New Cholesterol Guidelines Make Room for Non-Statin Therapy and CAC Screening

CHICAGO, IL (UPDATED)—New cholesterol guidelines from the American College of Cardiology (ACC) and American Heart Association (AHA) break ground by recommending ezetimibe and/or PCSK9 inhibition in selective high-risk patients and proposing noninvasive coronary artery calcium (CAC) screening to help make decisions about patients who fall into the gray zone for treatment.

Presented today at the AHA 2018 Scientific Sessions, the new guidelines—121 pages in length and 18 months in the making—include 72 recommendations, including 29 that are class I. In general, the ACC/AHA guidelines include a broad spectrum of support from numerous societies and recommend a “heart-healthy lifestyle” across the entire life span.

Richard Kovacs, MD (Indiana University School of Medicine, Indianapolis), vice president of the ACC, said the latest guidelines will help transform cardiovascular care and improve heart health. “High cholesterol is both often preventable and eminently treatable, but as we move into an era where care is personalized, how we treat individual patients can vary,” said Kovacs. “This guideline will give clinicians the tools that we need to have those conversations with patients about the most appropriate treatment for their high cholesterol.”

With Soldier Field, home to the National Football League’s Chicago Bears, just down the street, Kovacs said the new recommendations form the playbook but need to be implemented to have clinical benefit. “This new guideline gives us all the defensive strategies to risk stratify, to use coronary artery calcification scores, to use the new non-statin drugs, and to add all those things to what we can discuss with our patients as part of individual care [in order] to bring them to the goal. But it takes execution on the field,” he stressed.

While there is no target for ideal LDL cholesterol levels in the general population, the guideline recognizes, in principle, that lower is better. Ivor Benjamin

Neil Stone, MD (Northwestern University Feinberg School of Medicine, Chicago, IL), vice chair of the ACC/AHA writing committee, said there has been shift in care since the days of simply “knowing your cholesterol” number. “Now we’re talking about personalizing your risk,” said Stone. “It’s an evolution that has made a big difference.”

For his part, AHA President Ivor Benjamin, MD (Medical College of Wisconsin, Milwaukee), said the guidelines were drafted by experts and reviewers from 12 different medical organizations and are based on best clinical evidence. “It reinforces lifestyle modification and prevention and builds on the major shift in the ACC/AHA 2013 cholesterol recommendations [that] focused on identifying and addressing lifetime risks for cardiovascular disease,” said Benjamin.  

The 2018 guidelines emphasize that having high cholesterol “at any age” significantly increases the risk of cardiovascular disease and recommends early risk assessment, even among children and young adults. “While there is no target for ideal LDL cholesterol levels in the general population, the guideline recognizes, in principle, that lower is better,” said Benjamin.

What’s New in the Secondary Prevention Setting?  

In the secondary prevention setting, there is now a class I indication for reducing LDL cholesterol levels by 50% or more with a high-intensity statin (atorvastatin 40-80 mg and rosuvastatin 20-40 mg), or a maximally tolerated statin dose, in all patients with clinical atherosclerotic cardiovascular disease (ASCVD).

For ASCVD patients at very high risk, such as those with a history of multiple events or one major ASCVD event and multiple high-risk conditions—and with LDL cholesterol ≥ 70 mg/dL—the guidelines recommend adding ezetimibe to maximally tolerated statin therapy in order to lower LDL levels below the threshold (class IIa). If LDL still remains ≥ 70 mg/dL, adding a PCSK9 inhibitor such as alirocumab (Praluent; Regeneron/Sanofi) or evolocumab (Repatha; Amgen) is reasonable (class IIa), although the guidelines state that the long-term safely of the PCSK9 inhibitors is unknown.

“These guidelines now have a threshold for the use of non-statin medications in those at very high risk,” said Stone. “In other words, the most intensive LDL-lowering is reserved for those at the highest risk. That’s a very important concept.”

Moreover, the new guidelines also factor in the cost of the PCSK9 inhibitors, noting that based on the mid-2018 list prices, the economic value of the agents is uncertain. The cost-effectiveness analysis, however, does not take into account the most recent reductions in price announced by both drug manufacturers.

In other words, the most intensive LDL-lowering is reserved for those at the highest risk. Neil Stone

In patients with primary hypercholesterolemia who have LDL cholesterol levels ≥ 190 mg/dL, physicians should start with a high-intensity statin without calculating the 10-year risk of ASCVD (class I). If the LDL cholesterol level remains 100 mg/dL or higher, add ezetimibe (class IIa). Again, a PCSK9 inhibitor may be considered if LDL levels are still 100 mg/dL or greater after treating the patients with primary hypercholesterolemia with a statin and ezetimibe (class IIb).

