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New consensus document tackles nonstatin therapies for LDL reduction
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In a new expert consensus statement, the American College of Cardiology recommends trying lifestyle and statin therapies before nonstatin medical therapies in patients who require LDL lowering to manage cardiovascular disease risk.
“While evidence-based statin therapy remains the first-line standard of care for patients at risk for atherosclerotic [CVD], clinicians and patients may seek firmer and more specific guidance on adequacy of statin therapy and whether or when to use nonstatin therapies if response to statins is deemed inadequate,” writing committee chair Donald M. Lloyd-Jones, MD, ScM, FACC, chair of the department of medicine and Eileen M. Foell professor of heart research at Northwestern University Feinberg School of Medicine, said in a press release.
Before combination therapy is initiated, “it is imperative for clinicians and patients to engage in a discussion that includes the potential for net benefit, including absolute atherosclerotic [CVD] risk-reduction benefits and potential harms, prescribing considerations and patient preferences for treatment,” Lloyd-Jones said in the release.
The document is geared toward patients who meet at least one of the four criteria for statin therapy in the ACC/American Heart Association 2013 Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults: clinical atherosclerotic disease; LDL at least 190 mg/dL; age 45 to 70 years with diabetes and LDL 70 mg/dL to 189 mg/dL; or predicted 10-year atherosclerotic CVD risk at least 7.5%.
According to the document, at the time the cholesterol guideline was published, there were no data supporting use of nonstatin agents for LDL reduction with the goal of reducing risk for CVD events, but that has changed in the years since, with the publication of studies such as IMPROVE-IT and HPS2-THRIVE. The cholesterol guideline states that nonstatin therapies may be considered in patients who respond poorly to statins or cannot tolerate optimal doses.
In the new document, the writing committee listed the following factors to be considered in patients from the four groups that can benefit from statin therapy: adherence, lifestyle factors, intolerance of statins, how well other risk factors are controlled, and the percentage LDL reduction that should be achieved (a specific LDL target may be considered). They added that clinicians should discuss with patients the benefits, harms and preferences related to nonstatin therapy, and that response to therapy, lifestyle changes and adherence should be monitored.
Nonstatin options
If it is decided that a nonstatin therapy should be pursued, options to consider include referral to a lipid specialist and registered dietitian nutritionist, Zetia (ezetimibe, Merck), bile acid sequestrants and PCSK9 inhibitors, such as Praluent (alirocumab, Sanofi/Regeneron) and Repatha (evolocumab, Amgen). The PCSK9 inhibitors are reserved for consideration only in high-risk patients with clinical atherosclerotic CVD or those with familial hypercholesterolemia who have not had adequate LDL reduction on maximally tolerated statin therapy, according to Lloyd-Jones and colleagues, who noted that in the absence of long-term safety and efficacy data, use of PSCK9 inhibitors is not recommended for low-risk patients. Kynamro (mipomersen, Ionis Pharmaceutical/Genzyme), Juxtapid (lomitapide, Aegerion) and LDL apheresis may be considered by lipid specialists for patients with familial hypercholesterolemia, Lloyd-Jones and colleagues wrote.
An important part of the decision-making process is LDL percentage reduction and target thresholds, but these should not be considered automatic triggers for adding medication, instead factors to consider in the overall context of an individual’s clinical situation, the authors wrote.
- References:
- Lloyd-Jones DM. Dyslipidemia combo-therapy: a framework for clinical decision-making.
- Lloyd-Jones DM, et al. J Am Coll Cardiol. 2016;doi:10.1016/j.jacc.2016.03.519.
Disclosure: Lloyd-Jones reports no relevant financial disclosures. See the full document for a list of the relevant financial disclosures of the other authors and reviewers.
Perspective
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Robert H. Eckel, MD
This guideline enters a space that the 2013 ACC/American Heart Association guideline avoided (Stone NJ, et al.
This new guideline is based on expert opinion and recommends some well-founded steps to take for people who are not at their goal, using percent lowering and LDL levels under 100 mg/dL or 70 mg/dL with certain criteria. This is not necessarily a contradiction, but an attempt, I think, to make recommendations user friendly for health care professionals practicing preventive cardiology. The 2013 guideline did not preclude goal-setting behavior thats stated in the document it just said goal setting is not evidence based.
However, once the evidence-based guideline for statins is applied, I set goals for every patient. When we think about adding ezetimibe, a bile acid sequestrant or a PCSK9 inhibitor, we have to think of where are we are going, why we might be unsatisfied with the level of LDL cholesterol thats been achieved and that translates into a goal-setting behavior. First, I want to make sure a heart-healthy lifestyle is in place, and if not, I want the patient to see a dietitian and/or help with smoking cessation (Eckel RH, et al.
The ACC document effectively says that; it recommends considering the various options of who needs additional treatment noting the inadequate clinical trial data to support that decision. I think this is an attempt to be real-world in terms of where physicians might turn to consider additional therapies.
For example, patients with diabetes are defined first of all by the cholesterol guideline, so patients aged 40 to 75 years without known disease should be treated with a moderate-intensity statin. For patients with diabetes who have minimal to moderate risk, in my clinic Ill use LDL under 100 mg/dL as a treatment goal. In patients with more risk, say smokers, people with hypertension or modest renal insufficiency and/or lower HDL levels, I may set a primary prevention goal of LDL under 70 mg/dL.
Now, the IMPROVE-IT trial suggests that an LDL goal under 55 mg/dL may be better. In the subgroup analysis of IMPROVE-IT, it was the patients with diabetes who clearly benefited from ezetimibe and without patients with diabetes in the study, the findings may not have been significant. Thus, for a patient with diabetes and a history of a myocardial infarction, I would shoot for an LDL goal of under 55 mg/dL with the ezetimibe addition. The ongoing PCSK9 inhibitor trials, which have recruited over 70,000 patients, are going to help us know whether there is a trough that were going to reach in terms of maximum LDL lowering, but right now, my comfort zone in terms of the clinical trial evidence is a goal LDL nadir of under 55 mg/dL. The PCSK9 inhibitors may prove that its under 40 mg/dL. Well have to wait for those trials to be completed to be convincing one way or the other.
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