Thrombosis prophylaxis

Deep vein thrombosis (DVT) and pulmonary embolism (LE) are among the main causes of morbidity and mortality during hospitalization. Therefore, the development of DVT or LE should be prevented by appropriate prophylaxis (Herold 2018).

The indications for the type of thromboembolism prophylaxis:

According to the guidelines, basic measures (see therapy below) should be taken in:

• Patients with a low risk of VTE
• Patients with contraindication to medication-based thromboembolism prophylaxis
• Patients with medium and high risk in addition to drug prophylaxis (Encke 2015)

Drug prophylaxis of thromboembolism is indicated in the case of:

• Patients with medium and high risk (Encke 2015)

The annual incidence of symptomatic deep vein thrombosis in the general population is 90 to 130 per 100,000 inhabitants. The situation is different for hospital patients without appropriate prophylaxis. Here, the incidence varies greatly depending on the specialty. It ranges from 10 % (e.g. in internal medicine) to 80 % (e.g. multiple trauma [Encke 2015]).

The average risk of postoperative thromboembolic complications is estimated at about 30%. The mortality rate is 1 % (Eppsteiner 2010).

The individual risk of developing a thromboembolic complication is composed of expositional and dispositional factors.

Dispositional factors:

A high risk exists in patients with:

• a history of DVT or LE
• malignant diseases (the risk varies between medium and high)
• Therapy with sex hormones (e.g. in postmenopause) or treatment to block sex hormones (contraception or for tumour treatment). In both cases, the risk varies between medium and high (Encke 2015).

A medium risk exists in patients with:

• age over 60 years
• chronic cardiac insufficiency
• Adiposity with a BMI > 30 kg/m2
• venous thromboembolism (VTE) in first-degree relatives (Encke 2015).

A low risk is found in patients with:

• nephrotic syndrome
• severe varicosis
• Pregnancy and postpartum period (Encke 2015)

Exposure factors:

A low risk exists for:

• minor surgical interventions
• Injuries with no or little soft tissue damage
• Infections or diseases without bedriddenness
• Patients with central venous catheter or with port catheter
• if there is no or only a low dispositional risk, otherwise classification in the higher risk category (Encke 2015)

A medium risk exists for:

• longer duration of surgery
• joint immobilization of the lower extremity
• arthroscopically assisted surgical interventions on joints of the lower extremity
• acute heart failure (NYHA III / IV)
• acutely occurred severe decompensation of COPD without ventilation
• Infections or acute inflammatory diseases with strict bedriddenness
• malignant diseases requiring inpatient treatment
• if there is no or only a low dispositional risk, otherwise classification in the higher risk category (Encke 2015)

A high risk exists for:

• Apoplexy with leg paresis
• Sepsis
• Acute decompensated severe COPD with ventilation
• seriously ill patients who require intensive medical treatment (Encke 2015)

Laboratory diagnostics for further risk assessment of the individual VTE (venous thromboembolism) risk, such as determination of D-dimers, does not increase the predictivity of (postoperative) thromboembolism and is therefore not necessary (Encke 2015).

The determination of further laboratory findings for therapy, course, etc. are listed below under the individual substance groups of drug-based thrombosis prophylaxis.

Thrombosis prophylaxis includes both general basic measures and drug therapies (Herold 2018)

Basic measures:

General measures include (Herold 2018):

• early postoperative mobilization
• Implementation of active physiotherapy
• Bed rest should only be prescribed if its benefit is also proven
• Prescription of antithrombosis stockings or compression bandages (however, the additional benefit of AT stockings or compression bandages in addition to drug thrombosis prophylaxis has not been proven)
• intermittent pneumatic compression (IPC [ Encke 2015])
• all risk factors for DVT (deep vein thrombosis) should be considered, eliminated and treated if necessary. These include:
  • Immobilization
  • exsiccosis (also by forced diuresis)
  • respiratory insufficiency
  • systemic infections
  • heart failure
  • therapy with neuroleptics, estrogens, ovulation inhibitors, testosterone etc.
  • age over 60 years
  • et al.

