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Drotrecogin alfa activated in clinical practice and the current evidences

Abstracts

BACKGROUND AND OBJECTIVES: The debate on efficacy and patient safety related to the use of drotrecogin alfa (DrotAA) is timely, principally due to the negative results observed in clinical studies performed after the PROWESS study, and the economic cost-related impact of the drug on the healthcare system. The aim of this study was to review the main studies on the use of DrotAA in patients with severe sepsis. The focus was on drug efficacy-and patient safety-related issues. CONTENTS: Articles were selected by a MedLine search for studies on the use of DrotAA in patients with sepsis using the following key words: activated protein C; drotrecogin alfa; sepsis; septic shock; Xigris®. Additional references were retrieved from the studies initially selected. CONCLUSIONS: Mortality and bleeding complications associated with the use of DrotAA were more frequent in large observational studies than those reported in randomized trials. In the light of the current knowledge, routine use of DrotAA should be reevaluated until well-designed confirmatory clinical trials can clarify the true efficacy and safety of the drug and help identify the subgroup of patients that can benefit from use of DrotAA. Physicians should be cautious with the rapid transfer of evidences not well-documented, to the guidelines and recommendations practiced in the care and treatment of patients with severe sepsis.

activated protein C; drotrecogin alfa; mortality; sepsis; septic shock


JUSTIFICATIVA E OBJETIVOS: O debate sobre a segurança e eficácia da drotrecogina alfa (DrotAA) encontra-se na ordem do dia, principalmente, em função dos resultados negativos observados em ensaios clínicos subseqüentes ao PROWESS e do impacto econômico no sistema de saúde relacionado ao custo elevado do fármaco. O objetivo deste estudo foi rever os principais estudos sobre a utilização da DrotAA em pacientes com sepse grave, com ênfase nas questões ligadas a sua eficácia e segurança. CONTEÚDO: Foram selecionados artigos sobre a utilização da DrotAA em pacientes com sepse publicados nos últimos dez anos no MedLine. Os seguintes unitermos foram utilizados: activated protein C; drotrecogin alfa; sepsis; septic shock; Xigris®. Estudos referenciados nos artigos selecionados na busca também foram utilizados. CONCLUSÕES: As taxas de letalidades e as complicações hemorrágicas associadas com o uso do fármaco foram maiores em grandes estudos observacionais do que aquelas descritas previamente nos ensaios clínicos. A luz dos resultados atualmente disponíveis, o uso da DrotAA deve ser reconsiderado até que novos ensaios clínicos possam subsidiar com informações adicionais sobre eficácia, segurança e na identificação dos subgrupos de pacientes com sepse grave que porventura possam ter benefício com o uso deste medicamento. A DrotAA deve servir de exemplo para que haja maior cautela com a rápida transposição de evidências ainda em construção para recomendações e diretrizes de tratamento de pacientes com sepse grave.

choque séptico; drotrecogina alfa ativada; proteína-C ativada; sepse


REVIEW ARTICLE

Drotrecogin alfa activated in clinical practice and the current evidences*

Márcio SoaresI; Fernando Osni MachadoII; Viviane Bogado Leite TorresIII; Jorge Ibrain Figueira SalluhIV; André Carlos Kajdacsy-Balla AmaralV

IMD of the Center for Intensive Care of the Instituto Nacional de Câncer, Rio de Janeiro, RJ; Member of the Coordinating Committee of BRICNet - Brazilian Research in Intensive Care Network; Masters and MD of Clinical Medicine by UFRJ; Specialist in Intensive Care Medicine by AMIB; Scholarship in Research Productivity from CNPq

IIMD, Medical Director of the Intensive Care Services of the Hospital Universitário da Universidade Federal de Santa Catarina (UFSC); Ex-General Director of the Hospital Universitário da UFSC; Masters in Internal Medicine by UFSC; PhD by USP; Assistant Professor II by UFSC; Specialist in Intensive Care by AMIB

IIIMedical Resident in Intensive Care Medicine at Instituto Nacional de Câncer, Rio de Janeiro, RJ

