Medical Policy



Subject: Proprotein Convertase Subtilisin Kexin 9 (PCSK9) Inhibitors
Document #: DRUG.00078 Current Effective Date:    10/01/2017
Status: Reviewed Last Review Date:    05/04/2017

Description/Scope

This document addresses the use of PCSK9 inhibitors to reduce serum low-density lipoprotein cholesterol (LDL-C) levels in individuals with primary hypercholesterolemia who cannot tolerate or have not had an adequate response to the currently available lipid lowering therapies.  The PCSK9 protein regulates the metabolism of serum LDL-C by controlling the availability of the LDL receptors (LDLR) which remove LDL particles from the blood.  PCSK9 inhibitors are human monoclonal antibodies which selectively bind to the PSCK9 protein, freeing up a greater number of LDL receptors to remove the LDL-C particles, resulting in lower levels of serum LDL-C.

The U.S. Food and Drug Administration (FDA) has approved two PCSK9 inhibitors; alirocumab (Praluent® , Sanofi, Paris, France in collaboration with Regeneron, Tarrytown, NY) and evolocumab (Repatha® , Amgen, Thousand Oaks, CA).

Position Statement

Medically Necessary:

Alirocumab
Alirocumab is considered medically necessary when all the following criteria are met:

  1. Individual is age 18 years or older and is at high risk for Acute Coronary Syndrome (ACS) as identified by one of the following:
    1. Individual has Homozygous Familial Hypercholesterolemia (HoFH) confirmed by:
      1. Presence of two mutant alleles at the LDLR, apoB, PCSK9 or ARH adaptor gene locus; or
      2. An untreated LDL-C concentration greater than 500 mg/dL (13 mmol/L) or treated LDL-C greater than or equal to 300 mg/dL (7.76 mmol/L) and one of the following:
        1. Cutaneous or tendonous xanthoma before age of 10 years; or
        2. Untreated LDL-C levels consistent with heterozygous familial hypercholesterolemia in both parents (greater than 190 mg/dL); or
    2. Individual has Heterozygous Familial Hypercholesterolemia (HeFH) confirmed by:
      1. Presence of a mutation in LDLR, apolipoprotein B (ApoB), PCSK9 or ARH adaptor protein (LDLRAP1) gene; or
      2. World Health Organization (WHO)/Dutch Lipid Network Criteria with score of greater than eight points; or
    3. Individual has a history of clinical Atherosclerotic Cardiovascular Disease (ASCVD), including one or more of the following:
      1. Acute coronary syndromes;
      2. History of myocardial infarction (MI);
      3. Stable or unstable angina;
      4. Coronary or other arterial revascularization;
      5. Stroke;
      6. Transient ischemic attack (TIA);
      7. Peripheral arterial disease presumed to be of atherosclerotic origin;
        and
  2. Individuals who meet one or more of the following:
    1. Individual is a on high intensity statin therapy, or statin therapy at the maximum tolerated dose, where high intensity statin is defined as atorvastatin 40 mg or higher OR rosuvastatin 20 mg or higher; or
    2. Individual is statin intolerant, as defined by the National Lipid Association Statin Intolerance Panel and includes all of the following:
      1. Inability to tolerate at least two statins, with at least one started at the lowest starting daily dose; and
      2. Statin dose reduction is attempted for symptom and biomarker abnormality resolution, rather than discontinuation of statin therapy altogether; and
      3. Intolerable symptoms or abnormal biomarker changes are reversible upon statin discontinuation, but reproducible by re-challenge of statins, if clinically appropriate.  Statin re-challenge may be appropriate for individuals with all of the following:
        1. Symptomatic; and
        2. Creatine kinase is less than four times the upper limit of normal per laboratory reference range; and
        3. AST/ALT are less than three times the upper limit of normal per laboratory reference range; and
      4. Symptoms or biomarker abnormalities are not attributable to established predispositions or conditions recognized to increase the risk of statin intolerance, such as:
        1. Hypothyroidism;
        2. Drug interactions;
        3. Concurrent illness;
        4. Significant changes in physical activity/exercise;
        5. Underlying muscle disease;
          or
    3. Individual has a condition that is a contraindication for statin therapy including active liver disease, unexplained persistent elevation of serum transaminases, or pregnancy, which does not exist for alirocumab;
      and
  3. Individual is on ezetimibe in addition to statin therapy (applies to individuals on statin therapy only);
    and
  4. High risk individual has achieved suboptimal lipid lowering response, despite at least 90 days of compliant lipid lowering therapy and lifestyle modifications, where suboptimal response is defined:
    1. For individuals where initial LDL-C is known:
      1. Less than 50% reduction LDL-C;
    2. For individuals where initial LDL-C is unknown:
      1. Documented CVD and LDL-C remains greater than or equal to 70mg/dl; or
      2. No documented history of CVD and LDL-C remains greater than or equal to 100mg/dl.

Evolocumab
Evolocumab is considered medically necessary when all the following criteria are met:

  1. Individual is at High Risk for Acute Coronary Syndrome (ACS) as identified by:
    1. Individual is age 13 or older and has Homozygous Familial Hypercholesterolemia (HoFH) confirmed by one or more of the following:
      1. Presence of two  mutant alleles at the LDLR, apoB, PCSK9 or ARH adaptor protein gene locus; or
      2. An untreated LDL-C concentration greater than 500 mg/dL (13 mmol/L) or treated LDL-C greater than or equal to 300 mg/dL (7.76 mmol/L) and one of the following:
        1. Cutaneous or tendonous xanthoma before age of 10 years; or
        2. Untreated LDL-C levels consistent with heterozygous familial hypercholesterolemia in both parents (greater than 190 mg/dL);
          or
    2. Individual is age 18 years or older and has Heterozygous Familial Hypercholesterolemia (HeFH); confirmed by one or more of the following:
      1. Presence of a mutation in LDLR, ApoB, or PCSK9, ARH adaptor protein (LDLRAP1) gene; or
      2. WHO/Dutch Lipid Network Criteria with score of greater than eight points;
        or
    3. Individual has a history of clinical ASCVD, including one or more of the following:
      1. Acute coronary syndromes;
      2. History of MI;
      3. Stable or unstable angina;
      4. Coronary or other arterial revascularization;
      5. Stroke;
      6. TIA;
      7. Peripheral arterial disease presumed to be of atherosclerotic origin;
        and
  2. Individual meets one of the following:
    1. Individual is a on high intensity statin therapy, or statin therapy at the maximum tolerated dose, where high intensity statin is defined as atorvastatin 40 mg or higher or rosuvastatin 20 mg or higher; or
    2. Individual is statin intolerant, as defined by the National Lipid Association Statin Intolerance Panel and includes all of the following:
      1. Inability to tolerate at least two statins, with at least one started at the lowest starting daily dose; and
      2. Statin dose reduction is attempted for symptom and biomarker abnormality resolution, rather than discontinuation of statin therapy altogether; and
      3. Intolerable symptoms or abnormal biomarker changes are reversible upon statin discontinuation, but reproducible by re-challenge of statins; if clinically appropriate.  Statin re-challenge may be appropriate for individuals with all of the following:
        1. Symptomatic; and
        2. Creatine kinase is less than four times the upper limit of normal per laboratory reference range; and
        3. AST/ALT are less than three  times the upper limit of normal per laboratory reference range; and
      4. Symptoms or biomarker abnormalities are not attributable to established predispositions or conditions recognized to increase the risk of statin intolerance, such as:
        1. Hypothyroidism;
        2. Drug interactions;
        3. Concurrent illness;
        4. Significant changes in physical activity/exercise;
        5. Underlying muscle disease;
          or
    3. Individual has a condition that is a contraindication for statin therapy including active liver disease, unexplained persistent elevation of serum transaminases, or pregnancy, which does not exist for evolocumab;
      and
  3. Individual is on ezetimibe in addition to statin therapy (applies to individuals on statin therapy only);
    and
  4. High risk individual, excluding HoFH, has achieved suboptimal lipid lowering response, despite at least 90 days of compliant lipid lowering therapy and lifestyle modifications, where suboptimal response is defined:
    1. For individuals where initial LDL-C is known:
      1. Less than 50% reduction in LDL-C;
    2. For individuals where initial LDL-C is unknown:
      1. Documented CVD and LDL-C remains greater than or equal to 70mg/dl; or
      2. No documented history of CVD and LDL-C remains greater than or equal to 100mg/dl.

Continuation Therapy
Continuation therapy with PCSK9 inhibitors (alirocumab or evolocumab) is considered medically necessary when the following criteria are met:

  1. Criteria listed above have been met; and
  2. Documentation of LDL reduction has been provided.

Investigational and Not Medically Necessary: 

PCSK9 inhibitors (alirocumab or evolocumab) are considered investigational and not medically necessary when the above criteria are not met and for all other indications.

PCSK9 inhibitors (alirocumab or evolocumab) are considered investigational and not medically necessary when used concurrently with lomitapide or mipomersen.

Rationale

First-line statin drug therapy is considered the standard for the treatment of dyslipidemia due to their proven cardiovascular benefits.  The 2013 American College of Cardiology (ACC)/American Heart Association (AHA) Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults recommends statins as first-line therapy in primary and secondary prevention for all at-risk populations who can tolerate high or moderate intensity statin therapy.  Other lipid lowering therapies, such as ezetimibe, should be considered second-line options or adjunctive therapies for individuals needing additional cholesterol lowering or who can't tolerate moderate to high doses of statins.

Alirocumab (Praluent)
On July 24, 2015, the FDA granted approval for the use of Praluent as an adjunct to diet and maximally tolerated statin therapy in adults with heterozygous familial hypercholesterolemia or individuals with clinical ASCVD, who have been unable to sufficiently lower their LDL cholesterol on statin therapy. However, Praluent's effect on cardiovascular morbidity and mortality have not yet been determined.

The ODYSSEY program is a series of phase III trials designed to evaluate the safety and efficacy of alirocumab in multiple clinical populations.  This program includes 14 multinational trials and more than 23,500 participants (Kastelein, 2014).  The ODYSSEY Outcomes trial, with approximately 18,000 individuals with a recent history of acute myocardial infarction or unstable angina, aims to evaluate the effect of alirocumab in combination with intensive statin therapy, on future cardiovascular events.  The expected completion of ODYSSEY Outcomes trial is 2016 (Schwartz, 2014).  The primary outcome of interest will be the efficacy of alirocumab to reduce the rate cardiovascular events.

In the ODYSSEY MONO trial, the first ODYSSEY study to report results, Roth and colleagues (2014) compared alirocumab to ezetimibe as a monotherapy in individuals with hypercholesterolemia at moderate cardiovascular risk.  Eligible individuals included those with a 1% to 5% 10-year risk of fatal cardiovascular events based on the European Systematic Coronary Risk Estimation.  Participants were randomized to receive alirocumab plus ezetimibe placebo (n=52) or alirocumab placebo plus ezetimibe (n=51).  At week 12, the estimated proportions of those with ≥ 50% LDL-C reduction was 58% in the alirocumab arm versus 3% in the ezetimibe arm.  At week 24, least squares (LS) mean standard error (SE) LDL-C reductions from baseline were 47% (3) alirocumab versus 16% (3) ezetimibe; with a statistically significant LS mean SE difference between groups of -32% (4) (p<0.0001). The initial dose of alirocumab was 75 mg every 2 weeks.  Per protocol, if the LDL-C level was ≥ 100 mg/dl at week 12, individuals would be up-titrated to 150 mg.  However, due to administrative error, the up-titration was performed on those with LDL-C level ≥ 70 mg/dl, a total of 13 additional individuals.  An additional analysis was performed excluding those individuals.  Results were similar to initial overall analysis.  Rates of participants with at least one treatment-emergent adverse event (TEAE) were comparable between the two groups with 69% in the alirocumab group and 78% in the ezetimibe group.  A total of 5 (10%) individuals experiencing TEAEs in the alirocumab group and 4 (8%) individuals in the ezetimibe group discontinued study treatment.

Robinson and colleagues (2015) assessed 2341 high-risk cardiovascular participants receiving maximal statin therapy with or without other lipid lowering drugs in the ODYSSEY LONG TERM trial.  Eligible individuals included those with HeFH (established by genotyping or clinical criteria), those with a diagnosis of coronary heart disease (CHD) or those CHD risk equivalent individuals with an LDL-C level ≥ 70 mg per deciliter.  Participants were randomized to receive alirocumab or placebo in addition to high-dose or maximally tolerated statin therapy.  The study reported a significant reduction in LDL-C levels from baseline (-61.0% alirocumab versus 0.8% placebo; difference -61.9%; p<0.001).  Rates remained constant over the 78-week study period.  In a post hoc analysis, the alirocumab group rate of major adverse cardiovascular events was lower than the placebo group (1.7% versus 3.3% respectively; p=0.02).  However, the number of cardiovascular events was relatively small and confidence in the robustness of this data is limited.

