Cardionerds: A Cardiology Podcast

CardioNerds co-chairs Dr. Dinu Balanescu and Dr. Billy Joe Mullinax, along with FIT lead Dr. Shiavax Rao, discuss the evolving landscape of randomized controlled trials in pulmonary embolism with Dr. Jay Giri, interventional cardiologist, Associate Professor of Medicine, and Director of the Cardiovascular Catheterization Laboratories at the Hospital of the University of Pennsylvania. This episode examines the historical evidence behind systemic thrombolysis, the emergence of catheter-directed therapies and mechanical thrombectomy, and the landmark RCTs – STORM-PE, PEERLESS, HI-PEITHO, and PEERLESS II – that are reshaping intermediate-risk PE management. The discussion highlights challenges in PE trial design, the critical importance of clinical deterioration as an endpoint, and why this era represents an unprecedented wave of evidence generation in PE. Audio editing for this episode was performed by CardioNerds Intern, Dr. Julia Marques Fernandes.

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.

CardioNerds Pulmonary Embolism Page
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Pearls:

Systemic thrombolysis in intermediate-risk PE reduces hemodynamic decompensation but at the cost of ~1.5–2% intracranial hemorrhage risk – a near-zero net benefit that has driven the search for safer catheter-based alternatives.

“Focus on clinical deterioration, not mortality” – Due to crossover design in contemporary PE RCTs, control-arm patients who decompensate are rescued with advanced therapies, biasing mortality toward the null. Clinical deterioration is the most informative endpoint to watch in HI-PEITHO, PRAGUE-26, and PEERLESS II.

HI-PEITHO is the first large RCT to demonstrate that catheter-directed fibrinolysis plus anticoagulation significantly reduces the composite of PE-related death, cardiorespiratory decompensation, or PE recurrence versus anticoagulation alone (RR 0.39; 95% CI 0.20–0.77; P=0.005), with no intracranial hemorrhage in either arm.

The four major upcoming/recently reported PE RCTs (HI-PEITHO, PRAGUE-26, PEERLESS II, PE-TRACT) enroll progressively different risk populations – from the most enriched (HI-PEITHO) to the most permissive (PE-TRACT, which includes intermediate-low risk patients) – enabling a nuanced understanding of which patients benefit most from intervention.

PE device clearance follows a fundamentally different FDA pathway than structural heart devices (single-arm safety/efficacy studies vs. mandated RCTs), yet market forces and clinical need have ultimately driven industry and government to sponsor large-scale RCTs – a lesson in how evidence development can evolve organically alongside regulatory frameworks.

Notes:

Notes drafted by Dr. Shiavax Rao.

Question #1: What is the current evidence behind advanced PE therapies?

Systemic thrombolysis: Sixteen RCTs over 40 years (1972–2014) enrolling nearly 2,000 patients have studied systemic thrombolysis in intermediate-risk PE. The landmark PEITHO trial (n=1,006) showed that tenecteplase reduced the composite of death or hemodynamic collapse (2.6% vs. 5.6%; P=0.015), driven primarily by reduced hemodynamic decompensation (1.6% vs. 5.0%; P=0.002). However, this came at the cost of increased major bleeding (6.3% vs. 1.5%; P<0.001) and a ~2% rate of intracranial hemorrhage. Meta-analyses of systemic thrombolysis trials show a small absolute mortality benefit (~1–2%) that is closely offset by bleeding risk, explaining why guidelines have not broadly recommended systemic thrombolysis for intermediate-risk PE.

Catheter-directed thrombolysis (CDT): The ULTIMA trial (n=59) was the first RCT of ultrasound-assisted CDT (EkoSonic/EKOS system) vs. anticoagulation alone in intermediate-risk PE. CDT showed superior RV/LV ratio improvement at 24 hours (decrease of 0.30 ± 0.20 vs. 0.03 ± 0.16; P<0.001), but this difference was no longer significant at 90 days. The CANARY trial, initiated in Iran in 2019, was halted prematurely due to the COVID-19 pandemic but largely verified ULTIMA’s findings, with a signal that RV benefits may persist at 90 days.

Mechanical thrombectomy – single-arm data: The FLARE trial demonstrated a 25% reduction in RV/LV ratio at 48 hours with large-bore aspiration thrombectomy (FlowTriever). The EXTRACT-PE trial showed significant RV/LV ratio reduction with the Indigo aspiration system with a low major adverse event rate. The FLASH registry (FlowTriever) reported a mean 7.6 mmHg drop in mean PA pressure and RV/LV ratio decrease from 1.23 to 0.98 at 48 hours.

STORM-PE (2025): The first RCT of mechanical thrombectomy (computer-assisted vacuum thrombectomy [CAVT] with the Indigo/Penumbra system) vs. anticoagulation alone. One hundred patients were randomized across 22 sites. CAVT was superior for the primary endpoint of 48-hour RV/LV ratio reduction (0.52 vs. 0.24; difference 0.27; P<0.001), with earlier normalization of vital signs and comparable major adverse event rates (4.3% vs. 7.5%; P=0.681). Two PE-related deaths occurred in the CAVT arm. The trial was not powered for mortality or longer-term outcomes.

