discussion on acutr pulmonary thromboembolism, its diagnosis and managment

1. DR VIJAY K AGRAWAL 1
Acute PE - DIAGNOSIS AND MANAGEMENT

2. Disclosure Statement of Financial Interest
I DO NOT have a financial interest /
arrangement or affiliation with one
or more organizations that could be
perceived as a real or apparent
conflict of interest in the context of
the subject of this presentation.
NO

3. Quantifying the problem
Algorithm for diagnosis
- Initial Risk Stratification
-Clinical Prediction Rules
Goals of PE Management &
Treatment options
Clinical manifestations
Clinical Evidence of Alteplase in Acute PE
What do guidelines say ?
COVID 19 and PE
3

4. VENOUS THROMBOEMBOLISM
• Umbrella term that encompasses DVT and PE
Gay SE. An inside view of venous thromboembolism. Nurse Pract 2010;35:32-9

5. – It is the third most frequent cardiovascular disease with an
overall annual incidence of 100–200 per 100 000 inhabitants
• The reported annual incidence of VTEvaries widely,
ranging from :
• 53 to 162 per 100000 for DVT and
• 39 to 115.0 per 100000 for PE
*2019 ESC Guidelines on the diagnosis and management of acute pulmonaryembolism

7. *
2019ESC Guidelines on the diagnosis and management of acute pulmonary embolism

8. QUANTIFYING THE PROBLEM
8

9. Epidemiology of Venous Thrombo-Embolism
(DVT+PE) Global & India
<2.5 lac events p.a4
Is it underestimated
in India?
9 lac events p.a.2
7.5 lac events p.a.3
1. Goldhaber SZ. Pulmonary embolism thrombolysis: a clarion call for international collaboration. J Am Coll Cardiol 1992;19:246-7.
2. Cohen AT et al. Thromb Haemost. 2007;98:756-64;
3. Roger VL et al. Circulation 2012;125:e2-220;
4. Ray G et al. VTE- Indian Perspective, Med Update 2010; 20: 329-34.
More than 30
percent death
in acute PE

10. • By 3 months, 14% of patients with a proximal DVT and 17.5% with PE will
have died2,3
DVT/PE has a high mortality rate
10
1. Cohen AT et al. Thromb Haemost. 2007;98:756-64;
2. Vaitkus PT et al. Thromb Haemost 2005;93:76-9;
3. Goldhaber SZ et al. Lancet 1999;353:1386-9
Mortality
VTE kills
>370000
people in Europe
annually1
(DE, ES, FR, IT, SE, UK)
Total deaths from
AIDS
Breast cancer
Prostate cancer
Traffic accidents
combined
>

11. PE in India

12. DVT/PE can have serious long-term consequences
12
Long-term consequences
Recurrent VTE
Post-thrombotic syndrome
Venous ulceration
Chronic thromboembolic pulmonary hypertension

13. • Occurs in ~4% of survivors of
acute PE1
• Untreated CTPH has a 90%
mortality rate2.
If untreated, the high pulmonary arterial
pressure caused by vessel blockage and
constriction of the vessel wall can make it
difficult for the right ventricle to pump blood to
the lungs, which can lead to the development of
right heart failure.2
A serious complication of PE
13
CTPH = chronic thromboembolic pulmonary hypertension
1. Pengo V et al. N Engl J Med 2004;350:2257-64; 2. Tapson VF & Humbert M. Proc Am Thorac Soc 2006;3:564-7
Chronic thromboembolic pulmonary hypertension
Cumulativeincidenceof
symptomaticCTPH(%)
0.0
1.0
2.0
3.0
4.0
1 2 3 4 5 6 7 8 9 10 11
Time since first symptomatic PE (years)
N=223

14. RISK OF DEVELOPMENT OF PULMONARY EMBOLISM
• Studies have shown that hypercoagulability state, stasis and
local trauma to the vessel wall predisposes to PE

15. RISK OF DEVELOPMENT OF PULMONARY EMBOLISM
There is an extensive collection of predisposing environmental and genetic
Strong risk factors
• Fracture of lower limb
• Hospitalization for heart failure or
atrial fibrillation/flutter
• (within previous 3 months)
• Hip or knee replacement
• Major trauma
• Myocardial infarction (within
previous 3 months)
• Previous VTE
• Spinal cord injury

16. Moderate risk factors
• Arthroscopic knee surgery
• Autoimmune diseases
• Blood transfusion
• Central venous lines
• Intravenous catheters and leads
• Chemotherapy
• Congestive heart failure or respiratory failure
• Erythropoiesis-stimulating agents
• Hormone replacement therapy (depends on formulation)
• In vitro fertilization
• Oral contraceptive therapy
• Post-partum period
• Infection (specifically pneumonia, urinary tract
• infection, and HIV)
• Inflammatory bowel disease
• Cancer (highest risk in metastatic disease)
• Paralytic stroke
• Superficial vein thrombosis
• Thrombophilia

