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Danish HT* trial

November 4, 2012

Paid “experts” muddy the waters again

A secondary analysis in last month’s BMJ of the Danish Osteoporosis Prevention Study (DOPS) (click here) has tried to revive the idea that hormone therapy (HT) started soon after the menopause protects against heart disease.

DOPS participants, recently menopausal women (age 45-52), had been randomly allocated to HT or not, in an open-label trial.  After a mean follow up of 16 years a composite endpoint of “death, admission to hospital for myocardial infarction or heart failure” occurred in 16/502 women in the treated group v 33/504 in the controls, giving an adjusted hazard ratio of 0.49 (95% CI 0.27 to 0.89) and a nominal P value of 0.02.

The usual “experts” (John Stevenson, Howard Hodis*, Tobie de Villiers** and Rogerio Lobo***) dived in to persuade impressionable journalists (click here and here) that this shows that HRT is safe. They want official guidelines, which advise taking HT for symptoms only, and in the lowest dose and for the shortest time possible, to be rewritten. This is nonsense.

There are at least three reasons for taking the DOPS results with a pinch of salt.

  1. Although the deaths were probably completely ascertained, the difference (15 v 26) was not statistically significant. The open design makes the other components, myocardial infarction (1 v 4), and heart failure (1 v 7), which together generated the headline figure, susceptible to ascertainment bias.
  2. DOPS used envelope randomisation, which risks recruitment bias. At trial entry controls were older, a difference that was unlikely to have occurred by chance (P=0.007).
  3. There was no mention of the composite endpoint in the original trial protocol – the present authors dreamt it up post hoc. They claim they defined it before starting the analysis, but if you believe that you’ll believe anything. The senior author and some of the present authors have written dozens of papers based on the DOPS data set. It is implausible that they were unaware of trends when they decided to include say heart failure in the composite for the present analysis. No-one has ever previously suggested that HT causes or prevents heart failure. The BMJ press release, which states; “So authors from Denmark carried out a randomised trial over 10 years with additional six years of follow-up to establish whether HRT can reduce cardiovascular risk if it is started early after menopause”, is seriously misleading on this point.

At best this paper is hypothesis generating, rather than hypothesis testing.

The hypothesis – that HT is cardio-protective, or at least safe, when started early – has huge hurdles to overcome.  Every independent systematic review has concluded the opposite.  Sub analysis of the largest Women’s Health Initiative (WHI) trial data showed increased mortality among women starting HT within five years of the menopause (click here). Even if the data in the present study are unbiased, they amount to only 42 coronary events in total.  WHI alone had 335 such events, including 64 in women aged less than 60.

Klim MacPherson, writing in response to the present paper, (click here) reminds us of the coronary events in about 200 small efficacy trials in women soon after the menopause.  These data (click here and here), which often had to be extracted from the companies by legal threats, showed an increase in risk of cardiovascular events with HT.

Finally papers supporting HT tend to be disproportionately written by authors with ties to drug companies manufacturing such preparations (click here and here for more).  Two of the present paper’s eight authors, Pia Eiken, and Jens-Erik Beck Jensen acknowledge such conflicts of interest, but two more, Lars Køber and Lief Mosekild, do not.

Readers may be interested to learn that someone called Lars Køber is listed by the Danish Health and Medicines Authority (click here) as having 18 advisory board memberships or investigator interests in such companies, and someone called Lief Mosekild is listed as being an investigator with NPS Pharmaceutical and with Nycomed.

What a coincidence that they have the same names!

Jim Thornton

*Howard Hodis features in a Town hall meeting advocating HT sponsored by Wyeth (click here)

**Dr De Villers is an investigator in trials sponsored by MSD, Pfizer and Eli Lilly and serves on the advisory boards of Novartis (SA), Adcock Ingram and Servier.

***Rogerio Lobo features in our naming and shaming list here

*Hormone replacement therapy (HRT) changed to hormone therapy (HT) Jan 2016

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