CONCLUSIONS: Of 54 recommendations included in the 30 statements, 20 were strong and none was based on high-quality evidence, highlighting the need for further research
1. In patients with proximal DVT or pulmonary embolism (PE), we recommend long-term (3 months) anticoagulant therapy over no such therapy (Grade 1B).
2. In patients with DVT of the leg or PE and no cancer, as long-term (first 3 months) anticoagulant therapy,
#: we suggest dabigatran, rivaroxaban, apixaban, or edoxaban over vitamin K antagonist (VKA) therapy (all Grade 2B).
##: we suggest VKA therapy over low-molecular weight heparin (LMWH) (Grade 2C).
Remarks: We suggested VKA therapy over LMWH in patients without cancer for the following reasons: injections are burdensome; LMWH is expensive; there are low rates of recurrence with VKA in patients.
3. In patients with DVT of the leg or PE and cancer (“cancer-associated thrombosis”), as long-term (first 3 months) anticoagulant therapy,
we suggest LMWH over VKA therapy (Grade 2B), dabigatran (Grade 2C), rivaroxaban (Grade 2C), apixaban (Grade 2C), or edoxaban (Grade 2C). rivaroxaban and apixaban, and is overlapped with VKA therapy.
4. In patients with DVT of the leg or PE who receive extended therapy, we suggest that there is no need to change the choice of anticoagulant after the
first 3 months (Grade 2C).
Remarks: It may be appropriate for the choice of anticoagulant to change in response to changes in the patient’s circumstances or preferences during long-term or extended phases of treatment.
5. 5. In patients with a proximal DVT of the leg or
PE provoked by surgery, we recommend treatment
with anticoagulation for 3 months over (i) treatment
of a shorter period (Grade 1B), (ii) treatment of a
longer time-limited period (eg, 6, 12, or 24 months)
(Grade 1B), or (iii) extended therapy (no scheduled
stop date) (Grade 1B).
6. In patients with a proximal DVT of the leg or PE provoked by a nonsurgical transient risk factor, we recommend treatment with anticoagulation for 3 months over (i) treatment of a shorter period (Grade 1B) and (ii) treatment of a longer time-limited period (eg, 6, 12, or 24 months) (Grade 1B).
We suggest treatment with anticoagulation for 3 months over extended therapy if there is a low or moderate bleeding risk (Grade 2B) , and recommend treatment for 3 months over extended therapy if there is a high risk of bleeding (Grade 1B).
Remarks: In all patients who receive extended anticoagulant therapy, the continuing use of treatment should be reassessed at periodic intervals (eg, annually).
7. In patients with an isolated distal DVT of the leg provoked by surgery or by a nonsurgical transient risk factor,
we suggest treatment with anticoagulation for 3 months over other regimens.
Remarks: Duration of treatment of patients with isolated distal DVT refers to patients in whom a decision has been made to treat with anticoagulant therapy; however, it is anticipated that not all patients who are diagnosed with isolated distal DVT will be prescribed anticoagulants.
8. In patients with an unprovoked DVT of the leg (isolated distal or proximal) or PE, we recommend treatment with anticoagulation for at least 3 months
over other regimens.
Remarks: After 3 months of treatment, patients with unprovoked DVT of the leg or PE should be evaluated for the risk-benefit ratio of extended therapy. Duration of treatment of patients with isolated distal DVT refers to patients in whom a decision has been made to treat with anticoagulant therapy; however, it is anticipated that not all patients who are diagnosed with isolated distal DVT will be prescribed anticoagulants.
9. In patients with a first VTE that is an unprovoked proximal DVT of the leg or PE and who have a (i) low or moderate bleeding risk (see text), we suggest
extended anticoagulant therapy (no scheduled stop date) over 3 months of therapy (Grade 2B), and (ii) high bleeding risk (see text), we recommend 3 months of anticoagulant therapy over extended therapy (no scheduled stop date) (Grade 1B).
Remarks: Patient sex and D-dimer level measured a month after stopping anticoagulant therapy may influence the decision to stop or extend anticoagulant therapy (see text). In all patients who receive extended anticoagulant therapy, the continuing use of treatment should be reassessed at periodic intervals (eg, annually).
