Management of Atherosclerotic Heart Disease with Inclisiran

Patient Clinical Profile and Risk Assessment

• A patient with established atherosclerotic heart disease, nonobstructive coronary artery disease, and markedly elevated calcium score requires LDL-C goal of <70 mg/dL due to established coronary artery disease 1, 2
• Patients with pure hypercholesterolemia and established coronary artery disease may achieve LDL-C reductions with inclisiran treatment, with a goal of <70 mg/dL 2, 3
• Inclisiran has been shown to improve LDL-C levels from 98 mg/dL to 67 mg/dL in patients with established coronary artery disease, successfully achieving target goals 2, 3
• Documented statin intolerance with severe myalgias may require discontinuation of statin therapy and consideration of alternative non-statin therapies 4, 5

Rationale for Continued Inclisiran Treatment

Statin Intolerance Management

• The American College of Cardiology recommends alternative non-statin therapies for patients with documented statin intolerance to achieve LDL-C goals, especially in those with established ASCVD 1, 6
• Guidelines suggest that after statin intolerance is confirmed, alternative non-statin therapies should be considered to achieve LDL-C goals 2, 7

Efficacy of Inclisiran in Statin-Intolerant Patients

• Inclisiran has demonstrated efficacy in patients with statin intolerance, with LDL-C reductions maintained at approximately 45% through 4 years of treatment 7, 5
• The ORION-3 extension study showed that patients maintained an LDL-C reduction of 45% through the end of year 4, including those not taking statin therapy 3, 5

Cardiovascular Risk Reduction

• Exploratory analyses from ORION trials suggest potential cardiovascular benefit with inclisiran, showing a reduction in composite major adverse cardiovascular events (odds ratio 0.74; 95% CI 0.58-0.94) 8
• Patients with established ASCVD who achieve LDL-C reductions with inclisiran may experience a reduction in cardiovascular risk 2, 3

Advantages of Inclisiran

• Twice-yearly dosing schedule (after initial and 3-month doses) can significantly improve medication adherence compared to other injectable PCSK9 inhibitors 9, 8
• Inclisiran works through a different mechanism than statins or PCSK9 monoclonal antibodies, by inhibiting PCSK9 production at the intracellular level rather than binding to the protein extracellularly 1

Potential Pitfalls and Considerations

• While cardiovascular outcomes trials for inclisiran are still ongoing, significant LDL-C reduction achieved in patients with established ASCVD supports continued use 1, 7
• Regular monitoring of LDL-C levels should continue to ensure sustained efficacy 9, 8

Inclisiran (Leqvio) for Hypercholesterolemia Management

Clinical Appropriateness and Efficacy

• The American College of Cardiology recommends considering PCSK9 inhibition when LDL-C remains ≥70 mg/dL despite maximally tolerated statin plus ezetimibe therapy, and this patient's LDL of 129 mg/dL while on rosuvastatin and ezetimibe indicates the need for additional lipid-lowering therapy 10
• Inclisiran has demonstrated approximately 50% reduction in LDL-C levels in clinical trials, which would likely bring this patient's LDL to goal, with the ORION trials showing that inclisiran maintained LDL-C reductions of approximately 50% through day 510 with the twice-yearly dosing regimen 11

Safety and Limitations

• Unlike PCSK9 monoclonal antibodies (evolocumab and alirocumab), inclisiran does not yet have completed cardiovascular outcomes data showing reduction in cardiovascular events, with two cardiovascular outcomes trials (ORION-4 and VICTORION-2P) currently ongoing to assess the impact of inclisiran on major adverse cardiovascular events 10, 11

Medical Necessity and Appropriateness of Continued Inclisiran Therapy

Established Atherosclerotic Cardiovascular Disease (ASCVD)

• The patient has documented atherosclerotic heart disease, which qualifies her as having clinical ASCVD and places her at very high cardiovascular risk requiring intensive lipid-lowering therapy, according to the 2024 International Lipid Expert Panel guidelines and the American Diabetes Association 12, 13
• The 2024 International Lipid Expert Panel guidelines recommend LDL-C goals of <55 mg/dL for patients with established ASCVD, with consideration for <40 mg/dL in extreme risk patients, as stated in the Drugs journal 12

Guideline-Supported Use

• The 2024 International Lipid Expert Panel position paper includes inclisiran in the treatment algorithm for patients with ASCVD requiring additional LDL-C lowering beyond maximally tolerated statin therapy, as recommended in the Drugs journal 12
• The American College of Cardiology recommends inclisiran as an option for non-statin therapy in patients at very high risk of ASCVD who require additional LDL-C lowering, although the specific citation is not provided

Treatment Algorithm Rationale

• The patient has appropriately progressed through the guideline-recommended treatment algorithm, including maximally tolerated statin therapy and alternative PCSK9 inhibition with inclisiran, as outlined in the Drugs journal and the European Heart Journal 12, 14

Monitoring Requirements

• LDL-C should be assessed 4-12 weeks after inclisiran initiation or dose changes, and annually thereafter, according to the Diabetes Care journal and the European Heart Journal 13, 14
• Liver enzymes (ALT) should be measured before treatment and 8-12 weeks after starting therapy, as recommended in the European Heart Journal 14

Guideline Recommendation Against De-escalation

• The 2024 International Lipid Expert Panel explicitly states that it is not recommended to deescalate the treatment if well-tolerated, even if LDL-C goals are achieved, as long-term sustained LDL-C lowering provides cumulative cardiovascular benefit, according to the Drugs journal 12

Inclisiran Therapy for Patients with Clinical Atherosclerotic Cardiovascular Disease

Guideline-Based Justification for Medical Necessity

• Carotid atherosclerosis with >50% obstruction or symptomatic carotid artery disease qualifies as a CHD risk equivalent, placing patients in the highest risk category requiring an LDL-C goal of <70 mg/dL, according to the American Heart Association, as published in Circulation 15

Evidence of Efficacy and Safety

• Exploratory analyses from ORION 9-11 studies demonstrated significant reduction in composite major adverse cardiovascular events, providing evidence for cardiovascular benefit, although the citation is not provided in the original text, this fact is mentioned as part of the evidence for inclisiran's efficacy
• The American College of Cardiology is not cited in this article for any fact, however the 2024 International Lipid Expert Panel position is mentioned, but without a valid citation, the only valid citation is from Circulation 15