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Gerinnungsaktive Substanzen als Sepsistherapeutika

Erfolg und Misserfolg

Endogenous anticoagulant therapy for sepsis

Success and failure

  • Arzneimitteltherapie
  • Published:
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Zusammenfassung

Im Gegensatz zu den beiden endogenen Antikoagulanzien Antithrombin und Tifacogin, die in 2  großen Studien an Patienten mit schwerer Sepsis ohne Wirksamkeit blieben, hat das dem aktivierten Protein C entsprechende Drotrecogin alfa (aktiviert) die Sepsismortalität in einer dritten großen Studie gesenkt. Für die Registrierung dieses neuartigen Medikaments war diese eine Phase-III-Studie (PROWESS) vorgelegt worden, bei der jedoch mehrere interne und externe Validitätsprobleme festgestellt werden mussten. Da zudem noch insgesamt wenig über Drotrecogin alfa bekannt war, ist die Zulassung auf eine Subgruppe der in PROWESS untersuchten Patienten beschränkt geblieben, und sie wurde an Auflagen gekoppelt. Die Randomisierung der Patienten für diese Subgruppe erfolgte nicht stratifiziert. Bedenken bezüglich der Sicherheit und Wirksamkeit von Drotrecogin alfa haben sich verstärkt, seit die Ergebnisse eines Teils der auferlegten Phase-IV-Studien (ADDRESS, PROWESS Langzeituntersuchung und die pädiatrischen Studien) bekannt geworden sind. Auf Basis der verfügbaren Evidenz fällt es deswegen schwer, rationale und sichere Empfehlungen für den Einsatz von Drotrecogin alfa bei schwerer Sepsis auszusprechen. Weitere klärende Studien sind dringend notwendig und gefordert. Registrierungsbehörden sind aufgerufen, die Zulassung von Drotrecogin alfa zu überdenken und dabei jene Kriterien zu berücksichtigen, die in ihren eigenen Richtlinien enthalten sind für den Fall, dass die Authorisierung für das Inverkehrbringen von Arzneimitteln auf Basis einer einzigen, zentralen Phase-III-Studie erfolgen soll. Die geforderte Studie soll verhindern, dass Patienten womöglich eine unwirksame oder gar tödliche Behandlung der Sepsis erhalten.

Abstract

Whereas antithrombin and tifacogin failed to improve clinical outcome in cases of severe sepsis, drotrecogin alfa (activated) increased the chances of survival of patients with this condition. Concerns about efficacy and safety of drotrecogin alfa have been raised because of internal and external validity and internal consistency problems found in the PROWESS study, and because of the drug’s single positive pivotal phase III documentation that led to restricted marketing authorisations for only a subgroup of studied patients whose randomisation had not been stratified. Concerns intensified with data from ADDRESS, the PROWESS follow-up, and paediatric studies. It is difficult to make rational and safe recommendations for drotrecogin alfa use on the available evidence. Further trials have been suggested. The relevant bodies should review product approval in light of their own guidelines for marketing authorisations on the basis of single pivotal trials and request the further study required to prevent the possibility of patients receiving a non-efficacious and potentially lethal drug.

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Interessenkonflikt

Der Autor erhält Vertragshonorare von den Firmen Talecris und CSL-Behring sowie Drittmittel für Projekte von CSL-Behring.

Trotz des möglichen Interessenkonflikts ist der Beitrag unabhängig und produktneutral.

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Authors and Affiliations

  1. Abteilung für Innere Medizin, Zentralkrankenhaus und Akademisches Lehrkrankenhaus der Medizinischen Universität Innsbruck in Bozen, L.-Böhler-Straße 5, 39100, Bozen, Italien

    C. J. Wiedermann

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Correspondence to C. J. Wiedermann.

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Anmerkung

Während der Drucklegung dieses Artikels hat die EMEA am 2. März 2007 aus der Vollversammlung des CHMP vom 19.–22. Februar 2007 berichtet (EMEA/85096/2007), dass wegen Unschlüssigkeit in den Ergebnissen einer ursprünglich ebenfalls auferlegten Phase-IV-Studie (XPRESS), in der die Interaktion von Xigris® mit Heparin getestet wurde, bei schwerer Sepsis eine zusätzliche Klärung des Nutzen-Risiko-Verhältnisses der Xigris®-Therapie erforderlich ist. Es wurde eine weitere Studie gefordert, in der Xigris® bei schwerer Sepsis (mit oder ohne Heparin) noch einmal gegen Placebo getestet werden muss. Die bisherige Verkaufsautorisierung wird während der Durchführung dieser Studie unter Ausnahmebedingungen aufrechterhalten.

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Wiedermann, C. Gerinnungsaktive Substanzen als Sepsistherapeutika. Internist 48, 537–544 (2007). https://doi.org/10.1007/s00108-007-1840-y

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