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Diminishing returns in medical therapy

I’m a few months late, but I want to mention an editorial by Rodney Hayward that was published in The BMJ in December 2015. His topic is treatment of diabetes, but the principles he discusses also apply to other areas of medicine. The key concept is that even in high risk conditions such as diabetes, adding a second or third medication brings diminishing absolute returns as residual risk decreases as each additional treatment is added. He starts by describing the disturbing consequences of untreated or poorly managed diabetes, and how things have changed with modern therapies.

When I began my medical training in 1980, I commonly encountered patients whose bodies were ravaged by end stage complications of diabetes. These patients often had marked visual impairment, debilitating neuropathy, myopathies, and diabetes related renal insufficiency, well before age 65 years. I still occasionally see such individuals, but they are rare, and tend to come from the 10-15% of patients who still have poor glycemic control. Improvement in diabetes care is a medical success story, but increasing evidence suggests that overly aggressive treatment is an under-appreciated problem.

The problem is that focusing on relative treatment effects ignores the law of diminishing returns; past a certain point, additional reductions in HbA1c have limited benefit in absolute terms for most older patients with type 2 diabetes. Hayward explains:

Diminishing returns is a mathematical fact, not a theory. Try this simple experiment. Serially tear a piece of paper in half and throw one half away. You will notice that the relative effects never diminish (you reduce the piece of paper by half each time), but it doesn’t take long for the 50% you throw away to become tiny. The many patients with end stage diabetes we saw in the 1980s often spent years with poor control of both glycemia and blood pressure. They had no access to metformin, home blood glucose monitoring, angiotensin converting enzyme inhibitors, calcium channel blockers, and a host of other modern interventions. Each of these interventions substantially reduces disease progression and has an even larger effect on end stage diabetes complications. Because each intervention substantially reduces end stage complications, it should not be surprising that recent evidence has found intensive glycemic control to have a small absolute effect on end stage complications for most patients with type 2 diabetes. The law of diminishing returns predicts this result. Also, as the benefits of tighter glycemic control become smaller, the chances that treatment harms will outweigh treatment benefits become much greater.

Hayward ends by stating that the public good would best be served by focusing on the minority of diabetes patients who continue to be at substantial risk of diabetes-related morbidity and mortality and promoting more shared decision making with older diabetes patients who already have at least moderate blood glucose control.

The same principle of diminishing returns applies in other areas of medicine, such as in medications that reduce cardiovascular risk by lowering blood pressure or cholesterol. As the second and third medication is added, the patient’s risk of experiencing a cardiovascular event diminishes and in some cases a point can be reached where the absolute benefits become very small and it becomes difficult to tell whether benefits outweigh harms. When benefits become small, it can sometimes be hard to determine whether they exist at all or, perhaps, exist in only in patients with certain characteristics. See this post by Harlan Krumholz for a discussion of these issues in the area of treatment of high blood pressure.

In the area of cholesterol-lowering drugs, the new PCSK9 inhibitors have been in the news and I’ve previously discussed them on this blog (here, here and here). Two of these drugs, evolocumab and alirocumab, are approved in the U.S. and so far aren’t selling well. There are several reasons for that, including that the outcomes trials haven’t been completed yet and that the drugs are much more expensive than statins, almost all of which are available as generics. Another reason, related to the first two, is that insurance companies have imposed strict preauthorization requirements for these drugs. Another reason relates to the theme of this post, namely the diminishing returns from adding additional drugs. I’m going to take the treatment of heterozygous familial hypercholesterolemia (HeFH) as an example, specifically patients with HeFH who do not have clinical atherosclerotic cardiovascular disease and who are thus being treated to prevent a first event (i.e., “primary prevention”).

HeFH greatly increases the risk of developing premature atherosclerotic cardiovascular disease compared to individuals with normal levels of cholesterol. Before statins became available, the drugs that were available were not very effective. However, in recent decades, first moderate intensity and then high intensity statins were instituted as standard treatment of HeFH, often with additional drugs such as ezetimibe. According to UpToDate, atorvastatin can reduce LDL by up to 54% and rosuvastatin can reduce LDL by up to 63%. Ezetimibe can lower LDL by another 15% or so in patients on a statin. Given that most patients with HeFH have LDL in the 200s or below, a reduction of 50-60% achieves very reasonable LDL levels. There is evidence that even moderate doses of statins greatly reduce the risk of heart disease in HeFH patients who are being treated for primary prevention. A study published in JAMA in 2014 showed that young adults with HeFH have near-normal levels of atherosclerosis 10 years after initiation of statin therapy. The use of high intensity statins has been shown to greatly reduce the progression of atherosclerosis in adult HeFH patients (see here and here) even when compared to moderate statin therapy. Thus, HeFH patients who start treatment early and are able to reduce their LDL to normal or near-normal levels over many years with a statin or statin + ezetimibe often do not need an additional drug, as their risk is greatly reduced.

