Just what is the real risk (of cardiovascular morbidity and mortality for men on ADT)?

So a meta-analysis of data from multiple clinical trials has now shown rigorously something that we did, in fact, already know … that there was no excess incidence of cardiovascular mortality associated with androgen deprivation therapy (ADT) in clinical trials conducted to date in which use of ADT was compared to a placebo.

The paper by Nguyen et al., published yesterday in the Journal of the American Medical Association, is focused on this issue exclusively, and offers us an analysis of data from a total of 11 randomized clinical trials. For trial data to be eligible, the patients had to be treated with ADT that was based on use of an LHRH agonist (e.g., leuprolide acetate) or no immediate ADT at all (the control arm), there had to be complete information available on the incidence of cardiovascular mortality, and there had to be patient follow-up for a minimum of 1 year.

Based on data from these trials, Ngyuen and his colleagues showed the following:

  • The eight trials that met the study criteria included 4,141 patients.
    • 2,200 patients received ADT.
    • 1,941 patients were in the control arm (and received no immediate ADT).
    • Cardiovascular deaths occurred in 255/2,200 patients receiving ADT.
    • Cardiovascular deaths occurred in 252/1,941 men in the control arms
    • This difference was not statistically significant.
  • Among trials of long duration (i.e., 3 years or longer),
    • Cardiovascular deaths occurred in 11.5 percent of patients receiving ADT.
    • Cardiovascular deaths occurred in 11.5 percent of men in the control arms
    • This difference was not statistically significant.
  • Among trials of short duration (i.e., 6 months or less),
    • Cardiovascular deaths occurred in 10.5 percent of patients receiving ADT.
    • Cardiovascular deaths occurred in 10.3 percent of men in the control arms
    • This difference was not statistically significant.
  • Among 4,805 patients from 11 trials with overall death data,
    • Prostate cancer-specific mortality occurred in 13.5 percent of patients receiving ADT.
    • Prostate cancer-specific mortality occurred in 22.1 percent of men in the control arms.
    • All-cause mortality occurred in 37.7 percent of patients receiving ADT.
    • All-cause mortality occurred in 44.4 percent of men in the control arms.
    • Both of these differences were statistically significant.

Whether (ADT) causes excess cardiovascular deaths in men with prostate cancer is highly controversial. Several medical societies — and the U.S. Food & Drug Administration (FDA)  have issued warnings about this risk. In the current study, of data from men with progressive, unfavorable-risk prostate cancer, the use of ADT was not associated with an increased risk of cardiovascular death but was associated with a lower risk of prostate cancer-specific mortality and all-cause mortality.

Having said that, it does need to be acknowledged that men managed in clinical trials may do better in general than men being treated in the community. Men participating in clinical trials have been carefully selected according to predetermined criteria, and they are supposed to be carefully followed according to a predetermined protocol. As a consequence, it has to be accepted that men being treated “in the real world” (i.e., not in clinical trials) may well be at greater risk for cardiovascular morbidity and mortality than men being treated in clinical trials. Just how big this increased risk may really be is going to remain controversial.

Note: A commentary on this article on the Medscape web site today provides some additional insights related to this article. Specifically, it also addresses the issue of the different outcomes that may be observed in clinical trials and in day-to-day practice.

2 Responses

  1. This could be a major reason for the reduction in prostate cancer mortality here: ADT applied to less advanced disease diagnosed (still late) by PSA testing. Some researchers have been saying that for some years now.

  2. Dr. Mark Scholz is a medical oncologist who has treated hundreds of men with androgen deprivation therapy over many years. In his recent book (2010), he notes the possibility that ADT may actually have a favorable impact on cardiovascular health by making the blood thinner (somewhat fewer red blood cells), thereby making the blood volume easier for the cardiovascular system to handle, resulting in less stress on the vessels. This possibility could be consistent with the results of the meta-analysis; although statistical superiority for the ADT group was not seen, it could be that some men did better but with counterbalancing results for some who had more trouble than average. Other experts in ADT are still quite concerned about a potential adverse cardiovascular impact of ADT. More research would help.

    As mentioned in the Medscape article, patient characteristics, especially existing cardiovascular disease prior to ADT, may prove to be important in determining whether a patient has cardiovascular side effects from ADT. This question reminds me of the COX-2 story, with my own case as an example. I stopped 400 mg of Celebrex daily for prostate cancer back in 2006 when cardiovascular concerns in the medical community were strong enough to prompt my insurer to cease covering the drug. (I was also doing very well on triple ADT at the time I stopped.) Now, the cardiovascular concerns for Celebrex are considered to be mainly among patients who have existing cardiovascular risk factors. My insurer is again covering Celebrex for my case.

    For many years I’ve been doing what I can to promote my cardiovascular health, and my risk appears very low. However, as the Medscape article suggests, awareness and alertness to cardiovascular risks are wise for those of us on ADT.

    Thanks for reporting this encouraging news!

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