10. In patients with a second unprovoked VTE and who have a (i) low bleeding risk (see text), we recommend extended anticoagulant therapy (no scheduled stop date) over 3 months (Grade 1B); (ii) moderate bleeding risk (see text), we suggest extended anticoagulant therapy over 3 months of therapy (Grade 2B) ; or (iii) high bleeding risk (see text), we suggest 3 months of anticoagulant therapy over extended therapy (no scheduled stop date) (Grade 2B).
Remarks: In all patients who receive extended anticoagulant therapy, the continuing use of treatment should be reassessed at periodic intervals (eg, annually).
11. In patients with DVT of the leg or PE and active cancer (“cancer-associated thrombosis”), we recommend extended anticoagulant therapy (no scheduled stop date) over 3 months of therapy for
who (i) do not have a high bleeding risk, (Grade 1B),
or
(ii) have a high bleeding risk (Grade 2B).
Remarks: Reassessed annually.
12. In patients with an unprovoked proximal DVT or PE who are stopping anticoagulant therapy and do not have a contraindication to aspirin, we suggest
aspirin over no aspirin to prevent recurrent VTE (Grade 2B).
Remarks: Because aspirin is expected to be much less effective at preventing recurrent VTE than anticoagulants, we do not consider aspirin a reasonable alternative to anticoagulant therapy in patients who want extended therapy. However, if a patient has decided to stop anticoagulants, prevention of recurrent VTE is one of the benefits of aspirin that needs to be balanced against aspirin’s risk of bleeding and inconvenience. Use of aspirin should also be reevaluated when patients stop anticoagulant therapy because aspirin may have been stopped when anticoagulants were started.
13. In patients with acute isolated distal DVT of the leg and
(i) without severe symptoms or risk factors for extension (see text), we suggest serial imaging of the deep veins for 2 weeks over anticoagulation (Grade 2C)
or (ii) with severe symptoms or risk factors for extension (see text), we suggest anticoagulation over serial imaging of the deep veins (Grade 2C).
Remarks: Patients at high risk for bleeding are more likely to benefit from serial imaging. Patients who place a high value on avoiding the inconvenience of repeat imaging and a low value on the inconvenience of treatment and on the potential for bleeding are likely to choose initial anticoagulation over serial imaging.
14. In patients with acute isolated distal DVT of the leg who are managed with anticoagulation, we recommend using the same anticoagulation as for
patients with acute proximal DVT (Grade 1B).
15. In patients with acute isolated distal DVT of the leg who are managed with serial imaging, we
(i) recommend no anticoagulation if the thrombus does not extend (Grade 1B),
(ii) suggest anticoagulation if the thrombus extends but remains confined to the distal veins (Grade 2C), and
(iii) recommend anticoagulation if the thrombus extends into the proximal veins (Grade 1B).
16. In patients with acute proximal DVT of the leg, we suggest anticoagulant therapy alone over CDT (Grade 2C).
Remarks: Patients who are most likely to benefit from CDT (see text), who attach a high value to prevention of postthrombotic syndrome (PTS), and a lower value to the initial complexity, cost, and risk of bleeding with CDT, are likely to choose CDT over anticoagulation alone.
17. In patients with acute DVT or PE who are treated with anticoagulants, we recommend against the use of an inferior vena cava (IVC) filter(Grade 1B).
18. In patients with acute DVT of the leg, we suggest not using compression stockings routinely to prevent PTS (Grade 2B).
Remarks: This recommendation focuses on prevention of the chronic complication of PTS and not on the treatment of symptoms. For patients with acute or chronic symptoms, a trial of graduated compression stockings is often justified.
19. In patients with subsegmental PE (no involvement of more proximal pulmonary arteries) and no proximal DVT in the legs who have a
(i) low risk for recurrent VTE (see text), we suggest clinical surveillance over anticoagulation (Grade 2C) or
(ii) high risk for recurrent VTE (see text), we suggest anticoagulation over clinical surveillance (Grade 2C).
Remarks: Ultrasound (US) imaging of the deep veins of both legs should be done to exclude proximal DVT.
