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Acute Coronary Syndrome (ACS) — Comprehensive Overview

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Definition & Classification

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Epidemiology

• ~1.2 million hospitalizations annually in the United States for ACS
• ~two-thirds are NSTE-ACS

• 50% of NSTE-ACS patients are older than 65 years; nearly half are women

• Higher prevalence with atherosclerosis risk factors, peripheral vascular disease, or chronic inflammatory disorders (rheumatoid arthritis, psoriasis)

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Pathobiology

• Supply reduction: hypotension, severe anemia, hypoxemia
• Demand surge: tachycardia, severe hypertension, thyrotoxicosis
• Other causes: cocaine/methamphetamine use, Prinzmetal vasospasm, spontaneous coronary artery dissection (SCAD — especially in peripartum women), chemotherapy agents, or "triptans"

In Type 2 MI, therapy should target the underlying cause.

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Clinical Presentation & Diagnosis

• Older age, diabetes mellitus, extracardiac vascular disease
• Chest pain radiating to the left arm, neck, or jaw
• Symptoms similar to prior anginal episodes in patients with known CAD

• Persistent ST elevation → initiate reperfusion immediately (STEMI pathway)
• ST depression or T-wave inversion in ≥50% of NSTE-ACS
• A normal ECG does not exclude ACS (~5% of discharged patients with ACS had a normal initial ECG)
• Left circumflex territory ischemia may be missed on standard 12-lead → use posterior leads (V7–V9) or right-sided leads
• Deep (>2 mm) symmetrical anterior T-wave inversion → suggests significant LAD or left main stenosis

• High-sensitivity troponin can detect NSTEMI within 2 hours of symptom onset
• Serial troponins are required if initial is normal

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Risk Stratification

• Elevated troponin
• Dynamic ST changes
• Prior PCI or CABG
• Hemodynamic instability
• Sustained ventricular arrhythmias
• Reduced LVEF

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Management

Anti-Ischemic Therapy

• Oxygen: only if SpO₂ <90%
• Nitrates: sublingual → IV for ongoing ischemia/hypertension (avoid if hypotension or recent PDE5 inhibitor use)
• Beta-blockers: early oral therapy reduces ischemia; IV if refractory ischemia/tachycardia (avoid in decompensated HF, active bronchospasm)
• Morphine: cautious use; may mask symptoms and has been associated with adverse outcomes in some registry analyses

Antiplatelet Therapy

• Ticagrelor and prasugrel are more potent than clopidogrel with faster onset; prasugrel is contraindicated in prior stroke/TIA
• DAPT is typically maintained for 12 months post-ACS

Anticoagulation

• 1 mg/kg SC twice daily
• Superior to UFH in high-risk/biomarker-positive NSTE-ACS
• Dose-adjust in obesity (>120 kg), low weight (<60 kg), or CrCl <30 mL/min (target anti-Xa 0.5–1.5 IU/mL)
• Avoid in HIT history

Revascularization

Secondary Prevention (Post-ACS)

• ACE inhibitor / ARB: especially with reduced EF, hypertension, or diabetes
• High-intensity statin: all ACS patients regardless of baseline LDL (target LDL <70 mg/dL; consider <55 mg/dL with ezetimibe or PCSK9 inhibitor if needed)
• Beta-blocker: continue long-term (especially with reduced EF)
• Aldosterone antagonist: LVEF ≤40% with HF symptoms or diabetes
• DAPT for 12 months (duration may vary based on stent type, bleeding risk)
• Cardiac rehabilitation

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Special Considerations

• Consider in patients <40 years or with few risk factors
• Urine toxicology screen; avoid beta-blockers (unopposed alpha stimulation risk)

• ACS is more common and carries higher mortality in CKD patients
• LMWH dose adjustment required
• Contrast nephropathy risk during angiography must be managed (hydration, minimizing contrast)

• Presents as ACS, most often in peripartum women or those with vasculitis
• Conservative management often preferred over PCI

