Pulmonary Embolism: Drug Therapy

Therapeutic targets

  • Dissolution of the thrombus (thrombolysis/dissolution of the thrombus).
  • Secondary prophylaxis (measures intended to prevent further progression of a disease that has already occurred; see below).

Therapy recommendations

  • 2019 ESC Guidelines:Anticoagulation treatment should be given as soon as pulmonary embolism is suspected, if there is a moderate or high clinical probability, without waiting for the result of diagnostic imaging.
  • Intravenous thrombolysis as an emergency measure in hemodynamic deterioration ( class 1 recommendation) with different drug groups depending on the mortality risk (mortality risk). The current DGK (German Society of Cardiology) guideline distinguishes between high and nonhigh risk, depending on whether the patient is hemodynamically (“blood flow in the vessels“) unstable or stable.
    • In cases of high mortality risk, there is a clear indication for the use of thrombolytic drugs (rt-PA: recombinant tissue type plasminogen activator; alteplase) in addition to heparin therapy (unfractionated heparin, UFH).
    • In intermediate risk, the benefit of lysis (“dissolving the thrombus” is called questionable; treatment with unfractionated heparin (UFH) or synthetic heparin analogue.
    • Leg low risk; treatment with: low molecular weight heparin (NMH) (may decision); close monitoring required.
    • Young patients obviously benefit from thrombolysis, whereas elderly patients have a threefold risk of bleeding.
  • In addition, patients receive oxygen and adequate pain therapy.
  • Depending on the severity of pulmonary embolism, the following risk-adapted therapeutic regimens can be distinguished [mod. after 5, 10]:
    • High risk
      • Anticoagulation: UFH (/NMH)
      • Systemic thrombolysis (dissolution of a thrombus with the help of drugs) or surgical embolectomy (surgical removal of an embolus)
    • Intermediate-high risk (biomarkers (hsTnT ≥ 14 pg/ml or NT-proBNP ≥ 600 pg/ml) or evaluation RV dysfunction (right atrial dysfunction; TTE or CTPA) [both positive].
      • Anticoagulation: NMH/Fonda (/NOAK).
      • Inpatient admission (IMC/ICU for at least 48 hours), if hemodynamic instability → reperfusing therapy.
    • Intermediate-low risk (biomarkers (hsTnT ≥ 14 pg/ml or NT-proBNP ≥ 600 pg/ml) or evaluation RV dysfunction (right atrial dysfunction;TTE or CTPA) [one or none positive].
      • Anticoagulation: NMH/Fonda (/NOAK).
      • Inpatient admission (normal ward
    • Low risk
      • Anticoagulation: NMH/Fonda (/NOAK)
      • Early discharge/outpatient treatment
  • Secondary prophylaxis: see below.
  • Venous thromboembolism (VTE) prophylaxis: see below “Pulmonary embolism/prevention”.

Legend

Caveat. After three months of anticoagulation (anticoagulation) and occurrence of dyspnea (shortness of breath), think of: chronic thromboembolic pulmonary hypertension/ pulmonary hypertension (CTEPH; for more information, see “sequelae”).

Further indications

  • Statins reduce the risk of recurrent venous thromboembolism by 27% (95% CI [confidence interval] 21-32%); relative risk reduction for
    • Arterial pulmonary embolism by 25% (95% CI 4-42%).
    • Deep vein thrombosis of the leg 34% (95% CI 29-40%)

Absolute contraindications (contraindications) for thrombolysis:

  • Z.n. (Condition after) hemorrhagic insult (cerebral hemorrhage)/insult (stroke) of unknown etiology.
  • Z.n. ischemic insult in the last 6 months.
  • Z.n. craniocerebral trauma or neoplasia (tumor disease.
  • Z.n. major trauma / surgery in the last 3 weeks.
  • Z.n. head injury in the last 3 weeks.
  • Z.n.gastrointestinal bleeding (gastrointestinal bleeding) in the last month.
  • Non-compressible puncture sites
  • Bleeding tendency
  • Aortic dissection (synonym: aneurysm dissecans aortae) – acute splitting (dissection) of the wall layers of the aorta (main artery), with a tear of the inner layer of the vessel wall (intima) and a hemorrhage between the intima and the muscular layer of the vessel wall (outer media), in the sense of an aneurysm dissecans (pathological expansion of the artery).

