'The Patient Has the Power' in New AHA/ACC Cholesterol Guideline

November 20, 2018

CHICAGO – At its core, the American Heart Association (AHA) and American College of Cardiology (ACC) 2018 Guideline on the Management of Blood Cholesterol promotes a toolbox of "risk-enhancing factors" and other strategies to fine-tune primary-prevention recommendations in the majority of patients who fall into the broad intermediate-risk gray zone established by its atherosclerotic cardiovascular disease (ASCVD) risk calculator.

The calculator, slammed as a gateway to statin overtreatment after its inaugural appearance in the 2013 guidelines, is described in the new statement as more of launch point for shared decision-making.

"Physicians can use some of these risk-enhancing factors, or if needed, selectively consider a coronary artery calcium [CAC] score, to personalize that person's risk," said guideline coauthor Roger S. Blumenthal, MD, referring to another of the document's hallmarks, provocative to some: CAC imaging as a another statin-therapy decision tool.

The risk calculator "starts the discussion, but the patient really has the power," said Blumenthal, of Johns Hopkins University, Baltimore, to the theheart.org | Medscape Cardiology.

That may ease its acceptance in clinical practice. The 2013 guidelines had been "a massive departure from before," observed Amit Khera, MD, director of the preventive cardiology program at the University of Texas Southwestern Medical Center, Dallas.

The 2018 version "uses the same scaffold. They just filled in the blanks and added components. What they added were things that were giving people angst already," Khera, not a guideline coauthor, said in an interview.

"Think of this as our playbook," said Richard J. Kovacs, MD, Indiana University School of Medicine, Indianapolis, and ACC vice president, also not a coauthor, at a briefing for journalists on the guidelines, released November 10 at the American Heart Association Scientific Sessions 2018, and covered at that time by the theheart.org | Medscape Cardiology.

"Coaches write every play to score a touchdown, but it has to be executed on the field," Kovacs said. "This new guideline gives us all the defensive strategies to risk stratify."

"By and large, this is a much more thoughtful set of guidelines," said Steve Nissen, MD, Cleveland Clinic, also not a coauthor, to the theheart.org | Medscape Cardiology.

"A number of us were very critical of the 2013 guidelines. These guidelines address, appropriately, many of those concerns," he agreed.

Nissen lauded the new document for a restored emphasis on LDL-cholesterol thresholds as determinates of therapy, "aggressive use of targets," consideration of people older than 75 years and younger than 40, and respect for personalized risk-modifiers like family history and even C-reactive protein (CRP).

The only new recommendations with which he takes major issue, Nissen said, are those around CAC imaging. "I don't agree that radiating people with a CT scan to decide whether or not to give a drug that costs as little as $3 a month is good public health policy."

The new document also intensifies focus on special populations with their own ASCVD risk factors not always given due consideration in practice, including people with diabetes, women, and children and adolescents.

"It provides people with an understanding that the risk calculator, taken out of context, isn't nearly as effective as using it with other modifiers that may change your thinking," Nissen said. It acknowledges that "the risk calculator does work for populations, but doesn't necessarily work for individuals. And that's exactly right."

The 2018 document also breaks new ground by featuring a cost-effectiveness analysis focusing on the proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors.

These agents weren't in the arsenal in 2013, but since then, pivotal randomized trials have shown they can profoundly cut LDL-cholesterol levels given on top of statins. Yet for most of their postapproval existence, the drugs have been frustratingly costly and not often prescribed.

The value statement's verdict: the PCSK9 inhibitors, that is evolocumab (Repatha, Amgen) and alirocumab (Praluent, Sanofi/Regeneron), are "a relatively low-value proposition," Donald M. Lloyd-Jones, MD, told theheart.org | Medscape Cardiology.

Risk-Enhancing Factors: The Patient Has the Power

The risk-enhancing factors are "wiggle room for primary prevention that really has to be framed around the patient–clinician discussion," guideline coauthor Lynne T. Braun, PhD, Rush University Medical Center, Chicago, said in an interview.

The document says for patients at borderline ASCVD risk, that is with a 10-year risk of 5.0% to <7.5%, the presence of risk-enhancing factors would favor statin therapy with a class IIb recommendation. Statins would get a class I recommendation with a score in the intermediate-risk range of 7.5% to <20.0%. For patients with a score of 20% or higher, high-intensity statins are favored with a class I recommendation.

