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Catheter-directed thrombectomy          Massive and submassive PE          Justin McWilliams, MD and Scott Genshaft, MD   ...
42 y/o femaleChest painShortness of breath
   CT shows large bilateral saddle emboli   Blood pressure 84/58   Heart rate 110   O2 sat 90% on 4L NC   Bleeding ul...
Pulmonary artery pressure: 55/13
5 F pigtail rotationNo improvement
5 cm infusion lengthMcNamara lysiscatheter10 mg tPA givenacross each main PAStill no improvement
Repeat pigtail rotation
Remains hypotensiveTachycardic to 130s
6F Angiojet activatedacross clotHypotension andoxygenation improved
next morning
PE basics
pathophysiology of PEJaff MR et al. Management of massive and submassive pulmonary embolism, iliofemoral deep vein thrombo...
definitions     Massive PE: Acute PE with sustained hypotension      (SBP <90 mmHg) for at least 15 minutes without      ...
definitions     Submassive PE: Acute PE without systemic      hypotension but with either RV dysfunction or      myocardi...
definitions     Low-risk PE: Everybody else     Short-term mortality about 1%    Jaff MR et al. Management of massive an...
anticoagulation versus thrombolysis     Heparin allows passive reduction of thrombus size         No substantial improve...
treatment of PE   Systemic anticoagulation   IV thrombolytics       Standard FDA-approved therapy for PE with hemodynam...
ACCP 2012 recommendations     In patients with acute PE associated with      hypotension (eg, systolic BP <90 mmHg) who d...
Jaff MR et al. Management of massive and submassive pulmonary embolism, iliofemoral deep vein thrombosis, and chronicthrom...
contraindications to systemic lysisAbsolute                      Relative   Any prior intracranial       Age >75    hemo...
contraindications to systemic lysisHalf of all patients with acute PE have contraindications                     to system...
systemic lysis in massive PEThe good                                                               The bad     Recurrent ...
is there a better way?
catheter-directed therapy for                 massive PE
catheter-directed therapy (CDT)   Alternative or additive    treatment for massive PE   Wide variety of devices    and t...
techniques – pigtail rotation
techniques – balloon angioplasty
techniques – aspiration thrombectomy
techniques – rheolytic aspiration
techniques – ultrasound-aided thrombolysis
history of CDT for PE   Verstraete et al 1988: 34 randomized patients, no    benefit seen for PA lysis over IV systemic l...
ACCP 2008 recommendations     “For most patients with PE, we recommend against      use of interventional catheterization...
CDT: meta-analysis     Meta-analysis of CDT for massive PE         6 prospective, 29 retrospective uncontrolled studies ...
CDT: analysis of the meta-analysis     Pooled clinical success rate of 86.5%         96% received CDT as 1st adjunct to ...
IV tPA vs. CDT for massive PEIV tPA (ICOPER registry)                                                 CDT (Stanford meta-a...
CDT for massive PE: the good and badThe good                                                                   The bad1.  ...
CDT for massive PE: consensus statementsAHA 2011                                                                   ACCP 20...
CDT for massive PE: controversies   Should CDT replace IV tPA as first-line therapy at    institutions with expertise?   ...
PERFECT registry   Pulmonary Embolism Response to Fragmentation,    Embolectomy, & Catheter Thrombolysis   Prospective o...
Catheter-directed thrombectomy              for submassive PE
submassive pulmonary embolism
submassive pulmonary embolism     “No consensus on the exact definition of “submassive”      or “intermediate-risk” PE ex...
prognosticating in submassive PE     Imaging         Echocardiogram              Presence of RV dysfunction doubles all...
right heart dysfunction   RV:LV ratio > 0.9 has been shown to be a predictor of    in-hospital mortality     1.9% if RV/...
submassive pulmonary embolism
clinical outcomes of submassive PE   3-12 % inpatient mortality   1-5% develop Chronic Thromboembolic Disease with    PAH
ACCP 2012 guidelines for submassive PE  5.6.1.2. In most patients with acute PE not associated with  hypotension, we recom...
AHA 2011 guidelines for submassive PE   1. Fibrinolysis may be considered for patients with submassive acute PE    judged...
Piazza G, Goldhaber SZ. Management of submassive pulmonary embolism. Circulation 2010; 122:1124–1129
role of IR in submassive PE   Role of catheter directed treatment of submassive PE was slotted    for “Hot Topic” debate ...
Role for catheter treatment of submassivePE requires an answer to these questions   How important is rapid clearance of t...
Role for catheter treatment of submassivePE requires an answer to these questions   How important is rapid clearance of t...
role of thrombolysis in submassive PE   Registries have failed to show a survival benefit in    patients with submassive ...
role of thrombolysis in submassive PE   Meta-analysis of 9 randomized control trials of    thrombolytics and heparin in t...
role of thrombolysis in submassive PE     Management Strategies and Prognosis of Pulmonary      Embolism Trial 3       2...
1/27 UFH  2/ 7 t-PA  2/11
role of thrombolysis in submassive PE   Kline et al evaluated echocardiograms in patients with    submassive PE at the ti...