IVCoordinator of the Intensive Care Treatment of the Núcleo de Pesquisa Clinica em Medicina Intensiva and of Instituto Nacional de Câncer, Rio de Janeiro, RJ; Member of the Coordinating Committee of BRICNet - Brazilian Research in Intensive Care Network; Masters degree in Pneumology by UFRJ; Specialist in Intensive Medicine by AMIB

VScientific Consultant of the ICU Hospital Brasília (Network ESHO), Brasília, DF; Specialist in Intensive Medicine by AMIB

Address for correspondence

SUMMARY

BACKGROUND AND OBJECTIVES: The debate on efficacy and patient safety related to the use of drotrecogin alfa (DrotAA) is timely, principally due to the negative results observed in clinical studies performed after the PROWESS study, and the economic cost-related impact of the drug on the healthcare system. The aim of this study was to review the main studies on the use of DrotAA in patients with severe sepsis. The focus was on drug efficacy-and patient safety-related issues.

CONTENTS: Articles were selected by a MedLine search for studies on the use of DrotAA in patients with sepsis using the following key words: activated protein C; drotrecogin alfa; sepsis; septic shock; Xigris®. Additional references were retrieved from the studies initially selected.

CONCLUSIONS: Mortality and bleeding complications associated with the use of DrotAA were more frequent in large observational studies than those reported in randomized trials. In the light of the current knowledge, routine use of DrotAA should be reevaluated until well-designed confirmatory clinical trials can clarify the true efficacy and safety of the drug and help identify the subgroup of patients that can benefit from use of DrotAA. Physicians should be cautious with the rapid transfer of evidences not well-documented, to the guidelines and recommendations practiced in the care and treatment of patients with severe sepsis.

Key Words: activated protein C, drotrecogin alfa, mortality, sepsis, septic shock

INTRODUCTION

Sepsis is one of the main causes of admission to intensive care units (ICU) and, despite improvements in the care of patients followed-up in the last years; it is still associated to high mortality1-4. After a sequence of negative results in clinical trials using specific treatments, the PROWESS study showed a significant reduction of mortality by using drotregogin alfa activated (DrotAA) in patients with severe sepsis5. Based upon results of this phase 3 trial study the FDA (Food and Drug Administration) and various regulatory agencies sanctioned, under special circumstances, release of this drug for patients with sepsis and high risk of death (e.g. presence of multiple organ dysfunction or APACHE II > 25 points). Notwithstanding the initial enthusiasm, debate on the safety and efficacy of DrotAA is timely, primarily because of the negative outcomes in subsequent clinical trials and economic impact on the health system due to its high cost 6-12.

This study intended to review the leading studies on the utilization of DrotAA in patients with severe sepsis, stressing issues related to its efficacy and safety.

Articles on the use of DrotAA in patients with sepsis published in MedLine - PubMed (www.pubmed.gov) during the last ten years were selected. The following keywords were used: activated protein C; drotrecogin alfa; sepsis; septic shock; Xigris®. Studies mentioned in the articles selected were also used.

THE USE OF DROTRECOGIN ALFA ACTIVATED IN CLINICAL PRACTICE

Three large observational studies on the utilization of DrotAA in the "real world" were published13-15. In the first study, Bertolini et al. monitored the use of DrotAA in Italy, from July 2003 to March 2006, following a resolution of the Italian Health Ministry to carry out a drug-surveillance program13. Included were 668 patients from 134 ICUs, corresponding to approximately 80% of the patients who had used the drug in Italy during the period in question.

