Guidelines designed to lower the risk of atherosclerotic cardiovascular disease continue to spark controversy many months after their publication, primarily over two flash points: abandonment of cholesterol goals and the use of a new risk estimator. Some physicians welcome the changes and some abhor them. Others say it is time to step back and look at the bigger picture.
Third time was not the charm
The din of clanking forks and coffee cups had died down by the time Neil J. Stone, MD, took over the podium. He faced a ballroom of about 150 physicians, one third of whom minutes before had responded “hate them” to a question about their opinion of the American Heart Association/American College of Cardiology (AHA/ACC) guidelines. The guidelines were designed to help clinicians treat patients whose blood cholesterol may put them at risk of atherosclerotic cardiovascular disease-related events. “I have a tough task,” he acknowledged.
The dinner presentation had been scheduled midway through the ACC’s March scientific session in Washington, D.C., as an educational evening on lipids management. Stone, chair of the expert panel that published the prevention guidelines in November 2013, used the opportunity to clarify what the authors perceived as misinterpretations of the recommendations. The new guidelines had come under fire before the ink was dry for a risk assessment tool that critics said either underestimated or overestimated at-risk patients. Some physicians also voiced disappointment over recommendations based on accumulated findings from randomized controlled clinical trials and not other types of studies and expert opinion.
Trial data did not support the use of LDL targets in patients with high cholesterol, the expert panel determined, which was a tectonic shift from the Adult Treatment Panel III (ATP III) guidelines that had been the beacon in care for about a decade. In his presentation, Stone explained at three different times the need to get a lipid panel periodically to gauge response and adherence to statin treatment. One in five attendees still responded that the guidelines did not recommend cholesterol testing in an on-site poll.
“We have learned that we need to continue to repeat simple messages that reflect the guidelines,” says Stone, a cardiologist at Northwestern Memorial Hospital and a professor at Northwestern University Feinberg School of Medicine in Chicago. “We need to repeat simply our justification and we need to correct if people have mistakenly assumed what we said when actually we have not said it.”
The guidelines focus on patients in four different groups who are most likely to benefit from primary or secondary prevention treatment (Circulation online Nov. 12, 2013). They call for intensive or moderate statin therapy in patients with clinical atherosclerotic cardiovascular disease; with LDL cholesterol levels of 190 mg/dL or higher; with diabetes if they are between the ages of 40 and 75 (the age groups represented in trials); and those between 40 and 75 without diabetes but with LDL cholesterol levels between 70 and 189 with a 10-year risk of 7.5 percent or higher. The recommendations also include safety considerations, other strategies such as biomarker tests to help guide treatment decisions and discussions with patients before starting treatment.
“The strength of our guideline is that it is not an opinion-generated guideline,” Stone says. “It was based on as close adherence to the accumulated evidence as possible.”
Ta-ta to targets
The 2004 revised ATP III, in which Stone is a co-author, set treatment goals of less than 100 mg/dL in high-risk patients and less than 70 mg/dL in very high-risk patients (Circulation 2004;110:227-239). The new guidelines propose a “lowest is best” approach for LDL cholesterol without targets, a switch that some researchers who have studied the statistical underpinnings of cholesterol guidelines cheered.
“They should be commended on getting rid of the LDL targets,” says Rodney A. Hayward, MD, co-director of the Center for Practice Management and Outcomes Research at the Ann Arbor Veterans Affairs Healthcare System and a professor in the internal medicine department at the University of Michigan in Ann Arbor. “It was a brave move and it was the right move.”
For about a decade, Hayward and colleagues have been questioning the benefit of the use of cholesterol goals for treating at-risk patients. Their review of the evidence in ATP III and similar guidelines foreshadowed the changes proposed in 2013 (Ann Intern Med 2006;145:520-530). They found no support for the proposed treatment goals, no evidence that treatments other than statins were safe and effective and argued that overall cardiac risk rather than LDL cholesterol levels was a better predictor of cardiovascular events such as MI and stroke.
“It is not just a matter of over-treating based on a high LDL,” Hayward says. “The more concerning thing is the people who were not put on a statin because their LDL looked fine, but they have multiple risk factors.”
Even in high-risk patients, hyperlipidemia may be the tail wagging the dog in clinical decision making. While statin use has been shown to reduce the risk of future cardiovascular events in patients with diabetes and heart disease, these two groups were found to be passed over by physicians in a study that looked at statin use and risk factors in a nationally representative sample in the U.S. (Ann Fam Med 2014;12:215-223). The authors calculated that on a national level, 5.6 million patients with coronary artery disease and 9 million with diabetes who were older than 40 were not receiving regular statin therapy.
In their analysis, 8 percent of 16,712 participants in the 2010 Medical Expenditure Panel Survey had coronary artery disease, with 58 percent on statins. Of those patients with coronary artery disease but not hyperlipidemia, only 16 percent took statins. Another 11 percent of patients had diabetes and were older than 40 years, with 52 percent on statins. Of those with diabetes but not hyperlipidemia, only 12 percent were on statins.
“This research appears to point out the strength at which people focus on the diagnosis of hyperlipidemia,” says lead author Michael Edward Johansen, MD, MS, a family physician at Ohio State University in Columbus. “The diagnosis of hyperlipidemia was a really strong predictor of statin use in all populations: diabetics, coronary disease and the general population.”