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Key Points Summary

1. ACS = UA + NSTEMI + STEMI; distinguished by troponin and ECG
2. Core mechanism: plaque rupture → thrombus → ischemia/infarction
3. Diagnosis: ECG within 10 min + serial high-sensitivity troponins
4. Rx backbone: aspirin + P2Y₁₂ + anticoagulation + early revascularization
5. STEMI: primary PCI within 90 min is gold standard
6. NSTE-ACS high-risk: invasive strategy within 24 hours
7. Long-term: statin + beta-blocker + ACEi/ARB + DAPT + cardiac rehab

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Acute Coronary Syndrome (ACS): Deep & Wide Update

Aligned with AHA/ACC Guidelines + Recent Trial Evidence

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1. CLASSIFICATION & DEFINITIONS

• Type 1: Plaque rupture/erosion → thrombus → ischemia (classic ACS)
• Type 2: Supply-demand mismatch (tachyarrhythmia, severe anemia, hypotension, cocaine, SCAD, vasospasm)
• Type 3: Sudden cardiac death with presumed MI, no biomarkers available
• Types 4 & 5: PCI-related and CABG-related MI

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2. EPIDEMIOLOGY

• ~1.2 million ACS hospitalizations/year in the US
• ~two-thirds are NSTE-ACS; one-third STEMI

• 50% of NSTE-ACS patients are >65 years; ~45% are women

• Higher risk with atherosclerosis risk factors, peripheral vascular disease, chronic inflammatory diseases (RA, psoriasis), and CKD
• In-hospital STEMI mortality has fallen from ~20% to ~5% over 3 decades with reperfusion strategies

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3. PATHOBIOLOGY

Classic Mechanism (Type 1)

Plaque Instability Factors

• Thin fibrous cap, large lipid core, intraplaque hemorrhage
• Inflammatory infiltration (macrophages, T-lymphocytes)
• Shear stress at bifurcations

Inflammatory Hypothesis (CANTOS Trial — proof of concept)

SCAD (Spontaneous Coronary Artery Dissection)

• Increasingly recognized cause of ACS in peripartum women and patients with fibromuscular dysplasia or vasculitis
• Treated conservatively when possible (avoid PCI unless vessel is compromised, as wire can propagate dissection)

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4. DIAGNOSIS

ECG — Obtain and Interpret Within 10 Minutes (AHA Class I)

• STEMI criteria: ≥1 mm ST elevation in ≥2 contiguous limb leads; ≥2 mm in ≥2 contiguous precordial leads; new LBBB
• NSTE-ACS: ST depression, T-wave inversion, transient ST elevation
• Normal ECG does not exclude ACS (~5% of final ACS diagnoses had normal initial ECG)
• Use posterior leads (V7–V9) for circumflex territory; right-sided leads (V3R, V4R) for right ventricular MI
• Deep (>2 mm) symmetric anterior T-wave inversion = possible LAD/left main critical stenosis (Wellens pattern)
• Serial ECGs every 15–30 minutes in the first hour if initial is non-diagnostic

High-Sensitivity Troponin (hs-cTn) — The Major Diagnostic Advance

• Detects NSTEMI within 1–2 hours of symptom onset (vs 6 hours with conventional assays)
• AHA/ESC now endorse 0h/1h (or 0h/2h) rapid rule-in/rule-out algorithms using hs-cTn
• Rule-out: hs-cTn at 0h very low AND delta at 1h very small → 99% NPV; safe discharge
• Rule-in: absolute hs-cTn >5× URL at 0h OR delta rise ≥5 ng/L at 1h → high probability NSTEMI
• Allows >60% of patients to be triaged within 1–2 hours in the ED

Risk Scores

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5. INITIAL MANAGEMENT (BOTH NSTE-ACS AND STEMI)

Oxygen

• Only if SpO₂ <90% (Class I). Routine high-flow O₂ in normoxemic patients has no benefit and may worsen outcomes (increased coronary resistance from hyperoxia).

