Cardionerds: A Cardiology Podcast

CardioNerds (Drs. Billy Joe Mullinax, Dinu Balanescu, and Saahil Jumkhawala) discuss the 2026 American Heart Association (AHA)/American College of Cardiology (ACC) multisocietal guidelines for the evaluation and management of acute pulmonary embolism (PE) with Dr. Mark Creager, Director Emeritus of the Heart and Vascular Center at Dartmouth Health, past president of the AHA, and Chair of the Writing Committee for the 2026 AHA/ACC PE Guidelines. Audio editing by CardioNerds intern, Dr. Patrick Pekyi-Boateng.

Pulmonary embolism is one of the most rapidly evolving conditions in cardiovascular medicine. The 2026 AHA/ACC multisocietal guideline, endorsed by ten professional societies, is the first de novo comprehensive guideline dedicated exclusively to acute PE in adults. It introduces a new five-category A-E risk classification system, a Class I recommendation for the Pulmonary Embolism Response Team (PERT), updated guidance on anticoagulation and advanced reperfusion therapies, and a structured framework for post-PE follow-up and chronic thromboembolic pulmonary hypertension (CTEPH) screening. This episode walks through all of it, using a high-risk clinical case as the backbone.

Dr. Dinu Balanescu and Dr. Billy-Joe Mullinax are Co-chairs for the CardioNerds PE Series, developed in collaboration with the PERT Consortium.  

Enjoy this Circulation 2022 Paths to Discovery article to learn about the CardioNerds story, mission, and values.

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Pearls:

The 2026 guideline replaces “massive/submassive/low-risk” language with a new five-category A-E classification. Category A is subclinical/incidental PE; B is symptomatic with a low clinical severity score; C1-C3 stratifies intermediate-risk patients by right ventricular (RV) function and biomarkers; D1-D2 captures incipient cardiopulmonary failure (transient hypotension vs. normotensive shock with end-organ dysfunction); and E1-E2 is frank cardiopulmonary failure up to cardiac arrest. Each category carries a respiratory modifier (R) for hypoxemia, tachypnea, or need for supplemental oxygen.

PERT receives a Class I recommendation. Registry data show PERT reduces time to therapeutic anticoagulation, decreases unnecessary inferior vena cava (IVC) filter use, and shortens hospital and intensive care unit (ICU) length of stay. PERT is most impactful when advanced therapy decisions are on the table.

Low molecular weight heparin (LMWH) is now preferred over unfractionated heparin (UFH) for initial parenteral anticoagulation in most patients (Category C and above), given superior venous thromboembolism (VTE) recurrence reduction, predictable pharmacokinetics, no routine monitoring, and lower heparin-induced thrombocytopenia (HIT) risk. UFH is still preferred when imminent reperfusion is planned, in severe renal failure, or when rapid reversal may be needed. Categories A and B go straight to a direct oral anticoagulant (DOAC).

Advanced reperfusion therapies – systemic thrombolysis, catheter-directed thrombolysis (CDT), mechanical thrombectomy (MT), and surgical embolectomy – carry Class 2B recommendations for Category D PE because available trials used surrogate endpoints only. HI-PEITHO, which showed a composite 7-day benefit for CDT plus anticoagulation vs. anticoagulation alone, was published in March 2026 after guideline lock and could not influence the current document. More trials are coming (PEERLESS 2, PE-TRACT, PERSEVERE, TORPEDO).

Post-PE follow-up is now structured: outreach within 1 week of discharge, office visit with a PE-experienced clinician by 3 months, and active chronic thromboembolic pulmonary disease (CTEPD) and CTEPH screening at every visit for at least 1 year. Persistent symptoms or functional limitation beyond 3 months should trigger evaluation with a ventilation-perfusion (V/Q) scan, echocardiogram, and right heart catheterization (RHC).

Notes:

Notes drafted by Dr. Saahil Jumkhawala.

Why did the writing committee believe a new classification system was necessary in 2026?

The 2011 AHA scientific statement used “low-risk,” “submassive,” and “massive” categories – broad, imprecise, and insufficient for guiding modern management decisions. The 2019 European Society of Cardiology (ESC) guideline improved on this with low, intermediate-low, intermediate-high, and high-risk categories, but still did not capture many clinical, imaging, and laboratory variables with reliable prognostic data.

The writing committee wanted a classification system that:

Was more nuanced and captured the full clinical spectrum of PE severity

Incorporated the clinical, laboratory, and imaging variables with the strongest outcome data

Mapped directly to management decisions and could serve as a shared communication tool

The result is a five-category A-E system with subcategories and a respiratory modifier, easier to memorize and use in practice.

