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Prostate Cancer: Observational-Study Evidence Continues to Mount—ADT Associated with Increased Cardiovascular Risk

Kim, Meeri PhD

doi: 10.1097/01.COT.0000470197.17137.ae
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Another observational study has found a link between androgen-deprivation therapy (ADT) and an increased risk of cardiovascular disease, especially during the first six months of treatment for prostate. This finding was particularly significant for patients with a history of multiple cardiovascular disease events.

The retrospective study (JCO 2015;33:1243-1251) used data on filled prescriptions in the Swedish national health registers from 41,362 men with prostate cancer who received either anti-androgens or gonadotropin-releasing hormone (GnRH) agonists, or who underwent surgical orchiectomy for the period of 2006 to 2012. The patient cohort was compared with an age- and residency-matched, cancer-free control group.

Compared with the risk in healthy controls, the risk of cardiovascular disease was 21 percent higher for patients receiving GnRH agonists and 16 percent higher for those who underwent orchiectomy. On the other hand, patients who took anti-androgens actually had a lowered risk of cardiovascular disease. Also, men with a history of ischemic heart disease, arrhythmia, heart failure, or stroke—especially if they experienced the last event within one year of starting ADT—had an elevated likelihood for cardiovascular disease, regardless of the ADT modality.

These findings add to a growing number of observational studies that have shown an increased relative risk of cardiovascular disease in men with prostate cancer on ADT. Because the results of randomized clinical trials on ADT have failed to match those seen in these observational studies, though, the jury is still out on whether there is a definitive causal link between the two exists. However, this study does highlight the possible dangers of ADT for men with a history of cardiovascular events, which should be considered by any physician recommending treatment options, the researchers said.

“The main reason we conducted the study was because there was a discrepancy between data found in clinical trials versus randomized studies,” said the study's first author, Sean O'Farrell, BSc, MRes, an immunobiology PhD student at King's College London School of Medicine and part of the Immunosurveillance Lab at the Francis Crick Institute. “Men who are on androgen-deprivation therapy—whether an orchiectomy or GnRH agonists—are at an increased risk of cardiovascular disease versus a matched control population that was free of prostate cancer.”

In 2010, the U.S. Food and Drug Administration used a number of retrospective, database studies to support its decision to require a new risk label on GnRH agonists warning about an increased risk of diabetes, heart attack, sudden cardiac death, and stroke. Despite the plethora of observational evidence, though, a prospective study specifically designed to investigate the link between ADT and cardiovascular risk has not yet been undertaken.

“There certainly is suggestive evidence that this association may be real, but unfortunately we still don't have definitive evidence,” said Nancy Keating, MD, MPH, Professor of Health Care Policy at Harvard Medical School and a primary care physician at Brigham and Women's Hospital. “Observational studies, although many of them have been done very thoughtfully and very well, still raise a possible concern of confounding.”

This latest study, while still observational, does add new knowledge to the current understanding of how ADT may affect cardiovascular risk, the researchers said. Unlike some prior investigations, the database used contained information on specific types and duration of ADT, and also took each subject's history of prior cardiovascular events into account.

O'Farrell and his colleagues created a database based on the National Prostate Cancer Register of Sweden, which is nationwide and covers 98 percent of all newly diagnosed, biopsy-confirmed prostate cancers, a series of national health care registers, and the National Prescribed Drug Register. The latter included information on filled prescriptions of anti-androgens and GnRH agonists, including date of initiation, duration, and daily dosage.

The final cohort was made up of 41,362 men with prostate cancer, with each subject matched up with five comparison controls that were matched for both age and county of residence in Sweden:

  • Men with prostate cancer on ADT (n = 41,362): Anti-androgens (n = 10,656), gonadotropin-releasing hormone (GnRH) agonists (n = 26,959), and surgical orchiectomy (n = 3,747); and
  • Age- and residency-matched healthy controls (n = 187,785).

