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Wann sind Drug-eluting Stents als wirksam zu bezeichnen?

Eine kritische Analyse der aktuellen Datenlage

When are drug-eluting stents effective? A critical analysis of the presently available data

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Summary.

The use of drugeluting stents (DES) has tackled the “Achilles’ heel” of percutaneous coronary interventions (PCI) like no innovation before: the restenosis following initially successful PCI of de novo stenoses. Today, with DES, the pivotal clinical parameter TVF (target vessel failure) is in the upper single- digit range for “standard” lesions and 16% for long lesions.

Numerous studies have assessed the effects of various antiproliferative and antiinflammatory substances, like Sirolimus, Tacrolimus, Everolimus, ABT-578, Biolimus, Paclitaxel, QP2 as well as of other drugs, like Dexamethasone, 17-β-Estradiol, Batimastat, Actinomycin-D, Methotrexat, Angiopeptin, Tyrosinkinase inhibitors, Vincristin, Mitomycin, Cyclosporin, and also the C-myc antisense technology (Resten-NG, AVI-4126). At the time of this analysis, four DES are CE-certified and commercially available in Europe: The Cypher stent, releasing Sirolimus from a polymer (Cordis, J&J), the Taxus stent, releasing Paclitaxel from a polymer (Boston-Scientific), the V-Flex stent, releasing Paclitaxel without a polymer (Cook) and the Dexamet stent, releasing Dexamethasone from a PC coating (Abbott). Since more DES will be CE-certified soon, an increasing challenge vexes interventional cardiologists and health care providers: Which DES should be chosen for routine patient care?

A prerequisite for assessing the efficacy of DES are randomized, controlled trials. Registries, even with strong monitoring, are limited by the known restrictions, comparing data to historical controls. At the time of this analysis, only three drugs had proven their efficacy in 13 randomized studies in 5669 patients: Paclitaxel, Sirolimus and Everolimus, with 3815 patients in Paclitaxel studies, 1748 patients in Sirolimus studies and 106 patients in Everolimus studies.

For further analysis, it makes sense to divide the primary endpoints into non-clinical and clinical endpoints. Non-clinical primary endpoints are usually angiographic parameters, like the percentage of DS (diameter stenosis, ASPECT, ELUTES), the instent LLL (late lumen loss, RAVEL, FUTURE-II), the in-stent MLD (minimal lumen diameter, E-SIRIUS, C-SIRIUS) or, like in TAXUS-II, the IVUS-determined percentage of volume obstruction. Clinical primary endpoints were either MACE (major adverse cardiac events, TAXUS-I, FUTUREI), TVF (target vessel failure, DELIVER-I, SIRIUS) or TVR (target vessel revascularization, TAXUS-IV und TAXUS-VI). As ASPECT, ELUTES and DELIVER-I have shown, even a statistically significant effect on an angiographic primary endpoint does not necessarily translate into a significant clinical effect, which is completely absent in some such cases.

Since it is not the goal of PCI to improve angiographic parameters but rather to improve patients’ outcome, the choice of DES for routine treatment should be based on the results of randomized controlled studies with a clinical primary endpoint at an appropriate time interval. At the present time, these criteria have been met by only the Cypher and the Taxus stents.

Zusammenfassung.

Der Einsatz Medikamente freisetzender Stents (Drug-eluting Stents, DES) hat wie keine andere Innovation die „Achillesferse“ der perkutanen Koronarintervention (PCI), nämlich die Restenose nach initial erfolgreicher Behandlung von denovo Stenosen, beeinflusst. Mit den DES liegt heute der harte Parameter TVF (target vessel failure) für „Standard“ de-novo Stenosen im oberen einstelligen Bereich, für lange de-novo Stenosen bei 16%.

In zahlreichen Studien wurde die Wirkung unterschiedlicher antiproliferativer Substanzen, wie Sirolimus, Tacrolimus, Everolimus, ABT-578, Paclitaxel, QP2, sowie andere Substanzen wie Dexamethason, 17-β-Östradiol, Batimastat, Actinomycin-D, Methotrexat, Angiopeptin, Tyrosinkinase-Inhibitoren, Vincristin, Mitomycin, Cyclosporin, sowie die C-myc Antisense-Technologie (Resten-NG, AVI-4126) erprobt. In Europa sind zum Zeitpunkt dieser Analyse vier DES zugelassen und kommerziell erhältlich: Der aus einem Polymer Sirolimus freisetzende Cypher- Stent (Fa. Cordis, J&J), der aus einem Polymer Paclitaxel freisetzende Taxus-Stent (Fa. Boston-Scientific), der V-Flex-Stent (Paclitaxel ohne Polymer, Fa. Cook) und der aus einer PC-Schicht Dexamethason freisetzende Dexamet-Stent (Fa. Abbott). Da demnächst mit der CE-Zulassung weiterer DES zu rechnen ist, stellt sich für die interventionell Tätigen und die Kostenträger zunehmend die Frage, nach welchen Kriterien man die Wirksamkeit eines DES beurteilen soll.

Voraussetzung für die engere Auswahl von DES sind prospektive, randomisierte, kontrollierte Studien. Register—auch wenn sie einem noch so strengen Monitoring folgten, sind aufgrund der bekannten Limitationen des Vergleichs mit historischen Patientengruppen nur bedingt aussagekräftig. Bis zum Zeitpunkt dieser Analyse haben lediglich drei Substanzen in 13 randomisierten klinischen Studien an 5669 Patienten einen Wirkungsnachweis erbracht: Paclitaxel, Sirolimus und Everolimus. Insgesamt wurden 3815 Patienten in Paclitaxel-Studien, 1748 Patienten in Sirolimus- und 106 Patienten in Everolimus-Studien untersucht.

Für die weitere Analyse ist es sinnvoll, die primären Endpunkte in nicht-klinische und klinische zu unterteilen. Als nicht-klinische primäre Endpunkte dienten meist angiographische Parameter, wie die prozentuale DS (Diameterstenose, ASPECT, ELUTES), der in- Stent LLL (late lumen loss, RAVEL, FUTURE-II), der in-Stent MLD (minimaler Lumendurchmesser, E-SIRIUS, C-SIRIUS) oder wie in TAXUS-II, die mit IVUS gemessene prozentuale Volumenobstruktion. Als klinische primäre Endpunkte wurde entweder MACE (major adverse cardiac events, TAXUS-I, FUTURE-I), TVF (target vessel failure, DELIVER-I, SIRIUS) oder die TVR (target vessel revascularization, TAXUS-IV und TAXUS- VI) gewählt. Wie ASPECT, ELUTES und DELIVER-I gezeigt haben, kann trotz eines statistisch signifikanten Wirkungsnachweises auf einen angiographischen primären Endpunkt die klinische Wirkung nicht signifikant sein oder gar fehlen.

Da es nicht das primäre Ziel der PCI ist, angiographische Parameter zu verbessern, sondern den klinischen Verlauf der Patienten positiv zu beeinflussen, sollte in der Routinebehandlung denjenigen DES der Vorzug gegeben werden, die in einer randomisierten Studie ihre Wirkung auf einen klinischen primären Endpunkt bewiesen haben. Zum jetzigen Zeitpunkt ist das lediglich der Cypher- und der Taxus-Stent.

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    S. Silber F.A.C.C., F.E.S.C.

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Silber, S. Wann sind Drug-eluting Stents als wirksam zu bezeichnen?. Z Kardiol 93, 649–663 (2004). https://doi.org/10.1007/s00392-004-0143-8

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