Nitrates

• Sublingual → IV for ongoing ischemia, hypertension, or pulmonary edema
• Contraindications: SBP <90 mmHg, HR <50 or >100, right ventricular MI, PDE5 inhibitor use within 24–48h

Analgesia

• Morphine: use is now discouraged in NSTEMI (CRUSADE registry data show association with worse outcomes; may mask symptoms and slow P2Y₁₂ absorption)
• Preferred: titrated IV opioids only if pain is refractory; optimize nitrates first

Beta-Blockers

• Oral beta-blocker within 24 hours in hemodynamically stable patients (Class I)
• IV beta-blocker for refractory ischemia or tachyarrhythmia only
• Avoid in: decompensated HF, active bronchospasm, PR >0.24s, second/third degree AV block, SBP <90 mmHg, cardiogenic shock risk

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6. ANTIPLATELET THERAPY — UPDATED AHA EVIDENCE

Aspirin

• Loading dose 162–325 mg (chewed) → maintenance 75–100 mg daily indefinitely
• AHA Class I for all ACS

P2Y₁₂ Inhibitors — Major Updates

• 18,624 patients; ticagrelor reduced CV death/MI/stroke vs clopidogrel (9.8% vs 11.7%, p<0.001)
• Reduced CV mortality and total mortality; no increase in CABG-related bleeding
• Dyspnea (non-cardiac, usually mild) in ~14% — class effect of ticagrelor
• AHA gives ticagrelor Class I, Level B preference over clopidogrel in NSTE-ACS and STEMI

• Prasugrel superior to clopidogrel in PCI patients; but contraindicated in prior stroke/TIA, age ≥75, or weight <60 kg (excess bleeding)
• Net harm in medically managed patients → restricted to PCI setting

• TWILIGHT Trial: After 3 months of DAPT post-PCI (high-risk ACS/complex PCI), ticagrelor monotherapy (dropping aspirin) reduced BARC 2/3/5 bleeding by 44% vs continued DAPT, with no increase in ischemic events
• GLOBAL LEADERS Trial: Ticagrelor monotherapy after 1 month of DAPT showed non-significant reduction in composite endpoint vs 12-month DAPT + aspirin alone
• AHA/ACC 2023 guidance: After 1–3 months of DAPT post-ACS/PCI, P2Y₁₂ monotherapy (ticagrelor or clopidogrel) is a reasonable strategy in high-bleeding-risk patients (Class IIa)

Duration of DAPT — Updated Evidence

• DAPT Score: Guides extended therapy beyond 12 months (score ≥2 → benefit from extended DAPT)
• Prolonged DAPT (>12 months): May reduce ischemic events in very high-risk patients; weigh against bleeding risk

GP IIb/IIIa Inhibitors (Abciximab, Eptifibatide, Tirofiban)

• Role has markedly diminished with potent P2Y₁₂ inhibitors
• Now reserved for bail-out during PCI (large thrombus burden, no-reflow, thrombotic complication)
• Should NOT be given routinely upstream before angiography — increased bleeding, no outcome benefit
• Initiated at the time of PCI, continued 12–24h post-PCI

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7. ANTICOAGULATION — AHA/ACC FRAMEWORK

All ACS: Anticoagulation Mandatory (unless active major bleeding)

• 1 mg/kg SC BID; reduce to 1 mg/kg SC daily if CrCl <30 mL/min
• Adjust dose by anti-Xa level in obesity (>120 kg), low weight (<60 kg), CKD
• Avoid in HIT history

• Bolus 60 U/kg IV (max 4000 U) → infusion 12 U/kg/hr (max 1000 U/hr)
• Target aPTT 50–70 seconds (1.5–2.5× control)

• Reduced net adverse clinical events vs UFH + GP IIb/IIIa (less bleeding)
• Higher stent thrombosis rate (partially mitigated by prolonged infusion)
• AHA: reasonable alternative in STEMI PCI, especially HBR patients

• AUGUSTUS Trial: In AF patients post-ACS/PCI, apixaban + P2Y₁₂ (without aspirin) reduced bleeding vs VKA-based triple therapy with similar ischemic outcomes
• PIONEER AF-PCI: Rivaroxaban + P2Y₁₂ (without aspirin) also showed less bleeding
• AHA 2023: Triple therapy (OAC + aspirin + P2Y₁₂) only for first 1–4 weeks, then OAC + P2Y₁₂ dual therapy through 12 months; then OAC alone (Class IIa, Level B)

