How to reduce the risk of Major Adverse Cardiovascular Events (MACE)?

Reducing Major Adverse Cardiovascular Events (MACE)

To reduce MACE, implement a comprehensive cardiovascular risk reduction strategy centered on high-intensity statin therapy, antiplatelet therapy, blood pressure control targeting <130/80 mmHg, and in patients with type 2 diabetes and established atherosclerotic disease, add SGLT2 inhibitors or GLP-1 receptor agonists regardless of glycemic control needs. 1

Core Pharmacologic Interventions

Lipid Management

• Initiate high-intensity statin therapy immediately (atorvastatin 40-80 mg or rosuvastatin 20-40 mg daily) to reduce MACE by approximately 15% compared to moderate-intensity statins 1, 2
• Add ezetimibe if LDL-C remains ≥70 mg/dL on maximally tolerated statin therapy, which provides additional MACE reduction over 6 years 1
• Consider adding PCSK9 inhibitors for patients with LDL-C ≥70 mg/dL despite statin plus ezetimibe, achieving 15% relative risk reduction in MACE over 2-3 years 1
• For patients with LDL-C 55-69 mg/dL on maximally tolerated statin, adding nonstatin therapy is reasonable for further MACE reduction 1

Antiplatelet Therapy

• Prescribe aspirin 75-100 mg daily for all patients with established atherosclerotic disease to reduce MACE 3, 4
• Clopidogrel 75 mg daily is an alternative for aspirin-intolerant patients or may be preferred in peripheral artery disease 3, 5
• For high-risk PAD patients (prior amputation, CLTI, previous revascularization, heart failure, diabetes, multivessel disease, or eGFR <60), add rivaroxaban 2.5 mg twice daily to aspirin 100 mg daily to reduce both MACE and major adverse limb events by 24-28% 5
• Avoid long-term dual antiplatelet therapy (aspirin + clopidogrel) beyond 12 months post-ACS or 6 months post-revascularization due to bleeding risk without additional MACE benefit 5

Blood Pressure Management

• Target systolic BP <130 mmHg and diastolic BP <80 mmHg in all patients with atherosclerotic disease to reduce MACE 4
• Initiate ACE inhibitors or ARBs as first-line therapy in patients with hypertension and established atherosclerotic disease, which reduced MI, stroke, or vascular death by 25% in the HOPE trial 4
• Beta-blockers are not contraindicated in PAD and should be continued for at least 2 years post-MI 1, 4

Diabetes-Specific Therapies

• In patients with type 2 diabetes and established ASCVD or high cardiovascular risk, add SGLT2 inhibitors or GLP-1 receptor agonists to reduce MACE by 14% independent of glucose-lowering effects 1
• Specific agents with proven MACE reduction include dulaglutide, liraglutide, and injectable semaglutide (GLP-1 RAs), and empagliflozin, canagliflozin, and dapagliflozin (SGLT2 inhibitors) 1
• Combining SGLT2 inhibitors with GLP-1 receptor agonists is encouraged for synergistic cardiovascular and renal benefits 1
• Target HbA1c reduction of 0.9% or more amplifies MACE benefit, as each 1% increase in HbA1c confers 14.2% increased relative risk of MACE 1, 6

Additional Risk Reduction Strategies

Vaccination

• Administer annual influenza vaccination, which reduces cardiovascular events by approximately 37% in patients with established CVD 1
• Complete SARS-CoV-2 vaccination series including boosters, as patients with cardiovascular comorbidities have higher risk for thrombotic events and death with COVID-19 infection 1

Lifestyle Modifications

• Implement supervised exercise therapy for patients with symptomatic PAD, which demonstrated superior treadmill walking performance compared to primary stenting at 6 months in the CLEVER study 1
• Prescribe Mediterranean diet supplemented with extra-virgin olive oil or nuts, which significantly lowered MACE risk in high cardiovascular risk patients in the PREDIMED study 1
• Mandate smoking cessation as a critical intervention for all patients with atherosclerotic disease 1, 4

Anti-inflammatory Therapy

• Consider colchicine 0.5 mg daily in patients with established atherosclerotic disease or multiple risk factors, which reduces MI, stroke, coronary revascularization, and cardiovascular death 1
• Icosapent ethyl (IPE) may be considered in patients with triglycerides >135 mg/dL who have diabetes or ASCVD, as it reduces inflammation and MACE 1

Risk Stratification for Treatment Intensity

Very High Risk (>20% 5-year MACE risk)

Patients with established cardiovascular disease, prior MI, stroke, PAD with CLTI, or multiple vascular bed involvement 1, 7:

• Maximally intensive lipid therapy: high-intensity statin + ezetimibe + PCSK9 inhibitor if LDL-C ≥70 mg/dL 1
• Dual pathway inhibition (rivaroxaban 2.5 mg BID + aspirin) if high ischemic risk PAD without high bleeding risk 5
• SGLT2 inhibitor + GLP-1 RA if diabetic 1

High Risk (15-20% 5-year MACE risk)

Patients with ≥5 cardiovascular risk factors or familial hyperlipidemia 1:

• High-intensity statin + ezetimibe if LDL-C ≥70 mg/dL 1
• Single antiplatelet therapy 3
• ACE inhibitor or ARB for BP control 4

Moderate Risk (5-15% 5-year MACE risk)

Patients with 3-4 cardiovascular risk factors 1:

• High-intensity statin therapy 1
• Consider ezetimibe if LDL-C remains elevated 1
• Aggressive risk factor modification 1

Critical Pitfalls to Avoid

• Never use full-intensity oral anticoagulation monotherapy for PAD without another indication (e.g., atrial fibrillation), as it increases bleeding without reducing MACE or limb events 5
• Do not continue dual antiplatelet therapy beyond 12 months post-ACS or 6 months post-revascularization without specific high-risk features, as bleeding risk outweighs benefit 5
• Avoid de-escalating high-intensity statin therapy in patients tolerating treatment, even if very low LDL-C levels are achieved, as no safety concerns exist and benefit persists 1
• Do not withhold beta-blockers in patients with PAD and claudication, as they do not worsen walking capacity or limb events 4
• Monitor renal function closely when using ACE inhibitors or ARBs, particularly in bilateral renal artery stenosis 4

Monitoring and Follow-up

• Reassess lipid levels 4-12 weeks after initiating or adjusting lipid therapy, targeting LDL-C <70 mg/dL (ideally <55 mg/dL in very high-risk patients) 1
• Evaluate ischemic and bleeding risk at every follow-up visit for patients on dual pathway inhibition 5
• Monitor for bleeding complications particularly in the first 3 months of dual pathway therapy 5
• Assess clinical and functional status, medication adherence, and limb symptoms at least annually in PAD patients 5