In the patient 40 to 75 years with diabetes, the guidelines recommend starting treatment with a moderate-intensity statin without assessing the 10-year risk of ASCVD (class I). If the diabetic patient has multiple high-risk features, or is 50 to 75 years old, consider using a high-intensity statin (class IIa).  

Commenting on the guidelines, Amit Khera, MD (UT Southwestern Medical Center, Dallas, TX), said he appreciates the recognition that not all secondary prevention patients are alike. For example, a patient who has coronary artery disease but has been stable for many years is markedly different than someone who has had multiple recurrent ACS events coupled with diabetes, a strong family history, and other risk factors.

“Inputting some heterogeneity into secondary prevention is very valuable,” said Khera. “The person who has had coronary disease for 20 years and their LDL cholesterol is 72 mg/dL, I don’t think I’m going to do much. But the other one, the one with recurrent ACS, a lot of metabolic problems, high [lipoprotein(a)], a strong family history, and so on, then 72 mg/dL is not going to be OK in that person. They are not the same patient.”  

In addition, Khera, said the new guidelines will help provide guidance on when and how to use the PCSK9 inhibitors. One drawback, though, is that they might “box decision-making” in a little given the stepwise algorithmic approach advocated by the writing committee. This could have implications with respect to reimbursement. “I’m not saying it’s the wrong approach, it just cuts both ways,” he told TCTMD, noting that physicians had a fair amount of discretion in using the drugs prior to the new guidelines.  

Treatment Threshold vs Treating to Target

Speaking about thresholds for treatment as opposed to treating to target, Sidney Smith Jr, MD (University of North Carolina, Chapel Hill), a member of the writing committee, said the group thought “long and hard” about when to initiate treatment with ezetimibe or PCSK9 inhibitors in statin-treated patients. For patients who failed to achieve a more than 50% reduction in LDL cholesterol with statins, or had levels 70 mg/dL or greater on treatment, these additional agents could further reduce ASCVD risk.

“We didn’t get to a point where we could say that having an LDL cholesterol level of 51 mg/dL and taking it down to 28 mg/dL, for example, would actually result in an improvement,” said Smith. The IMPROVE-IT study, as well as the PCSK9 inhibitor trials, really showed a large clinical benefit among patients who achieved the target of less than 70 mg/dL, said Smith.

To TCTMD, Steven Nissen, MD (Cleveland Clinic, OH), said there is a lot to like in the 2018 cholesterol guidelines. For example, the concept of “lower is better” is front and center in the new recommendations and there is a push to treat high-risk ASCVD patients more aggressively when LDL cholesterol levels are 70 mg/dL or greater. If such a patient receives ezetimibe or alirocumab/evolocumab, there is no doubt they will lower their LDL cholesterol levels well below the 70-mg/dL threshold, said Nissen.

Importantly, the new cholesterol guidelines also recommend treatment of older and younger people when appropriate, said Nissen. Some of the key criticisms of the 2013 guidelines, including “the idea of giving a statin and just walking away,” are now gone. In fact, he added, the 2018 cholesterol guidelines recommend lipid monitoring 4 to 12 weeks after starting statin therapy in order to check on adherence and treatment effect, as well as continued monitoring 3 to 12 months thereafter. 

“The [new guidelines] are back to a more thoughtful approach,” said Nissen.   

Targeting the Primary Prevention Patient

Like the 2013 recommendations, the 2018 ACC/AHA cholesterol guidelines emphasize a discussion about the pros and cons of starting statin therapy for the primary prevention of ASCVD. That discussion should include a review of major risk factors—cigarette smoking, blood pressure, LDL cholesterol levels, and the 10-year risk of ASCVD, among others—as well talk about the benefits of lifestyle therapy, the potential for drug-drug interactions, and cost considerations. Patient preferences and values should be incorporated into this shared decision-making model.

For adults aged 40 to 75 years without diabetes, LDL cholesterol levels ≥ 70 mg/dL, and a 10-year ASCVD risk 7.5% or greater, the recommendation is a moderate-intensity statin if the discussion of treatment options favors it (class I). If treatment is started, the goal is to reduce LDL levels by 30% or more. If the patient’s 10-year risk exceeds 20%, then reduce LDL cholesterol levels by 50% or more, according to the guidelines.

In primary prevention, the ACC/AHA finally open the door to using CAC screening to help guide treatment decisions (class IIa indication). For those at intermediate risk—defined as those with a 10-year risk between 7.5% and 19.9%—and a CAC score of zero, treatment with statins may be withheld or delayed unless the patient smokes, has diabetes, or a strong family history of ASCVD (class IIa). A CAC score of 1 to 100, on the other hand, tips the balance toward statin therapy (class IIa). Other “risk-enhancing” factors, such as persistently elevated LDL cholesterol (≥ 160 mg/dL), a family history of ASCVD, metabolic syndrome, chronic kidney disease, and inflammatory disorders, among others, also suggest intermediate-risk patients should be started on statin therapy.