Medicationmeasures (Herold 2018):

Drug measures for thromboprophylaxis include anticoagulants. This group of drugs includes:

• 1. heparin
• 2. factor Xa inhibitors for s.c. application
• 3. factor Xa inhibitors for oral use, so-called NOAKs (new oral anticoagulants) or DOAKs (direct oral anticoagulants)
• 4. direct thrombin inhibitors
• 5. vitamin K antagonists

Start of treatment for VTE prophylaxis (Encke 2015): In Germany, perioperative heparin VTE prophylaxis is started preoperatively, whereas in the United States it is started postoperatively and then with mostly higher doses. However, there are no data on the efficacy or safety of starting therapy. Only in CNS procedures has an increased risk of bleeding been demonstrated with preoperative administration of low-molecular-weight heparin.

In elective surgical procedures, therapy with fondaparinux, dabigatran etexilate, and rivaroxaban is always started postoperatively. The time intervals are drug-specific and can be found in the respective product information. For fondaparinux, for example, the minimum time interval between the end of surgery and the first administration of medication is 6 h. This interval can, however, also be longer without efficacy. However, this interval can be extended up to 20 h without loss of efficacy.

In traumatized patients, the risk of thrombosis should always be weighed against any bleeding complications.

In nonsurgical patients, it is recommended to start VTE prophylaxis close to the time of thrombosis risk.

Duration of treatment for VTE prophylaxis (Encke 2015): Therapy should be given for as long as there is a risk of thromboembolism. Care should be taken to ensure that there are no gaps in care when patients are discharged from inpatient treatment to the postinpatient phase (e.g., outpatient treatment, rehabilitation).

1. heparin: heparin belongs to the group of mucopolysaccharides. It potentiates the effect of antithrombin (AT) and inhibits thrombin and also factor Xa through the heparin-AT complex. Therefore, if a patient is AT deficient, the antithrombotic effect of heparin cannot fully develop (Herold 2018).

A differentiation is made between fractionated (also called low molecular weight heparin = NMH or low molecular weight heparin = LMWH ) and unfractionated (UFH) heparin. UFH has a shorter half-life (1- 2 h) and should be given in the presence of renal insufficiency. The NMH has a half-life of 4 h and is indicated in all other patients with a heparin indication (Herold 2018).

Because both fractionated and unfractionated heparin are nonplacental, both can be used during gravidity (Herold 2018).

Heparin results in a 75% risk reduction for deep vein thrombosis and a 50% risk reduction for embolism (Herold 2018).

Antidote: The antidote to heparin is protamine. 1,000 I.U. of heparin is neutralized by 1 ml of protamine 1000 Roche (Herold 2018). However, with low molecular weight heparin, only a partial effect is found, varying from 35% to 80% (Lüllmann 2010).

The side effects of protamine can be:

• drop in blood pressure
• anaphylactic reaction
• in case of overdose, there may be a risk of bleeding, as protamine inhibits fibrin polymerization (Herold 2018).

Indication:

• In low dosage for thrombosis prophylaxis.
• In full dosage for deep vein thrombosis and stage I and II pulmonary embolism.

The unfractionated heparin is indicated exclusively in patients with renal insufficiency. The fractionated heparin (NMH) for all other patients with appropriate indication (Herold 2018).

Contraindication:

• Heparin allergy
• History of HIT II (if HIT II was triggered by unfractionated heparin, fractionated heparin (NMH) is also contraindicated thereafter).
• in full dosage the contraindications are similar to those of fibrinolysis (see d.)

Side effects:

• Bleeding:

These depend on the dosage of heparin, so close monitoring of blood counts is indicated with high dosage. With low-dose heparinization, there is no obligatory laboratory control (Herold 2018).

In the case of treatment with fractionated heparin, no controls are generally required with weight-adjusted dosing (König 2013).

With full heparinization, the risk of intracerebral hemorrhage is 0.2% (Herold 2018).

