Thrombolysis in Submassive PE

1
Thrombolysis in Submassive PE

• Adam Oster
• Grand Rounds
• April 4, 2002

2
Guiding Questions

• Should we identify normotensive PE patients
  with RV dysfunction (submassive PE)?
• Should these patients be considered for
  thrombolytic therapy?

3
Patient Subgroups
PULMONARY EMBOLUS DIAGNOSED OR SUSPECTED
HEMODYNAMICALLY UNSTABLE
HEMODYNAMICALLY STABLE
NO EVIDENCE OF RIGHT HEART STRAIN
WITHOUT SIGNS OF HYPO PERFUSION
WITH SIGNS OF ORGAN HYPOPERFUSION (INCL. CARDIAC
ARREST)
EVIDENCE OF RIGHT HEART STRAIN
4
Outline

• Studies demonstrating the natural history of PE
  with RV dysfunction
• Trials evaluating thrombolytics in PE with RV
  dysfunction
• Special topics
• evidence for thrombolytics in PE with shock and
  during CPR for PE-related arrest
• role of TTE by EPs

5
History

• Randomised trials comparing thrombolytics to
  heparin
• UPET 1970 -- prospective, Randomised.
• USET
• PIOPED 1990
• Levine et al. 1990
• PAIMS 2. 1992
• Goldhaber et al. 1993
• Non-randomized
• Dalla-Volta, 1993
• Konstantanindes, 1997
• Hamel, 2001

6

• Should we attempt to identify normotensive PE
  patients with right heart strain?

7
Pathophysiology Review

• Normal RV has a narrow range over which it can
  compensate for acute increases in afterload. The
  pericardium has a limited ability to distend.
• Increased RV afterload elevation in RV
  wall pressures dilation and hypokinesis of
  the RV wall
• shift of intraventricular septum towards left
  ventricle (tricuspid regurgitation) and decreased
  LV output.

8
Grifoni et al. Short-Term Clinical Outcome of
Patient With Acute Pulmonary Embolism, Normal
Blood Pressure and Echocardiographic Right
Ventricular Dysfunction. Circulation, 101. 2000,

• Prospective clinical outcome study
• 209 consecutive patients with documented PE
• all patients had an TTE within 1 hr of admission
• patients stratified into one of four groups
• results only for in-hospital period

9
Grifoni et al, Circulation, 2000.

• 4 groups
• Shock (N28,13.4)
• SBPlt100 with signs of organ hypoperfusion
• Hypotensive without signs of shock (N19, 9.1)
• Normotensive with RV strain (N65, 31.1)
• Normotensive without RV strain (N97, 46.4)

10
Grifoni et al, Circulation, 2000.

• Patients with hypotension/shock (22, N47)
• Mortality 19
• Normotensive without evidence of RV strain
  (46.5, n97)
• 0 PE-related deaths
• Normotensive with RV strain (31.1, N65)
• 10 (n6) clinically deteriorated due to PE
  recurrence
• 5 (n3) PE-related deaths

11
Grifoni et al, Circulation, 2000.

• Positive predictive value of echocardiography was
  low
• NPV was 100
• good tool for screening low risk patients
• The detection of RV dysfunction defines a subset
  of patients with short-term risk of PE-related
  mortality.

12
Ribeiro et al. Echocardiography Doppler in
Pulmonary Embolism Right Ventricular Dysfunction
as a Predictor of Mortality Rate. American Heart
Journal, 134. 1997.

• RV dysfunction at diagnosis of PE is a predictor
  of mortality
• 126 consecutive PE patients assessed by TTE on
  day of diagnosis
• stratified into 2 groups based on severity of RV
  systolic dysfunction on TTE
• (A) normal to mildly hypokinetic and
• (B) moderate to severely hypokinetic
• Follow-up TTE within 1 year

13
Ribeiro et al. American Heart Journal, 1997.

• 56 patients in group A and 70 in group B
• baseline characteristics similar (except over
  twice as many with symptoms gt14days (sig.),
  malignancy and CHF (NS)in B)
• In-hospital PE mortality all in group B (n9),
  p0.002
• 1 year overall mortality rate 15.1 (n19)
• group A, 7.1 (n4) mortality, all non-PE.
• group B, 27.7 (n15) mortality, 9 due to PE
  (p0.04)
• Group B
• RR for in-hospital death 6.0 (95 CI 1.1 to
  111.5)
• RR for death within 1 year 2.4(95 CI 1.2 to 4.5)
  
• (malignancy RR 3.0).

