Pulmonary%20thromboembolism Treatment

Inpatient Versus Outpatient Management

• Intermediate- to high-risk patients w/ the following features should be managed in a hospital setting
  • Hemodynamic instability
  • Oxygen saturation (O₂ sat) <90%
  • Active bleeding or at risk for major bleeding
  • Currently on full-dose anticoagulants during assessment
  • Severe pain
  • With comorbidities requiring hospital confinement
  • With chronic kidney disease stage 4/5 or severe hepatic disease
  • Socioeconomic reasons eg unfavorable living conditions, concern over treatment compliance
• Low-risk PE patients without abovementioned criteria should be considered for home treatment or early discharge
• Patients w/ symptomatic PE should initially be treated in the hospital because of:
  • Decreased cardiorespiratory reserve
  • Complications
  • Monitoring of INR to guide Warfarin therapy

Parenteral Anticoagulants

• Heparin should be administered in patients w/ intermediate or high clinical probability of PE before imaging studies are performed & in low probability patients once PE is confirmed
• If PE occurs postoperatively, Heparin therapy should not be started until 12-24 hours after major surgery & after consultation w/ surgeon
  
  • Treatment could be delayed even longer if there is any evidence of bleeding from the surgical site
• Both subcutaneous low molecular weight heparin (SC LMWH) or intravenous unfractionated heparin (UFH) short course treatments are recommended for objectively confirmed non-massive PE
  
  • Either LMWH or UFH is appropriate for the initial treatment of PE

Thrombolysis

General Therapeutic Principles

• Studies have shown a more rapid improvement in radiographic & hemodynamic abnormalities in acute massive PE patients who received thrombolytic agents & anticoagulant agents over conventional anticoagulant agents alone
  • There was no clinically relevant outcomes for death rate or for the resolution of symptoms

Massive PE

• The use of thrombolytic therapy in PE should be individualized
  
  • Patients w/ hemodynamically unstable PE who are at low risk of bleeding are the most appropriate candidates
• Thrombolytic therapy is recommended in high-risk PE presenting w/ cardiogenic shock &/or persistent arterial hypotension
• Thrombolytic therapy may also be considered in patients w/
  
  • Compromised oxygenation
  • Free-floating right ventricular thrombus or patent foramen ovale documented by echocardiography
  • Massive hemodynamically significant PE without systemic hypotension or profound hypoxemia

Non-massive PE

• The use of thrombolytic therapy in non-high-risk patients (hemodynamically stable patients w/ echocardiographic evidence of RV dysfunction) is controversial
  
  • Further studies are needed to show a clinically relevant improvement in the benefit-risk ratio of thrombolytic treatment over traditional anticoagulant therapy in these patients
• Thrombolytic therapy should not be used in patients w/ low-risk PE

Adrenergic Agonists

• Should be considered for patients w/ low cardiac index & normal blood pressure (BP) or w/ impending hypotension

Dobutamine

• Considered 1st-line agent to treat right-sided heart failure & cardiogenic shock
• Affects vasodilatation of both systemic & pulmonary vascular beds, increases myocardial contractility while decreasing right-sided filling pressures

Dopamine

• Has also been used for hemodynamic support in pulmonary embolism (PE) patients
• Use may be limited by the development of tachycardia

Epinephrine

• May be effective when shock complicates acute PE
• Vasoconstrictor effect similar to Norepinephrine, inotropic effect more due to potent beta₁ stimulation rather than beta₂ effect, accounting for improved pulmonary vascular resistance

Norepinephrine

• May be appropriate in acute massive PE when there is profound hypotension
• Stimulates both alpha-adrenergic (inducing vasoconstriction) & beta₁-adrenergic receptors (augmenting cardiac contractility) resulting in improved systemic blood pressure, cardiac output, pulmonary vascular resistance, & right ventricular pressure
• Combination w/ other vasoactive agents such as Dobutamine needs further evaluation

Nitric Oxide Inhalation

• May be indicated in patients w/ pulmonary hypertension & a patent foramen ovale
• Based on clinical studies, may improve the hemodynamic status & gas exchange in patients w/ PE
  

Parenteral Anticoagulants

Unfractionated Heparin (UFH)

• Intravenous (IV) UFH treatment in PE is well-established
• UFH should be considered as a 1st dose bolus & when rapid reversal of effect may be required, as in patients w/ high-risk of bleeding
• Should be given as initial anticoagulation for patients w/ PE presenting w/ shock or hypotension, also referred to as high-risk PE or clinically massive PE
• Preferred over LMWH in patients w/ severe renal failure
• IV UFH has been proven effective in the therapy of PE & deep vein thrombosis (DVT)
  
  • Studies have shown a reduced mortality rate when UFH has been used to treat VTE disease
  • Recurrence of VTE is unusual when UFH is infused at a rate that prolongs the aPTT >1.5 times the control value & when adequate levels are reached within 24 hours
• IV UFH typically requires hospitalization w/ frequent monitoring & dose adjustment
  • aPTT should be measured 4-6 hours after bolus injection, then 3 hours after each dose adjustment, or once daily when the target therapeutic dose has been attained
• Heparin-induced thrombocytopenia is a rare but serious complication

Low-molecular-weight heparin (LMWH)

• Eg Dalteparin, Enoxaparin, Nadroparin, Tinzaparin 
• LMWH is now preferred over UFH in patients w/ acute non-massive PE
• A number of studies have shown that LMWH has equal efficacy to UFH in patients w/ non-massive PE
• Patients w/ symptomatic PE should initially be treated in the hospital because of:
  