• Increase in transaminases: Transaminases may increase during heparinization. However, this increase is reversible and occurs in approximately 60% of cases (Herold 2018).
• Osteoporosis: Heparin treatment lasting more than one month leads to osteoporosis with reduction in bone density in approximately 30% of patients. Fractures occur in 2%-3% of cases (Kasper 2015).
• Heparin-induced thrombocytopenia:

2 forms of heparin-induced thrombocytopenia are indistinguishable:

1. Type I (HIT I): This form is also known as the "non-immunological early form". It occurs during treatment with unfractionated heparin. In this case, there is a drop in platelets by max. 30% of the initial value in the first 5 days of therapy. This side effect occurs in approximately 5% of patients and regresses spontaneously. Discontinuation of heparin therapy is not required (Herold 2018).
2. Type II (HIT II): This form is also referred to as "immunological antibody-induced HIT or immune-mediated HIT". In this case, there is antibody formation against the platelet factor- 4 heparin complex with a drop in the platelet count and increased thrombin formation and the associated risk of vascular occlusion. HIT II occurs in about 3% of cases when UFH is administered and in about 0.1% when NMH is used (i.e., 30 times less frequently than under UFH). HIT II manifests itself approximately 5 - 10 days after the start of treatment. In already sensitized patients, symptomatology occurs within a few hours after the first heparin administration (Herold 2018).

Laboratory chemistry shows a decrease in the platelet count. In the majority of cases, the number drops to values between 40,000 to 80,000 platelets, and in about 10% the platelets do not fall below 150,000 / µL. In parallel, or in 20% of patients already one to two days before the platelet drop, vascular occlusions occur in 50% to 70% of cases. If the latter are treated with an increase in the heparin dose, the most severe complications may occur. The ratio of venous to arterial vessel occlusion is 5:1, and approximately 50% of patients develop pulmonary embolism as a complication (Greinacher 2003).

The mortality rate of HIT II is 30% and permanent damage (e.g. amputations, residual effects after apoplexy, etc.) is found in up to 20% of cases. Only early diagnosis and new therapeutic options can reduce these rates (Picker 2004). Mortality is now 6% to 7% and amputations are 5% to 6% (Greinacher 2003).

Vascular occlusion and/or thrombocytopenia occurring during heparin therapy should always be considered as HIT II and antibodies against platelet factor-4 heparin complex should be determined by ELISA or HIPA test. A negative result excludes HIT II (Herold 2018).

Therapy of HIT II: If HIT II is detected, immediately discontinue heparin and avoid any heparin-containing drugs and substances (e.g., also in ointments, catheter lavages, etc.). This also includes the heparinoid danaparoid, as this shows cross-reactivity with heparin in 5% to 10% (Herold 2018). A switch should be made to heparin-free direct thrombin inhibitors, such as.

• Lepirudin (Refludan)
• Argatroban (Argatra)

Fibrinolysis may be required if thrombi are severe.

Administration of platelet concentrates should be avoided at all costs because of the risk of "white clot syndrome" (platelet-rich thrombi). The patient must be informed of the significance and of the possibility of recurrence of HIT II and be given an appropriate identification card or have the condition recorded in the patient's medical record (Herold 2018).

Interactions under heparin therapy:

Elevated blood glucose levels may occur with heparin therapy (Herold 2018).

Dosage: Treatment with unfractionated heparin for thromboprophylaxis:

• 3 x 5,000 I.U. s. c./ d or alternatively.
• 2 x 7.500 I.E. s. c./ d

Thromboprophylaxis with fractionated (low molecular weight) heparin should start 2- 12 h preoperatively. The following drugs are available (Herold 2018):

• Certoparin (Mono- Embolex) 1 x 3,000 I.U. / d.
• Dalteparin (Fragmin) 1 x 2,500 to 5,000 I.U. / d
• Enoxaparin (Clexane) 1 x 20 mg to 40 mg / d
• Nadroparin (Fraxiparin) 1 x 2,850 I.U. / d
• Reviparin (Clivarin) 1 x 13.8 mg / d
• Tinzaparin (Innohep) 1 x 3,500 I.U. / d

Note: In renal insufficiency and in cases of doubt, anti- Xa activity should be determined to monitor therapy. The PTT- value is not suitable for therapy monitoring (Herold 2018).

