REVIEW OF THERAPIES FOR PULMONARY EMBOLISM

1. REVIEW OF THERAPIES FOR
PULMONARY
THROMBOEMBOLISM
Dr NIHANTH REDDY V
DrNB RESIDENT - CARDIOLOGY

2. REFERENCES
• BRAUNWALD HEART DISEASE, 12TH EDITION
• JOURNAL OF AMERICAN COLLEGE OF CARDIOLOGY : Acute
Pulmonary Embolism With an Emphasis on an Interventional
Approach http://dx.doi.org/10.1016/j.jacc.2015.12.024
• MEDICINA : Review of Medical Therapies for the Management of
Pulmonary Embolism https://doi.org/10.3390/medicina57020110
• AMERICAN HEART ASSOCIATION : Interventional Therapies for Acute
Pulmonary Embolism: Current Status and Principles for the
Development of Novel Evidence

3. INTRODUCTION
• Pulmonary Embolism manifests with a wide spectrum of acuity
ranging from mild to severe.
• Rapid and accurate risk stratification is of paramount importance
• The three key components for risk stratification are:
(1) Clinical evaluation
(2) Assessment of right ventricular size and function and
(3) Analysis of cardiac biomarkers to determine whether there is right
ventricular microinfarction.

4. RISK STRATIFICATION
• The American Heart Association (AHA)/European Society of Cardiology (ESC) classifies
pulmonary embolism into :
1. High risk (Massive) : Hypotension, defined as a systolic blood pressure <90 mmHg, a
drop of >40 mm Hg for at least 15 minutes or need for vasopressor support. They
account for ≈5% of hospitalized patients with PE and have an average mortality of
≈30% within 1 month.
2. Intermediate risk (Sub massive) : Defined as occurring in normotensive patients with
evidence of right ventricular (RV) strain by echocardiogram, computed tomography
(CT) scan, or RV injury and pressure overload detected by an increase in cardiac
biomarkers such as troponins or brain natriuretic hormone. Observational cohorts,
both prospective and retrospective, have identified higher mortality rates in this
population, with the range being 3% to 15% over a period of 7 to 90 days.
3. Low risk : Account for 40% to 60% of hospitalized patients with PE and have an
average mortality of ≈1% within 1 month

5. • Despite a high case fatality rate, most patients with massive and
submassive PE continue to be treated conservatively with
anticoagulation alone.
• This has prompted alternate, intensive treatment options, including
systemic fibrinolysis, catheter-based therapy, and surgical
embolectomy

6. BUILDING AN
ACUTE PE TEAM
AND
MANAGEMENT
PATHWAY
PERT PROTOCOL

7. DIAGNOSTIC APPROACH AND MANAGEMENT STRATEGY FOR ACUTE
PULMONARY EMBOLISM

8. OPD VS IPD
HESTIA
CRITERIA

9. PREDICTORS OF PROGNOSTIC RISK : PESI SCORE AND SIMPLIFIED PESI
SCORE
Patients with a score of o are at low risk for PE
Scores >/ 1 are considered at high risk for PE

10. PRE-INTERVENTION
• Unless contraindicated, anticoagulation should be initiated when PE is suspected, prior to additional
work-up
• After confirmation, the first question is whether the PE is low risk versus sub- massive to massive
• Hemodynamically stable patients without evidence of RV strain are at low risk, may not require
PERT activation, and can be treated with anticoagulation alone.

11. ER PE PROTOCOL
UTILIZING PERT
CONSULTATION
AND SIMPLIFIED
PESI SCORE

12. PARENTARAL ANTICOAGULATION
• Anticoagulation is the cornerstone of treatment for acute PE
• Current anticoagulation management guidelines prefer direct oral anticoagulants (DOAC) for initial
and long-term therapy for treating PE
• Dabigatran, rivaroxaban, apixaban, and edoxaban are preferred over vitamin K antagonist (VKA)
therapy
• Low molecular weight heparin (LMWH) may be considered for treatment as an alternative to
DOACs and VKA therapy
• The duration of anticoagulant therapy for PE is three months, at minimum, which may be extended
or indefinite in selected circumstances
• In patients with a PE provoked by surgery or a nonsurgical transient risk factor, the recommended
duration of anticoagulation is three months

13. • In patients with an unprovoked PE, bleeding risk determines the duration, but in patients with high
bleeding risk, the duration remains at three months. In low to moderate bleeding risk, the duration of
therapy becomes indefinite
• Bleeding remains a concern with anticoagulation therapy.

