From: Trish Groves <[log in to unmask]>
To: [log in to unmask]
Sent: Saturday, 13 October 2012, 18:17
Subject: Re: effects of HRT on CVD events RCT
Thanks, Ben
Your point's very important, but it's unusual for a single paper to change practice, and neither the paper nor the press release suggested that the findings here were sufficiently definitive to warrant that.
Here's the BMJ press release, which we posted alongside the paper:
http://www.bmj.com/press-releases/2012/10/10/hrt-taken-10-years-significantly-reduces-risk-heart-failure-and-heart-atta
I certainly hope that Klim will send a Rapid Response: we'd be very pleased to post it. And if it's at all reassuring, I can say (somewhat cryptically) that the reviewers who saw the paper were the right ones and were fully aware of the relevant evidence base.
Best wishes
Trish
Dr Trish Groves
Deputy editor, BMJ
and Editor-in-chief, BMJ Open
+44 207 383 6018
bmj.com - the open access journal
bmjopen.bmj.com
BMJ Group: http://group.bmj.com
twitter @trished
From: "Djulbegovic, Benjamin" <[log in to unmask]>
To: [log in to unmask]
Date: 13/10/2012 16:25
Subject: Re: effects of HRT on CVD events RCT
Sent by: "Evidence based health (EBH)" <[log in to unmask]>
Hi Trish,
Thanks for this reply.
I am aware of logistical complexities of mandating doing a SR/MA from the trialists. I am also not sure how well the Lancet policy is enforced- I have certainly seen the papers in which the authors did perform SR/MA and those where only cursory reference to a “systematic” review process had been made.
However, if the goal of a RCT is to inform physicians’ decision-making, it is not clear to me how it is possible to “discuss [the] completed trial in the light of the totality of existing evidence without doing “your own systematic review"? After the BMJ published this latest HRT trial, what should I, as a practitioner do? (Re-)start prescribing HRT (with a goal to prevent heart disease, osteoporosis, improve life expectancy etc)? The only way I can really make this decision is to understand the results of this trial after it was pooled with other similar trials (assessing bias & getting estimate of the impact of random error, of course, remains integral part of this process).
I am cc my reply to Iain as it appears that I have misunderstood his writings.
Many thanks for willingness to engage in an open dialogue with the authors and representatives of the public (which is how I see my role). I hope other editors will follow your example.
Ben
Ps re the HRT paper, I do suggest that you commission a rapid response/review (SR/MA) from Klim or his colleagues to settle the question.
From: Trish Groves [mailto:[log in to unmask]]
Sent: Saturday, October 13, 2012 10:31 AM
To: Djulbegovic, Benjamin; EVIDENCE-BASED-HEALTH
Subject: Re: effects of HRT on CVD events RCT
Hi Ben
Thanks for the prompt.
This is a good question, but a much misunderstood one.
Doing a systematic review takes expertise that not all triallists have, and reporting one properly takes a whole paper.
So insisting on doing and then reporting a new systematic review in the discussion section of every RCT papers is neither feasible or desirable - what use is a systematic review that's mentioned in a couple of sentences and is impossible to evaluate?
If you ask Iain directly (which I've done), he says it's not what he ever intended.
He meant that triallists should ensure before writing their protocol, let alone their paper, that the trial will add to what's known (by searching properly for relevant systematic reviews) and should discuss their completed trial in the light of the totality of existing evidence.
That's not the same at all as "do your own systematic review."
The Lancet's instructions for authors asks for a section in the discussion that puts the results into context and says, for RCTs, "authors are invited [ie not mandated] to either report their own up to date systematic review or cite a recent systematic review of other trials".
Most Lancet authors take the second option, and that's fine.
At the BMJ we ask for a structured discussion in every paper:
www.bmj.com/about-bmj/resources-authors/article-types/research
This includes a subsection on "strengths and weaknesses in relation to other studies, discussing important differences in results".
Every paper also has a box stating what was already known and what the study adds.
For the record, the Schierbeck et al study you're discussing did that, citing previous RCTs and meta-analyses.
Anyway, do please bring to bmj.com (via Rapid Responses) the debate that's taking place on this listserve. We will, of course, ask the authors to respond in turn.