Risk-Enhancing Factors "Favor Statin Therapy" in Nondiabetics aged 40–75 at Intermediate Risk* (10-Year ASCVD Risk 7.5% to <20.0%)
Family history of premature ASCVD Chronic kidney disease
LDL-C persistently ≥160 mg/dL (≥4.1 mmol/L) Metabolic syndrome
Triglycerides persistently ≥175 mg/dL (≥1.97 mmol/L) History of pre-eclampsia or premature menopause
Chronic inflammatory disorders (including rheumatoid arthritis, psoriasis, lupus, and chronic HIV) When available: apolipoprotein B ≥130  mg/dL, CRP ≥2.0 mg/L, ankle-brachial index <0.9, and lipoprotein(a) ≥50 mg/dL
High-risk ethnic groups (for example, South Asian ancestry)  
*Risk-enhancing factors "may favor statin therapy" in patients at borderline risk (10-year risk ASCVD risk 5.0% to <7.5%)


The risk-enhancement factors are a positive step, Pradeep Natarajan, MD, MMSc, told theheart.org | Medscape Cardiology. After release of the 2013 guideline, "I think it was clear that a lot of people were being offered statins who didn't necessarily appreciate the strong recommendation."

The earlier document was widely perceived as urging a risk score of ≥7.5% as a trigger for initiating statins, "and with a flat cut-off, there were a lot of providers pushing this, and patients were not always on board."

The new document appropriately lets clinicians calculate patients' statin eligibility "but then separately think about statin suitability," said Natarajan, director of preventive cardiology at Massachusetts General Hospital, Boston, and not an author of the guideline.

But it is unclear how clinicians are to weigh the different risk-enhancing factors in their conversations with patients who have intermediate-risk scores, he said.

"Most of the people who are going to have this conversation are not cardiologists; they're going to be primary care doctors. A lot of patients fit into this bin. Now, are they going to be happy going through a list of risk factors for which the conferred effect is not well quantified?"

The risk calculator provides a hard number, he noted, but add the risk enhancements "and you don't know how the needle moves."

Still Unsure About Statins? CAC as Arbiter

The guideline promotes CT imaging for determining a CAC score for use by clinicians and intermediate-risk patients on the fence about whether to initiate statins even after consideration of the risk enhancers. It represents a key new way observational studies figure into the recommendations.

"I like the way they put it, in that, if the patient can't decide or the clinician can't decide, or the conversation is going around and around — and I've had many conversations like that — I think coronary artery calcium is helpful in that scenario," Mariell Jessup, MD, the AHA's chief science and medical officer but not a coauthor on the document, said in an interview.

For patients with a CAC score of 0, even those with risk-enhancement factors, it's reasonable not to take a statin, the document says; that may well occur for half of patients scanned.

"That's a new paradigm," Natarajan said about using CAC imaging to "de-risk" patients in the broad intermediate-risk range so they can potentially avoid statin therapy.

Statins would be recommended for patients with a CAC score ≥100 Agatston units. But for patients in the indeterminate range of 1 to 99 Agatston units, the decision might be to initiate a statin. If the patient does not start on a statin, the CAC scan should be repeated at least 2 years later.

"If it's zero, great, we can avoid therapy probably for 5 to 10 years, and then reassess where we are. If it's very high, above 100, we really should have you on a statin, because you're someone who's on a fast track to an event," Lloyd-Jones said.

"As long as it's put in its proper perspective, it's a terrific tool in the right person for the right question," said Neil J. Stone, MD, Northwestern University, Chicago, at a media briefing on the 2018 guidelines.

"I don't think it's really evidence-based," Nissen said. "We don't have evidence that using a CT scan to decide who to treat actually improves outcomes, and I'm a little surprised that that advocacy crept into the guidelines."

"If there was a composite score that incorporated everything, that would be most ideal. But to make the ultimate decision, it's going to be much more compelling to know the burden of subclinical atherosclerosis," said Natarajan.

"I think we will see primary care providers reaching for coronary calcium, because it kind of encapsulates that risk from the risk-enhancing factors," he said. "You get a score and it's something that you can hang your hat on."

And, "I think the absence of coronary calcium can be very compelling to both a patient and provider, and reassuring in withholding a statin, at least for some period of time."

Resurgent Thresholds and Targets

Initiate a moderate-intensity statin in nondiabetics aged 40 to 75 years with a 10-year ASCVD risk of ≥7.5% and with LDL-C levels ≥70 mg/dL (≥1.8 mmol/L) if statin therapy is favored after a discussion of risk factors; reduce LDL-C levels by ≥30%, or by ≥50% if 10-year risk is at least 20%, the document recommends.

The renewed focus on LDL-C treatment targets "anchors clinicians on specific well-validated biomarkers that are correlated with cardiovascular disease risks," Natarajan said. "I think this is much easier and much more tangible."

But their comeback may not change current practice by much, he added, because, "to be honest, many clinicians were still using treatment targets anyway."

Those with diabetes and LDL-C levels ≥70 mg/dL can be started on a moderate-intensity statin without figuring out their 10-year ASCVD risk score, the guideline states. Patients with severe primary hypercholesterolemia, with LDL-C ≥190 mg/dL (≥4.9 mmol/L), can similarly go straight to a high-intensity statin.

In secondary prevention, "high-intensity statin therapy or maximally tolerated statin therapy" should aim to lower LDL-C by at least 50%.

