ADT Ups Risk for Heart Failure in Men With Prostate Cancer

Pam Harrison

August 30, 2017

Androgen deprivation therapy (ADT) significantly elevates the risk for heart failure in men without preexisting cardiovascular disease (CVD) who are undergoing treatment for localized prostate cancer, a large prospective cohort study suggests.

The same treatment strategy also increases the risk for both arrhythmias and conduction disorders in men with preexisting CVD, the cohort study indicates.

"The implication is that patients with localized prostate cancer should be followed to minimize the health effects of androgen deprivation therapy on the cardiovascular system," Reina Haque, PhD, MPH, Kaiser Permanente Southern California, Pasadena, California, said in a statement.

"Patients should consider lifestyle changes, and physicians should actively monitor the patient's health for early signs of heart disease," she added.

The study was published online August 24 in the British Journal of Cancer.

The study utilized records from patients enrolled in the Kaiser Permanente healthcare system in California from 1998 to 2008.

For the study, the researchers focused on 7637 men with newly diagnosed localized prostate cancer who were initially treated with active surveillance and were followed through to 2010.

About 30% of this group (n = 2170) received ADT, the study authors note.

ADT was given in the form of gonadotropin-releasing hormone (GnRH) analogues, including leuprolide (multiple brands), goserelin (Zoladex, TerSera Therapeutics), or triptorelin (multiple brands), with or without an oral antiandrogen. The antiandrogens were flutamide (Eulexin, Schering), bicalutamide (Casodex, AstraZeneca), or nilutamide (Nilandron, Concordia) for combined androgen blockade, the authors note.

Exposure to ADT occurred during a median of 3.4 years of follow-up. It was given either as primary or salvage therapy. Men in this ADT cohort were followed for a maximum of 13 years.

Of the ADT cohort, 78% did not have preexisting CVD, and the remaining 22% did, the investigator note. Among men who received ADT, the prevalence of preexisting CVD was slightly higher, at 22.5%, than it was among men who did not receive ADT, for whom the prevalence of preexisting CVD was 21.5%.

"After adjusting for all other covariates including CVD medications in the multivariate models, men exposed to ADT were 27% more likely to develop heart failure than non-exposed men," Dr Haque and colleagues report.

However, when the analysis was confined to men without preexisting CVD, exposure to ADT was associated with an 81% increased risk for heart failure (adjusted hazard ratio [HR] = 1.81).

Interestingly, the risk for heart failure was not increased in men with preexisting CVD who were also exposed to ADT (adjusted HR = 1.00).

On the other hand, men with preexisting CVD were 44% more likely to develop an arrhythmia following treatment with ADT (HR = 1.44), the investigators add.

The same group of men also had more than a threefold higher risk of developing a conduction disorder following exposure to ADT (HR = 3.11), they add.

The increased risk for heart failure in ADT-exposed men without preexisting CVD and arrhythmias and conduction disorders in ADT-exposed men with preexisting CVD remained following a sensitivity analysis that controlled for body mass index and smoking.

Conversely, the investigators found that undergoing ADT did not increase the risk for ischemic heart disease, stroke, or any other CVD in either group of men.

Multiple mechanisms might explain the increased risk for certain cardiovascular disorders in the setting of androgen deficiency, the authors comment. They note that low testosterone levels are known to increase fat mass and that fat is a well-recognized risk factor for both heart failure and arrhythmias.

"The findings allow men with localized prostate cancer to consider the positive and negative effects of androgen deprivation therapy and discuss it with their physicians," Dr Haque said.

"If they move forward with the therapy, patients should work with their physicians to adjust their lifestyle to reduce the risk of cardiovascular disease," she adds.

Unanswered Questions

Asked by Medscape Medical News to comment on the study, Marc Garnick, MD, professor of medicine, Harvard Medical School and the Beth Israel Deaconess Medical Center, Boston, Massachusetts, pointed out that it is not clear who the patient population studied here consisted of, because the patients in this study were initially assigned to receive active surveillance.

"Such a patient population is generally treated with curative intent when such treatments are needed and often do not require ADT," Dr Garnick said in an email.

However, the real unanswered question from the data presented from this study relates to both the type and doses of ADT used as well as the duration of treatment, Dr Garnick suggested.

"Without this type of granularity, it is virtually impossible to assign any cause-and-effect relationship, given the differing cardiovascular risks associated with varying androgen modifying agents," he explained.

Although prior research has shown that testosterone deficiency can lengthen the QT interval, the study authors did not report this, nor did they report on the types of arrhythmias developed.

While some studies point to an increase in cardiac adverse events and associated lipid and glucose homeostasis parameters with ADT, "the categorization of the cohort studied here adds little meaningful understanding to this most important topic," Dr Garnick commented.

"Physicians will, this study notwithstanding, still need to assess the known benefits of ADT vs its adverse events, some of which can be significant, and advise patients accordingly," he concluded.

The authors have disclosed no relevant financial relationships. Dr Garnick is editor-in-chief of the Harvard Medical School annual report on prostate disease and website.

Br J Cancer. Published online August 24, 2017. Abstract

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