5/20112/2012
chronic thromboembolic disease
Role for catheter treatment of submassivePE requires an answer to these questions   How important is rapid clearance of t...
comparative effectiveness of IV tPA vs. CDTfor submassive PE   We don’t know   Literature regarding catheter based appro...
submassive PE: pigtail delivery of tPA
submassive PE: Angiojet
submassive PE: thrombectomy andovernight thrombolysis
submassive PE: pulse-spray lysis
evidence needed   Clinical benefits of escalation of therapy for acute PE    beyond anticoagulation?     Reduction of mo...
active clinical trials   PERFECT   PEITHO   ULTIMA   SEATTLE I and II
ongoing clinical trials   PEITHO STUDY       Pulmonary Embolism Thrombolysis trial       Prospective, multicenter, rand...
PEITHO trial criteria
PEITHO trial design
ULTIMA trial   ULTrasound Accelerated ThrombolysIs of PulMonAry    Embolism   Comparison of ultrasound-accelerated throm...
ULTIMA trial   Primary endpoint     Reduction of RV/LV ratio: RV/LV ratio will be      measured by echocardiography at b...
SEATTLE II   Submassive and massive pulmonary Embolism    treatment with AcceleraTed ThromboLysis thErapy   Question: Wi...
SEATTLE II   Primary outcomes     RV:LV Diameter Ratio measured at 48 hours     Major bleeding at 72 hours   Inclusion...
summary   The role of early thrombolysis in treatment of massive    and submassive PE is not well defined and currently  ...
Stanford PE protocol   Massive PE       Anesthesia involved when possible       8F sheath into common femoral vein, sel...
Proposed CDT recommendations by JVIR     SBP <90 mmHg or drop >40 mmHg     Cardiogenic shock with hypoxia     Circulato...
systemic thrombolysisPotential benefits             Potential harm   More rapid symptom            Hemorrhage    resolut...
systemic thrombolysis     In hemodynamically unstable patients, systemic lysis      reduces recurrent PE and death (OR 0....
Intraclot lytic injection is essential     Proximal vortex    Schmitz-Rode T, Kilbinger M, Gunther RW. Simulated flow pat...
catheter-directed lysis     111 patients with massive PE had CDT         200k-500k units of urokinase in situ         M...
ACCP 2012 recommendations     “In patients with acute PE associated with      hypotension and who have (i) contraindicati...
devices and techniques   Pigtail rotation       Cheap, easy, accessible, can debulk proximal emboli   Aspiration thromb...
Catheter-guided lysis     25 patients with massive PE had 33 catheter interventions          EKOS in 15          Standa...
CDT devices/techniques   Pigtail rotation (314)   Pigtail rotation with adjunctive measures (94)   Aspiration thrombect...
Intrapulmonary administration of Lytics   A study from 1992 found no signification difference between IV    and PA admini...
tPA Contraindications   Active internal bleeding   History of CVA in last 6 months?   Recent neurosurgery or head traum...
Relative CI to tPA   Recent major surgery   CV disease   Recent GI or GU bleeding   Recent trauma   SBP >175 or DBP >...
Major hemorrhage from tPA     Independent predictors of major hemorrhage in PE      patients treated with systemic tPA   ...
Major hemorrhage from tPA     Acute MI: 5% major, 1% intra-cerebral     Acute PE (Fiumura): 19% major, 5% intra-cerebral...
Controversies   Bradyarrhthymia and hemolysis from rheolytic    thrombectomy   Fears of vascular perforation   “A doubl...
Meta-analysis   0 RCTs   6 prospective trials   29 retrospective reviews   594 patients   All level 2 and 3 evidence...
CASE: Thrombectomy followed by overnightperipheral thrombolysis     Initial               3 days later
Role for catheter treatment of submassivePE requires an answer to these questions   How important is rapid clearance of t...
thrombolysis and hemorrhage   Half of patients have a contraindication to thrombolysis   20% major hemorrhage rate when ...
OnGOING CLINICAL TRIALS   PERFECT 1     Pulmonary Embolism Response to Fragmentation,      Embolectomy, & Catheter Throm...
ACCP 2012 recommendations     In patients with acute PE associated with      hypotension (eg, systolic BP <90 mmHg) who d...
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  1. 1. Catheter-directed thrombectomy Massive and submassive PE Justin McWilliams, MD and Scott Genshaft, MD UCLA Interventional Radiology
  2. 2. 42 y/o femaleChest painShortness of breath
  3. 3.  CT shows large bilateral saddle emboli Blood pressure 84/58 Heart rate 110 O2 sat 90% on 4L NC Bleeding ulcer 2 mo ago
  4. 4. Pulmonary artery pressure: 55/13
  5. 5. 5 F pigtail rotationNo improvement
  6. 6. 5 cm infusion lengthMcNamara lysiscatheter10 mg tPA givenacross each main PAStill no improvement
  7. 7. Repeat pigtail rotation
  8. 8. Remains hypotensiveTachycardic to 130s
  9. 9. 6F Angiojet activatedacross clotHypotension andoxygenation improved
  10. 10. next morning
  11. 11. PE basics
  12. 12. pathophysiology of PEJaff MR et al. Management of massive and submassive pulmonary embolism, iliofemoral deep vein thrombosis, and chronicthromboembolic pulmonary hypertension: a scientific statement from the American Heart Association. Circulation 2011; 123:1788-1830.