PEERLESS (2025): The first RCT comparing two interventional strategies head-to-head – large-bore mechanical thrombectomy (FlowTriever) vs. CDT – in 550 patients with intermediate-risk PE. The primary hierarchical win ratio composite favored LBMT (win ratio 5.01; 95% CI 3.68–6.97; P<0.001), driven primarily by fewer clinical deterioration/bailout events (1.8% vs. 5.4%; P=0.04) and substantially less post-procedural ICU use (41.6% vs. 98.6% admission rates). No significant differences in mortality, intracranial hemorrhage, or major bleeding were observed. RV/LV ratio reduction was similar between arms. LBMT was associated with shorter hospital stays and fewer 30-day readmissions.

Question #2: What are the challenges with conducting RCTs in PE?

Crossover and rescue therapy: Unlike early TAVR trials where control-arm patients could not cross over to the device arm, contemporary PE trials allow crossover upon clinical deterioration. This is ethically necessary given available therapies but biases mortality toward the null, making it unlikely that any individual trial – or even a meta-analysis of the four major trials (~2,400–3,000 patients combined) – will demonstrate a mortality difference.

Heterogeneity of intermediate-risk PE: Two patients meeting ESC intermediate-high risk criteria (RV dysfunction + elevated troponin) can look clinically very different – one may be tachypneic on 5 liters of oxygen, while another is comfortable on room air. This heterogeneity complicates enrollment, endpoint detection, and generalizability.

Endpoint selection: Early PE trials relied on surrogate imaging endpoints (RV/LV ratio, PA pressure reduction, Miller score). While these demonstrate proof-of-concept, they have not moved guidelines. Clinically relevant endpoints – mortality, clinical deterioration, functional status, quality of life – are needed but require larger sample sizes and longer follow-up.

Funding and maturation of the field: Trials require buy-in from government or industry funders. It took time for the field to mature enough to estimate effect sizes for trial powering, accumulate sufficient operator experience to ensure internal validity, and for industry to recognize that market adoption required randomized evidence despite existing FDA clearance.

FDA regulatory pathway: PE devices are cleared via a 510(k) pathway requiring single-arm studies (~100–150 patients) demonstrating safety and RV/LV ratio improvement – a much lower bar than the pre-market approval pathway requiring RCTs mandated for structural heart devices (e.g., TAVR, MitraClip). While this has enabled rapid innovation and market competition, it initially reduced the incentive for industry-sponsored RCTs.

Question #3: What are the upcoming/recently reported RCT trials in PE?

HI-PEITHO (published 2026, NEJM): Multinational adaptive-design RCT of ultrasound-facilitated CDT (EkoSonic system, alteplase 2 mg bolus + 1 mg/hr/catheter × 7 hours) plus anticoagulation vs. anticoagulation alone in 544 patients with enriched intermediate-high risk PE (RV/LV ≥1.0, elevated troponin, plus ≥2 of: SBP ≤110, HR ≥100, RR >20). Primary composite of PE-related death, cardiorespiratory decompensation/collapse, or symptomatic PE recurrence within 7 days: 4.0% intervention vs. 10.3% control (RR 0.39; 95% CI 0.20–0.77; P=0.005). Effect driven by reduced cardiorespiratory decompensation. Major bleeding at 7 days: 4.1% vs. 2.2% (P=0.32). No intracranial hemorrhage in either arm. Clinical deterioration measured using the National Early Warning Score (NEWS), a validated ordinal scoring system incorporating vital signs – more sensitive at detecting decompensation than binary clinical criteria.

PRAGUE-26: Czech Republic government-sponsored RCT with a design essentially identical to HI-PEITHO in terms of sample size and primary endpoint, but using standard (non-ultrasound-assisted) CDT catheters in the interventional arm. Enrolling well; results anticipated in the near term.

PEERLESS II: Industry-sponsored (Inari/Boston Scientific) RCT of large-bore mechanical thrombectomy (FlowTriever) plus anticoagulation vs. anticoagulation alone in up to 1,200 patients with enriched intermediate-high risk PE (enrichment criteria slightly less stringent than HI-PEITHO). Five-component hierarchical primary endpoint assessed via win ratio: (1) mortality, (2) clinical deterioration (defined by binary clinical criteria – pressor initiation, SBP <90 for sustained period, mechanical circulatory support, or significant respiratory decompensation/intubation – a less sensitive measure than NEWS), (3) recurrent PE admission, (4) non-deterioration-based bailout crossover at day 3, and (5) 48-hour dyspnea score. The larger sample size compensates for the less sensitive clinical deterioration definition.

PE-TRACT: NIH-sponsored, open-label, assessor-blinded RCT of CDT (any FDA-cleared device – CDT or mechanical thrombectomy, strategy trial) plus anticoagulation vs. anticoagulation alone in 500 patients with intermediate-risk PE (most permissive enrollment – includes intermediate-low risk patients). Co-primary endpoints at 3 months (peak VO₂ on cardiopulmonary exercise testing) and 12 months (NYHA functional class), analyzed sequentially. Designed to answer the longer-term functional question rather than early clinical deterioration.

Question #4: What does the future of PE research look like?

