Niereninsuffizienz bei Patienten mit einem thromboembolischen Ereignis: Prävalenz und klinische Implikationen.

Zusammenfassung

Hintergrund und Fragestellung | Die Bestimmung der Nierenfunktion ist von besonderer Bedeutung bei Auswahl und Dosierung der initialen Antikoagulation von Patienten mit einem thromboembolischen Ereignis, da zahlreiche Antikoagulanzien über die Niere ausgeschieden werden. Insbesondere für Patienten, die eine schwer eingeschränkte Nierenfunktion aufweisen, steigt das Risiko einer Akkumulation der Wirkstoffe und somit das Risiko von Blutungskomplikationen. In den aktuellen Fachinformationen der zur Therapie zugelassenen Wirkstoffe sowie den aktuellen AWMF-Leitlinien wird diesem Aspekt besondere Aufmerksamkeit gewidmet. So sind einige Wirkstoffe in dieser Patientengruppe kontraindiziert, für einige Wirkstoffe wird eine erhöhte Kontrollintensität (anti-Xa) empfohlen und für den Wirkstoff Enoxaparin ist eine Dosisreduktion vorgesehen. Ziel dieser Übersichtsarbeit ist die Beantwortung folgender Fragen:

• Wie hoch ist die Prävalenz der Niereninsuffizienz bei Patienten mit venöser Thromboembolie (VTE)?

• Welche Daten zur initialen Antikoagulationsbehandlung von niereninsuffizienten VTE-Patienten und zu mit der Behandlung korrespondierenden klinischen Ergebnissen (Rezidive, Blutungsereignisse und Mortalität) sind verfügbar?

Methodik | Es wurde eine systematische Datenbanksuche und eine Bewertung der verfügbaren englisch- und deutschsprachigen Literatur des Zeitraumes von Januar 2004 bis Januar 2014 durchgeführt. Dabei wurden lediglich Publikationen in die Übersichtsarbeit aufgenommen, die als quantitative Forschung bezeichnet werden können.

Ergebnisse | Insgesamt konnten 1135 Studien identifiziert werden, von denen letztlich 37 in die Übersichtsarbeit eingeschlossen wurden.

Die Prävalenz einer Kreatinin-Clearance (KrCl) unter 60 ml / min lag zwischen 12,3 und 71,9 % der VTE-Patienten. Die Prävalenz einer KrCl unter 30 ml / min betrug 3,3–13,6 %. Die großen Unterschiede sind ganz wesentlich durch verschiedene Patientenkollektive zu erklären.

Eine KrCl < 30 ml / min war ein unabhängiger Prädiktor für Mortalität und fatale Lungenembolie, evtl. auch für schwere Blutungen bei der Therapie von VTE-Patienten. Dabei ist sie vermutlich auch schon ein Prädiktor für das Auftreten eines VTE-Ereignisses.

Die Daten zeigen auch, dass zahlreiche Antikoagulanzien zur Akkumulation neigen und so, beispielhaft, eine Standarddosis Enoxaparin zu höheren Blutungsraten in der VTE-Therapie führt als eine angepasste Dosis Enoxaparin. Zu anderen niedermolekularen Heparinen (NMH) und zu unfraktionierten Heparinen (UFH) gab es weitaus weniger umfangreiche Daten. Allein zur Sicherheit von Certoparin und Tinzaparin konnten eigene Studien in der betrachteten speziellen Patientengruppe identifiziert werden.

Keine der identifizierten Studien zeigt Effektivitäts- und / oder Sicherheitsvorteile der UFH- im Vergleich zur NMH-Therapie bei VTE-Patienten mit stark eingeschränkter Nierenfunktion; vielmehr kann nach aktueller Studienlage deren Nachteiligkeit angenommen werden. Die Evidenz beruht allerdings auf observationalen Studien bzw. Registerdaten.

Schlussfolgerung | Die Kenntnis der Fachinformation der initialen Antikoagulanzien ist unerlässlich, da diese nähere Auskünfte zu Dosierungsschemata bzw. zur Kontraindikation einiger Substanzen präzisieren. Die aktuelle AWMF-Leitlinie ist hinsichtlich der Empfehlung von UFHs als Option erster Wahl bei KrCl < 30 ml / min zu diskutieren.

Abstract

Background and study objectives | The assessment of the renal function of patients with a deep vein thrombosis / pulmonary embolism (VTE patients) is of utmost importance for the selection / dosage of an agent in the initial anticoagulation management of these patients because the majority of available anticoagulants are cleared renally. Specifically, there is a high risk of drug accumulation and subsequent bleedings in patients with severe renal insufficiency. Consequently, specific recommendations have been made for the initial anticoagulation management of these patients in both product labels and AWMF treatment recommendations: some drugs should not be used in these patients, for other drugs a careful use, intensified screening (anti-Xa), or, in the case of enoxaparin, a dose-adjustment are recommended.

This literature review aimed to answer the following questions:

• What is the prevalence of renal insufficiency in VTE patients?

• Which data are available with regard to the real-world initial anticoagulation management and corresponding clinical outcomes (recurrent VTE events, bleedings, mortality) of these patients?

Methodology | We did a systematic review of existing publications in german or english published in 2004–2014. Only quantitative analyses have been included in the review.

Results | We identified 1,135 publications, 37 of them were included in our review. The prevalence of renal insufficiency in VTE patients, defined as CrCl < 60 ml / min, was reported to be 12.3 %-71.9 % related to all VTE patients. The prevalence of severe renal insufficiency, defined as CrCl < 30 ml / min, was reported to be 3,3 %-13,6 %. The substantial ranges in reported prevalences are mainly due to differences in the characteristics of patients addressed in the different publications.

A CrCl < 30 ml / min is an independent predictor for both mortality and lethal recurrent pulmonary embolism, possibly also for severe bleedings in VTE patients. In addition to that, a severe renal insufficiency may also be a predictor for the probability that a first VTE event occurs.

Several anticoagulants approved for the initial anticoagulation management of VTE patients face the risk of drug accumulation in renally insufficent patients. So, for example, a standard enoxaparin dosage was shown to be associated with elevated bleeding risk compared to adjusted enoxaparin dosage in renally insufficient patients. However, similar data do not exist for other low molecular weight heparins (LMWHs) or unfractioned heparins (UFHs). Only for two LMWHs, Certoparin and Tinzaparin, safety data with regard to renally insufficient patients have been published so far.

None of the included studies showed advantages of UFH therapy in comparison to LMWH therapy in initial anicoagulation management of VTE patients. In contrast to that, available evidence shows disadvantageous efficacy / safety of UFH in comparison to LMWH treatment. However, this evidence is not based on head-to-head comparisons but is derived from registry and observational study data only.

Conclusion | A detailed knowledge of product labels is of utmost importance in the inital anticoagulation treatment of VTE patients because several agents may not be used in the addressed patients with severe renal insufficiency at all while others may be used based on specific dosage / surveillance schemes only. We also recommend to critically appraise the current AWMF treatment guidline because it still recommends initial anticoagulation management with UFHs in VTE patients with severe renal insufficiency. Available data do not support that recommendation.

Schlüsselwörter

Niereninsuffizienz - Thromboembolie - initiale Antikoagulation - Prävalenz Niereninsuffizienz

Keywords

renal impairment - thrombosis - initial anticoagulation - prevalence renal insufficiency

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