The control group (n = 1181) was comprised of patients, eligible for DrotAA who were not given the medication, selected from a program of infection surveillance. Mortality in the ICU was significantly higher in the control group than in those treated with DrotAA (55% versus 46.4%, p= 0.0004). However, patients treated with DrotAA were younger and had a higher prevalence of trauma and surgical procedures and in the multivariate analysis, the use of DrotAA did not continue to be associated with survival (p = 0.434). Furthermore, in stratified analysis according to the type of admission, use of DrotAA was associated with higher mortality in patients who underwent elective surgery [OR = 2.79 (IC 95%, 1.31-5.97)]. In the second study, Kanji et al. carried out a retrospective analysis on the use of DrotAA in 261 patients admitted, from March 2003 to February 2004, in 37 ICUs (57% of the total) in the provinces of Ontario and Quebec, Canada14. There was no control group in this study and overall mortality was 45%. Use of DrotAA in the first 12h after diagnosis of severe sepsis was associated with reduction of mortality [OR = 0.51 (IC 95%, 0.28-0.92)]. In the third study, Wheeler et al., retrospectively evaluated 274 patients, treated with DrotAA in five American teaching institutions15. In this study, also without a control groups, overall hospital mortality was of 42% being significantly lower in patients given the drug on the day of diagnosis of sepsis than in those given it in the following days (33% versus 40% and 52%, p = 0.016). However, it is noteworthy that observations of the last two studies are subject to bias in selection and treatment access (patients who receive DrotAA late, may have had late access to the hospital and ICU and have received other inadequate interventions).

Two findings common to these studies are particularly relevant. The mortality rates (42% or more) were substantially higher than those described in the PROWESS (24.7% and 30.8%)5, ENHANCE (25.3%)16, and ADDRESS (20.5% and 20.6%)7 studies, although the authors attributed such results to greater severity of their patients, especially a greater number of organ dysfunctions13-15. However, these values are similar to those described in various studies with patients having both severe sepsis and septic shock1-4. In the BASES and "Sepse Brasil" studies, mortality rates of patients with severe sepsis were 34% and 47% and the patients with septic shock were 52% and 65% respectively3-4. However, the most important observation was the higher incidence of severe hemorrhagic events in the three studies (10% in the Canadian, 10.9% in the Italian; 4.4% in the American), almost all during administration of DrotAA. In the PROWESS, ENHANCE and ADDRESS studies, rates of severe hemorrhagic events were of 3.5%, 6.5% and 3.9%, respectively. Likewise, due to greater severity of patients, risk of bleeding might be higher than in the clinical trials. However, bleeding incidence was not influenced by the severity of patients in other studies17. This finding agrees with the literature, where a higher number of adverse events are more frequent in the observational than in the randomized studies18. In the Canadian study, hospital mortality rate was significantly higher in patients with hemorrhagic events (68% versus 42.7%, p = 0. 015) and use of DrotAA in patients with a contraindication for use was associated with increase of these adverse events [OR = 2.7 (IC 95%, 1.1-6.5)]. In this study, 20% of patients had relative contraindications and 2% had absolute contraindication for DrotAA. In the Italian study a higher mortality was noted in patients presenting with severe bleedings associated to DrotAA, (57.5% versus 44.9%, p = 0.041). In this study an extremely relevant finding was the high frequency of off-label use of the drug detected in 19.1% of patients.

IMPLICATIONS IN THE ASSESSMENT OF EFFICACY, DRUG-SURVEILLANCE AND SAFETY OF PATIENTS

Drug-surveillance and safety of patient related issues must be addressed. Results of the three studies13-15, together with the two ADDRESS7 and RESOLVE6 studies, impose significant considerations about safety and efficiency of DrotAA in patients with sepsis. The ADDRESS study included adult patients with severe sepsis and "low risk of death", that is to say a single organic dysfunction or with APACHE II score < 25 points7. However, although the required sample size had been estimated at 11,444 patients, this study was stopped early after interim analysis of 2,640 patients (23% of the planned), for lack of benefit (mortality rates of 20.5% for the placebo group and 20.6% for the group treated with DrotAA, p = 0.98) and by the increased incidence of severe hemorrhagic events (2.2% versus 3.9%, p = 0.01). Although the ADDRESS study was not designed to evaluate use of DrotAA in more severe patients, due to the dual possibility of assessing the severity of the patient, patients with an APACHE II score < 25 points but with more than one organic dysfunction and patients with one organic dysfunction and APACHE II score > 24 were included. In the analyses of these sub-groups of "greater severity" (according to the inclusion criteria for use of the drugs in Europe and in the USA respectively), there were no noticeable differences in the mortality rate of patients receiving placebo or DrotAA. The RESOLVE study evaluated pediatric patients with severe sepsis and was designed to include some 3,000 patients6. However this study also was interrupted at the second interim analysis, after inclusion of 477 patients (15.9% of planned), due to lack of benefit (17.5% mortality for the placebo group and 17.2% for the group treated with DrotAA, p = 0.93) and a tendency towards increased risk of bleeding in the central nervous system, in patients with < 60 days (4.6% versus 2.1%, p = 0.13). The PROWESS study, planned to include 2,280 patients was also stopped early after inclusion of 1,690 patients (74% of the planned), but in this case due to benefit , since in the second interim analysis a lower mortality was observed in the group treated with DrotAA (24.7% versus 30.8%, p = 0.006)5 . However, there was not enough power to properly assess the occurrence of severe bleedings [3.5% (30/850) in the group treated with DrotAA versus 2% (17/840) in the placebo group, p = 0.06] In a simulation, with projection for the initially desired sample size in which frequencies of adverse events in the two groups would be maintained, this difference would become statistically significant [3.5% (40 events in the DrotAA group) versus 2% (23 events in the placebo group), p = 0.04].