Unprecedented evidence generation: Across STORM-PE, PEERLESS, HI-PEITHO, PEERLESS II, PE-TRACT, PRAGUE-26, PEITHO-3, and high-risk PE trials (PERSEVERE, TORPEDO-NL), approximately 8–9 RCTs are enrolling or recently completed – an unparalleled volume of comparative evidence in any cardiovascular subspecialty over such a short period.

Guideline impact: The 2026 AHA/ACC PE Guideline already reflects the evolving evidence landscape, with Class 2a–2b recommendations for CDT and MT in select PE categories. Results from HI-PEITHO, PEERLESS II, PRAGUE-26, and PE-TRACT have the potential to substantially strengthen these recommendations, particularly if clinical deterioration endpoints are positive.

PERT evolution: As evidence clarifies which patients benefit from intervention, PERT programs may transition from primarily clinical decision-making bodies to systems-of-care delivery engines – analogous to STEMI systems – focused on efficient, protocol-driven care and real-world evidence generation for quality improvement.

Innovation ecosystem: The relatively permissive FDA clearance pathway has fostered a competitive device landscape with multiple manufacturers and device types, contrasting with the prolonged duopoly in the TAVR space. This competition may drive technological improvement and more favorable economics.

Caution with real-world evidence: While real-world evidence is valuable for quality improvement and systems-of-care assessment, it should be used cautiously for comparative effectiveness analyses due to irreconcilable confounding and limitations in causal inference. RCTs remain the gold standard for comparative questions.

References:

★ Rosenfield K, Klok FA, Piazza G, et al. Ultrasound-facilitated, catheter-directed fibrinolysis for acute pulmonary embolism. N Engl J Med. 2026;394(22):2131-2141. doi:10.1056/NEJMoa2503539

★ Lookstein RA, Konstantinides SV, Weinberg I, et al. Randomized controlled trial of mechanical thrombectomy with anticoagulation versus anticoagulation alone for acute intermediate-high risk pulmonary embolism: primary outcomes from the STORM-PE trial. Circulation. 2026;153(1):21-34. doi:10.1161/CIRCULATIONAHA.125.077232

★ Jaber WA, Gonsalves CF, Stortecky S, et al. Large-bore mechanical thrombectomy versus catheter-directed thrombolysis in the management of intermediate-risk pulmonary embolism: primary results of the PEERLESS randomized controlled trial. Circulation. 2025;151(5):260-273. doi:10.1161/CIRCULATIONAHA.124.072364

★ Gonsalves CF, Gibson CM, Stortecky S, et al. Randomized controlled trial of mechanical thrombectomy vs catheter-directed thrombolysis for acute hemodynamically stable pulmonary embolism: rationale and design of the PEERLESS study. Am Heart J. 2023;266:128-137. doi:10.1016/j.ahj.2023.09.002

★ Sista AK, Troxel AB, Tarpey T, et al. Rationale and design of the PE-TRACT trial: a multicenter randomized trial to evaluate catheter-directed therapy for the treatment of intermediate-risk pulmonary embolism. Am Heart J. 2025;281:112-122. doi:10.1016/j.ahj.2024.11.016

★ Giri J, Sista AK, Weinberg I, et al. Interventional therapies for acute pulmonary embolism: current status and principles for the development of novel evidence: a scientific statement from the American Heart Association. Circulation. 2019;140(20):e774-e801. doi:10.1161/CIR.0000000000000707

★ Zhang RS, Maqsood MH, Sharp ASP, et al. Efficacy and safety of anticoagulation, catheter-directed thrombolysis, or systemic thrombolysis in acute pulmonary embolism. JACC Cardiovasc Interv. 2023;16(22):2781-2793. doi:10.1016/j.jcin.2023.09.014
Additional References

Rosovsky RP, Konstantinides SV, Moriarty JM, et al. A prospective, multicenter, randomized controlled trial evaluating anticoagulation alone vs anticoagulation plus computer assisted vacuum thrombectomy for the treatment of intermediate-high-risk acute pulmonary embolism: rationale and design of the STORM-PE study. Am Heart J. 2025;288:1-14. doi:10.1016/j.ahj.2025.03.018

Klok FA, Piazza G, Sharp ASP, et al. Ultrasound-facilitated, catheter-directed thrombolysis vs anticoagulation alone for acute intermediate-high-risk pulmonary embolism: rationale and design of the HI-PEITHO study. Am Heart J. 2022;251:43-53. doi:10.1016/j.ahj.2022.05.011

Creager MA, Barnes GD, Giri J, 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;87(7):e77-e206. doi:10.1016/j.jacc.2025.11.027

Piazza G. Advanced management of intermediate- and high-risk pulmonary embolism: JACC focus seminar. J Am Coll Cardiol. 2020;76(18):2117-2127. doi:10.1016/j.jacc.2020.05.028

Zuo Z, Yue J, Dong BR, et al. Thrombolytic therapy for pulmonary embolism. Cochrane Database Syst Rev. 2021;4(4):CD004437. doi:10.1002/14651858.CD004437.pub6

Kroupa J, Buk M, Weichet J, et al. A pilot randomised trial of catheter-directed thrombolysis or standard anticoagulation for patients with intermediate-high risk acute pulmonary embolism (CANARY). EuroIntervention. 2022;18(8):e657-e665. doi:10.4244/EIJ-D-22-00194