The Leap to Nonstatin Drug Therapy

Another drug class can be added in patients with a history of multiple ASCVD events "or one major ASCVD event and multiple high-risk conditions" in whom LDL-C levels persist at ≥70 mg/dL despite maximal statins, the guideline states.

"The first thing, of course, is to make sure patients are truly taking maximal statin therapy. Repeat the lipid panel, make sure it's accurate, be sure they are adhering to lifestyle modification," Sidney C. Smith Jr, MD, University of North Carolina at Chapel Hill, said at the media briefing.

In that setting, maximally tolerated ezetimibe is the recommended second-tier lipid-modifying drug therapy. But if LDL-C stays above the 70 mg/dL threshold, "adding a PCSK9 inhibitor is reasonable."

The recommendations on when to add nonstatin agents, and which to add, are largely about how the high cost of PCSK9 inhibitors restricts access to them, Natarajan said. "If these medicines were much cheaper, I don't think we'd even be having this discussion about very-high-risk ASCVD and not-very-high-risk ASCVD."

Natarajan further observed that the FDA rejected ezetimibe's bid for a secondary-prevention indication even though IMPROVE-IT showed an outcomes benefit associated with the drug on top of statins in patients with history of acute coronary syndromes. Moreover, he noted, evolocumab is already FDA-approved for secondary prevention.

Yet, the new guideline prefers that secondary-prevention patients be on maximally tolerated statins and ezetimibe before they resort to a PCSK9 inhibitor, he said. "It's fascinating that it is basically a recommendation for an off-label use of ezetimibe."

Nonstatin Value vs Cost

Treatment with one of the PCSK9 inhibitors is "worth doing in very high-risk patients if you're not getting the LDL down, but we're not saying this is a highly cost-effective move," said Lloyd-Jones.

That's probably true, he said, even accounting for the nearly 60% evolocumab price cut recently announced by Amgen, to $5850 per year; the annual cost of both PCSK9 inhibitors had until this year been set at about $14,000.

Amgen's move follows the steep alirocumab price reduction to which Regeneron and Sanofi agreed with Express Scripts earlier this year in exchange for the drug's listing as the sole PCSK9 inhibitor in the company's national formulary.

Nissen said the PCSK9 inhibitors seem poised for much broader use in practice after their prices come down, given the guideline's generally favorable view of them for persistently elevated LDL-C levels and despite caveats regarding their use.

A number of experts consulted by theheart.org | Medscape Cardiology said the new document likely influenced the companies' efforts to make their respective PCSK9 inhibitors available at lower cost. Their expensive products had not been selling well, for sure, but then came added pressure from the developing guideline value statement and recommendations relegating the drugs to third-tier status.

Also likely influential, they said, was what had been the impending public release of the ODYSSEY OUTCOMES study here at the AHA sessions. That analysis concluded that alirocumab would meet the cost-effectiveness threshold of $100,000 per quality-life-year (QALY) gained were it priced at $6319 annually.

The guideline value statement focused on PCSK9 inhibitors at their pre-2018 price point, primarily because it derives entirely from the peer-reviewed, published literature, observed Mark Hlatky, MD, Stanford University School of Medicine, California.

However, it did compare QALY values for the PCSK9-inhibitors at different hypothetical price points with those of control therapies in the relevant randomized trials, he noted when formally presenting the analysis at the AHA sessions.

In six of seven different cost-effectiveness models in the overall analysis, PCSK9 inhibitors came in at greater than $150,000 per QALY, that is, in the low-value zone. They cost about $140,000 per QALY in the remaining model. None of the models pegged the drugs as high value; that is, costing less than $50,000 per QALY.

"The most important thing about the results is that every single model that we looked at predicted that the cost over the patients' lifetime would be considerably higher using the PCSK9-inhibitor strategy," Hlatky said.

However, "the higher the patient's risk, the more benefit from it, and the value improves." That was true regardless of the annual price used in the models, he said; higher-risk patients consistently received more value from PCSK9 inhibitors.

Cleary, their cost-effectiveness compared with statins and ezetimibe should improve after the recently announced drops in price. "But would it be enough to reclassify them being of low value to being of intermediate value, for instance? We don't know for sure how it's going to turn out," Hlatky said.

"They do remain quite expensive, even after price cuts, especially compared with generic statins. So it's clinically and economically sound to use other agents first in secondary prevention, and to make sure they are being used."

None of the authors of the guideline document had relevant disclosures; they include Blumenthal, Lloyd-Jones, Braun, Stone, Smith, and Hlatky. Kovacs discloses consulting or serving on an advisory board for Eli Lilly, Biotie Therapies, and Teva Pharmaceuticals. Nissen, Khera, and Jessup had no disclosures. Natarajan discloses receiving research grants from Amgen unrelated to PCSK9 inhibitors.

J Am Coll Cardiol. Published online November 10, 2018. Article, Executive summary, Systematic review

Circulation. Published online November 10, 2018. Article, Executive summary, Systematic review

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