Editors

BirgittaSalmela

PirjoMustonen

Antithrombotic Agents in Primary Health Care

Essentials

Antithrombotic treatment is used to prevent and treat arterial and venous thromboses and thromboembolic complications.
There are three main groups of antithrombotic agents: anticoagulants, antiplatelet drugs and thrombolytic agents.
The characteristics and indications for use of the groups and individual agents vary. This article discusses these on a general level, from the general practitioner's viewpoint.

Principles

The aim of antithrombotic therapy is to prevent the formation of arterial and venous thrombi, to prevent the further enlargement of existing thrombi and to dissolve any already formed thrombi.
- Arterial thrombosis develops on the surface of a ruptured atherosclerotic plaque in areas of strong blood flow. The thrombus will contain a large amount of platelets whilst the amount of fibrin is small.
- Venous thrombosis develops in areas of sluggish blood flow. The thrombus will contain mainly fibrin and red cells; the proportion of platelets is smaller than in arterial thrombosis.
Drug groups
- Anticoagulants: prevent the normal functioning of the coagulation system (reduce the formation of fibrin)
- Antiplatelet drugs
- Thrombolytic drugs: dissolve an existing thrombus

Classification of antithrombotic agents

Anticoagulants	Antiplatelet drugs	Thrombolytic drugs
Inhibitor of the synthesis of vitamin K-dependent clotting factors Warfarin Heparins Low molecular weight heparins (LMWH) Enoxaparin Dalteparin Tinzaparin Unfractionated heparin^®) Danaparoid Direct factor X inhibitors Apixaban Rivaroxaban Edoxaban Indirect factor X inhibitors Fondaparinux Direct thrombin inhibitors Argatroban Bivalirudin Dabigatran Agents targeting other parts of the coagulation system Antithrombin	Aspirin (acetylsalicylic acid) Dipyridamole Aspirin+dipyridamole combination product Platelet ADP receptor antagonists Clopidogrel Prasugrel Ticagrelor Cangrelor Platelet glycoprotein IIb/IIIa receptor antagonists Eptifibatide Tirofiban	Alteplase Tenecteplase

Anticoagulants

Antiplatelet drugs

Thrombolytic drugs

Inhibitor of the synthesis of vitamin K-dependent clotting factors

Warfarin

Heparins

Low molecular weight heparins (LMWH)
- Enoxaparin
- Dalteparin
- Tinzaparin
Unfractionated heparin^®)
Danaparoid

Direct factor X inhibitors

Apixaban
Rivaroxaban
Edoxaban

Indirect factor X inhibitors

Fondaparinux

Direct thrombin inhibitors

Argatroban
Bivalirudin
Dabigatran

Agents targeting other parts of the coagulation system

Antithrombin

Aspirin (acetylsalicylic acid)

Dipyridamole
Aspirin+dipyridamole combination product

Platelet ADP receptor antagonists

Clopidogrel

Prasugrel

Ticagrelor
Cangrelor

Platelet glycoprotein IIb/IIIa receptor antagonists

Eptifibatide
Tirofiban

Alteplase
Tenecteplase

In addition to agents used in primary health care, the table also includes some agents used in a hospital setting (in italics), and these are not discussed elsewhere in this article.

The main indications for anticoagulants Duration of Anticoagulant Therapy in Venous Thromboembolism, Warfarin or Antiplatelet Therapy for Stroke Prevention in Patients with Non-Valvular Atrial Fibrillation, Direct Oral Anticoagulants Versus Vitamin K Antangonists in Non-Valvular Atrial Fibrillation are prevention and treatment of thrombosis and thromboembolic complications

in patients with atrial fibrillation
in patients with a mechanical heart valves prosthesis (warfarin alone)
in patients with a heart assist device
after extensive myocardial infarction or intracardiac thrombus in a patient with severe heart failure
in venous thrombosis (lower limbs, upper limbs, internal organ veins, portal vein, hepatic veins, mesenteric veins, cerebral venous sinuses) and in pulmonary embolism.
See articles Indications for and implementation of anticoagulant therapy in atrial fibrillationIndications for and Implementation of Anticoagulant Therapy in Atrial Fibrillation, Direct oral anticoagulants Direct Oral Anticoagulants, Warfarin therapy Warfarin Therapy