17. RISK OF DEVELOPMENT OF PULMONARY EMBOLISM
Note : In upto 25% of patients with confirmed PEhave no, as yet, identifiable
predisposing factors
*Risk factors in pulmonary embolism, 1976 sep;143(3):385-90
*The ESC2019
Weak risk factors
• Bed rest >3 days
• Diabetes mellitus
• Arterial hypertension
• Immobility due to sitting (e.g. prolonged car or air
travel)
• Increasing age
• Laparoscopic surgery (e.g. cholecystectomy)
• Obesity
• Pregnancy
• Varicose veins

19. Definition of haemodynamic instability, which delineates
acute high-risk pulmonary embolism
Need for
cardiopulmonary
resuscitation
Systolic BP < 90 mmHg or
vasopressors required
to achieve a BP >_90 mmHg
despite adequate
filling status
And
End-organ hypoperfusion (altered
mental status; cold,
clammy skin; oliguria/anuria;
increased serum lactate)
Systolic BP < 90 mmHg or
systolic BP drop >_40
mmHg, lasting longer than 15
min and not caused by
new-onset arrhythmia,
hypovolaemia, or sepsis

20. Aim of Diagnosis & Management
Suspected PE
• Symptoms
• Signs
Treatment
•LMWH
•UFH
•Fibrinolysis
•Catheter
•Surgical
Investigations
• ECG
• 2D Echo
• Enzymes
• US
• CT PA
Clinical Prediction
Rules
• Wells Score
• Geneva Score
• Simplified Wells
Score
• Simplified Geneva
Score
Risk Stratification
• High Risk
• Intermediate
Risk
• Low Risk

21. DIAGNOSIS OF PE
It’s challenging, because symptoms
and sign are nonspecific and
diagnostic tests are either imperfect
or invasive

22. CLINICAL PRESENTATION
‘Confirmed PE’is defined asa probability of PEhigh enough to indicate the need for pe-specific Rx, and
‘
lo
Ex
w
c
r
lu
is
d
k.
edPE’asa probability of PElow enough to justify withholding pe-specific RXwith an acceptably

23. CLINICALPRESENTATION
• In the Prospective Investigation Of Pulmonary Embolism Diagnosis II (PIOPED II)
trial:
– Patients with PEhad a range of signs and symptoms.
– Common signs were tachypnea (54%) and tachycardia (24%).
– The most common symptoms were :
• Dyspnea, usually of onset within seconds, at rest or with exertion (73%),
• Pleuritic pain (44%),
• Calf or thigh pain (44%),
• Calf or thigh swelling (41%), and
• Cough (34%)
• The PIOPEDII trial observed a sensitivity of 83% and a specificity of 96%
*Clinical characteristics of patients with acute pulmonary embolism: data from PIOPED II. Stein PD, Beemath A, Matta 2007

24. ALGORITHM FOR DIAGNOSIS

25. Assessment of
clinical (pre-test) probability
Because of the variable nature of the presentation of PE, the
evaluation largely depends on the likelihood of PE and the
stability of the patient.
There are scoring systems to assist in the determination of
likelihood of PE and thromboembolic events.

26. Diagnostic scoring systems - the
“Wells criteria and Geneva score”
are often used.

27. The Wells clinical prediction rule

28. The revised Geneva clinical prediction rule
ESC guidelines. European Heart Journal (2019) 00, 1- 61

29. The simplified Wells rule
“PE unlikely” (1 points, 2.3%-9.4% PE risk)
“PE likely”(>1 points, 28%-52% PE risk)
The simplified Geneva score
“PE unlikely”(2 points, 13% - 19% PE risk)
“PE likely”(>2 points, 28% to 35% PE risk)
Score  2 + normal D-Dimer, 3% PE risk
From: Menno V. Huisman and Frederikus A. Klok. BLOOD, 2013 121: 4443-4448

30. Kline JA, Mitchell AM, Kabrhel C, et al: J Thromb Haemost 2: 1247, 2004.
If all criteria are met, probability of developing clinically
diagnosed VTE is <2 %
8
components