15. SOME SAILENT FEATURES ABOUT
PARENTERAL ANTICOAGULANTS
• UFH : Derived from porcine or bovine tissue.
• Works by inactivating thrombin (IIa) and factor Xa via antithrombin
• Short half-life ranges from 0.5 to 1.5 h, which makes UFH the anticoagulant
of choice in patients with PE. This is particularly the case in patients with
high bleeding risk, critical illness, or who need a surgical/invasive
procedure
• Unique metabolism and clearance through the reticuloendothelial system,
which make it a desirable option for patients with poor and/or unstable
renal function
• Heparin Induced Thrombocytopenia (HIT) poses a concern with UFH use in
the treatment of PE, with the overall incidence being reported to be up to
7% in patients with a mortality of 20% to 30%

16. • Adverse drug reactions of concern are thrombocytopenia and major bleeding,
such as intracranial and gastrointestinal bleeds. Another side effect of concern is
the significant reduction in bone density reported in about 30% of adult patients
and the symptomatic bone fractures that occur in 2% to 3% of adult patients
receiving heparin for at least 1 month or more

17. • LMWH : LMWHs, including enoxaparin and dalteparin, are defined as having a
mean molecular weight that is less than 50% of that of UFH.
• They offer the advantage of consistent anticoagulant effect administered
subcutaneously
• Currently the preferred anticoagulant for active malignancy and pregnancy.
• Routine anti-Xa monitoring is generally not recommended for enoxaparin
but can be considered in patients with severe or unstable renal function
and obese patients with a BMI ≥ 40 kg/m2 (or >190 kg) who will be on
enoxaparin for longer than 1 to 2 weeks

18. • VKA : VKAs such as warfarin continue to play a role in PE treatment, particularly
in patients with severe renal insufficiency, antiphospholipid syndrome, and
financial constraints who are unable to afford DOACs
• International Normalized Ratio (INR) monitoring is recommended for warfarin
monitoring
• Although initially an INR increase may be observed, patients might be in a
hypercoagulable state during the first few days of warfarin therapy due to the
drug’s long half-life, slow depletion of factor II, and rapid depletion of
anticoagulant protein C
• Due to this initial hypercoagulable state, bridging with UFH, LMWH, or
fondaparinux for at least 5 days and until the INR reaches the therapeutic range
of 2 to 3 is recommended
• Not only does the INR monitoring pose a limitation for warfarin use, but its vast
food and drug interactions also limit the desire to initiate warfarin for long-term

19. • DOAC’S :
• Apixaban is an oral direct factor Xa inhibitor approved for stroke risk
reduction and deep venous thrombosis (DVT) prophylaxis
• Rivaroxaban is a direct factor Xa inhibitor
• Renal elimination of Rivaroxaban accounts for approximately 36% of
unchanged drug, its use in patients with a CrCL < 30 mL/min is not
advised, and <15 mL/min employment is contraindicated
• Dabigatran (Pradaxa®) is a DOAC that works as a direct thrombin (IIa)
inhibitor. The dose for PE treatment is 150 mg orally twice a day after 5 to
10 days of parenteral anticoagulation in patients with adequate renal
function (CrCl > 30 mL/min)

21. ADVANCED THERAPIES FOR PULMONARY
EMBOLISM
• Systemic thrombolysis
• Catheter directed thrombolysis
• Surgical embolectomy
• IVC filters