2. factor Xa inhibitors for s. c. use:

A heparin analog with factor Xa- inhibition is the pentasaccharide fondaparinux (trade name Arixtra®).

Antidote: Protamine is NOT effective as an antidote in this case (Herold 2018).

The drug Andexanet alfa (trade name Ondexxy®) has been granted conditional approval by the European Commission as an antidote for Factor Xa inhibitors, but no results were reported for fondaparinux in the study that was the basis for approval (Connolly 2019).

Indication (Herold 2018):

• of thromboembolism prophylaxis
• deep vein thrombosis
• of pulmonary embolism (LE)

Contraindication:

• severe renal insufficiency

The following side effects may occur:

• anemia
• liver function disorders
• Edema
• thrombocytopenia etc.

Dosage: Because of the long half-life of 17 h to 21 h it is given only 1 x/ d s.c. in the following dosage:

• For thrombosis prophylaxis: 2.5 mg s.c./day (start therapy 6 h after surgery).
• for the treatment of DVT and LE, the manufacturer's weight-dependent instructions should be followed.

Platelet count control or coagulation monitoring are not required.

However, in renal insufficiency, there is a risk of accumulation. This can be monitored with control of the anti- Xa test. According to Encke (2015), a reduction in the dose to 1.5 mg/day s.c. should generally be made from a creatinine clearance of 20 - 50 ml / min.

3. factor Xa inhibitors for oral use, so-called NOAK (new oral anticoagulants) or DOAK (direct oral anticoagulants).

They include the following agents:

• Rivaroxaban
• Apixaban
• Edoxaban

Because the NOAKs or DOAKs are eliminated renally, the German Drug Commission (AkdÄ) generally advises against the use of these drugs if creatinine clearance is < 30 ml / min (Herold 2018).

Antidote: An antidote for the factor Xa inhibitors is under investigation. This is andexanet alfa. If bleeding occurs, prothrombin complex concentrates are currently given. In cases of existing renal insufficiency with a creatinine clearance below 30 ml/min, the German Drug Commission (AkdÄ) advises against therapy with all DOAK (Herold 2918).

Note: Antidote - Addendum: According to a recent report in ÄrzteZeitung of May 8, 2019, a conditional marketing authorization has now been granted by the European Commission for the antidote Andexanet alfa (trade name Ondexxy®). A market launch is expected in Germany in the second half of 2019.

Re 3: Rivaroxaban (Xarelto®):

Antidote: The above-mentioned antidote Andexanet alfa (trade name Ondexxy®) has now been approved. A market launch is expected in the second half of 2019 (see above).

Indications:

• Prophylaxis and therapy of deep vein thrombosis
• Prophylaxis and therapy of pulmonary embolism
• Thromboembolism prophylaxis for non-valvular atrial fibrillation

Contraindication besides those of anticoagulants (Encke 2015):

• Pregnancy
• Lactation
• severe renal insufficiency
• moderate to severe hepatic impairment (rivaroxaban is eliminated both renally and hepatically).

The following side effects are possible:

• gastrointestinal discomfort, etc.

Interaction: There is an interaction with CYP3A4-dependent drugs (e.g. antihypertensives, antifungals, benzodiazepines, chemotherapeutics, immunosuppressants, macrolides, SSRIs, neuroleptics, opioids, statins, tricyclic antidepressants, etc.).

Dosage: For thromboembolism prophylaxis in atrial fibrillation:

• 1 x 20 mg / d (dose adjustment in liver and kidney dysfunction [Encke 2015]).
• For prophylaxis or therapy of LE and DVT, please consult the manufacturer's instructions.

Re 3: Apixaban (Eliquis®).