Zuin M, Lang I, Chopard R, et al. Innovation in catheter-directed therapy for intermediate-high-risk and high-risk pulmonary embolism. JACC Cardiovasc Interv. 2024;17(20):2390-2408. doi:10.1016/j.jcin.2024.07.037

Harvey JJ, Huang S, Uberoi R. Catheter-directed therapies for the treatment of high risk (massive) and intermediate risk (submassive) acute pulmonary embolism. Cochrane Database Syst Rev. 2022;8(8):CD013083. doi:10.1002/14651858.CD013083.pub2

Kim JM, Horbal SR, Mewaldt C, et al. Mechanical thrombectomy and catheter-directed thrombolysis in acute pulmonary embolism: trends and practice patterns in the PERT Consortium Registry (2016-2024). J Am Coll Cardiol. 2026;87(13):1271-1283. doi:10.1016/j.jacc.2025.12.044

Planer D, Yanko S, Matok I, et al. Catheter-directed thrombolysis compared with systemic thrombolysis and anticoagulation in patients with intermediate- or high-risk pulmonary embolism: systematic review and network meta-analysis. CMAJ. 2023;195(24):E833-E843. doi:10.1503/cmaj.221655

Farmakis IT, Binder H, Chopard R, et al. Reperfusion strategies for acute pulmonary embolism: design and rationale of RECONNECT-PE – a living systematic review and meta-analysis. Am Heart J. 2026;295:107365. doi:10.1016/j.ahj.2026.107365

Rashedi S, Leyva H, Hamade N, et al. Fibrinolytic therapy for thromboembolic diseases: approved indications and future directions. J Am Coll Cardiol. 2025;86(14):1395-1416. doi:10.1016/j.jacc.2025.07.048

Creager MA, Barnes GD, Giri J. A field in transition: catheter-based therapy in the 2026 AHA/ACC acute pulmonary embolism guideline. J Am Coll Cardiol. 2026;87(13):1284-1288. doi:10.1016/j.jacc.2026.01.024

CardioNerds (Drs. Apoorva Gangavelli, Rebecca Garber, and Tina Reddy discuss INOCA with Dr. Claire Raphael. Audio editing by CardioNerds Academy intern, student doctor Pacey Wetstein.

This episode was produced as part of the CardioNerds Academy curriculum by House Einthoven under the guidance of House Chief, Dr. Apoorva Gangavelli, and Academy Program Director, Dr. Gurleen Kaur. A matching review article will be published in US Cardiology Review, the official journal of CardioNerds.

Non-obstructive coronary artery disease (CAD) is more common than often recognized, particularly in women and individuals with risk factors like diabetes or hypertension. Conditions such as INOCA, ANOCA, and MINOCA can cause ischemia and chest pain despite “clean” angiograms, often due to microvascular dysfunction, coronary spasms, or subtle plaque. Diagnosing these conditions requires advanced imaging or invasive studies to assess blood flow and vessel function. Treatment focuses on reducing cardiovascular risk with aspirin, statins, ACE inhibitors, or ARBs, and managing symptoms with beta-blockers or calcium channel blockers. The key takeaway: A normal angiogram doesn’t rule out disease, and these patients need a comprehensive, evidence-based approach to care.

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

CardioNerds Pulmonary Embolism Page
CardioNerds Episode Page
CardioNerds Academy
Cardionerds Healy Honor Roll

CardioNerds Journal Club
Subscribe to The Heartbeat Newsletter!
Check out CardioNerds SWAG!
Become a CardioNerds Patron!

Pearls:

When patients present with chest pain but do not have obstructive coronary artery disease, the story does not end there! Other pathologies that must be ruled out include spontaneous coronary artery disease (SCAD), coronary vasospasm, microvascular disease, Takotsubo, and cardiomyopathy. A TTE can help rule out other pathologies. Cardiac MRI can help identify myocardial fibrosis, scarring, or edema that may suggest prior events or alternative diagnoses. 

About 60-70% of INOCA cases are in women. However, it is estimated that about half of the patients with so-called “normal” angiograms actually have positive stress tests. Patients with elevated troponins are more likely to have recurrent events. Patients with INOCA are more likely to come back to the ER multiple times before getting diagnosed. These patients have a 1.4x increased risk of adverse cardiovascular events (such as HFpEF, MI, and recurrent hospitalizations for cardiac chest pain). 

INOCA is a complex condition with a variety of causes, primarily linked to microvascular disease. Within microvascular disease, there are different “endotypes” (types or subcategories) classified by specific characteristics. In centers that conduct microvascular testing, patients are categorized as endothelium-independent or endothelium-dependent, based on their responses to adenosine or acetylcholine during testing. Additionally, microvascular disease can be classified as either structural or functional, depending on the results of tests measuring microvascular resistance.

The field is moving towards the term ANOCA, or angina with non-obstructive coronary arteries, to include patients with anginal symptoms without objective ischemia. 

The field is moving toward using genotyping and hemodynamic testing to guide first-line therapies for microvascular disease, a heterogeneous condition. Current treatments mostly come from obstructive coronary artery disease, but specialized approaches—like the coronary sinus reducer—may offer unique benefits for microvascular disease.