Clinical surveillance can be supplemented by serial US imaging of the proximal deep veins of both legs to detect evolving DVT (see text). Patients and physicians are more likely to opt for clinical surveillance over anticoagulation if there is good cardiopulmonary reserve or a high risk of bleeding.
20. In patients with low-risk PE and whose home circumstances are adequate, we suggest treatment at home or early discharge over standard discharge (eg, after the first 5 days of treatment) (Grade 2B)
21. In patients with acute PE associated with hypotension (eg, systolic BP<90 mm Hg) who do not have a high bleeding risk, we suggest systemically
administered thrombolytic therapy over no such therapy (Grade 2B).
22. In most patients with acute PE not associated with hypotension, we recommend against systemically administered thrombolytic therapy (Grade 1B).
23. In selected patients with acute PE who deteriorate after starting anticoagulant therapy but have yet to develop hypotension and who have a low bleeding risk, we suggest systemically administered thrombolytic therapy over no such therapy (Grade 2C).
Remarks: Patients with PE and without hypotension who have severe symptoms or marked cardiopulmonary impairment should be monitored closely for deterioration. Development of hypotension suggests that thrombolytic therapy has become indicated.
Cardiopulmonary deterioration (eg, symptoms, vital signs, tissue perfusion, gas exchange, cardiac biomarkers) that has not progressed to hypotension may
also alter the risk-benefit assessment in favor of thrombolytic therapy in patients initially treated with anticoagulation alone.
24. In patients with acute PE who are treated with a thrombolytic agent, we suggest systemic thrombolytic therapy using a peripheral vein over CDT
(Grade 2C).
Remarks: Patients who have a higher risk of bleeding with systemic thrombolytic therapy and who have access to the expertise and resources required to do CDT are likely to choose CDT over systemic thrombolytic therapy.
25. In patients with acute PE associated with hypotension and who have (i) a high bleeding risk, (ii) failed systemic thrombolysis, or (iii) shock that is
likely to cause death before systemic thrombolysis can take effect (eg, within hours), if appropriate expertise and resources are available, we suggest catheter-assisted thrombus removal over no such intervention (Grade 2C).
Remarks: Catheter-assisted thrombus removal refers to mechanical interventions, with or without catheter directed thrombolysis.
26. In selected patients with chronic thromboembolic pulmonary hypertension (CTEPH) who are identified by an experienced thromboendarterectomy team, we suggest pulmonary thromboendarterectomy over no pulmonary thromboendarterectomy (Grade 2C).
Remarks: Patients with CTEPH should be evaluated by a team with expertise in treatment of pulmonary hypertension. Pulmonary thromboendarterectomy is
often lifesaving and life-transforming. Patients with CTEPH who are not candidates for pulmonary thromboendarterectomy may benefit from other mechanical and pharmacological interventions designed to lower pulmonary arterial pressure.
27. In patients with acute upper extremity DVT (UEDVT) that involves the axillary or more proximal veins, we suggest anticoagulant therapy alone over
thrombolysis(Grade 2C).
Remarks: Patients who (i) are most likely to benefit from thrombolysis (see text); (ii) have access to CDT; (iii) attach a high value to prevention of PTS; and (iv) attach a lower value to the initial complexity, cost, and risk of bleeding with thrombolytic therapy are likely to choose thrombolytic therapy over anticoagulation alone.
28. In patients with UEDVT who undergo thrombolysis, we recommend the same intensity and duration of anticoagulant therapy as in patients with UEDVT who do not undergo thrombolysis (Grade 1B).
29. In patients who have recurrent VTE on VKA therapy (in the therapeutic range) or on dabigatran, rivaroxaban, apixaban, or edoxaban (and are
believed to be compliant), we suggest switching to treatment with LMWH at least temporarily (Grade 2C).
Remarks: Recurrent VTE while on therapeutic-dose anticoagulant therapy is unusual and should prompt the following assessments: (1) reevaluation of whether there truly was a recurrent VTE; (2) evaluation of compliance with anticoagulant therapy; and (3) consideration of an underlying malignancy. A temporary switch to LMWH will usually be for at least 1 month.
