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Preventive use of carvedilol for anthracycline-induced cardiotoxicity: a systematic review and meta-analysis of randomized controlled trials

Präventive Anwendung von Carvedilol bei Anthrazyklin-induzierter Kardiotoxizität: systematische Übersicht und Metaanalyse randomisierter kontrollierter Studien

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Abstract

Background

Clinical or subclinical cardiotoxicity is a concern for cancer patients receiving anthracycline-based chemotherapy. Carvedilol is promising for preventing anthracycline-induced cardiotoxicity (AIC). This review appraised the preventive effects of carvedilol against AIC based on randomized controlled trials (RCTs).

Methods

The Cochrane Collaboration Central Register of Controlled Trials, PubMed, and Embase databases were searched from inception to March 27, 2018. RCTs using carvedilol for the prevention of AIC were selected. Risk of bias and methodological quality were assessed. Meta-analysis was conducted, when applicable, for the trial endpoints; otherwise the data were analyzed descriptively.

Results

Nine RCTs comprising 717 patients were selected. The risk of bias was unclear and the methodological quality differed substantially. Data pooling of five eligible studies indicated no decreased mortality in patients receiving carvedilol (risk difference = −0.02, 95% CI: −0.07–0.04, p = 0.57, I2 = 44%). The impact on the incidence of left ventricular systolic dysfunction (LVSD) was inconsistently reported but meta-analysis was not applicable due to discordant LVSD definitions. Data pooling of eight studies and a subgroup analysis indicated a higher left ventricular ejection fraction (LVEF) with substantial heterogeneity in the carvedilol group (mean difference [MD] = 5.23, 95% CI: 2.20–8.27, p = 0.0007, I2 = 95%, and MD = 4.65, 95% CI: 0.67–8.64, p = 0.02, I2 = 90%, respectively). Further analysis of echocardiographic parameters and biomarkers showed weak evidence of improvement in diastolic function and troponin I level by carvedilol administration.

Conclusion

Preventive use of carvedilol in patients undergoing anthracycline-based chemotherapy may be associated with a reduced incidence of LVSD, higher LVEF value, better diastolic function, and lower troponin I level. RCTs with larger sample size and longer follow-up are needed to verify these findings.

Zusammenfassung

Hintergrund

Eine klinische oder subklinische Kardiotoxizität ist von Belang für Tumorpatienten, die eine Chemotherapie auf Anthrazyklinbasis erhalten. Carvedilol ist vielversprechend bei der Prävention der Anthrazyklin-induzierten Kardiotoxizität (AIC). In der vorliegenden Übersichtsarbeit wurde die präventive Wirkung von Carvedilol gegen AIC anhand randomisierter kontrollierter Studien (RCT) beurteilt.

Methoden

Die Datenbanken The Cochrane Collaboration Central Register of Controlled Trials, PubMed und Embase wurden von Beginn ihres Bestehens bis 27. März 2018 durchsucht. Ausgewählt wurden RCT mit Anwendung von Carvedilol für die Prävention der AIC. Das Risiko einer Verzerrung (Bias) sowie die methodische Qualität wurden eingeschätzt. Für die Studienendpunkte wurde, wenn möglich, eine Metaanalyse durchgeführt; andernfalls wurden die Daten deskriptiv ausgewertet.

Ergebnisse

Ausgewählt wurden 9 RCT mit 717 Patienten. Das Risiko einer Verzerrung war unklar, und die methodische Qualität unterschied sich wesentlich. Das Daten-Pooling von 5 geeigneten Studien ergab keine erhöhte Mortalität bei Patienten, die Carvedilol erhielten (Risikodifferenz = −0,02; 95 %-Konfidenzintervall, 95 %-KI: −0,07 bis 0,04; p = 0,57; I2 = 44 %). Auswirkungen auf die Inzidenz linksventrikulärer systolischer Dysfunktion (LVSD) wurden uneinheitlich angegeben, aber eine Metaanalyse war wegen abweichender LSVD-Definitionen nicht durchführbar. Das Daten-Pooling von 8 Studien und eine Subgruppenanalyse ergaben eine höhere linksventrikuläre Ejektionsfraktion (LVEF) bei substanzieller Heterogenität in der Carvedilolgruppe (mittlere Differenz, MD: 5,23; 95 %-KI: 2,20–8,27; p = 0,0007; I2 = 95 % bzw. MD = 4,65; 95 %-KI: 0,67–8,64; p = 0,02; I2 = 90 %). Die weitere Analyse echokardiographischer Parameter und Biomarker zeigte eine schwache Evidenz für die Verbesserung der diastolischen Funktion und des Troponin-I-Spiegels durch Gabe von Carvedilol.

Schlussfolgerung

Der präventive Einsatz von Carvedilol bei Patienten mit Chemotherapie auf Anthrazyklinbasis geht möglicherweise mit verminderter Inzidenz einer LVSD, höherem LVEF-Wert, besserer diastolischer Funktion und niedrigerem Troponin-I-Spiegel einher. Zur Bestätigung dieser Erkenntnisse sind RCT mit größerem Stichprobenumfang und längerem Follow-up erforderlich

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Authors’ contributions

Dr. Yilin Mao proposed the idea of this work and participated in the literature survey; Dr. Jie Li designed the study protocol and participated in the literature survey, data extraction, and analysis; Dr. Muhammad Daniyal and Dr. Tao Zhan carried out the study protocol, and Dr. Tao Zhan wrote and revised the manuscript. All authors read and approved the final manuscript.

Funding

This study was funded by the Natural Science Foundation of Hunan Province (2016JJ4068) and the Education Department of Hunan Province (16A160).

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Authors and Affiliations

  1. Hunan University of Chinese Medicine, 300 Xueshi Rd., Yuelu District, 410208, Changsha, Hunan, China

    T. Zhan &  J. Li

  2. Department of Integrated TCM and Western Medicine, The First Hospital of Changsha, 410005, Changsha, Hunan, China

    T. Zhan

  3. TCM and Ethnomedicine Innovation & Development Laboratory, School of Pharmacy, Hunan University of Chinese Medicine, 410208, Changsha, Hunan, China

    M. Daniyal

  4. Department of Geriatric Medicine, The Second Affiliated Hospital, Hunan University of Chinese Medicine, 233 North Cai’e Rd., Kaifu District, 410005, Changsha, Hunan, China

    Y. Mao

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Zhan, T., Daniyal, M., Li, J. et al. Preventive use of carvedilol for anthracycline-induced cardiotoxicity: a systematic review and meta-analysis of randomized controlled trials. Herz 45 (Suppl 1), 1–14 (2020). https://doi.org/10.1007/s00059-018-4779-y

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