  13. 13. definitions Massive PE: Acute PE with sustained hypotension (SBP <90 mmHg) for at least 15 minutes without other cause  Or drop in SBP >40 mmHg  Or pulselessness/cardiac arrest  Or HR <40 with signs or symptoms of shock Massive PE inpatient mortality is 15-50% Jaff MR et al. Management of massive and submassive pulmonary embolism, iliofemoral deep vein thrombosis, and chronic thromboembolic pulmonary hypertension: a scientific statement from the American Heart Association. Circulation 2011; 123:1788-1830.
  14. 14. definitions Submassive PE: Acute PE without systemic hypotension but with either RV dysfunction or myocardial necrosis  RV dysfunction could include:  RV dilation on echo or CT (RV diameter/LV diameter >0.9)  Elevation of BNP (>90 pg/mL)  EKG changes (new RBBB, anteroseptal ST changes, anteroseptal TWI)  Myocardial necrosis is defined as troponin I >0.4 ng/mL Inpatient mortality of submassive PE is 5-12% Jaff MR et al. Management of massive and submassive pulmonary embolism, iliofemoral deep vein thrombosis, and chronic thromboembolic pulmonary hypertension: a scientific statement from the American Heart Association. Circulation 2011; 123:1788-1830.
  15. 15. definitions Low-risk PE: Everybody else Short-term mortality about 1% Jaff MR et al. Management of massive and submassive pulmonary embolism, iliofemoral deep vein thrombosis, and chronic thromboembolic pulmonary hypertension: a scientific statement from the American Heart Association. Circulation 2011; 123:1788-1830.
  16. 16. anticoagulation versus thrombolysis Heparin allows passive reduction of thrombus size  No substantial improvement in first 24 hours  65-70% reduction in perfusion defect by 7 days Thrombolysis actively promotes hydrolysis of fibrin  Convert native circulating plasminogen into plasmin  Plasmin cleaves fibrin, lysing the thrombus  30-35% reduction in perfusion defect in first 24 hours  65-70% reduction in perfusion defect by 7 days Jaff MR et al. Management of massive and submassive pulmonary embolism, iliofemoral deep vein thrombosis, and chronic thromboembolic pulmonary hypertension: a scientific statement from the American Heart Association. Circulation 2011; 123:1788-1830.
  17. 17. treatment of PE Systemic anticoagulation IV thrombolytics  Standard FDA-approved therapy for PE with hemodynamic instability  100 mg tPA IV over 2 hours Catheter directed therapy – uncertain indications  Thrombolytic infusion  Mechanical thrombolysis  Mechanical thrombectomy Surgical embolectomy
  18. 18. ACCP 2012 recommendations In patients with acute PE associated with hypotension (eg, systolic BP <90 mmHg) who do not have a high bleeding risk, we suggest systemically administered thrombolytic therapy over no such therapy (Grade 2C) Guyatt GH, et al. Executive summary: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians evidence-based practice guidelines. Chest 2012;141: 2 suppl 7S-47S.
  19. 19. Jaff MR et al. Management of massive and submassive pulmonary embolism, iliofemoral deep vein thrombosis, and chronicthromboembolic pulmonary hypertension: a scientific statement from the American Heart Association. Circulation 2011; 123:1788-1830.
  20. 20. contraindications to systemic lysisAbsolute Relative Any prior intracranial  Age >75 hemorrhage  Current anticoagulation Brain AVM or tumor  Pregnancy CVA in last 3 months  Noncompressible vascular Active bleeding or puncture bleeding diathesis  Traumatic/prolonged CPR Recent surgery  Internal bleeding in last encroaching on spinal month canal or brain  Uncontrolled HTN (SBP >180 or DBP >110) Recent significant head  Remote stroke trauma  Major surgery in last 3 weeks
  21. 21. contraindications to systemic lysisHalf of all patients with acute PE have contraindications to systemic lysisPiazza G, Goldhaber SZ. Management of submassive pulmonary embolism. Circulation 2010; 122:1124-1129.
  22. 22. systemic lysis in massive PEThe good The bad Recurrent PE or death is  Overall major bleeding rate reduced from 19.0% to 9.4% of ~20% compared to heparin alone  Intracranial hemorrhage rate ~3% 30% reduction in PA pressures  Effects not immediate (2 hour infusion + time for drug 15% increase in cardiac to work) index  Many patients are Noninvasive contraindicated Marshall PS, Mathews KS, Siegel MD. Diagnosis and management of life-threatening pulmonary embolism. J Intensive Care Med 2011;26:275-294.
  23. 23. is there a better way?