Apixaban shows a significantly lower overall risk profile with a lower rate of mortality and bleeding complications compared to rivaroxaban: RR (95% CI) VTE- rate / VTE- associated mortality: 0.93 (0.59, 1.46). Bleeding complications: 0.47 (0.63, 0.61).

Apixaban compared with edoxaban (Jähne 2017):

RR (95% CI) VTE- rate/VTE-associated mortality: 1.01 (0.63, 1.63) Bleeding complications: 0.54 (0.41, 0.69).

Antidote: The above-mentioned antidote Andexanet alfa (trade name Ondexxy) has now been approved. A market launch is expected in the second half of 2019.

Indications are:

• Thromboembolism prophylaxis after hip or knee TEP.
• Thromboembolism prophylaxis for non-valvular atrial fibrillation
• Therapy of deep vein thrombosis
• Therapy of pulmonary embolism

Side effects may include:

• Bleeding
• Increase in liver enzymes
• among others.

Contraindications are, in addition to those of anticoagulants (Encke 2015):

• Pregnancy
• Lactation
• severe renal insufficiency
• see also manufacturer's instructions
• moderate to severe hepatic impairment (apixaban is eliminated both renally and hepatically).

Druginteraction: There is an interaction with CYP3A4-dependent drugs (e.g., antihypertensives, antifungals, benzodiazepines, chemotherapeutics, immunosuppressants, macrolides, SSRIs, neuroleptics, opioids, statins, tricyclic antidepressants, and others).

Dosage

• for thromboembolism prophylaxis after hip or knee TEP 2 x 2.5 mg/d, start 12-24 h postoperatively
• for thromboembolism prophylaxis in non-valvular atrial fibrillation 2 x 5 mg/d.

A possible dose reduction can be found in the manufacturer's instructions.

3.: Edoxaban (trade name Lixiana®)

Antidote: The antidote andexanet alfa (trade name Ondexxy) has been granted conditional approval by the European Commission, however, no results were reported for Edoxan in the study that was the basis for approval (Connolly 2019).

Indications are:

• Prophylaxis of deep vein thrombosis.
• Prophylaxis of pulmonary embolism
• Therapy of deep vein thrombosis
• Therapy of pulmonary embolism
• Thromboembolism prophylaxis in non-valvular atrial fibrillation

There are interactions with:

• Ciclosporin
• Dronedarone
• Erythromycin
• Ketoconazole
• a. o. (see also manufacturer's instructions)

Dosage:

• 1 x 60 mg/d

Dose reduction may be indicated in renal insufficiency.

Direct thrombin inhibitors: Dabigatran, trade name Pradaxa, is one of the direct thrombin inhibitors. This is an oral thrombin inhibitor that belongs to the NOAK group and is eliminated renally by up to 80%. Since it is thus a predominantly renally excreted substance, regular monitoring of renal function is required before and during therapy (Herold 2918).

Antidote: The antidote is idarucizumab (trade name Praxbind®, dosage: 2 x 2.5 g i.v.).

Indications for treatment with direct thrombin inhibitors are:

• Thromboembolism prophylaxis after hip or knee TEP
• Thromboembolism prophylaxis in non-valvular atrial fibrillation
• Therapy of deep vein thrombosis
• Therapy of pulmonary embolism

Contraindication:

• Renal insufficiency with a creatinine clearance of less than 30 ml/min (serious bleeding is possible).
• Gravidity and lactation
• otherwise see Manufacturer's instructions

Side effects may occur

• gastrointestinal symptoms
• severe bleeding in renal insufficiency

Interactions may occur with the following drugs:

• Ciclosporin
• levostatin
• simvastatin
• tacrolimus
• triazole antifungals
• and others.

Concurrent treatment of the above drugs with direct thrombin inhibitors should be avoided.