How do we apply the new five-category system at the bedside? What data points drive category assignment, and what is the significance of the respiratory modifier?

Category A – Subclinical/Incidental PE

Asymptomatic; PE found incidentally (e.g., on staging computed tomography (CT) for cancer)

Often subsegmental; typically appropriate for outpatient management

Category B – Symptomatic, Low Severity

Chest pain or dyspnea, but simplified Pulmonary Embolism Severity Index (sPESI) = 0

B1: subsegmental PE; B2: non-subsegmental PE

Outpatient management appropriate unless confounding comorbidity present

Category C – Symptomatic, Elevated Severity Score (analogous to ESC intermediate risk)

C1: normal RV size/function, normal biomarkers

C2: abnormal RV function OR elevated biomarker (one of the two)

C3: both abnormal RV function AND at least one elevated biomarker

Respiratory modifier (R): oxygen saturation (SpO2) <90%, respiratory rate (RR) >30, or need for supplemental O2

Category D – Incipient Cardiopulmonary Failure

D1: transient hypotension (systolic blood pressure (SBP) <90 mmHg, but responsive/self-resolving)

D2: normotensive shock – SBP >90 mmHg but with end-organ dysfunction (elevated lactate, rising creatinine)

Respiratory modifier (R): >6 L nasal cannula O2 or non-rebreather mask required

Category E – Frank Cardiopulmonary Failure

E1: recurrent or persistent hypotension with cardiogenic shock

E2: refractory cardiogenic shock or cardiac arrest

Respiratory modifier (R): hypoxemic or ventilatory respiratory failure

Mr. Osis (our case patient): tachycardic, transient SBP 84 mmHg, lactate 3.4, requiring 3L O2 – classified as D1R.

What is the evidence behind the Class I PERT recommendation, and when should PERT be involved in the context of the new triage system?

PERT provides:

Improved risk stratification through multidisciplinary input

Expert guidance on selection and timing of advanced therapies

Implementation of evidence-based protocols

Education of the broader care team

PERT composition varies by institution but may include: pulmonary/critical care, general cardiology, interventional cardiology, cardiac surgery, vascular surgery, hematology/oncology, emergency medicine, and pharmacy.

Published data supporting Class I recommendation:

Reduced time to therapeutic anticoagulation

Decreased unnecessary IVC filter placement

Shorter hospital and ICU length of stay

Possible mortality reduction (data conflicting across registries)

PERT is most impactful in Category C3 and above, particularly when advanced therapy decisions are being contemplated – though the guideline does not restrict PERT activation to any specific category threshold.

What does the 2026 guideline say about initial anticoagulation choice (UFH vs. LMWH)?

LMWH is the preferred initial parenteral anticoagulant for most patients with acute PE (Category C and above).

Meta-analytic evidence: LMWH reduces recurrent VTE more effectively than UFH without increasing bleeding

Predictable pharmacokinetics – no routine activated partial thromboplastin time (aPTT) monitoring required

Lower incidence of HIT

UFH is preferred when:

Imminent advanced reperfusion is anticipated (systemic lysis, MT, surgical embolectomy, or extracorporeal membrane oxygenation (ECMO) cannulation)

Severe renal dysfunction (unpredictable LMWH pharmacokinetics)

Rapid reversibility needed

Categories A and B: proceed directly to a DOAC (no parenteral bridge needed).

DOACs are preferred over vitamin K antagonists (VKA) for long-term therapy in most patients, including most with cancer-associated PE.

Exception: LMWH preferred for luminal gastrointestinal (GI) or genitourinary (GU) malignancies due to bleeding risk

DOACs are contraindicated in pregnancy; LMWH is generally used throughout gestation and for at least 6 weeks postpartum

How does the guideline navigate Category D1-D2 patients? What is the evidence base for the Class 2B recommendation for advanced therapies, and how do we choose between CDT and MT?

All advanced reperfusion therapies carry a Class 2B recommendation for Category D PE:

Class 2B = “may be considered” – the intervention can be used, but evidence is less certain

Applies to: systemic thrombolysis, CDT, MT, and surgical embolectomy

Why Class 2B? Available trials at the time of guideline finalization (early fall 2025) relied on surrogate endpoints:

ULTIMA: CDT vs. anticoagulation alone – surrogate RV/LV ratio endpoint

OPTALYSE: CDT dose-finding – surrogate endpoints

STORM-PE: surrogate endpoints

PEERLESS (New England Journal of Medicine, 2024): MT vs. CDT – included mortality, intracranial hemorrhage (ICH), major bleed, ICU admission, but was not vs. anticoagulation alone

HI-PEITHO (published March 2026 at the ACC annual meeting – after guideline lock):

7-day composite of PE-related death, clinical decompensation/collapse, or PE recurrence

Primary outcome favored CDT plus anticoagulation vs. anticoagulation alone

Composite driven primarily by clinical decompensation/collapse

Could not be incorporated into current recommendations

Upcoming trials expected to provide hard-outcome data: PEERLESS 2, PE-TRACT, PERSEVERE, TORPEDO.

