# Secondary Prevention in ASCVD -- ACC/AHA 2018

## Clinical ASCVD Definition

Clinical ASCVD includes any of the following conditions of atherosclerotic origin:
- Acute coronary syndrome (ACS): STEMI, NSTEMI, or unstable angina
- History of myocardial infarction (MI)
- Stable angina
- Coronary or other arterial revascularization (PCI, CABG, carotid endarterectomy, peripheral vascular intervention)
- Stroke (ischemic, atherosclerotic origin)
- Transient ischemic attack (TIA)
- Peripheral artery disease (PAD), including aortic aneurysm of atherosclerotic origin

## Statin Therapy in ASCVD

### Age <= 75 Years
- Initiate high-intensity statin therapy to reduce LDL-C by >= 50% (Class I, Level of Evidence A).
- **Preferred agents:** Atorvastatin 40--80 mg/day or Rosuvastatin 20--40 mg/day.
- If high-intensity statin is not tolerated, use maximally tolerated statin dose (Class I, Level of Evidence A).

### Age > 75 Years
- It is reasonable to continue high-intensity statin if already established and tolerated (Class IIa, Level of Evidence B-R).
- It is reasonable to initiate moderate- or high-intensity statin therapy after evaluating the potential for ASCVD risk reduction, adverse effects, and drug interactions, as well as patient frailty and preferences (Class IIb, Level of Evidence C-LD).

## Very High-Risk ASCVD

Patients are classified as very high-risk if they have a history of multiple major ASCVD events OR one major ASCVD event with multiple high-risk conditions.

### Major ASCVD Events (Must Have >= 2, OR 1 Major + High-Risk Conditions)
- Recent ACS (within the past 12 months)
- History of MI (other than the recent ACS event above)
- History of ischemic stroke
- Symptomatic peripheral arterial disease (claudication with ABI < 0.85, or previous revascularization or amputation)

### High-Risk Conditions
- Age >= 65 years
- Heterozygous familial hypercholesterolemia
- History of prior coronary artery bypass surgery or percutaneous coronary intervention outside of the major ASCVD events
- Diabetes mellitus
- Hypertension
- Chronic kidney disease (eGFR 15--59 mL/min/1.73 m2)
- Current smoking
- Persistently elevated LDL-C >= 100 mg/dL (>= 2.6 mmol/L) despite maximally tolerated statin therapy
- History of congestive heart failure

## LDL-C Escalation Pathway in Very High-Risk ASCVD

The following stepwise approach applies to patients classified as very high-risk ASCVD:

1. **Step 1: Maximally tolerated high-intensity statin therapy.**
   - Goal: Reduce LDL-C by >= 50% from baseline.
   - Atorvastatin 40--80 mg/day or Rosuvastatin 20--40 mg/day.

2. **Step 2: If LDL-C remains >= 70 mg/dL (>= 1.8 mmol/L) on maximally tolerated statin, add ezetimibe 10 mg/day** (Class IIa, Level of Evidence B-R).
   - Ezetimibe reduces LDL-C by an additional 13--20%.

3. **Step 3: If LDL-C remains >= 70 mg/dL (>= 1.8 mmol/L) on maximally tolerated statin PLUS ezetimibe, adding a PCSK9 inhibitor may be considered** (Class IIb, Level of Evidence A).
   - **Alirocumab:** 75 mg subcutaneous injection every 2 weeks (may increase to 150 mg every 2 weeks if additional LDL-C reduction needed).
   - **Evolocumab:** 140 mg subcutaneous injection every 2 weeks OR 420 mg subcutaneous injection once monthly.
   - PCSK9 inhibitors reduce LDL-C by 50--60%.
   - Note: Long-term safety beyond 3 years is uncertain. At mid-2018 list prices, PCSK9 inhibitors have low cost-effectiveness ($150,000+ per QALY).

## Non-Very-High-Risk ASCVD (Standard Secondary Prevention)

For patients with clinical ASCVD who do NOT meet very high-risk criteria:

1. **High-intensity statin therapy** (reduce LDL-C by >= 50%) (Class I, Level of Evidence A).
2. If on maximally tolerated statin and LDL-C remains >= 70 mg/dL: Consider adding ezetimibe (Class IIa, Level of Evidence B-R).
3. PCSK9 inhibitors are generally reserved for very high-risk patients.

## Monitoring in Secondary Prevention

- Obtain fasting lipid panel 4 to 12 weeks after statin initiation or dose adjustment (Class I, Level of Evidence A).
- Repeat lipid panel every 3 to 12 months as needed.
- Assess adherence and percentage LDL-C response relative to baseline.
- If expected percentage reduction is not achieved, assess adherence, reinforce lifestyle modifications, and evaluate secondary causes before intensifying therapy.

## Special Populations in Secondary Prevention

### Post-ACS Patients
- High-intensity statin should be initiated or continued during hospitalization for ACS (Class I, Level of Evidence A).
- Reassess LDL-C at 4--12 weeks to determine adequacy of LDL-C percentage reduction.

### Heart Failure With ASCVD
- In patients with NYHA Class II--III heart failure of ischemic origin already on statin, it is reasonable to continue statin therapy (Class IIa, Level of Evidence B-R).
- Do NOT initiate statin therapy for the sole purpose of treating heart failure (Class III: No Benefit, Level of Evidence A).

### Patients on Concurrent Anticoagulation
- In patients with clinical ASCVD on concomitant anticoagulation therapy, consider potential drug interactions. Avoid simvastatin > 20 mg with amiodarone, amlodipine, or ranolazine due to myopathy risk.

## Limitations

- The 2018 guideline does not specify an absolute LDL-C target for secondary prevention; instead, it uses percentage LDL-C reduction and threshold-based escalation.
- PCSK9 inhibitor cost-effectiveness is a significant consideration and may limit access.
- Evidence for statin initiation in secondary prevention patients > 75 years is limited; individualized decision-making is recommended.
