SCARLET

Effect of Recombinant Human Soluble Thrombomodulin on Mortality in Patients with Sepsis-Associated Coagulopathy

JL Vincent et al. 2019; doi:10.1001/jama.2019.5358

Clinical Question

  • In adult patients with sepsis-associated coagulopathy does the administration of human recombinant thrombomodulin (rhsTM) compared to placebo reduce 28 day mortality?

Background

  • The presence of a sepsis-associated coagulopathy and its severity has been independently associated with an increased hospital mortality
  • Haematological manipulation in patients with septic shock is a controversial area following the PROWESS and PROWESS-SHOCK trials involving Activated Protein C (Drotrecogin Alfa)
  • ART123 is a rhsTM, and acts as co-factor with thrombin in the activation of Protein C
  • A Phase 2b study had shown the use of rhsTM to be safe, and there was a suggestion of efficacy (although this was not statistically proven) when 28 day mortality was analysed

Design

  • Randomised, double-blind, placebo controlled phase III trial
    • Randomisation stratified by site with a block size of 4
    • Allocation in a 1:1 ratio
  • Consent sought prospectively
  • All potential patients discussed with a physician from one of the 2 regional coordinating  centres to confirm the inclusion criteria (listed below)
  • Window 1 (24 hours) commenced when a patient with suspected or confirmed bacterial infection developed either organ dysfunction or coagulopathy
  • Window 2 (12 hours) commenced from when the other inclusion criteria of organ dysfunction is met and allowed for discussion with coordinating centres, consent and randomisation
    • Window length changed from 15 hours to 40 hours from first qualifying measure during the study to enable more time for participant identification and enrolment
  • Study supported by Asahi-Kasei Pharma America Corporation (involved in design, collection, management, and analysis)

Setting

  • 319 sites in 27 countries
  • Patients enrolled from October 2012 – March 2018

Population

  • Inclusion Criteria:
    • > 18 years old and
    • clinical objective evidence of bacterial infection with a known site of infection (from clinical, microbiological and radiological evidence) and SIRS response (WBC count and temperature) and
      • WBC < 4000/mm³ or > 12000/mm³
      • Temperature < 36ºC or > 38ºC
    • concurrent cardiovascular and/or respiratory dysfunction and
      • vasopressors to maintain MAP > 65 mmHg following adequate fluid resuscitation
      • mechanical ventilation and P/F ratio < 250 (or < 200 if respiratory infection)
    • coagulopathy
      • INR > 1,4 (not explained by another known aetiology)
      • Platelets 30 – 150 x 109
  • Exclusion:
    • Multiple, but important ones include:
      • Platelets < 30 x 109
      • Use of anticoagulants / antiplatelets in three days prior to receiving study drug (except DVT prophylaxis, aspirin < 325mg per day, heparin locks, and anticoagulation for RRT)
      • Recent CVA, trauma with increased risk of bleeding (< 3 months), GI Bleed (6 weeks, unless corrective interventional procedure), completion of surgery that may be haemorrhagic within prior 12 hours of study drug, bleeding diathesis or hereditary hypercoagulable state
      • Renal dysfunction (chronic necessitating RRT, or acute with oliguria > 48 hours to receiving study drug
  • Sample size of 800 calculated to provide 80% power at a 5% 2 level α level based on an ARR of 8% (24% placebo and 16% rhsTM)
    • 405 allocated to placebo and 395 rhsTM
  • Well balanced baseline characteristics of both control and rhsTM groups with regards to demographics, coagulation, illness severity, organ dysfunction, and site of infection

Intervention

  • ART-123 – a recombinant human soluble thrombomodulin
    • 0.06mg/kg/d (max 6mg/day) for 6 consecutive days
    • given as IV bolus or diluted in 50mls 0.9% saline for 15 minute infusion
    • must be administered within 4 hours from closure of window 2

Control

  • Matching placebo
    • supplied in identically labelled, individual glass ampoules containing the same volume (1ml)

Management common to both groups

  • Other treatment guided as per clinical state, no specified similarities in treatment

Outcome

  • Primary outcome:
    • 28 Day Mortality
      • 26.8% rhsTM vs 29.4% placebo
      • ARR 2.55% (95% CI -3.68% to 8.77%)
  • Subgroup Analyses
    • Pre-specified
      • Non significant mortality difference in those with higher severity score (APACHE II > 25) or concomitant heparin use
      • No other pre-specified or post-hoc subgroup significant with respect to 28 day mortality
      • In those with a baseline INR > 1.4 the Kaplan-Meier Plot does show a suggestion of reduced mortality
        • The ARR is 4.01% (-3.04 to 11.06%) compared to an ARI of 5.45% for those with a baseline INR < 1.4 (-6.68% to 17.59%)
    • Coagulation Markers
      • At day 6 the plasma D-dimer concentration, Prothrombin fragment F1.2 (a marker of thrombosis) and thrombin-antithrombin complex levels were lower
      • In a post-hoc analyses the change from baseline of these markers was statistically significantly greater (p < 0.5) in the rhsTM group
  • Safety Outcome:
    • Adverse Event Rate at day 28 (including major bleeding this includes life threatening, resulting in serious morbidity or  >6 units packed red blood cells over 2 days)
      • Serious Adverse Events 52% rhsTM vs. 50% placebo
      • Serious Major Bleeding 5.8% rhsTM vs 4% placebo

Authors’ Conclusions

  • The administration of rhsTM to patients with sepsis-associated coagulopathy did not significantly reduce 28 day mortality

Strengths

  • Given the mortality trend and safety profile shown in the phase 2b study any study that tries to improve sepsis mortality is worthwhile
  • Multi-centre, international, randomised and double-blind with similar baseline characteristics increase external validity
    • However, 55/159 sites enrolled only one patient
  • Sensible inclusion of need for vasopressors and/or mechanical ventilation as a selection criteria
  • The collection of coagulation markers and the findings are interesting however I am not sure what clinical outcome this reduction in markers would translate to?
  • Well reported safety outcomes important (reported in supplementary material) to allow clinicians
  • Design minimises bias:
    • Selection bias minimised by need to discuss with coordinating centres
    • Performance and Detection bias minimised by strict blinding protocols
    • Attrition bias low (16 patients randomised but not included)

Weaknesses

  • Decision to extend time window for treatment meant that ~ 20% of study population no longer had a coagulopathy by time of drug administration
  • Sample calculations based on 8% difference, previous Phase 2b study had only shown a difference of 3.8% (17.8% in rhsTM group vs 21.56% in placebo)
  • As with any sepsis trial the population is heterogenous
  • Some of the reported outcomes (including the subgroup analysis of INR <1.4 or > 1.4 and reduction from baseline in coagulation markers) were post-hoc analyses (the author’s quite rightly highlight the need to interpret these with caution)

The Bottom Line

  • Based on this study I will not be advocating for the use of rhsTM in patients with a septic coagulopathy
  • The continued research into improving outcomes of this cohort of patients should be continued given its independent association with hospital mortality

External Links

Metadata

Summary author: George Walker @hgmwalker89
Summary date: 14 June 2019
Peer-review editor: Duncan Chambler

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