For Mr. Osis (post-op day 2, fresh anastomosis): systemic lysis and CDT carry high bleeding risk. MT is the most attractive option if hemodynamic deterioration progresses; anticoagulation alone with close monitoring is reasonable if he remains stable.

In a Category E patient with major bleeding contraindications, how does the guideline structure the decision between systemic lysis, catheter-based therapies, surgical embolectomy, and venoarterial (VA)-ECMO?

Category E1 (persistent hypotension with cardiogenic shock) – four options:

Systemic thrombolysis: Class I in the absence of contraindications (alteplase 100 mg over 2 hours)

CDT: Class 2B; a bleeding-conscious alternative to systemic lysis

MT: Class 2A for selected E1 patients

Surgical pulmonary embolectomy: Class 2A for selected E1; Class 2B in Category D when lysis fails or is contraindicated; preferred when cardiac surgery resources are available, and there is obstructing right heart thrombus or patent foramen ovale (PFO) clot

VA-ECMO: explicitly endorsed in the 2026 guideline as a bridge to recovery, lysis-after-stabilization, MT, or surgical embolectomy in refractory cardiopulmonary collapse. Best outcomes when initiated early (pre-arrest is better than peri-arrest).

Reduced-dose thrombolysis (25-50 mg alteplase): considered in patients with moderate bleeding risk; possible improvement in RV function with less bleeding, though mortality benefit unproven.

Temporary mechanical circulatory support (MCS) – including Impella RP, ProtekDuo, and surgical right ventricular assist device (RVAD) – may bridge selected patients with refractory RV failure; data are observational and best deployed at centers with dedicated PE or shock teams.

For Mr. Osis (post-op day 2 with fresh anastomosis): systemic lysis and CDT are essentially contraindicated. The PERT decision favored MT on VA-ECMO, which is consistent with the 2026 guideline framework for Category E patients with major bleeding contraindications.

What is the structure of post-PE follow-up, and how do we approach anticoagulation duration in a patient with cancer-associated PE?

Within 1 week of discharge: outreach or clinic visit (at minimum a phone call) to confirm anticoagulation adherence, assess for bleeding, and review symptoms.

By 3 months: in-person office visit with a PE-experienced clinician to assess symptom trajectory and determine anticoagulation duration.

Provoked PE with a resolved transient risk factor: 3-6 months is generally sufficient

Unprovoked PE or persistent risk factors: extended anticoagulation generally warranted

Cancer-associated PE: continue anticoagulation while cancer is active or under treatment (Class I)

At every visit for at least 1 year: actively screen for CTEPD/CTEPH – ask about exertional dyspnea, fatigue, and functional decline.

PERT or post-PE clinic models are associated with better adherence to follow-up and earlier CTEPH detection in registries.

When does residual dyspnea after PE trigger a structured CTEPH workup, and what is the recommended diagnostic pathway?

Approximately 50% of patients have residual symptoms at 3 months post-PE.

After 3 months of therapeutic anticoagulation, persistent dyspnea or functional limitation triggers evaluation for CTEPD (chronic thromboembolic pulmonary disease) – this is a Class I recommendation.

Diagnostic pathway:

Echocardiogram: persistent RV dysfunction is a Class 2A indication for further evaluation

V/Q scan: first-line imaging for CTEPH evaluation

CT pulmonary angiography (CTPA): confirmatory imaging

RHC: required to confirm CTEPH (mean pulmonary arterial pressure (PAP) >20 mmHg with pulmonary vascular resistance (PVR) >2 Wood units (WU) on anticoagulation)

Cardiopulmonary exercise test (CPET): Class 2A option for patients with functional limitation but no overt pulmonary hypertension (PH) (CTEPD without H)

Confirmed CTEPH: refer to an expert center for pulmonary endarterectomy (PEA) candidacy assessment, balloon pulmonary angioplasty (BPA), or PH-targeted medical therapy (riociguat, treprostinil).