  • Decreased cardiorespiratory reserve
  • Complications
  • Monitoring of international normalized ratio (INR) to guide Warfarin therapy
• The use of LMWH is safe, effective, may shorten hospital stay & improve the quality of life for patients
• Monitoring of platelet count is necessary before treatment initiation & on the 5th day, then every 2-3 days if LMWH treatment is continued
• LMWH is not recommended for high-risk PE w/ hemodynamic instability

Fondaparinux

• Also a preferred initial treatment for PE
• Heparin assay (anti-factor Xa) has been used to monitor effects of Fondaparinux
• Obtain a platelet count prior to the start of therapy & periodically to check for any bleeding
• Not recommended for high-risk PE w/ hemodynamic instability & those w/ severe renal impairment
• Recommended for patients w/ known history of heparin-induced thrombocytopenia

Duration of Therapy

• Acute phase treatment w/ UFH, LMWH, or Fondaparinux should be continued for at least 5-7 days after the initiation of Warfarin & until therapeutic INR is stable & ≥2 (range: 2.0-3.0) for 2 consecutive days

Non-Vitamin K Oral Anticoagulants (NOACs)

• Eg Apixaban, Edoxaban, Rivaroxaban, Dabigatran etexilate
• Long-term anticoagulant treatment of PE is for prevention of fatal & nonfatal recurrent venous thromboembolic events & complications

Apixaban

• A direct factor Xa inhibitor that effectively prevents thrombin generation
• W/ significantly lower bleeding risk compared to Warfarin & other vitamin K antagonists

Dabigatran etexilate

• A direct thrombin inhibitor that effectively prevents thrombin generation
• Studies have shown that Dabigatran is comparable to Warfarin for the treatment of PE
  
  • Dabigatran also effectively prevents recurrence of DVT w/ or w/o PE, & bleeding incidences

Edoxaban

• A direct factor Xa inhibitor that effectively prevents thrombin generation
• May be used for treatment PE in patients treated w/ parenteral anticoagulant for 5-10 days

Rivaroxaban

• A direct factor Xa inhibitor that effectively prevents thrombin generation
• An alternative treatment for parenteral anticoagulants in the initial treatment of patients w/ high clinical pretest probability
• Studies have shown that Rivaroxaban is comparable to Warfarin for the prevention of PE

Warfarin

• Should be started only when VTE has been reliably confirmed
  
  • Start on day 1 of Heparin therapy, except in patients w/ suspected hypercoagulable state (Protein C or Protein S deficiency) wherein adequate anticoagulation w/ Heparin is needed before start of treatment to prevent Warfarin-induced skin necrosis or other transient hypercoagulable complications
• Bolus dose is not effective, therefore it requires at least 5 days to achieve its full effect
  
  • Thus, it is recommended that Warfarin therapy overlap w/ Heparin at least 5 days until therapeutic INR is stable & ≥2 x 2 consecutive days
• Therapy w/ Warfarin remains unsatisfactory
  
  • High rate of major bleeding despite optimal attempts at dose adjustment by INR

Thrombolysis

Antithrombotics

• Eg Alteplase (r-tPA), Reteplase, Streptokinase, Urokinase
• Alteplase (r-tPA)
  
  • Has comparable thrombolytic capacity to Streptokinase & Urokinase but can be administered for a shorter duration (2 hours)
  • Preferred thrombolytic agent because of its shorter administration time
• Streptokinase or Urokinase
  
  • These 2 agents have similar thrombolytic effects in PE & have been shown to resolve PE comparatively at 24 hours & 3x that as seen w/ Heparin alone
  • 12 hours of Urokinase has equivalent thrombolytic efficacy to 24 hours of Streptokinase

Investigational Drugs

• Tenecteplase is a tissue plasminogen activator that is approved for acute myocardial infarction & is currently being studied for PE in the context that it has better half life & fibrin specificity compared to Alteplase

• A considerable number of deaths occur within the 1st few hours after massive pulmonary embolism (PE) & therefore appropriate supportive therapy could have a major role in pulmonary embolism (PE) w/ circulatory failure

O₂ Supplementation

• May be necessary in patients w/ hypoxemia
• Consider monitoring of O₂ saturation & give supplementary O₂ if necessary

Mechanical Ventilation

• May be needed temporarily in patients who appear toxic & hypoxic
• Care should be taken to limit its hemodynamic adverse effects
  
  • Positive intrathoracic pressures induced by mechanical ventilation, may reduce venous return & worsen right ventricular (RV) failure

Hemodynamic Support

Fluid Loading

• Fluids may be administered initially & cautiously, but other vasoactive therapy should promptly follow
• Aggressive fluid challenge is not recommended
  
  • May worsen RV function by causing ventricular overstretch, leading to decreased contractility
    
    

• Absolute contraindications to thrombolysis in a life-threatening situation are rarely a factor for treatment

Absolute Contraindications to Thrombolysis

• Hemorrhagic stroke or stroke of unknown origin
• Ischemic stroke within the last 6 months
• Presence of benign/malignant tumor or damage within the CNS
• Major surgery, trauma, or injury within the past 3 weeks
• GI bleeding within the last 30 days
• Known bleeding risk

Relative Contraindications

• Transient ischemic attack within the past 6 months
• On oral anticoagulants
• Uncontrolled severe hypertension (SBP >180 mmHg, DBP >100 mmHg)
• Pregnancy or within 1 week postpartum
• Recent traumatic CPR
• Infective endocarditis
• Advanced liver disease
• Active peptic ulcer
• Puncture of a non-compressible vessel