31. Investigations
• ECG
• 2D Echo
• Enzymes
• CUS
• CT PA
• New complete or incomplete
RBBB
• Anteroseptal ST elevation or
depression
• Anteroseptal T-wave inversion
ECG
• RV dilation (apical 4-chamber RV diameter
divided by LV diameter > 0.9)
• RV systolic dysfunction
• Interventricular septal shift or bowing
• Estimated RVSP >40 mm Hg
• Sensitivity 31-52%; Specificity 87-96%
Echo
•Elevation of D-Dimer (>500 g/L)
•Elevation of N-terminal pro-BNP (>500
pg/mL)
•Elevation of troponin I (>0.4 ng/mL)
•Elevation of troponin T (>0.1 ng/mL)
Enzymes

32. • Simple 4 point: 2 groin, 2 popliteal
fossae
• Sensitivity 39%; Specificity 99%
Compressed
Ultra
Sonography
• RV dilation (4-chamber RV
diameter divided by LV diameter
>0.9)
• Thrombus upto segmental level
• Sensitivity 83%; Specificity 96%
CTPA
• Gold standard
• Sensitivity 100%; Specificity 90PA
Investigations
• ECG
• 2D Echo
• Enzymes
• CUS
• CT PA
• Normal, Low, Intermediate, High probability
• Single mismatched segmental perfusion
defect (PPV 88%)
• In cases when CT PA is contraindicated
• High proportion of inconclusive results
V Q Scan

34. Diagnostic algorithm for patients with suspected high-risk pulmonary
embolism presenting with haemodynamic instability.
ESC guidelines. European Heart Journal (2019) 00, 1- 61

35. Diagnostic algorithm for patients with suspected pulmonary
embolism without haemodynamic instability.
ESC guidelines. European Heart Journal (2019) 00, 1- 61

36. Initial risk stratification of acute PE
Eur Heart J doi:10.1093/eurheartj/ehu283 2014

37. Pulmonary Embolism Severity Index
USING PESI OR sPESI
Eur Heart J doi:10.1093/eurheartj/ehu283 2014

38. Classification of patients with acute PE based on early
mortality risk
Eur Heart J doi:10.1093/eurheartj/ehu283 2014

39. Goals of PE management
1. Prevention of death from the current embolic event.
2. To reduce the chances of recurrent embolic events, and
3. To minimize long term morbidity due to the event.

40. Treatment of Acute PE
Pharmacological
Treatment
•UFH
•LMWH/ FONDAPARINUX
•NOAC – NON-VIT k ANTAGONIST ORAL ANTICOADULANTS
•Fibrinolysis
•Catheter directed thrombolysis
•Surgical thrombectomy
•IVC filters
Anticoagulation and thrombolytic are
the mainstay of medical treatment
Journal of The Association of Physicians of India Vol. 63 December 2015
• Oxygen
• IV fluid
• NIV/ HFNC /MV
• VASOPRESSORES &
INOTROPES
• ECMO

41. Anticoagulation
• In high risk PE, anticoagulation with UFH should be started without delay.
• LMWH or fondaparinux is recommended as an initial treatment for most
patients with non-high risk PE.
• UFH, LMWH or fondaparinux should be continued for at least 5 days and may
be replaced by vitamin K antagonists only when target INR levels for > 2
consecutive days is achieved.
Recommendations
Anticoagulation should be started at
the earliest for patients with
intermediate or high clinical
probability of PE and having no
contraindications to anticoagulation
Journal of The Association of Physicians of India Vol. 63 December 2015

42. Thrombolysis In Acute PE

43. Disclaimer
• Please note that information discussed in this presentation is
meant for educational purposes and may contain off–label
information
• Please refer the current locally approved prescribing information
of each product for dosage, indication, contraindications,
precautions and other safety information.

44.  Thrombolytic Therapy ~ Background
Faster clot lysis
Dissolves obstruction
May reverse RV failure
Dissolves much of source
Decrease risk of recurrence
Well tolerated PE
~ excellent prognosis
Risks:
~ major hemorrhage:
1.8 – 6.3%
~ ICH: 1.2%
Thrombolysis for Pulmonary Embolism

45. Treatment
Eur Heart J doi:10.1093/eurheartj/ehu283 2014
*This is the accelerated regimen for rtPA in pulmonary embolism; it is not officially approved, but it is sometimes used in extreme
haemodynamic instability such as cardiac arrest.
*

47. Contraindications of Thrombolytic Therapy
Eur Heart J doi:10.1093/eurheartj/ehu283 2014

48. Alteplase in Acute Massive Pulmonary Embolism
A total dose of 100 mg should be administered in 2 hours. The most
experience available is with the following dose regimen:
- 10 mg as an intravenous bolus over 1 - 2 minutes followed by
- 90 mg as an intravenous infusion over two hours
In patients with a body weight below 65 kg
- 10 mg as an IV bolus over 1-2 minutes followed by
- an intravenous infusion upto a maximum total dose of 1.5mg/kg
Dose and Administration
ACTILYSE PI INDIA 2019