  24. 24. catheter-directed therapy for massive PE
  25. 25. catheter-directed therapy (CDT) Alternative or additive treatment for massive PE Wide variety of devices and techniques, with the goal of rapidly reducing clot burden  Thrombus fragmentation  Thrombus aspiration  Intra-thrombus lytic administration
  26. 26. techniques – pigtail rotation
  27. 27. techniques – balloon angioplasty
  28. 28. techniques – aspiration thrombectomy
  29. 29. techniques – rheolytic aspiration
  30. 30. techniques – ultrasound-aided thrombolysis
  31. 31. history of CDT for PE Verstraete et al 1988: 34 randomized patients, no benefit seen for PA lysis over IV systemic lysis (50 mg tPA)  Administered lytics into the main trunk of the PA  Did not place lytic directly into thrombus  No mechanical fragmentation or aspiration of the thrombus Tapson et al 1994: Animal model showed that intra-thrombus administration of lytic was faster and more effective  Improves exposure of drug to thrombus surface Fava et al 1997: 17 patients, intraclot fragmentation + lysis produced clinical improvement in 88% Dozens more studies over the next decade, all observational, using a wide variety of devices, lytic agents, regimens
  32. 32. ACCP 2008 recommendations “For most patients with PE, we recommend against use of interventional catheterization techniques except in selected highly compromised PE patients who are unable to receive thrombolytic therapy because of bleeding risk, or whose critical status does not allow sufficient time for thrombolytic therapy to be effective.” Kearon C et al. Antithrombotic therapy for venous thrombembolic disease:American College Chest Physicians evidence-based clinical practice guidelines (8th edition). Chest 2008;133:454S-545S.
  33. 33. CDT: meta-analysis Meta-analysis of CDT for massive PE  6 prospective, 29 retrospective uncontrolled studies (level 2)  Total 594 patients  Variety of techniques, most commonly pigtail rotation (70%) combined with intraclot lysis [on-table (67%) and/or via infusion catheter (60%)] Clinical success in 86.5%  Stabilized hemodynamics, resolved hypoxia, and survival to discharge  Compare to 77% survival rate in ICOPER Major hemorrhage in 2.4%, only one case of cerebral hemorrhage (0.2%)  Compare to 22% major hemorrhage rate and 3% cerebral hemorrhage rate in ICOPER Catheter-directed therapy may be considered a first-line treatment option in lieu of IV tPA Kuo WT, et al. Catheter-directed therapy for the treatment of massive pulmonary embolism: systematic review and meta-analysis of modern techniques. J Vasc Interv Radiol 2009;20:1431-1440.
  34. 34. CDT: analysis of the meta-analysis Pooled clinical success rate of 86.5%  96% received CDT as 1st adjunct to heparin (no prior systemic lysis)  33% initiated with mechanical treatment alone – no on-table lytic drug Minor complication rate 8%  Groin hematoma  Bradycardia, renal insufficiency, hemoglobinuria, hemoptysis, heart block (all Angiojet)  Embolus dislocation  PA dissection Major complication rate 2.4%  Large groin hematoma (pRBC)  Non-cerebral hemorrhage (pRBC)  Severe hemoptysis  Renal failure  Central vascular perforation causing tamponade  5 deaths (all Angiojet) – bradycardia, apnea, widespread distal embo, ICH Kuo WT, et al. Catheter-directed therapy for the treatment of massive pulmonary embolism: systematic review and meta-analysis of modern techniques. J Vasc Interv Radiol 2009;20:1431-1440.
  35. 35. IV tPA vs. CDT for massive PEIV tPA (ICOPER registry) CDT (Stanford meta-analysis) 2454 patients, global  594 patients, global 304 treated with IV lysis  All treated with mechanical thrombectomy +/- catheter-directed lysis 1/3 were hemodynamically unstable  All hemodynamically unstable 23% PE mortality  13.5% PE mortality 22% major complications  2.4% major complications 3% cerebral hemorrhage  <0.2% cerebral hemorrhage Kuo WT, et al. Catheter-directed therapy for the treatment of massive pulmonary embolism: systematic review and meta-analysis of modern techniques. J Vasc Interv Radiol 2009;20:1431-1440.
  36. 36. CDT for massive PE: the good and badThe good The bad1. Less invasive than surgery 1. No universal protocol 2. Off-label use2. Can quickly debulk central PE, without needing 2 hour infusion 3. Limited availability/expertise3. Useful when IV tPA fails or is 4. May delay treatment if angio contraindicated suite not ready 5. Fear of complications (Angiojet)4. Appears safer than systemic lysis (~20 mg tPA vs. 100 mg tPA) Guyatt GH, et al. Executive summary: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians evidence-based practice guidelines. Chest 2012;141: 2 suppl 7S-47S. Jaff MR et al. Management of massive and submassive pulmonary embolism, iliofemoral deep vein thrombosis, and chronic thromboembolic pulmonary hypertension: a scientific statement from the American Heart Association. Circulation 2011; 123:1788-1830.
  37. 37. CDT for massive PE: consensus statementsAHA 2011 ACCP 20121. Reasonable for patients with 1. Suggested for massive PE with massive PE and contraindication to thrombolysis contraindications to lysis (class (grade 2C) IIa) 2. Suggested for massive PE with failed thrombolysis (grade 2C)2. Reasonable for patients with massive PE who remain unstable after systemic lysis 3. Suggested for massive PE with (class IIa) shock likely to cause death within hours (grade 2C) Guyatt GH, et al. Executive summary: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians evidence-based practice guidelines. Chest 2012;141: 2 suppl 7S-47S. Jaff MR et al. Management of massive and submassive pulmonary embolism, iliofemoral deep vein thrombosis, and chronic thromboembolic pulmonary hypertension: a scientific statement from the American Heart Association. Circulation 2011; 123:1788-1830.