In the 2015 ODYSSEY COMBO II trial, Cannon and colleagues compared the safety and efficacy of alirocumab to ezetimibe as add-on therapy to maximally tolerated statin therapy in high-risk cardiovascular individuals with inadequately controlled hypercholesterolemia.  Eligible individuals included those with documented cardiovascular disease (CVD) and LDL-C ≥ 70 mg/dL or no documented history of CVD but who were at high cardiovascular risk and had LDL-C ≥ 100 mg/dL.  Participants were randomized to receive subcutaneous (SQ) alirocumab plus oral placebo (n=479) or SQ placebo plus oral ezetimibe (n=241).  At week 24, the differences were significant.  The mean ± standard error (SE) reductions in LDL-C from baseline were -50.6 ± 1.4% in the alirocumab arm and -20.7 ± 1.9% in the ezetimibe arm with a mean SE difference of -29.8 (95% Confidence Interval (CI), -34.4 to -25.3; p<0.0001).  Mean LDL-C concentrations dropped rapidly in both groups in the first 4 weeks, the alirocumab arm to a greater extent, and remained constant through week 52.  Overall, 71.2% of the alirocumab arm and 67.2% of the ezetimibe arm reported treatment-emergent adverse events (TEAEs) over a mean of 58 ± 19 weeks.  These TEAEs resulted in treatment discontinuation in 7.5% of the alirocumab group and 5.4% of the ezetimibe group.  Results will continue to be reported through 104 weeks.  The study did report slightly higher cardiovascular events in the alirocumab group (4.8%) vs. ezetimibe group (3.7%). 

In the ODYSSEY COMBO I study, Kereiakes and colleagues (2015) evaluated the efficacy and safety of alirocumab as an add-on therapy in high-risk individuals with inadequately controlled hypercholesterolemia despite maximally tolerated daily statin, with or without other lipid-lowering therapy.  The trial included 316 individuals randomized to receive either alirocumab or a matching placebo in addition to their current therapy.  At week 24, the intention-to-treat (ITT) analysis results showed an LDL change in the alirocumab group of -48.2% (-52.0% to -44.4%) compared to -2.3% (-7.6% to 3.1%) for the placebo group (p<0.0001).  These results were sustained throughout the 52-week study period.  Reported treatment adverse event rates were similar across both groups.  A total of 6.6% (13/197) of the alirocumab group developed anti-alirocumab antibodies; the presence of these antibodies was transient in 7 of the individuals despite continued treatment.  The presence of these antibodies were not associated with any specific clinical events. 

Evolocumab (Repatha)
On August 27, 2015, the FDA granted approval for the use of Repatha as an adjunct to diet and maximally tolerated statin therapy in adults with heterozygous or homozygous familial hypercholesterolemia or individuals with clinical ASCVD, who have been unable to sufficiently lower their LDL cholesterol on statin therapy.  However, Repatha's effect on cardiovascular morbidity and mortality have not yet been determined.  

The FDA accepted the Biologics License Application (BLA) for evolocumab in November 2014.  The BLA consists of data from 10 phase III trials which evaluated the safety and efficacy of evolocumab in approximately 6800 individuals.  Studied groups included individuals with elevated cholesterol on statins with or without other lipid-lowering therapies; individuals who cannot tolerate statins; individuals with heterozygous familial hypercholesterolemia (HeFH); and individuals with homozygous familial hypercholesterolemia (HoFH).

Koren and colleagues (2014) reported on the results of the MENDEL-2, a randomized controlled, phase III monotherapy trial to compare biweekly and monthly evolocumab with placebo and oral ezetimibe in those with hypercholesterolemia.  The trial included 614 participants with LDL-C levels ≥ 100 and < 190 mg/dl and a 10-year Framingham coronary heart disease risk score of ≤ 10%.  Participants were randomized to receive evolocumab (n=306), ezetimibe (n=154) or placebo (n=155).  At 12 weeks, LDL-C levels had decreased from baseline by an average of 57.0% (95% CI, -59.5% to -54.6%) with biweekly evolocumab versus 0.1% (95% CI, -3.2% to 3.4%) with placebo and 17.8% (95% CI, -21.0% to -14.5%) with ezetimibe (p<0.001).  All individuals in the evolocumab group realized a reduction in baseline LDL-C levels as compared to approximately 92% of the ezetimibe group.  Treatment-emergent adverse event rates were comparable between all groups, 44% for each group.  These adverse events lead to study treatment discontinuation in 7 (2.3%) in the evolocumab group, 5 (3.2%) of the ezetimibe group and 6 (3.9%) of the placebo group.

The randomized controlled, double-blinded GAUSS-2 trial of 307 participants reported by Stroes and colleagues (2014) assessed the effectiveness and safety of evolocumab against ezetimibe in individuals with hypercholesterolemia intolerant to at least two statins.  Participants were randomized to receive evolocumab plus placebo (n=205) or ezetimibe plus placebo (n=102) either biweekly or monthly.  Mean percent reductions from baseline at a 10-12 week mean were 56.1% (95% CI, 59.7% to 52.5%) biweekly and 55.3% (95% CI, 58.3% to 52.3%) monthly as compared to ezetimibe at 36.9% (95% CI, 42.3% to 31.6%) and 38.7% (95% CI, 43.1% to 34.3%), respectively (p<0.001).  After 12 weeks, LDL-C levels in the evolocumab group were reduced by 53%-56% compared to a 37%-39% reduction in the ezetimibe group (p<0.001).  Treatment adverse events leading to study discontinuation were reported in 6 of the evolocumab group and 14 of the ezetimibe group. 

In a trial assessing the effect of evolocumab on cardiovascular events, 4465 participants of earlier phase II or III trials were recruited into two open-label, randomized trials (OSLER-1 and OSLER-2).  Eligible individuals included those who had elevated LDL-C levels without history of lipid therapy, those on statin therapy with or without ezetimibe with incomplete response, statin tolerant individuals or those with HeFH with continued LDL-C elevation despite statin therapy.  Participants were randomized to receive evolocumab with standard therapy (n=2976) or standard therapy (n=1489) over a 1-year period.  Data from both trials were combined.  At 12 weeks, the LDL-C level was significantly lower in the evolocumab group versus standard therapy with the LDL-C reduced by 61% (95% CI, 59 to 63; p<0.001).  Serious adverse event occurrences were 7.5% in each group.  The authors noted that the evolocumab group reported more neurocognitive adverse events; however, the rate of these events was low (< 1%).  Researchers used the Kaplan–Meier method to estimate the rate of cardiovascular events at 1 year: 0.95% in the evolocumab group versus 2.18% the standard therapy group (Hazard ratio, [HR] 0.47; 95% CI, 0.28- 0.78; p=0.003).  The authors note that while it is plausible to suggest PCSK9 inhibitors will affect cardiovascular outcomes similar to statins as they have the same mechanism of action, currently, there is no data to support this (Sabatine, 2015).

