Love 'Em or Leave 'Em: Experts on Both Sides Debate the New Lipid Guidelines

January 20, 2014

DALLAS, TX and WASHINGTON, DC — It has been two months since the new clinical guidelines for the treatment of cholesterol were published[1], and feedback is starting to slowly emerge as clinicians begin incorporating the recommendations into clinical practice.

The American College of Cardiology (ACC) and American Heart Association (AHA) guidelines, which were developed in conjunction with the National Heart, Lung, and Blood Institute (NHLBI), were a radical departure from previous iterations, most notably in their abandonment of LDL-cholesterol targets. In the past, clinicians were advised to treat patients with cardiovascular disease to less than 100 mg/dL or the optional goal of less than 70 mg/dL.

As reported by heartwire at the time, the expert panel stated there was simply no evidence from randomized, controlled clinical trials to support treatment to a specific target. As a result, the new guidelines make no recommendations for specific LDL-cholesterol or non-HDL targets for the primary and secondary prevention of atherosclerotic cardiovascular disease.

Dr Stanley Hazen

For one clinician, Dr Stanley Hazen (Cleveland Clinic, OH), the strict adherence to only clinical-trial data is a limitation and not a strength of the new guidelines.

"First, it ignores a wealth of information on the pathophysiology of the disease process. Second, it presumes that the reason trials are designed is to answer guideline questions," he told heartwire . "They aren't. Trials are designed by pharmaceutical companies trying to get claims issued on their drugs. More important, the absence of randomized clinical-trial data does not justify inaction if LDL cholesterol remains elevated."

Accelerating Vascular Age

In his commentary published January 8, 2014 in the Cleveland Clinic Journal of Medicine, Hazen, along with first author Dr Chad Raymond (Cleveland Clinic, OH), lay out their concerns with the clinical guidelines and highlight some of the shortcoming with the new recommendations[2].

For Hazen, there are multiple reasons that physicians should continue to treat to specific LDL-cholesterol targets, the first and foremost being that patients are different and no single treatment fits such a large and heterogeneous patient population at risk for cardiovascular disease and stroke. The guidelines simply call for a moderate- or high-dose statin in high-risk patients depending on the clinical scenario and no subsequent assessment of LDL cholesterol.

"In the very highest-risk patients, the ones with extraordinarily high levels of cholesterol, those who get maximally tolerated statins, if there is still a substantial LDL-cholesterol burden, they are going to have substantial residual risk," he said. "The preponderance of data in aggregate shows that there is higher residual risk proportionate to the LDL level that's remaining. The new guidelines completely ignore the pathophysiology of the disease process—a disease that takes decades to develop."

The clinical guidelines are unique among documents past in that the emphasis is strictly on statin therapy rather than LDL-cholesterol-lowering medications more generally. In individuals with atherosclerotic cardiovascular disease, high-intensity statin therapy—such as rosuvastatin (Crestor, AstraZeneca) 20 to 40 mg or atorvastatin 40 to 80 mg—should be used to achieve at least a 50% reduction in LDL cholesterol unless otherwise contraindicated or when statin-associated adverse events are present. In that case, doctors should use a moderate-intensity statin. Similarly, for those with LDL-cholesterol levels >190 mg/dL, a high-intensity statin should be used with the goal of achieving at least a 50% reduction in LDL-cholesterol levels.

For Hazen, the new clinical guidelines "turn back the clock on cardiovascular disease prevention" and have the potential to both overtreat older low-risk patients and undertreat those who are young yet are at higher lifetime risk.

For example, he cites a 25-year-old man who presents because his 45-year-old father just died from a heart attack. He has a fasting total cholesterol level of 310 mg/dL, HDL cholesterol of 50 mg/dL, triglyceride level of 400 mg/dL, and LDL cholesterol of 180 mg/dL. Even with the strong family history of premature coronary disease, because of his young age, the current guidelines do not suggest treatment because they do not apply to those less than 40 years old. However, even if his age were 40, his calculated 10-year risk would be <7.5% based on a new and controversial risk calculator published alongside the guidelines.

"I can't imagine there is a lipidology expert or cardiologist out there who would think that this patient does not deserve aggressive preventive efforts and intervention," said Hazen. "It is lifetime risk and lifetime exposure to higher LDL cholesterol that contributes to the disease process. Ignoring that scientific fact in a document whose focus is on treating cholesterol to prevent cardiovascular disease is simply illogical."

