Treatments for advanced prostate cancer that suppress testosterone, a hormone (also called an androgen) that drives the malignant cells to grow and spread, are collectively referred to as androgen deprivation therapies, or ADT. These therapies can significantly extend lifespans in men who have the disease, but they also have a range of challenging side effects.
In 2004, Dr. Marc Garnick, Gorman Brothers Professor of Medicine at Harvard Medical School and Beth Israel Deaconess Medical Center, and editor in chief of HarvardProstateKnowledge.org, reported that in some men, an ADT drug called aberelix lengthens the time it takes for cardiac cells to recharge electrically between beats. Known as the QT interval, this measure is determined with the use of an electrocardiogram. Prolonged QT intervals are worrying because in rare instances they induce potentially fatal heart rhythms. In fact, the FDA has withdrawn several approved medications from the market after they were associated with drug-induced lengthening of the QT interval, leading to documented cases of either fatal or nonfatal cardiac arrhythmias. The decision to withdraw a drug in these cases is based on the strength of the evidence linking to these sorts of cardiac outcomes.
Now a French research team is reporting that many widely used forms of ADT are linked to these sorts of cardiac side effects and their potential consequences. The study was led by Dr. Joe-Elie Salem, a cardio-oncologist at Sorbonne University in Paris.
One of testosterone’s normal effects in the body is to shorten QT intervals. Salem was aware from prior research that the intervals are longer — and the risk of potentially fatal heart attacks greater — in women than in men, possibly because women have lower testosterone levels than men do.
Would ADT — because it suppresses testosterone — elevate risks for men in a similar way that naturally low levels of the hormone do in women? That’s what Dr. Salem and his team wanted to know.
To find out, they combed through a global database of more than 17 million adverse drug reactions reported by doctors, patients, and pharmaceutical companies between 1967 and 2018.
Their investigation showed that seven out of the 10 hormone therapies evaluated were disproportionately associated with prolonged QT intervals, abnormal heart rhythms, or sudden death. The link with sudden death was strongest with enzalutamide, a second-generation ADT drug used after weaker front-line testosterone-suppressing drugs fail.
The frequency of prolonged QT, abnormal heart rhythms, or sudden death among men taking hormonal therapy in the general population is unknown. But in an email, Dr. Salem wrote that the combined incidence is “probably low — less than 1%.”
Importantly, the tendency towards prolonged QT intervals has a range of causes, and some men are born with it — this is called congenital long QT. Dr. Salem and his colleagues are now planning a study that they hope will allow clinicians to predict in advance which men face the greatest risks of these heart problems when taking hormone-suppressing therapy.
In the meantime, Dr. Salem recommends that men have a baseline electrocardiogram before starting testosterone-suppressing treatments. If abnormalities are noted before or after the treatments begin, he says, patients should be monitored further, and taken off any other drugs they might be taking that also have QT prolonging effects. The list of these drugs is quite extensive, and includes various antihistamines, antidepressants, antipsychotics, and antibiotics, among others.
“This new research reflects ongoing efforts to assess cardiac risk factors among men taking ADT, and underscores the need to better understand how prolonged QT intervals cause irregular heart rhythms,” Dr. Garnick said. “This is important because men are not routinely screened with a baseline electrocardiogram before beginning ADT. Future research is needed to determine if a longer baseline QT interval when starting on ADT should be monitored during the course of treatment.”