Nicholls and colleagues (2016) reported on the Global Assessment of Plaque Regression With a PCSK9 Antibody as Measured by Intravascular Ultrasound (GLAGOV) trial which evaluated coronary atherosclerosis progression in statin- treated (moderate or high intensity) individuals with at least one epicardial coronary stenosis of 20% or greater on clinically indicated coronary angiography.  In a multicenter, double-blind, placebo-controlled, randomized, controlled trial (RCT), individuals received monthly injections of either 420 mg evolocumab (n=484) or a placebo (n=484) with the primary endpoint being the nominal change in percent atheroma volume (PAV) from baseline to week 78 as measured by serial intravascular ultrasonography (IVUS) imaging.  Final data was available for approximately 87% of those who began the study.  There was no change in the PAV in the placebo group (0.05%, p=0.78 compared with baseline); the evolocumab group decreased by 0.95% (p<0.001) compared with baseline.  The between-group difference is reported as -1.0% (95% CI, -1.8% to -0.64%; p<0.001).  There was no difference in treatment effect when individuals were stratified according to baseline LDL-C levels.  While the authors reported numerically fewer adverse cardiovascular outcomes in the evolocumab group compared to the placebo group (12.2% versus 15.3%), nonfatal myocardial infarctions (2.1% versus 2.9%), and coronary revascularization procedures (10.3% versus 13.6%), they also noted that the study was not powered to assess effects on cardiovascular events.  These results are encouraging, but further studies are still needed to assess the effects of PCSK9 inhibition on clinical outcomes.

In 2017, Sabatine and colleagues reported on the outcomes of a randomized, double-blind, placebo-controlled trial which included 27,564 individuals with atherosclerotic cardiovascular disease and LDL cholesterol levels of 70 or higher who were receiving statin therapy.  Individuals were randomly assigned to receive biweekly or monthly evolocumab or a placebo.  The primary efficacy endpoint was the composite of cardiovascular death, myocardial infarction, stroke, hospitalization for unstable angina, or coronary revascularization.  A key secondary endpoint was limited to the composite of cardiovascular death, myocardial infarction, or stroke.  The LDL levels were lowered by 59% from baseline compared to the placebo.  The primary endpoint occurred in 1344 individuals (9.8%) in the evolocumab group compared to 1563 individuals (11.3%) in the placebo group (HR 0.85; 95% CI, 0.79-0.92; p<0.001).  The secondary endpoint occurred in 816 individuals (5.9%) in the evolocumab group and in 1013 individuals (7.4%) in the placebo group (HR 0.80; 95% CI, 0.73-0.88; p<0.001).  The addition of evolocumab to statin therapy reduced the risk of the more serious cardiovascular events by 20% and all cardiovascular events by 15% over the course of the median 26 months follow-up.  However, there was no observed effect of evolocumab on cardiovascular mortality.  The authors noted "In terms of individual outcomes, evolocumab had no observed effect on cardiovascular mortality, and hence P values for other outcomes should be considered exploratory."  Studies with longer term follow-up are needed to evaluate the long-term effects of evolocumab therapy.

Several ongoing trials are underway to evaluate the long-term efficacy and tolerability of evolocumab.  These studies include the EBBINGHAUS (Evaluating PCSK9 Binding antiBody Influence oN coGnitive HeAlth in High cardiovascUlar Risk Subjects) study which will assess neurocognitive changes in evolocumab therapy and is estimated to be completed in 2017.  The FOURIER study will address whether the additional evolocumab-related decrease in LDL-C levels will result in a decrease in cardiovascular events in individuals with CVD.

Published clinical trials indicate PCSK9 inhibitors reduce LDL-C by 48% to 66% in individuals at high risk for CV events (HeFH or non-HeFH) treated with maximum tolerated doses of a statin, with or without other lipid lowering agents; such as ezetimibe (Kereiakes, 2015; Koren, 2015; McKinney, 2012; Raal, 2015; Robinson, 2015; Sabatine, 2015).  PSCK9 inhibitors reduced LDL-C by approximately 30% more than adding ezetimibe to statins (Cannon, 2015; Roth, 2014).  However, data has not been published to demonstrate that use of PSCK9 inhibitors result in greater reduction in CV events compared to statins alone or in combination with other lipid lowering agents.  Trials investigating CV outcomes are ongoing with anticipated completion in 2017 and 2018.

There is no consensus on an optimal LDL-C target treatment level.  The authors of the ACC/AHA 2013 Guidelines on the Treatment of Blood Cholesterol removed specific LDL-C treatment target goals from their recommendations for either primary or secondary prevention of ASCVD.  The authors noted that while there is RCT evidence to support that the use of maximally tolerated statin intensity therapy reduced ASCVD events, there were no studies which have assessed specific LDL-C goals against improved ASCVD outcomes.  In addition, the authors noted, "As of yet, there are no data to show that adding a nonstatin drug(s) to high-intensity statin therapy will provide incremental ASCVD risk reduction benefit with an acceptable margin of safety."

The 2016 ACC Expert Consensus Decision Pathway on the Role of Non-Statin Therapies for LDL-Cholesterol Lowering in the Management of Atherosclerotic Cardiovascular Disease Risk provides expert consensus recommendations on the use of PCSK9 inhibitors.  The consensus states that in individuals with clinical ASCVD with or without comorbidities, PCSK9 inhibitors may be considered if maximally tolerated statins and either ezetimibe and/or BAS provide less than 50% LDL-C reduction from baseline or LDL-C continues to be greater or equal to 70 mg/dL.  The authors note that in individuals with a baseline LDL-C of greater than or equal to 190 mg/dL (not due to secondary causes) on maximally tolerated statin therapy with 50% or less reduction in LDL-C, "either ezetimibe or a PCSK9 inhibitor may be considered in combination with maximally tolerated statin therapy".  The expert consensus did not involve formal systematic reviews, grading of evidence, or synthesis of evidence.

The European Society of Cardiology (ESC) and the European Atherosclerosis Society (EAS) do provide treatment targets in their 2011 Guidelines for the Management of Dyslipidaemias.  The ESC/EAS authors noted an absolute reduction in the LDL-C level to < 70 mg/dL or a relative reduction of at least 50% allows for the optimal benefit for CVD risk reduction.  The 2014 National Lipid Association guidelines include tiered recommendations based upon individual risks: LDL-C target < 100 mg/dL in high risk individuals, LDL-C target < 70 mg/dL or a ≥ 50% LDL-C reduction when the goal of < 70 mg/dL cannot be reached for individuals at very high CVD risk.