So which HeFH patients do need an additional LDL-lowering therapy, such as a PCSK9 inhibitor? To my knowledge, there are no risk calculators available to guide decisions in this area. HeFH patients who start with very high LDL, who can’t tolerate high doses of statins or can’t tolerate statins at all, who started treatment late, who have additional cardiovascular risk factors, or who have had imaging that shows significant subclinical atherosclerosis, are going to be at higher risk, on average. There is quite a bit of uncertainty involved, as with estimation of cardiovascular risk in general. In addition, there are personal preferences involved, as people vary greatly in terms of how much risk they are willing to live with.

Interestingly, a task force of the International Atherosclerosis Society just published a consensus statement in The Lancet Diabetes & Endocrinology that discusses some of the factors involved in determining cardiovascular risk in FH. Although the criteria they propose for use of additional therapies are more stringent than I foresee being adopted in the U.S., the paper contains some very useful discussion of the heterogeneity of cardiovascular risk in FH and ways of trying to predict who is at higher risk. I’m pasting in their proposed criteria below, in case anyone is interested, but I do recommend the entire paper.

proposed criteria for severe FH

Thoughts on the recent PCSK9 inhibitor studies

Two studies on the PCSK9 inhibitors evolocumab and alirocumab were recently published in the New England Journal of Medicine (see here and here). See this story by Larry Husten for the details. Evolocumab and alirocumab are monoclonal antibodies that are in development and are seeking FDA approval based on LDL-cholesterol reduction this year.  The two studies were not designed to answer the question of whether evolocumab and alirocumab prevent cardiovascular events. Rather, the studies measured LDL reduction and tabulated adverse events over a 52- or 78-week time period. Among the adverse events being tabulated were cardiovascular events and there were fewer cardiovascular events in the patients who were in the evolocumab and alirocumab groups, as compared to patients who received placebo or usual care. One of the studies had prespecified an exploratory analysis of cardiovascular events. For the other study the investigators did a post hoc analysis of certain cardiovascular events. Neither study was powered (i.e., big and long enough) to provide a reliable estimate of the benefits of these drugs in reducing heart attacks, strokes and deaths. In other words, statistically speaking the studies were pretty thin gruel and the companies as well as the investigators acknowledge that fact. So, as of now, we really do not know that these drugs reduce the risk of cardiovascular events, let alone by how much. Nor do we really know how safe the drugs are. All these studies tell us is that as of now these drugs appear to be progressing satisfactorily along the path to approval and we just have to be patient for a couple of years until the results of the outcomes trials are available.
Fortunately, the sponsors have started large cardiovascular outcomes trials in high risk patients (e.g., the alirocumab trial will involve 18,000 patients and a minimum of 1613 primary endpoint events and a minimum two year followup — see here for a description of the trial).
I suggest taking a look at this short video of Harlan Krumholz speaking from the conference — I completely agree with his comments (website registration may be required). I also agree with the editorial by Donald Lloyd-Jones and Neil Stone, in which they state:

The ODYSSEY LONG TERM and OSLER studies whet our appetites for further results that show cardiovascular benefit and documented safety, even at substantially lower LDL cholesterol ranges than achieved before. However, it would be premature to endorse these drugs for widespread use before the ongoing randomized trials, appropriately powered for primary end-point analysis and safety assessment, are available. Reports from several lipid treatment trials provide important object lessons in this regard. Two trials of niacin revealed lower levels of LDL cholesterol and lipoprotein(a) when niacin was added to statin therapy but no net clinical benefit and very worrisome signals of harm. A randomized, controlled trial of torcetrapib reminds us that “off-target” effects can scuttle a promising drug. And the recent long-awaited presentation of results of a trial in which ezetimibe was added to moderate-intensity statin therapy in high-risk patients showed only modest benefit, though with excellent safety.

