Debate reveals lack of clarity on cholesterol guidelines

BOSTON — Two clinicians and thought leaders in the field of cardiology engaged in a spirited debate at the annual Cardiometabolic Health Congress over how to move forward in practice with the current U.S. cholesterol guidelines.

In the end, comments from Jennifer G. Robinson, MD, MPH, director of the prevention intervention center at the College of Public Health, University of Iowa, and Roger S. Blumenthal, MD, director of the Johns Hopkins Ciccarone Center for the Prevention of Heart Disease, converged more than diverged.

Jennifer G. Robinson

“There’s more agreement than disagreement,” said debate moderator Christie M. Ballantyne, MD, director of the center for cardiovascular disease prevention, Baylor College of Medicine. “This is actually true for guidelines around the world.”

Treatment thresholds

Robinson, who was vice chair for the 2013 American College of Cardiology/American Heart Association Guidelines on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults, discussed the concept of a potential for net benefit from cholesterol-modifying therapy.

Roger S. Blumenthal

Mostly focusing on LDL, she said the same framework could apply PCSK9 inhibitors, possibly CETP inhibitors and omega-3 fatty acids in discussing how to add benefit for patients on maximum statin therapy.

Robinson said although the guidelines moved away from LDL targets and caused a bit of a controversy, she supported the change.

“The fundamental problem with LDL levels — other than them turning into thresholds and not treating high-risk patients who will benefit from this reduction — is it doesn’t incorporate any thought about the patient’s benefit from treatment,” she said during the presentation.

Christie M. Ballantyne

With an LDL goal of < 70 mg/dL, the person with an LDL of 75 mg/dL would be treated the same as a person with an LDL of 120 mg/dL, she explained.

Outcomes data show that patients with achieved LDL levels < 50 mg/dL had a greater relative risk reduction than those who achieved levels of < 70 mg/dL or < 100 mg/dL, and a meta-analysis of high-intensity statins indicated that plaque regression continues with LDL levels as low as 15 mg/dL.

“Goals are familiar; you’ve all integrated those into your thought processes,” she said. “The problem is they often lead to the wrong decision-making for that specific patient.”

Robinson touched on an app, validated in population-based studies, that follows the net benefit concept of the 2013 ACC/AHA guidelines.

“We need an app for people on a statin,” she said. “We really need to figure out what the risk of that person is to determine the benefit of adding another drug.”

Based on the guidelines, Robinson said clinicians should maximize statin therapy, emphasize adherence to lifestyle and statin therapy, and consider adding non-statins in high-risk patients who might experience an overall atherosclerotic CVD risk reduction from additional LDL lowering.

Within the context of the guidelines, Robinson said clinicians could add non-statin therapies to a treatment regimen for patients with less than 50% LDL reduction who are unable to tolerate a high-intensity statin, with a preference for those agents shown to decrease ASCVD events.

Robinson argued for the use of “LDL thresholds as triggers for decision points” and gave examples of categories to follow, based on randomized clinical trial data. She covered considerations including efficacy, safety and tolerability, cost, adherence and patient preferences as part of the threshold approach.

Robinson closed by cautioning clinicians to ensure a second drug leads to an LDL reduction of at least 15%.

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Targets and goals

Encapsulating the 2013 ACC/AHA guidelines, Blumenthal said therapies are allocated based on estimated 10-year ASCVD risk, and there are no fixed targets, unlike the prior guidelines, with the aim for primary prevention in low-risk groups at least a 30% LDL reduction and in high-risk groups at least a 50% LDL reduction.

“One of the issues that a lot of clinicians have to deal with is that it’s hard to assess the LDL reduction we get,” he said.

Patients who present with MI or ACS may show “falsely-low” LDL levels, and patients who begin therapy with high LDL may not reach “clinically-optimal” LDL levels, he explained.

“We can add anything if patients have an LDL > 190 mg/dL, but the guidelines dissuade us if it’s below 190 mg/dL,” he said. “I agree that we only want to use proven therapies.”

Blumenthal argued the guidelines did not emphasize enough that “lower is better” with proven therapies and barely touched on the advantages of non-HDL.

“I tell patients we clearly get the biggest bang for our buck on the maximum-tolerated statin, but we also have a compelling amount of data that says on-treatment levels of non-HDL are associated with better outcomes the lower they are.”

Blumenthal discussed evidence on CVD benefits of further LDL reductions, including the IMPROVE-IT trial, which showed that ezetimibe added to simvastatin (Vytorin, Merck) was associated with better clinical outcomes than simvastatin alone (Zocor, Merck) in high-risk ACS patients. A caveat, he said, is the study population had recent ACS and the outcomes may not apply to all patients. For the primary endpoint of death from CV causes, major coronary event or nonfatal stroke, a 6% to 7% RR reduction is “not dramatic” he said.

“The data [are] such that we have a high event rate, and we need to do a better job,” he said.

Blumenthal also discussed the proven therapies of statins and ezetimibe (Zetia, Merck); he noted that clinicians could also consider including a fibrate or niacin in certain subgroups.

“When we talk to patients, we have to tell them we do have a lot of data that lower is better now with proven therapies,” Blumenthal said.

He suggested that an LDL level < 70 mg/dL and non-HDL of < 100 mg/dL is a goal that clinicians and patients should strive for. “Maybe we’re not going to strive right away with the addition of a second or third medicine, but we should really strive for better lifestyle habits,” he said.

Raising the idea of targets during a clinician-patient risk discussion is important, he said.

“Clinicians and patients are used to targets,” he said. For example, he noted that endocrinologists discuss targets with patients following glucose levels with HbA1C, monitoring thyroid levels with TSH and free T4, and that gout and BP require observation.

“We don’t just give an ACE inhibitor and call it a day. We add on other medicines and try to get it down lower,” he said.

Overall picture

Determining the right goal for a patient is something for which clinicians should strive, but “we’re not there yet,” Robinson said in closing remarks.

“As we move forward in our argument of goals vs. thresholds, our job is to take care of patients,” she said. “It’s personalized therapy to figure out if they have the potential to benefit from the added therapy; it’s not doing things because it’s easy, convenient or easier for us to think about one number.”

Blumenthal conceded in closing comments that goals may lead clinicians to the wrong decision-making, and reiterated opting for therapies with confirmed efficacy.

“If we can rely on what has been proven, we can push the lifestyle even harder,” he said. “We need the data, and hopefully in the next few years we’ll have some other compelling data with other proven classes of medicines.”

Providing his final thoughts, Ballantyne underscored the points agreed upon and offered his views on why they differ where they do.

“Everyone agrees that you need to assess risk. Everyone agrees that you need to optimize lifestyle and statin therapy including adherence,” he said. “There’s agreement that you need to follow-up and measure lipids … and that the intensity of therapy, particularly add-on therapy, depends upon the risk of the patient and level of LDL cholesterol.”

The disagreement tends to surface where evidence is lacking, in particular around determining at what level to add a second agent, according to Ballantyne

“There will be more data coming in, and there’s enough information now that we can agree that there are levels that are going to be too high,” he said. Moving forward, he noted that further guidance will be helpful for clinicians. – by Allegra Tiver

Reference:

Blumenthal RS, and Robinson JG. IMRPOVE-IT: How Do We Go Forward with the Guidelines? Presented at: Cardiometabolic Health Congress; Oct. 21-24, 2015; Boston.

Disclosure: Blumenthal and Robinson report no relevant financial disclosures.