14
Ribeiro et al. American Heart Journal, 1997.

• Subgroup analysis of patients without cancer
  (n101)
• In-hospital mortality
• Group A 0
• Group B 7.7 (N4/52)
• 1 year cumulative mortality
• Group A 2, (N1)
• Group B 9.8, (N5)

15

• Should patients with RV dysfunction be
  considered for thrombolytic therapy?

16
Goldhaber, S. et al. Alteplase versus Heparin in
Acute Pulmonary Embolism Randomised Trial
Assessing Right-Ventricular Function and
Pulmonary Perfusion. The Lancet. 1993, no 8844.
vol 341.

• Thrombolysis plus heparin is better than heparin
  alone in reversing echo evidence of RV
  dysfunction
• Prospective and randomized, non-consecutive.
• 99 hemodynamically stable PE patients
• PE confirmed by high probability V/Q and/or
  pulmonary angiogram
• excluded if at high risk of adverse hemorrhage.
• all had TTE assessments of right ventricular wall
  motion at baseline, then repeated at 3 and 24
  hours.
• Angiograms were obtained at baseline and at 24h

17
Goldhaber et al. The Lancet. 1993.

• 46 patients randomized to rt-PA followed by
  heparin and 55 to heparin alone
• Endpoints mortality, recurrent PE and major
  bleeding (72h)
• Followed for 14 days for adverse outcomes (PE
  recurrence or death), or longer if in hospital.
  72 hrs for bleeding.

18
Goldhaber et al. The Lancet. 1993.

• Results
• follow-up echo (89 patients)
• rtPA group vs heparin
• 3 hrs -- greater improvement in RV wall motion
  (p0.01)
• 24 hrs -- 39 improved, 2 worse vs 17 improved
  and 17 worse vs 17 improvement and 17 worse in
  heparin group (p0.005)
• follow-up angiogram at 24hrs (95 patients)
• rtPA vs heparin -- mean absolute improvement in
  pulmonary perfusion of 14.6 vs 1.5 in heparin
  (plt0.0001).

19
Goldhaber et al. The Lancet. 1993

• Subgroup analysis
• patients with right ventricular hypokinesis on
  echo (N36)
• rtPA -- 89 improvement, 6 worsened
• heparin -- 44 improvement, 28 worsened (p0.03)
• Deaths
• 2 in heparin group (1 refractory CA and 1 with CI
  to tPA)
• Recurrent PEs
• rtPA -- none
• heparin -- 5 (2 fatal)
• Significant hemorrhage
• heparin -- 1
• rtPA -- 3

20
Goldhaber et al. The Lancet. 1993.

• Conclusions
• rtPA group
• improved right heart function at 24 hours
• improvement in pulmonary perfusion
• decrease in recurrent PEs
• lower rate of death
• Strong points
• randomization and similarities between groups
• echo and angiogram readers blinded to treatment
  and timing in relation to therapy
• Limitations
• non-blinded to clinicians and open-labeled
• no long -term morbidity or mortality data

21
Konstantinides, et al. Association Between
Thrombolytic Treatment and the prognosis of
hemodynamically Stable Patients with Major
Pulmonary Embolism Results of a Multicenter
Registry. Circulation, 96. 1997

• Early thrombolysis favorably affects in-hospital
  clinical outcome.
• Multicentred, registry study
• 719 consecutive patients analyzed 73 PE
  confirmed by one or more imaging study
• evidence of either increased right ventricular
  afterload or pulmonary hypertension based on TTE
  or cath.
• all patients hemodynamically stable
• also included patients who were hypotensive
  (SBPlt90) without signs of shock and those on low
  dose (lt5mcg/kg/min) dopamine.