For Mr. Osis at 3 months (tricuspid annular plane systolic excursion (TAPSE) 16 mm, estimated pulmonary artery systolic pressure (PASP) 48 mmHg, exertional dyspnea): V/Q scan and RHC are indicated, with referral to a CTEPH center given high pre-test probability.

Special populations: PE in pregnancy, cancer-associated PE, clot-in-transit, and IVC filters.

Pregnancy:

DOACs and warfarin are contraindicated (fetal harm, miscarriage risk)

LMWH is preferred throughout pregnancy and for at least 6 weeks postpartum

Anti-Xa monitoring is recommended in patients at weight extremes or with renal disease

After delivery, LMWH or warfarin can be continued; insufficient data on DOACs in breastfeeding

Cancer-associated PE:

DOACs (apixaban, edoxaban, rivaroxaban) are first-line for most patients

LMWH preferred for luminal GI or GU malignancies due to mucosal bleeding risk

Long-term management: reduced-dose apixaban (2.5 mg twice daily) or rivaroxaban after the initial treatment period may be considered

Continue anticoagulation while cancer is active

Clot-in-transit (right heart thrombus):

High-risk finding warranting active intervention

Guideline endorses mechanical or surgical thrombectomy for removal

IVC filters:

Indicated only when anticoagulation is contraindicated in the setting of acute PE

Use retrievable filters with a planned removal strategy

Routine IVC filter use is not recommended – PERT implementation has already driven down unnecessary filter use significantly

References:

Creager MA, et al. 2026 AHA/ACC/ACCP/ACEP/CHEST/SCAI/SHM/SIR/SVM/SVN Guideline for the Evaluation and Management of Acute Pulmonary Embolism in Adults. J Am Coll Cardiol. 2026. Available at: https://www.jacc.org/

Konstantinides SV, et al. 2019 ESC Guidelines for the diagnosis and management of acute pulmonary embolism. Eur Heart J. 2020;41(4):543-603. doi:10.1093/eurheartj/ehz405. Available at: https://pubmed.ncbi.nlm.nih.gov/31504429/

Jaff MR, et al. Management of Massive and Submassive Pulmonary Embolism, Iliofemoral Deep Vein Thrombosis, and Chronic Thromboembolic Pulmonary Hypertension: A Scientific Statement From the American Heart Association. Circulation. 2011;123(16):1788-1830. doi:10.1161/CIR.0b013e318214914f. Available at: https://pubmed.ncbi.nlm.nih.gov/21422387/

Piazza G, et al; HI-PEITHO Investigators. Catheter-Directed Thrombolysis in Intermediate-High-Risk Pulmonary Embolism. N Engl J Med. 2026. Available at: https://www.nejm.org/doi/10.1056/NEJMoa2503980

Bhatt DL, et al; PEERLESS Investigators. Mechanical Thrombectomy for Intermediate-Risk Pulmonary Embolism. N Engl J Med. 2024;391:2099-2110. doi:10.1056/NEJMoa2407772. Available at: https://pubmed.ncbi.nlm.nih.gov/39555838/

Creager MA, Geary J, Barnes J. Evidence and Future Directions in Acute Pulmonary Embolism Management. J Am Coll Cardiol. 2026. Available at: https://www.jacc.org/

This episode is part of our comprehensive Decipher the Guidelines Series covering the 2025 ACC/AHA/ACEP/NAEMSP/SCAI Guideline for the Management of Patients With Acute Coronary Syndromes.

The following question refers to Section 4.4 of the 2025 ACS Guidelines.

The question is asked by Thomas Jefferson medical student and CardioNerds Academy Intern Dr. Grace Qiu, answered first by University of Miami cardiology fellow and member of the CardioNerds Interventional Cardiology Council Dr. Saahil Jumkhawala, and then by expert faculty Dr. Binita Shah.

Dr. Binita Shah is an associate professor of medicine, interventional cardiologist, Director for research in Interventional Cardiology, and Director of the Department of Medicine Clinical Investigator Track at NYU. She is also an associate director of interventional cardiology and director of the transcatheter valve program at the VA New York Harbor Healthcare System. She was a member of the 2025 ACS Guidelines writing committee.





Question #6

A 64-year-old male with a history of hypertension and dyslipidemia presents to the emergency department with crescendo angina. His ECG shows ST-segment depression in leads V4–V6, and high-sensitivity troponin levels are significantly elevated. A diagnosis of NSTE-ACS is made, and the patient is scheduled for an early invasive strategy with percutaneous coronary intervention (PCI). Which of the following parenteral anticoagulants is NOT recommended for use as a standalone agent during the PCI procedure itself?