Statistical analysis revealed an increased risk of incident cardiovascular disease for men on GnRH agonists and who underwent orchiectomy as compared with controls, while men on anti-androgens had a lower likelihood. The former groups remained at risk even if they had no history of cardiovascular disease.

After the risk ratios were calculated for the two years before and after initiation of ADT, subjects were found to be at even more increased risk for cardiovascular disease after initiation of GnRH agonists or castration. Those with two or more cardiovascular events, with the latest occurring within the last year before ADT initiation, were at the highest risk within the first six months of treatment. The risk then decreased in both the anti-androgen and GnRH groups, but remained high in men after orchiectomy.

“It was in the first six months that the risk was really high no matter what type of anti-androgen therapy you got, and men who had a history of cardiovascular disease were always at the highest risk—those who had two or more cardiovascular events in their lifetime,” O'Farrell said.

Hazard ratios for cardiovascular disease peaked during the first year for all groups receiving ADT, which suggests that any changes due to androgen deprivation occur shortly after beginning treatment and may be due to an acute direct drug effect of ADT on cardiovascular function, he said. For instance, one possible mechanism could be that testosterone has a cardioprotective effect that becomes interrupted by ADT.

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Monitor for Side Effects

“Men, particular those who have a history of cardiovascular disease, should be monitored for side effects, and perhaps some prophylaxis could be applied at that point,” O'Farrell said. “Everyone who is on androgen-deprivation therapy should be advised and counseled for cardiovascular disease—if possible in that first year.”

Also, hormone therapy has other consequences that should be considered by physicians before prescribing such drugs to their patients. Such potential side effects like obesity and insulin resistance, although not likely to be the origin of the acute increased cardiovascular risk examined in this study, can still be harmful.

“I think there are a lot of men getting these drugs when there's no proven benefit, but we know there are proven harms,” Keating said. “There's some pretty comprehensive data now that these drugs cause insulin resistance which can lead to diabetes, loss of bone mass, hot flashes, fatigue, loss of muscle mass and gain of fat mass around the belly, and a lot of other problems that can have consequences.”

NANCY KEATING, MD, MPH

NANCY KEATING, MD, MPH

MARIJO BILUSIC, MD, PHD

MARIJO BILUSIC, MD, PHD

She stressed that doctors and patients should weigh the risks and benefits of such treatment on a case-by-case basis. For men whose disease has metastasized, for example, hormone therapy has been shown to be effective and increase rates of survival—but patients should still be closely monitored for side effects and risk factors.

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Controversial

Also asked for his perspective for this article, Marijo Bilusic, MD, PhD, a medical oncologist at Fox Chase Cancer Center, said: “It's a very controversial topic—there is a lot of debate in the community, and we don't have a clear answer yet. For my patients, I disclose the risk of cardiovascular disease and check blood pressure/cholesterol within three months of starting hormone therapy and treat those aggressively. I tell my patients to try to exercise, diet, stop smoking.”

He stresses that retrospective studies cannot establish a clear-cut relationship, only a suggestion of one, and a prospective study designed to answer this question specifically will have to be taken on.

“Even the FDA has labeled that there may be a risk of increased cardiovascular disease, but there's no prospective study that has confirmed that relationship,” Bilusic said. “The design of [prospective studies that have been done] was not to show the harmfulness of hormones, the goal of the study was to cure the patient—and then they measured the side effects.”

He noted that because the randomized trails were not designed to look at the difference, many of them looked at cardiovascular death, not events like heart attacks, and also used subjects younger and healthier than men in the average population. Such a cohort would naturally be at less at risk for heart disease, and the results wouldn't be applicable to older men.

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Over-prescribed

Both Keating and Bilusic agree that hormones are likely over-prescribed for patients, even for indications where there is no evidence of efficacy. For example, many physicians initiate hormone therapy for patients with rising levels of prostate-specific antigen even though retrospective studies suggest that such early intervention has no impact on survival.

“I don't think we should avoid treating people who are likely to benefit,” Keating summed up, “but I do think we should be more careful about using these drugs in all men—not just those who have cardiovascular disease.”

Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
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