22. SYSTEMIC THROMBOLYSIS
• There are three dosing intensities in systemic thrombolysis :
(1)Full-dose systemic
(2)Half-dose systemic or
(3)Low-dose catheter-directed therapy.
• Intravenous (IV) fibrinolysis has been considered the primary intensive therapy option in
patients with high-risk PE
• FDA has approved Alteplase for high-risk PE, in a dose of 100 mg delivered through a
peripheral vein as a continuous infusion over 2 hours, without concomitant heparin.
• Patients who receive fibrinolysis up to 14 days after onset of new symptoms or signs can
likely benefit from systemic thrombolysis

23. CONTRAINDICATIONS
TO FIBRINOLYSIS IN
HIGH-RISK
PULMONARY
EMBOLISM

24. THROMBOLYTIC AGENTS IN ACUTE PULMONARY EMBOLISM

25. • In patients receiving 50mg versus full-dose 100mg of alteplase for PE,
studies demonstrated that half-dose fibrinolysis was associated with an
increased requirement for treatment escalation driven largely by rescue
fibrinolysis and catheter-directed therapy
• Furthermore, rates of hospital mortality, intracranial bleeding,
gastrointestinal hemorrhage and anemia were similar.
• A meta-analysis of trials including patients with massive PE showed a
reduction in the composite of recurrent PE and death with use of IV
fibrinolytic agents
• Univariate analysis of a large inpatient sample found that among unstable
patients with PE, use of IV fibrinolytic therapy was associated with a lower
mortality rate

26. • Patients with submassive PE were better represented in randomized trials.
• The MAPPET (Management, Strategies and Prognosis of Pulmonary
Embolism)-3 trial randomized 256 patients with PE and pulmonary
hypertension or RV dysfunction to 100 mg of IV alteplase or placebo
infused over 2 h plus anticoagulation. IV alteplase was associated with a
lower risk of further need to escalate the treatment and with a similar risk
of death. Mortality was lower than expected in both groups
• The PEITHO (Pulmonary Embolism Thrombolysis) trial randomized 1,006
patients with submassive PE to Tenecteplase or placebo. The PEITHO trial
showed a reduction in the primary endpoint of hemodynamic collapse at 7
days with Tenecteplase, but a significant increase in hemorrhagic stroke

27. • Taken together, these studies show that the use of IV fibrinolytic
therapy in patients with massive or submassive PE leads to
improved hemodynamic stabilization and, possibly, a lower risk
of recurrent PE and PE-attributed death. However, this benefit
comes with an increased risk of severe bleeding and intra-
cranial hemorrhage

28. CATHETER BASED THERAPIES

29. CATHETER DIRECTED THERAPIES
• AIM : To relieve obstruction quickly and restore pulmonary blood flow, thus
improving cardiac output and converting a hemodynamically unstable
situation into a stable one
• This is accomplished with reduced or no doses of fibrinolytic agents
• Catheter-directed therapies (CDT) might include clot fragmentation,
aspiration, and low-dose fibrinolytic injection.
• The simplest and most performed catheter-based therapy is a local, slow
infusion of a fibrinolytic agent through low-profile catheters placed in the
obstructed pulmonary artery (PA)
• Catheter Directed Fibrinolysis is best suited for more stable patients or
those who have been hemodynamically stabilized, as thrombus resolution
may take several hours.

30. • For unstable patients who require immediate intervention and/or
those with contraindication to fibrinolysis, mechanical thrombus
fragmentation, debulking, or aspiration of occlusive thrombi may
be attempted.
• Potential complications of any catheter-based therapy may
include pulmonary arterial injury, pericardial tamponade, major
bleeding, hemodynamic deterioration, distal embolization and
“no-reflow” phenomenon, and access site bleeding.