30. In patients who have recurrent VTE on long-term LMWH (and are believed to be compliant), we suggest increasing the dose of LMWH by about
one-quarter to one-third (Grade 2C).
Remarks: Recurrent VTE while on therapeutic-dose anticoagulant therapy is unusual and should prompt the following assessments: (1) reevaluation of whether there truly was a recurrent VTE; (2) evaluation of compliance with anticoagulant therapy; and (3) consideration of an underlying malignancy.
It takes about 3 months to complete “active treatment” of venous thromboembolism (VTE), with further treatment serving to prevent new episodes of thrombosis (“pure secondary prevention”).
Consequently, VTE should generally be treated for either 3 months or indefinitely (exceptions will be described in the text).
The decision to stop anticoagulants at 3 months or to treat indefinitely is dominated by the long-term risk of recurrence, and secondarily influenced by the risk of bleeding and by patient preference.
VTE provoked by a reversible risk factor, or a first unprovoked isolated distal (calf) deep vein thrombosis (DVT), has a low risk of recurrence and is usually treated for 3 months.
VTE associated with active cancer, or a second unprovoked VTE, has a high risk of recurrence and is usually treated indefinitely.
The decision to stop anticoagulants at 3 months or to treat indefinitely is more finely balanced after a first unprovoked proximal DVT or pulmonary embolism (PE).
Indefinite anticoagulation is often chosen if there is a low risk of bleeding, whereas anticoagulation is usually stopped at 3 months if there is a high risk of bleeding.
The decision to continue anticoagulation indefinitely after a first unprovoked proximal DVT or PE is strengthened if the patient is male, the index event was PE rather than DVT, and/or d-dimer testing is positive 1 month after stopping anticoagulant therapy.
Low molecular weight heparin (LMWH)
Used for prophylaxis and management of systemic thromboembolism
More predictable anticoagulant response than unfractionated heparin
SUPPLIED
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Lovenox Intravenous Inj Sol: 1mL, 100mg
BOXED WARNING ----- Epidural anesthesia, lumbar puncture, spinal anesthesia
For the treatment of venous thromboembolism (VTE) including acute deep venous thrombosis (DVT) or pulmonary embolism (PE).
■ For inpatient treatment of DVT with or without PE.
Subcutaneous dosage
enoxaparin 1 mg/kg/dose subcutaneously every 12 hours or 1.5 mg/kg/dose subcutaneously every 24 hours.
Both regimens have been shown to be equivalent to continuous IV heparin in clinical trials.
Oral warfarin is typically begun within 72 hours of initiation of enoxaparin; however clinical practice guidelines recommend starting a vitamin K antagonist on day 1 of enoxaparin treatment.
Enoxaparin is discontinued when the targeted warfarin INR is achieved and a minimum of 5 days of enoxaparin administration has elapsed.
The average duration of enoxaparin treatment is 7 days, with up to 17 days well-tolerated in clinical trials.
■ For the outpatient treatment of acute DVT not associated with PE, in conjunction with warfarin.
Subcutaneous dosage
enoxaparin 1 mg/kg/dose subcutaneously every 12 hours.
Warfarin therapy should be administered when appropriate (usually within 72 hours of enoxaparin initiation).
Continue enoxaparin for a minimum of 5 days and until a therapeutic oral anticoagulant effect has been achieved.
In clinical trials, thromboembolism recurrence with enoxaparin (5.3%) was similar to inpatient treatment with continuous IV heparin (6.7%). Episodes of major bleeding were also similar. Enoxaparin patients spent an average of 1.1 days in the hospital compared to 6.5 days for the heparin group. The average duration of enoxaparin treatment is 7 days, with up to 17 days well-tolerated in clinical trial
■ For the treatment of DVT or PE in patients with cancer†.
Subcutaneous dosage
enoxaparin 1 mg/kg/dose subcutaneously every 12 hours or 1.5 mg/kg/dose subcutaneously every 24 hours.
The rate of recurrence of VTE in patients with active cancer is high; therefore, extended therapy is recommended unless there is a very high risk of bleeding.
Clinical practice guidelines recommend treatment of VTE with low molecular weight heparin (LMWH) for over 3 months if the risk of bleeding is not high.
