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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.

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