Adverse Events
Published data report PCSK-9 inhibitors were well tolerated in clinical trials of a year or less duration.  Most common adverse events were a slightly higher incidence of injection site reactions and nasopharyngitis (alirocumab).  Incidence of neurocognitive events was rare, but slightly higher in clinical trials with alirocumab: amnesia, memory impairment, or confusional state (0.9% vs. 0.3%).  Neurocognitive events are being assessed as part of ongoing large, CV outcome trials.

There is no data regarding the safety of concurrent use of alirocumab with lomitapide or mipomersen.  The FDA requires strict risk evaluation and mitigation strategies (REMS) programs for both lomitapide and mipomersen.  Studies are needed to evaluate whether potential benefits of combining these therapies outweigh potential risks.  

Background/Overview

There are several established risk factors for the development of atherosclerotic cardiovascular disease.  Dyslipidemia is one of those known risk factors and statin therapy is an established treatment to lower cholesterol and reduce the risk of acute cardiovascular events.  Statins can reduce LDL-C levels by as much as 50%, and reduce ASCVD risk by 15% to 37% (Ahn, 2015).  However, statin treatments leave gaps in coverage among certain populations.  Some individuals are unable to tolerate statin therapy for various reasons.  Statin therapy can result in high rates of side effects such as muscle symptoms including myalgia, muscle cramps, or weakness.  Up to 25% of individuals experience statin-induced myopathy and are unable to tolerate and must discontinue statin therapy (Talameh, 2014).  Other individuals have existing comorbidities, such as active liver disease, which preclude the use of statins.  These contraindications will vary according to each statin.  Contraindications, warnings, and precautions, including those related to hepatic dysfunction are defined for each statin according to the manufacturer's prescribing information.  Still other individuals are unable to achieve target cholesterol goals despite optimal dyslipidemia therapies currently available.

Familial Hypercholesterolemia
Familial hypercholesterolemia (FH) is an inherited condition caused by genetic mutations which cause high levels of LDL-C at an early age.  It is estimated that less than one percent of individuals with FH (heterozygous and homozygous forms) in the United States (U.S.) have been diagnosed.  There are two types of FH.  Heterozygous FH (HeFH) is the more common type occurring in approximately 1 in 200 to 500 individuals.  Individuals with HeFH have one altered copy of a cholesterol-regulating gene.  Over 80% of individuals with FH have been shown to have mutations in the LDLR, apolipoprotein B (Apo B), low-density lipoprotein receptor adaptor protein 1 (LDLRAP1), or PCSK9 genes.  Heterozygous FH results from one mutation of these genes while homozygous FH results from more than one mutation either within the same gene or different genes (Singh, 2015).  It can cause LDL-C levels twice as high as normal (for example, > 190 mg/dL).  Homozygous FH (HoFH) is the rare, more severe form, occurring in approximately one in a million individuals.  Individuals with HoFH have two altered copies of cholesterol-regulating genes (one from each parent).  It can cause LDL-C levels more than six times as high as normal (for example, 650-1,000 mg/dL).  

Definitions

Acute coronary syndrome: An umbrella term for situations where the blood supplied to the heart muscle is suddenly blocked, such as heart attack or unstable angina.

AHA/ACC 10 year Atherosclerotic Cardiovascular Disease (ASCVD) Risk Calculator: Available at: http://tools.acc.org/ASCVD-Risk-Estimator/.  Accessed on April 10, 2017.

Atherosclerotic cardiovascular disease (ASCVD): Conditions resulting from buildup of plaque within the inner walls of the arteries.  These conditions include acute coronary syndromes, history of MI, stable or unstable angina, coronary or other arterial revascularization, stroke, TIA, or peripheral arterial disease presumed to be of atherosclerotic origin.

Cholesterol: A waxy substance in our blood manufactured in the liver and obtained from the diet which is used to build and maintain healthy cells. Excess cholesterol can form plaque between layers of artery walls, making it harder for the heart to circulate blood and can cause clots.

WHO/Dutch Lipid Network Criteria for Heterozygous Familial Hypercholesterolemia (FH) Diagnosis in Adults1 :

Criteria Points
Group 1: Family History  
  1. Known premature CHD (< 55 years in men, < 60 years in women) or
  2. Known LDL cholesterol > 95th percentile by age and gender for country
  3. Tendon xanthoma and/or corneal arcus or
  4. Children aged < 18 years with LDL-C > 95th percentile by age, gender for country
1
1
2
2
Group 2: Personal Clinical History  
  1. Premature CHD (< 55 years in men, < 60 years in women)
  2. Premature cerebrovascular or peripheral vascular disease (< 55 years in men, < 60 years in women)
2
1
Group 3: Clinical Exam  
  1. Tendom xanthoma
  2. Corneal arcus in person aged < 45 years
6
4
Group 4: LDL-C level  
  • > 325 mg/dL (> 8.5 mmol/L)
  • 251-325 mg/dL (6.5-8.4 mmol/L)
  • 191-250 mg/dL (5.0-6.4 mmol/L)
  • 155-190 mg/dL (4.0-4.9 mmol/L)
8
5
3
1
Group 5: Genetic testing  
  1. Causative mutation in LDLR, ApoB, or PCSK9 gene
8

Scoring : The highest single score in each group is considered.
Definite FH:> 8 points; Probable FH: 6-8 points; Possible FH: 3-5 points; Unlikely FH: 0-2 points

1 World Health Organization. Familial hypercholesterolemia—report of a second WHO Consultation. Geneva, Switzerland: World Health Organization, 1999. Available at: http://whqlibdoc.who.int/hq/1999/WHO_HGN_FH_CONS_99.2.pdf?ua=1. Accessed on April 10, 2017.

Dyslipidemia: An elevation in the levels low density lipoprotein (LDL) cholesterol and/or triglycerides or a decrease in the levels of high density lipoprotein (HDL) in the blood.  Dyslipidemia is a risk factor for cardiovascular disease.

Low density lipoprotein (LDL): A group of proteins within the blood which binds to cholesterol and carries it throughout the body. Low density lipoproteins promote atherosclerosis.

Statin intolerance: Adverse symptoms or objective findings attributed by the individual (or provider) to the statin and in most cases perceived by the individual to interfere unacceptably with activities of daily living, leading to a decision to stop or reduce statin therapy.

