Perspective in Circulation: Cardiovascular Quality and Outcomes

Recently, I joined the editorial board of Circulation: Cardiovascular Quality and Outcomes, the American Heart Association journal that focuses on quality of care and outcomes research. As my readers know, I became interested in cardiovascular disease because my daughter has heterozygous familial hypercholesterolemia, a genetic disease that cause high LDL-cholesterol and can lead to premature heart disease. I wrote this perspective for the November issue on how engaged patients can help bring about positive change in health care.

Society for Participatory Medicine Tweetchat Series

The Society for Participatory Medicine is launching a tweetchat series this Saturday, Sept. 14 at 3pm EST. The chat will be led by Casey Quinlan (@MightyCasey); Ileana Balcu (@Yogileana); and Carla Berg (@Confluently).

SPM will be hosting a tweetchat on the 2nd and 4th Saturdays of the month.  The second tweetchat will be Saturday, Sept. 28 from the floor of Stanford Medicine X, where a number of SPM members will be in attendance.

The first chat on 9/14 will focus on:

  1. What is participatory medicine?
  2. How has peer-to-peer healthcare impacted you?

Anyone interested in healthcare is invited to join in.

Go to tchat.io and plug in the hashtag #s4pm at 3pm Eastern this coming Saturday.

H/T Ileana Balcu

Addendum 9/14/13:  The transcript of the 9/14 tweetchat is available here.

BMJ: Clinical trial data for all drugs in current use must be available for independent scrutiny

In an impassioned editorial, BMJ editor Fiona Godlee calls on the pharmaceutical industry to release clinical trial data on all approved drugs, and on medical journals to publish industry-funded trials only when there is a commitment to make patient-level data available on reasonable request.  She states that the BMJ will require this commitment for all clinical trials of drugs and devices, whether industry-funded or not, beginning in January 2013.  In addition, BMJ is publishing online all correspondence between Roche and the Cochrane Collaboration researchers regarding the oseltamivir (Tamiflu) data.  More on the battle for Tamiflu data here.

Addendum 11/2/2012:  read Pharmalot’s coverage here.

BMJ editor: Open letter to Roche about oseltamivir trial data

In BMJ:

Roche promised in 2009 to release full reports from clinical trials of oseltamivir in response to an investigation by the BMJ and the Cochrane Collaboration.  In this open letter to John Bell, regius professor of medicine at Oxford University and a Roche board member, the BMJ’s editor in chief further urges the company to disclose the full data.

Read the full letter here.

Background here.

Ben Goldacre on missing data and publication bias

Ben Goldacre at Strata Conference

Here is a video of Ben Goldacre speaking at the Strata Conference in London earlier this month (H/T Chris Southan).

I also recommend his book, Bad Pharma:  How drug companies mislead doctors and harm patients, which goes into detail on how missing data and publication bias distort the medical literature and harm patients.

 

Johns Hopkins to launch Center for Drug Safety and Effectiveness

Johns Hopkins is launching a new Center for Drug Safety and Effectiveness.  Via G. Caleb
Alexander,

On Wednesday, October 24, we will launch the Johns Hopkins Center for Drug Safety and Effectiveness, a collaborative effort of the Bloomberg School of Public Health and Johns Hopkins Medicine.  The Center will fulfill its mission by supporting individuals engaged in research, training, clinical programs and public service to optimize the safe and effective use of prescription medicines in the United States and around the world.
We are delighted that Dr. Mark McClellan will deliver the inaugural lecture for the Center on October 24 at 4:00 PM, with a reception to follow.

Article in Korean Circulation Journal retracted for plagiarism

In March of this year, Larry Husten reported on CardioBrief that a review article in the Korean Circulation Journal by Chang Gyu Park and Ju Young Lee appeared to plagiarize from a review article in the Journal of the American College of Cardiology by Franz Messerli and Gurusher Panjrath.  In April, Husten reported that the article was being investigated by the publishing committee of the Korean Society of Cardiology and Korean Association of Medical Journal Editors.  It has just come to my attention that the KCJ article has been retracted.  Here is the notice:

On July 31, 2011, Korean Circulation Journal (KCJ) published a review article by Park et al. regarding the J-curve in hypertension and coronary artery diseases. However, a possibility of plagiarism has been raised in this article.

The Editorial Board of KCJ has examined the review article and has requested the Committee for Publication Ethics of Korean Association of Medical Journal Editors (KAMJE) to provide an adequate conclusion. After thorough investigation, the Committee for Publication Ethics of KAMJE and the Editorial Board of KCJ have concluded that the article is seriously plagiarizing from an article by Messeri (sic) et al.

In this regard, on May 8, 2012, the Executive Committee of the Korean Society of Cardiology has finally decided to retract the article completely. We apologize for any inconvenience this may have caused.

My earlier post on this is here.