Treatment includes sublingual nitroglycerin, ACE inhibitors/ARBs, and beta-blockers. Remember to also treat any additional comorbidities, such as diabetes, hypertension, and hyperlipidemia. Unfortunately, many of these patients may still have refractory chest pain, so it is important to reassure them. These patients can still exercise, but they may be hesitant to do so for fear of having chest pain. Cardiac rehab may be helpful for these patients as it helps them build up their tolerance.

References

Lawton JS, Tamis-Holland JE, Bangalore S, et al; Writing Committee Members. 2021 ACC/AHA/SCAI guideline for coronary artery revascularization: a report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. Circulation. 2022;145(3):e18-e114. doi:10.1161/CIR.0000000000001039

Hwang D, Park S, Koo B-K. Ischemia with nonobstructive coronary artery disease. JACC: Asia. 2023;3(2):169-180. doi:10.1016/j.jacasi.2023.01.004

Yukselen Z, Majmundar V, Dasari M, Kumar PA, Singh Y. Chest pain risk stratification in the emergency department: current perspectives. Open Access Emerg Med. 2024;16:29-43. doi:10.2147/OAEM.S419657

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 5.2.1 of the 2025 ACS Guidelines.

The question is asked by Thomas Jefferson medical student and CardioNerds Academy Intern Dr. Grace Qiu, answered first by Henry Ford Interventional cardiology fellow and member of the CardioNerds Interventional Cardiology Council Dr. Li Pang, and then by expert faculty Dr. Michelle O’Donoghue.

Dr. O’Donoghue is a cardiologist, senior investigator with the TIMI Study Group, and Associate Professor of Medicine at Harvard Medical School who holds the McGillycuddy-Logue Endowed Chair in Cardiology at Brigham and Women’s Hospital. She was the Vice Chair of the Writing Committee for the 2025 ACS Guidelines.





Question #2

A 63-year-old woman presented to the emergency room for chest pain. She described having exertional chest pain for the past two months and had an episode of severe pain after dinner 3 days ago. She went to bed and slept it off.  She told her children today at a family gathering, and was immediately brought to the ED by her daughter. She has a history of hypertension and hyperlipidemia. She was asymptomatic and normotensive in the ED. Labs show a down-trending troponin and an elevated NT-proBNP but are otherwise unremarkable. Her ECG showed Q waves with ST elevation in V2-V4. She was treated with aspirin and heparin drip, and taken to the cath lab. Coronary angiogram showed complete proximal LAD occlusion with right-to-left collaterals, without significant residual disease elsewhere. She remains asymptomatic and is stable, both hemodynamically and electrically.

What is the next best step with regard to reperfusion and anti-thrombotic management?

A

Proceed with primary PCI to LAD 

B

Medical management with aspirin and enoxaparin 

C

Medical management with aspirin and clopidogrel

D

Medical management with aspirin and ticagrelor

 





Answer #2

Explanation 

The Correct answer is D

In patients who are stable with STEMI and have a totally occluded infarct-related artery >24 hours after symptom onset and are without evidence of ongoing ischemia, acute severe HF, or life-threatening arrhythmia, PPCI should not be performed due to lack of benefit. (Class 3, LOE B-R)

The benefit of PPCI begins to diminish after >12 hours from symptom onset, but there appears to be continued benefit through approximately 24 hours. 

In stable asymptomatic patients with an occluded artery >48 hours after symptom onset, routine PCI has not been shown to be beneficial in the absence of ongoing ischemia. The relative utility of routine PCI for asymptomatic patients with STEMI between 24 and 48 hours from symptom onset is less rigorously tested.

PCI is not recommended for an occluded infarct-related artery if the patient is asymptomatic and has a completed infarct. MACE outcomes were similar in those with an occluded infarct-related artery who underwent medical therapy versus those who underwent PCI 3 to 28 days after an MI (Occluded Artery Trial [OAT]), and results were no different at 7-year follow-up. Similar findings were noted in the DECOPI (Desobstruction Coronaire en Post-Infarctus) trial, which enrolled patients with an occluded artery and Q waves on the ECG presenting 2 to 15 days after symptom onset.

However, coronary revascularization should be considered for patients with late presentations with continued signs and symptoms of ischemia, including cardiogenic shock, acute severe HF, persistent angina, and life-threatening arrhythmias. 

Main Takeaway

In patients who are stable with STEMI who have a totally occluded infarct-related artery >24 hours after symptom onset and are without evidence of ongoing ischemia, acute severe HF, or life-threatening arrhythmia, PPCI should not be performed due to lack of benefit.

Guideline Loc.

Section 5.2.1

CardioNerds (Amit and Dan), Billy Joe Mullinax, and Saahil Jumkhawala discuss the long term management of pulmonary embolism with Dr. Soophia Naydenov.  The episode focuses on the approach to patients who struggle with persistent symptoms like dyspnea and fatigue even after completing the acute phase of anticoagulation. This spectrum of disease, ranging from mild post-PE impairment to chronic thromboembolic pulmonary hypertension (CTEPH), requires a structured follow-up. The discussion covers the critical importance of identifying CTEPH early, the necessary timelines for follow-up, and the appropriate objective screening tools and invasive testing to guide patient care toward full functional recovery. Audio editing by CardioNerds academy intern, Grace Qiu.

