A recent systematic review and meta-analysis evaluated the cardiotoxicity of the standard first-line treatment of non-Hodgkin lymphoma, i.e., cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) or CHOP with rituximab (R-CHOP). This paper, which followed Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, included 137 clinical trials and observational studies representing 21,211 patients. Articles cited in PubMed, EMBASE, or the Cochrane Library database from April 1984 to June 2019 were included in the analysis.

To determine risk, the systematic review and meta-analysis assessed the number and severity (or grade) of cardiovascular adverse effects (CVAEs), the number of patients for whom treatment was possibly associated with the cause of death, and the number of patients with clinical or subclinical heart failure (HF). The focus of this paper was to identify the proportion of patients with Grade 3 to Grade 4 CVAEs and HF. 

According to the common terminology criteria for adverse events, Grade 3 adverse events are severe or medically significant but not immediately life-threatening; involve a hospitalization or prolongation of hospitalization; are disabling; and limit self-care activities of daily living. Grade 4 adverse events are life-threatening and require urgent intervention to mitigate the sequelae.

The 137 studies were further broken down into 165 subgroups based on variations in treatment protocols, such as the number of cycles, intervals between cycles, and different dosing regimens. Of these 165 subgroups, 85 involved the administration of CHOP, 76 included the use of R-CHOP, and four incorporated both regimens. Among these various subgroups, 82% of patients received standard doses of CHOP/R-CHOP.

Of the 165 treatment subgroups, 96 subgroups (derived from 77 of the 137 studies) reported on the proportion of patients with Grade 3-4 CVAEs. This yielded a range of 0% to 15.1% with a low pooled proportion of 2.35%. Only 47 subgroups (representing 38 studies) reported on the occurrence of overall HF for a pooled proportion of 4.62%. Among 30 subgroups (based on 23 studies), the proportion of Grade 1-2 CVAEs was higher, at 8.52%. 

The proportion of possible treatment-related cardiac deaths ranged from 0% to 5.6%, with a pooled  proportion of 0.03% based on data from 134 studies involving 15,055 patients. 

Female gender and age over 65 years were independently associated with a significantly increased risk of CVAEs. Despite long-established awareness about anthracyclines’ cardiotoxicity, screening for this AE was low. Active screening for HF following administration of CHOP/R-CHOP significantly increased the risk of identifying overall HF, from 1.64% to 11.72%. 

Patients who receive anthracyclines should be assessed for the development of left ventricular dysfunction for at least 1 year following therapy.

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