Women vote

Compare and contrast: two review articles on ezetimibe

For the past several years I have been following the ezetimibe controversy (see these posts on Gooznews and this blog here, here, here, here, here, here, here, here, here, here, here, here, here, here, and here).  In my view, we continue to lack evidence of ezetimibe’s clinical benefit, or even safety, 10 years after FDA approval.

I have a Google Scholar Alert for ezetimibe, so often links to articles on ezetimibe arrive in my email inbox.  Recently, two review articles on ezetimibe were published that were a study in contrasts.  The first, by Sheila Doggrell, takes a skeptical view toward ezetimibe and reaches the following conclusion:

The comparison of clinical trials with simvastatin and ezetimibe alone and together has clearly shown that simvastatin decreases LDL-cholesterol and this is associated with improved clinical outcomes. Also, ezetimibe alone or in the presence of simvastatin lowers LDL-cholesterol. However, ezetimibe alone or in the presence of simvastatin has not been shown to have any irrefutable beneficial effects on clinical outcomes. Thus, until/unless the use of ezetimibe is clearly shown to improve clinical outcomes, its use should be largely restricted to clinical trials investigating clinical outcomes, and ezetimibe should not be used routinely in everyday practice.

The second, by Binh An Phan, Thomas Dayspring and Peter Toth, takes a much more optimistic view:

In the current treatment of cardiovascular disease, many subjects fail to reach LDL-C targets or remain at high risk for CHD events despite optimal statin and medical therapy. Ezetimibe inhibits intestinal cholesterol absorption and is effective in lowering cholesterol as monotherapy or in combination with statins in several populations, including those with FH, sitosterolemia, and insulin resistance. Significant controversy has been generated regarding the clinical effectiveness of ezetimibe, particularly after the publication of ENHANCE and ARBITER-6 despite both trials having significant methodological flaws that limited their ability to evaluate the benefit of ezetimibe. Growing data suggest that ezetimibe in combination with statin has a positive effect on the progression of atherosclerosis and reduces cardiovascular events in subjects at risk for CHD, including those with chronic kidney disease. Results from IMPROVE-IT are forthcoming and may help to guide better the use of ezetimibe in very high-risk CHD populations. Until that time and based upon the current available data, ezetimibe should remain a viable adjunct to statin therapy in the treatment of hypercholesterolemia.

Dr. Phan and colleagues find reasons to dismiss the negative results of ENHANCE and ARBITER 6-HALTS as due to “methodological flaws” and use copious amounts of hand-waving to find support for ezetimibe in the SEAS and SHARP trials, even though those trials compared the combination of simvastatin and ezetimibe with placebo and thus can tell us nothing about what, if anything, ezetimibe added to those results.  Could the differing views of Doggrell and Phan et al. have anything to do with the fact that Dr. Doggrell declares no conflicts of interest relating to ezetimibe, while Phan, Dayspring and Toth declare the following conflicts:

Binh An Phan is a speaker for Abbott. Thomas Dayspring consults for Abbott, GSK, Health Diagnostic Labs, Kowa Company, Eli Lilly, Merck, Genentech, The Roche Group, Genzyme, and Omthera. He is on the Lecture Bureau for Abbott, GSK, Health Diagnostic Labs, Kowa, Eli Lilly, LipoScience, Merck. Peter P Toth is a speaker for Abbott, AstraZeneca, Amylin, Boehringer-Ingelheim, GSK, Kowa, Merck and consults for Abbott, Aegerion, AstraZeneca, Atherotech, Genzyme, Genentech, Kowa, and Merck.

It is not too surprising that authors who are consultants and on the speaker’s bureau for Merck would take a favorable view of ezetimibe.  What is surprising is that anyone would take their word for it.

References

Doggrell SA. The ezetimibe controversy — can this be resolved by comparing the clinical trials with simvastatin and ezetimibe alone and together? Expert Opin. Pharmacother. (2012) 13(10):1469-1480.

Phan BAP, et al. Ezetimibe therapy:  mechanism of action and clinical update. Vascular Health and Risk Management 2012:8:415-427.

Addendum, May 5, 2015:  Unfortunately, the GoozNews blog is no longer up on the web.

Alzheimer’s disease, familial hypercholesterolemia, and clinical trials

Welcome Jesse Ballenger to the blogosphere.  Jesse is a historian who specializes in the history of medicine and is the author of Self, Senility and Alzheimer’s Disease in Modern AmericaGary Schwitzer alerted me to Jesse’s post on Gina Kolata’s recent Sunday New York Times piece, How Do You Live Knowing You Might Have an Alzheimer’s Gene?, as well as to the existence of his blog, To Conquer Confusion:  A Historian’s Perspective on the Science and Experience of Alzheimer’s Disease and Dementia.  Jesse has both praise and criticism for Kolata’s story, and his post brings needed perspective on the history of research on Alzheimer’s as well as on the choice on Kolata’s part to present only the very optimistic views of certain Alzheimer’s researchers who “say that within a decade there could be a drug that staves off brain destruction and death.”  I agree with him that “Kolata should have raised questions about this claim, and talked to experts not directly involved in the research who are far less optimistic about its potential to so quickly lead to effective treatments.”  So please go read his post.

