Is Leqvio (Inclisiran) medically indicated for a 65-year-old female with hypercholesterolemia, intolerant to statins, and no history of clinical atherosclerotic cardiovascular disease (ASCVD)?

Medical Necessity Determination for Leqvio (Inclisiran) in This Patient

Leqvio is NOT medically indicated for this 65-year-old female because she lacks documented clinical atherosclerotic cardiovascular disease (ASCVD) and does not meet the severe primary hypercholesterolemia threshold required for approval. 1

Rationale for Denial

Critical Missing Criteria: No ASCVD History

The patient has no documented history of clinical ASCVD, which is the primary pathway for inclisiran approval. 1 Clinical ASCVD specifically includes:

• Acute coronary syndrome or myocardial infarction 1
• Stable or unstable angina 1
• Coronary or other arterial revascularization 1
• Stroke or transient ischemic attack 1
• Peripheral artery disease including aortic aneurysm (all of atherosclerotic origin) 1

The case documentation explicitly states "No cardiac history documented," which disqualifies her from the first approval pathway. 1

Failure to Meet Severe Hypercholesterolemia Criteria

The patient's LDL-C of 123 mg/dL does not meet the threshold for severe primary hypercholesterolemia. 1 The alternative approval pathway requires:

• Untreated baseline LDL-C ≥190 mg/dL (before any lipid-lowering therapy) 1
• Current LDL-C ≥100 mg/dL 1
• Statin intolerance meeting specific criteria 1

While her current LDL-C of 123 mg/dL exceeds 100 mg/dL, there is no documentation of an untreated baseline LDL-C ≥190 mg/dL, which is mandatory for this pathway. 1

Statin Intolerance Does Not Meet Defined Criteria

The patient's statin-related adverse effects do not meet the stringent criteria for documented statin intolerance required for PCSK9 inhibitor approval. 1 The policy specifically requires:

• Statin-associated muscle symptoms with creatine kinase (CK) elevation >3 times upper limit of normal (ULN) 1
• OR statin-associated CK elevation ≥10 times ULN 1

Her documented CK level of 76 U/L (reference range 30-223 U/L) is well within normal limits, not elevated above the ULN threshold. 1 While she experienced fatigue, leg pain, and acute kidney injury on pravastatin, these symptoms without the required CK elevation do not meet the policy's definition of statin intolerance for PCSK9 inhibitor approval. 1

Appropriate Treatment Algorithm for This Patient

Step 1: Optimize Statin Therapy First

Before considering any non-statin therapy, the patient should trial alternative statins at varying intensities. 1 The ACC/AHA guidelines emphasize:

• She only tried pravastatin (a moderate-intensity statin) 1
• Multiple other statins should be attempted including rosuvastatin 5-10 mg, atorvastatin 10-20 mg, or fluvastatin 1
• Lower-intensity or alternate-day dosing strategies should be explored 1
• The maximum tolerated intensity of statin should be established before adding non-statin therapy 1

Step 2: Add Ezetimibe as First-Line Non-Statin Therapy

If the patient cannot tolerate any statin at any dose, ezetimibe 10 mg daily is the appropriate first-line non-statin therapy. 1, 2 The 2022 ACC Expert Consensus Decision Pathway clearly positions ezetimibe before any PCSK9 inhibitor. 1, 2

Step 3: Reassess Risk and LDL-C Goals

Without ASCVD, this patient's LDL-C goal is less stringent than the <70 mg/dL threshold used in the policy criteria. 1 For primary prevention in a 65-year-old:

• Calculate 10-year ASCVD risk using the Pooled Cohort Equation 1
• Consider risk-enhancing factors (family history, metabolic syndrome, chronic inflammatory conditions) 1
• If intermediate risk (7.5-20%), consider coronary artery calcium scoring to guide intensity of therapy 1

Step 4: PCSK9 Inhibitors Only After Exhausting Other Options

Even if she eventually qualifies, PCSK9 monoclonal antibodies (evolocumab, alirocumab) are preferred over inclisiran due to proven cardiovascular outcomes data. 2, 3 Inclisiran lacks completed cardiovascular outcomes trials until 2026-2027. 2

Common Pitfalls to Avoid

Do not confuse statin-related symptoms with policy-defined statin intolerance. 1 Many patients experience muscle symptoms on statins without meeting the CK elevation thresholds required for PCSK9 inhibitor approval. 1

Do not skip the stepwise approach to lipid management. 1, 2 Guidelines universally recommend: maximally tolerated statin → add ezetimibe → consider PCSK9 inhibitor only if targets remain unmet. 1, 2

Do not assume all elevated cholesterol warrants aggressive therapy. 1 Without ASCVD or severe primary hypercholesterolemia (baseline LDL-C ≥190 mg/dL), the intensity of lipid-lowering should match the patient's absolute cardiovascular risk. 1

Documentation Needed for Potential Future Approval

If the patient develops ASCVD or if additional information becomes available:

• Document untreated baseline LDL-C (before any lipid-lowering therapy) to determine if ≥190 mg/dL 1
• Trial and document intolerance to at least 3 different statins at varying doses with specific CK measurements 1
• Measure CK levels during symptomatic periods to document if >3× ULN 1
• Document trial of ezetimibe and resulting LDL-C levels 1, 2
• Screen for secondary causes of hyperlipidemia (hypothyroidism, nephrotic syndrome, medications) 1