Antiplatelet drugsAntiplatelet Therapy for Prevention of Death, Myocardial Infarction, and Stroke, Antiplatelet Drugs for Prevention of Restenosis after Peripheral Endovascular Treatment, Antiplatelet Therapy for Acute Ischaemic Stroke, ASA for Hypertension are used
- for secondary prevention of arterial thrombosis and, in patients with obstructive arterial disease, for prevention of thrombosis
- in the treatment of acute arterial thrombosis
- in patients with biological heart valves
- in association with invasive procedures involving arteries.
A combination of an anticoagulant and antiplatelet drugAntiplatelet and Anticoagulation for Patients with Prosthetic Heart Valves, is used
- in the treatment of acute arterial thrombosis
- in association with invasive therapeutic procedures involving arteries
  - After invasive treatment, treatment is continued with antiplatelet drugs alone, unless there are other indications for anticoagulation (such as atrial fibrillation, venous thrombosis, history of cerebral infarction).
  - The doctor performing the procedure defines the antithrombotic medication and the duration of use of combination products, in particular.
  - In unclear situations, the specialized care unit that treated the patient should always be consulted.
- in some patients at a high risk of thrombosis for other reasons (e.g. some patients with prosthetic heart valves or with antiphospholipid antibody syndrome).
Systemic or local thrombolytic therapy can (unless there are contraindications) Thrombolysis for Acute Deep Vein Thrombosis, Surgery Versus Thrombolysis for Initial Management of Acute Limb Ischaemia be used to manage
- extensive life-threatening haemodynamically unstable pulmonary embolism
- massive venous thrombosis involving the lower or upper limbs
- acute myocardial or cerebral infarction and
- arterial thrombosis of the lower or upper limbs
- to dissolve blockages in order to maintain vascular access necessary for dialysis or in other situations where a patent long-term catheter is needed.
- Thrombolytic treatment is given by a specialized care unit or sometimes by an initial treatment unit after consulting specialized care (myocardial infarction, pulmonary embolism).

Risk of bleeding

Always assess the risk factors for bleeding.
- Kidney or liver failure
- Untreated or poorly controlled hypertension (particularly systolic pressure > 160 mmHg increases the risk of bleeding)
- Severe anaemia (haematocrit < 30%)
- Severe thrombocytopenia (platelets < 50-100 × 10⁹ /l)
- History of severe bleeding or an increased risk of such bleeding (haemorrhagic disease, brain haemorrhage, gastrointestinal bleeding, metastasis, vascular malformation, oesophageal varices)
- Advanced age, frailty
- Patients on anticoagulants should be provided with instructions for what to do in case of problems (such as gastroenteritis leading to severe dehydration).

Laboratory tests and monitoring of treatment

Before starting anticoagulant therapy, the risk of bleeding must be assessed, basic laboratory tests must be done, and it must be confirmed that the patient has no contraindications for anticoagulant therapy or for the specific drug.
- Basic blood count with platelet count (Hb and platelets), plasma creatinine (eGFR Gfr Calculator), ALT, PT or INR and APTT
- Patient card
In addition, safety monitoring of anticoagulant therapy must be planned and organized; see Direct Oral Anticoagulants and Indications for and Implementation of Anticoagulant Therapy in Atrial Fibrillation.
At follow-up visits, it should additionally be confirmed that during the therapy the patient has not developed any contraindication or need to change anticoagulants due to potential drug interaction or kidney failure, for instance.

WarfarinWarfarin for Preventing Stroke in Patients with Non-Valvular Atrial Fibrillation and No History of Cerebral Ischaemia, Optimal Loading Dose of Warfarin for the Initiation of Oral Anticoagulation