Coding

The following codes for treatments and procedures applicable to this document are included below for informational purposes. Inclusion or exclusion of a procedure, diagnosis or device code(s) does not constitute or imply member coverage or provider reimbursement policy. Please refer to the member's contract benefits in effect at the time of service to determine coverage or non-coverage of these services as it applies to an individual member.  

When services may be Medically Necessary when criteria are met: 

HCPCS    
J3490 Unclassified drug [when specified as alirocumab (Praluent) or evolocumab (Repatha)]  
J3590 Unclassified biologics [when specified as alirocumab (Praluent) or evolocumab (Repatha)]  
     
ICD-10 Diagnosis  
E78.00 Pure hypercholesterolemia, unspecified
E78.01 Familial hypercholesterolemia
E78.1 Pure hyperglyceridemia
E78.2 Mixed hyperlipidemia
E78.4-E78.5 Other and unspecified hyperlipidemia
G45.0-G45.9 Transient cerebral ischemic attacks and related syndromes
I20.0-I20.9 Angina pectoris
I21.01-I21.A9 Acute myocardial infarction
I22.0-I22.9 Subsequent ST elevation (STEMI) and non-ST elevation (NSTEMI) myocardial infarction
I23.7 Postinfarction angina
I24.0-I24.9 Other acute ischemic heart diseases
I25.10-I25.9 Chronic ischemic heart disease
I63.00-I63.9 Cerebral infarction
I65.01-I65.9 Occlusion and stenosis of precerebral arteries, not resulting in cerebral infarction
I66.01-I66.9 Occlusion and stenosis of cerebral arteries, not resulting in cerebral infarction
I67.2 Cerebral atherosclerosis
I67.82 Cerebral ischemia
I69.00-I69.998 Sequelae of cerebrovascular disease
I70.0-I70.92 Atherosclerosis
I73.9 Peripheral vascular disease, unspecified
Z83.42 Family history of familial hypercholesterolemia
Z86.73 Personal history of transient ischemic attack (TIA), and cerebral infarction without residual deficits
Z95.1 Presence of aorto coronary bypass graft
Z95.5 Presence of coronary angioplasty implant and graft
Z95.820-Z95.828 Presence of other vascular implants and grafts
Z98.61 Coronary angioplasty status
Z98.62 Peripheral vascular angioplasty status

When services are Investigational and Not Medically Necessary:
For the procedure codes listed above when criteria are not met or for all other diagnoses not listed; or when the code describes a procedure indicated in the Position Statement section as investigational and not medically necessary.

References

Peer Reviewed Publications:

  1. Ahn CH, Choi SH. New drugs for treating dyslipidemia: beyond statins. Diabetes Metab J. 2015; 39(2):87-94.
  2. Banach M, Rizzo M, Toth PP, et al. Statin intolerance—an attempt at a unified definition. Position paper from an International Lipid Expert Panel. Arch Med Sci. 2015; 11(1):1-23.
  3. Blom DJ, Hala T, Bolognese M, et al.; DESCARTES Investigators. A 52-week placebo-controlled trial of evolocumab in hyperlipidemia. N Engl J Med. 2014; 370(19):1809-1819.
  4. Cannon CP, Cariou B, Blom D, et al. Efficacy and safety of alirocumab in high cardiovascular risk patients with inadequately controlled hypercholesterolaemia on maximally tolerated doses of statins: the ODYSSEY COMBO II randomized controlled trial. Eur Heart J. 2015; 36(19):1186-1194.
  5. Colhoun HM, Robinson JG, Farnier M, et al. Efficacy and safety of alirocumab, a fully human PCSK9 monoclonal antibody, in high cardiovascular risk patients with poorly controlled hypercholesterolemia on maximally tolerated doses of statins: rationale and design of the ODYSSEY COMBO I and II trials. BMC Cardiovasc Disord. 2014; 14:121.
  6. Desai NR, Giugliano RP, Zhou J, et al. AMG 145, a monoclonal antibody against PCSK9, facilitates achievement of national cholesterol education program-adult treatment panel III low-density lipoprotein cholesterol goals among high-risk patients: an analysis from the LAPLACE-TIMI 57 trial (LDL-C assessment with PCSK9 monoclonal antibody inhibition combined with statin thErapy-thrombolysis in myocardial infarction 57). J Am Coll Cardiol. 2014; 63(5):430-433.
  7. Desai NR, Kohli P, Giugliano RP, et al. AMG145, a monoclonal antibody against proprotein convertase subtilisin kexin type 9, significantly reduces lipoprotein(a) in hypercholesterolemic patients receiving statin therapy: an analysis from the LDL-C Assessment with Proprotein Convertase Subtilisin Kexin Type 9 Monoclonal Antibody Inhibition Combined with Statin Therapy (LAPLACE)-Thrombolysis in Myocardial Infarction (TIMI) 57 trial. Circulation. 2013; 128(9):962-969.
  8. Gaudet D, Kereiakes DJ, McKenney JM, et al. Effect of alirocumab, a monoclonal proprotein convertase subtilisin/kexin 9 antibody, on lipoprotein(a) concentrations (a pooled analysis of 150 mg every two weeks dosing from phase 2 trials). Am J Cardiol. 2014; 114(5):711-715.
  9. Giugliano RP, Desai NR, Kohli P, et al.; LAPLACE-TIMI 57 Investigators. Efficacy, safety, and tolerability of a monoclonal antibody to proprotein convertase subtilisin/kexin type 9 in combination with a statin in patients with hypercholesterolaemia (LAPLACE-TIMI 57): a randomised, placebo-controlled, dose-ranging, phase 2 study. Lancet. 2012; 380(9858):2007-2017.
  10. Kastelein JJ, Robinson JG, Farnier M, et al. Efficacy and safety of alirocumab in patients with heterozygous familial hypercholesterolemia not adequately controlled with current lipid-lowering therapy: design and rationale of the ODYSSEY FH studies. Cardiovasc Drugs Ther. 2014; 28(3):281-289.
  11. Kereiakes DJ, Robinson JG, Cannon CPet al. Efficacy and safety of the proprotein convertase subtilisin/kexin type 9 inhibitor alirocumab among high cardiovascular risk patients on maximally tolerated statin therapy: the ODYSSEY COMBO I study. Am Heart J. 2015; 169(6):906-915.
  12. Koren MJ, Giugliano RP, Raal FJ, et al.; OSLER Investigators. Efficacy and safety of longer-term administration of evolocumab (AMG 145) in patients with hypercholesterolemia: 52-week results from the Open-Label Study of Long-Term Evaluation Against LDL-C (OSLER) randomized trial. Circulation. 2014; 129(2):234-243.
  13. Koren MJ, Lundqvist P, Bolognese M, et al.; MENDEL-2 Investigators. Anti-PCSK9 monotherapy for hypercholesterolemia: the MENDEL-2 randomized, controlled phase III clinical trial of evolocumab. J Am Coll Cardiol. 2014; 63(23):2531-2540.
  14. Koren MJ, Roth EM, McKenney JM, et al. Safety and efficacy of alirocumab 150 mg every 2 weeks, a fully human proprotein convertase subtilisin/kexin type 9 monoclonal antibody: a Phase II pooled analysis. Postgrad Med. 2015; 127(2):125-132.
  15. Li C, Lin L, Zhang W, et al. Efficiency and safety of proprotein convertase subtilisin/kexin 9 monoclonal antibody on hypercholesterolemia: a meta-analysis of 20 randomized controlled trials. J Am Heart Assoc. 2015; 4(6):e001937.
  16. McKenney JM, Koren MJ, Kereiakes DJ, et al. Safety and efficacy of a monoclonal antibody to proprotein convertase subtilisin/kexin type 9 serine protease, SAR236553/REGN727, in patients with primary hypercholesterolemia receiving ongoing stable atorvastatin therapy. J Am Coll Cardiol. 2012; 59(25):2344-2253.
  17. Navarese EP, Kolodziejczak M, Schulze Vet al. Effects of proprotein convertase subtilisin/kexin type 9 antibodies in adults With hypercholesterolemia: a systematic review and meta-analysis. Ann Intern Med. 2015; 163(1):40-51.
  18. Nicholls SJ, Puri R, Anderson T, et al. Effect of evolocumab on progression of coronary disease in statin-treated patients: The GLAGOV randomized clinical trial. JAMA. 2016; 316(22):2373-2384.
  19. Nissen SE, Stroes E, Dent-Acosta RE, et al; GAUSS-3 Investigators. Efficacy and tolerability of evolocumab vs ezetimibe in patients with muscle-related statin intolerance: the GAUSS-3 randomized clinical trial. JAMA. 2016; 315(15):1580-1590.Peterson AS, Fong LG, Young SG. PCSK9 function and physiology. J Lipid Res. 2008; 49(7):1595-1599.
  20. Raal FJ, Giugliano RP, Sabatine MS, et al. Reduction in lipoprotein(a) with PCSK9 monoclonal antibody evolocumab (AMG 145): a pooled analysis of more than 1,300 patients in 4 phase II trials. J Am Coll Cardiol. 2014; 63(13):1278-1288.
  21. Raal FJ, Honarpour N, Blom DJ, et al.; TESLA Investigators. Inhibition of PCSK9 with evolocumab in homozygous familial hypercholesterolaemia (TESLA Part B): a randomised, double-blind, placebo-controlled trial. Lancet. 2015a; 385(9965):341-350.
  22. Raal FJ, Stein EA, Dufour R, et al.; RUTHERFORD-2 Investigators. PCSK9 inhibition with evolocumab (AMG 145) in heterozygous familial hypercholesterolaemia (RUTHERFORD-2): a randomised, double-blind, placebo-controlled trial. Lancet. 2015b; 385(9965):331-340.
  23. Robinson JG, Farnier M, Krempf  M, et al.; ODYSSEY LONG TERM Investigators. Efficacy and safety of alirocumab in reducing lipids and cardiovascular events. N Engl J Med. 2015; 372(16):1489-1499.
  24. Robinson JG, Nedergaard BS, Rogers WJ, et al. Effect of evolocumab or ezetimibe added to moderate- or high-intensity statin therapy on LDL-C lowering in patients with hypercholesterolemia: the LAPLACE-2 randomized clinical trial. JAMA. 2014; 311(18):1870-1882.
  25. Roth EM, McKenney JM, Hanotin C, et al. Atorvastatin with or without an antibody to PCSK9 in primary hypercholesterolemia. N Engl J Med. 2012; 367(20):1891-1900.
  26. Roth EM, Taskinen MR, Ginsberg HN, et al. Monotherapy with the PCSK9 inhibitor alirocumab versus ezetimibe in patients with hypercholesterolemia: results of a 24 week, double-blind, randomized Phase 3 trial. Int J Cardiol. 2014; 176(1):55-61.
  27. Sabatine MS, Giugliano RP, Keech AC, et al; FOURIER Steering Committee and Investigators. Evolocumab and clinical outcomes in patients with cardiovascular disease. N Engl J Med. 2017 Mar 17. [Epub ahead of print]
  28. Sabatine MS, Giugliano RP, Wiviott SD, et al.; Open-Label Study of Long-Term Evaluation against LDL Cholesterol (OSLER) Investigators. Efficacy and safety of evolocumab in reducing lipids and cardiovascular events. N Engl J Med. 2015; 372(16):1500-1509.
  29. Schwartz GG, Bessac L, Berdan LG, et al. Effect of alirocumab, a monoclonal antibody to PCSK9, on long-term cardiovascular outcomes following acute coronary syndromes: rationale and design of the ODYSSEY outcomes trial. Am Heart J. 2014; 168(5):682-689.
  30. Singh S, Bittner V. Familial hypercholesterolemia--epidemiology, diagnosis, and screening. Curr Atheroscler Rep. 2015; 17(2):482.
  31. Stroes E, Colquhoun D, Sullivan D, et al.; GAUSS-2 Investigators. Anti-PCSK9 antibody effectively lowers cholesterol in patients with statin intolerance: the GAUSS-2 randomized, placebo-controlled phase 3 clinical trial of evolocumab. J Am Coll Cardiol. 2014; 63(23):2541-2548.
  32. Talameh JA, Kitzmiller JP. Pharmacogenetics of Statin-Induced Myopathy: A Focused Review of the Clinical Translation of Pharmacokinetic Genetic Variants. J Pharmacogenomics Pharmacoproteomics. 2014; 5(2). pii: 128.
  33. White CM. Therapeutic potential and critical analysis of the PCSK9 monoclonal antibodies evolocumab and alirocumab. Ann Pharmacother. 2015; 49(12):1327-1335.

