Monthly Archives: January 2012

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.

Abbott Laboratories sponsors review article on its own drug

A review article in a medical journal is an attempt to summarize the current state of research on a particular topic.  A review article does not present original research but rather collects and interprets the research that has been done, describes gaps in the research and controversies that exist, and how to apply the research in clinical practice.  A review article can be a good starting point to get a grasp of a topic.  However, because the authors are generally experts on the topic they are discussing, they often have a point of view that may not be obvious to someone not expert in the field. 

But what if the agenda for the article were out in the open?  What if, say, a drug company sponsored a review article on its own drug and paid a medical journal to publish it?  That appears to have happened with this review article on fibrates in a journal called Reviews in Cardiovascular Medicine, published by MedReviews, LLC.  The acknowledgment discloses the following:

Abbott Laboratories, Inc., provided funding to MedReviews, LLC.  No funding was provided to authors.  Abbott Laboratories, Inc. had the opportunity to review and comment on the publication content; however, all decisions regarding content were made by the authors.

So, while it is unclear who produced the initial draft of the article, Abbott Laboratories reviewed and commented on the article before publication and paid the publisher for publishing the article.  Abbott just happens to sell two fibrates, TriCor and Trilipix.

Never having heard of this journal, I looked at the journal’s website and confirmed that it is a peer-reviewed journal and is indexed in PubMed and Medline.  It’s editorial board includes some well-known academic physicians.  The website also discloses that MedReviews has formed a partnership with the California Chapter of the American College of Cardiology.

I’m having a hard time understanding why anyone would want to spend their time reading a medical journal that publishes review articles that have such a high level of involvement from a commercial enterprise with a vested interest in the topic.  I’m also having a hard time understanding why the California Chapter of the ACC and the members of the editorial board would want to be associated with this journal.

H/T Harlan Krumholz.

Addendum January 7, 2012:  Howard Brody has weighed in on the Hooked:  Ethics, Medicine, and Pharma blog.

Addendum January 10, 2012:  Also see this post on Pharmalot blog.

Addendum February 3, 2012:  Also see this post by Kevin Lomangino on the Health News Watchdog blog and this followup post by Howard Brody.

Addendum August 16, 2012:  See this followup post by Kevin Lomangino on the Health News Watchdog blog.

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