22
Konstantinides, et al. Circulation. 1997

• primary end-point -- overall 30-day mortality
• secondary endpoints -- PE recurrence, major
  bleeding

23
Konstantinides, et al. Circulation. 1997

• Treatment decisions made at discretion of
  physician
• 23.5 (n169) received thrombolytic therapy
  within 24h of diagnosis followed by heparin
• remaining patients treated with heparin alone
• unless the physician thought that they required
  thrombolytics after the first 24h of heparin.

24
Konstantinides, et al. Circulation. 1997

• Findings
• overall 30d mortality higher in heparin group
  11.1 vs 4.7 (p0.016).
• thrombolytic treatment was found by multivariate
  analysis to be the only independent predictor of
  survival (OR 0.46 for in-hospital death)
• 95 CI 0.21 to 1.00
• thrombolytic group
• lower rates of recurrent PE (7.7 vs. 18.7,
  p0.001)
• higher rates of major bleeding events (21.9 vs
  7.8, p0.001)
• ICH and deaths due to bleeding were the same in
  the two groups

25
Konstantinides, et al. Circulation. 1997

• Subgroup analysis
• patients with a dilated right ventricle on echo
• 30 day mortality in (N380) 10 compared with
  4.1 in those without (p0.018), a 58 reduction
  in mortality.
• 58 reduction in mortality in patients treated
  with thrombolytics (4.7 vs 11.1 heparin,
  p0.16)

26
Konstantinides, et al. Circulation. 1997

• Limitations
• study design
• non-randomised, heterogeneous thrombolytic
  regimens
• many patients had clinical signs of disease
  severity
• more with chronic lung disease in UF heparin
  group
• choice of treatment was at the discretion of the
  physician
• selection bias is likely
• distribution of many clinical variables were
  statistically different between the two groups
  (esp. age, pre-existing CHF, higher in heparin)
• major end point analyses required multivariate
  regression model to account for the unequal
  distribution of clinical variables

27
Konstantinides, et al. Circulation. 1997

• 40 of patients thrombolysed had
  contraindications to lytics
• 25 in the heparin group crossed over and
  received thrombolytics. This data was not
  reported.

28
Hamel et al. Thrombolysis or Heparin Therapy in
Massive Pulmonary Embolism With Right Ventricular
Dilation. Chest, 2001. Vol. 1201.

• There is a benefit to thrombolysis over heparin
  in stable PE patients with RVD
• Retrospective, cohort study of 153 consecutive
  patients
• PE confirmed by, V/Q or angiography
• RV function evaluated by TT E on admission
• 64 patients in each treatment group were matched
  on the basis of RV/LV diameter ratio
• perfusion scans repeated on day 7 to 10 or
  earlier if recurrent PE suspected

29
Hamel et al. Chest, 2001.

• Inclusion criteria
• included PIOPED criteria for high prob. V/Q
• Pulmonary vascular obstruction gt40 on V/Q or
  Miller index of 20/34
• RV to LV ratio of gt0.6 in absence of LV or Mv
  disease
• Exclusion criteria
• SBP lt90
• contraindications to thrombolysis
• inotropes
• syncope prior to presentation

30
Hamel et al. Chest, 2001.

• thrombolysis versus heparin
• higher mean relative improvement in lung scan at
  7-10 days (54 vs 42, p0.01)
• gt50 relative improvement in lung scan perfusion
  defect seen in 57 (vs 37)
• at day 7-10 follow-up scan, average defect equal
  between two groups

31
Hamel et al. Chest, 2001.

• PE recurrence
• rates were the same in both groups, 4.7 (N3).
• Mortality
• 4 (6.3) in thrombolytic and 0 in heparin (NS)
• Bleeding events
• 6 severe, 3 intracranial significantly higher in
  thrombolytic group. 4 died as a result. (15.6,
  N10 vs 0, p0.001)

32
Hamel et al. Chest, 2001.

• Retrospective, case-controlled, consecutive
  patients
• small numbers
• Two groups comparable at baseline for historic
  factors, RV dysfunction, LS defect and all free
  of signs of PE severity
• LS defect, RV/LV ratio and higher PAP higher in
  thrombolysis group (not significant)
• heterogeneous treatment regimen in thrombolytic
  group

33
Levine et al. A Randomised Trial of a Single
Bolus Dosage Regimen of Recombinant Tissue
Plasminogen Activator in Patients with Acute
Pulmonary Embolism. Chest. 1990. 981473.