The clinical trials stopped early due to benefit, have merited special attention. Montori et al. evaluated the frequency and quality of such clinical trials published in the last years19. From a total of 143 studies, 92 (64%) were published in medical journals with the highest impact factor (N Engl J Med, JAMA, Ann Intern Med, Lancet and BMJ). Notwithstanding, the authors noted that these studies: a) are becoming more frequent; b) are usually sponsored by industry; c) often fail to adequately report relevant information about the decision to stop early; d) present implausibly large treatment effects, particularly when the number of events is small; and recommend that clinicians should view the results of such trials with skepticism. In that review, Critical care ranked, fourth in the order of frequency of these studies. The OPTIMIST20 trial which assessed the response to use of recombinant tissue factor pathway inhibitor (tifacogin) on mortality of patients with severe sepsis is a fair example of the issues related to clinical trials stopped early. In the first interim analysis, a significant decrease of mortality (29% versus 39%, p = 0.006) was observed in patients treated with tifacogin. Yet, the study was continued until the sample reached the planned size. This difference of the endpoint magnitude initially observed, was totally reversed with pursuance of the study and end mortality was similar between groups. Use of tifacogin was associated to a higher rate of bleedings. Similar performances have already been perceived in other areas of Medicine21,22. Findings of OPTIMIST associated to the negative outcomes of the ADDRESS and RESOLVE studies suggest the possible influence of chance in the results of the PROWESS study.

DrotAA is one among many examples of treatments incorporated in the practice in Critical Care practice based upon results of a single phase 3 studies. The new flexibilization of drug release policies adopted by the FDA (fast-track) came to meet the needs for treatment of patients with severe diseases when time is the key element, such as antiretrovirals for treatment of the acquired immunodeficiency syndrome (AIDS) and chemotherapy for treatment of advanced tumors. This program consists of accelerating the approval of a new drug based upon results of preliminary studies23,24. However, final approval of these drugs has to rely on confirmatory trials (phases 3 or 4) on the benefit and safety of the drug, as well as permit identification of subgroups of patients that would benefit most from the treatment, thereby avoiding costs of inefficient treatments and patient loss of an opportunity for a more appropriate treatment. There are many recent examples of treatments and devices whose efficacy and safety are questionable and many were withdrawn from the market due to subsequent studies25-29. Phase 4 studies are especially important for drug-surveillance since a phase 3 study, even with inclusion of 2,000 or 3,000 patients, is not acceptable to identify occurrence of less frequent, although potentially severe or fatal, adverse events30.

As for DrotAA, it is remarkable that prior to publication of the PROWESS study, there were no publications on pre-clinical studies that suitably described their mechanisms of action. Indeed DrotAA's anticoagulant and anti-inflammatory roles31 as well as the prognostic impact of protein C levels in patients with severe sepsis and ISRS were clarified only recently32-34.

