Pulmonary embolism medical therapy

Associate Editors-in-Chief: Ujjwal Rastogi, MBBS [mailto:urastogi@perfuse.org]

Overview
In most cases, anticoagulant therapy is the mainstay of treatment. Acutely, supportive treatments, such as oxygen or analgesia, are often required.

Massive PE causing hemodynamic instability (marked decreased oxygen saturation, tachycardia and/or hypotension) is an indication for thrombolysis, the enzymatic destruction of the clot with medication. Some advocate, the usage of thrombolytic, if right ventricular dysfunction is demonstrated on echocardiography.

Anticoagulation

 * Salient Features:
 * Prevent further clot formation, so should be started as early as possible.
 * It has no effect on pre-existing clot lysis.
 * It has no effect in decreasing the size of thrombus.
 * In most cases, anticoagulant therapy is the mainstay of treatment. It includes Heparin, Low molecular weight heparins (such as enoxaparin and dalteparin), or Factor Xa inhibitors (fondaparinux). These are administered initially, while Warfarin therapy is commenced (this may take several days, usually while the patient is in hospital).

Warfarin therapy often requires frequent dose adjustment and monitoring of the INR. In PE, INRs between 2.0 and 3.0 are generally considered ideal.

If another episode of PE occurs under warfarin treatment
 * The INR window may be increased to e.g. 2.5-3.5 (unless there are contraindications) or
 * Anticoagulation may be changed to a different anticoagulant e.g. low molecular weight heparin.

In patients with an underlying malignancy, low molecular weight heparin is favored over warfarin based on the results of the CLOT trial.

Similarly, pregnant women are often maintained on low molecular weight heparin to avoid the known teratogenic effects of warfarin.

Warfarin therapy is usually continued for 3-6 months, or "lifelong" if there have been previous DVTs or PEs, or none of the usual risk factors is present. An abnormal D-dimer level at the end of treatment might signal the need for continued treatment among patients with a first unprovoked pulmonary embolus.

Anticoagulations should be used with caution, because certain conditions like pericardial tamponade and aortic dissection can mimic Pulmonary Embolism, but the use of anticoagulants is contraindicated in these medical conditions.

Thrombolysis
Thrombolysis can be used in cases of severe PE, when surgery is not immediately available or possible (e.g. peri-arrest or during cardiac arrest). The only trial that addressed this issue had 8 patients; the four receiving thrombolysis survived, while the four who received only heparin died.

The use of thrombolysis in moderate PE is still debatable. The aim of the therapy is to dissolve the clot, but there is an attendant risk of bleeding or stroke.

No large clinical trial has demonstrated mortality benefit of thrombolytic therapy. However, it helps in the following ways
 * 1) It accelerates clot-lysis, thereby relieving acute PE.
 * 2) It improves Right Ventricular function.
 * 3) It improves pulmonary perfusion and cardiovascular function.

Major risk factor associated with thrombolytic therapy are:
 * Increased risk of major hemorrhage (intracranial hemorrhage, retroperitoneal hemorrhage).
 * Massive bleeding leading directly to hospitalization or death.

To read more about dosage, contraindications and guidelines, click here.

Direct Xa inhibitor
These are a class of anticoagulant drugs which act directly upon Factor X in the coagulation cascade, without using antithrombin as a mediator. Advantages of orally administered direct Xa inhibitors lie in the fact that they have a predictable effect, do not require frequent monitoring or re-dosing, are given through the mouth and not by injection and have few (known) drug interactions. Disadvantages include the currently limited prospective experience and the theoretical interactions with statin medication, as they are metabolized at least in part by the same cytochrome enzyme, CYP3A4.

Dosage
The American College of Cardiology (ACC) Foundation and the American Heart Association (AHA) have proposed the following dosage schedule for the use of thrombolytics: Loading dose:250 000 IU over 30 min. Maintenance dose:100 000 IU/h over 12–24 hr. Accelerated regimen: 1.5 million IU over 2 hr. Loading dose:4400 IU/kg over 10 min. Maintenance dose:4400 IU/kg/h over 12–24 hr. Accelerated regimen: 3 million IU over 2 hr. 100 mg over 2 hr or 0.6 mg/kg over 15 min (maximum dose 50 mg).
 * Streptokinase
 * Urokinase
 * Recombinant tissue plasminogen activator (rtPA)

Another validated nomogram has proposed the following dosage.
 * Low molecular weight heparin
 * Enoxaparin : 1 mg/Kg body weight (twice daily).
 * Tinzaparin : 175 U/Kg body weight (once daily).


 * Factor Xa Inhibitors
 * Fondaparinux :
 * Patient weighing less than 50 Kg (110 lb) : 5 mg (once daily).
 * Patient weighing 50 Kg (110 lb) to 110 Kg (220 lb): 7.5 mg (once daily).
 * Patient weighing more than 100 Kg (220 lb) : 10 mg (once daily).