• rt-PA will benefit pulmonary perfusion in
  patients with PE and demonstrated perfusion
  deficits
• Inclusion -- symptomatic patients with either
  high probability V/Q or angiographically proven
  PE and no contraindications to thrombolytics.
• Excluded if hypotensive or hemodynamically
  unstable
• All patients received heparin bolus. Then
  randomized to either rt-PA (0.6mg/kg, given as a
  bolus over 2min) or placebo.
• 10 day study period

34
Levine et al. Chest. 1990

• End-points were gt50 improvement in perfusion
  defect over baseline and major bleeding events
• intracranial, retroperitoneal, requires
  transfusion gt2U or fall in Hgb gt20g/L

35
Levine et al. Chest. 1990

• 58 patients randomized (33 to rt-PA) and groups
  were comparable for baseline characteristics.
• Comparison lung scans (at 24h and 7days)
  available for 57
• At 24 hours
• rt-PA group -- 34.4 demonstrated a greater than
  50 improvement in perfusion scan (12 improved
  gt50 in the placebo group (p0.017).
• Mean absolute improvement of 9.7 in rt-PA (5.2
  in placebo, p0.07)

36
Levine et al. Chest. 1990

• At 7 days
• no statistically significant difference in lung
  scan resolution
• No recurrent PEs in either group
• No major bleeding episodes

37
Dalla-Volta, S. et al. Alteplase Combined With
Heparin Versus Heparin in the Treatment of Acute
Pulmonary Embolism. Plasminogen Activator Italian
Multicentre Study 2 (PAIMS 2). Journal of the
American College or Cardiology 1992. 20 520.

• tPA will result in more rapid improvement in
  angiographic and hemodynamic variables.
• Open, parallel, multicenter, randomized trial,
  N36.
• PE confirmed by angiogram with PA pressures
  recorded.
• all patients hemodynamically stable
• excluded if contraindications to thrombolytics
• all patients received bolus UF heparin then
  Randomised to rt-PA or heparin
• follow-up angiogram at end of randomized
  treatment (2hrs), subset had lung scans at 7 and
  30d.

38
Dalla-Volta, S. et al. JACC. 1993

• Interim data analyzed for first 32 patients
  randomized
• study terminated due to gt3 SD (plt0.01) in the
  difference between the angiographic index of the
  two groups
• patients treated with rt-PA
• decrease in Miller Score (mean 28.3 to 24.8) at 2
  hours
• decrease in mean PA pressure (mean of 30.2mmHg to
  21.4mmHg, plt0.01).
• CI increased from 2.1 to 2.4 L/min/m2, plt0.01
• patients treated with heparin
• no change in Miller Score or CI
• increase in PA pressure, plt0.001.

39
Dalla-Volta, S. et al. JACC. 1993

• Patient Subset with 7 and 30day follow-up
  perfusion scans
• No difference in Miller Scores (plt0.05)
• Bleeding complications
• 14/20 in tPA had, 3 were severe (Hb decreased by
  gt50g/L)
• 6/16 and 2 severe in heparin group (NS)
• Deaths
• 2 in tPA group (ICH, tamponade).

40
Summary of Studies To-Date

• Grifoni -- RVD confers increased risk of death
  and PE recurrence.
• Ribeiro -- extent of RVD correlates with early
  and late death
• Levine -- early improvement in scan but no
  benefit at 7 days
• Goldhaber -- improved short-term hemodynamics and
  lower rate of short-term rec. PE and death.
  Randomised, non-blinded.
• Konstantinides -- lower rate of mortality in
  subgroup of pts with RVD and thrombolysis.
  Non-randomized, groups sig. different at
  baseline.
• Dalla-Volta negative for mortality
• Hammel no better survival (mortality higher in
  thrombolysis group) and higher rate of serious
  bleeding.

