Cardiac failure in patients treated with azacitidine, a pyrimidine analogue: Case reports and disproportionality analyses in Vigibase

Abstract

Aims: Azacitidine (AZA), a pyrimidine analogue, is validated for high-risk myelodysplastic syndrome or low-blast acute myeloid leukaemia in unfit patients for more intensive treatment. This study assessed the putative link between cardiac failure (CF) and AZA exposure.Methods: Cases of CF in patients treated with AZA were retrospectively collected and described from several centres of the Groupe Francophone des Myélodysplasies. A description analysis and a disproportionality analysis using Vigibase, the WHO Global Individual Case Safety Reports (ICSRs) database, were conducted on ICSRs by the Standardized MedDRA Queries (SMQ broad) cardiac failure and by preferred terms cardiac failure and cardiac failure acute. The reported odds ratio (ROR) and its 95% 2-sided confidence interval was computed by comparing the proportion of CF reports with the suspected drug (AZA) and the proportion of reports of the same adverse drug reaction with all other suspected drugs in the database during the same period. Results:In the 4 case reports, all patients presented a cardiovascular history. In 1 patient, CF recurred after AZA re-challenge. The pharmacovigilance analysis in Vigibase retrieved 307 ICSRs of CF (SMQ) with AZA. Significant disproportionality signals associated with AZA were identified by using the SMQ cardiac failure (ROR 1.3) and the preferred terms cardiac failure (ROR 5.1) and cardiac failure acute (ROR 23.2). Conclusion:This study points to the potential role of AZA in the occurrence of CF. Cardiac evaluation before AZA initiation and regular monitoring of cardiac function during AZA treatment should be performed in patients with a history of cardiovascular disease. K E Y W O R D Santicancer drugs, drug safety, heart failure

Repurposing From Oncology to Cardiology: Low-Dose 5-Azacytidine Attenuates Pathological Cardiac Remodeling in Response to Pressure Overload Injury

“…Taken together with our previous study, that demonstrated that treatment of SHRs with 10 mg/kg 5aza actually lead to improved ejection fraction, these data suggest that treatment with low-dose 5aza may lead to improved cardiac function in the setting of pressure overload. This is important because a recent study identified four oncology cases (out of a database of over 9000 adverse events) where high-dose 5aza treatment was associated with alterations in ejection fraction and temporary symptoms of heart failure [31]. Unfortunately it is impossible to know whether the cardiac events reported were caused by 5aza treatment or related to the ongoing disease process.…”

“…This is important because a recent study identified 4 oncology cases (out of a database of over 9000 adverse events) where high-dose 5aza treatment was associated with alterations in ejection fraction and temporary symptoms of heart failure. 31 Unfortunately it is impossible to know whether the cardiac events reported were caused by 5aza treatment or related to the ongoing disease process. For example, myelodysplastic syndromes are associated with a complex array of systemic complications such as chronic anaemia 32 and iron overload.…”

Epigenetic modifier alpha-ketoglutarate modulates aberrant gene body methylation and hydroxymethylation marks in diabetic heart

“…Spallota et al . also reported a similar observation, who showed that 5mC and its oxidative intermediate product 5hmC accumulate in cardiac mesenchymal cells isolated from T2D patients, cardiac tissue of STZ-induced diabetes and HFD-fed mice [ 19 ]. The current study also demonstrated that the genomic distribution of the 5mC and 5hmC peaks was significantly enriched in gene body regions, particularly in intronic regions (Fig.…”

“…While the use of different epigenetic modulators, such as cytidine analogs 5-azacytidine and decitabine, as DNMT inhibitors for cancer treatment, is well documented, the therapeutic potential of these modulators is limited due to their lower stability and cytotoxicity. Additional side effects from treatment with these drugs were also reported in cancer patients with other comorbidities, such as T2D or cardiac disorders [ 16 – 19 ]. Moreover, the use of non-nucleoside analogs such as hydralazine and procainamide is also limited because of their specificity for DNMT1 and side effects such as autoimmune diseases [ 20 ].…”

Adverse Event Profile of Azacitidine: Analysis by Route of Administration Using Japanese Pharmacovigilance Database

“…Other serious AEs detected included TLS, organizing pneumonia, and cardiac failure signals. These AEs did not differ in frequency from those of the target drug in clinical trials and were reported only on a case-report basis, with only a few reports in Japanese patients [46–49]. TLS often develops early in the course of treatment and follows a lethal course; this study suggested that it occurs within about 1 week of treatment.…”