A

Fondaparinux

B

Bivalirudin

C

Unfractionated Heparin

D

Enoxaparin





Answer #6

Explanation

The correct answer is A. 

The choice of parenteral anticoagulation for a patient with Non-ST-Elevation Acute Coronary Syndrome (NSTE-ACS) undergoing Percutaneous Coronary Intervention (PCI) is governed by both efficacy in preventing ischemic events and the safety profile regarding bleeding.

The following are the recommended Agents for PCI:

Unfractionated Heparin (UFH): In patients with NSTE-ACS, intravenous unfractionated heparin (UFH) is useful to reduce ischemic events (Class 1, LOE C-EO).

Bivalirudin: This direct thrombin inhibitor is recommended as an alternative to UFH. In patients with NSTE-ACS undergoing PCI, bivalirudin may be reasonable as an alternative to UFH to reduce bleeding and mortality (Class 2b, LOE B-R)

Enoxaparin: In patients with ACS, intravenous enoxaparin may be considered as an alternative to UFH at the time of PCI to reduce ischemic events (Class 2B, LOE B)

In patients with ACS, fondaparinux should not be used to support PCI because of the risk of catheter thrombosis (Class 3: Harm; LOE B-R). The primary reason is due to the risk of catheter thrombosis. Large-scale trials (notably the OASIS-5 trial) demonstrated that using fondaparinux alone during PCI led to a significantly higher rate of thrombus formation on the diagnostic and therapeutic catheters. In the OASIS-5 trial, an increase was observed in the rate of catheter-related thrombus with fondaparinux compared with enoxaparin (0.9% versus 0.4%). Similar results were observed in the OASIS-6 trial, in which a higher rate of guiding-catheter thrombosis and more coronary complications with fondaparinux were observed when used during PCI.

Main Takeaway

– Parenteral anticoagulation for a patient with Non-ST-Elevation Acute Coronary Syndrome (NSTE-ACS) undergoing Percutaneous Coronary Intervention (PCI) is governed by both efficacy in preventing ischemic events and the safety profile regarding bleeding.

Expert Suggestions

When to consider AC other than UFH prior to and during PCI.

Considerations around patients with HIT.

Guideline Loc.

Section 4.4

This episode is part of our comprehensive Decipher the Guidelines Series covering the 2025 ACC/AHA/ACEP/NAEMSP/SCAI Guideline for the Management of Patients With Acute Coronary Syndromes.

The following question refers to Section 4.3 of the 2025 ACS Guidelines.

The question is asked by Thomas Jefferson medical student and CardioNerds Academy Intern Dr. Grace Qiu, answered first by Cleveland Clinic interventional and structural cardiology fellow and member of the CardioNerds Interventional Cardiology Council Dr. Eunice Dugan, and then by expert faculty Dr. Binita Shah.

Dr. Binita Shah is an associate professor of medicine, interventional cardiologist, Director for research in Interventional Cardiology, and Director of the Department of Medicine Clinical Investigator Track at NYU. She is also an associate director of interventional cardiology and director of the transcatheter valve program at the VA New York Harbor Healthcare System. She was a member of the 2025 ACS Guidelines writing committee.





Question #5

A 64-year-old woman with NSTE-ACS is taken to the cardiac catheterization laboratory. She is P2Y12 inhibitor-naive as she was unable to tolerate oral intake due to severe nausea and vomiting. Coronary angiography reveals a high-grade, thrombotic lesion in the mid-Right Coronary Artery. The interventionalist decides to initiate an intravenous P2Y12 inhibitor before proceeding with PCI. Which of the following is the most appropriate management strategy?

A

Administer Cangrelor as a 30 mcg/kg IV bolus followed by a 4 mcg/kg/min infusion for at least 2 hours or the duration of PCI, whichever is longer.

B

Administer Eptifibatide (GP IIb/IIIa inhibitor) as a routine double-bolus followed by an infusion to replace the need for P2Y12 inhibition.

C

Delay the procedure for 2 hours to allow for the administration and absorption of 600 mg of oral Clopidogrel.

D

Administer Cangrelor as a 180 mcg/kg bolus followed by a 2 mcg/kg/min infusion for exactly 1 hour.





Answer #5

Explanation

The correct answer is A. 

Cangrelor is the only intravenous P2Y12 inhibitor currently available. It is a direct-acting, intravenous antagonist of the P2Y12 receptor characterized by rapid and potent platelet inhibitory effects, with restoration of platelet function occurring within 1 hour of drug discontinuation. It also has a very short half-life (3–6 minutes).

Among patients with ACS undergoing PCI who have not received a P2Y12 inhibitor, intravenous cangrelor may be reasonable to reduce periprocedural ischemic events (Class 2B; LOE B-R).

