This editorial refers to ‘Identification of anticancer drugs associated with atrial fibrillation: analysis of the WHO pharmacovigilance database’, by J. Alexandre et al., pp. 318–326.
Atrial fibrillation (AF) is the most common sustained arrhythmia in the general population with a prevalence of 1.5–2%. Patients with malignancies are at increased risk of developing AF, as cancer and AF share several common risk factors, such as ageing and cardiometabolic disease, while cancer therapy, including surgery and systemic anticancer agents, and cancer itself may predispose to AF (Figure 1).
Risk factors and triggers for developing atrial fibrillation in cancer patients. CVD, cardiovascular disease.
The relationship between cancer and AF seems to be bidirectional. Healthy patients with new-onset AF seem to have an increased long-term risk of developing cancer,1 while patients with newly diagnosed cancer seem to be at an increased risk of developing AF, with the highest incidence during the first 90 days from cancer diagnosis.2 The risk of AF, though, extends well beyond the diagnosis and treatment periods, even in mild forms of malignancies, indicating the complex pathogenesis of this arrythmia in cancer.3
Peri-operative AF related to cancer surgery is quite common, especially in thoracic surgery (for lung and oesophageal cancer). For lung surgery, the reported incidence varies according to the surgical procedure from 2–4% after wedge resection to 20–30% after pneumonectomy,4 while for oesophageal cancer the prevalence is between 4% and 10%.5 Preceding chemotherapy increases the risk of post-operative AF, highlighting the additive effect of cancer therapies on cardiotoxicity risk.
A number of systemic anticancer agents have been related to AF (Table 1).6–10 In this issue of the journal, Alexandre and colleagues identified 19 anticancer drugs associated with AF using information extracted from the World Health Organization pharmacovigilance database, Vigibase®.11 In nine of these agents, the association with AF is reported as new (given in italics in Table 1), but reports for four of them (bold italics in Table 1) can actually be found in the literature (lenalidomide, nilotinib, docetaxel, and obinutuzumab).12–15 All anticancer drugs with a newly reported association with AF (pomalidomide, ponatinibe, midostaurin, azacytidine, and clofarabine) are indicated for the treatment of haematological malignancies and, when administered as part of multidrug regimes, increase AF risk.
Anticancer medications associated with atrial fibrillation
| Category* | Specific drugs |
|---|---|
| Alkylating agents | Cisplatin, cyclophosphamide, ifosfamide, melphalan, dacarbazine, 4-hydroperoxycyclophosphamide |
| Androgen deprivation therapy | |
| Antiandrogen | Abiraterone |
| Gonadotropin-releasing hormone antagonists | Degarelix |
| Anthracyclines | Doxorubicin, mitoxandtrone, daunorubicin, idarubicin |
| Antioestrogen | Tamoxifen |
| Antimetabolites | 5FU, azathioprine, capecitabine, gemcitabine, methotrexate, pentostatin, leucovorin, azacytidine, clofarabine |
| Aromatase inhibitors | |
| Bcr-Abl inhibitors | Dasatinib, nilotinib, ponatinib |
| Biological factors | Interleukin-2, iinterferons |
| Bruton kinase inhibitor | Ibrutinib |
| CAR T-cell therapy | Tisagenlecleuce |
| HDAC inhibitors | Romidepsin |
| Histone deacetylase inhibitors | Vorinostat, despipeptide, belinostat |
| Immune check point inhibitors | Ipilimumab, nivolumab, pembrolizumab |
| Immunomodulators | Aldesleukin, lenalidomide, pomalidomide, linomide |
| Miscellaneous | Arsenic trioxide, trabectedin |
| Monoclonal antibodies | Alemtuzumab, cetuximab, obinutuzumab, ofatumumab, rituximab, pertuzumab |
| HER2 inhibitors | Trastuzumab, etaracizumab |
| mTOR inhibitors | Everolimus |
| Protein kinase inhibitors | 7-Hydroxy-staurosporine |
| Taxanes | Docetaxel, paclitaxel, gemcitabine/vinorelbine |