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8. REVASCULARIZATION

STEMI — Time-Sensitive Reperfusion

• AHA/ACC targets: door-to-balloon ≤90 min (PCI-capable hospital) or ≤120 min (transfer from non-PCI hospital)
• "First medical contact to device time" now replaces door-to-balloon
• pPCI reduces mortality, reinfarction, and stroke vs fibrinolysis in 23 RCT meta-analysis
• Preferred over fibrinolysis in all eligible patients when achievable within time limits

• Administer within 10 min of STEMI diagnosis (≤30 min of ED arrival)
• Preferred fibrin-specific agents: Tenecteplase (single weight-based bolus), Alteplase
• In patients >75 years: streptokinase preferred over fibrin-specific agents (less intracranial bleeding risk)
• Fibrinolysis + PCI ("pharmacoinvasive strategy"): If fibrinolysis is given, angiography should follow within 3–24 hours for all patients; emergent PCI if failed reperfusion (ongoing symptoms/ST elevation at 60–90 min)

• Prior intracranial hemorrhage (any time)
• Stroke of unknown type within 6 months
• CNS neoplasm, AVM
• Recent major surgery/trauma/head injury within 3 weeks
• GI bleeding within 1 month
• Suspected aortic dissection
• Non-compressible punctures in last 24h

• Transradial > transfemoral for primary PCI; reduced access-site bleeding, vascular complications, and 30-day mortality (RIVAL, MATRIX trials)

• pPCI should be considered if signs of ongoing ischemia, hemodynamic instability, or arrhythmia
• Stable, asymptomatic patients presenting 12–48h: pPCI still reasonable
• After >48 hours (stable, asymptomatic chronic total occlusion): routine PCI has no benefit over medical management alone (OAT Trial)

• Immediate pPCI of culprit vessel (Class I)
• CULPRIT-SHOCK Trial: PCI of culprit-only vessel at initial procedure is preferred over immediate multivessel PCI in cardiogenic shock — reduced 30-day mortality/RRT composite
• Intra-aortic balloon pump (IABP): no longer routinely recommended (IABP-SHOCK II trial — no mortality benefit)
• Impella or ECMO: used in select refractory shock; evidence still evolving

• COMPLETE Trial: Complete revascularization (staged PCI of non-culprit vessels) during index hospitalization or within 45 days significantly reduced CV death/MI vs culprit-only PCI — AHA Class IIa (now Class I in 2023 update)
• Staged complete revascularization is now the standard of care

NSTE-ACS — Timing of Invasive Strategy

• Preferred over PCI in: left main disease, 3-vessel disease with complex anatomy, diabetes with multivessel disease, reduced LVEF + multivessel disease
• DAPT should be held before CABG: clopidogrel/ticagrelor ≥5 days, prasugrel ≥7 days (aspirin continued)

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9. SECONDARY PREVENTION — POST-ACS PHARMACOTHERAPY

Statins — Intensive LDL Lowering

• High-intensity statin (atorvastatin 40–80 mg or rosuvastatin 20–40 mg) for ALL ACS patients regardless of baseline LDL
• AHA/ACC 2022 Lipid Target: LDL-C <70 mg/dL (Class I); ideally <55 mg/dL in very high-risk
• Add ezetimibe if LDL-C not at goal after 4–6 weeks (Class I, Level B)
• Add PCSK9 inhibitor if still above target (Class I, Level B):
  • Evolocumab (FOURIER Trial): 59% LDL reduction; 15% reduction in CV death/MI/stroke at 2.2 years in post-ACS/CAD patients
  • Alirocumab (ODYSSEY OUTCOMES Trial): In post-ACS patients, alirocumab reduced MACE and all-cause mortality vs placebo; greatest benefit in LDL >100 mg/dL
• Inclisiran (siRNA PCSK9 inhibitor, every 6 months dosing): ORION trials show 50%+ LDL reduction — now approved as adjunct; outcome data pending