Dosing Strategy:

Bolus: 30mcg/kg IV bolus administered rapidly (under 1 minute) before PCI begins.

Infusion: 4 mcg/kg/min IV infusion.

Duration: The infusion must run for at least 2 hours or for the duration of the PCI, whichever is longer.

Transition to Oral Therapy:

Ticagrelor: 180mg can be given at any time (during or after the infusion).

Prasugrel/Clopidogrel: loading dose must be given immediately after the infusion is stopped. Giving these earlier can lead to a drug-drug interaction where the Cangrelor prevents the active metabolite from binding to the receptor.

In the CHAMPION PHOENIX trial, cangrelor was studied versus clopidogrel in patients undergoing PCI for acute or stable coronary syndromes. Cangrelor was administered as an intravenous bolus prior to PCI followed by an infusion for at least 2 hours or for the duration of the procedure, whichever was longer. In the control arm, clopidogrel was administered as a 600- or 300-mg loading dose immediately before or after PCI. At 48 hours, the primary endpoint of all- cause death, MI, ischemia-driven revascularization, or stent thrombosis was significantly reduced with cangrelor, with similar effects observed among those presenting with NSTE-ACS or STEMI.

Glycoprotein IIb/IIIa receptor inhibitors are parenterally administered drugs that block platelet aggregation by preventing platelet cross-linking via fibrinogen or von Willebrand factor binding to the glycoprotein IIb/IIIa receptor. Routine administration of GP IIb/IIIa inhibitors before PCI is not recommended and is associated with increased bleeding without improving ischemic outcomes. (Class 3 – No Benefit). In

current practice, the role of glycoprotein IIb/IIIa receptor inhibitors is largely limited to adjunctive use at the time of PCI in patients with large thrombus burden or as

“rescue” or “bailout” therapy in patients with PCI complications such as no-reflow or persistent or recurring thrombus at the lesion.

B is incorrect. Routine “upstream” or periprocedural use of GP IIb/IIIa inhibitors (GPI) is Class 3 (No Benefit) for most patients. Large trials (like EARLY-ACS) showed that routine GPI use significantly increases major bleeding without a proportional decrease in ischemic events compared to modern P2Y12 inhibitors. 

C is incorrect. In patients with NSTE-ACS or STEMI who are already in the lab, delaying the procedure to wait for oral drug absorption is not recommended. 

D is incorrect. The correct bolus is 30mcg/kg. Cangrelor must be infused for at least 2 hours or the duration of the PCI, whichever is longer. Stopping at 1 hour would leave a “gap” in platelet inhibition before an oral agent can take effect. Because Cangrelor’s half-life is only 3–6 minutes, a premature stop increases the risk of acute stent thrombosis.

Main Takeaway

Cangrelor may be reasonable among patients with ACS undergoing PCI who have not received a P2Y12 inhibitor to reduce periprocedural ischemic events (Class 2b, LOE B-R).

Guideline Loc.

Section 4.3.3-4.3.4

This episode is part of our comprehensive Decipher the Guidelines Series covering the 2025 ACC/AHA/ACEP/NAEMSP/SCAI Guideline for the Management of Patients With Acute Coronary Syndromes.

The following question refers to Sections 4.3.2 and 4.4 of the 2025 ACS Guidelines.

The question is asked by Thomas Jefferson medical student and CardioNerds Academy Intern Dr. Grace Qiu, answered first by University of Miami cardiology fellow and member of the CardioNerds Interventional Cardiology Council Dr. Saahil Jumkhawala, and then by expert faculty Dr. Binita Shah.

Dr. Binita Shah is an associate professor of medicine, interventional cardiologist, Director for research in Interventional Cardiology, and Director of the Department of Medicine Clinical Investigator Track at NYU. She is also an associate director of interventional cardiology and director of the transcatheter valve program at the VA New York Harbor Healthcare System. She was a member of the 2025 ACS Guidelines writing committee.





Question #4

A 78-year-old man with a history of hypertension and controlled type 2 diabetes presents to a rural emergency department with 90 minutes of persistent, crushing, substernal chest pain. His ECG reveals 3-mm STE in leads V1 through V4. The nearest PCI-capable center is approximately 140 minutes away by ground transport, and air transport is unavailable due to weather. The patient refuses transfer to another facility for the duration of this admission. The clinical team decides to proceed with fibrinolytic therapy using weight-based Tenecteplase (TNK). Which of the following is the most appropriate initial antithrombotic regimen to accompany the fibrinolytic agent?

