Pulmonary embolism

Overview 
Theory 
Diagnosis 
Management 
Follow up 
Resources 

Hemodynamically unstable patients require urgent primary reperfusion, anticoagulation, and supportive care.[21]

For patients at intermediate risk of a poor outcome, anticoagulation and ongoing monitoring is required. Reperfusion is generally employed as a rescue therapy if decompensation occurs.

Patients at low risk of a poor outcome can be managed as outpatients, taking into account the patient’s personal circumstances, and as long as all the following criteria are met:[21]

Clinically stable with good cardiopulmonary reserve
No contraindications such as recent bleeding, severe renal or liver disease, or severe thrombocytopenia (i.e., <50,000/mm³)
Expected adherence to treatment
The patient feels well enough to be treated at home.

Patients who are incidentally diagnosed with asymptomatic PE should receive the same initial and long-term anticoagulation as those with comparable symptomatic PE.[21]

Classification of severity

Several classification systems have been employed to describe the severity of PE, and short-term mortality may be assessed by clinical prediction tools such as the Pulmonary Embolism Severity Index (PESI) or simplified PESI scores.[155]

The term "submassive" has been applied to PE with significant anatomic extent, but with normotension, and massive describes anatomically extensive PE complicated by shock or hypotension.

The European Society of Cardiology categorizes PE as:

High risk when presenting with hemodynamic instability (shock or hypotension)
Intermediate-high risk when presenting without hemodynamic instability but with evidence of right ventricular (RV) dysfunction on imaging, abnormal cardiac biomarkers and clinical parameters of severity (such as a high PESI score)
Intermediate-low risk when presenting without hemodynamic instability, with either evidence of RV dysfunction on imaging or elevated cardiac biomarkers (but not both) and clinical parameters of severity (such as a high PESI score)
Low risk when none of these factors are present.

Suspected PE with shock or hypotension

High-risk patients (presenting with shock or hypotension [i.e., systolic BP <90 mmHg]) require aggressive treatment with primary reperfusion, anticoagulation, and supportive therapy.

Supportive therapies and empiric anticoagulation (unless contraindicated) should be instituted without delay.[21] Unfractionated heparin (UFH) may be preferred in this population; most clinical studies of interventional therapies have used heparin as the anticoagulant component of the regimen.[4]

Supportive therapies

Local resuscitation protocols should be followed.

Respiratory support

Supplemental high-concentration oxygen should be administered, targeting oxygen saturations of 94% to 98% (or 88% to 92% in patients at risk of hypercapnic respiratory failure).[156]
Intubation and mechanical ventilation may be necessary for patients with severe hypoxemia/respiratory failure. Mechanical ventilation can lead to hypotension, so BP should be monitored closely.
Tracheal intubation: animated demonstration
How to insert a tracheal tube in an adult using a laryngoscope.
Bag-valve-mask ventilation: animated demonstration
How to use bag-valve-mask apparatus to deliver ventilatory support to adults. Video demonstrates the two-person technique.

Intravenous fluids

If systolic BP is <90 mmHg, intravenous fluids should be given. Acute right ventricular failure with resulting low systemic output is the leading cause of death in patients with PE.[4]
Studies indicate that aggressive volume expansion is of no benefit, and may even worsen right ventricular function by causing mechanical overstretch, or by reflex mechanisms that depress contractility. However, modest fluid challenge (i.e., 500 mL crystalloid) may be of benefit in patients with PE, a low cardiac index, and normal BP.[160]

Vasoactive agents

If systolic BP is <90 mmHg, vasopressors may be given in parallel with (or while waiting for) pharmacologic, surgical, or interventional reperfusion treatment.[4]
Norepinephrine may improve right ventricular function and right ventricular coronary perfusion.[4] However, its use should probably be limited to hypotensive patients.[4]
Dobutamine enhances contractility with an increase in stroke volume and cardiac output. However, its systemic vasodilatory effect can lead to hypotension.[4]
Epinephrine combines the beneficial properties of norepinephrine (vasoconstriction with increased right ventricular perfusion, positive inotropy) and dobutamine (positive inotropy), but without the vasodilatory effects associated with the latter.[161]

Initiation-phase anticoagulation (5-21 days)

Patients who present with suspected PE should receive an anticoagulant dosed according to the initiation phase of therapy (the initial period following PE diagnosis, lasting 5-21 days depending on the drug selected), unless contraindicated.[4][21][162] If PE is subsequently excluded, anticoagulation can be discontinued. In patients with confirmed PE, anticoagulation should be adjusted to the treatment-phase dose after completion of the initiation phase and should continue for at least 3 months.[4][21][95]