Trials of extended enoxaparin in the treatment of VTE in patients with cancer have not demonstrated a difference in terms of recurrence or major bleeding between extended treatment with enoxaparin vs. warfarin.
■ For the treatment of DVT or PE in pregnant females†.
Subcutaneous dosage
Pregnant Females†
enoxaparin 1 mg/kg/dose subcutaneously every 12 hours or 1.5 mg/kg/dose every 24 hours throughout pregnancy.
Because enoxaparin requirements may change as pregnancy progresses due to changes in volume of distribution and glomerular filtration rate, twice daily dosing is preferred by some clinicians. However, many clinicians use a once-daily regimen to simplify administration and enhance compliance.
Observational studies have not shown an increase in the risk of recurrence with once daily dosing compared to twice daily dosing.
Dose adjustments during pregnancy remains controversial. Due to the lack of data demonstrating a correlation with therapeutic anti-Xa concentrations and safety or efficacy, clinical practice guidelines suggest routine monitoring with anti-Xa concentrations is difficult to justify.
Enoxaparin should be discontinued 24 hours prior to elective induction of labor or cesarean section. An anticoagulant should be administered for at least 6 weeks postpartum, for a minimum of 3 months of therapy.
For thrombosis prophylaxis.
NOTE: Mechanical methods of prophylaxis should be used in patients who are at high risk of bleeding or as an adjunct to anticoagulant-based prophylaxis.
Standard thromboembolism prophylaxis
enoxaparin 1 mg/kg subcutaneously every 12 hours. Guidelines recommend LMWH in combination with oral anticoagulants until the INR is within the therapeutic range for 2 consecutive days.
■ For arterial thromboembolism prophylaxis† in patients after prosthetic heart valves† surgery.
Standard thromboembolism prophylaxis.
■ For venous thromboembolism (VTE) prophylaxis including deep venous thrombosis (DVT) prophylaxis or pulmonary embolism prophylaxis.
• Moderate risk Adults undergoing general surgery (e.g., minor procedure, with additional risk factors; non-major surgery for patients 40 to 60 years with no risk factors; major surgery in patients younger than 40 years with no risk factors†)
Guidelines suggest a dose of 3,400 anti-factor Xa International Units or less of LMWH subcutaneously once daily (equivalent to 34 mg or less per day of subcutaneous enoxaparin);
20 mg subcutaneously once daily is the dose most studied during 'low-dose' enoxaparin DVT/PE prophylaxis studies.
Higher doses of 40 to 60 mg/day subcutaneously are associated with an increased risk of bleeding and the risk of bleeding may outweigh the benefit in this at moderate-risk population.
Previous guidelines have suggested starting the LMWH 1 to 2 hours before surgery, followed by once daily postoperatively.
• Higher risk Adults, patients undergoing abdominal surgery, or Geriatric undergoing general surgery (e.g., non-major surgery in patients older than 60 years or with additional risk factors; major surgery in patients older than 40 years or with additional risk factors)
• Adults after orthopedic hip replacement surgery
40 mg subcutaneously once daily or 30 mg subcutaneously every 12 hours. Guidelines recommend LMWH as the preferred agent for antithrombotic prophylaxis for patients undergoing total hip replacement surgery. Prophylaxis should start 12 hours or more preoperatively or postoperatively and continue for a minimum of 10 to 14 days after surgery; up to 35 days is recommended. The use of an intermittent pneumatic compression device (IPCD) during the hospital stay is encouraged.
• Adults after orthopedic knee replacement surgery
30 mg + DITTO
• Adults after orthopedic hip fracture surgery†
40 mg + DITTO
• General medical Adult patients with risk factors for DVT due to restrictive mobility during acute illness (e.g., moderate to severe congestive heart failure, severe respiratory disease, or patients who are confined to bed and have 1 or more of the following risk factors: active cancer, history of VTE, sepsis, acute neurological disease, and inflammatory bowel disease)
40 mg subcutaneously once daily for 14 days or less.