Put it to the test
Chad Raymond, DO, of the Cleveland Clinic Heart and Vascular Institute’s preventive cardiology section, describes the guideline writers’ fidelity to randomized clinical trial data as noble. But after an analysis that applied the guidelines to hypothetical patients in the four targeted populations, he and his colleagues chose a hybrid approach for their practice. In a commentary, they recommended combining elements of ATP III and the new guidelines by retaining LDL cholesterol goals but also using the concept of a global risk assessment (Cleveland Clinic Journal of Medicine 2014;81:11-19).
The Cleveland physicians are not enamored with targets, per se, but rather the potential reduction in residual risk with lower LDL cholesterol levels. They also point to their clinical experience and understanding of patient perceptions and motivators. “A lot of patients like having a target and having a goal,” Raymond explains. “When they don’t have a goal, we have found in our experience, they are less apt to take more interest in their care.”
Just as some physicians under ATP III may obsess over lipid values at the cost of overlooking key risk factors such as diabetes, inflammatory disease or poor lifestyle habits, the new risk estimator also may compel clinicians to “treat the risk score” rather than provide individualized care. For instance, a 60-year-old woman with rheumatoid arthritis and a 10-year risk score of 3 percent wouldn’t hit the 7.5 percent threshold until age 70, the Cleveland team calculated. Men over 65 years old, on the other hand, ring in with a risk score of 7.5 percent even if they are healthy.
“I do strongly believe it has the potential to over-treat and under-treat,” Raymond says. Based on nonrandomized findings on inflammatory markers and an increased risk of atherosclerotic cardiovascular disease, he and his colleagues would start the woman on statin therapy. “That is where the clinician experience plays a role.”
The guideline writers saw a benefit with as low as a 10-year risk of 5 percent, Stone says, but chose 7.5 percent to be conservative. Hayward emphasizes that no risk tool is completely accurate and all overestimate or underestimate, depending on the patient population. Tools based on mostly white, healthy volunteers may underestimate minorities and people with compromised health, and vice versa.
Nor is 7.5 percent meant to be a line in the sand, according to Stone. “It wasn’t to say that 7.4 doesn’t get a statin and 7.53 does get a statin. The idea was risk estimation of 7.5 or more opens the conversation.” The guidelines make a point of engaging patients in a conversation about their risk factors before initiating any statin therapy.
Like Raymond, Hayward advises physicians to look beyond the number and incorporate what they know about that individual patient such as diet, activity level and other healthy or unhealthy behaviors into decisions. “Using the calculator gets us in the ballpark but it is wrong to think of that number as a single number rather than a range,” he says. But he also sees the guidelines falling short by not providing concrete guidance to physicians about the course of action in ambiguous cases.
“At what point do you switch to, ‘This is something you might want to consider’ in a full discussion versus, ‘We recommend this,’” Hayward poses. “I recommend when the benefit is so high I feel medically obligated. The predominant thing is when the benefit is small the risk should also be small, but it is an individual decision.”
That gray zone may include a large number of patients who previously were not treated with statins. According to one analysis, the new guidelines would expand the eligible patient population to 43.2 million compared with ATP III, with up to 12.8 million people not having cardiovascular disease (N Engl J Med online March 19, 2014). Johansen questions the societal benefit of treating many low-risk patients and calls instead for more emphasis on ensuring that high-risk patients who will achieve the most benefit are treated.
The great unknown
Expanding statin treatment to so many new patients may have unintended consequences, particularly in those whose benefit may be years off. One possible change, to physicians’ consternation, may be a sense of carte blanche among users.
One study that evaluated statin treatment trends over time found that as statin use picked up steam in the U.S., caloric intake increased in users (JAMA Intern Med online April 24, 2014). In 1999-2000, statin users took in fewer calories than nonstatin users, suggesting they followed a healthy diet. But statin users’ caloric intake was 9.6 percent greater in 2009-2010 compared with statin users in 1999-2000 while there was no significant increase for nonusers. Fat intake initially was lower in statin users compared with nonusers, then increased 14.4 percent while fat intake initially increased and then decreased over time in nonusers.
Senior author Martin F. Shapiro, MD, PhD, chief of general internal medicine at University of California, Los Angeles School of Medicine, observes that when patients begin statin therapy they often see their LDL cholesterol levels drop dramatically. “They may feel less pressure to control their diet even if the doctor tells them to do so,” he says. “It is all the calories and none of the guilt. People like to be able to consume and not have consequences for what they do.”
Shapiro raises questions about other health consequences with statin therapy, particularly over the long term. Statins are associated with a small increased risk of diabetes. In some patients, statin use may lead to muscle aches. One observational study found that older men on statins were slightly less active than nonusers (JAMA Intern Med online June 9). In younger patients, could long-term use have a detrimental effect that becomes apparent in old age?
“We tend to think of medications as innocent until proven guilty and extending them constitutional rights is not in the best interest of our patients,” Hayward says. Statins have shown their worth over five to 10 years but not over several decades, he points out.
The risk estimator, in the end, may prove to be a powerful ally in the battle again atherosclerotic cardiovascular disease. Raymond praises its simplicity and its ability to visually show patients their 10-year or lifetime risk and the benefits of modifying risk factors such as smoking or obesity.
The goal is to reduce risk, Stone says, and the estimator may help achieve that, with or without prescribing statins. “If we can inform patients of the benefits of understanding not only the risk assessment but also why a heart-healthy lifestyle makes sense, which groups benefit from statins and whether the statin makes sense for them, then we have taken a big prevention step.”