Thrombolytic therapy in pulmonary embolism

1
Thrombolytic therapy in pulmonary embolism

• Presented by Ri ???
• Instructor P ???

2
Chief complaint

• A 59 year-old woman, for another treatment to
  pulmonary embolism with respiratory failure
  status post intubation

3
Brief history

• She has history of Af with RVR on regular
  medicine control.
• Abdominal fullness was noted in Nov.2005 and
  abdominal echo revealed a solid mass at left side
  of pelvis, 7 cm in size and hydronephrosis.
• She was transferred to ??? hospital on
  Nov.26.2005. Debulking with retroperitoneal tumor
  excision and LN dissection was done Dec.2.2005.
• Post operative course was smooth but left leg
  edema was noted.

4
Brief history

• Sudden onset of shortness of breath was noted on
  Dec.10.2005.
• Respiratory failure was noted and intubation was
  done.
• Chest CT showed low density filling defect, 4 cm,
  in the pulmonary trunk , left main pulmonary
  artery and bilateral pulmonary with suspected
  pulmonary embolism.
• Heparin has been adminstrated since Dec.17.2005.
  She was transferred to NTUH for further
  management on Dec.24.2005.

5
Past history

• 1. HTN () , DM nil
• 2. Smoking(-), Alcoholism (-)
• 3. Surgery Retroperitoneal SCC with right
  inguinal LN metastasis, s/p debulking with
  retroperitoneal tumor excision and LN dissection
  in Dec.2005
• 4. Allergy denied
• 5. Family history non-contributory

6
Course and management

• After transferred to ICU, fever was noted and
  Tazocin was administrated.
• Fever work-up was done and sputum culture
  revealed Pseudomonus aeruginosa.
• Cardiac echo revealed LVEF 72 with mild MR and
  moderate TR. Duplex revealed bilateral DVT(LltR).
• Sudden onset of dyspnea with desasuration was
  noted. Auto peep was found. Ventilator with
  pressure control with muscle relaxant were
  administrated.

7
Course and management

• Chest, abdomen, pelvis and lower extremity CT
  showed left main trunk embolization, left iliac
  mass at previous OP area and massive thrombus of
  common iliac vein, left femoral, and left
  popliteal vein.
• IVC filter with t-PA catheter thrombolysis was
  done. Hypotension and deoxygenation were noted,
  in spite of high inotropic agents use.
• DNR was signed on 12/26. The patient died of
  sepsis, pulmonary embolism and retroperitoneal
  SCC at 1325pm on Dec.26.2005.

8
Introduction

• Deep vein thrombosis (DVT) and acute pulmonary
  embolism (PE) are two manifestations of the same
  disorder, venous thromboembolism.
• DVT of the lower extremity is subdivided into
  either calf vein or proximal vein (popliteal,
  femoral, or iliac vein) thrombosis.

9
Introduction

• Proximal vein thrombosis is of greater importance
  clinically, since it is more commonly associated
  with serious disease.
• Over 90 percent of cases of acute PE are due to
  emboli emanating from the proximal veins of the
  lower extremities.

10
GENERAL OBJECTIVES

• Prevent further clot extension, acute PE, and
  recurrence of thrombosis, late complications (
  postphlebitic syndrome and chronic thromboembolic
  pulmonary hypertension).
• Anticoagulant therapy is indicated for patients
  with symptomatic proximal DVT, since pulmonary
  embolism will occur in approximately 50 percent
  of untreated individuals, most often within days
  or weeks of the event

11
Treatment of acute pulmonary embolism and DVT

• HEPARIN THERAPY
• -- Unfractionated heparin
• -- Low molecular weight heparin
• ORAL ANTICOAGULANT THERAPY
• -- Warfarin
• THROMBOLYTIC THERAPY
• -- Urokinase
• -- Streptokinase
• -- Alteplase
• INFERIOR VENA CAVAL INTERRUPTION

12
HEPARIN

• Simultaneous initiation of heparin (either
• unfractionated or low-molecular weight) and
  oral
• warfarin
• --The standard anticoagulant regimen for venous
• thromboembolism in all medically stable
  patients.

