Catheter Directed Thrombolysis: The Magic Bullet for Submassive Pulmonary Embolism?

Background: When evaluating therapeutic options for PE, there are three categories in my mind: Subsegmental, Submassive, and Massive. For simplicity sake lets just say subsegmental PEs get treated with anticoagulation and massive PEs get treated with thrombolysis. The submassive category is a bit trickier. For example the PEITHO trial looked at full dose systemic fibrinolysis, tenecteplace in intermediate-risk pulmonary embolism and found a reduced risk of death or cardiovascular collapse by 56% but this was offset by an almost 5-fold increased risk of major bleeding and 10-fold increased risk of intracranial hemorrhage compared to anticoagulation alone. The MOPETT Trial on the other hand, looked at half dose systemic tPA for submassive PE and found that there was a significant reduction in pulmonary artery systolic pressures at 28 months vs usual care, with no increase in intracranial hemorrhage but failed to show any statistical mortality benefit compared to anticoagulation alone. Maybe a more simple answer to the submassive PE group would be to do catheter directed thrombolysis at lower doses than given with systemic fibrinolysis.

What Study are we Evaluating?

Piazza G et al. A prospective, Single-Arm, Multicenter Trial of Ultrasound-Facilitated, Catheter-Directed, Low-Dose Fibrinolysis for acute Massive and Submassive Pulmonary Embolism: The SEATTLE II Study. JACC 2015; 8(10): 1382 – 92. PMID: 26315743

What They Did:

• Prospective, Single-Arm, Multicenter Trial from 22 sites across the United States
• Evaluate the Safety and Efficacy of Ultrasound-Facilitated, Catheter-Directed, Low-Dose Fibrinolysis
• Initiation of anticoagulation + 24mg of tissue-plasminogen activator (t-PA) at 1mg/hr with single catheter for 24hrs or 1mg/hr/catheter for 12hrs with bilateral catheters
• Patients with proximal PE and Right Ventricle to Left Ventricle Ratio (RV:LV) ≥9 on Chest CT
• Inclusion Criteria: Massive or submassive PE AND symptoms ≤14d AND RV/LV diameter ratio ≥9 on contrast-enhanced CT.
• Exclusion Criteria: CVA/TIA, Head Trauma, Active Intracranial or Intraspinal Diseases Within 12 Months, Major Surgery Within 7 days, Recent Active Bleeding from a Major Organ, Hct <30%, Plts <100,000/uL, INR >3, Serum Cr > 2mg/dL, SBP <80mmHg despite vasopressor or inotropic support

Outcomes:

• Primary Safety Outcome: Major Bleeding within 72hrs of initiation
• Primary Efficacy Outcome: Change in the Chest CT Measured RV/LV diameter ratio within 48hrs of procedure initiation

Definitions:

• Severe or Life-Threatening Bleed = ICH or Bleeding that Caused Hemodynamic Compromise and Required Intervention
• Moderate Bleeding = Required Blood Transfusion but did not Result in Hemodynamic Compromise
• Mild Bleeding = Did NOT meet criteria for Severe or Moderate Bleeding
• Massive PE = PE with Syncope, Systemic Arterial Hypotension, Cardiogenic Shock, or Resuscitated Cardiac Arrest
• Submassive PE = Normotensive with PE and Evidence of RV Dysfunction
• Modified Miller Index Score = I had to look this up, so figured I would share. Quantifies the amount of clot burden seen on CT. This is a score that goes from 0 – 16, with 16 being the highest. The breakdown is that there are 9 segmental branches of the right lung and 7 segmental branches in the left lung totaling 16 segments. For each segment that has a filling defect, one point is assigned. If there is a more proximal filling defect then the number of segmental branches affected distally would be totaled up. For example a filling defect in the right main pulmonary artery would score 9 points.