A Massive Paradigm Shift

Speaking with heartwire , Dr James de Lemos (University of Texas Southwestern Medical Center, Dallas) suspects there remains some hesitancy on the part of practicing primary-care physicians to adopt the guidelines, mainly because they are a "massive paradigm shift that dramatically changes the approach to disease." He said while there are always early adopters, there have been some questions as to which major journals and cardiology organizations would line up behind them (and nearly all have, with the exception of the American Association of Clinical Endocrinologists ).

For cardiologists, on the other hand, the shift to focus on four specific types of patients is not so dramatic, because these are patients they routinely see in clinical practice. For de Lemos, it is reasonable to focus on at-risk patients and treat according to that level of risk. He still incorporates measuring LDL-cholesterol levels, however, noting that the measurement can provide some reassurance or concern depending on the threshold achieved with treatment, dietary changes, and exercise.

Dr Mariel Jessup

To heartwire , Dr Mariel Jessup (University of Pennsylvania, Philadelphia), the president of the AHA, said that immediately following their publication many of her colleagues began implementing the guidelines and using the new calculator for risk assessment. In doing so, they identified patients on statins who did not require the lipid-lowering drugs as well as patients who weren't on them but should be.

"In the first week, we were all coming to terms with what contributes to risk," said Jessup. She added that she hasn't heard a great deal of criticism about the guidelines and believes most physicians are getting on board with the new changes.

She noted that a member of the Penn faculty recently delivered medical grand rounds on the new lipid guidelines and while it was mostly positive, one criticism that arose was the emphasis on randomized, controlled clinical-trial data. Jessup said that even though the new guidelines focus on clinical-trial data, this does not negate findings from observational or epidemiological studies.

Dr Roger Blumenthal

Dr Roger Blumenthal (Johns Hopkins Ciccarone Preventive Cardiology Center, Baltimore, MD), on the other hand, predicts a return to LDL treatment goals in the not-so-distant future.

"I think the guidelines will revert back to the way they were once we get a positive study showing that adding another agent to a statin reduces risk," Blumenthal said. He predicts positive results with anacetrapib (Merck, Whitehouse Station, NJ), the novel cholesteryl ester transfer protein (CETP) inhibitor, or one of the investigational proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, when given on top of statins. "When that happens, the new randomized controlled trial data would support going lower than what would be achieved with giving just 40 mg or 80 mg of atorvastatin."

In very selected patients, Blumenthal still aggressively targets to low LDL levels, even if this requires adding a second agent. For example, in patients treated with a statin, LDL cholesterol might be reduced to 80 mg or so, but triglyceride levels remain high or HDL cholesterol is low. He notes that the ACCORD study with fenofibrate was borderline nonsignificant in patients with low HDL cholesterol and high triglyceride levels. Beyond fibrates, he notes there have been angiographic studies published in support of the "lower-is-better" hypothesis.

Jessup said that most physicians understand why the LDL targets were eliminated, but many institutions used the thresholds as a performance measure. Penn Health, for example, used the number of patients treated to the old LDL-cholesterol targets as an internal marker of performance for physicians in internal medicine and general practice. "As you struggle to come up with an easily defined target that you can use to talk about quality in a large practice, and not just among cardiologists, that's one less target you can use," said Jessup.

Concerns Among Clinicians as Well

Dr Rita Redberg

Dr Rita Redberg (University of California, San Francisco) also has significant concerns about the new guidelines, albeit for entirely different reasons. An outspoken critic when the guidelines were presented, her views have not changed, telling heartwire that she is already looking forward to the next version of the cholesterol guidelines. When they were first published and presented, Redberg, along with Dr John Abramson (Harvard Medical School, Boston, MA), argued that statins were beneficial for individuals with heart disease but do not reduce the risk of death in individuals with a 10-year risk of cardiovascular disease of less than 20%.

"I have not been implementing these guidelines because I don't think they're in the best interests of my patients, and I really do look forward to the revisions," she said. "I'm all for looking at risk, and I'm all for targeting prevention strategies on the basis of risk, so I think this is a strong point of the new guidelines. However, that is really undermined by the risk calculator, in which anybody over age 65 basically needs to be on a statin. I don't think the data support this."

The new cholesterol guidelines weathered a rough roll-out their first week when Drs Paul Ridker and Nancy Cook (Brigham and Women's Hospital, Boston, MA) calculated the 10-year risk of cardiovascular events in three large-scale primary prevention cohorts—the Women's Health Study (WHS), the Physicians' Health Study (PHS), and the Women's Health Initiative Observational Study (WHI-OS)—and found the new algorithm overestimated the risk by 75% to 150%.