Warfarin prevents the synthesis of vitamin K-dependent clotting factors.
- As warfarin affects the synthesis of clotting factors in the liver, the onset of action is slow (the delay from initial dosing to full effect is approximately 5-6 days).
Doses vary from patient to patient and require the monitoring of the international normalized ratio (INR). Special algorithms are available and are useful in the the dose adjustment of warfarin. Find out about locally available guidance and algorithms.
- For dosage table of warfarin therapy, see Warfarin Therapy.
Indications: the prevention and treatment of deep venous thrombosis and pulmonary embolism, prevention and treatment of cardiogenic thromboembolism associated with atrial fibrillation, prosthetic heart valves or serious heart diseases.
- In the treatment of acute thrombosis, a LMWH in therapeutic doses should always be used at first concomitantly with warfarin. Heparin should not be withdrawn until two consecutive INR readings within the target range have been achieved with at least 24 hours between the readings. Usually the concomitant use of warfarin and heparin is continued for the minimum of 5 days.
Warfarin has numerous interactions with various dietary factors and drugs (see pharmacopoeia and relevant databases for more details).
Crosses the placenta and may cause foetal damage. As a general rule, should not be used during pregnancy. Not excreted in breast milk, so does not prevent breast-feeding.
The effect can be reversed with vitamin K, prothrombin complex concentrate (PCC) or fresh frozen plasma.
See the article Warfarin therapy Warfarin Therapy.

Low molecular weight heparins (LMWHs) Vitamin K Antagonists or Low-Molecular Weight Heparin for Venous Thromboembolism, Anticoagulation for the Long Term Treatment of Venous Thromboembolism in Patients with Cancer

Enoxaparin and its biosimilars, dalteparin and tinzaparin
- As the different LMWH products are not identical and their indications vary slightly, it is not recommended that the products are unnecessarily interchanged. This also applies to the biosimilars of enoxaparin.
- Tinzaparin is a good choice in kidney failure since it does not accumulate in prophylactic doses, but on therapeutic doses, even tinzaparin can accumulate in patients with severe kidney failure.
Administered subcutaneously once or twice daily. In special situations, may also be given intravenously.
Laboratory monitoring is not usually required, but anti-FXa assays may be indicated, for example in children, during pregnancy, in kidney failure, in obese and underweight patients as well as in those at an increased risk of bleeding.
Indications: prevention and treatment of venous thrombosis and pulmonary embolism, treatment of acute coronary syndrome, arterial thrombosis in the limbs and, in selected cases, cerebrovascular disturbances.
Indicated instead of warfarin for long-term therapy during pregnancy and also in patients at an increased risk of thrombosis (particularly in the treatment of venous thrombosis and pulmonary embolism in patients with cancer and sometimes, in antiphospholipid antibody syndrome, for example), in whom a thrombus may develop despite warfarin therapy.
Protamine sulphate only partially reverses the effect of dalteparin (50%) and enoxaparin (40%); the effect of tinzaparin is better reversed (80%).
The development of heparin-induced thrombocytopenia (HIT) is possible, but the risk is only 1/10 as compared with unfractionated heparin.
- Should HIT develop the patient must not be administered heparin in any form (for example, flushing with heparin to maintain the patency of cannulas is contraindicated).
- An alternative anticoagulant must be chosen individually for the patient (danaparoid, argatroban, fondaparinux or bivalirudin).
- Warfarin may be started only after the thrombocytopenia is corrected. An alternative parenteral anticoagulant should be administered alongside with warfarin until a stable therapeutic INR level is reached.
- See HIT also in the article Prevention of venous thromboembolism Prevention of Venous Thromboembolism.

Fondaparinux Treatment for Superficial Thrombophlebitis of the Leg

Fondaparinux is administered subcutaneously once daily.
Indirect factor X inhibitor
Indications: treatment of venous thrombosis or pulmonary embolism concomitantly with warfarin for the first few treatment days, prevention of thrombosis especially in the presence of high risk factors and in acute coronary syndrome.
- Fondaparinux should be stopped immediately when the target INR range has been achieved since the half-life of fondaparinux is 17 hours. The half-life of LMWHs is 4 hours.
Can usually also be used in HIT.
Mainly eliminated in the urine. Due to the risk of accumulation, the dose should be reduced in moderate kidney failure. Use is not recommended in severe kidney failure, at least not long term. According to the data supplied in the Summary of Product Characteristics, fondaparinux should not be used if the GFR is less than 30 ml/min.
Not recommended during pregnancy or breast-feeding.

