Androgen deprivation therapy for advanced prostate cancer—both gonadotropic-releasing hormone (GnRH) agonists and the newer agents abiraterone and enzalutamide—have been linked to cardiac adverse drug reactions, especially in individuals with pre-existing cardiac conditions. It’s still unknown whether the newer agents elevate cardiac risk compared with the older medications or each other.
Using the world’s largest pharmacovigilance database, Eugene B. Cone, MD, a fellow in the Division of Urology at Brigham and Women’s Hospital, Quoc-Dien Trinh, MD, director of Ambulatory Clinical Operations for the division and co-director of the Prostate Cancer Center at Dana-Farber Brigham Cancer Center, and colleagues determined the risk of cardiac adverse events is increased substantially with abiraterone and not at all with enzalutamide. They detail their findings in EClinicalMedicine.
The researchers consulted VigiBase, where since 1967 the World Health Organization has collected more than 20 million safety reports of suspected adverse drug reactions (ADRs) from more than 130 countries. The reports come from clinicians, patients, pharmaceutical companies, and other sources.
The team identified all cardiovascular ADRs captured by VigiBase at any time for patients taking standard doses of:
- A GnRH agonist (leuprolide, goserelin, triptorelin or histrelin) but not abiraterone or enzalutamide
- Abiraterone but not enzalutamide
- Enzalutamide but not abiraterone
Patients taking abiraterone or enzalutamide were assumed to be taking a GnRH agonist or antagonist concomitantly.
The researchers conducted a disproportionality analysis. If the proportion of individuals taking one of the androgen deprivation drugs who reported a specific cardiac ADR was significantly higher than the proportion taking any other drug in the database who experienced the same ADR, the disproportionality signal suggested an association between drug and ADR.
Frequency of Events
2,433 cardiac ADRs were associated with the androgen deprivation therapies studied. The most frequent were myocardial infarction (MI) (n=696) and heart failure (HF) (n=555), and these were also the most frequently fatal ADRs, with death noted in 28% and 26% of reports, respectively.
Most ADRs were reported outside a clinical trial (77%), highlighting the real-world value of this study.
Risk With Each Drug
The researchers present the results of the disproportionality analysis using reporting odds ratios (ROR). These have larger confidence intervals than relative risk ratios but are functionally equivalent.
The significant associations were:
- Any cardiac event—ROR, 1.59
- HF—ROR, 2.06
- MI—ROR, 1.80
- Any cardiac event—ROR, 1.21
- HF—ROR, 3.02
- MI—ROR, 1.35
- Arrhythmia—ROR, 2.04
Enzalutamide—not associated with increased odds of cardiac ADRs overall or with any subtype.
Time to Onset
Most cardiac ADRs occurred at least six months after initiation of therapy, and ≥10% occurred more than two years later. The mean time to onset was more than one year for MI (438 days) and almost as long for HF (353 days).
Guidance for Prescribers
The results for enzalutamide are somewhat unexpected since grade 3 or higher cardiac ADRs have been reported in some clinical trials. Prior studies have shown tissue levels of androgen can rise when enzalutamide is combined with a GnRH agonist, and it’s possible these higher levels are somehow cardioprotective.
These findings preliminarily suggest enzalutamide is better suited than abiraterone for patients with prostate cancer who have significant cardiac comorbidities. At a minimum, they should be discussed when educating patients about the cardiac risks of both traditional and newer forms of androgen deprivation therapy.