Date Published: February 20, 2019
Publisher: Public Library of Science
Author(s): Daniel Caldeira, Daniela Alves, João Costa, Joaquim J. Ferreira, Fausto J. Pinto, Ralf Bender.
Ibrutinib is an oral covalent inhibitor of Bruton’s tyrosine kinase approved for the treatment of patients with chronic lymphocytic leukemia (CLL), mantle cell lymphoma and Waldenstrӧm’s macroglobulinemia. Ibrutinib has an increased risk of atrial fibrillation but the mechanism is unknown, and hypertension may play a role in the pathogenesis of this adverse drug reaction.
We aimed to review the risk of hypertension and atrial fibrillation as adverse events associated with ibrutinib through a systematic review with meta-analysis of randomized controlled trials (RCTs) retrieved in December 2018 on MEDLINE, EMBASE, CENTRAL and ClinicalTrials.gov. The data were pooled using random-effects meta-analyses using the risk ratio (RR) with the 95% confidence interval (95%CI). The confidence on the pooled estimates was ascertained through the grading of recommendations assessment, development, and evaluation (GRADE) approach.
There were 8 eligible RCTs (2580 patients), all reporting safety data of interest. Ibrutinib was associated with a significant increase in the risk of hypertension with a RR of 2.82 (95%CI 1.52–5.23) with moderate quality evidence. Ibrutinib increased significantly the risk of atrial fibrillation with a RR of 4.69 (95%CI 2.17–7.64) with high quality evidence.
Ibrutinib was associated with significantly increased risks of both hypertension and atrial fibrillation.
Ibrutinib is the first-in-class oral covalent inhibitor of Bruton’s tyrosine kinase that has been approved for the treatment of patients with chronic lymphocytic leukemia (CLL), mantle cell lymphoma (MCL) and Waldenstrӧm’s macroglobulinemia (WM) due to its efficacy. Despite the significant favourable impact in the hematologic conditions, Ibrutinib increases significantly the risk of atrial fibrillation (AF) . The mechanisms leading to AF are not well established, but it is known that arterial hypertension is associated with increased risk of this dysrhythmia . Yet, the safety data from ibrutinib ‘s trials regarding reported adverse events of hypertension is heterogenous.
In this study, we performed systematic review with meta-analysis which is a well-known method to evaluate specific safety aspects of drugs using the cumulative evidence from clinical trials [3, 4].
We found 8 eligible RCTs with 2580 patients (54.7% treated with ibrutinib) (Fig 1) [19–26]. The trial with the smaller sample size had 150 patients (iNNOVATE) and the largest had 578 patients (HELIOS). All the trials, with exception of the RAY trial [22, 27] had an open-label design (Fig 2). There were 2 placebo-controlled trials and 6 active controlled studies. None of the trials was designed for systematically search for hypertension or atrial fibrillation (high risk of selective reporting bias) (Fig 2). All the trials allowed crossovers from control to ibrutinib arm, with rates reaching 40% as occurred in iNNOVATE study . Only the RESONATE-2 trial did not allow crossovers during the study (low risk of bias in ‘Other bias’ in Fig 2). The main characteristics of the included studies are depicted in Table 1 and the risk of bias plot in Fig 2 and Figure A in S1 File. Blood pressure measurements frequency was reported in half of the studies, only 3 studies reported the when ECG were performed (Table 1). About 75% of the studies reported the adverse events using CTCAE (Table 1).
In this systematic review with meta-analysis, we showed that ibrutinib was significantly associated with an increased risk of hypertension in randomized controlled trials. Hypertension was considered a common adverse event of ibrutinib in the Summary of Product Characteristics of ibrutinib , but the data was solely derived from the rates of reporting in clinical studies or during post marketing surveillance without a formal comparison with a control arm. In this systematic review we also confirmed with new published trials that ibrutinib was associated with atrial fibrillation.
Our results suggest that ibrutinib increases significantly the risks of hypertension and atrial fibrillation. The pooled data for hypertension had moderate quality evidence, and high-quality evidence for atrial fibrillation. Whether hypertension is a crucial factor for ibrutinib-induced atrial fibrillation is still unknown.