  38. 38. CDT for massive PE: controversies Should CDT replace IV tPA as first-line therapy at institutions with expertise?  Delay in treatment? Should CDT be an adjunctive treatment to IV tPA?  Perform in all patients, stopping the IV infusion once the angio suite is ready?  Perform only in patients where IV tPA did not work? What regimen should be used?  Which mechanical thrombectomy device is best?  Should on-table lysis be performed?  Should prolonged intra-thrombus lytic infusion be performed? What contraindications are truly contraindications for CDT?
  39. 39. PERFECT registry Pulmonary Embolism Response to Fragmentation, Embolectomy, & Catheter Thrombolysis Prospective observational trial Primary outcome measures  Resolution of hypoxia (post-procedure and 3 months)  Survival from acute PE (post-procedure and 3 months)  Stabilization of hemodynamics (post-procedure and 3 months) Estimated completion in 2014
  40. 40. Catheter-directed thrombectomy for submassive PE
  41. 41. submassive pulmonary embolism
  42. 42. submassive pulmonary embolism “No consensus on the exact definition of “submassive” or “intermediate-risk” PE exists to date.” Normotensive patient with predictors of poor outcome Evidence that several factors predict poor outcome in normotensive patients with PE PEITHO Investigators, American Heart Journal, Volume 163, Issue 1, Jan 2012, Pg 33-38
  43. 43. prognosticating in submassive PE Imaging  Echocardiogram  Presence of RV dysfunction doubles all-cause mortality at 3 months  Useful to differentiate low-risk from submassive PE  CTA  Signs of RV strain correlate well with echo Cardiac biomarkers  Troponin I  Released from RV in response to pressure overload and RV ischemia/infarction  Meta-analysis: elevated troponin increases mortality risk of PE 6-fold  Troponin I <0.07 ng/mL has 98% negative predictive value for in-hospital mortality  BNP  Neurohormone sythesized and released by the ventricles in response to strain  May take several hours after onset of RV strain to see increased BNP  BNP <50-85 has 99% negative predictive value for death in normotensive patients  Because of high NPV, a low troponin or BNP level may mean echo not needed D-dimer  93% sensitive for segmental PE or larger, 50% sensitive for subsegmental PE  D-dimer <1500 mcg/mL has 99% NPV for 3-month all-cause mortality Marshall PS, Mathews KS, Siegel MD. Diagnosis and management of life-threatening pulmonary embolism. J Intensive Care Med 2011;26:275-294.
  44. 44. right heart dysfunction RV:LV ratio > 0.9 has been shown to be a predictor of in-hospital mortality  1.9% if RV/LV < 0.9  6.6% if RV/LV > 0.9Fremont B, Pacouret G, Jacobi D. CHEST 2008;133:358-362
  45. 45. submassive pulmonary embolism
  46. 46. clinical outcomes of submassive PE 3-12 % inpatient mortality 1-5% develop Chronic Thromboembolic Disease with PAH
  47. 47. ACCP 2012 guidelines for submassive PE 5.6.1.2. In most patients with acute PE not associated with hypotension, we recommend against systemically administered thrombolytic therapy (Grade 1C). 5.6.1.3. In selected patients with acute PE not associated with hypotension and with a low risk of bleeding whose initial clinical presentation or clinical course after starting anticoagulant therapy suggests a high risk of developing hypotension, we suggest administration of thrombolytic therapy (Grade 2C). 5.6.2.2. In patients with acute PE, when a thrombolytic agent is used, we suggest administration through a peripheral vein over a pulmonary artery catheter (Grade 2C).
  48. 48. AHA 2011 guidelines for submassive PE 1. Fibrinolysis may be considered for patients with submassive acute PE judged to have clinical evidence of adverse prognosis (new hemodynamic i stability, worsening respiratory insufficiency, severe RV dysfunction, or major myocardial necrosis) and low risk of bleeding complications (Class IIb; Level of Evidence C). 2. Fibrinolysis is not recommended for patients with low-risk PE (Class III; Level of Evidence B) or submassive acute PE with minor RV dysfunction, minor myocardial necrosis, and no clinical worsening (Class III; Level of Evidence B). 3. Either catheter embolectomy or surgical embolectomy may be considered for patients with submassive acute PE judged to have clinical evidence of adverse prognosis (new hemodynamic instability, worsening respiratory failure, severe RV dysfunction, or major myocardial necrosis) (Class IIb; Level of Evidence C). 4. Catheter embolectomy and surgical thrombectomy are not recommended for patients with low-risk PE or submassive acute PE with minor RV dysfunction, minor myocardial necrosis, and no clinical worsening (Class III; Level of Evidence C).
  49. 49. Piazza G, Goldhaber SZ. Management of submassive pulmonary embolism. Circulation 2010; 122:1124–1129
  50. 50. role of IR in submassive PE Role of catheter directed treatment of submassive PE was slotted for “Hot Topic” debate at SIR 2012 Rationale for CDT in submassive PE  Rapid debulking of thrombus  Prevention of adverse outcomes  Early  Worsening right ventricular afterload/cardiac ischemia, respiratory compromise  Late  Chronic thromboembolic disease and pulmonary hypertension  Limit dose of thrombolytic  Reduction in hemorrhage rate
  51. 51. Role for catheter treatment of submassivePE requires an answer to these questions How important is rapid clearance of thrombus?  Role of thrombolysis How does the effectiveness of catheter directed thrombolysis compare to systemically delivered lytic agents?
