Incidence, definitions and outcomes of anthracycline induced subclinical and clinical left ventricular dysfunction: a systematic review and meta-analysis
Authors: Farooqui N , De Melo Jr J F , Kailash V , Aburmilah A , Abozied O , Abbasi M , Siontis K , Paludo J , Ruddy K J , Herrmann J 
Published: October 2024

Abstract

Purpose
To assess incidence and risk factors for anthracycline-induced left ventricular dysfunction, and associated mortality in order to inform patients and providers of the risk, as well as for clinical trial endeavours.

Background
Anthracyclines (ACs) are very effective cancer therapeutics, but their use is confronted by the risk of cardiotoxicity. Estimates of AC-induced cardiotoxicity based on systematic analyses are limited and have not recently been defined. We present here a systematic review and meta-analysis of the incidence of anthracycline induced subclinical (AC-LVD) and clinical LV dysfunction (AC-CHF) and AC-CHF related mortality in non-liposomal AC recipients over the last 3 decades.

Methods
We searched Ovid MEDLINE(R), Embase, Cochrane Database and other major databases from their inception until June 22, 2023 for studies examining the rate of AC induced cardiomyopathy in patients receiving ACs and anthraquinones for haematologic, breast (BC) and sarcomatous malignancies. Covidence was used to aid with the management of our systematic review. Screening of abstracts and data extraction was independently performed by 2 reviewers.

Results
6,365 abstracts were reviewed, of which 74 were included in the final analysis. 72 studies (n=41,138) reported data on AC-LVD, and 47 studies (n=27,012) reported data on AC-CHF. The average age was 53 years and 50% of the patients were female. Data on cardiac function at baseline was available in only 70% of the studies. Overall, AC-LVD occurred in 8.2% (95% CI 6.8%-10.2% I2 97%) (Fig 1). AC-CHF was noted in 2.2% (95% CI 1.6% to 2.9%, I2 91%) (Fig 2A), mortality related to decompensated AC-CHF was 0.5% (95% CI 0.3%-0.9%, I2 88%) (Fig 2B) while total mortality rate among AC recipients was 24.9% (95% CI 14.8-38.7%, I2 99%). Incidence of AC-LVD was higher in doxorubicin recipients (vs other ACs 10.5% vs 5-5.6%), studies from North America & Asia (vs other regions; 9.3-9.6% vs 6.7%), and prospective studies (vs retrospective studies; 8.7% vs 7.5%). AC-LVD was more common in BC patients (vs other cancers; 8.7% vs 3.5-7.2%) while AC-CHF was more common in lymphoma patients (8.5% vs 1.6-4.1%). AC-LVD was 4.6 times (95% CI 1.2-17.1, p=0.02) more likely in patients with a mean age &gt;70 (vs &lt;70). 21 definitions for AC-LVD were used across the studies. The most common definition (15 studies; n=7904) was "any decline in LVEF from baseline" resulting in a 5.8% rate of AC-LVD.

Conclusions
AC-LVD and AC-CHF has been reported in up to 10% and 3% of AC recipients, respectively. AC-CHF related mortality occurs in &lt;1% of anthracycline recipients and has a 2-3% share in overall mortality among these patients. The type of malignancy and anthracycline can influence the rate of AC-LVD, AC-CHF and AC-CHF related mortality. Global region, age of the patient population and study design also seem to influence incidence rates. There is noteworthy heterogeneity in definitions for cardiotoxicity across studies.