| Tyrosine kinase inhibitors | Sunitib, sorafenib cetuximab, crizotinib |
| Multikinase inhibitors | Midostaurin, lapatinib, dasatinib, imatinib, nilotinib, sorafenib, ponatinib, vemurafenib |
| Proteasome inhibitors | Bortezomib |
| Type II topoisomerase inhibitors | Etoposide, amsacrine |
| Vascular endothelial growth factor inhibitors | Bevacizumab |
| Vinca alkaloids |
| Category* | Specific drugs |
|---|---|
| Alkylating agents | Cisplatin, cyclophosphamide, ifosfamide, melphalan, dacarbazine, 4-hydroperoxycyclophosphamide |
| Androgen deprivation therapy | |
| Antiandrogen | Abiraterone |
| Gonadotropin-releasing hormone antagonists | Degarelix |
| Anthracyclines | Doxorubicin, mitoxandtrone, daunorubicin, idarubicin |
| Antioestrogen | Tamoxifen |
| Antimetabolites | 5FU, azathioprine, capecitabine, gemcitabine, methotrexate, pentostatin, leucovorin, azacytidine, clofarabine |
| Aromatase inhibitors | |
| Bcr-Abl inhibitors | Dasatinib, nilotinib, ponatinib |
| Biological factors | Interleukin-2, iinterferons |
| Bruton kinase inhibitor | Ibrutinib |
| CAR T-cell therapy | Tisagenlecleuce |
| HDAC inhibitors | Romidepsin |
| Histone deacetylase inhibitors | Vorinostat, despipeptide, belinostat |
| Immune check point inhibitors | Ipilimumab, nivolumab, pembrolizumab |
| Immunomodulators | Aldesleukin, lenalidomide, pomalidomide, linomide |
| Miscellaneous | Arsenic trioxide, trabectedin |
| Monoclonal antibodies | Alemtuzumab, cetuximab, obinutuzumab, ofatumumab, rituximab, pertuzumab |
| HER2 inhibitors | Trastuzumab, etaracizumab |
| mTOR inhibitors | Everolimus |
| Protein kinase inhibitors | 7-Hydroxy-staurosporine |
| Taxanes | Docetaxel, paclitaxel, gemcitabine/vinorelbine |
| Tyrosine kinase inhibitors | Sunitib, sorafenib cetuximab, crizotinib |
| Multikinase inhibitors | Midostaurin, lapatinib, dasatinib, imatinib, nilotinib, sorafenib, ponatinib, vemurafenib |
| Proteasome inhibitors | Bortezomib |
| Type II topoisomerase inhibitors | Etoposide, amsacrine |
| Vascular endothelial growth factor inhibitors | Bevacizumab |
| Vinca alkaloids |
Listed in alphabetical order.
Agents identified by Alexandre and colleagues11 as new associations with AF are shown in italics; agents not previously associated with AF are shown in bold italics.
Anticancer medications associated with atrial fibrillation
| Category* | Specific drugs |
|---|---|
| Alkylating agents | Cisplatin, cyclophosphamide, ifosfamide, melphalan, dacarbazine, 4-hydroperoxycyclophosphamide |
| Androgen deprivation therapy | |
| Antiandrogen | Abiraterone |
| Gonadotropin-releasing hormone antagonists | Degarelix |
| Anthracyclines | Doxorubicin, mitoxandtrone, daunorubicin, idarubicin |
| Antioestrogen | Tamoxifen |
| Antimetabolites | 5FU, azathioprine, capecitabine, gemcitabine, methotrexate, pentostatin, leucovorin, azacytidine, clofarabine |
| Aromatase inhibitors | |
| Bcr-Abl inhibitors | Dasatinib, nilotinib, ponatinib |
| Biological factors | Interleukin-2, iinterferons |
| Bruton kinase inhibitor | Ibrutinib |
| CAR T-cell therapy | Tisagenlecleuce |
| HDAC inhibitors | Romidepsin |
| Histone deacetylase inhibitors | Vorinostat, despipeptide, belinostat |
| Immune check point inhibitors | Ipilimumab, nivolumab, pembrolizumab |
| Immunomodulators | Aldesleukin, lenalidomide, pomalidomide, linomide |
| Miscellaneous | Arsenic trioxide, trabectedin |
| Monoclonal antibodies | Alemtuzumab, cetuximab, obinutuzumab, ofatumumab, rituximab, pertuzumab |
| HER2 inhibitors | Trastuzumab, etaracizumab |
| mTOR inhibitors | Everolimus |
| Protein kinase inhibitors | 7-Hydroxy-staurosporine |
| Taxanes | Docetaxel, paclitaxel, gemcitabine/vinorelbine |
| Tyrosine kinase inhibitors | Sunitib, sorafenib cetuximab, crizotinib |
| Multikinase inhibitors | Midostaurin, lapatinib, dasatinib, imatinib, nilotinib, sorafenib, ponatinib, vemurafenib |
| Proteasome inhibitors | Bortezomib |