CONCLUSIONS

The rush to transfer evidences still being gathered, for recommendation and treatment guidelines of patients with severe sepsis, is a matter of concern that has been subject of intense debate35-38. In the light of the current evidence, the use of DrotAA must be reconsidered until new clinical trials contribute with additional information on the efficacy, safety and identification of subgroups of patients with severe sepsis that may possibly benefit from use of this drug. This statement must be underscored because various questionings about the possible biases and failures in the method of the PROWESS study have not yet been adequately answered30,40.

REFERENCES

  • 01. Vincent JL, Sakr Y, Sprung CL, et al. Sepsis in European intensive care units: results of the SOAP study. Crit Care Med, 2006;34:344-353.
  • 02. Annane D, Vignon P, Renault A, et al. Norepinephrine plus dobutamine versus epinephrine alone for management of septic shock: a randomised trial. Lancet, 2007;370:676-684.
  • 03. Sales Jr JA, David CM, Hatum R, et al. Sepse Brasil: estudo epidemiológico da sepse em unidades de terapia intensiva brasileiras. Rev Bras Ter Intensiva, 2006;18:9-17.
  • 04. Silva E, Pedro Mde A, Sogayar AC, et al. Brazilian Sepsis Epidemiological Study (BASES study). Crit Care, 2004;8:R251-R260.
  • 05. Bernard GR, Vincent JL, Laterre PF, et al. Efficacy and safety of recombinant human activated protein C for severe sepsis. N Engl J Med, 2001;344:699-709.
  • 06. Nadel S, Goldstein B, Williams MD, et al. Drotrecogin alfa (activated) in children with severe sepsis: a multicentre phase III randomised controlled trial. Lancet, 2007;369:836-843.
  • 07. Abraham E, Laterre PF, Garg R, et al. Drotrecogin alfa (activated) for adults with severe sepsis and a low risk of death. N Engl J Med, 2005;353:1332-1341.
  • 08. Friedrich JO, Adhikari NK, Meade MO - Drotrecogin alfa (activated): does current evidence support treatment for any patients with severe sepsis? Crit Care, 2006;10:145.
  • 09. Eichacker PQ, Natanson C - Increasing evidence that the risks of rhAPC may outweigh its benefits. Intensive Care Med 2007;33:396-399.
  • 10. Machado FO - Medicina baseada em consciência social. Rev Bras Ter Intensiva, 2007;19:279-280.
  • 11. Opal SM - Can we RESOLVE the treatment of sepsis? Lancet, 2007;369:803-804.
  • 12. Costa V, Brophy JM - Drotrecogin alfa (activated) in severe sepsis: a systematic review and new cost-effectiveness analysis. BMC Anesthesiol 2007;7:5.
  • 13. Bertolini G, Rossi C, Anghileri A, et al. Use of Drotrecogin alfa (activated) in Italian intensive care units: the results of a nationwide survey. Intensive Care Med, 2007;33:426-434.
  • 14. Kanji S, Perreault MM, Chant C, et al. Evaluating the use of Drotrecogin alfa (activated) in adult severe sepsis: a Canadian multicenter observation study. Intensive Care Med, 2007;33:517-523.
  • 15. Wheeler A, Steingrub J, Schmidt GA, et al. A retrospective observational study of drotrecogin alfa (activated) in adults with severe sepsis: comparison with a controlled clinical trial. Crit Care Med, 2008;36:14-23.
  • 16. Vincent JL, Bernard GR, Beale R, et al. 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.
  • 17. Ely EW, Laterre PF, Angus DC, et al. Drotrecogin alfa (activated) administration across clinically important subgroups of patients with severe sepsis. Crit Care Med 2003; 31:12-19.
  • 18. Papanikolaou PN, Christidi GD, Ioannidis JP - Comparison of evidence on harms of medical interventions in randomized and nonrandomized studies. CMAJ, 2006;174:635-641.
  • 19. Montori VM, Devereaux PJ, Adhikari NK, et al. Randomized trials stopped early for benefit: a systematic review. JAMA, 2005;294:2203-2209.