 * Unfractionated heparin 
 * Loading Dose: 80 IU/Kg or 5000 IU
 * Mantainace Dose: 18 IU/Kg/Hr to achieve a target aPTT 1.5 to 2.5 times the normal value.


 * Thrombolytics
 * In patient with cardiac arrest:
 * Alteplase (FDA-appointed)
 * 50-mg IV bolus
 * May repeat 50-mg IV bolus in 15 min if no return of spontaneous circulation (ROSC)
 * Reteplase
 * 20-U IV bolus
 * Tenecteplase
 * 0.5-mg/kg IV bolus (max 50mg)
 * In patients with massive and submassive PE:
 * Alteplase (FDA-approved)
 * 10-mg IV bolus
 * Followed by 90 mg IV infusion over 2 hrs.
 * Reteplase
 * 10-U IV bolus
 * Followed in 30 mins by another 10-U IV bolus.
 * Tenecteplase
 * 0.5-mg/kg IV bolus (max 50mg)

ESC Guidelines treatment High-risk pulmonary embolism (DO NOT EDIT)
{{cquote|

Class I
1. Anticoagulation with unfractionated heparin should be initiated without delay in patients with high-risk PE. (Level of Evidence: A)

2. Systemic hypotension should be corrected to prevent progression of RV failure and death due to PE. (Level of Evidence: C)

3. Vasopressive drugs are recommended for hypotensive patients with PE. (Level of Evidence: C)

Class IIa
4. Dobutamine and dopamine may be used in patients with PE, low cardiac output and normal blood pressure. (Level of Evidence: B)

Class III
5. Aggressive fluid challenge is not recommended. (Level of Evidence: B)

Class I
6. Oxygen should be administered in patients with hypoxaemia.(Level of Evidence: C)

7. Thrombolytic therapy should be used in patients with high-risk PE presenting with cardiogenic shock and/or persistent arterial hypotension.(Level of Evidence: A)

8. Surgical pulmonary embolectomy is a recommended therapeutic alternative in patients with high-risk PE in whom thrombolysis is absolutely contraindicated or has failed.(Level of Evidence: C)

Class IIb
9.Catheter embolectomy or fragmentation of proximal pulmonary arterial clots may be considered as an alternative to surgical treatment in high-risk patients when thrombolysis is absolutely contraindicated or has failed. (Level of Evidence: C) }}

ESC Guidelines treatment Non-high-risk pulmonary embolism (DO NOT EDIT)
{{cquote|

Class I
1. Anticoagulation should be initiated without delay in patients with high or intermediate clinical probability of PE while diagnostic workup is still ongoing. (Level of Evidence: C)

2. Use of LMWH or fondaparinux is the recommended form of initial treatment for most patients with non-high-risk PE. (Level of Evidence: A)

3. In patients at high risk of bleeding and in those with severe renal dysfunction, unfractionated heparin with an aPTT target range of 1.5–2.5 times normal is a recommended form of initial treatment. (Level of Evidence: C)

4. Initial treatment with unfractionated heparin, LMWH or fondaparinux should be continued for at least 5 days and (Level of Evidence: A) may be replaced by vitamin K antagonists only after achieving target INR levels for at least 2 consecutive days (Level of Evidence: C)

Class IIb
5. Routine use of thrombolysis in non–high-risk PE patients is not recommended, but it may be considered in selected patients with intermediate-risk PE (Level of Evidence: B)

Class III
6. Thrombolytic therapy should be not used in patients with low-risk PE (Level of Evidence: B) }}

ESC Guidelines Recommendations Long-term treatment (DO NOT EDIT)
{{cquote|

Class I
1. For patients with PE secondary to a transient (reversible) risk factor, treatment with a VKA is recommended for 3 months.(Level of Evidence: A)

2. For patients with unprovoked PE, treatment with a VKA is recommended for at least 3 months. (Level of Evidence: A)

3. For patients with a second episode of unprovoked PE, long-term treatment is recommended. (Level of Evidence: A)

4. In patients who receive long-term anticoagulant treatment, the risk/benefit ratio of continuing such treatment should be reassessed at regular intervals. (Level of Evidence: C)

5. In patients with PE, the dose of VKA should be adjusted to maintain a target INR of 2.5 (range 2.0–3.0) regardless of treatment duration. (Level of Evidence: A)

Class IIb
6. Patients with a first episode of unprovoked PE and low risk of bleeding, and in whom stable anticoagulation can be achieved, may be considered for long-term oral anticoagulation. (Level of Evidence: B)

Class IIa
7. For patients with PE and cancer, LMWH should be considered for the first 3–6 months (Level of Evidence: B) after this period, anticoagulant therapy with VKA or LMWH should be continued indefinitely or until the cancer is considered cured. (Class I,Level of Evidence: C)}}

Guidelines Resources

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