisson C, Beale R, Calandra T, Dhainaut JF, Gerlach H, Harvey M, Marini JJ, Marshall J, Ranieri M, Ramsay G, Sevransky J, Thompson BT, Townsend S, Vender JS, Zimmerman JL, Vincent JL; International Surviving Sepsis Campaign Guidelines Committee; American Association of Critical-Care Nurses; American College of Chest Physicians; American College of Emergency Physicians; Canadian Critical Care Society; European Society of Clinical Microbiology and Infectious Diseases; European Society of Intensive Care Medicine; European Respiratory Society; International Sepsis Forum; Japanese Association for Acute Medicine; Japanese Society of Intensive Care Medicine; Society of Critical Care Medicine; Society of Hospital Medicine; Surgical Infection Society; World Federation of Societies of Intensive and Critical Care Medicine. Surviving Sepsis Campaign: international guidelines for management of severe sepsis and septic shock: 2008. Crit Care Med. 2008;36(1):296-327. Erratum in: Crit Care Med. 2008;36(4):1394-6.
• 15. Clinicaltrials.gov [Internet].[published 1993 Jan 1 last updated 2008 May 19 Bethesda: U.S. National Institute of Health; c2008. [cited 2008 Sept 16] . Available from: http://www.clinicaltrials/ct2/search.gov

Publication Dates

• Publication in this collection
  04 Nov 2008
• Date of issue
  Sept 2008