Optimal tPA dose/duration using US guided catheter directed thrombolysis for intermediate risk PE

Author: Nimish Bhatt, PGY-2

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Question:

• What is the lowest optimal tPA dose and delivery duration using ultrasound facilitated catheter directed thrombolysis (USCDT) for treatment of acute intermediate risk (submassive) PE?

Background:

• Limited studies on thombolysis of submassive PEs secondary to fear of Intracranial hemorrhage (ICH)
• USCDT – high frequency, low power ultrasound waves – shown in animal/in-vitro models to separate fibrin strands and increase surface area for tPA
  • ULTIMA trial: RV-LV diameter ratio improved at 24h with USCDT vs. AC alone,
    no major bleeding events
  • SEATTLE II trial: RV-LV diameter ratio improved at 48h, major bleeding rate of 10% but no ICH events

Article Reviewed:

• “A Randomized Trial of the Optimum Duration of Acoustic Pulse Thrombolysis
  Procedure in Acute Intermediate-Risk Pulmonary Embolism,” Tapson, Victor F et al, JACC Vol 11 No 14 2018

Methodology:

• Population:
  • US and Europe centers
  • 101 patients – Age 18-75 years
  • Submassive PE in at least 1 main or proximal lobar pulmonary artery, with PE symptoms for <14d, normal Systolic BP, RV-LV diameter ratio <0.9 on Chest CTA
• Outcomes
  • 48 +/- 6 hr after USCDT start
  • Primary:
    • Change in RV-LV diameter Ratio by CTA from baseline
  • Secondary:
    • Change from baseline in embolic burden (modified Miller Score)
• Design
  • Multicenter, parallel-group study
  • 4 regimens
    • Arm 1: USCDT x2hr, tPA 2mg/hr per catheter
    • Arm 2: USCDT x2hr, tPA 1mg/hr per catheter
    • Arm 3: USCDT x6hr, tPA 1mg/hr per catheter
    • Arm 4: USCDT x6hr, tPA 2mg/hr per catheter
    • All also got AC with heparin or low-molecular weight heparin
  • USCDT: done in suite by IR or Cardiologist or vascular surgery within 48hr of diagnostic CTA – 1 vs. 2 catheters placed for unilateral vs. bilateral PEs respectively
    • Procedure was to be stopped if recurrent PE, clinical deterioration, or bleeding in critical organ or with Hg drop >2 or requiring 2U pRBCs
  • Labs: CBC, aPTT, INR, BUN, Cr baseline + 4h post procedure + 48h post procedure; Troponin and BNP included but not required
• Excluded:
  • Stroke,
  • TIA,
  • head trauma,
  • active intracranial/intraspinal disease within 1yr,
  • recent active bleeding from a major organ within 1mo,
  • major surgery within 7d,
  • SBP <90 or use of vasopressors,
  • hematocrit <30%,
  • platelet <100k,
  • INR >3,
  • Cr >normal,
  • hematologic disease involving platelet number or function,
  • high risk for catastrophic bleeding,
  • hx of HIT,
  • Catheter based pharmacomechanical treatment of PE within 3d of the study,
  • cardiac arrest requiring CPR,
  • evidence of irreversible neurological compromise,
  • life expectancy <1yr,
  • use of thombolytics or glycoprotein IIb/IIIa receptor antagonists <3d before USCDT procedure,
  • allergy/hypersensitivity to tPA or contrast (unless mild-moderate and steroid can be used),
  • active cancer (unless nonmelanoma primary skin cancer)

Primary Results:

• RV-LV Diameter ratio:
  • 
• Modified Miller score:
  • 
• No bleeding in Arm 1 72h post start of procedure
• 4 patients had total of 5 major bleeding events and 1 death (arm 4, man developed ICH with CTH findings suggestive of AV malformation)
• 7 patients had clinically relevant nonmajor bleeding in the first 72h
• 1 patient (arm 3) had sympomatic recurrent PE confirmed on CTA, 18d after start

Strengths:

• Randomized
• All imaging studies read by a central lab in blinded manner
• Including RV-LV diameter and Miller score can compare importance of RV-LV diameter ratio and clot burden
• The unilateral PEs were equally distributed among the arms
• All arms demonstrated statistically significant improvement in both outcomes

Limitations:

• Population: not large study especially when divided amongst 4 arms
• Arm 3 had more women, Arm 4 had lower weight/BMI
• Arm 4 stopped after ICH developed – thought to be related to thrombolysis (patient may have been high risk to begin with)
• 86% of patients had bilateral PEs
• # of patients with unilateral PEs too small to analyze meaningfully
• One ICH happened attributed to USCDT, another likely due to redosing of systemic tPA after recurrent massive PE
• Other delivery catheters not compared with one another when used with USCDT

Discussion:

• All arms showed that lower dose thrombolytic therapy with shorter infusion times for submassive PE patients resulted in statistically significant improvement in RV-LV diameter ratio (about 25% decrease in each arm) and modified Miller score (improvement increased as the tPA dose and infusion duration increased) and with low major bleeding rates
• This suggests that there isn’t a direct correlation between the pulmonary arterial
  embolic burden and RV dilation
  • Pouiseuille’s Law? – increases in functional vessel radius can improved
    perfusion even if the clot burden has not decreased much

Conclusion:

• USCDT using lower doses and shorter infusions of thrombolytic therapy in acute
  intermediate-risk PE is associated with
  • an improvement in RV-LV diameter ratio and
  • a reduction in the clot burden at 48h
• This should be further studied and refined in future trials