13
HEPARIN

• Monitor the response, using either the activated
  partial thromboplastin time (aPTT) or heparin
  levels, and to titrate the dose to the individual
  patient.
• Critical therapeutic level of heparin, as
  measured by the aPTT, is 1.5 times the mean of
  the control value or the upper limit of the
  normal aPTT range, with a target range (aPTT
  ratio) of 1.5 to 2.5

14
HEPARIN

• Experimental studies and clinical trials have
• established that the efficacy of heparin
  therapy
• depends upon achieving a critical therapeutic
  level
• of heparin within the first 24 hours of
  treatment,
• usually via a continuous heparin infusion
• Heparin infusion of 1000 IU/hr and who had an
• aPTT ratio of lt1.5 times control for three
  days or
• more threefold increase in the risk of
  recurrent
• venous thromboembolism

15
Low molecular weight heparin

• Greater bioavailability when given by
• subcutaneous injection
• The duration of the anticoagulant effect is
• greater (once or twice daily)
• The anticoagulant response is highly correlated
• with body weight, permitting administration
  of a
• fixed dose
• -- Laboratory monitoring is not necessary
  except
• in pregnancy, morbid obesity and renal
  failure
• Less likely to induce thrombocytopenia

16
THROMBOLYSIS FOR PE
17
INDICATIONS
Patients with massive PE associated with
hemodynamic compromise are reasonable candidates
for intravenous thrombolytic therapy.
18
Echocardiography

• May reveal findings which strongly suggest
  massive and hemodynamically significant PE
• -- Right ventricular dilation and/or
  hypokinesis. Even in the absence of systemic
  hypotension or profound hypoxemia
• Such findings suggest the need for aggressive
  intervention, including consideration of
  thrombolytic therapy. This criterion for
  administration of lytic agents is not utilized by
  all practitioners, and remains the subject of
  investigation.

Grifoni, S, Olivotto, I, Cecchini, P, et al.
Short-term clinical outcome of patients with
acute pulmonary embolism, normal blood pressure,
and echocardiographic right ventricular
dysfunction. Circulation 2000 1012817.
19
CONTRAINDICATIONS

• These should be particularly scrutinized if
  lytic therapy is considered

20
Therapeutic regimens of Acute PE
21
General guidelines for administration
Buller, HR, Agnelli, G, Hull, RD, et al.
Antithrombotic therapy for venous thromboembolic
disease the Seventh ACCP Conference on
Antithrombotic and Thrombolytic Therapy. Chest
2004 126401S.
22
About administration

• Intravenous route
• -- primary method of delivery
• Rapid infusion
• -- Shorter regimens may not only prove
  efficacious but also reduce the risk of
  hemorrhagic complications
• Catheter-directed therapy
• -- for massive PE, may induce major bleeding

23
Catheter-directed therapy

• Local delivery of streptokinase
• -- Extensive lysis (by perfusion scan and
  pulmonary arteriography at 12 to 24 hour
  follow-up)
• Intrapulmonary versus peripheral alteplase
• -- no advantage over the intravenous route
• Direct delivery into clot
• --Enhanced thrombolysis, relatively low doses
  (in an animal model of PE)
• -- Could prove advantageous over the
  intravenous route

24
THROMBOLYSIS FOR PE

• Urokinase versus heparin (By Urokinase Pulmonary
  Embolism Trial (UPET) )
• Thrombolysis was hastened in patients receiving
  UK compared with those treated with heparin when
  pulmonary arteriograms and lung perfusion scans
  were examined 24 hours after treatment
• -- The difference between the two groups
  diminished
• -- No difference in the frequency of
  recurrent PE or in mortality rate within two
  weeks of therapy
• Bleeding complications in this trial were
  relatively high. Further experience with
  thrombolytic therapy has suggested that adverse
  effects are reduced.
• One limitation to this study small number of
  patients with potentially life-threatening
  embolic disease (only 7 percent classified as
  having massive PE with shock).