A

Clopidogrel 300 mg loading dose; Enoxaparin 30 mg IV bolus followed by 1.0 mg/kg SC every 12 hours.

B

Clopidogrel 75 mg (no loading dose); Enoxaparin 0.75 mg/kg SC every 12 hours (no IV bolus).

C

Ticagrelor 180 mg loading dose; Unfractionated heparin (UFH) weight-based IV bolus and infusion.

D

Prasugrel 10mg (no loading dose); Fondaparinux 2.5 mg IV bolus followed by 2.5 mg SC daily.





Answer #4

Explanation

(3-8 min to read)

The correct answer is B. 

Clopidogrel is the only P2Y12 inhibitor with a Class 1 recommendation for use alongside fibrinolytic therapy to reduce death and MACE (Class 1, LOE A). Of note, pharmacodynamic variability in response to clopidogrel has been well described, and hyporesponders may be at increased risk of MACE and stent thrombosis when treated with clopidogrel after PCI. Other P2Y12 inhibitors such as ticagrelor and prasugrel are more potent than clopidogrel and achieve more rapid onset of inhibition of platelet activation but with increased risk of bleeding compared with clopidogrel.

When administered concurrently with fibrinolytic as the reperfusion strategy, clopidogrel is recommended to be administered with a loading dose (300 mg, then 75 mg daily) for patients <75 years of age and starting without a loading dose (75

mg daily) for patients ≥75 years of age. In patients treated with a fibrinolytic agent who are undergoing subsequent PCI, either clopidogrel or ticagrelor (age

<75 years, within 24 hours after a fibrinolytic agent) or prasugrel (>24 hours after a fibrinolytic agent) are alternatives to support PCI. 

Parenteral anticoagulation is recommended for all patients with ACS, irrespective of the initial treatment strategy, to treat the underlying pathophysiologic process (coronary atherothrombosis) and reduce the risk of recurrent MACE. The choice of a parenteral anticoagulant can be complex because it is influenced by various factors, including vascular access site, renal function, and concomitant use of other antiplatelet or anticoagulant agents. In patients with STEMI treated with fibrinolytic

therapy, parenteral anticoagulation is recommended before and after fibrinolytic therapy to reduce ischemic events.

In patients with STEMI who received fibrinolytic therapy and who are not planned for an invasive approach (as with the patient in the question stem), enoxaparin is the preferred anticoagulant over UFH. In the ExTRACT-TIMI 25 study, enoxaparin until hospital discharge or for a maximum of 8 days (whichever came first) was compared with UFH administered for at least 48 hours. The primary endpoint of death or nonfatal recurrent MI through 30 days occurred in 12% in the UFH group compared with 9.9% in the enoxaparin group. In a meta-analysis of 14 randomized trials, UFH did not reduce reinfarction or death in patients treated with fibrinolytic therapy. In contrast, low-molecular- weight heparin reduced the risk of reinfarction and death compared with placebo and the risk of reinfarction. 

In patients >75 years of age, the dosing must be modified: Omit the initial 30 mg IV bolus. Reduce the subcutaneous dose to 0.75 mg/kg (instead of the standard 1.0 mg/kg). The first two SC doses should also be capped at a maximum of 75 mg each.

After receiving the fibrinolytic and adjusted antithrombotics, the patient should be transferred to a PCI center to facilitate immediate or early catheterization depending on the clinical circumstances, if this is in-line with the patient’s wishes. Hospitals should have transfer protocols in place to allow for a seamless transfer to the PCI-capable facility as soon as it is safe to do so. A detailed assessment of clinical status is critical to determine the timing of angiography.
 

A is incorrect: This is the standard dose for patients under 75 years of age. In a 78-year-old, the IV bolus of Enoxaparin and the Clopidogrel load significantly increase the risk of a fatal brain bleed.

B is incorrect: Ticagrelor is not recommended as an adjunct to fibrinolysis in the 2025 ACS guidelines.

D is incorrect: While fondaparinux may be used alongside lytic therapy when not planning an invasive strategy, prasugrel does not have a Class 1 recommendation for use with fibrinolytic therapy.

Main Takeaway

– Clopidogrel is the only P2Y12 inhibitor with a Class 1 recommendation for use alongside fibrinolytic therapy

Guideline Loc.

Sections 4.3.2 and 4.4

Table 10

This episode is part of our comprehensive Decipher the Guidelines Series covering the 2025 ACC/AHA/ACEP/NAEMSP/SCAI Guideline for the Management of Patients With Acute Coronary Syndromes. 

The following question refers to Section 3.2 of the 2025 ACS Guidelines.

