SGEM#163: Shuffle off to Buffalo to Talk Thrombolysis for Acute Pulmonary Embolism

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Date: October 6th, 2016

Reference: Piazza et al. A Prospective, Single-Arm, Multicenter Trial of Ultrasound-Facilitated, Catheter-Directed, Low-Dose Fibrinolysis for Acute Massive and Submassive Pulmonary Embolism. JACC 2015

Guest Skeptic: Dr. Essie Reed is one of the Chief Residents in the Department of Emergency Medicine at the University of Buffalo.

Case: A 75-year-old female with a past medical history of hypertension and non-insulin dependent diabetes presents with chest pain. She describes the pain as sharp, stabbing, and exacerbated with deep inspiration. She reports associated shortness of breath. She denies syncope, nausea, and diaphoresis. The pain has been present for one week, and is nearly constant. She reports that she traveled to Florida to visit her grandchildren three weeks ago. She has no fever, chills, cough, or sputum production. She is complaining of ongoing chest pain, 5/10, increased to 7/10 when asked to breathe deeply for the exam.

On examination, she is hemodynamically stable, lungs are clear and the heart is regular without murmurs. Her skin is warm and dry and she is generally well appearing. The EKG shows sinus rhythm with a rate of 80bpm.

The patient has negative serial troponins. Pain is unchanged after nitroglycerin, but improved with morphine. She eventually developed tachycardia, with a heart rate 125bpm, but remained normotensive. A CTA is performed demonstrating a submissive pulmonary embolism in the right pulmonary artery is made with RV/LV diameter ratio >0.9. The Pulmonary Embolism Response Team is paged and bedside ECHO performed confirming RV dysfunction.

Background: A pulmonary embolism (PE) can be a life-threating condition. The 2015 Chest Guidelines recommend systemically administered thrombolytic therapy in patients with acute PE associated with hypotension (systolic BP<90mmHg) who do not have a high risk of bleeding (Kearon et al 2016).

In patients with acute PE associated with hypotension (eg, systolic BP <90 mm Hg) who do not have a high bleeding risk, we suggest systemically administered thrombolytic therapy over no such therapy (Grade 2B).

Treating patients with full-dose systemic thrombolytics can reduce the risk of death but also increases the risk of major bleeding including hemorrhagic stroke (Chatterjee et al JAMA 2014). To mitigate the risk of bleeding while still maintaining efficacy, low-dose thrombolysis has been tried. Reviews of the literature suggest that this may be a reasonable strategy (Zhang et al 2014) especially in patients with a high risk of bleeding (Brandt et al 2015).

A new method being studied to treat submassive and massive PEs is ultrasound-facilitated catheter-directed thrombolysis (CDT). A small randomized control trial of 59 patients demonstrated that compared to anticoagulation alone, ultrasound-facilitated CDT improved right ventricular function compared with anticoagulation alone with no major bleeding observed (Kucher et al 2014).

However, the Chest Guideline still suggest systemic thrombolytic therapy using a peripheral vein over CDT in patients with acute PE who are treated with thrombolytic agents. They do note that patients with a higher risk of bleeding and have access to CDT are likely to choose CDT over systemic thrombolytic therapy.

In patients with acute PE who are treated with a thrombolytic agent, we suggest systemic thrombolytic therapy using a peripheral vein over catheter directed thrombolysis (CDT) (Grade 2C).
- Remarks: Patients who have a higher risk of bleeding with systemic thrombolytic therapy and who have access to the expertise and resources required to do CDT  are likely to choose CDT over systemic thrombolytic therapy.

Clinical Question: Is ultrasound-facilitated, catheter directed, low-dose fibrinolysis safe and effective to for patients with acute massive or submassive pulmonary embolism?

Population: Adult patients (18 years or older) with a proximal PE (filling defect in at least one main or lobar pulmonary artery) with symptoms of less than two weeks and RV/LV diameter ratio of at least 0.9 on contrast-enhanced chest CT.
- Massive PE: Defined as syncope, systemic arterial hypotension, cardiogenic shock or resuscitated cardiac arrest.
- Submassive PE: Defined as normotensive patients with PE and evidence of RV dysfunction.
  - Major exclusion: Stroke or transient ischemic attack, head trauma, or other active intracranial or intraspinal disease within 12 months; major surgery within 7 days; recent active bleeding from a major organ; hematocrit <30%; platelets <100,000/ml; International Normalized Ratio >3; serum creatinine >2 mg/dl; and systolic blood pressure <80 mm Hg despite vasopressor or inotropic support (Online Appendix). Obesity was defined as a clinical diagnosis of obesity in the medical record.
- Intervention: Full-dose IV unfractionated heparin plus ultrasound-facilitated, catheter-directed, low-dose tPA (1mg/h for 24hrs for unilateral PE and 1mg/hr for 12h for bilateral PE through two devices).
- Comparison: None
- Outcome:
  - Primary Efficacy: Change in RV/LV diameter ratio from baseline on contrast-enhanced chest CT at 48hrs (+/-6hr).
  - Primary Safety: Major bleeding within 72hrs classified by the GUSTO bleeding criteria.