The Urokinase Pulmonary Embolism Trial
A national cooperative study. Circulation 1973
47(Suppl II)1.
25
THROMBOLYSIS FOR PE

• Urokinase versus heparin
• Phase 2 of the UPET evaluated 12 and 24 hour
  infusions of UK and a 24 hour infusion of SK
• -- No difference in mortality was
  demonstrated among the treatment groups.
• -- The extent of thrombolysis was greater
  than that in heparin-treated patients.
• -- Thrombolytic therapy was associated
  with more rapid reduction of vascular obstruction
  and earlier hemodynamic improvement.

Urokinase-Streptokinase Embolism Trial Phase 2
results. A cooperative study. JAMA 1974
2291606.
26
THROMBOLYSIS FOR PE

• Alteplase versus heparin
• A randomized controlled trial of alteplase plus
  heparin versus placebo plus heparin was conducted
  in 256 patients.
• -- Therapy with alteplase was associated
  with a decreased need for escalation of therapy
  (10 versus 25 percent )
• -- In-hospital mortality did not differ
  significantly between groups.
• Limitations of this study include possible
  undertreatment of the control group, because
  heparin was not dosed according to weight.
• -- In addition, because only about 30
  percent of patients in each group had
  echocardiographic evidence of right ventricular
  dysfunction, it is possible that the study was
  underpowered to detect a treatment effect
  specific to these patients.

Konstantinides, S, Geibel, A, Heusel, G, et al.
Heparin plus alteplase compared with heparin
alone in patients with submassive pulmonary
embolism. N Engl J Med 2002 3471143
27
THROMBOLYSIS FOR PE

• Alteplase versus urokinase
• One study compared alteplase (100 mg administered
  intravenously over two hours) with a 24-hour
  infusion of UK (2000 U per pound bolus followed
  by continuous infusion at 2000 U/pound per hour).
  The primary end points were improvement by
  pulmonary arteriography at two hours and by
  perfusion scan at 24 hours.
• -- Moderate or marked improvement on
  arteriogram at two hours was much more common in
  patients treated with alteplase (59 versus 13
  percent).
• -- The alteplase-treated patients had
  received the entire dose of thrombolytic therapy
  (100 mg of alteplase) by the time of the two hour
  outcome measurement whereas the UK-treated
  patients had received only part of the total
  dosage to be administered.-- Improvement in lung
  scan reperfusion at 24 hours was identical in the
  two treatment groups.

Goldhaber, SZ, Kessler, CM, Heit, J, et al. A
randomized controlled trial of recombinant tissue
plasminogen activator versus urokinase in the
treatment of acute pulmonary embolism. Lancet
1988 2293.
28
THROMBOLYSIS FOR PE

• Alteplase versus urokinase
• At present, the alteplase regimen in which 100 mg
  is administered intravenously over two hours is
  the most rapidly administered protocol that is
  currently approved for use in the United States

29
Long-term outcome

• Almost all studies have demonstrated the
  superiority of thrombolysis (in particular with
  alteplase) over heparin in terms of resolution of
  both radiographic and hemodynamic abnormalities
  when measurements were made within the first 24
  hours, this advantage appears to be short-lived.
• Repeat echocardiograms obtained seven days after
  treatment of 40 patients with either heparin or
  alteplase revealed no significant differences in
  ventricular dimensions. In addition, the trials
  have not demonstrated a difference either in
  mortality rate or in resolution of symptoms.

Konstantinides, S, Tiede, N, Geibel, A, et al.
Comparison of alteplase versus heparin for
resolution of major pulmonary embolism. Am J
Cardiol 1998 82966.
30
Long-term outcome

• Measurement of diffusing capacity and capillary
  volumes at two weeks and one year after treatment
  showed that patients receiving thrombolytic
  therapy had higher diffusing capacity and lung
  capillary volumes compared to those receiving
  heparin.
• Follow-up of the same group of 23 patients for an
  average of seven years following initial therapy
  showed that patients who had been treated with
  thrombolytic therapy had lower pulmonary artery
  pressure and pulmonary vascular resistance
  compared to patients who had received heparin.
• The clinical significance of these changes awaits
  further prospective trials.