49. Clinical Evidence of
Alteplase in Acute PE
Key Clinical Trials of Systemic Thrombolysis in Patients With
Submassive PE

50. PAIMS 2: Plasminogen activator Italian multicenter study

51. • Patients: 101 stable pts with acute PE
• Groups: rtPA100 mg/2h (n=46) and heparin alone (n=55)
• Design: randomized, double-blind
• Follow-up: 24 hours after the beginning
of treatment
Result In the rtPA group:
• Improvement of RV function.
• Reduction of RV dimensions (echo)
• Improvement of pulmonary perfusion (lung
scan)
• no PE recurrence

52. To study the effect of alteplase vs.
urokinase in 45 patients with PE
Evaluated Clot lysis
Lancet1988; 2:293

53. • 12 centers, 63 patients randomized to urokinase and alteplase followed by
heparin
At 2 hr Total Pulmonary
Resistance decreased by
18 ±
22 % 36 ±
17 %
UROKINASE ALTEPLASE
P<0.0009
Continuous monitoring of pulmonary
arterial pressure, Cardiac Index and total
pulmonary resistance revealed that these
variables improved faster in
alteplase group with persistently
significant intergroup differences from 30
min to up to 3-4hr

54. Fifty patients with massive
pulmonary embolism were
randomly allocated either to a
1oo mg 2 h infusion of
alteplase or streptokinase

55. Chest 2010;137;254-262
Methodology
Prospective, randomized, multicenter trial was conducted in which 118 patients with acute PTE
and either hemodynamic instability or massive pulmonary artery obstruction were randomly
assigned to receive a treatment regiment of either rt-PA at 50 mg/2 h (n =65) or 100 mg/2 h (n =
53)
The efficacy was determined by observing the improvements of right ventricular dysfunctions
(RVDs) on echocardiograms, lung perfusion defects on ventilation perfusion lung scans, and
pulmonary artery obstructions on CT angiograms
The adverse events, including death, bleeding, and PTE recurrence, were also evaluated

56. Results
Progressive improvements in RVDs, lung perfusion defects, and pulmonary artery
obstructions were found to be similarly significant in both treatment groups
Three (6%) patients in the rt-PA 100 mg/2 h group and one (2%) in the rt-PA 50 mg/2 h group died
as the result of either PTE or bleeding
Importantly, the 50 mg/2 h rt-PA regimen resulted in less bleeding tendency than the 100 mg/2 h
regimen (3% vs 10%), especially in patients with a body weight , 65 kg (14.8% vs 41.2%, P 5 .049)
No fatal recurrent PTE was found in either group

59. IV. WHAT DO GUIDELINES SAY?

60. ESC guidelines. European Heart Journal (2019) 00, 1- 61
ESC PE 2019 GUIDELINES

61. ESC guidelines. European Heart Journal (2019) 00, 1- 61
ESC PE 2019 GUIDELINES

62. ESC guidelines. European Heart Journal (2019) 00, 1- 61

63. Acute PE &
COVID-19

64. Disclosure………
• No one is expert about this topic…
• Tip of iceberg knowledge about disease…..
• Daily changing information from International & ? National literature
• Frequently changing government advisory and guidelines….
• Different hospitals ………… Different problems….. Different
solutions………

65.  The incidence of PE is reported to be around 2.6–8.9% of COVID-
19 in hospitalized patients
Up to one-third of those requiring intensive care unit (ICU)
admission, despite standard prophylactic anticoagulation.
 Observational data show that 7-39% of patients with COVID-19
infection who require mechanical ventilation have acute PE/DVT.
 Possible pathophysiology..
Due to direct and indirect pathologic consequences of COVID-
19, complement activation, cytokine release, endothelial
dysfunction, and interactions between different types of
blood cells leading to hypercoagulable state.

66. How do we diagnose pulmonary embolism (PE) if we cannot perform CTPA or
V/Q lung scan because the patient must remain in isolation or is too
unstable?
1. Rely on clinical assessment based on history, physical findings and
other tests.
Likelihood of PE is moderate to high in those with
• signs or symptoms of DVT,
• unexplained hypotension or tachycardia,
• unexplained worsening respiratory status, or
• traditional risk factors for thrombosis (e.g., history of thrombosis, cancer, hormonal therapy).
2. If feasible, consider doing –
• Bilateral compression ultrasonography (CUS) of the legs,
• Echocardiography or
• Point-of-care ultrasonography (POCUS).
(These tests can confirm thrombosis if proximal DVT is documented on CUS or if a
clot-in-transit is visualized in the main pulmonary arteries on echocardiography
or POCUS, but they cannot rule out thrombosis if clot is not detected.)