| Type II topoisomerase inhibitors | Etoposide, amsacrine |
| Vascular endothelial growth factor inhibitors | Bevacizumab |
| Vinca alkaloids |
| Category* | Specific drugs |
|---|---|
| Alkylating agents | Cisplatin, cyclophosphamide, ifosfamide, melphalan, dacarbazine, 4-hydroperoxycyclophosphamide |
| Androgen deprivation therapy | |
| Antiandrogen | Abiraterone |
| Gonadotropin-releasing hormone antagonists | Degarelix |
| Anthracyclines | Doxorubicin, mitoxandtrone, daunorubicin, idarubicin |
| Antioestrogen | Tamoxifen |
| Antimetabolites | 5FU, azathioprine, capecitabine, gemcitabine, methotrexate, pentostatin, leucovorin, azacytidine, clofarabine |
| Aromatase inhibitors | |
| Bcr-Abl inhibitors | Dasatinib, nilotinib, ponatinib |
| Biological factors | Interleukin-2, iinterferons |
| Bruton kinase inhibitor | Ibrutinib |
| CAR T-cell therapy | Tisagenlecleuce |
| HDAC inhibitors | Romidepsin |
| Histone deacetylase inhibitors | Vorinostat, despipeptide, belinostat |
| Immune check point inhibitors | Ipilimumab, nivolumab, pembrolizumab |
| Immunomodulators | Aldesleukin, lenalidomide, pomalidomide, linomide |
| Miscellaneous | Arsenic trioxide, trabectedin |
| Monoclonal antibodies | Alemtuzumab, cetuximab, obinutuzumab, ofatumumab, rituximab, pertuzumab |
| HER2 inhibitors | Trastuzumab, etaracizumab |
| mTOR inhibitors | Everolimus |
| Protein kinase inhibitors | 7-Hydroxy-staurosporine |
| Taxanes | Docetaxel, paclitaxel, gemcitabine/vinorelbine |
| Tyrosine kinase inhibitors | Sunitib, sorafenib cetuximab, crizotinib |
| Multikinase inhibitors | Midostaurin, lapatinib, dasatinib, imatinib, nilotinib, sorafenib, ponatinib, vemurafenib |
| Proteasome inhibitors | Bortezomib |
| Type II topoisomerase inhibitors | Etoposide, amsacrine |
| Vascular endothelial growth factor inhibitors | Bevacizumab |
| Vinca alkaloids |
Listed in alphabetical order.
Agents identified by Alexandre and colleagues11 as new associations with AF are shown in italics; agents not previously associated with AF are shown in bold italics.
Pharmacovigilance in oncology is critical in the light of the exponential development of novel anticancer treatments. Vigibase® has already been used extensively to describe adverse events related to cancer therapy with the critical advantage of individual case safety reports from >130 countries all over the world. ‘Big data’ extracted from large pharmacovigilance databases in oncology and cardio-oncology are valuable as clinical trials for drug efficacy may not be able to detect rare adverse events. However, the use of pharmacovigilance databases in this regard is limited by the lack of information about the clinical context, namely the past medical history of the patient (preceding chemotherapy or surgery, pre-existing AF, or relevant cardiovascular disease or risk factors in this case) and the concurrently administered medications that may have a significant impact on the explored association. Additional limitations include polypharmacy, drug–drug, and drug–disease interactions, pharmacogenetics, special populations such as elderly patients, and under-reporting of adverse drug reactions.
Considering the complex pathophysiological mechanisms underlying the relationship between cancer and AF, it is impossible to allow concrete conclusions on a clear aetiological association of the identified medications with AF in this population based only on the signal identified from such databases. Prospective clinical and experimental studies are needed with the identified medications to confirm the causal relationship and explore the pathophysiological mechanisms behind it.
Conflict of interest: none declared.
The opinions expressed in this article are not necessarily those of the Editors of the European Heart Journal – Cardiovascular Pharmacotherapy or of the European Society of Cardiology.
References
Lenalidomide: new drug.