Best wishes
Trish
Dr Trish Groves, Deputy editor BMJ, and Editor-in-Chief BMJ Open
bmj.com
bmjopen.bmj.com
Twitter @trished
(By Blackberry: please forgive any typos)
From: "Djulbegovic, Benjamin" [[log in to unmask]]
Sent: 13/10/2012 13:48 GMT
To: [log in to unmask]
Subject: Re: effects of HRT on CVD events RCT
Indeed, Klim
So, what happens if the latest study is pooled with all other (eligible) studies? I believe that some journals mandate ( Lancet, not sure about BMJ and other journals) placing the findings of the latest study in the context of the totality of existing evidence. Iain Chalmers & Mike Clarke ( cc on this reply) have convincingly argued that all research should start with research synthesis ( systematic review to justify uncertainties to undertake a new clinical trial) and finish with systematic review ( placing findings of the study in the context of all available evidence). If this is not done, (reigniting old) confusion is bound to happen.
Because some of the members of this group are editors, I want to directly invite them to respond to this challenge: why their journals have not adopted the Lancet policy of mandating systematic review from all authors submitting a clinical trial report ( at least RCT) to their journals? Specifically, it would be good to hear from the BMJ editors: was this oversight or they do not think such policy should be put in place?
In a new age of transparency and democratization of scientific discourse, I hope we hear from the editors as this is really important issue.
Thanks
Ben
On Oct 13, 2012, at 4:52 AM, "Klim McPherson" <[log in to unmask]> wrote:
Thanks Anoop,
My rapid response:
Schierbeck and colleagues suggested that “initiation of hormone replacement therapy in women early after menopause significantly reduces the risk of the combined endpoint of mortality, myocardial infarction, or heart failure” [1]. They invoke the age hypothesis, which remains one of the abiding critiques of the WHI study, namely that women well past the menopause in WHI responded differently to exogenous hormones than do symptomatic menopausal women, with respect to cardiovascular risk.
All such arguments have perforce to ignore the only double blind placebo controlled studies of such symptomatic women, a synthesis of which was published in the BMJ [2] and then the Lancet [3] including unpublished studies (a process resisted by the manufacturers) and summarised in the BMJ [4]. The evidence from a synthesis of some 200-efficacy studies submitted for licensing of HRT products strongly suggests that the risk is the same as found among older women in WHI as among women with menopausal symptoms. Purveyors of the age hypothesis need to take on board all of the evidence, especially from well-controlled RCT’s.
Yours,
Klim McPherson
New College
Oxford OX1 3BN
References
Schierbeck LL, Rejnmark L, Tofteng CL, Stilgren L, Eiken P, Mosekilde L, Køber L, Jensen JE. Effect of hormone replacement therapy on cardiovascular events in recently postmenopausal women: randomised trial. BMJ 2012; 345: e6409.
Hemminki E, McPherson K. Impact of postmenopausal hormone therapy on cardiovascular events and cancer: Pooled data from clinical trials. BMJ; 1997; 315:149-153.
Hemminki, E, McPherson K. The value of drug-licensing documents in studying the effect of postmenopausal hormone therapy on cardiovascular disease. Lancet, 2000; 355: 566 – 8
McPherson K, Hemminki E. Synthesising licensing data to assess drug safety. BMJ, Feb 2004; 328: 518-520
From: Anoop Balachandran <[log in to unmask]>
Reply-To: Anoop Balachandran <[log in to unmask]>
Date: Friday, 12 October 2012 13:45
To: "[log in to unmask]" <[log in to unmask]>
Subject: Re: effects of HRT on CVD events RCT
My comments:
1. The sample size is small. In the WHI study, they had 17,000 in one arm and 10,000 in other arm. So the CI's were very wide.