67. Does a normal D-dimer level effectively rule out PE/DVT ?
• Yes- A normal D-dimer level provides reasonable confidence that
PE/DVT is not present.
• Although the false negative rate of D-dimer testing is unknown in
covid 19 population, low rates of 1 – 2% using highly sensitive D-
dimer assays have been reported in other high risk populations.
• Radiological imaging is not necessary when the D-dimer level is
normal in the context of low pre-test probability.
“As ‘baseline’ D-dimer levels are higher in patients with COVID-
19, current studies are evaluating whether a different (higher)
cut-off value for D-dimer would be more useful in excluding VTE
in these patients.”

68. If D-dimer levels change from normal to abnormal, or rapidly
increase on serial monitoring, is this indicative of PE/DVT ?
An elevated D-dimer level does not confirm a diagnosis of PE/DVT in a patient
with COVID-19 because the elevated D-dimer may result from the COVID-19
infection or other causes.
If possible, CTPA and/or bilateral CUS should be performed to
investigate for PE/DVT.
It is important to determine if there are any new clinical findings that indicate
acute PE/DVT and if there are other causes of high D-dimer levels, such as
secondary infection, myocardial infarction, renal failure, or coagulopathy.
(Published data have shown that the majority of patients with progressive,
severe COVID-19 infection with acute lung injury/ARDS have very high D-dimer
and fibrinogen levels, independent of the presence or absence of VTE. )

69. What are the risks and benefits of empiric therapeutic anticoagulation
in COVID-19 patients?
RISK
•Major bleeding
•Specially in
those with risk
factors for
bleeding, such
as older age,
liver or renal
impairment, and
previous history
of bleeding.
Benefits
• COVID-19 infection is associated
with high morbidity and mortality
due to microvascular pulmonary
thrombosis or PE - Having
undiagnosed or untreated PE may
worsen patient outcomes.
• Anti-inflammatory effects of
heparin/LMWH may offer benefit
• Anti-viral mechanisms have been
demonstrated for factor Xa
inhibitors in animal studies.
Ideally - Objective imaging to confirm a diagnosis of PE/DVT should, if possible, be
done prior to starting therapeutic anticoagulation.

70. Are there any clinical scenarios in which empiric therapeutic
anticoagulation would be considered in COVID-19 patients?
If no contraindications for therapeutic anticoagulation and there is no
possibility of performing imaging studies to diagnose PE or DVT, empiric
anticoagulation has been proposed in the following scenarios:-
• Intubated patients who develop sudden clinical and laboratory findings
highly consistent with PE, such as desaturation, tachycardia, increased
central venous pressure or pulmonary artery wedge pressure, or evidence of
right heart strain on echocardiogram, especially when chest X-ray and/or
markers of inflammation are stable or improving.
• Patients with physical findings consistent with thrombosis, such as superficial
thrombophlebitis, peripheral ischemia or cyanosis, thrombosis of dialysis
filters, tubing or catheters, or retiform purpura (branching lesions caused by
thrombosis in the dermal and subcutaneous vasculature).
• Patients with respiratory failure, particularly when D-dimer and/or fibrinogen
levels are very high, in whom PE or microvascular thrombosis is highly
suspected and other causes are not identified (e.g., ARDS, fluid overload).

71. If a patient is empirically started on anticoagulation for suspected PE,
how long should they be anti-coagulated? What if later investigation
shows no evidence of PE?
• All patients with COVID-19 who are started on empiric therapeutic
anticoagulation for presumed or documented PE should be given a
minimum course of 3 months of the therapeutic regimen (provided the
patient tolerates treatment without serious bleeding).
• Thrombus resolution can occur within a few days of effective
anticoagulation, so negative results from delayed testing should not be
interpreted as implying PE or DVT was not previously present.
• At 3 months, therapeutic anticoagulation can stop, provided the patient
has recovered from COVID-19 and has no ongoing risk factors for
thrombosis or other indications for anticoagulation (e.g. prolonged
immobilization or atrial fibrillation)

72. SUMMARY
•VTE clinically presenting as DVT or PE, is globally the
third most frequent acute cardiovascular syndrome
behind myocardial infarction and stroke.
•Thrombolytic therapy is recommended in all
patients with high risk PE, unless contraindicated.
•Routine use of primary systemic thrombolysis is not
recommended in patients with intermediate-or low-
risk PE.
ESC guidelines. European Heart Journal (2019) 00, 1- 61