The absolute AIs must be put into perspective in the case of life-threatening pulmonary embolism. There remains then the active internal bleeding and recently occurred spontaneous intracerebral hemorrhage (ICB; cerebral hemorrhage). Relative contraindications to thrombolysis:

  • Z.n. TIA (transitory ischemic attack/perfusion disorder of the brain causing neurologic deficits that completely resolve within 24 hours) in the past 6 months.
  • Oral anticoagulation (OAK; inhibition of blood clotting.
  • Pregnancy until 1 week post partum (after delivery).
  • Z.n. traumatic cardiopulmonary resuscitation (resuscitation).
  • Refractory arterial hypertension (blood pressure that is not controlled even with administration of ≥ 3 antihypertensive/antihypertensive medications in sufficient dosage including a diuretic/dewatering medication).
  • Advanced liver disease
  • Bacterial endocarditis (inflammation of the inner lining of the heart)
  • Active peptic ulcer (ulcer caused by the attack of gastric acid on the gastric mucosa pre-damaged by, for example, Helicobacter pylori infection).

Long-term coagulation

Therapeutic target

Secondary prophylaxis.

Therapy recommendations

Anticoagulation with:

  • New oral anticoagulants (NOAK/NOAC; direct oral anticoagulants, DOAK): apixaban, dabigatran, edoxaban, and rivaroxaban (ESC guideline: class 1 recommendation) or vitamin K antagonists (phenprocoumon) alternatively. Note: According to the recommendation of the European Society of Cardiology (ESC) guideline, a direct oral anticoagulant (DOAK) is preferable to vitamin K antagonists for low to intermediate risk [see guidelines below].
  • See also note below on thromboembolism prophylaxis with acetylsalicylic acid (not as effective as anticoagulation, but still significantly better than no prophylaxis).

Note: contraindications to NOAKs (ESC guideline: class III recommendation): severe renal insufficiency (ierenschwäche), pregnancy and lactation; patients with antiphospholide syndrome.

Duration of oral anticoagulation

Note: Routine clinical evaluation 3-6 months after acute pulmonary embolism is recommended (ESC guidelines: recommendation grade I).

Clinical constellation Duration
First thromboembolism
Reversible risk factors 3 months
Idiopathic or thrombophilia 6-12 months
Combined thrombophilia (e.g., factor V mutation + prothrombin mutation) or antiphospholid antibody syndrome 12 months
Chronic diseases leading to thrombophilia indefinite time
Recurrent (recurring) thromboembolism Continuous therapy
Active malignancy (cancer) Continuous therapy

“Pro/con” criteria for prolonged maintenance therapy with anticoagulants

Criterion Per Contra
Recurrence (recurrence of thrombosis) Yes no
Bleeding risk low high
Anticoagulation quality, previous good bad
Gender Man Woman
D-dimers (after end of therapy) ↑ normal
Residual thrombus (residual thrombos) Present absent
Thrombus localization proximal distal
Thrombus extension Long-stretch short-range
Thrombophilia (increased tendency to thrombosis), severe Yes no
Patient request For this against

Legend

  • az.B. Antiphospholipid syndrome (APS; antiphospholipid antibody syndrome).
  • bz. B. heterozygous factor V Leiden or heterozygous prothrombin mutation (factor II mutation).

Current ESC recommendations are:

Duration of anticoagulation Extension of anticoagulation >3 months recommended Prolongation of anticoagulation > 3 months should be considered
  • Therapeutic anticoagulation for ≥ 3 months: all patients with LE (class IA recommendation).
  • Patients with a first event secondary to a transient/reversible “major” risk factor: cessation of anticoagulation after 3 months (class IB recommendation).
  • Patients with a recurrent event (not associated with a transient/reversible “major” risk factor): sustained oral anticoagulation (class IB recommendation).
  • Patients with an antiphospholipid syndrome: permanent oral anticoagulation (class IB recommendation).
  • In patients with a first event without an identifiable risk factor (Class IIaA recommendation).
  • In patients with a first event associated with a persistent risk factor (other than antiphospholipid syndrome) (class IIaC recommendation).
  • In patients with a first event, associated with a transient/reversible “minor” risk factor (Class IIaC recommendation).