Author’s Conclusions: “Ultrasound-facilitated, catheter-directed, low-dose fibrinolysis decreased RV dilation, reduced pulmonary hypertension, decreased anatomic thrombus burden, and minimized intracranial hemorrhage in patients with acute massive and submassive PE.”

Quality Checklist for Observational Studies:

Did the study address a clearly focused issue? Yes
Did the authors use an appropriate method to answer their question? No
Was the cohort recruited in an acceptable way? Yes
Was the exposure accurately measured to minimize bias? Yes
Was the outcome accurately measured to minimize bias? Yes
Have the authors identified all-important confounding factors? Unsure
Was the follow up of subjects complete enough? No
How precise are the results? Unsure
Do you believe the results? Yes
Can the results be applied to the local population? Unsure – It depends on your local services. They did have 22 sites (urban, non-urban, teaching and non-teaching hospital).
Do the results of this study fit with other available evidence? Yes

Key Results: 150 patients with PE (31 massive and 119 submassive) and a mean age of 59 years.

Primary Efficacy: Significant decrease in mean difference RV/LV diameter ratio

Mean difference RV/LV diameter ratio -0.42 +/-0.36 SD (P<0.0001)

Primary Safety: Major bleeding within 30 days 15/150 (10%)

Severe: 1/150 (0.7%) groin vascular access site hematoma with transient hypotension requiring vasopressor support.
Moderate: 14/150 (9.3%)

Note: There were four deaths (three in-hospital and one out-patient within 30 days) and no intracranial hemorrhages.

Conflicts of Interest (COI) – Many authors on this trial had declared COI. This does not make the data wrong but should make us more skeptical of the study and the interpretation.

No Comparison Group – This is the major limitation with this study. Without comparing it to anticoagulation alone, half-dose systemic fibrinolysis or full-dose fibrinolysis, it is not possible to comment on the efficacy and safety of ultrasound-facilitated, catheter-directed, low-dose fibrinolysis in comparison to these other treatments.

Incomplete Data – There were a significant number of patients who did not have their CT measurement at 48hrs (23%). While they observed no difference in baseline data, primary outcome or in-hospital mortality it does weaken the results.

Surrogate Markers: RV/LV diameter ratio is a surrogate marker and what are needed are patient oriented, clinically relevant endpoints.

Comment on authors’ conclusion compared to SGEM Conclusion: We generally agree that ultrasound-facilitated CDT improved surrogate outcomes with no observed intracranial hemorrhages in patients with acute massive of submassive PE.

Bonus#1: Dr. Jeff Kline

Dr. Jeff Kline

Dr. Kline is an expert in the field of acute pulmonary embolism. He is the editor in chief of AEM, creator of Pulmonary Embolism Rule-out Criteria (PERC) Rule and has published extensively in the area of PE (Kline et al 2014).

We asked Dr. Kline to review our critical appraisal and give us feedback. We specifically asked him to help us write with the SGEM Bottom Line and clinical application. Listen to the podcast to hear his response.

SGEM Bottom Line: Ultrasound-facilitated CDT is associated with a low intracranial hemorrhage rate in patients with acute massive or submassive pulmonary embolism but it is difficult to comment on efficacy without a comparison group?

Case Resolution: Anticoagulation is initiated. Thrombolysis is discussed with the patient as an option. As she remained hemodynamically stable, and age >65 and being diabetic places her at increased risk of bleeding, CDT is offered. She decided on CDT and the treatment is successful without any major bleeding.

Clinical Application: In certain centers and in certain PE patients with high risk of bleeding, ultrasound-facilitated CDT may be as effective and may have a lower intracranial hemorrhage potential than full-dose systemic thrombolytics but more data in needed. The existing evidence is still stronger for systemic thrombolytics over ultrasound-facilitated CDT for hypotensive PE patients.

Dr. Essie Reed

What do I tell my patient? You have a large blood clot in your lung. It is in the artery that travels from your heart to your lungs on the right side. This can be life threatening and is currently putting a strain on your heart.

This can be treated with a clot busting medication. However, due to your age and diabetes, you are at higher risk of bleeding from the clot busting medication.

One option is to place a special catheter that reaches all the way to the site of the clot. This catheter stays there for 24hrs and uses a lower dose of the clot busting medicine. It also has an ultrasound device on the catheter that delivers high-frequency sound wave. The ultrasound waves are thought to help the clot busting medicine work better.

This special catheter is a new way to treat blood clots in the lung. There is not as much evidence for this option but it seems to work well and is associated with less bleeding in the brain.

Bonus#2: Dr. David M. Zlotnick

Dr. David Zlotnick

Dr. Zlotnick is one of the intervention cardiologist at the University of Buffalo and the Medical Director of the Pulmonary Embolism Response Team for the Gates Vascular Institute.

We asked him as the local expert and someone who performs CDT to comment on the case and the paper reviewed. Listen to the podcast to hear what he has to say.

Keener Kontest: Last weeks’ winner was Andrew Bohn from Wright Patterson Air Force Base hospital. Andrew knew Dr. Claude Beck is credited with the first successful clinical defibrillation in a human patient.

Listen to the podcast for this weeks’ question. If you think you know the answer send it to TheSGEM@gmail.com with “keener” in the subject line. The first correct answer will receive a cool skeptical prize.

Thank you to the University of Buffalo EM program for inviting me to present Grand Rounds.