Dosage:

• For thromboembolism prophylaxis in atrial fibrillation 2 x 150 mg/day, dose reduction if necessary in the presence of risk factors.
• for therapy of DVT or LE please follow the manufacturer's instructions

Note: Guidelines recommend a dose of 220 mg/day in patients from the first postoperative day. In patients older than 75 years and with moderately impaired renal insufficiency, the dose should be reduced to 150 mg/day (Encke 2015). In upcoming surgeries under existing therapy with direct thrombin inhibitors, the procedures can possibly be performed without bridging - in contrast to vitamin K antagonists. An exception is renal insufficient patients. In these patients, dabigatran should be discontinued 1 - 4 days before the planned intervention.

5 Vit. K antagonists (VKA):

One of the vitamin K antagonists is coumarin, the chemical compound phenprocoumon (PPC). In Germany, two coumarin derivatives are available, which differ only in their half-life (Lüllmann 2010):

• Phenprocoumon with a half-life of 4-6 days (Marcumar®, Falithrom® et al.)
• Warfarin with a half-life of 1.5 - 2 days

Antidote: The antidote is vitamin K1 (trade name Konakion®). In addition, immediate heparinization should be given and corticosteroids should be administered (Herold 2918). Since Konakion® only stops its anticoagulant effect after about 24 h, additional PPSB preparations and blood transfusions can be given in acute severe bleeding (Piper 2012).

Indication ((Lüllmann 2010):

• Thromboembolism prophylaxis (risk of VTE recurrence is reduced to normal level).
• Thromboembolism prophylaxis in non-valvular atrial fibrillation.
• Therapy of thrombosis

Note:Coumarins are also effective in existing:

• APC resistance
• Protein C deficiency
• protein S deficiency

Contraindications:

• Diseases with increased risk of bleeding (e.g. renal failure, hemorrhagic diathesis, hepatic parenchymal disease, severe thrombocytopenia, etc.).
• Diseases with v. a. a lesion of the vascular system (e.g. gastrointestinal ulcers, uncontrolled hypertension, apoplexy, endocarditis lenta, retinopathies with bleeding risk, cerebral artery aneurysms, etc.)
• chronic alcoholism
• seizure disorders
• cavernous pulmonary tuberculosis
• nephrolithiasis
• Gravidity (from the 6th SSW [Encke 2015])
• Lactation
• lack of compliance of the patient
• et al.

Side effects:

• Bleeding (the risk of intracranial hemorrhage is about 0.3%/year at an INR of 2.0 to 3.0)
• Hair loss
• hepatitis (rarely occurring)
• gastrointestinal complaints
• Coumarin-induced skin necrosis (in the presence of protein C deficiency, these may occur together with a tendency to thrombosis due to passive hypercoagulability during the cessation period of coumarin treatment).

Interaction:

An increase in the effect of coumarins with an increase in the INR- value can lead to:

• NSAIDs (by displacement of coumarins from protein binding)
• Antibiotics (through reduced enteric vitamin K formation or, in the case of erythromycin and clarithromycin, through inhibition of the degradation of phenprocoumon).
• Exchange resins such as cholesterol or lipid-lowering agents in lipid metabolism disorders (due to reduced enteral absorption of vitamin K)
• Platelet aggregation inhibitors (e.g. ASA)
• Heparin
• Fibrinolytics (e.g. streptokinase, urokinase for thrombolysis)
• Numerous other medications (see manufacturer's instructions; if necessary, carry out close INR checks).

The following can lead to a reduction in the coumarin effect with a lowering of the INR value:

by enzyme induction in the liver:

• Barbiturates
• Antiepileptic drugs
• Rifampicin
• a. o.
• Digitalis
• Diuretics
• Corticosteroids
• Vitamin K-rich food (such as cabbage, spinach, etc.)
• a. o.

Dosage: Before a planned anticoagulation, the Quick- value or INR- value must first be determined. During initiation of treatment with coumarins, overlapping therapy with heparin should be given initially, otherwise there is no initial protection against thrombosis. Heparin therapy can be discontinued when the INR reaches the therapeutic range. Therapy is monitored by determining the thromboplastin time. This can be done by determining the Quick- value or the INR- value (International Normalized Ratio). The INR value was developed to ensure an internationally comparable standard of therapy with anticoagulants. The INR value is opposite to the Quick value. For standard anticoagulation, the therapeutic INR value is between 2.0 and 3.0. For stronger anticoagulation with INR values above 3.0, increased bleeding complications must be expected.