Note: If oral anticoagulation is indicated in patients with acute pulmonary embolism-and unless there is a contraindication to an NOAK-the NOAK and not a vitamin K antagonist should be used (ESC Guidelines: recommendation grade 1).Contraindications to NOAKs include lupus anticoagulant syndrome, severe renal insufficiency (renal impairment), pregnancy, and lactation (breastfeeding). Other indications

  • The WARFASA study and another study demonstrate that acetylsalicylic acid (ASA) also has a relevant effect in preventing venous thromboembolism recurrence (risk reduction in event rate of approximately 33% versus 90% with the administration of vitamin K antagonists, VKA); administration of ASA after discontinuation of oral anticoagulation is an option in the presence of cardiovascular risk factors.
  • In high-risk patients with pulmonary embolism, it appears reasonable to continue anticoagulation for six months by 18 months. In a placebo-controlled trial using the oral vitamin K antagonist warfarin, recurrent symptomatic venous thromboembolism occurred less in 78% of cases.
  • NOAKs/direct oral anticoagulants (DOAKs).
    • Bachte: For dabigatran and edoxaban, prior therapy with low-molecular-weight heparins is provided. Apixaban and rivaroxaban can be used without prior administration of a low-molecular-weight heparin. Apixaban and rivaroxaban can be used without prior administration of a low-molecular-weight heparin.
    • Therapy recommendations for DOAK in obesity:
      • Body weight ≤ 120 kg or a BMI ≤ 40 kg /m2 no dose adjustments.
      • BMI > 40 kg /m2 or body weight > 120 kg, VKA (see above) should be used or trough and peak level measurements of DOAK should be taken
        • If level measurements fall within the expected ranges, the respective dosage can be left in place.
        • If the level measurements are below the expected ranges, a VKA should rather be used.
  • If anticoagulant therapy is discontinued after a thromboembolic first venous event, there is an increased risk of recurrence.
  • Rivaroxaban may cause hemorrhage into the vitreous of the eyes, which does not necessarily require discontinuation of the drug.

Note: Patients with antiphospholipid syndrome should not be treated with direct oral anticoagulants (DOAKs).Pharmacologic properties NOAKs/direct oral anticoagulants (DOAKs).

Apixaban Dabigatran Edoxaban Rivaroxaban
Target Xa Thrombin IIa Xa Xa
Application 2 TD (1-) 2 TD 1 TD 1 (-2) TD
Bioavailability [%] 66 7 50 80
Time to peak level [h] 3-3,5 1,5-3 1-3 2-4
Half-life [h] 8-14 14-17 9-11 7-11
Elimination
  • Renal: 25%
  • Hepatic: 25%
  • Intestinal: 50%
  • Renal: 80%
  • Renal: 30%
  • Intestinal: 70 %
  • Renal: 30%
  • Hepatic: 70%
For renal insufficiency contraind. Creatinine clearance: < 15 ml/min contraind. Creatinine clearance: < 30 ml/min contraind. Creatinine clearance: < 30 ml/min contraind. Creatinine clearance: < 15 ml/min
Interaction CYP3A4 potent P-GP inhibitorRifampicin, amiodarone, PP! CYP3A4 CYP3A4 inhibitor

Further notes

  • If anticoagulant therapy is discontinued after a thromboembolic first venous event, there is an increased risk of recurrence.
  • The WARFASA study and another study demonstrate that acetylsalicylic acid (ASA) also has a relevant effect in preventing venous thromboembolism recurrence (risk reduction in event rate of approximately 33% versus 90% with the administration of vitamin K antagonists, VKA); administration of ASA after discontinuation of oral anticoagulation is an option in the presence of cardiovascular risk factors.
  • Therapy recommendations for DOAK in obesity:
    • Body weight ≤ 120 kg or a BMI ≤ 40 kg /m2 no dose adjustments.
    • BMI > 40 kg /m2 or body weight > 120 kg, VKA (see above) should be used or trough and peak level measurements of DOAK should be taken
      • If level measurements fall within the expected ranges, the respective dosage can be left in place.
      • If the level measurements are below the expected ranges, a VKA should rather be used.

Pulmonary embolism in cancer