The question is asked by Thomas Jefferson medical student and CardioNerds Academy Intern Dr. Grace Qiu, answered first by Cleveland Clinic interventional and structural cardiology fellow and member of the CardioNerds Interventional Cardiology Council Dr. Eunice Dugan, and then by expert faculty Dr. Binita Shah.

Dr. Binita Shah is an associate professor of medicine, interventional cardiologist, Director for research in Interventional Cardiology, and Director of the Department of Medicine Clinical Investigator Track at NYU. She is also an associate director of interventional cardiology and director of the transcatheter valve program at the VA New York Harbor Healthcare System. She was a member of the 2025 ACS Guidelines writing committee.





Question #3

A 55-year-old woman is brought to the Emergency Department after an out-of-hospital cardiac arrest. She had a witnessed collapse with an initial shockable rhythm. Return of Spontaneous Circulation (ROSC) was achieved after 15 minutes of Advanced Cardiac Life Support (ACLS). Her post-resuscitation ECG shows diffuse ST-segment depression but no ST-segment elevation. She remains comatose.

Which of the following is the most appropriate next step in her management regarding coronary angiography?

A

Immediate emergency coronary angiography (within 2 hours) should be performed.

B

Routine emergency coronary angiography is not recommended in the absence of ST-segment elevation or hemodynamic instability.

C

Coronary angiography should be delayed for at least 72 hours to allow for neurological recovery.

D

Fibrinolytic therapy should be administered immediately if the patient cannot reach a cath lab within 90 minutes.





Answer #3

Explanation

The correct answer is B.

In resuscitated patients who are comatose after cardiac arrest, electrically and hemodynamically stable, and without evidence of STEMI, immediate angiography is not recommended due to lack of benefit (Class 3: No Benefit; LOE A)

Patients who have been resuscitated after cardiac arrest and are noncomatose or who are comatose with favorable prognostic features and with evidence of STEMI, should undergo PPCI to improve survival. (Class 1; LOE B-NR).

For patients such as this one, a delayed or selective approach should be taken once the patient is stabilized. Early angiography should not be denied solely based on a comatose state, but it should be deferred if there are clear non-cardiac causes for the arrest or if the patient’s overall prognosis is futile.

A is incorrect because recent evidence shows no benefit to “emergency” PPCI for stable patients without ST-elevation.

C is incorrect because while we wait for stability, we don’t necessarily have a fixed 72-hour “mandatory” delay for the heart if ischemia is suspected.

D is incorrect, as fibrinolysis is generally not indicated for post-arrest patients without clear STEMI and carries risks in a post-CPR setting due to potential trauma.

The MIRACLE2 Score is a tool for neuroprognostication. It helps clinicians estimate the likelihood of a poor neurological outcome at 6 months. A high score suggests that the benefit of an invasive procedure may be outweighed by the severity of the brain injury.

Components of MIRACLE2:

M – Missed (unwitnessed) arrest
I – Initial non-shockable rhythm
R – Reactive pupils at ROSC
A – Age (points increase significantly at >60 and >80)
C – Rhythm change (e.g., VF to PEA)
L – Low pH (pH < 7.20)
E – Epinephrine (any dose given)

Clinical Threshold: A score of >5 indicates a high risk of poor neurological recovery, which may lead a Heart Team to favor stabilization over immediate emergency angiography in patients without ST-elevation.

Early recognition of STEMI in resuscitated patients and direct transfer to a PCI-capable center is associated with improved survival. Survival-to-hospital discharge in the patient who is comatose with out-of-hospital cardiac arrest is <10% regardless of etiology. Those with a witnessed arrest and a shockable rhythm have improved survival. 

Outcomes for patients with STEMI who are awake after resuscitated cardiac arrest are comparable to patients with STEMI who were not in cardiac arrest. For this reason, patients with cardiac arrest who have achieved return of spontaneous circulation (ROSC) and are awake with STEMI on ECG are candidates for PPCI. However, care should be individualized in the comatose patient with rapid assessment of the patient’s clinical features and cardiac arrest characteristics before proceeding with invasive angiography. In contrast, patients who are stable without ST-segment elevation after out-of-hospital cardiac arrest do not require immediate coronary angiography. Coronary angiography in this setting can be deferred pending further risk stratification.

Main Takeaway

Patients with cardiac arrest and STEMI who have been resuscitated should preferentially be transferred by EMS to a PPCI-capable center. Certain prognostic scores can help risk stratify patients prior to catheterization.

Guideline Loc.

Section 3.2. Management of Patients Presenting With Cardiac Arrest