In the case of Quick or INR values that are initially in the normal range, the following dosage can be started in adults:

• Marcumar® 3 mg 2 x 1 tbl/d for the first 3 days, then dose adjustment according to the result of the INR value.

Alternatively, the preparation Falithrom 3 mg can be given in the same dosage. Foods rich in vitamin K (such as broccoli, cabbage, spinach, etc.) do not have to be avoided during therapy, but they should not be consumed in excess and spread over the week. All drugs with an increased risk of bleeding (e.g., NSAIDs, antiplatelet agents, etc.) should be avoided during treatment with coumarins. If short-term therapy with NSAIDs proves unavoidable, it should be given only with additional administration of a proton pump inhibitor (e.g., omeprazole 20 mg/d).

Patients who require long-term anticoagulation should be introduced to coagulation self-management (e.g., with CoaguCheck) if they are suitable. Studies have shown that this improves the quality of the setting:

• the risk of bleeding can be reduced
• the number of thromboembolic complications decreases
• the survival rate increases

The INR value should optimally be more than 70 % in the target range. After discontinuation of coumarin therapy, the prolonged bleeding time normalizes after 7 - 14 days. In studies, tapering of coumarins has not been shown to be more beneficial than abrupt discontinuation.

It has been shown in numerous randomized studies that anticoagulants, especially heparin, can reduce the risk of VTE by up to 50% (Encke 2015).

The risk of VTE when physical measures alone are used is increased after a metastudy with adequate blinding (RR 1.73; 95% CI 1.04-2.86).

(Eppsteiner 2010)

If surgery becomes necessary in a patient who is already receiving medication to prevent thromboembolism, the risk of bleeding due to anticoagulation should be weighed against the risk of thromboembolism after stopping anticoagulation in each individual case.

1. vitamin K antagonists:

If therapy with vitamin K antagonists:

• the risk of bleeding is low, a temporary reduction of the dose should be made with a target INR of 1,5.
• If there is a medium risk of bleeding and a high risk of thromboembolism, the vitamin K antagonist should be discontinued until the 1st day after surgery. Studies have shown that bridging the risk of thromboembolism with heparin is not successful. However, the risk of bleeding increased under heparin.
• If there is a high risk of bleeding and/or low risk of thromboembolism, it is recommended to discontinue the vitamin K antagonist preoperatively and to perform the operation at a time when the INR value has returned to normal.

If acute bleeding occurs as a complication of anticoagulation with vitamin K antagonists, or if emergency surgery becomes necessary, the following procedure is recommended:

• Immediate discontinuation of medication and administration of PPSB infusions (human prothrombin concentrate) until coagulation has normalized. The target value is an INR of < 1.5 or a Quick of > 50%.

2. NOAK

The EHRA (European Heart Rhythm Association) recommends that patients receiving anticoagulation with NOAK preparations pause the anticoagulants before a planned surgical procedure. The duration of this break depends on the patient:

• the type of surgery
• the half-life of the drug in question (see manufacturer's specifications)
• the renal function of the patient

Bridging with heparin is generally not recommended. If acute bleeding occurs as a complication of anticoagulation with NOAK, or if emergency surgery becomes necessary, the following procedure is recommended:

• in case of bleeding, administration of prothrombin complex concentrates
• The antidote Andexanet alfa (trade name Ondexxy), which is effective with NOAK, has been granted a conditional approval by the European Commission according to a current report in the ÄrzteZeitung of 08.05.2019. A market launch in Germany is expected in the second half of 2019.
• Dabigatran: If dabigatran is used for anticoagulation, the antidote Idarucizumab (Praxbind®, dosage: 2 x 2.5 g i.v. [Bischoff 2016]) should be administered and contact should be made with the appropriate centres.

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