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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.
 
 

“Be Brave”

In January, I blogged about an open letter by Harlan Krumholz and Rodney Hayward to the panel that is currently engaged in writing new guidelines for cholesterol management.  As discussed in my post, their letter challenges the committee to replace the current “treat to target” paradigm with a “tailored treatment” approach.  This has been one of my more popular posts of all time, and people often find my blog by Googling “Krumholz Hayward open letter” and the like.  It also has been discussed on CardioExchange.  So I knew their paper had created a bit of a buzz in the cardiology community.  Well, it appears that some in that community are not happy that someone is challenging the current paradigm.  Dr. Krumholz reports on CardioExchange that he was approached by an influential person and asked to stop speaking out on the new approach he is advocating:

I had an experience the other week that reminded me that speaking your mind has its challenges. I was approached by someone with influence who asked me to cease my discussions on a particular topic. The reason was oblique – and I was told that people are viewing me negatively because my views are strong and wondering if there are conflicts of interest that are influencing me. In essence, I was told that people are whispering about me – though no names were given.

Now this topic was part of a scientific debate that has strong implications for guidelines and performance measures – and, well, patients. It is a situation where I am questioning conventional wisdom – and the long held beliefs by many individuals. I am trying to do so respectfully – and through the use of evidence – but still it is questioning dogma.

This conversation prompted me to write a message to my younger colleagues urging them to stand up for what they believe – and be willing to speak truth to power. I quote my friend Victor Montori, who eloquently advised a junior colleague about how to manage a concern about whether to express an opinion that was likely to be viewed negatively by her superiors. That person had been told to hold opinions tight until he had more grey hair. Victor starts by saying: ‘I have struggled with this issue for years. Turns out that this is a common struggle for those who find themselves unable to stay silent in the face of waste, error, low integrity, or abuse.’

The message Dr. Krumholz wrote is in the form of an editorial in Circulation:  Cardiovascular Quality and Outcomes, entitled “A Note to My Younger Colleagues … Be Brave.”  The editorial is open access, so I urge you to go read it in its entirety, but I’m going to quote this paragraph, which seems key:

If you take the path toward clarity, I guarantee that you will occasionally find people who will disparage you. They may seek to undermine you, find ways to marginalize you, and try to incriminate you. They may come from directions that surprise you. Powerful ideas often attract attacks that focus more on individuals than ideas. If you raise inconvenient truths or voice uncomfortable opinions, particularly if they threaten someone’s comfortable status quo, then you will discover much about the character of those with whom you disagree. But always take the high road, engage in dialogue about ideas and evidence, and be motivated by the opportunity to best serve patients and the public. You will not regret it.

Although I am not a physician, I certainly recognize and have experienced the issues Dr. Krumholz is describing in my own life.  Speaking uncomfortable truths often isn’t considered nice and doesn’t win popularity contests, but it is necessary for progress to be made.  So I will keep covering this controversy, and I invite you to read Dr. Krumholz’s editorial and then let me know your thoughts.

Addendum:  Here are comments by Ben Goldacre on Dr. Krumholz’s editorial.

Hayward and Krumholz: Open Letter to the Adult Treatment Panel IV of the National Institutes of Health

Rodney Hayward and Harlan Krumholz have published an open letter to the committee that is currently engaged in writing updated guidelines for cardiovascular risk reduction.  Their letter challenges the committee to replace the current “treat to target” paradigm with a “tailored treatment” approach, as discussed below.

The primary focus of the current set of guidelines, ATP III , was a strategy of treating patients to target LDL-cholesterol levels, known as the “treat to target” paradigm.  Moreover, the “cutpoints,” or triggers, for initiating therapy are also based on LDL levels, with higher risk patients having lower cutpoints.  However, as Hayward, Krumholz and colleagues have previously argued (see here, here and here), the treat to target paradigm was not based on the results of clinical trials, since no major randomized controlled trial has tested the benefits of treating patients to LDL targets.  Rather, the trials have used fixed doses of lipid-lowering drugs.

Hayward and Krumholz argue that LDL levels are not particularly useful in assessing the 2 factors that help determine the benefit of a treatment for an individual patient:  (1) risk of morbidity and mortality in the absence of treatment (baseline risk) and (2) the degree to which the treatment reduces that risk.  For calculating baseline risk, LDL is only one of several factors that are considered, including age, gender, smoking, blood pressure, HDL, and family history of premature cardiovascular disease and in most cases contributes little to the estimate of cardiovascular risk.  For the second factor, clinical trials of statins demonstrate that the relative benefits of statins are not substantially related to pretreatment LDL levels.  Thus, a high risk person may have low LDL levels and a low risk person may have high LDL levels and the high risk person will derive more absolute benefit more from treatment even though his or her LDL is low (illustrated in this table).