  52. 52. Role for catheter treatment of submassivePE requires an answer to these questions How important is rapid clearance of thrombus?  Role of thrombolysis How does the effectiveness of catheter directed thrombolysis compare to systemically delivered lytic agents?
  53. 53. role of thrombolysis in submassive PE Registries have failed to show a survival benefit in patients with submassive PE Jaff 2011
  54. 54. role of thrombolysis in submassive PE Meta-analysis of 9 randomized control trials of thrombolytics and heparin in treatment of acute PE  461 patients included in analysis  Mortality  4.6% lytic  7.7% heparin  Bleeding  12.9% lytic (2.1% fatal)  8.6% heparin  Recurrence of PE slightly decreased in lytic group Agnelli. Arch Internal Medicine 2002
  55. 55. role of thrombolysis in submassive PE Management Strategies and Prognosis of Pulmonary Embolism Trial 3  256 patients randomized to  100 mg tPA administered IV over 2 hours followed by infusion of unfractionated heparin  Placebo + heparin  tPA group had lower rate of in-hospital death or escalation of care  Largely attributed to escalation of care Konstantinides S, Geibel A, Heusel G, Heinrich F, Kasper W. Heparin plus alteplase compared with heparin alone in patients with submassive pulmonary embolism. N Engl J Med 2002; 347:1143–1150.
  56. 56. 1/27 UFH  2/ 7 t-PA  2/11
  57. 57. role of thrombolysis in submassive PE Kline et al evaluated echocardiograms in patients with submassive PE at the time of diagnosis and at 6 months  Two groups  Heparin  tPA + heparin  Pts treated with tPA had a greater median decrease in pulmonary systolic pressure  22 mmHg vs 2 mmHg  6 months – PA pressure elevated in 27% of pts treated with only heparin  50% of patients had symptoms of PAH Kline JA, Steuerwald MT, Marchick MR, Hernandez-Nino J, Rose GA. Prospective evaluation of right ventricular function and functional status 6 months after acute submassive pulmonary embolism: frequency of persistent or subsequent elevation in estimated pulmonary artery pres- sure. Chest 2009; 136:1202–1210.
  58. 58. 5/20112/2012
  59. 59. chronic thromboembolic disease
  60. 60. Role for catheter treatment of submassivePE requires an answer to these questions How important is rapid clearance of thrombus?  Role of thrombolysis How does the effectiveness of catheter directed thrombolysis compare to systemically delivered lytic agents?
  61. 61. comparative effectiveness of IV tPA vs. CDTfor submassive PE We don’t know Literature regarding catheter based approach is limited to case series and meta-analyses
  62. 62. submassive PE: pigtail delivery of tPA
  63. 63. submassive PE: Angiojet
  64. 64. submassive PE: thrombectomy andovernight thrombolysis
  65. 65. submassive PE: pulse-spray lysis
  66. 66. evidence needed Clinical benefits of escalation of therapy for acute PE beyond anticoagulation?  Reduction of mortality  Prevention of chronic thromboembolic disease Improved outcomes with catheter directed thrombolyis vs systemic thrombolysis?  More effective?  Reduced hemorrhage?
  67. 67. active clinical trials PERFECT PEITHO ULTIMA SEATTLE I and II
  68. 68. ongoing clinical trials PEITHO STUDY  Pulmonary Embolism Thrombolysis trial  Prospective, multicenter, randomized, double-blind  IV Tenecteplase + UFH vs UFH  Randomized within 2 hours of dx of PE with RV dysfunction and myocardial injury  Primary outcome  Death or hemodynamic collapse within 7 days  Safety outcomes  Related to hemorrhage  Long term follow-up  Death  Echo evaluation for PAH and RV dysfunction
  69. 69. PEITHO trial criteria
  70. 70. PEITHO trial design
  71. 71. ULTIMA trial ULTrasound Accelerated ThrombolysIs of PulMonAry Embolism Comparison of ultrasound-accelerated thrombolysis through the EKOS catheter system vs systemic anticoagulation with heparin Two arm, prospective, randomized Experimental arm: low-dose (<20 mg) r-tPA + full dose IV heparin Control arm: IV heparin alone
  72. 72. ULTIMA trial Primary endpoint  Reduction of RV/LV ratio: RV/LV ratio will be measured by echocardiography at baseline and at 24 hours Inclusion criteria  Patients with acute PE symptoms < 14 days.  CT evidence of PE in at least one main or proximal lower lobe pulmonary artery  RV/LV end diastolic diameter ratio is ≥ 1.0
  73. 73. SEATTLE II Submassive and massive pulmonary Embolism treatment with AcceleraTed ThromboLysis thErapy Question: Will t-PA delivered via the EKOS catheter + IV heparin decrease the ratio of RV to LV diameter within 48 hours in patients with massive or submassive PE? Single arm, prospective study All pts get catheter directed t-PA + IV UFH PE diagnosed on CT Submassive inclusion  RV:LV ratio > 0.9 on CT angiography
  74. 74. SEATTLE II Primary outcomes  RV:LV Diameter Ratio measured at 48 hours  Major bleeding at 72 hours Inclusion criteria  CT evidence of proximal PE Age ≥ 18 years AND  PE symptom duration ≤14 days AND  Massive PE or  Submassive PE  (RV:LV ≥ 0.9 on contrast-enhanced chest CT)