31. • FRAGMENTATION AND ASPIRATION. Fragmentation and aspiration of PE may be
helpful in stabilizing patients with massive PE, especially when systemic fibrinolysis is
contraindicated or has failed
• By rotating a pigtail catheter in the PA, the PE can be fragmented
• The aim is to reduce the load on the RV by partially relieving the obstruction in the main
PA branches
• Fragmentation is frequently combined with local infusion of small-dose fibrinolytic agents
(e.g., 4 to 10 mg of tissue-type plasminogen activator [t-PA]), delivered either at the time
of the procedure or subsequently via an infusion catheter left in place.
• Concomitant aspiration can reduce the risk of worsening obstruction

32. • Fragmentation can also be performed by inflation of an angioplasty balloon, with care to
keep inflation in larger vessels and to choose a balloon smaller than the artery diameter
• Aspiration can be attempted using regular 8-F guide catheters or specialized catheters.
• One of the first aspiration catheters was the Greenfield embolectomy catheter which
consisted of a suction cup at the tip of a straight catheter.
• Other specialized devices used to treat peripheral thrombi have also been used off-label
to treat PE. These include the 10-F Aspirex thrombectomy catheter (Straub Medical,
Wangs, Switzerland), currently un- available in the United States, which combines
rotational thrombus fragmentation with aspiration
• The Angio jet Rheolytic Thrombectomy System utilizes the Venturi-Bernoulli effect, using
multiple high- velocity saline jets introduced through the distal tip, creating a low-pressure
vacuum through small slits in the catheter that can entrain and fragment thrombi

34. ANGIOVAC DEVICE
• The AngioVac Cannula (Angiodynamics, Latham, New York),
a 22-F venous catheter that can remove soft thrombi utilizing
the centrifugal pump and venous reinfusion cannula
• Limitations of this device include the large dual sheaths
required for access, leading to a higher likelihood of bleeding
complications, and the relatively stiff suction catheter, which
is difficult to maneuver into the RV and PA

35. FLOWTRIEVER DEVICE
• The FlowTriever Infusion Aspiration System
requires a 22-F venous sheath and consists of 3
parts: the Flow Restoration Catheter, which is
made up of 3 self-expanding nitinol disks; the
Aspiration Guide Catheter; and the Retraction
Aspirator Device.
• The FlowTriever device is advanced over the wire
and into the thrombus, where the expandable
disks are deployed.
• The disks and disrupted thrombus are then
retracted and removed through the aspiration
catheter.
• Limitations include the large size requirement of
the access sheath, and manipulation of the large-
bore catheter into the PA.

36. PENUMBRA INDIGO
ASPIRATION CATHETER
• It consists of a pump, 6- to 8-F straight or angled
catheters, and a Separator device
• It is approved for thrombus removal in both
peripheral arterial and venous systems. An
advantage is that it only requires an 8-F venous
sheath and can be placed into the PA system
quickly, in an over-the-wire technique
• Once placed proximal to the clot, the
thrombectomy catheter is advanced while suction
is supplied with the ACER pump

37. EKOS CATHETER

38. ANTICOAGULATION BEYOND THREE MONTHS
• Maintenance of anticoagulation post-intervention is critical to prevent recurrent clot formation
• Patients who have had a recent catheter-based intervention are at risk of access site bleeding
• One strategy to potentially reduce bleeding risk is to hold the heparin drip for 1 to 2 h after sheath
removal, then restart without a bolus.
• Warfarin is administered on the night of the procedure, and parenteral anticoagulation and warfarin
are overlapped until the international normalized ratio is 2 to 3 for at least 24 h, as per American
College of Chest Physicians guidelines
• No specific guidelines on initiation of anticoagulants post catheter directed therapies

39. SURGICAL
EMBOLECTOMY
• Surgical embolectomy has reemerged for
the management of patients with high-risk
PE or intermediate-high-risk PE with
severe right ventricular dysfunction and
clinical deterioration despite
anticoagulation, in whom contraindications
preclude thrombolysis
• Surgical embolectomy can also be used as
rescue therapy for patients whose PE is
refractory to thrombolysis.
• Results are best when patients undergo
surgery before they become pressor-
dependent and before the onset of
cardiogenic shock and multisystem organ
failure.
• Extraction is limited to directly visible clots.

40. IVC FILTERS
• Placement of an inferior vena cava (IVC) filter is indicated in
patients with acute PE who have absolute contraindications to
anticoagulation or in patients who have recurrent PE, despite
adequate anti- coagulation

41. PADUA
PREDICTION
SCORE

42. REGIMENS FOR VENOUS
THROMBOEMBOLISM
PREVENTION

43. THANK YOU