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.

CardioNerds Pulmonary Embolism Page
CardioNerds Episode Page
CardioNerds Academy
Cardionerds Healy Honor Roll

CardioNerds Journal Club
Subscribe to The Heartbeat Newsletter!
Check out CardioNerds SWAG!
Become a CardioNerds Patron!

Acronyms

PE: Pulmonary Embolism

PERT: Pulmonary Embolism Response Team

CTEPH: Chronic Thromboembolic Pulmonary Hypertension

QL: Quality of Life

VTE: Venous Thromboembolism

DASH: D-dimer, Age, Sex, History of non-provoked PE (a risk score)

CPET: Cardiopulmonary Exercise Testing

PFTs: Pulmonary Function Tests

VQ Scan: Ventilation-Perfusion Scan

DOACs: Direct Oral Anticoagulants

TPA: Tissue Plasminogen Activator (Thrombolytics)

ECMO: Extracorporeal Membrane Oxygenation

Pearls:

Post-PE “Syndrome” is a Spectrum: It is more accurately a spectrum of disease (sequelae of PE) rather than a single syndrome, ranging from mild fatigue/dyspnea to the most severe form, CTEPH.

Structured Follow-up is Mandatory: All PE survivors need a structured follow-up, typically with checkpoints at 3, 6, 12, and 16–24 months, with the primary goal being to detect CTEPH, the deadliest, yet potentially curable, disease on the spectrum.

Screening Should Be Objective and Practical: When screening for persistent symptoms, use objective assessment tools like the Post-VTE Functional Status (PVFS) scale or the Modified Medical Research Council (MMR-C) scale, as highly comprehensive but cumbersome tools (like the PE Quality of Life questionnaire) may not be practical for routine clinical use. Recurrence Risk Scores Aid in Anticoagulation Duration: Simple scores like the DASH score or the HERDO2 score (for women) can provide guidance when considering the continuation versus discontinuation of anticoagulation after the initial treatment phase.

Invasive Testing for Persistent Symptoms: If a patient remains symptomatic at the 6-month mark despite normal non-invasive testing (chest X-ray, ECG, PFTs, six-minute walk, echo, VQ scan, CPET), consider invasive testing such as Right Heart Catheterization (RHC) at rest or with exercise, or an invasive CPET.

Notes:

Notes drafted by Saahil Jumkhawala.

1. The Spectrum of Post-PE Disease

The term “post-PE syndrome” should be used with caution, as it refers to a spectrum of disease rather than a single entity.

This spectrum includes symptoms (sequelae) that exist in a patient’s life following an incidental PE event that they did not have before.

On one extreme is Chronic Thromboembolic Pulmonary Hypertension (CTEPH):

The definition is clear, but it is the most deadly type, though thankfully rare (2% to 4%).

It involves a residual clot and pulmonary hypertension identifiable at rest.

In the middle is Chronic Thromboembolic Disease (CTED):

Patients may have residual defects seen on a VQ or CT scan, but they do not have pulmonary hypertension.

On the other side is a milder disease, which can include fatigue, dyspnea, or a patient’s perceived impairment, where the definitions of CTEPH and CTED are not met, but the patient remains symptomatic.

2. Structured Follow-up and Screening for Post-PE Symptoms

Structured follow-up is key for all PE survivors, though the structure may vary based on available resources (PCP, Cardiology, Pulmonary, or multidisciplinary clinic).

Recommended Timeline for Follow-up: Data from studies like ELOPE and FOCUS suggest checkpoints at 3, 6, 12, and up to 16 to 24 months.

This timeline is designed to identify patients who may develop CTEPH.

88% of patients who develop CTEPH will be identified within about a year.

A structured follow-up can reduce the delay in CTEPH diagnosis from 10–12 months to 4–6 months.

Personal Practice Note: A quick 2–3 week/30-day check-in is recommended for severely ill patients (e.g., those who had TPA, profound shock, or ECMO support) to ensure medication compliance, manage symptoms, and identify red flags.

Screening Tools (Objective Assessment):

The first step is an inventory of patient symptoms, leaning toward objective rather than subjective assessment.

Recommended Simple Tools:

Modified Medical Research Council (MMR-C) for dyspnea evaluation.

Post-VTE Functional Status (PVFS) scale.

The Pulmonary Embolism Quality of Life (QL) questionnaire is comprehensive but long, making it tedious and better suited for research.

Future Utility: Technology (AI/electronic tools) may assist in administering these questionnaires before the clinic visit, presenting the information as a “dashboard” for the provider.

3. Management of Persistent Symptoms and Further Testing

Initial Non-Invasive Tests (Often done at 3 months):

Echocardiogram

VQ Scan

Full PFTs

Six-minute walk

CPET

Further Evaluation for Persistent Symptoms (e.g., at 6 months): If non-invasive tests (Chest X-ray, ECG, CPET) are normal but symptoms persist, more invasive testing should be considered as the patient has not returned to baseline.