  75. 75. summary The role of early thrombolysis in treatment of massive and submassive PE is not well defined and currently under active investigation IRs have the tools and skills to perform catheter directed treatment of acute PE  Infusion of lytic agents  Mechanical thrombolysis and thrombectomy Theoretical rationale for catheter directed treatment of PE  Rapid clot debulking  Reduction of lytic agent (decreased hemorrhage)
  76. 76. Stanford PE protocol Massive PE  Anesthesia involved when possible  8F sheath into common femoral vein, select main PA  Measure pulmonary pressures (if time)  Bury pigtail into clot  Administer bolus of tPA (start with 10 mg per lung)  Pigtail fragmentation  Conclude the procedure when hemodynamic improvement with resolution of shock is achieved, regardless of angiographic results. Submassive PE  Treated with CDT if there is RV strain or severe hypoxia  No bolus dose, no fragmentation  Place infusion catheter across clot and perform low-dose infusion PERFECT registry
  77. 77. Proposed CDT recommendations by JVIR SBP <90 mmHg or drop >40 mmHg Cardiogenic shock with hypoxia Circulatory collapse requiring CPR RV strain +/- pulm HTN Precapillary pulm HTN Widened A-a O2 gradient (>50 mmHg) Clinically severe PE with CI to anticoagulation or lytic therapy Uflacker R. Interventional therapy for pulmonary embolism. J Vasc Interv Radiol 2001;12:147-164
  78. 78. systemic thrombolysisPotential benefits Potential harm More rapid symptom  Hemorrhage resolution  ~20% major hemorrhage Stabilization of  ~3% cerebral respiratory and heart hemorrhage function Reduction of RV damage Reduced risk of chronic PE with pulmonary HTN Increased probability of survival
  79. 79. systemic thrombolysis In hemodynamically unstable patients, systemic lysis reduces recurrent PE and death (OR 0.45) No proven advantage of one lytic over another 2-hour infusion provides faster results and less risk compared to longer infusions Unfractionated heparin should be stopped when decision to deliver lytics is made; then resumed after infusion without a bolus [?] Greatest benefit when delivered within 48 hours of symptom onset Marshall PS, Mathews KS, Siegel MD. Diagnosis and management of life-threatening pulmonary embolism. J Intensive Care Med 2011;26:275-294.
  80. 80. Intraclot lytic injection is essential Proximal vortex Schmitz-Rode T, Kilbinger M, Gunther RW. Simulated flow pattern in massive pulmonary embolism: significance for selective intrapulmonary thrombolysis. Cardiovasc Intervent Radiol 1998;21:199-204.
  81. 81. catheter-directed lysis 111 patients with massive PE had CDT  200k-500k units of urokinase in situ  Mechanical fragmentation in 85% (pigtail rotation +/- balloon angioplasty)  Catheter placed most obstructed segment and infused 100k units/hr for mean 22 hours  Heparin to achieve PTT 2-2.3x normal Technical success in 100% On table fragmentation + initial bolus did not reduce mean PAP Mean PA pressure reduced from 40 to 25 mmHg at conclusion of lysis  Mean PA pressure was 20 mmHg at 30-90 day follow-up (only 6% had mean PA pressure >25 mmHg) 4 major complications (4%), 1 death  1 cerebral hemorrhage (death)  1 gluteus hematoma  1 GI hemorrhage  1 jugular DVT De Gregorio et al. Endovascular treatment of a haemodynamically unstable massive pulmonary embolism using fibrinolysis and fragmentation. Experience in 111 patients in a single centre. Why don’t we follow ACCP recommendations?
  82. 82. ACCP 2012 recommendations “In patients with acute PE associated with hypotension and who have (i) contraindications to thrombolysis, (ii) failed thrombolysis, or (iii) shock that is likely to cause death before systemic thrombolysis can take effect (eg, within hours), if appropriate expertise and resources are available, we suggest catheter-assisted thrombus removal over no such intervention (Grade 2C)” Guyatt GH, et al. Executive summary: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians evidence-based practice guidelines. Chest 2012;141: 2 suppl 7S-47S.
  83. 83. devices and techniques Pigtail rotation  Cheap, easy, accessible, can debulk proximal emboli Aspiration thrombectomy  8F guide catheter Balloon maceration  Sized smaller than target artery Angiojet  Used in 11% of cases but accounts for 76% of major complications  28% major complication rate  Bradyarrhythmia, heart block, hemoglobinuria, hemoptysis,death Ekos  Ultrasound-aided lysis infusion Others not available at UCLA: Amplatz thrombectomy device, Straub Aspirex catheter, Helix ClotBuster, etc
  84. 84. Catheter-guided lysis 25 patients with massive PE had 33 catheter interventions  EKOS in 15  Standard CDT in 18 EKOS showed more effective thrombus removal  EKOS group had complete thrombus removal in 100%  CDT group had complete thrombus removal in 50%, partial thrombus removal in 14% EKOS group had lower mean time of lysis (17 vs. 25 hours) Treatment-related hemorrhagic complication rate lower for EKOS (0% vs. 21%) Mortality similar (9.1% for EKOS, 14.2% for CDT) Lin PH, et al. Comparison of percutaneous ultrasound-accelerated thrombolysis versus catheter-directed thrombolysis in patients with acute massive pulmonary embolism. Vascular 2009;17 Suppl 3:S137-47.