In a phase 3 trial, treatment with enoxaparin resulted in a significantly lower incidence of DVT when compared with placebo (4.4% vs. 11.9%) after 14 days of treatment. The reduced incidence was maintained at 3 months of follow-up. There were no significant differences in adverse reactions between the treatment group and placebo except for ecchymosis at the injection site. Additionally, enoxaparin 40 mg subcutaneously once daily was associated with a significant decrease in the incidence of VTE as compared to enoxaparin 20 mg subcutaneously once daily, or placebo (incidence of DVT was 5.5% for enoxaparin 40 mg, 15% for enoxaparin 20 mg, and 14.9% for placebo; RR of enoxaparin 40 mg vs. placebo 0.37, 95% CI 0.22 to 0.63, p less than 0.001).
• Female Adults undergoing major gynecologic surgery for benign disease, no additional risk factors†
• Female Adults undergoing extensive gynecologic surgery for malignancy†
• Adults undergoing laparoscopic surgery†
• Adults undergoing vascular surgery†
• Adults undergoing major open urologic procedure (including high-risk)†
• Adults undergoing neurosurgery†
• Adults undergoing elective spinal cord surgery†
• Adults with trauma†
• Adults with acute spinal cord injury†
• Adults with acute ischemic stroke and impaired mobility†
• Adults considered to be at high-risk for VTE that are undergoing flights more than 6 hours in duration†
• Infants, Children, and Adolescents 2 months to 17 years†
• Neonates and Infants younger than 2 months†
■ For deep venous thrombosis (DVT) prophylaxis in pregnant females.
NOTE: In all pregnant women with a history of DVT, the use of graduated elastic stockings (ES) is recommended both antenatally and postpartum.
•
•
•
• Pregnant females with 2 or more episodes of DVT and/or long-term anticoagulation (e.g., single episode of DVT, idiopathic or associated with thrombophilia)
1 mg/kg subcutaneously every 12 hours with resumption of long-term anticoagulation postpartum.
■ For thrombosis prophylaxis in pregnant patients with prosthetic heart valves†.
■ For thrombosis prophylaxis and/or for pulmonary embolism prophylaxis in patients at increased risk after sustaining an acute MI (e.g., ST segment elevation MI, severe LV dysfunction, CHF, history of systemic or pulmonary embolism, 2D echo evidence of mural thrombus, or atrial fibrillation).
■ For arterial thromboembolism prophylaxis† in patients with atrial fibrillation who are undergoing elective cardioversion.
■ For thrombosis prophylaxis in patients with obesity†.
■ For the treatment of cerebral thromboembolism† (e.g., cerebral venous sinus thrombosis†).
■ For coronary artery thrombosis prophylaxis and the prevention of ischemic complications in patients with acute coronary syndrome (ACS), including patients undergoing percutaneous coronary intervention (PCI)†.
■ For patients with unstable angina (UA), non-ST-segment elevation myocardial infarction (NSTEMI), or non-Q-wave myocardial infarction.
■ For the prevention of pregnancy loss and/or thrombosis in patients with antiphospholipid antibody syndrome† (APLA).
In pregnant women with APLA and >= 2 early pregnancy losses, >= 1 late pregnancy loss, preeclampsia, intrauterine growth restriction (IUGR), or abruption.
Antepartum aspirin and enoxaparin 40 mg subcutaneous once daily.
Maintain anti-factor Xa level of 0.2 to 0.6 International Units/mL.
■ For periprocedural anticoagulation† (bridge therapy) in patients with atrial fibrillation, mechanical heart valve, or venous thrombosis who require an interruption in oral anticoagulant therapy.
Diagnostic Criteria for the diagnosis of antiphospholipid syndrome
In the UK, the diagnosis of antiphospholipid syndrome is met if one clinical criteria and one laboratory criteria is met.
Clinical Criteria:
■ Vascular thrombosis – 1 or more clinical episode(s) of arterial, venous or small-vessel thrombosis.
■ Pregnancy morbidity – 3 or more unexplained consecutive spontaneous abortions before 10 weeks gestation OR 1 or more premature birth(s) of a normal neonate before the 34 weeks gestation because of eclampsia or severe pre-eclampsia OR 1 or more unexplained deaths of morphologically normal fetuses at or beyond the 10th week of gestation.