41
Take Home

• RV dysfunction proportionately increases the risk
  of death in PE (8 to 14)
• Severity of RV dysfunction correlates with worse
  prognosis
• TTE can identify low-risk population
• Thrombolytic therapy results in prompt (approx
  24h) improvement in RV function, PA pressures and
  lung scan deficit
• Any benefit to thrombolysis does not appear to be
  present after ?24hrs.
• Likely does not decrease risk of recurrent PEs

42
Thrombolytics in Severe Shock or During CPR in
Fulminant Pulmonary Embolism?

• Fulminant PE can produce CA in approx. 40 of
  cases
• Mortality ranges from 65 to 95
• Multiple purported mechanisms
• RV strain, AMI, arrhythmia.
• PEA or asystole

43
Patient Subgroups
PULMONARY EMBOLUS DIAGNOSED OR SUSPECTED
HEMODYNAMICALLY UNSTABLE
HEMODYNAMICALLY STABLE
NO EVIDENCE OF RIGHT HEART STRAIN
WITHOUT SIGNS OF HYPO PERFUSION
WITH SIGNS OF ORGAN HYPOPERFUSION (INCL. CARDIAC
ARREST)
EVIDENCE OF RIGHT HEART STRAIN
44
Jerjes-Sanchez C. et al. Streptokinase and
Heparin versus Heparin Alone in Massive Pulmonary
Embolism A Randomised Controlled Trial. Journal
of Thrombosis and Thrombolysis. 1995.

• Prospective and Randomised trial, N8
• all had massive PE and in cardiogenic shock
• high prob. V/Q, with abnormal RH echo or
• gt9 obstructed segments on V/Q
• autopsy in 3
• no significant baseline differences between the
  two groups, except time elapsed from onset of
  symptoms to randomization (2.5 vs 34.75hrs)
• 100 survival in streptokinase plus heparin group
  
• 100 mortality in heparin group
• no bleeding complications

45
Thrombolytics in Severe Shock or During CPR in
Fulminant Pulmonary Embolism?

• Ruiz Bailen M. et al., Thrombolysis During
  Cardiopulmonary Resuscitation in Fulminant
  Pulmonary Embolism A Review. Critical Care
  Medicine. 2001. Vol 29, No. 11.
• single cases and small series demonstrate
  promising outcomes when PE suspected clinically.
• Kurkciyan et al. 2000
• retrospective, N42 (thrombolysis 21, 21 no
  treatment)
• 9.5 survival in thrombolysis vs 4.5 in no
  treatment
• ROSC in 81 vs 33.3
• Survival from 9.5 to 100 (Sienblenlist, 1990
  Sigmund, 1991 Hopf, 1991 Bittiger, 1991
  Scheeren, 1994)

46
Moore, et al. Determination of Left Ventricular
Function by Emergency Physician Echocardiography
of Hypotensive Patients. Academic Emergency
Medicine, vol. 9, no. 3, 2002.

• Prospective, observational study, convenience
  sample of 51.
• EPs with prior US training underwent focused echo
  training
• inclusion symptomatic hypotension
• exclusion trauma, CPR, ECG of AMI
• EPs estimation of EF
• compared with cardiologist correlation
  coefficient of 0.86
• between cardiologists 0.84
• EP categorization of EF,
• agreement 84 (kappa 0.61)

47
Relationship between degree of RV dysfunction and
degree of perfusion scan deficits

• Wolfe, 1994. N90
• degree of perfusion deficit greater in patients
  with RVD (54 vs 30, plt0.001)
• all patients with recurrent PE in group with
  initial RVD, plt0.01
• Ribiero, 1998
• correlation between RVD and perfusion scan
  deficit but wide CI.
• Miller, 1998. N64
• failed to demonstrate a correlation between RVD
  and perfusion deficit