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Un-stabilizing the Stable PE

CASE

63 y/o M with PMH of CHF, CKD, CAD, DM II (on insulin), Sinus bradycardia (pacemaker), substance abuse, HIV, history of pulmonary embolism (previously on apixaban) who presented to the ED with 4 days of shortness of breath at rest, bilateral leg swelling, and resolved chest pain over two days.

  • Stable vital signs

  • Exam positive for chronic leg swelling

  • HEART score: 6; PERC: 3; WELLS: 4.5

  • Down trending troponin (initial 0.04), EKG at baseline

  • Negative lactate, bilateral duplex ultrasound, and CXR

  • High pro-BNP, AKI (inc BUN 38, dec GFR 42, inc Cr from baseline 1.8)

  • CTA chest showed extensive new pulmonary embolisms (PEs) involving the distal aspects of the bilateral main pulmonary arteries and bilateral multi-lobar, segmental, and subsegmental pulmonary arteries (figure).

  • No visible heart strain on bedside echo

Clinical Question: Once a PE diagnosis is made, what is the treatment in the acute setting of a hemodynamically stable patient?


SUMMARY OF EVIDENCE

Categorization of PE: presence or absence of hemodynamic stability

  • Hemodynamically unstable = "massive" or "high-risk"

    • Systolic blood pressure <90 mmHg or a drop in systolic blood pressure of ≥40 mmHg from baseline for a period >15 minutes or hypotension[1]

    • Treatment priority: restore perfusion with IV fluid, vasopressors, and/or oxygenation

  • Hemodynamically stable + associated right ventricular strain = "submassive" or "intermediate-risk"

  • Hemodynamically stable + no evidence of right ventricular strain = "low-risk"

Hemodynamically stable PEs comprise a majority of PE presentations.


Thrombolytics vs. Anticoagulation

This branchpoint has been a longstanding controversial topic in the treatment of PEs. Many studies over decades have shown thrombolytics are more efficacious than anticoagulation in improving acute occlusion for any PEs, but they have not always explored the clinical outcomes.[2]


One meta-analysis from 2014 of 11 studies of 1,833 patients explored the use of thrombolysis to heparin for the initial treatment in stable acute PEs. They found statistically significant increased risks for major bleeds (OR 2.83), intracranial hemorrhage (OR 2.36), and fatal bleeding (OR 1.84) with no significant reduction for all-cause death (OR 0.68) or recurrent PE (OR 0.44).3 The study demonstrates that thrombolytics can be impartial in the benefits of their use but also have the risk for more harm in comparison to heparin in the acute setting in stable patients.[3] Conversely, another metanalysis from 2014 of 15 studies of 1,247 patients with moderate acute PEs found that when compared to anticoagulation, thrombolytic usage significantly reduced recurrent PEs and death (OR 0.37) and increased risk for non-major bleeding (OR 4.12) yet insignificantly increased risk for major bleeding (OR 1.34).[4]


The following year another meta-analysis systematically reviewed 15 studies of 2,057 patients with acute PEs and found thrombolytic therapy to significantly reduce overall mortality (OR 0.59) compared to heparin; however, this was no longer statically significant once high-risk PEs were excluded from the dataset (OR 0.64).[5] Furthermore, like many prior studies, this study remained consistent in findings of increased bleeding with thrombolytic usage.5 Similarly, another previous meta-analysis found that thrombolytics, when compared to anticoagulants, only significantly reduced mortality when hemodynamically unstable patients were included in the analysis, but it was no longer significant when excluded.[6]


Right Ventricular Strain

One meta-analysis from 2014 of 12 studies of 3,283 patients with hemodynamically stable acute PEs found 37.3% had right ventricular dysfunction (RVD) via an echocardiogram.[7] When comparing the short-term mortality of those with and without RVD, mortality was 13.7% compared to 6.5%, respectively (OR 2.29) and this has been concluded in multiple studies.[7,8] In this intermediate stratification of stable patients with RVD, one study comparing thrombolytic usage to anticoagulants showed decreased death (2.6%) but increased risk of hemorrhagic stroke (2.0%) and major extracranial hemorrhage (6.3%), presenting similar concerns as with prior studies.[9]


Predominantly, guidelines have recommended starting on anticoagulation for hemodynamically stable patients but remain open to thrombolytics for patients with RVD with precaution for added bleeding risks and in-hospitalization monitoring.[8,10] Thus, risk stratification with RVD is a critical component of PE treatment of stable patients.[1,11]


Catheter Directed Thrombolysis (CDT)

Apart from throbolysis, another consideration for submassive/intermediate risk PEs is CDT.[12]

One study of 59 patients in this category compared those receiving only anti-coagulation to those receiving ultrasound assisted CDT and found the average decrease in RV/LV ratio over 24 hours to be 0.03±0.16 versus 0.30±0.20 (P<0.001), respectively – with minimal difference in other outcomes such as mortality and bleeding.[13] There have been other studies that have looked at both massive and submassive PEs that have found positive clinical outcome including improved RVD with minimal to no increased risk of bleeding (3,4,5).[14-17]


RECOMMENDATIONS

  1. Once a PE is identified in a hemodynamically stable patient, start the patient on anticoagulants

  2. Concurrently, it is important to risk stratify the patient by determining any signs of right heart strain through an echocardiogram, as this can change management and disposition.