ApixabanFactor Xa Inhibitors Versus Vitamin K Antagonists for Preventing Embolism in Patients with Atrial Fibrillation

Apixaban is a direct factor X inhibitor.
Indications: the prevention of venous thrombosis in association with hip or knee replacement surgery, and prevention of thromboembolism in patients with non-valvular atrial fibrillation as well as treatment (no need to combine with LMWH) and prevention of recurrence of deep vein thrombosis and pulmonary embolism
No routine laboratory monitoring of drug effect is required.
In problematic situations, the effect may be monitored by anti-FXa determination calibrated for apixaban. The assay is needed only in special situations and its interpretation requires expertise. The “regular” anti-FXa method used for testing the effect of LMWH may be used if it is necessary to rule out an effect: if the result is normal, there is no apixaban effect.
Renal function as well as the patient's age and weight must be taken into account in dosage. The dose should be reduced in severe kidney failure. Not recommended if the GFR is less than 15 ml/min.
Not to be used during pregnancy or breast-feeding.
The incidence of intracranial haemorrhage is lower than during warfarin therapy.
Drug interactions that are significant and should be considered in dosage occur less frequently than with warfarin; see 4 and the up-to-date English website of EHRA http://www.NOACforAF.eu as well as locally available drug databases for further details.
Interferes with several clotting factor tests and their interpretation.
Must be stopped for at least 48 hours before elective procedures with high risk of bleeding and at least 24 hours before elective procedures with low risk of bleeding. If possible, the time interval between urgent procedures and the last dose should be at least 12 hours.
A specific antidote (andexanet alfa) has been granted marketing authorization, but due to the short half-life of apixaban, an antidote is usually not needed other than possibly in case of emergency surgery, bleeding in critical areas or massive trauma. Use of the antidote requires expertise; for more detail, see 5. It is likely that the effect of apixaban can be at least partially reversed with prothrombin complex concentrate.

Rivaroxaban Factor Xa Inhibitors Versus Vitamin K Antagonists for Preventing Embolism in Patients with Atrial Fibrillation

Rivaroxaban is a direct factor X inhibitor.
Indications: the prevention of venous thrombosis in patients undergoing hip or knee replacement surgery, prevention of thromboembolism in patients with non-valvular atrial fibrillation, prevention of atherothrombotic events after acute coronary syndrome, treatment of severe occlusive disease of the lower extremities, venous thrombosis and pulmonary embolism (does not require the concomitant administration of a LMWH) and prevention of recurrent venous thrombosis and pulmonary embolism after acute deep venous thrombosis.
No routine laboratory monitoring of drug effect is required. If necessary, the pharmacological effect can be monitored with anti-FXa assays calibrated for rivaroxaban. The assay is needed only in special situations and its interpretation requires expertise.
The anti-FXa method may be used if it is necessary to rule out an effect: if the result is normal, there is no rivaroxaban effect.
Not to be used during pregnancy or breast-feeding.
The dose should be reduced in moderate to severe kidney failure. Not recommended if the GFR is less than 15 ml/min.
The incidence of intracranial haemorrhage is lower and that of gastrointestinal bleeding is higher than during warfarin therapy.
Drug interactions that are significant and should be considered in dosage occur less frequently than with warfarin. See 4 and the up-to-date English website of EHRA http://www.NOACforAF.eu as well as locally available drug databases for further details.
Interferes with several clotting factor tests and their interpretation.
Must be stopped for at least 48 hours before elective procedures with high risk of bleeding and at least 24 hours before elective procedures with low risk of bleeding. If possible, the time interval between urgent procedures and the last dose should be at least 12 hours.
A specific antidote (andexanet alfa) has been granted marketing authorization, but due to the short half-life of rivaroxaban, an antidote is usually not needed other than possibly in case of emergency surgery, bleeding in critical areas or massive trauma. Use of the antidote requires expertise; for more detail, see 5. The effect of rivaroxaban can be at least partially reversed with a larger than normal dose of prothrombin complex concentrate (PCC).

Edoxaban

Edoxaban is a direct inhibitor of factor X and belongs to the same group with apixaban and rivaroxaban.
Indications: prevention of thromboembolism in patients with non-valvular atrial fibrillation as well as treatment and prevention of recurrence of deep vein thrombosis and pulmonary embolism
No routine laboratory monitoring of drug effect is required. If necessary, the pharmacological effect can be monitored with anti-FXa assays calibrated for edoxaban. The assay is needed only in special situations and its interpretation requires expertise.
Not to be used during pregnancy or breast-feeding.
Dose calculation is necessary for patients with moderately severe to severe kidney failure, low body weight (below 60 kg) or concomitantly taking any of the following P glycoprotein inhibitors: ciclosporine, dronedarone, erythromycin or ketoconazole.
Not recommended if the GFR is less than 15 ml/min.
Must be stopped for at least 48 hours before elective procedures with high risk of bleeding and at least 24 hours before elective procedures with low risk of bleeding. If possible, the time interval between urgent procedures and the last dose should be at least 12 hours.