Results:

• 150 patients included in analysis
  • 31 with massive PE
  • 119 with submassive PE

• Efficacy Outcomes
  • Mean RV/LV diameter ratio decreased from baseline 48hrs post procedure (1.55 vs 1.13)
  • Mean pulmonary artery systolic pressure decreased from baseline 48hrs post procedure (51.4mmHg vs 36.9mmHg)
  • Modified Miller Index Score decreased from baseline 48hrs (22.5 vs 15.8)
• Safety Outcomes
  • 1 severe bleeding event occurred with 72hrs of procedure (Groin hematoma with transient hypotension)
  • 15 moderate bleeding events occurred within 72hrs of procedure (10% of patients)
  • NO intracranial hemorrhage

Strengths:

• Enrolled 150 patients in 9 months
• Patient population was 50% female and 50% male with diverse ethnicities allowing for generalization to many practice settings

Limitations:

• No comparison (i.e. anticoagulation alone, full dose or half dose systemic thrombolysis) or placebo arms
• Several patients did not undergo follow up chest CT or echo and missing data could have biased results in favor of greater or even diminished efficacy of treatment benefit.
• All the endpoints were surrogate endpoints (i.e. RV/LV diameter, pulmonary pressures, Modified Miller Index), but there was no mention of quality of life measurements.
• Interestingly, one of the safety outcomes was bleeding at 72 hours. The reason this is interesting is if you look at the pharmacokinetics of tPA the half life is approximately 5 minutes and with the terminal elimination phase being approximately 40 minutes. Stated another way half of tPA is cleared from the plasma within 5 minutes after discontinuation and approximately 80% cleared from the plasma at 10 minutes. So how does one know if the bleeding events were from the tPA in and of itself or the anticoagulation after the procedure? Wouldn’t a better safety outcome been to have looked for bleeding at 15 or 27 hours, depending on whether you got 12 hours vs 24 hours of tPA, and then 72 hours?

Discussion:

• In this study there was a 25% decrease in CT-measured RV/LV diameter ratio at 48 hours, a 30% decrease in pulmonary arterial systolic pressure by the end of the procedure, and a 30% decrease in pulmonary artery angiographic obstruction over 48 hours with zero intracranial hemorrhages.
• A decrease in RV/LV ratio is a surrogate marker of improvement in morbidity and functional status, but is not a clinical endpoint. Further studies would be required to see if this surrogate endpoint correlates with clinical outcomes (i.e. Hemodynamic Collapse, Quality of Life, and Mortality).

Author Conclusion: Ultrasound-facilitated, catheter-directed, low-dose fibrinolysis decreased RV dilation, reduced pulmonary hypertension, decreased anatomic thrombus burden, and (Compared to systemic thrombolytic reports) minimized intracranial hemorrhage in patients with acute massive and submassive PE.

Clinical Take Home Point: In patients with massive and submassive PEs, catheter directed, reduced dose thrombolysis is safer than systemic thrombolysis, and may be the magic bullet for submassive PEs, but further studies with comparison arms and clinically meaningful outcomes are still needed.

References:

1. Piazza G et al. A prospective, Single-Arm, Multicenter Trial of Ultrasound-Facilitated, Catheter-Directed, Low-Dose Fibrinolysis for acute Massive and Submassive Pulmonary Embolism: The SEATTLE II Study. JACC 2015; 8(10): 1382 – 92. PMID: 26315743
2. Meyer G et al. Fibrinolysis for Patients with Intermediate-Risk Pulmonary Embolism. NEJM 2014; 370(15): 1402 -11. PMID: 24716681
3. Sharifi et al. Moderate pulmonary embolism treated with thrombolysis (from the “MOPETT” Trial). Am J Cardiol 2013; 111 (2): 273 – 277. PMID: 23102885
4. Kuo WT et al.Pulmonary Embolism Response to Fragmentation, Embolectomy, and Catheter Thrombolysis (PERFECT): Initial Results From a Prospective Multicenter Registry. CHEST 2015; 148 (3): 667 – 73. PMID: 25856269
5. Kucher N et al. Randomized, Controlled Trial of Ultrasound-Assisted Catheter-Directed Thrombolysis for Acute Intermediate-Risk Pulmonary Embolism. Circulation. 2014;129(4):479-486. PMID: 24226805

Post Peer Reviewed By: J. Scott Wieters (Twitter: @EMedCoach)