Repeat VQ scan or echocardiogram if symptoms have changed.

Right Heart Catheterization (RHC) at rest or with exercise.

Invasive CPET.

PA gram (Pulmonary Angiogram) to assess vasculature.

4. Recurrence Risk and Anticoagulation Duration

The decision to continue or discontinue anticoagulation depends on the patient’s risk factors, the situation of the PE (provoked or unprovoked), presence of active cancer, and patient preference.

Recurrence Risk Scores:

Simple scores are preferred for practicality.

DASH Score.

HERDO2 Score (particularly for women).

The Vienna Score can be considered if the question is whether to restart anticoagulation after a disruption.

Role of D-dimer in Abbreviation: While D-dimer can be used to guide the decision to restart anticoagulation after a planned pause (if D-dimer is high, resume), patient symptoms are preferable to guide management decisions like early abbreviation.

5. Prevention of Post-PE Syndrome

Currently, there is no clear tool known to prevent the post-PE syndrome/spectrum of disease.

Best Current Advice for Prevention/Recovery:

Anticoagulation compliance.

Pulmonary rehabilitation, which aids in faster recovery.

General precautions, such as smoking cessation and body weight management.

Future Research: Ongoing trials are investigating whether acute management strategies (e.g., using thrombolytics in intermediate-risk PE) can prevent long-term sequelae. (The PYTHO trial did not show a reduced rate of CTEPH in intermediate-risk PE patients who received thrombolytics).

References:

Khan, F., Tritschler, T., Kahn, S. R., & Rodger, M. A. “Venous Thromboembolism.” The Lancet, vol. 398, no. 10294, 2021, pp. 64-77. doi:10.1016/S0140-6736(20)32658-1.

Kearon, C., & Kahn, S. R. “Long-Term Treatment of Venous Thromboembolism.” Blood, vol. 135, no. 5, 2020, pp. 317-325. doi:10.1182/blood.2019002364.

Kahn, S. R., & de Wit, K. “Pulmonary Embolism.” The New England Journal of Medicine, vol. 387, no. 1, 2022, pp. 45-57. doi:10.1056/NEJMcp2116489.

Di Nisio, M., van Es, N., & Büller, H. R. “Deep Vein Thrombosis and Pulmonary Embolism.” The Lancet, vol. 388, no. 10063, 2016, pp. 3060-3073. doi:10.1016/S0140-6736(16)30514-1.

Chopard, R., Albertsen, I. E., & Piazza, G. “Diagnosis and Treatment of Lower Extremity Venous Thromboembolism: A Review.” JAMA, vol. 324, no. 17, 2020, pp. 1765-1776. doi:10.1001/jama.2020.17272.

CardioNerds (Drs. Rawan Amir, Tripti Gupta, and Alysha Joseph) discuss the fundamentals of adult congenital heart disease (ACHD) surgery with Dr. Elizabeth Stephens.  Audio editing by CardioNerds academy intern, Grace Qiu. 

Using a case of a young adult undergoing a Ross procedure, the episode walks through what happens in the operating room—from induction and intraoperative transesophageal echocardiography (TEE) to cardiopulmonary bypass (CPB), myocardial protection, and surgical repair. The discussion highlights key concepts including cardioplegia, cross-clamp and bypass times, hypothermic circulatory arrest, and the complexity of redo sternotomy. This episode provides learners with a practical framework to interpret operative reports, anticipate postoperative physiology, and better collaborate with surgical teams.

This episode was produced by the CardioNerds ACHD Council and planned by Dr. Rawan Amir. 

CardioNerds Adult Congenital Heart Disease Page
CardioNerds Episode Page

Pearls

“LV distension kills patients.”
Preventing left ventricular distension with appropriate venting and awareness of aortic insufficiency is critical to intraoperative safety. 

TEE can change the surgical plan in real time.
Findings such as underestimated aortic regurgitation, mitral pathology, or a PFO may directly alter cannulation and cardioplegia strategy. 

Cross-clamp time = myocardial ischemic time; bypass time = systemic stress.
Both are key predictors of postoperative complications including renal injury, bleeding, and ventricular dysfunction. 

Redo sternotomy risk is driven by anatomy, not just number.
Aorta adherent to the sternum, conduit position, and chamber pressurization define risk more than the number of prior surgeries. 

Think longitudinally—ACHD surgery is lifetime planning.
Surgical materials and strategies must account for future interventions, especially in younger patients.

Notes:

Notes drafted by Dr. Alysha Joseph, aided by generative artificial intelligence.

What are the key steps in congenital cardiac surgery from incision to closure?

Preoperative planning is multidisciplinary, involving surgeon, anesthesia, cardiology, and ICU teams; high-risk inductions (e.g., critical AS, Williams syndrome) are identified early

TEE is performed immediately after induction to reassess anatomy and may reveal new findings (e.g., underestimated AI, mitral disease, PFO)

Median sternotomy is performed, followed by creation of a pericardial well to optimize exposure

Heparin is administered prior to cannulation; arterial and venous cannulas are placed for initiation of CPB

Cross-clamp is applied and cardioplegia delivered to arrest the heart, allowing a still and protected operative field

Surgical repair (e.g., Ross procedure) is performed, followed by de-airing, cross-clamp removal, and reperfusion

Patient is weaned from bypass with TEE reassessment, hemostasis achieved, and chest closed

What is cardioplegia and how is it delivered?

