Recent Cardiotoxicity Case Reports for Patients Using Imbruvica Alone or When Combined With Other Drugs


(Posted by Tom Lamb at Drug Injury Watch)


Just about two years ago, in mid-October 2019, we posted these two articles, “Patients Treated With Imbruvica Had Increased Rate Of Fatal Cardiac Events Compared To Conventional Chemotherapy“, and “Imbruvica-Related Hypertension And Associated Serious Side Effects Examined In New Medical Study.”  Since then, we have seen various case reports of heart-related Imbruvica side effects in the medical literature, both when patients used only Imbruvica and when Imbruvica was used in combination with certain other drugs.

In this new article, we point out a few of the medical journal articles and news reports about heart-related Imbruvica side effects that have been published in the past 12 months.

We start with a June 2021 report from ThePharmaLetter, “Imbruvica: new safety signal for use with rituximab and ACE inhibitors” about the European Medicines Agency (EMA) issuing a new safety signal for Imbruvica with rituximab:

As part of its advice on safety-related aspects to other European Medicines Agency committees, the Pharmacovigilance Risk Assessment Committee (PRAC) last week discussed a direct healthcare professional communication (DHPC) containing important safety information for Imbruvica (ibrutinib).

This DHPC aims to inform healthcare professionals about a new safety signal of sudden or cardiac death with Imbruvica when used in combination with rituximab and angiotensin-converting enzyme (ACE) inhibitors. The signal was recognized following a review of the findings of a clinical trial….

An interim analysis of the clinical trial suggested that the risk of sudden or cardiac death in patients on an ACE inhibitor when entering the study was increased in patients randomized to [Imbruvica (ibrutinib)] and rituximab, compared to those randomized to fludarabine, cyclophosphamide and rituximab.

While the PRAC is reviewing the signal, as a precautionary measure, for patients with [chronic lymphocytic leukemia (CLL)] currently receiving [Imbruvica (ibrutinib)] plus rituximab together with an ACE inhibitor, the PRAC advises healthcare professionals to reconsider the treatment strategy.

Next is a September 2021 MedPage Today news report, “Ibrutinib for CLL Tied to Higher Heart Risks vs Chemotherapy“, about there being increased risks for atrial fibrillation, bleeding, and heart failure seen in a Canadian cohort of patients using Imbruvica:

Use of the Bruton tyrosine kinase (BTK) inhibitor ibrutinib (Imbruvica) was linked with cardiovascular risks in patients with chronic lymphocytic leukemia (CLL), according to results of a population-based cohort study.

Over 3 years, the incidence of atrial fibrillation (AF)-related healthcare contact was 22.7% in patients treated with [Imbruvica (ibrutinib)] compared with 11.7% in patients who received chemotherapy, risk of hospital-diagnosed bleeding was 8.8% and 3.1%, respectively, and risk of heart failure (HF) was 7.7% and 3.6%, reported Husam Abdel-Qadir, MD, PhD, of Women’s College Hospital in Toronto, and colleagues.

There were no significant differences in the risk of ischemic stroke or acute myocardial infarction between the two groups, they noted in the Journal of Clinical Oncology.

For more details about these heart-related Imbruvica side effects, we refer you to the underlying medical study article, “Cardiovascular Risk Associated With Ibrutinib Use in Chronic Lymphocytic Leukemia: A Population-Based Cohort Study“, which was published online on August 31, 2021, by the Journal of Clinical Oncology.

Lastly, there is this November 2020 Healio article, “Link between ibrutinib-related hypertension, heart problems necessitates close monitoring“, which provides some key findings from several different medical journal articles about research focused on heart-related Imbruvica side effects. From the Conclusions part of that Healio article:

[Chronic lymphocytic leukemia (CLL)] is a disease of the elderly. Real-world evaluations suggest many patients initiated on [Imbruvica (ibrutinib)] have significant comorbidities, many of them cardiovascular.

Hypertension — an important risk factor for the development of atrial fibrillation — may occur at a much higher rate in real-world practice settings than reported in clinical trials.

Patients should be monitored for the development of new or worsened hypertension, particularly early in the therapy course.

Intervention with antihypertensive medications for patients with hypertension may prevent [major adverse cardiac events (MACE)], including atrial fibrillation. It does not appear that any class of antihypertensives is preferred for hypertension management among these patients.

Treatment of new-onset hypertension, as well as prevention of worsening hypertension and atrial fibrillation development, makes it easier for patients to remain on [Imbruvica (ibrutinib)] without dose modification or interruption.

But if you still want to learn more about this cardiotoxicity drug safety issue for Imbruvica, we give you this “extra” item to consider, “Ibrutinib’s Cardiotoxicity-An Opportunity for Postmarketing Regulation“, published by JAMA Oncology (subscription required) in February 2021, which starts as follows:

[Imbruvica (ibrutinib)] is an irreversible inhibitor of Bruton tyrosine kinase (BTK) that is indicated for multiple hematological malignancies, including previously untreated chronic lymphocytic leukemia (CLL). This drug is known to have cardiotoxic properties, probably due to off-target inhibition of another kinase. While in randomized trials ibrutinib has been demonstrated to increase survival, some studies have demonstrated fatal toxic effects associated with the drug. This was most obvious in a 3-arm study of CLL in which the 2 [Imbruvica (ibrutinib)] arms were associated with a 7% rate of death during treatment or within 30 days after treatment cessation, compared with a 1% rate of death in the control arm.

We will continue to monitor the medical literature for more analysis of heart-related Imbruvica side effects, as well as watch for possible action by drug safety regulators such as the FDA and the EMA in the future. Medical & Legal Information About Drug Side Effects
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