The Use of Thrombolytics in Pulmonary Embolism

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The Use of Thrombolytics in Pulmonary Embolism

• Internal Medicine Resident
• Grand Rounds
• October 13,1998
• Pamela Harm, M.D.

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Case Presentation

• HPI 80 yowf with PMH significant for HTN, CAD,
  a fib, PUD admitted to NCBH on 8/1/98 with chief
  complaint of SOB. SOB began in 6/98 when she was
  admitted to NCBH. Patient was r/o for MI and had
  negative DSE. Pt was admitted to Northern Hosp.
  Of Surry County in late July with continued SOB,
  was treated with IV antibiotics and D/Ced after 8
  days. Re-presented to NHSC on the same day with
  continued SOB and subsequently was transferred to
  NCBH.
• PMH as above All procainamide SH
  nonsmoker, no etoh
• PE VSS, Afeb, chest clear, otherwise
  unremarkable
• Labs/Data CXR cardiomegaly, clear lung fields.
  EKG Atrial fibrillation, rate 84, inferior q
  waves, no st segment or t wave changes. WBC 18.1
  Bun 60, Cr 2.0, CO2 13

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Hospital Course

• Admitted to Cards A ruled out for MI, Rx with
  macrolide for bronchitis
• Hospital day 3 found to be markedly more
  tachypneic, placed on heparin, V/Q scan ordered
• Echocardiogram EF 45, hypokinetic RV with
  apical AK, echodensity in RV outflow tract most
  c/w thrombus, moderate TR, PA pressure of 61 mmHg
• Suffered respiratory decompensation, transferred
  to CCU.
• Continued to do poorly, developed nosocomial
  pneumonia, was made DNR
• CT scan of chest Total occlusion of right
  pulmonary artery, partial occlusion of left
  pulmonary artery.
• Based on CT scan plans were made with
  interventional radiology for further treatment,
  but ML expired prior to this

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Urokinase vs. Heparin

• UPET trial in 1970- first RCT to look at Lytics
  in PE
• 160 patients with PA-gram proven PE
• Subdivided to groups 1S, 1M, 2S, 2M depending on
  extent of PE and hemodynamic stability
• Prior to randomization underwent V/Q scans, PA
  catheterization
• Received 12 hour UK infusion followed by heparin
  vs. heparin alone
• End points Follow up PA-gram, PA catheter
  measurements, repeat V/Q scans

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UPET Results

• Follow up angiograms showed 44 improvement in UK
  treated group compared to 7 in the heparin group
• Follow up V/Q scans showed statistically
  significant improvement in UK group at 24 hours
  compared to heparin group
• Decrease in all right sided pressures and
  increase in arterial oxygenation in UK group, no
  significant improvement in heparin group

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Percent Improvement in V/Q Scans
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Subgroup Analysis

• All UPET patients were divided in subgroups
  depending on the extent of PE and hemodynamic
  stability
• Patient groups 1 and 2 represented stable and
  unstable patients respectively
• Patient groups M and S represented massive and
  submassive PE respectively
• Patients with large angiographic obstruction and
  severe mismatching on V/Q scans had the greatest
  degree of resolution with UK, a trend not seen in
  heparin group

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UPET Conclusions

• Thrombolysis with Urokinase offers more rapid,
  but not more complete radiographic resolution of
  PE
• UK resulted in lower right heart and PA pressures
• Hypotensive patients with a massive PE treated
  with UK had the greatest improvement
  radiographically

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t-PA vs. Heparin in RCT

• PAIMS-2 trial in 1992 randomized 36 patients with
  angiographically proven PE to receive 100mg t-PA
  followed by heparin vs. heparin alone
• Angiograms and right heart catheterization
  measurements were obtained at baseline and at 2
  hours
• V/Q scans were done at 7 and 30 days

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PAIMS-2 Results

• Significant angiographic improvement was seen in
  the t-PA group
• Significant decrease in pulmonary artery pressure
  was also seen in the t-PA group
• Follow up V/Q scans showed no significant
  difference

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Comparison of ThrombolyticsStreptokinase vs.
Urokinase

• UPET Phase II compared Streptokinase, 12 and 24
  hour Urokinase infusions
• Study adopted the same protocol as UPET phase I
  (endpoints included RH cath, V/Q scans, and PA
  grams)
• UPET phase I was control group
• No differences between all 3 groups

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Comparison of Thrombolyticst-PA vs. Urokinase

• t-PA compared with UK in 1988 RCT
• Pts received 2 hr t-PA infusion or 24 hr UK
  infusion
• Endpoints included 2 hour PA gram and PA catheter
  numbers, and 24 hour V/Q scans
• t-PA showed improvement in 2 hour PA grams and PA
  catheter numbers, no improvement seen in UK group
• No difference in 24 hour V/Q scans

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Effects of t-PA on Right Ventricular Preformance