Beta-Blockers

• Continue indefinitely post-ACS with reduced EF (LVEF ≤40%)
• In patients with normal EF: evidence for long-term benefit is less robust; AHA recommends ≥3 years; duration tailored to individual
• Carvedilol, metoprolol succinate, bisoprolol preferred

ACE Inhibitors / ARBs

• Start within 24 hours in STEMI or NSTEMI with: LVEF ≤40%, HF, anterior MI, hypertension, or diabetes (Class I)
• ARB substituted if ACE inhibitor intolerant
• ARNI (sacubitril/valsartan): In post-MI patients with LVEF ≤40%, ARNI is superior to ACE inhibitor in preventing HF hospitalization and CV death (PARADISE-MI Trial — sacubitril/valsartan vs ramipril: numerically favored ARNI; AHA 2022 gives Class IIb)

Aldosterone Antagonism (MRA)

• Eplerenone or spironolactone: post-MI with LVEF ≤40% and HF symptoms or diabetes; reduces sudden death and mortality (EPHESUS Trial)
• Finerenone (non-steroidal MRA): primary data in CKD/diabetes; outcomes post-ACS pending

Anti-Inflammatory Therapy — The New Frontier

• ~4,700 post-MI patients (average 30 days post-MI); colchicine 0.5 mg daily vs placebo
• Significant reduction in composite endpoint: CV death, resuscitated cardiac arrest, MI, stroke, urgent angina revascularization (5.5% vs 7.1%, p=0.02)
• Driven primarily by reductions in stroke and urgent revascularization
• Standard of care therapy in background (aspirin, P2Y₁₂, statin, beta-blocker); PCI in 93%

• Colchicine 0.5 mg daily in stable chronic coronary disease (~84% prior ACS)
• Significant reduction in MACE, but non-cardiovascular death was slightly higher in treatment arm (cause uncertain; possible confounding)
• AHA/ACC 2023 Guideline update: Colchicine 0.5 mg daily is a Class IIa recommendation for secondary prevention post-ACS

• Anti-IL-1β antibody; reduced MACE by ~15% in high hs-CRP post-MI patients
• Not FDA-approved for CV indication (excess fatal infections); proof-of-concept for inflammatory mechanism

GLP-1 Agonists in High-Risk CAD/Post-ACS

• LEADER (liraglutide), SUSTAIN-6 (semaglutide), REWIND (dulaglutide): All showed MACE reduction in T2DM patients with established CVD
• Semaglutide specifically reduces MI and stroke; AHA 2023 gives Class I for GLP-1 RA use in T2DM with established ASCVD to reduce CV events

SGLT2 Inhibitors Post-ACS

• EMPA-REG OUTCOME (empagliflozin), CANVAS (canagliflozin), DECLARE-TIMI 58 (dapagliflozin): Significant reductions in CV death and HF hospitalization in T2DM with ASCVD
• DAPA-MI Trial (2023): Dapagliflozin in post-MI patients regardless of diabetes status — reduced development of new-onset T2DM, worsening HF, and atrial fibrillation; awaiting full outcomes data
• AHA Class I for SGLT2i in T2DM + established ASCVD or high CV risk

Cardiac Rehabilitation

• Class I, Level A post-ACS
• Exercise-based rehab reduces CV mortality ~25%, improves functional capacity, quality of life, adherence to medications
• Referral should occur before hospital discharge

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10. SPECIAL POPULATIONS

Elderly Patients (>75 years)

• Atypical presentations more common (dyspnea, fatigue, syncope rather than chest pain)
• Higher risk of bleeding with antiplatelet/anticoagulant therapy; radial access preferred
• pPCI preferred over fibrinolysis (streptokinase over fibrin-specific agents if fibrinolysis must be used)
• After Eighty study: invasive strategy still beneficial even in octogenarians
• Frailty assessment essential: frail patients have disproportionately worse outcomes and need individualized therapy
• Beta-blockers provide greater absolute mortality reduction at older age
• Statins beneficial up to early 80s; evidence thinner beyond age 80