IMPROVE-IT trial

The long-awaited IMPROVE-IT trial was presented last month at the American Heart Association Scientific Sessions. Here are the presentation slides:

IMPROVE-IT was a trial that tested the ability of ezetimibe (Zetia) to lower the risk of heart attacks and strokes when added to simvastatin. See Larry Husten’s background post here, and if you type “ezetimibe” in the search box on this blog or on the Gooznews blog, you will find some previous posts of mine relating to ezetimibe. I admit I was a bit surprised that the trial was positive. I was expecting it to be negative, based on the negative results of the ENHANCE trial. Still, the benefit was small, a 6.4% reduction in risk of the primary endpoint (composed of cardiovascular death, heart attack, unstable angina requiring hospitalization, coronary revascularization, and stroke). In the high-risk trial participants — all patients who had been hospitalized for acute coronary syndrome within the 10 days before randomization — this translated to a 2% absolute benefit over 7 years. Of note, there was no reduction in all-cause or cardiovascular mortality.

I only want to make a few comments now, but I intend to write more when the trial is published. First, a 6.4% reduction is risk is a very small benefit, and many people would only consider that reduction in risk meaningful in a high risk population. Second, it is regrettable that we had to wait 12 years after the drug’s approval to find out whether it improves outcomes.

Here are great summaries by Larry Husten and Matt Herper. And here is a video of Harlan Krumholz giving his take on the results.

Addendum, May 5, 2015:  Unfortunately, the GoozNews blog is no longer up on the web. I asked Merrill Goozner what happened and he said he decided to stop paying the annual fee for the website. So the posts I wrote on ezetimibe for GoozNews are no longer up.

Assessment 2020 blog

I am a member of the Assessment 2020 task force of the American Board of Internal Medicine (ABIM). The task force is looking at how to improve the assessment of physicians for purposes of board certification. We are seeking to engage physicians and the public in a conversation about physician assessment, quality of care, and what skills physicians need to provide effective, safe, efficient, and patient-centered care.

We’ve started a blog and so far there are posts up by Harlan Krumholz and Richard Baron (introducing the blog), Bob Wachter (on diagnostic error), and Ben Chesluk (on teamwork). Please go take a look and let us know what you think.

“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.

More commentaries on data sharing

In the May 2012 issue of The Scientist, Data Diving:  What lies untapped beneath the surface of published clinical trial analyses could rock the world of independent review.  Discusses the problem of missing data and how it affects the reliability of systematic reviews.

On the Scientific American website, a guest post by cardiologist and researcher Jalees Rehman, Open Science and Access to Medical Research.  Rehman discusses the special challenges of sharing clinical research, including the need to maintain patient confidentiality and the need for independent institutions to interpret the data in an unbiased manner so that vulnerable patients are not misled or given false hope.

In the November 21, 2011 issue of the Medical Journal of Australia, Time to mandate data release and independent audits for all clinical trials, by Ian Haines and George Gabor Miklos.  Here are the last two paragraphs:

Medical journals and their editors have a choice — to be viewed as “an extension of the marketing arm of pharmaceutical companies,” or to be beacons of transparent data processes that inform clinicians, improve patient treatment, and provide high standards on which governments, health care providers and patients can have confidence.

Medical journals should demonstrate strong leadership by mandating open access to detailed clinical trial protocols and de-identified raw study data.  They should insist on independent audits of data, concomitant publication of an “accompanying abstract,” and lodgement of the data in independent databases; these three actions should be a precondition for publication.  (citations omitted)

Finally, in Science Translational Medicine, Learning from Hackers:  Open-Source Clinical Trials, by Adam Dunn, Richard Day, Kenneth Mandl and Enrico Coiera.  Behind a paywall, but here’s a news article in Australian Life Scientist and a post on Dunn’s blog.

See my previous posts on data sharing here and here.

Krumholz: “I think maybe we have a chance to turn the world upside down just a bit”

The Patient-Centered Outcomes Research Institute’s mission is to fund health research that offers patients and caregivers the information they need to make medical decisions.  The PCORI Board of Governors has adopted the following working definition of “patient-centered outcomes research.”

Patient-Centered Outcomes Research (PCOR) helps people and their caregivers communicate and make informed health care decisions, allowing their voices to be heard in assessing the value of health care options. This research answers patient-centered questions such as:

    1. “Given my personal characteristics, conditions and preferences, what should I expect will happen to me?”
    2. “What are my options and what are the potential benefits and harms of those options?”
    3. “What can I do to improve the outcomes that are most important to me?”
    4.  “How can clinicians and the care delivery systems they work in help me make the best decisions about my health and healthcare?”