Laboratory Criteria
■ Lupus anticoagulant – present in the plasma on 2 or more occasions, at least 12 weeks apart.
■ Anticardiolipin antibody – present in medium or high titre (>40 IgG GPL units or IgM phospholipid [MPL] units, or >99th percentile) on 2 or more occasions, at least 12 weeks apart.
■ Anti-beta2-glycoprotein I – present in serum or plasma (in titre >90th percentile) on 2 or more occasions, at least 12 weeks apart.
Testing for Lupus Anticoagulant
Partial Thromboplastin Time (PTT)
Dilute or Modified Russell's Viper Venom Test (dRVVT or MRVVT)
Prothrombin Time (PT)
Kaolin Plasma Clotting Time (KCT)
Warfarin
For prophylaxis of arterial and/or venous thromboembolism in patients with antiphospholipid antibody syndrome.
Clinical practice guidelines suggest a moderate-intensity INR range (INR 2—3) rather than higher intensity (INR 3—4.5) for patients with previous arterial or venous thromboembolism.
Low-dose aspirin (LDA) is recommended for asymptomatic aPL carriers, patients with systemic lupus erythematosus without prior thrombotic or obstetric APS, and non-pregnant women with a history of obstetric APS only, all with high-risk aPL profiles.
Patients with APS and first unprovoked venous thrombosis should receive long-term treatment with vitamin K antagonists (VKA) with a target international normalised ratio (INR) of 2–3. In patients with APS with first arterial thrombosis, treatment with VKA with INR 2–3 or INR 3–4 is recommended, considering the individual’s bleeding/thrombosis risk.
Rivaroxaban should not be used in patients with APS with triple aPL positivity. For patients with recurrent arterial or venous thrombosis despite adequate treatment, addition of LDA, increase of INR target to 3–4 or switch to low molecular weight heparin may be considered.
Women with prior obstetric APS, combination treatment with LDA and prophylactic dosage heparin during pregnancy is recommended.
In patients with recurrent pregnancy complications, increase of heparin to therapeutic dose, addition of hydroxychloroquine or addition of low-dose prednisolone in the first trimester may be considered.
Overarching principles
Risk stratification in aPL-positive individuals should include determination of the presence of a high-risk aPL profile (defined as any of the following: multiple aPL positivity, lupus anticoagulant or persistently high aPL titres), history of thrombotic and/or obstetric APS, coexistence of other systemic autoimmune diseases such as SLE, and the presence of traditional cardiovascular risk factors.
A high-risk aPL profile includes any of the following:
lupus anticoagulant (LAC; most closely related to thrombosis)
double aPL positivity (any combination of LAC, ACL Abs or antibeta2 glycoprotein I antibodies) or triple positivity (all three subtypes)
persistently high aPL titres (by the aPL score and Global Anti-Phospholipid Syndrome (GAPSS) Score)
General measures for aPL-positive individuals should include screening for and strict control of cardiovascular risk factors (smoking cessation; management of hypertension, dyslipidaemia and diabetes; and regular physical activity) in all individuals and particularly those with a high-risk aPL profile, screening for and management of venous thrombosis risk factors, and use of LMWH in high-risk situations such as surgery, hospitalisation, prolonged immobilisation and the puerperium.
Patient education and counselling on treatment adherence, INR monitoring in patients treated with VKA, use of perioperative bridging therapy with LMWH for patients on oral anticoagulants, oral contraceptive use, pregnancy and postpartum period, postmenopausal hormone therapy, and lifestyle recommendations (diet, exercise) are important in the management of APS.