Sharma, GVRK, Burleson, VA, Sasahara, AA. Effect
of thrombolytic therapy on pulmonary-capillary
blood volume in patients with pulmonary embolism.
N Engl J Med 1980 303842. Sharma, GVRK,
Folland, ED, McIntyre, KM, et al. Longterm
hemodynamic benefit of thrombolytic therapy in
pulmonary embolic disease (abstract). J Am Coll
Cardiol 1990 1565A.
31
RECOMMENDATIONS

• The use of thrombolytic agents in the treatment
  of venous thromboembolism
• -- individualized and requires further
  investigation.
• Hemodynamically unstable PE or massive
  iliofemoral thrombosis
• -- the best candidates for thrombolytic
  therapy.

32
Conclusion

• The primary therapy for acute pulmonary embolism
  is anticoagulation with heparin and warfarin to
  prevent additional thromboembolism.
• Thrombolysis, why not?
• -- Heparin for well-tolerated PEs extremely
  good prognosis
• -- Inherent risk of thrombolysis bleeding
• -- The most effective thrombolytic period
  missed (extensive bronchial collateral
  circulation )

33
Conclusion

• The role of thrombolytic therapy in the
  management of acute massive pulmonary embolism
  remains controversial
• Although there is more rapid dissolution of
  venous thromboemboli, the risk of serious
  bleeding with thrombolysis remains a concern(
  intracerebral hemorrhage occurs more frequently
  with thrombolytic agents than with heparin).

34
Conclusion

• Thrombolytic therapy can play an important role
  in the management of acute pulmonary embolism
• -- PE associated with systemic hypotension in
  the absence of absolute contraindications.
• -- Echcardiographic evidence of thrombus in
  the right ventricle
• -- Severely compromised oxygenation,
  respiratory failure

35
Conclusion

• Catheter-directed therapy with low-dose
• thrombolytic therapy can be considered
• Direct intraembolic therapy may be superior to
  intravenous therapy
• Acceptable time window for administration
  2 weeks
• The shorter interval between the onset of
  symptoms and the initiation of therapy, the
  greater response

36

• Thank you for your attention!

37
RECOMMENDATIONS

• From the evidence-based recommendations of the
  Seventh American College of Chest Physicians
  (ACCP) Consensus Conference on Antithrombotic
  Therapy

Buller, HR, Agnelli, G, Hull, RD, et al.
Antithrombotic therapy for venous thromboembolic
disease the Seventh ACCP Conference on
Antithrombotic and Thrombolytic Therapy. Chest
2004 126401s
38
RECOMMENDATIONS

• Therapy of acute deep vein thrombosis or
  pulmonary embolism should be initiated with IV
  heparin adjusted to prolong the APTT to a range
  that corresponds to a plasma heparin level of 0.3
  to 0.7 U/mL

39
RECOMMENDATIONS

• Heparin therapy should be continued for at least
  five days.
• Oral anticoagulation should be overlapped with
  heparin therapy for four to five days.
• Heparin and warfarin therapy can be initiated
  simultaneously, with heparin therapy discontinued
  on day five or six if the INR has been
  therapeutic for two consecutive days.
• Longer periods of initial heparin therapy may be
  considered in the case of massive pulmonary
  embolism or iliofemoral thrombosis.

40
RECOMMENDATIONS

• LMW heparin may be used in place of
  unfractionated heparin.
• Dosing requirements are individualized for each
  product.

41
RECOMMENDATIONS

• Long-term anticoagulation should be continued for
  at least 12 weeks using oral anticoagulants to
  prolong the INR to 2.0 to 3.0.

42
RECOMMENDATIONS

• First thromboembolic event in the context of a
  reversible risk factor
• -- treated for three to six months
• Idiopathic first thromboembolic event
• -- full six months of treatment.
• Recurrent venous thrombosis or a continuing risk
  factor -- treated indefinitely.

43
RECOMMENDATIONS

• IVC filter placement is recommended when
• -- anticoagulation is contraindicated
• -- recurrent thromboembolism despite adequate
  anticoagulation
• -- chronic recurrent embolism with pulmonary
  hypertension
• -- situations with a high-risk of recurrent
  embolization
• -- conjunction with the performance of
  pulmonary embolectomy or endarterectomy