  • 20. 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.
  • 21. Wheatley K, Clayton D - Be skeptical about unexpected large apparent treatment effects: the case of an MRC AML12 randomization. Control Clin Trials, 2003;24:66-70.
  • 22. Pocock S, Wang D, Wilhelmsen L, et al. The data monitoring experience in the Candesartan in Heart Failure Assessment of Reduction in Mortality and morbidity (CHARM) program. Am Heart J, 2005;149:939-943.
  • 23. Roberts TG Jr, Chabner BA - Beyond fast track for drug approvals N Engl J Med, 2004;351;501-505.
  • 24. Mitka M - Accelerated approval scrutinized: confirmatory phase 4 studies on new drugs languish. JAMA, 2003;289:3227-3229.
  • 25. Lynch TJ, Bell DW, Sordella R, et al. Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med, 2004;350:2129-2139.
  • 26. Stone GW, Moses JW, Ellis SG, et al. Safety and efficacy of sirolimus- and paclitaxel-eluting coronary stents. N Engl J Med, 2007;356:998-1008.
  • 27. Bresalier RS, Sandler RS, Quan H, et al. Cardiovascular events associated with rofecoxib in a colorectal adenoma chemoprevention trial. N Engl J Med, 2005;352:1092-1102.
  • 28. Chen HJ, Bloch KJ, Maclean JA - Acute eosinophilic hepatitis from trovafloxacin. N Engl J Med, 2000;342:359-360.
  • 29. Watkins PB, Whitcomb RW - Hepatic dysfunction associated with troglitazone. N Engl J Med, 1998; 338:916-917.
  • 30. Vlahakes GJ - The value of phase 4 clinical testing. N Engl J Med, 2006;354:413-415.
  • 31. Kerschen EJ, Fernandez JA, Cooley BC, et al. Endotoxemia and sepsis mortality reduction by non-anticoagulant activated protein C. J Exp Med, 2007;204:2439-2448.
  • 32. Shorr AF, Bernard GR, Dhainaut JF, et al. Protein C concentrations in severe sepsis: an early directional change in plasma levels predicts outcome. Crit Care, 2006;10:R92.
  • 33. Borgel D, Bornstain C, Reitsma PH, et al. A comparative study of the protein C pathway in septic and nonseptic patients with organ failure. Am J Respir Crit Care Med, 2007;176:878-885.
  • 34. Brunkhorst F, Sakr Y, Hagel S, et al. Protein C concentrations correlate with organ dysfunction and predict outcome independent of the presence of sepsis. Anesthesiology, 2007;107:15-23.
  • 35. Salluh JIF, Bozza FA, Soares M, et al. Brás Cubas, a sepse e as evidências: reflexões sobre a Surviving Sepsis Campaign. Rev Bras Ter Intensiva, 2006;18:328-330.
  • 36. Eichacker PQ, Natanson C, Danner RL - Surviving sepsispractice guidelines, marketing campaigns, and Eli Lilly. N Engl J Med, 2006;355:1640-1642.
  • 37. Singer M - The Surviving Sepsis guidelines: evidence-based ... or evidence-biased? Crit Care Resusc, 2006;8:244-245.
  • 38. Salluh JIF, Bozza FA, Bozza PT - Surviving sepsis campaign: a critical reappraisal. Shock, in press.
  • 39. Mackenzie AF - Activated protein C: do more survive? Intensive Care Med, 2005;31:1624-1626.
  • 40. Macias W - Activated protein C: do more survive? Intensive Care Med, 2006;32:605-607.
  • Endereço para correspondência:
    para Correspondência
    Dr. Márcio Soares
    Núcleo de Pesquisa Clínica em Medicina Intensiva
    Instituto Nacional de Câncer - INCA
    Centro de Tratamento Intensivo - 10o Andar
    Pça. Cruz Vermelha, 23
    20230-130 Rio de Janeiro, RJ
    Fone: (21) 2506-6120; Fax: (21) 2294-8620
    E-mail:
  • *
    Recebido do Instituto Nacional de Câncer, Rio de Janeiro, RJ
  • Publication Dates

    • Publication in this collection
      16 July 2008
    • Date of issue
      June 2008

    History

    • Received
      29 Feb 2008
    • Accepted
      04 Apr 2008
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