REFERENCES

1. El Hussein MT, Habib J. CHEST: Mnemonic approach to manage pulmonary embolism. The Nurse Practitioner. 2022;47(8):22-30.

2. Konstantinides S, Geibel A, Olschewski M, et al. Association between thrombolytic treatment and the prognosis of hemodynamically stable patients with major pulmonary embolism: results of a multicenter registry. Circulation. 1997;96(3):882-888.

3. Riera-Mestre A, Becattini C, Giustozzi M, Agnelli G. Thrombolysis in hemodynamically stable patients with acute pulmonary embolism: a meta-analysis. Thrombosis research. 2014;134(6):1265-1271.

4. Chen H, Ren C, Chen H. Thrombolysis versus anticoagulation for the initial treatment of moderate pulmonary embolism: a meta-analysis of randomized controlled trials. Respir Care. Dec 2014;59(12):1880-7. doi:10.4187/respcare.03197

5. Marti C, John G, Konstantinides S, et al. Systemic thrombolytic therapy for acute pulmonary embolism: a systematic review and meta-analysis. Eur Heart J. Mar 7 2015;36(10):605-14. doi:10.1093/eurheartj/ehu218

6. Wan S, Quinlan DJ, Agnelli G, Eikelboom JW. Thrombolysis compared with heparin for the initial treatment of pulmonary embolism: a meta-analysis of the randomized controlled trials. Circulation. Aug 10 2004;110(6):744-9. doi:10.1161/01.Cir.0000137826.09715.9c

7. Cho JH, Kutti Sridharan G, Kim SH, et al. Right ventricular dysfunction as an echocardiographic prognostic factor in hemodynamically stable patients with acute pulmonary embolism: a meta-analysis. BMC Cardiovascular Disorders. 2014;14(1):1-9.

8. Bova C, Pesavento R, Marchiori A, et al. Risk stratification and outcomes in hemodynamically stable patients with acute pulmonary embolism: a prospective, multicentre, cohort study with three months of follow‐up. Journal of Thrombosis and Haemostasis. 2009;7(6):938-944.

9. Meyer G, Vicaut E, Danays T, et al. Fibrinolysis for patients with intermediate-risk pulmonary embolism. N engl j med. 2014;370:1402-1411.

10. Leidi A, Bex S, Righini M, Berner A, Grosgurin O, Marti C. Risk Stratification in Patients with Acute Pulmonary Embolism: Current Evidence and Perspectives. Journal of clinical medicine. 2022;11(9):2533.

11. Maraziti G, Cimini LA, Becattini C. Risk stratification to optimize the management of acute pulmonary embolism. Expert Review of Cardiovascular Therapy. 2022;(just-accepted)

12. Patel N, Patel NJ, Agnihotri K, et al. Utilization of catheter‐directed thrombolysis in pulmonary embolism and outcome difference between systemic thrombolysis and catheter‐directed thrombolysis. Catheterization and cardiovascular interventions. 2015;86(7):1219-1227.

13. Kucher N, Boekstegers P, Müller OJ, et al. Randomized, controlled trial of ultrasound-assisted catheter-directed thrombolysis for acute intermediate-risk pulmonary embolism. Circulation. 2014;129(4):479-486.

14. Xue X, Sista AK. Catheter-directed thrombolysis for pulmonary embolism: the state of practice. Techniques in vascular and interventional radiology. 2018;21(2):78-84.

15. Kuo WT, Banerjee A, Kim PS, et al. Pulmonary embolism response to fragmentation, embolectomy, and catheter thrombolysis (PERFECT): initial results from a prospective multicenter registry. Chest. 2015;148(3):667-673.

16. Mostafa A, Briasoulis A, Telila T, Belgrave K, Grines C. Treatment of massive or submassive acute pulmonary embolism with catheter-directed thrombolysis. The American journal of cardiology. 2016;117(6):1014-1020.

17. Piazza G, Hohfelder B, Jaff MR. A prospective, single-arm, multi-center trial of Ekosonic endovascular system and activase for treatment of acute pulmonary embolism (PE).(SEATTLE II). https. clinicaltrials gov/shows/NCT01513769.

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