To answer these questions, PCOR:

    • Assesses the benefits and harms of preventive, diagnostic, therapeutic, palliative, or health delivery system interventions to inform decision making, highlighting comparisons and outcomes that matter to people;
    • Is inclusive of an individual’s preferences, autonomy and needs, focusing on outcomes that people notice and care about such as survival, function, symptoms, and health related quality of life;
    • Incorporates a wide variety of settings and diversity of participants to address individual differences and barriers to implementation and dissemination; and
    • Investigates (or may investigate) optimizing outcomes while addressing burden to individuals, availability of services, technology, and personnel, and other stakeholder perspectives.

Listen to this inspirational speech by PCORI Board of Governors member Harlan Krumholz, at the PCORI National Patient and Stakeholder Dialogue, February 27, 2012:

http://youtu.be/sKOMDFnqkoY

Addendum:  see also these posts by Josh Freeman and Richard Lehman and articles in the April 18, 2012 issue of JAMA.

The “thermostat model” of health care utilization

Danil Makarov and colleagues have an interesting paper in the April 2012 issue of Health Affairs entitled “Appropriate And Inappropriate Imaging Rates for Prostate Cancer Go Hand In Hand By Region, As If Set By Thermostat.”  Using data from the SEER-Medicare database, the researchers examined regional differences in imaging for prostate cancer patients.  The SEER program of the National Cancer Institute collects information about cancer site, stage, and histology for cancer patients from sixteen geographic regions.  For cancer patients who are included in the SEER database and are covered by Medicare, information is available on Medicare claims for health care services.  The sample consisted of 48,148 prostate cancer patients aged 66-85 who were diagnosed with prostate cancer in 2004 or 2005.

The patients were divided into low- and high-risk groups.  According to the 2002 guidelines of the National Comprehensive Cancer Network, which were in effect at the time, high-risk patients should receive imaging such as bone scans, MRIs and CT scans under certain circumstances.  In low-risk patients, all imaging was considered inappropriate except CT scans for planning purposes in patients undergoing external beam radiation therapy.

The researchers found that overall rates of imaging varied among the different SEER regions.  Imaging appropriateness was not uniformly worse in regions with high rates of overall imaging.  Rather, regions with high overall imaging rates had higher rates of inappropriate imaging and higher rates of appropriate imaging.  Men with high-risk prostate cancer were more likely to receive appropriate imaging if they lived in areas with higher rates of inappropriate imaging.  The authors call this the “thermostat model” of health care utilization.  Dividing the regions into quartiles according to rates of inappropriate imaging of low-risk men, in quartile 4 (highest rate of inappropriate imaging), the odds ratio for men with high-risk prostate cancer receiving appropriate imaging was 1.75, with odds ratios in the next two quartiles being 1.48 and 1.04.

The authors state that their analysis suggests that

efforts to lower inappropriate use of imaging may simultaneously lower appropriate use of imaging because the two appear to be coupled.  Therefore, policy measures aimed simply at limiting inappropriate imaging in regions with high resource use could have the unintended consequence of decreasing imaging for those patients for whom such care is indicated. 

and

Policies will need to be multifaceted to break down the thermostat-like relationship between inappropriate and appropriate health care use.  Accountable care organizations will need clearly defined quality metrics for a broad range of conditions.  They will also need well-designed systems to ensure that the right patients are getting the right tests and procedures — and that costs are not contained at the expense of quality.  Cost-control policies must selectively educate providers to change their behavior and reduce the use of unnecessary care, while still ensuring appropriate care.  Such efforts could take on many forms:  profiling physicians who inappropriately overuse resources, linking payment to appropriate utilization criteria, or providing rewards and incentives to physicians and organizations that optimize resource use.

Danil V. Makarov, Rani Desai, James B. Yu, Richa Sharma, Nitya Abraham, Peter C. Albertson, Harlan M. Krumholz, David F. Penson, Cary P. Gross.  Appropriate And Inappropriate Imaging Rates For Prostate Cancer Go Hand In Hand By Region, As If Set By Thermostat.  Health Affairs 31:4 (2012).

Addendum 4/23/2012:  see also Jeff Levin-Scherz’s post on his Managing Healthcare Costs blog.