Women

• Underrepresented in major trials (~30% of enrollees)
• More likely to have atypical presentation, older age at ACS, more comorbidities
• Higher bleeding risk with antithrombotic therapy
• More non-obstructive CAD (MINOCA — MI with non-obstructive coronary arteries)
• AHA recognizes sex-specific risk factors: pregnancy complications, premature menopause, autoimmune diseases

CKD and ACS

• ACS is 2–10× more common in CKD; markedly higher mortality
• Troponin interpretation: chronically elevated baseline hs-cTn in CKD — delta change over time most reliable
• Dose-adjust LMWH (anti-Xa monitoring), avoid routine fondaparinux if CrCl <20
• Contrast nephropathy risk: minimize contrast volume, IV hydration (isotonic saline), hold nephrotoxins
• PCSK9 inhibitors are effective and safe regardless of CKD stage (no dose adjustment needed)

MINOCA (MI with Non-Obstructive Coronary Arteries)

• Diagnosed when angiography shows <50% stenosis; accounts for ~5–10% of MI
• Causes: plaque disruption, coronary vasospasm, microvascular dysfunction, SCAD, myocarditis, Takotsubo
• OCT or IVUS useful to identify occult plaque rupture or dissection
• Management: treat underlying cause; ACE inhibitor + statin + aspirin usually initiated

Cocaine/Stimulant-Induced ACS

• Mechanism: vasospasm + thrombosis + increased demand
• Beta-blockers contraindicated (unopposed alpha stimulation worsens vasospasm)
• Benzodiazepines + nitrates first-line; phentolamine (alpha-blocker) if vasospasm predominant
• PCI as needed; fibrinolysis often avoided due to cocaine coagulopathy risk

Takotsubo Cardiomyopathy (Stress Cardiomyopathy)

• Mimics STEMI (ST elevation, troponin elevation) but coronaries are normal/non-obstructive
• Transient apical ballooning; usually triggered by emotional/physical stress
• Managed supportively; most recover within weeks
• LV thrombus risk if apical akinesis — anticoagulate
• AHA: Rule out SCAD and coronary obstruction first; then manage as stress cardiomyopathy

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11. COMPLICATIONS OF ACS

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12. AHA/ACC 2023 GUIDELINE — KEY NEW RECOMMENDATIONS SUMMARY

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13. EMERGING & FUTURE DIRECTIONS

• Lipoprotein(a) [Lp(a)]: Strong independent risk factor for ACS; not modifiable by statins or PCSK9i. Pelacarsen (antisense Lp(a) inhibitor) and olpasiran (siRNA) in late-phase trials (HORIZON, OCEAN-a studies)
• Anti-inflammatory combinations: Colchicine + statin + PCSK9i combinations under study
• Oral FXa inhibitors for secondary prevention: ATLAS-ACS 2 TIMI 51 — rivaroxaban 2.5 mg BID added to DAPT reduced CV death/MI/stroke (15% RRR) but increased bleeding; use in select high-ischemic/low-bleeding-risk patients post-ACS
• SMART-DATE/STOPDAPT trials: 6-month DAPT followed by P2Y₁₂ monotherapy may be adequate even post-ACS PCI in East Asian populations
• AI-aided ECG interpretation: Emerging tools for automated STEMI-equivalent recognition (e.g., posterior MI, Wellens)
• High-sensitivity troponin point-of-care testing: Moving toward 30-minute rule-out algorithms in pre-hospital and community settings

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• Goldman-Cecil Medicine International Edition, Ch. 57–58
• Fuster and Hurst's The Heart, 15th Edition, Ch. 18
• Braunwald's Heart Disease, 2-Vol Set, Ch. 101 & 13
• Tintinalli's Emergency Medicine, Ch. 49
• PLATO, TRITON-TIMI 38, TWILIGHT, COMPLETE, COLCOT, LoDoCo2, CANTOS, CULPRIT-SHOCK, FOURIER, ODYSSEY OUTCOMES, AUGUSTUS, PARADISE-MI, After Eighty, VERDICT trialsThat's a complete deep-dive across all 13 domains. Here's a quick orientation to the content above:

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