Hayward and Krumholz also argue that treating to LDL targets can lead to treatments that have not been shown to be safe.  The treat to target approach can mean initiating treatment in patients at a relatively young age, leading to potentially many years of statin treatment.  The long-term safety of this approach is not yet known.  In addition, the perceived need to reach an LDL target often leads to the addition of nonstatin drugs such as niacin and ezetimibe when the maximum dose of a statin is reached and the patient’s LDL is still above goal.  The benefit and safety of adding these drugs on top of statin therapy has not yet been demonstrated.

The “tailored treatment” approach Hayward and Krumholz advocate bases intensity of statin treatment on a person’s 5- or 10-year cardiovascular risk.  In a previous paper, Hayward et al. tested a tailored treatment model of primary prevention using 5-year coronary artery disease (CAD) risk and compared it with the treat to target approach.  In their model, a person with 5% to 15% risk would be prescribed 40 mg simvastatin and a person with greater than 15% risk would be prescribed 40 mg atorvastatin.  Using this simulated model, the tailored treatment approach was found to prevent more CAD events while treating fewer persons with high-dose statins as compared to the treat to target approach.

For the reasons stated above, the tailored treatment approach does appear to me to be superior to the treat to target approach.  At the same time, I note that the decision to take a statin is a personal decision.  For primary prevention, the absolute benefit for most people of taking a statin over a 5 or 10 year period is small.  Each person should calculate their baseline risk (there are online risk calculators for this), look at how much their risk can be lowered with a statin, and ask themselves if the benefit seems worth it to them in terms of cost, inconvenience and possible side effects (including a small increase in risk of developing diabetes).

In addition, I note that neither approach is designed to apply to patients with heterozygous familial hypercholesterolemia (FH).  Due to the very high risk of premature coronary heart disease in FH patients (approximately 85% of male FH patients and 50% of female FH patients will suffer a coronary event by age 65 if untreated), the treatment paradigm for FH patients is that all are treated with statins starting in childhood or early adulthood (not everyone agrees that it is necessary to start treatment in childhood but that’s a topic for another day).  In other words, FH patients are treated based on their lifetime risk, not their 5- or 10-year risk.

References

Hayward RA, Krumholz HM.  Three reasons to abandon low-density lipoprotein targets:  an open letter to the Adult Treatment Panel IV of the National Institutes of Health.  Circ Cardiovasc Qual Outcomes.  2012:5;2-5.

Hayward RA, Hofer TP, Vijan S.  Narrative review:  lack of evidence for recommended low-density lipoprotein treatment targets:  a solvable problem.  Ann Intern Med.  2006;145:520-530.

Krumholz HM, Hayward RA.  Shifting views on lipid lowering therapy.  BMJ. 2010;341:c3531.

Hayward RA, Krumholz HM, Zulman DM, Timbie JW, Vijan S.  Optimizing statin treatment for primary prevention of coronary artery disease.  Ann Intern Med.  2010;152:69-77.

Rind DM.  Intensity of lipid lowering therapy in secondary prevention of coronary heart disease.  In:  Freeman MW, Sokol HN, eds.  UpToDate.  19.3 ed.

Sunday links

David Rind recently revived his blog Evidence in Medicine and has a post up on the SHARP trial.  The SHARP trial, which I discussed recently on this blog and on Gooznews, is the basis for Merck’s application for a new indication for its drugs Vytorin (ezetimibe/simvastatin) and Zetia (ezetimibe).  David explains why the results in SHARP are consistent with previous evidence on the effect of statins in patients with chronic kidney disease, both pre-dialysis and on dialysis.

Kevin Lomangino has an article up on the “portfolio diet,” which is a diet that emphasizes foods that lower cholesterol.  Kevin explains that most of the cholesterol-lowering from this diet comes from the inclusion of foods containing added plant sterols.  As I previously discussed on this blog, while plant sterols lower LDL, their effect on cardiovascular events is unknown, making the portfolio diet a bit of a crapshoot healthwise.

Review of CNN special “The Last Heart Attack”

I have a guest  post up on Gary Schwitzer’s blog critiquing Sanjay Gupta’s promotion of calcium scans and overhyping of extreme diets.

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