With the 2018 guidelines including risk-enhancing factors and use of CAC screening, when needed, “we’re essentially endorsing and expanding the scope of the risk discussion,” said Stone.

Debating the Role of CAC Screening

In a separate special report on the use of risk assessment tools to guide decision-making in primary prevention, the pooled cohort equations again take center stage, but the writing committee concedes they underestimate risk in patients from certain racial/ethnic groups, those with lower socioeconomic status, and those with inflammatory diseases while overestimating risk in patients with higher socioeconomic status and those closely connected with the healthcare system.

Speaking with the media, Stone said the pooled cohort equations “start the conversation” about patient risk. For the patients at intermediate risk, or even borderline risk (5% to less than 7.5%), if there is some uncertainty about starting statin therapy after a discussion about risk-enhancing factors, Stone said CAC screening can serve as a “tiebreaker.”

Like Stone, Donald Lloyd-Jones, MD (Northwestern University Feinberg School of Medicine, Chicago, IL), lead author of the report on risk assessment, said the primary prevention trials did show a clinical benefit of statin therapy in patients at intermediate risk for ASCVD. However, several observational studies, including MESA, BioImage, and others, have shown that a CAC score of zero identified patients with such a low 10-year risk of ASCVD they could effectively avoid statin therapy.

“When you synthesize the data, we felt comfortable saying not to delay the statin forever, but to delay or defer is reasonable,” Lloyd-Jones told TCTMD. “You can recheck the CAC score in 5 years and if you see a rapid increase in the CAC score, or the clinical situation has changed and there are new risk-enhancing factors, then a statin absolutely. But I think there is just so much data on how to use CAC screening—especially in the context of the pooled cohort equations—we really felt comfortable with a IIa recommendation.”

Lloyd-Jones also noted that the 2013 cholesterol guidelines were criticized for putting too many patients on statins and CAC screening has the potential to help appropriate patients stay off the lipid-lowering therapy. Moreover, they are not recommending CAC screening for every patient at borderline or intermediate risk. Instead, the test is to be reserved for patients undecided about treatment or where there is clinical uncertainty.

“This is a way to actually get a lot smarter about the diagnosis and appropriate treatment,” said Lloyd-Jones. Moreover, noninvasive imaging with CAC screening can be used as tool to facilitate better adherence to medication, particularly when patients see evidence of their disease, he added.

Khurram Nasir, MD (Yale University School of Medicine, New Haven, CT), a longtime proponent of CAC screening, praised the guideline writers for incorporating the imaging modality into the cholesterol guidelines. The use of CAC screening is the “first big step” away from the risk factor-based approach to one where physicians make more precise decisions based on whether there is evidence of disease.

There is no data to suggest deciding on statin therapy based on a calcium test improves outcomes. Steven Nissen

“This will not happen in the next few years, but I’m pretty confident that in the next decade, this notion will deeply be imbedded in routine clinical practice,” Nasir told TCTMD. He hopes that including CAC screening in the new guidelines will remove reimbursement barriers by payers who claim the test is experimental or unproven. “CAC is no more a screening test, but rather a decision tool and we can no longer accept access is limited to only those who can afford it versus those who need it,” said Nasir.

Despite such enthusiasm, Nissen remains unconvinced, lamenting the cost and radiation exposure required to decide whether to use a drug that costs as little as $3 per month. “I don't think it makes sense,” he told TCTMD. “It's not evidence-based. There is no data to suggest deciding on statin therapy based on a calcium test improves outcomes.”

To TCTMD, Stone said there are some patients “who just aren’t sure” if they should proceed with statin therapy after a conversation with their doctor. “For many of them, a calcium score of zero can alleviate their concern about starting a statin. Likewise, getting a high calcium score makes it clear that they should go ahead with treatment. Again, this is not for ‘most’ patients,” said Stone. “Most patients should get a statin, but there are people who want or need to know more. They want to personalize the decision to point of knowing whether they really, really need it.”

ACC President Mary Norine Walsh, MD (St. Vincent Heart Center, Indianapolis, IN), stressed that shared decision-making is particularly important in patients deciding on lifelong medical therapy. She stressed the importance of risk assessment using the pooled cohort equations and that patients should not be running out for CAC testing on their own accord. “What people have been doing in cities all over is advertising CAC scoring,” said Walsh, noting that she’s even seen specials or discounts for mom and dad on Mother’s or Father’s Day. “You don’t start with CAC score—you start with individualized risk and then decide.”