  85. 85. CDT devices/techniques Pigtail rotation (314) Pigtail rotation with adjunctive measures (94) Aspiration thrombectomy Infusion catheter Balloon Amplatzer thrombectomy device Oasis, Hydrolyser AngioJet Rotarex Wire disruption
  86. 86. Intrapulmonary administration of Lytics A study from 1992 found no signification difference between IV and PA administration of tPA 1 Patients received 100 mg tPA IV or in the PA No significant difference in outcomes Conclusion: IV and PA administration of tPA equally effective in PE BUT  Administration of tPA was NOT directly into the clot Current preferred administration of lytics into thrombosed vessels is through multisidehole infusion catheters placed directly into clot  Increases the surface area of the clot exposed to lytics  Avoids lost dose from preferential flow of lytic into nonthrombosed vessels Goldhaber
  87. 87. tPA Contraindications Active internal bleeding History of CVA in last 6 months? Recent neurosurgery or head trauma Intracranial AVM, aneurysm or tumor Known bleeding diathesis Severe uncontrolled HTN
  88. 88. Relative CI to tPA Recent major surgery CV disease Recent GI or GU bleeding Recent trauma SBP >175 or DBP >110 Acute pericarditis Subacute bacterial endocarditis Severe hepatic or renal disease Pregnancy Hemorrhagic ophthalmic conditions Septic thrombophlebitis Advanced age >75 Patients on oral anticoagulants
  89. 89. Major hemorrhage from tPA Independent predictors of major hemorrhage in PE patients treated with systemic tPA  Cancer  Elevated INR  DM  Hemodynamic instability Fiumara et al. Predictors of major hemorrhage following fibrinolysis for acute pulmonary embolism. Am J Cardiol 2006;97:127-129..
  90. 90. Major hemorrhage from tPA Acute MI: 5% major, 1% intra-cerebral Acute PE (Fiumura): 19% major, 5% intra-cerebral Acute PE (Goldhaber): 22% major, 3% intra-cerebral Bovill EG et al. Ann Int Med 1991;115:256-265 Fiumara et al. Predictors of major hemorrhage following fibrinolysis for acute pulmonary embolism. Am J Cardiol 2006;97:127-129. Goldhaber et al. Lancet 1999;353:1386-89.
  91. 91. Controversies Bradyarrhthymia and hemolysis from rheolytic thrombectomy Fears of vascular perforation “A double-edged sword” chest 2007 vs. shining saber chest 2008
  92. 92. Meta-analysis 0 RCTs 6 prospective trials 29 retrospective reviews 594 patients All level 2 and 3 evidence Reported indications were severe shock, cardiopulmonary arrest, contraindication to IV tPA, failure of IV tPA
  93. 93. CASE: Thrombectomy followed by overnightperipheral thrombolysis Initial 3 days later
  94. 94. Role for catheter treatment of submassivePE requires an answer to these questions How important is rapid clearance of thrombus?  Role of thrombolysis How does the effectiveness of catheter directed thrombolysis compare to systemically delivered lytic agents? Can catheter directed therapy achieve the same results as systemic lytic therapy at a lower dose of the lytic agent?  Reduce hemorrhage?
  95. 95. thrombolysis and hemorrhage Half of patients have a contraindication to thrombolysis 20% major hemorrhage rate when systemic lytics administered  3-5% hemorrhagic stroke Case series of ten patients with massive PE treated with catheter directed ultrasound-accelerated thrombolysis Reteplase (0.5 mg)  Heparin not simultaneously delivered  No major complications  1 patient with nonfatal hemoptysis  1 patient with small groin hematoma
  96. 96. OnGOING CLINICAL TRIALS PERFECT 1  Pulmonary Embolism Response to Fragmentation, Embolectomy, & Catheter Thrombolysis  A prospective observational study to evaluate the safety and effectiveness data of catheter-directed therapy (CDT) including percutaneous mechanical thrombectomy (PMT) for treatment of acute pulmonary embolism (PE) NCT01097928
  97. 97. ACCP 2012 recommendations In patients with acute PE associated with hypotension (eg, systolic BP <90 mmHg) who do not have a high bleeding risk, we suggest systemically administered thrombolytic therapy over no such therapy (Grade 2C) In most patients with acute PE not associated with hypotension, we recommend against systemically administered thrombolytic therapy (Grade 1C) In patients with acute PE when a thrombolytic agent is used, we suggest administration through a peripheral vein over a pulmonary artery catheter (Grade 2C) Guyatt GH, et al. Executive summary: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians evidence-based practice guidelines. Chest 2012;141: 2 suppl 7S-47S.

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