European Societies Consensus Statement on PCSK9 Inhibitors: Guidance for Very High CV Risk Patients

Landmesser U, Chapman MJ, Farnier M, et al.
European Society of Cardiology/European Atherosclerosis Society Task Force Consensus Statement on Proprotein Convertase Subtilisin/Kexin Type 9 Inhibitors: Practical Guidance for Use in Patients at Very High Cardiovascular Risk. Eur Heart J 2016;Nov 9:[Epub ahead of print].

The following are key points to remember from this European Society of Cardiology/European Atherosclerosis Society Task Force Consensus Statement on Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) Inhibitors:

  1. The main purpose of this consensus document is to discuss the appropriate clinical use of PCSK9 antibodies in patients at very high cardiovascular (CV) risk who have substantially elevated low-density lipoprotein cholesterol (LDL-C) levels on maximal statin/ezetimibe therapy. The Task Force recommendations aimed to support allocating a highly effective LDL-C lowering therapy, while also taking account of financial restraints within healthcare budgets.
  2. For patients at very high risk of premature atherosclerotic cardiovascular disease (ASCVD), including those with familial hypercholesterolemia (FH) without ASCVD, elevated LDL-C is common. High LDL-C levels are prevalent in both FH and non-FH patients in the acute secondary prevention setting. Polygenic effects may account for an elevated LDL-C concentration, as reflected by genetic risk scores. The European guidelines target LDL-C to <70 mg/dl in patients at very high CV risk. Despite high-intensity statins and ezetimibe, a significant portion of patients will remain above this goal.
  3. Recent studies identifying the role of PCSK9, a member of the serine protease family, playing a key role in regulation of hepatic LDL receptor activity, led to the rapid development of PCSK9 inhibition as an innovative therapeutic approach to improve control of elevated LDL-C levels. Several clinical studies with different monoclonal antibodies against circulating PCSK9, either alone or in addition to statin therapy, have confirmed profound reductions of LDL-C levels (by up to about 60%). PCSK9 inhibitors are well tolerated, injection site reactions occur in about 5% in clinical trials, and there is no increase in the frequency of creatine kinase (CK) elevations, myalgia, or muscle symptoms. A recent meta-analysis has suggested a possible signal for increased frequency of neurocognitive events, which is now being evaluated.
  4. This consensus document focuses on three priority groups: 1) patients at very high risk not at LDL-C goal, with documented ASCVD (clinical or unequivocal on imaging, with plaque on coronary angiography or carotid ultrasound), including those with progressive ASCVD (i.e., repeated acute coronary syndromes [ACS], repeated unplanned coronary revascularizations, or repeated ischemic strokes within 5 years of the index event), or diabetes mellitus with target organ damage or with a major risk factor such as marked hypercholesterolemia or marked hypertension; 2) patients with FH without ASCVD; and 3) patients in any of these groups with statin intolerance. Patients with severe chronic kidney disease (estimated glomerular filtration rate <30 ml/min/1.73 m2) are at very high risk, but have been excluded from the clinical trials.
  5. For patients at very high risk, lowering LDL-C levels to the goal of <70 mg/dl and/or achieving ≥50% LDL-C reduction when this goal cannot be reached is a Class I, Level of Evidence A recommendation. One of the concerns is that only 35-40% of patients with a recent ACS or stable coronary artery disease attain the LDL-C goal, and adherence is a major issue. The Task Force recommends considering a PCSK9 antibody therapy in very high risk patients as defined above, who despite recommended maximally tolerated statin plus ezetimibe therapy require more than 50% reduction in LDL-C levels (i.e., with LDL-C levels >140 mg/dl to reach <70 mg/dl), and in rapidly progressive ASCVD or those with additional risk factors, increasing the absolute risk an LDL-C threshold of >100 mg/dl.
  6. Standardized screening for FH in patients with substantially elevated LDL-C levels is recommended. The modified Dutch Lipid Clinic Network Criteria, in which a score is derived from the LDL-C level, the family and personal history of premature ASCVD, and the presence of tendon xanthomas or corneal arcus, is one possible approach, and genetic testing where available can be helpful for management of families.
  7. Although FH is one of the most common inherited conditions, in about 1 in 200–250 individuals, the vast majority of heterozygous FH (HeFH) patients are undetected until after an acute event. The causative gene defect may have variable impact on the severity of HeFH, thus, treatment decisions are currently guided by the LDL-C level and the presence of other risk factors that indicate a very high CV risk. These include diabetes mellitus, lipoprotein (a) >50 mg/dl, marked hypertension, and premature familial ASCVD (<55 years in men and <60 years in women). Treatment should be initiated early since the age of starting treatment is a key determinant of later phenotypic severity. Patients should be titrated to the maximally tolerated dose of a high-intensity statin; if LDL-C levels are still above recommended goal of <70 mg/dl in patients with ASCVD, and <100 mg/dl in patients without ASCVD), adding ezetimibe is recommended before consideration of a PCSK9 inhibitor.
  8. The panel proposed that until results from major outcomes trials are reported, the PCSK9 antibody treatment may be considered for severe FH patients with ASCVD (as discussed above), as well as those without ASCVD (clinical or on imaging) and LDL-C >200 mg/dl despite maximally tolerated statin/ezetimibe therapy, or >175 mg/dl if additional risk factors. For homozygous FH (HoFH) patients, lipid-lowering therapy, including LDL apheresis where available, should be started as early as possible. The Task Force recommends considering evolocumab treatment for HoFH patients except those with confirmed negative/negative LDL receptor mutations (ineffective) for whom lomitapide may be a preferred option.
  9. Patients who complain of muscle symptoms and have a CK level <10-fold the upper limit of normal (ULN) should receive counseling to emphasize the clinical benefits of statin therapy. After a statin washout, patients with CK either normal ≥4x ULN but <10x ULN at baseline and with recurrent symptoms should successively undertake two dechallenges/rechallenges with separate statins, started at the lowest recommended daily dose; an additional statin challenge is recommended for patients with CK either normal or <4x ULN at baseline. Patients with no symptoms after statin washout should continue statin treatment. All patients should be uptitrated to the maximally tolerated statin dose wherever possible, and ezetimibe should be considered in patients not at LDL-C goal.
  10. The Task Force recommends that very high risk patients (as defined) intolerant of at least two statins at any dose, with muscle symptoms and/or CK elevation, and with substantially elevated LDL-C levels despite ezetimibe therapy, may be considered for treatment with a PCSK9 antibody.
  11. Based on the approved indications for alirocumab and evolocumab, it is estimated that up to 80% of ASCVD patients in Europe would be eligible for PCSK9 inhibition for secondary prevention, which would not be sustainable based on cost.
  12. There remain a number of unanswered questions regarding the clinical use of PCSK9 monoclonal antibody therapy including long-term safety, impact on regression vs. progression of atherosclerotic plaque and plaque stability, impact on neurocognitive function and immunogenic effects, and cost-effectiveness in patient populations at different levels of classic risk. Clinical trials will answer most of the questions soon. More data will be needed in patients with coronary disease with comorbidities, including moderate-to-severe chronic kidney disease.

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