Cardioplegia is a potassium-rich solution that arrests myocardial activity and reduces metabolic demand

Most commonly used solution in the U.S. is Del Nido cardioplegia, originally developed for pediatric myocardium

Delivery strategies include:

Antegrade (via aortic root) – standard approach 

Ostial (direct coronary delivery) – used when aortic root cannot be relied upon 

Retrograde (via coronary sinus) – useful in severe AI or coronary disease

NOTE: Severe aortic regurgitation can impair antegrade delivery and requires alternative strategies and LV venting 

What do cross-clamp time and bypass time represent clinically?

Cross-clamp time = duration of myocardial ischemia while the heart is arrested

Bypass time = total duration on CPB, reflecting systemic exposure to non-physiologic circulation

Prolonged cross-clamp time (>2–3 hours) increases risk of myocardial dysfunction, especially with poor baseline function

Longer bypass time is associated with increased risk of renal injury, coagulopathy, and bleeding

These metrics often reflect both case complexity and intraoperative challenges

What is hypothermic circulatory arrest (HCA) and when is it used?

HCA involves complete cessation of blood flow to allow a bloodless surgical field

Typically used in complex aortic arch repairs

Patients are cooled to ~18°C to reduce metabolic demand and protect organs

Duration is ideally limited to <30 minutes to minimize neurologic injury

Adjuncts include:

Antegrade cerebral perfusion (ACP) – provides targeted brain perfusion 

Retrograde cerebral perfusion (RCP) – less effective for oxygen delivery 

What makes redo congenital cardiac surgery high risk?

Re-entry risk depends on anatomical relationships:

Aorta adherent to sternum (especially midline) poses high risk of catastrophic bleeding 

RVOT conduits or pressurized chambers near sternum increase injury risk

Loss of peripheral vascular access from prior procedures limits bailout options

Accumulated comorbidities (renal, hepatic dysfunction) increase perioperative risk

Diastolic dysfunction and ventricular impairment complicate weaning from bypass

Complexity of planned repair and institutional/surgeon experience significantly influence outcomes 

What does “venting the ventricle” mean and why is it important?

Venting refers to decompression of the left ventricle using a cannula (often via right superior pulmonary vein)

Prevents LV distension, which can impair myocardial protection and lead to hemodynamic collapse

Particularly important in the presence of aortic insufficiency or inadequate forward flow

Failure to adequately vent can result in arrhythmias, poor recovery, and adverse outcomes

What materials are used in congenital surgery and how do they impact long-term care?

Common patch materials include bovine pericardium (durable, non-stretch), Dacron, Gore-Tex, and autologous pericardium

Conduits (e.g., homografts, Contegra, Hancock) are used to connect cardiac structures and often contain valves

Most materials do not grow with the patient and are prone to calcification over time

Surgical decisions must consider future transcatheter or surgical interventions

Limited availability of certain graft sizes (e.g., pulmonary homografts) impacts real-world decision-making

References:

1. Salis, S. et al. Cardiopulmonary bypass duration is an independent predictor of morbidity and mortality after cardiac surgery. J Cardiothorac Vasc Anesth. 2008;22(6):814-822. doi:10.1053/j.jvca.2008.08.004

2. Al-Sarraf, N. et al.  Cross-clamp time is an independent predictor of mortality and morbidity in low- and high-risk cardiac patients. International journal of surgery (London, England). 2011; 9(1):104–109. https://doi.org/10.1016/j.ijsu.2010.10.007

3. Weiland, A. P. et al. Physiologic principles and clinical sequelae of cardiopulmonary bypass. Heart & lung : the journal of critical care. 1986;15(1):34–39.

4. Park, C. B. et al. Identifying patients at particular risk of injury during repeat sternotomy: analysis of 2555 cardiac reoperations. The Journal of thoracic and cardiovascular surgery. 2010;140(5):1028–1035. https://doi.org/10.1016/j.jtcvs.2010.07.086

5. Morales, D. L. et al. Repeat sternotomy in congenital heart surgery: no longer a risk factor. The Annals of thoracic surgery. 2008; 86(3):897–902. https://doi.org/10.1016/j.athoracsur.2008.04.044

6. Francica, A. et al. Cardioplegia between Evolution and Revolution: From Depolarized to Polarized Cardiac Arrest in Adult Cardiac Surgery. Journal of clinical medicine. 2021;10(19):4485. https://doi.org/10.3390/jcm10194485

7. Ghia, S. et al. Hypothermic Circulatory Arrest in Adult Aortic Arch Surgery: A Review of Hypothermic Circulatory Arrest and its Anesthetic Implications. Journal of cardiothoracic and vascular anesthesia. 2023; 37(12): 2634–2645. https://doi.org/10.1053/j.jvca.2023.08.139

8. Peivandi, A. D. et al. Grafts and Patches: Optimized but Not Optimal Materials for Congenital Heart Surgery. Pediatric cardiology. 2023;44(5):996–1002. https://doi.org/10.1007/s00246-023-03153-6