Kolata describes an American family in which many members are afflicted with early-onset Alzheimer’s caused by an autosomal dominant mutation.  Because the mutation is dominant, each affected family member has a 50% chance of passing the mutation on to each of his or her chidren.  The story is tragic and brought to my mind the emotions I experienced in 2001, when my daughter was diagnosed with heterozygous familial hypercholesterolemia (heFH) at age 8.  This is a genetic disease that causes very high LDL-cholesterol from birth and if untreated leads to early heart disease in a high percentage of patients.  At the time, I was only vaguely aware that there was a history of heart disease in my husband’s family and that his mother had had a heart attack.  At the urging of my daughter’s cardiologist, we asked my husband’s mother for more details and learned that her father had died of a heart attack at 35 and her brother, her only sibling, died of a heart attack at 40.  My mother-in-law suffered her first heart attack at age 58.  My husband inherited the mutation but has only a mild case, and my mother-in-law had never been told anything other than that she had high cholesterol, so my daughter’s diagnosis was the first occasion anyone in the family realized that the family history of early heart attacks was caused by a mutation.  Fortunately, unlike the case of Alzheimer’s disease, the risk associated with heFH can now be greatly reduced if patients are treated from an early age with a statin.  Homozygous FH patients, who have two copies of an FH mutation, are not so lucky and usually must undergo LDL apheresis on a regular basis.

Back to Kolata’s article:  I want to expand a little on a comment I wrote on Jesse’s post.  My comment related to Kolata’s comparison between the development of statins and the development of drugs to prevent Alzheimer’s.  As described in Kolata’s article, certain drugs in development are being tested in persons who are carriers of an Alzheimer’s mutation but have not yet developed symptoms of the disease.  The patients will receive one of several drugs or a placebo, and will be monitored for the development of certain biomarkers and, importantly, for the development of memory problems.  Kolata states that “Statins, the drugs that are broadly prescribed to block the body’s cholesterol synthesis, were first found effective in studies of people who inherited a rare gene that led to severe and early heart disease.”

The disease Kolata is presumably referring to is FH, but whether her statement is accurate depends on how one defines “effective.”  Early in the development of statins, after they had been tested in animals, they were given to a few patients with homozygous FH and heterozygous FH, as described in this 1992 article in the Journal of Lipid Research.  However, at that time the drugs were only being tested for their ability to lower LDL and for safety.  LDL-lowering is a surrogate endpoint.  If by “effective” one means the prevention of heart attacks and other cardiovascular events, the statement is inaccurate. When statins came on the market in the late 1980s, FH patients were excluded from the clinical trials that were conducted to show than statins not only lowered LDL but also prevented heart attacks, strokes and death. It was considered unethical to give an FH patient a placebo. To this day, no randomized controlled trial of statins with clinical endpoints has been done in FH patients and it is unlikely that one will ever be done. 

Direct evidence of the effectiveness of statins in heFH includes two observational studies, one of patients in a British registry and one of patients in a Dutch registry.  In addition, the ASAP trial compared a high dose statin with a moderate dose statin in heFH patients, but the endpoint was carotid intima media thickness, “IMT” (i.e., thickness of the carotid artery measured by ultrasound).  There was also a trial of statin vs. placebo in teenage FH patients using IMT as an endpoint.  In addition, many trials of statins have shown a benefit in non-FH patients with elevated LDL and it is reasonable to assume that this benefit would carry over to FH patients.

Thus, the comparison between the trials of investigational Alzheimer’s drugs in mutation carriers and the testing of statins in FH patients is not particularly apt.  The Alzheimer’s trials in patients with hereditary Alzheimer’s will be measuring the development of clinical symptoms of Alzheimer’s (i.e., memory loss, confusion, etc.).  The tests of statins in FH patients looked only at the effect of the drug on a surrogate endpoint (i.e., LDL-lowering) and no trials with clinical endpoints (i.e., heart attacks and other cardiovascular events and death) were done in FH patients.

References

Endo A.  The discovery and development of HMG-CoA reductase inhibitors. J. Lipid Res. 1992 33:(11) 1569-82. 

Neil A, Cooper J, Betteridge J, et al. Reductions in all-cause, cancer, and coronary mortality in statin-treated patients with heterozygous familial hypercholesterolaemia: a prospective registry study. Eur Heart J 2008; 29: 2625-2633.

Versmissen J, Oosterveer DM, Yazdanpanah M, et al. Efficacy of statins in familial hypercholesterolaemia: a long term cohort study. BMJ 2008; 337: a2423.
 
Sijbrands E.  Inhibition of PCSK9 in Familial Hypercholesteolemia.  The Lancet, Early Online Publication, 26 May 2012.