2 No placebo-controlled group.
here is a rapid response for that article in BMJ:
Schierbeck and colleagues suggested that “initiation of hormone replacement therapy in women early after menopause significantly reduces the risk of the combined endpoint of mortality, myocardial infarction, or heart failure” [1]. However, after a closer look at their study, the results do not appear so straightforward.Indeed, after a mean duration of 10.1 years of randomised treatment in 1006 women, the primary endpoint occurred in 17 fewer subjects (33 vs 16) in treated group than in control group. However, women in the control group were 0.47 years (about 5.7 months) older than those in the treated group [1].In the cardiovascular secondary prevention trial Cholesterol and Recurrent Events (CARE) [2], patients were randomized to 40 mg daily of the cholesterol-lowering drug pravastatin or placebo. In the 4159 participants, statin therapy was associated with 97 fewer revascularizations [2]. It has been calculated that the average delay of revascularization was 0.09 years (33 days) over 5 years [3]. Although it is difficult to make a similar calculation for the study by Schierbeck and colleagues [1], it seems unlikely that the projected delay on 10 years of the events defined in the primary endpoint would be longer. In other words, although the authors adjusted the composite endpoint’s results for age, the apparent significant beneficial results may have been seriously flawed.Furthermore, the assumption that heart protection in fertile women is mediated by premenopausal levels of female hormones is not consistent with epidemiological findings that premenopausal hysterectomy essentially cancels the protection, even in cases with preservation of functioning ovaries [4]. On the contrary, these data [4] suggest that an intact uterus has an important role in the protection of premenopausal women, and likely this is related to the beneficial effect of iron depletion in menstruating women [5] (i.e., the iron hypothesis suggested by Sullivan more than 30 years ago [6]).If you torture numbers enough they will say anything you want.Luca Mascitelli, MD
Comando Brigata alpina “Julia”, Udine 33100, ItalyMark R. Goldstein, MD, FACP
NCH Healthcare Group, Naples, FL, USAREFERENCES1. Schierbeck LL, Rejnmark L, Tofteng CL, Stilgren L, Eiken P, Mosekilde L, Køber L, Jensen JE. Effect of hormone replacement therapy on cardiovascular events in recently postmenopausal women: randomised trial. BMJ 2012; 345: e6409.2. Sacks FM, Pfeffer MA, Moye LA, et al, for the Cholesterol and Recurrent Events Trial Investigators. The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. N Engl J Med 1996; 335: 1001–9.3. Bassan M, Panush N. Treating hypercholesterolemia—without the hype. Am J Cardiol 1997; 79: 1001–3.4. Kannel WB, Levy D. Menopause, hormones, and cardiovascular vulnerability in women. Arch Intern Med 2004; 164: 479-81.5. Mascitelli L, Goldstein MR, Pezzetta F. Explaining sex difference in coronary heart disease: is it time to shift from the oestrogen hypothesis to the iron hypothesis? J Cardiovasc Med (Hagerstown) 2011; 12: 64-5.6. Sullivan JL. Iron and the sex difference in heart disease risk. Lancet 1981; 1: 1293-4.
On Thu, Oct 11, 2012 at 9:57 AM, healingjia Price <[log in to unmask]> wrote:
As one who enjoyed profound and immediate benefits I would like to still see this replicated as a blind, industry free trial and also wonder if strategic genomic analysis would be helpful. The 8% rate is a concern what was exclusion criteria?
Amy
Amy Price
Empower 2 Go
Building Brain Potential
Http://empower2go.org
Sent from my iPad
On 11 Oct 2012, at 02:38 PM, "Klim McPherson" <[log in to unmask]> wrote:
I would be fascinated to know the dispassionate opinion of this group on a quite large trial of HRT v nothing which appears to negate a great deal of evidence from other RCT's on the effect of HRT on CVD and breast cancer in particular.
It is not blind (does that matter and how much). It is funded by HRT Pharma, most of the PI's have advisory roles with the companies. 8% of eligible patients were recruited into the trial ………..
Where should it sit in the panoply of evidence on the safety of HRT ??
This is an important question because of the unambiguous and profound benefits of HRT for menopausal symptoms but particularly bone density loss, and hence the 'need' to downplay possible harms.
http://www.bmj.com/content/345/bmj.e6409
Your opinions would be greatly valued.
Klim McPherson MA Phd FFPH FMedSci
Visiting Professor of Public Health Epidemiology
Nuffield Dept Obstetrics & Gynaecology
Emeritus Fellow of New College
University of Oxford
Mobile 07711335993
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