Recommendations
Primary thromboprophylaxis in aPL-positive subjects
1. In asymptomatic aPL carriers (not fulfilling any vascular or obstetric APS classification criteria) with a high-risk aPL profile with or without traditional risk factors, prophylactic treatment with LDA (75–100 mg daily) is recommended
2. In patients with SLE and no history of thrombosis or pregnancy complications:
A. With high-risk aPL profile, prophylactic treatment with LDA is recommended
B. With low-risk aPL profile, prophylactic treatment with LDA may be considered
3. In non-pregnant women with a history of obstetric APS only (with or without SLE), prophylactic treatment with LDA after adequate risk/benefit evaluation is recommended
Secondary thromboprophylaxis in APS
4. In patients with definite APS and first venous thrombosis:
A. Treatment with VKA with a target INR 2–3 is recommended
B. Rivaroxaban should not be used in patients with triple aPL positivity due to the high risk of recurrent events. DOACs could be considered in patients not able to achieve a target INR despite good adherence to VKA or those with contraindications to VKA (eg, allergy or intolerance to VKA)
C. In patients with unprovoked first venous thrombosis, anticoagulation should be continued long term
D. In patients with provoked first venous thrombosis, therapy should be continued for a duration recommended for patients without APS according to international guidelines. Longer anticoagulation could be considered in patients with high-risk aPL profile in repeated measurements or other risk factors for recurrence
5. In patients with definite APS and recurrent venous thrombosis despite treatment with VKA with target INR of 2–3:
A. Investigation of, and education on, adherence to VKA treatment, along with frequent INR testing, should be considered
B. If the target INR of 2–3 had been achieved, addition of LDA, increase of INR target to 3–4 or change to LMWH may be considered
6. In patients with definite APS and first arterial thrombosis:
A. Treatment with VKA is recommended over treatment with LDA only
B. Treatment with VKA with INR 2–3 or INR 3–4 is recommended, considering the individual’s risk of bleeding and recurrent thrombosis. Treatment with VKA with INR 2–3 plus LDA may also be considered
C. Rivaroxaban should not be used in patients with triple aPL positivity and arterial events. Based on the current evidence, we do not recommend use of DOACs in patients with definite APS and arterial events due to the high risk of recurrent thrombosis
7. In patients with recurrent arterial thrombosis despite adequate treatment with VKA, after evaluating for other potential causes, an increase of INR target to 3–4, addition of LDA or switch to LMWH can be considered
Obstetric APS
8. In women with a high-risk aPL profile but no history of thrombosis or pregnancy complications (with or without SLE), treatment with LDA (75–100 mg daily) during pregnancy should be considered
9. In women with a history of obstetric APS only (no prior thrombotic events), with or without SLE:
A. With a history of ≥3 recurrent spontaneous miscarriages <10th week of gestation and in those with a history of fetal loss (≥10th week of gestation), combination treatment with LDA and heparin at prophylactic dosage during pregnancy is recommended
B. With a history of delivery <34 weeks of gestation due to eclampsia or severe pre-eclampsia or due to recognised features of placental insufficiency, treatment with LDA or LDA and heparin at prophylactic dosage is recommended considering the individual’s risk profile
C. With clinical ‘non-criteria’ obstetric APS such as a the presence of two recurrent spontaneous miscarriages <10th week of gestation, or delivery ≥34 weeks of gestation due to severe pre-eclampsia or eclampsia, treatment with LDA alone or in combination with heparin might be considered based on the individual’s risk profile
D. With obstetric APS treated with prophylactic dose heparin during pregnancy, continuation of heparin at prophylactic dose for 6 weeks after delivery should be considered to reduce the risk of maternal thrombosis )
10. In women with ‘criteria’ obstetric APS with recurrent pregnancy complications despite combination treatment with LDA and heparin at prophylactic dosage, increasing heparin dose to therapeutic dose or addition of HCQ or low-dose prednisolone in the first trimester may be considered. Use of intravenous immunoglobulin might be considered in highly selected cases
11. In women with a history of thrombotic APS, combination treatment of LDA and heparin at therapeutic dosage during pregnancy is recommended
CAPS
12. A. Prompt treatment of infections by early use of anti-infective medications in all aPL-positive individuals and minimisation of interruptions in anticoagulation or low INR level in patients with thrombotic APS are recommended to prevent the development of CAPS
B. For first-line treatment of patients with CAPS, combination therapy with glucocorticoids, heparin and plasma exchange or intravenous immunoglobulins is recommended over single agents or other combinations of therapies. Additionally, any triggering factor (eg, infections, gangrene or malignancy) should be treated
In patients with refractory CAPS, B cell depletion (eg, rituximab) or complement inhibition (eg, eculizumab) therapies may be considered .