Data sharing as a moral imperative

In the USA at least, the data legally belong to trialists on the grounds that it requires work to create knowledge from data. But science, particularly medical science, is essentially an enterprise conducted for moral reasons. We need to do not just what is legal but what is right. As such, we must take into account the probable wishes of the patients who give us their blood, fill in our questionnaires and die on our trials. It is difficult to believe that any patient on my trial, who completed complex questionnaires so diligently over such a long period of time, would really have wanted me to keep the data for myself rather than share it with others for the benefit of medical science in general.  Vickers AJ.  Whose data set is it anyway?  Sharing raw data from randomized trials.  Trials.  2006;7:15.

Every day, patients and their caregivers are faced with difficult decisions about treatment. They turn to physicians and other healthcare professionals to interpret the medical evidence and assist them in making individualized decisions.  Unfortunately, we are learning that what is published in the medical literature represents only a portion of the evidence that is relevant to the risks and benefits of available treatments. In a profession that seeks to rely on evidence, it is ironic that we tolerate a system that enables evidence to be outside of public view.  Krumholz HM. Open Science and Data Sharing in Clinical Research: Basing Informed Decisions on the Totality of the Evidence. Circulation: Cardiovascular Quality and Outcomes. 2012;5: 141-142

We are all patients, and will all face questions about what medical treatments to pursue.  Some questions are trivial and unimportant, others can mean the difference between life and death.  We rely on evidence-based medicine to give us reliable information about the risks and benefits associated with medical interventions, but a disturbing amount of evidence indicates that the medical literature is not always reliable.  Many clinical trials are not published within a reasonable time after completion or are never published at all.  Missing data leads to systematic reviews that are based on only a portion of the trials that were conducted, which can affect the results in unknown and unpredictable ways.  Missing data may in some cases hold important information about risk, as in the case of Vioxx (rofecoxib).  Merck had data several years before Vioxx was withdrawn from the market that showed the drug increased the risk of heart attacks, but most of the data was unpublished and out of public view.  In other cases, clinical trials are published but the data are reported in a misleading and biased way, as when a negative trial is presented so as to appear positive, or analyses showing harm are omitted.

What is to be done?  What can we do to make evidence-based medicine more evidence-based?  Four commentaries in the March 2012 issue of Circulation:  Cardiovascular Quality and Outcomes discuss how making clinical research data available outside individual drug and device companies or research groups could greatly add to the depth and reliability of our knowledge.  Currently, with certain exceptions, access to most clinical trial data is restricted to the investigators or the funders.  Harlan Krumholz, in an editor’s perspective, outlines the key concepts:

Now is the time to bring data sharing and open science into the mainstream of clinical research, particularly with respect to trials that contain information about the risks and benefits of treatments in current use. This could be accomplished through the following steps:

    1. Post, in the public domain, the study protocol for each published trial. The protocol should be comprehensive and include policies and procedures relevant to actions taken in the trial.

    2. Develop mechanisms for those who own trial data to share their raw data and individual patient data.

    3. Encourage industry to commit to place all its clinical research data relevant to approved products in the public domain. This action would acknowledge that the privilege of selling products is accompanied by a responsibility to share all the clinical research data relevant to the products’ benefits and harms.

    4. Develop a culture within academics that values data sharing and open science. After a period in which the original investigators can complete their funded studies, the data should be de-identified and made available for investigators globally.

    5. Identify, within all systematic reviews, trials that are not published, using sources such as clinicaltrials.gov and regulatory postings to determine what is missing.

    6. Share data.

It must be acknowledged that there are many obstacles — political, cultural, financial — to accomplishing these goals.  Some of these obstacles are discussed in the other three commentaries, which are open access and which I urge you to read:

Spertus, JA.  The Double-Edged Sword of Open Access to Research Data.  Circulation:  Cardiovascular Quality and Outcomes.  2012;5;143-144.

Ross JS, Lehman R, Gross CP.  The Importance of Clinical Trial Data Sharing:  Toward More Open Science.  Circulation:  Cardiovascular Quality and Outcomes.  2012;5;238-240.

Gotzsche PC.  Strengthening and Opening Up Health Research by Sharing Our Raw Data.  Circulation:  Cardiovascular Quality and Outcomes.  2012;5;236-237.

Whatever the difficulties, the current situation is clearly intolerable.  Patients deserve reliable information on the risks and benefits of medical treatments and the subjects of clinical trials deserve that their contributions be fully used to benefit other patients.

Addendum March 26, 2012:  Please also see these posts by Jim Murray and Gary Schwitzer.

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.

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