Dabigatran Dabigatran Versus Vitamin K Antagonists in Non-Valvular Atrial Fibrillation, Dabigatran Versus Lmwhs for Thromboprophylaxis after Total Hip or Knee Replacement

Dabigatran is a direct thrombin inhibitor.
Indications: prevention of venous thrombosis in association with hip or knee replacement surgery, and prevention of thromboembolism in patients with non-valvular atrial fibrillation as well as treatment and prevention of recurrence of deep vein thrombosis and pulmonary embolism.
The efficacy of dabigatran need not be monitored by routine laboratory tests.
APTT and thrombin time provide an approximate indication of the anticoagulation intensity achieved. If thrombin time is normal, there is no dabigatran effect.
Interferes with several clotting factor tests and their interpretation (e.g. INR).
More accurate measurement of drug effect in special situations requires a thrombin time test calibrated for dabigatran, which requires expertise to interpret.
Not to be used during pregnancy or breast-feeding.
Eliminated in the urine, and the elimination half-life is fairly long at 12-17 hours.
Accumulates in kidney failure. Should not be used in severe kidney failure (GFR < 30 ml/min). Dose reduction or changing the anticoagulant should be considered in patients with high bleeding risk and moderate kidney failure (GFR 30-50 ml/min).
The incidence of intracranial haemorrhage is lower and that of gastrointestinal bleeding is higher than during warfarin therapy.
Drug interactions that are significant and should be considered in dosage occur less frequently than with warfarin. See 4 and the up-to-date English website of EHRA http://www.NOACforAF.eu and locally available drug databases for further details.
Must be stopped for at least 48 hours before elective procedures with high risk of bleeding and at least 24 hours before elective procedures with low risk of bleeding. The withdrawal times are longer in kidney failure. If possible, the time interval between urgent procedures and the last dose should be at least 12 hours.
The anticoagulation effect of dabigatran may be reversed in an emergency by a specific antidote (idarucizumab; see national guidelines; see also 5). The administration of prothrombin complex concentrate or recombinant activated factor VII (rFVIIa) may be considered if bleeding is life-threatening; however, insufficient evidence exists on their efficacy.

Aspirin (acetylsalicylic acid, ASA) Antiplatelet Therapy for Prevention of Death, Myocardial Infarction, and Stroke, Antiplatelet Therapy for Patients with Non-Valvular Atrial Fibrillation, Antiplatelet Drugs for Prevention of Restenosis after Peripheral Endovascular Treatment, Antiplatelet Therapy for Acute Ischaemic Stroke, ASA for Hypertension

The dose is 50-100 mg orally once daily.
In acute coronary syndrome 250 mg should be chewed in order to hasten the effect.
Indications: prevention of arterial thrombosis in coronary artery disease, cerebrovascular disorders and peripheral arterial disease.
May also be beneficial as follow-up treatment after anticoagulant therapy for venous thrombosis in patients who also are at an increased risk of arterial thrombosis.
After stopping therapy, the effect will in practice persist for about 5 days (the effect will dissipate completely after about 10 days when a complete platelet turnover has been achieved).

Dipyridamole Dipyridamole for Preventing Vascular Events

Dipyridamole is available as a single drug and as a combination product with aspirin.
The combination product is taken twice daily and is used, among other indications, for the secondary prevention of ischaemic stroke and TIA.
- In the event of severe headaches during treatment initiation, the patient may take one combination capsule at bedtime and low-dose aspirin in the morning. The usual regime of the combination product twice daily should be reintroduced after one week.
Acts as a platelet function inhibitor and vasodilator.
The effect lasts for about 10 hours.