Government Agency, Medical Society, and Other Authoritative Publications:

  1. American Heart Association. 2013 Prevention Guidelines Tools. Cardiovascular (CV) Risk Calculator. Available at: http://tools.acc.org/ASCVD-Risk-Estimator/ . Accessed on April 10, 2017.
  2. Biologics License Application for Evolocumab. Submitted May 7, 2015. Available at: http://www.fda.gov/downloads/advisorycommittees/committeesmeetingmaterials/drugs/endocrinologicandmetabolicdrugsadvisory
    committee/ucm450076.pdf. Accessed on April 10, 2017.
  3. Cholesterol. Centers for Disease Control and Prevention. Last Reviewed January 19, 2017. Available at: http://www.cdc.gov/nchs/fastats/cholesterol.htm. Accessed on April 10, 2017.
  4. European Association for Cardiovascular Prevention & Rehabilitation, Reiner Z, Catapano AL, De Backer G, et al.; ESC Committee for Practice Guidelines (CPG) 2008-2010 and 2010-2012 Committees. ESC/EAS Guidelines for the management of dyslipidaemias: the Task Force for the management of dyslipidaemias of the European Society of Cardiology (ESC) and the European Atherosclerosis Society (EAS). Eur Heart J. 2011; 32(14):1769-1818. Available at: http://eurheartj.oxfordjournals.org/content/ehj/32/14/1769.full.pdf.  Accessed on April 10, 2017.
  5. Jacobson TA, Ito MK, Maki KC, et al. National Lipid Association recommendations for patient-centered management of dyslipidemia: Part 1- executive summary. J Clin Lipidology. 2014; 8(5):473-488. Available at: http://www.lipidjournal.com/article/S1933-2874(14)00274-8/pdf. Accessed on April 10, 2017.
  6. Jacobson TA, Maki KC, Orringer CE, et al; NLA Expert Panel. National Lipid Association recommendations for patient-centered management of dyslipidemia: Part 2. J Clin Lipidol. 2015; 9(6 Suppl):S1-S122. Available at: http://www.lipidjournal.com/article/S1933-2874(15)00380-3/pdf. Accessed on April 10, 2017.
  7. Mozaffarian D, Benjamin EJ, Go AS, et al.; American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Heart disease and stroke statistics—2015 update: a report from the American Heart Association. Circulation. 2015;131:e1-e294.
  8. Nordestgaard BG, Chapman MJ, Humphries SE, et al; European Atherosclerosis Society Consensus Panel. Familial hypercholesterolaemia is underdiagnosed and undertreated in the general population: guidance for clinicians to prevent coronary heart disease: consensus statement of the European Atherosclerosis Society. Eur Heart J. 2013; 34(45):3478-3490a. Available at: http://eurheartj.oxfordjournals.org/content/ehj/early/2013/08/15/eurheartj.eht273.full.pdf. Accessed on April 10, 2017.
  9. Praluent™ (alirocumab). FDA Advisory Committee Briefing Document. BLA 125559.  Meeting date June 9, 2015. Available at: http://www.fda.gov/downloads/advisorycommittees/committeesmeetingmaterials/drugs/endocrinologicandmetabolicdrugsadvisory
    committee/ucm449867.pdf.  Accessed on April 10, 2017.
  10. Praluent [Product Information], Tarrytown, NY.  Regeneron Pharmaceuticals, Inc. October 2015. Available at: https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=446f6b5c-0dd4-44ff-9bc2-c2b41f2806b4&type=display . Accessed on April 10, 2017.
  11. Repatha [Product Information], Thousand Oaks, CA. Amgen Pharmaceuticals, Inc. August 2015. Available at http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/125522s000lbl.pdf . Accessed on April 10, 2017.
  12. Stone NJ, Robinson JG, Lichtenstein AH, et al.; American College of Cardiology/American Heart Association Task Force on Practice Guidelines. 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation. 2014; 129(25 Suppl 2):S1- S45. Available at http://circ.ahajournals.org/content/129/25_suppl_2/S1.full.pdf+html. Accessed on April 10, 2017.
  13. Writing Committee, Lloyd-Jones DM, Morris PB, et al. 2016 ACC Expert Consensus Decision Pathway on the Role of Non-Statin Therapies for LDL-Cholesterol Lowering in the Management of Atherosclerotic Cardiovascular Disease Risk: A Report of the American College of Cardiology Task Force on Clinical Expert Consensus Documents. J Am Coll Cardiol. 2016; 68(1):92-125.
Websites for Additional Information
  1. American Heart Association.  Information on cholesterol. Updated April 21, 2014. Available at: http://www.heart.org/HEARTORG/Conditions/Cholesterol/AboutCholesterol/About-Cholesterol_UCM_001220_Article.jsp. Accessed on April 10, 2017.
  2. Genetics Home Reference. PCSK9. Reviewed March 2007. Available at: http://ghr.nlm.nih.gov/gene/PCSK9. Accessed on April 10, 2017.
  3. National Institutes of Health (NIH). National Heart, Lung and Blood Institute  How Is High Blood Cholesterol Treated? Updated March 30, 2016. Available at: http://www.nhlbi.nih.gov/health/health-topics/topics/hbc/treatment. Accessed on April 10 2017.
  4. U.S. National Library of Medicine. Familial Hypercholesterolemia. Reviewed March 5, 2016. Available at: http://www.nlm.nih.gov/medlineplus/ency/article/000392.htm. Accessed on April 10, 2017.
Index

Alirocumab
Cholesterol
Dyslipidemia
Evolocumab
Human Monoclonal Antibody
Praluent
PCSK9 inhibitor
Repatha
Statin

The use of specific product names is illustrative only. It is not intended to be a recommendation of one product over another, and is not intended to represent a complete listing of all products available.

Document History
Status Date Action
  10/01/2017 Updated Coding section with 10/01/2017 ICD-10-CM diagnosis code and descriptor changes.
Reviewed 05/04/2017 Medical Policy & Technology Assessment Committee (MPTAC) review.  Updated Rationale and References sections.
Reviewed 02/02/2017 MPTAC review. Updated formatting in Position Statement section. Updated Rationale, References and Websites sections.
Revised 08/04/2016 MPTAC review. Revised position statement to add "when the above criteria are not met" to an investigational and not medically necessary statement. Minor formatting changes to other position statements; removed a redundant "gene" term from the HeFH definition criteria, spelled out all numbers under 10 and made criteria formatting consistent between both drugs. Updated Rationale, Definitions, References and Websites. Updated formatting in Position Statement section. Updated Coding section with 10/01/2016 ICD-10-CM changes and removed ICD-9 codes.
Revised 09/18/2015 MPTAC review.  Revised Position Statement adding evolocumab (Repatha) as medically necessary when criteria are met. Added evolocumab to the investigational and not medically necessary statements when criteria are not met. Updated Description, Rationale, Definitions, Coding, References and Websites for Additional Information sections.
New 08/06/2015 MPTAC review.  Initial document development.