• 101 hemodynamically stable patients with positive
  angiograms or high probability V/Q scans
• Patients had echocardiographic assessment of RV
  function prior to randomization
• Randomized to 100 mg t-PA or heparin
• Echocardiograms followed at 3hours and 24 hours
• Baseline and 24 hour V/Q scans done
• Also evaluated rate of recurrent PE

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• Significantly lowered RVEDA in t-PA group, not
  seen in heparin group
• V/Q scans significantly improved in t-PA group,
  no change in heparin group
• Rate of recurrent PE not significantly different

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Summary of Randomized Controlled Trials

• SK, UK and t-PA all show significant improvement
  in post treatment angiograms, PA catheter
  measurements compared to heparin
• All thrombolytics showed more rapid, but not more
  complete resolution in V/Q scans
• t-PA results in significantly improved RV
  function when compared with heparin
• No significant differences between UK and SK
• t-PA results in more rapid angiographic clot
  lysis compared to UK
• Pts with massive PE in shock had greatest degree
  of improvement
• No study evaluated pts with duration of symptoms
  gt 14 days

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SO WHAT?????
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Dont Go Dying on Me!

• Jim Carrey
• Dumb and Dumber

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• No study had proven reduction in recurrent PE,
  cor pulmonale, or mortality
• Most studies have been limited by small number of
  patients enrolled and relatively low mortality of
  PE

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Who Should Receive Thrombolytics for Acute PE?

• Based on RCT, patients with high chance of
  mortality in first 24 to 48 hours of presentation
  should be considered for thrombolysis (if
  symptoms present lt 14 days)
• Some authors also recommend screening stable
  patients echocardiographically and including RV
  dysfunction as an indication for thrombolysis

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Thrombolytics for Hemodynamically Stable Patients
with RV DysfunctionGarbage or Gospel?

• Pros
• Mortality of PE pts with RV dysfunction greater
  than with normal function
• Improved mortality seen in pts with abnormal RV
  function who receive lytics vs. heparin

• Cons
• Mortality data derived from non-randomized
  retrospective analysis
• Correlation between RV dysfunction and V/Q scans
• Additional risk of bleeding
• Cost

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Cost analysis

• 500,000 cases/year X 95475,000 stable pts
• 475,000 X 179/echo 85,025,000
• 40 X 475,000 190,000 pts with RV hypokinesis
• 190,000 X 2750/t-PA dose 522,500,000
• 607,525,000 in additional costs

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FDA Approved Thrombolytic Regimens for PE

• Streptokinase 250,000 IU as a loading dose over
  30 minutes, followed by 100,000 U/hr for 24 hours
• Urokinase 4400 IU/kg as a loading dose over 10
  minutes, followed by 4400 IU/kg/hr for 12-24
  hours
• t-PA 100mg over 2 hours

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Contraindications

• History of CVA or other CNS disease
• Hypertension (SBPgt180 or DBPgt110)
• Trauma or Surgery within past 14 days
• History of internal bleeding within past 3-6
  months
• Known bleeding diathesis
• Pregnancy

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Rate of Complications

• Most data regarding thrombolytic associated
  bleeding comes from AMI studies
• CNS bleeding rates from AMI trials range from
  0.2 to 1.6
• Overall bleeding complications stated at 5 when
  coronary angiography not involved, 30 when
  angiography involved
• Data may not be applicable to PE population

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Complications Continued

• Retrospective analysis of thrombolysis in PE was
  done in two papers
• Analysis of 719 PE patients cited rate of overall
  bleeding in lytic group as 21.9 vs. 7.8 in
  heparin group. Rate of ICH in lytic group was
  1.2 vs. 0.4 in heparin group
• Analysis of 312 patients with PE who received
  t-PA, UK, or SK cited rate of overall bleeding at
  20 and rate of CNS bleeding of 7.5

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Relative Risks of Bleeding with Thrombolytics
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• 21.9 risk of bleeding in lytic group
• 7.8 risk of bleeding in heparin group
• ARR21.9-7.814.1
• NNT1/14.17
• If hemodynamically stable patients with RV
  dysfunction are treated with heparin instead of
  lytics approximately 26,000 bleeding
  complications could possibly be avoided

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Other Options

• Surgical Embolectomy
• Catheter Based Embolectomy
• Catheter Fragmentation
• Intraembolic thrombolytics
• IVC interruption devices

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Summary

• Role of thrombolytics in PE remains limited due
  to lack of mortality benefit, associated risks,
  and relatively good prognosis in treated PE
• Patients critically ill secondary to PE should be
  considered for lytic therapy
• Role of thrombolysis in stable patients with RV
  dysfunction not well defined, probably not
  indicated yet
• Overall bleeding risk approximately 20 age,
  angiography and obesity are risk factors. Rate of
  ICH is 1.2 to 7.5

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• Thank You!
• Dr. R. Duncan Hite
• Dr. Andrew Namen
• Dr. Raquel Watkins

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THE END