Clopidogrel Clopidogrel and Aspirin in Acute ST-Segment Elevation Myocardial Infarction (STEMI), Clopidogrel Plus Aspirin Vs Aspirin Alone for Preventing Cardiovascular Events, Antiplatelet Agents for Intermittent Claudication

For oral use; the loading dose of clopidogrel is 300-600 mg, followed by a maintenance dose of 75(-150) mg/day.
Platelet ADP receptor antagonist
Indications
- Instead of aspirin for those allergic to aspirin
- During and after acute coronary syndrome as well as for the prevention of stent thrombosis co-administered with aspirin for a set time period
- Secondary prevention of cerebrovascular events as an alternative to aspirin+dipyridamole
- Peripheral arterial disease
Maximal effect is achieved in 5-6 days after medication is commenced. After stopping clopidogrel, its irreversible platelet inhibiting effect will take the same length of time to dissipate (the complete effect is over in about 10 days, after the renewal of platelets).
Whether and when it is necessary to interrupt the medication before surgical intervention depends on the indication for the drug therapy and the risk of bleeding associated with the procedure.

Prasugrel

The loading dose of prasugrel is 60 mg, followed by 10 mg or 5 mg.
Platelet ADP receptor antagonist
Used as prescribed by a cardiologist for the treatment of acute coronary syndrome leading to PCI and, combined with aspirin, for further treatment for a specified period (as an alternative to ticagrelor or clopidogrel).
The effect starts within one hour from the loading dose; clearly faster than with clopidogrel.
The effect is irreversible; will dissipate 7-10 days after stopping the drug.
More potent than clopidogrel, but has more bleeding complications.
Surgical interventions during therapy are associated with a greater risk of bleeding than during clopidogrel therapy.
The individual response to prasugrel varies, but the variation and drug resistance are clearly less significant than with clopidogrel.
Contraindications include a history of TIA or stroke; administration to patients ≥ 75 years of age only after careful consideration.
Thrombolytic therapy is contraindicated if the patient is using prasugrel.
In life-threatening or severe haemorrhage some of the pharmacological effect of prasugrel can be reversed with platelet transfusions.

Ticagrelor

The loading dose of ticagrelor is 180 mg, followed by 90 mg twice daily; for long-term prevention of myocardial infarction in high-risk patients 60 mg twice daily.
Platelet ADP receptor antagonist
Used combined with aspirin for the treatment of acute coronary syndrome and for further treatment for a specified time or for long-term treatment of high-risk patients as prescribed by a cardiologist.
The effect starts and dissipates more quickly than with clopidogrel; the duration of effect is about 12 hours.
- Exhibits reversible binding to the receptor and, therefore, its effect dissipates more quickly than with clopidogrel or prasugrel. However, it is still recommended that ticagrelor is discontinued 5 days before, for example, coronary bypass surgery.
Surgical interventions during ticagrelor therapy are associated with a greater risk of bleeding than during clopidogrel therapy.
Dyspnoea may occur as an adverse effect; after consulting specialized care, the drug should be changed to clopidogrel, as necessary (continuing with the maintenance dose after a loading dose).
Platelet infusion should be considered in life-threatening or severe haemorrhage, even though it is less effective than in reversing the effect of clopidogrel or prasugrel.

Alteplase Thrombolysis for Acute Ischaemic Stroke

Indications: acute ST-elevation myocardial infarction, acute pulmonary embolism associated with high risk of death and leading to haemodynamic collapse (shock, hypotension) and acute ischaemic stroke.
Alteplase is administered on the basis of body weight; an intravenous bolus dose followed by an infusion.
Short half-life of 4-8 minutes, allows for invasive procedures to be carried out soon after the infusion.
For thrombolysis, the contraindications must first be excluded; see Acute Coronary Syndrome and Myocardial Infarction.

Tenecteplase

Tenecteplase is indicated in acute ST-elevation myocardial infarction. Additionally, it is used as an alternative (off label) to alteplase in pulmonary embolism associated with high risk of death and leading to haemodynamic collapse.
Administered on the basis of body weight as a single intravenous bolus.
The half-life is about 20 minutes.
For thrombolysis, the contraindications must first be excluded; see Acute Coronary Syndrome and Myocardial Infarction.

References

Steffel J, Verhamme P, Potpara TS et al. The 2018 European Heart Rhythm Association Practical Guide on the use of non-vitamin K antagonist oral anticoagulants in patients with atrial fibrillation. Eur Heart J 2018;39(16):1330-1393. [PubMed]
Cuker A, Burnett A, Triller D et al. Reversal of direct oral anticoagulants: Guidance from the Anticoagulation Forum. Am J Hematol 2019;94(6):697-709. [PubMed]

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