Dr James de Lemos

To de Lemos, the controversial aspect of the new guidelines remains in the primary-prevention population. For those without cardiovascular disease but who have LDL-cholesterol levels ranging from 70 mg/dL to 189 mg/dL and a 10-year risk of cardiovascular disease >7.5%, physicians can initiate treatment with a statin. Given the controversy surrounding the risk calculator, there have been suggestions that people who don't need statins will receive treatment.

"It doesn't mean the concept is flawed," de Lemos told heartwire , "but it just might not be ready to implement widely." As a result, he suspects that physicians might be keeping the risk calculator at arm's length until it is studied and debated further. As for his own use, de Lemos said he doesn't calculate 10-year risk in every patient, even though he is fairly aggressive with initiating statin therapy, and that his decisions are more intuitive and empirical, something which he doesn't see changing.

Jessup said the risk calculator, as well as the clinical guidelines, will be updated as new information emerges. While she was not able to speak to specifics, Jessup is aware of researchers testing the predictive strength of the risk calculator in different cohorts to see how well it performs. In general, she said the calculator performs reasonably well.

Some Docs Finding the Calculator Helpful

Dr Sekar Kathiresan

Dr Sekar Kathiresan (Massachusetts General Hospital, Boston, MA), who runs a primary-prevention clinic, does use the new clinical guidelines and the new risk calculator to inform his decisions about whether or not to start patients with a moderate- or high-dose statin. He said Ridker and Cook raise a valid scientific point in terms of how well it is calibrated, but this should be put in perspective, given that physicians for the past 20 years or so have used the Framingham Risk Score, a score derived from a few thousand white individuals from one town in the US. The new risk equation increases the population sampled, includes different ethnicities, and is derived from more than one geographic area.

"Is the pooled-cohort equation perfect?" he asked. "No, it won't be perfect, because it's an attempt to estimate risk on a sample of 25 000 people."

Blumenthal made similar comments, telling heartwire that the risk calculator is a better way to estimate risk in women and African Americans, for example. Given that the risk calculator might overestimate risk, he expands his definition of intermediate risk to include patients with a 5% to 15% 10-year risk of cardiovascular disease. In doing so, even if the risk calculator overestimates by a factor of two, they have some wiggle room in discussing care with the patient.

In addition, Blumenthal said the guidelines emphasize a discussion with the patient about care in those with a 10-year risk exceeding 7.5%, just as would be done with an intermediate-risk patient. The discussion can lead to further refinement of risk by taking family history into account or by performing a computed tomography (CT) scan to assess coronary artery calcium (CAC).

To Kathiresan, moving away from LDL-cholesterol targets will require some time before they become readily accepted, mainly because physicians have gotten used to the targets. For the most part, though, he views the changes to the guidelines as more of a "tweak."

"I don't find them as radical as some people do," Kathiresan told heartwire . "I actually think the major thing that was accomplished was taking the focus away from using medications to change lab tests and to now focus on medication proven to reduce the risk of disease. This is a huge plus for the new guidelines."

In cardiology, the evidence base is very rich, with many trials and millions of dollars spent to evaluate whether specific medicines work to reduce disease risk in specific clinical situations, he added. This is the evidence that should be used to inform clinical practice. For this reason, he entirely agrees with the new focus on statins and not simply lipid-lowering agents.

"There is an incredible amount of inappropriate use of both niacin and fibrates in the US, all based on the fact that they change lab tests," said Kathiresan. "The clinical-trial evidence for those two medicines is disappointingly poor."

Hazen is a coinventor on pending and issued patents held by the Cleveland Clinic relating to cardiovascular diagnostics and therapeutics. He is a paid consultant to the Cleveland Heart Lab, Esperion, Liposciences, Merck, Pfizer, and Procter & Gamble. He has received research funds from Abbott, Astra Zeneca, Cleveland Heart Lab, Esperion, Liposciences, Procter & Gamble, and Takeda. In addition, he is entitled to royalty payments for inventions/discoveries related to cardiovascular diagnostics and therapeutics from Abbott Laboratories, Cleveland Heart Lab, Esperion, Frantz Biomarkers, and Liposciences . de Lemos acknowledges grant support from Roche Diagnostics and Abbott Diagnostics and has consulted for Diadexus. Kathiresan reports serving as a consultant to Merck, Pfizer, Celera, and Alnylam. Jessup, Blumenthal, and Redberg report no conflicts of interest.

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