Parenteral anticoagulation

Initiation-phase parenteral anticoagulation should be started in patients with high or intermediate clinical (pre-test) PE probability while awaiting results of diagnostic imaging. If a parenteral anticoagulant (UFH, low molecular weight heparin [LMWH], or fondaparinux) is prescribed, it should overlap with the initiation of a vitamin K antagonist (VKA). Parenteral anticoagulation with UFH for a minimum of 5 days is reserved for patients with high-risk PE in whom primary reperfusion (i.e., systemic thrombolytic therapy or embolectomy) is considered.[4][21]

In patients with intermediate-high or intermediate-low risk PE, LMWH or fondaparinux are the preferred parenteral anticoagulants in the initiation phase due to lower rates of major bleeding and heparin-induced thrombocytopenia.

Parenteral anticoagulation can be stopped once a therapeutic international normalized ratio (INR) of 2.0 to 3.0 has been established and at least 5 days overlap with VKA has elapsed.[4][95] UFH has a short half-life, is easy to monitor, and is readily reversed by protamine.[4]

Direct oral anticoagulants (DOACs)

Two of the direct-acting oral anticoagulants, rivaroxaban and apixaban, may be prescribed without the need for pretreatment with a parenteral anticoagulant. However, both dabigatran and edoxaban require lead-in therapy with a parenteral anticoagulant for 5-10 days.[21]

One meta-analysis found that direct oral anticoagulants have similar efficacy to a heparin/VKA regimen, but with reduced risk of major bleeding (relative risk 0.61, 95% CI 0.21 to 0.68).[95][163] Similarly, a network analysis reported few statistically significant differences between a LMWH/VKA combination and other anticoagulant treatment strategies (for venous thromboembolism [VTE]); however, UFH/VKA may be the least effective strategy, and apixaban initiation may be associated with lowest risk of bleeding.[164]

DOACs do not require drug-level or hemostatic monitoring, have a rapid onset of action, and are short-acting. They do not interact with food, but they can interact with other pharmacotherapeutic agents and require serum creatinine monitoring. Dabigatran can be reversed with idarucizumab. Andexanet alfa is approved by the Food and Drug Administration and the European Medicines Agency for the reversal of apixaban- and rivaroxaban-mediated anticoagulation in patients with life-threatening or uncontrolled bleeding. At present there is no approved reversal agent for edoxaban.

There are limited or no data supporting the use of DOACs in conjunction with thrombolytic therapy during the initiation phase. After the patient has been stabilized, clinicians should adopt a shared decision-making process for selecting treatment phase anticoagulation in this patient population, considering both limitations in evidence and pragmatics of care.

Specific patient populations

A VKA is recommended for patients with severe renal impairment (creatinine clearance <30 mL/minute).[21] Apixaban is also suitable for use in patients with severe renal dysfunction or end-stage renal disease, though evidence for use in this patient population is limited.[165]

The American College of Chest Physicians (ACCP) recommends apixaban, edoxaban, or rivaroxaban over LMWH for the initiation phase in patients with active cancer (cancer-associated thrombosis).[21] DOACs (particularly edoxaban and rivaxobaran) are associated with a higher risk of gastrointestinal bleeding than LMWH. In patients with luminal gastrointestinal cancer, the ACCP recommends apixaban or LMWH as preferred agents.[21] [ ] The American Society of Hematology (ASH) recommends rivaroxaban, apixaban, or LMWH for initiation-phase anticoagulation in patients with active cancer; ASH acknowledges that this recommendation is conditional based on very low-certainty evidence.[166]

LMWH is preferred in patients with severe hepatic impairment and coagulopathy.[4]

Health professionals should refer to the label and/or local formularies before prescribing a DOAC for a patient with renal or hepatic impairment.

Fondaparinux carries a low risk of inducing heparin-induced thrombocytopenia (HIT) and appears to be effective for patients with suspected or confirmed HIT.[4][167] It is contraindicated in patients with severe renal impairment.[4]

Pregnancy

LMWH is recommended for women who are pregnant (weight-adjusted dose) or who may be pregnant.[4][168] It does not cross the placenta, and routine monitoring is not generally required.[4][169][170] Other anticoagulants, including VKAs, may cross the placenta with attendant risk of fetal adverse effects.[4][21] DOACs are contraindicated in pregnancy.[4][171]

Clinical surveillance is recommended over anticoagulation in patients with subsegmental PE (i.e., no involvement of more proximal pulmonary arteries) who do not have proximal deep venous thrombosis (DVT) in the legs, and who are at low risk for recurrent VTE. Clinical surveillance involves informing patients about the clinical signs and symptoms of progressive thrombosis to watch for and the need to be reassessed if these are present.[21]

Primary reperfusion in patients with shock or hypotension

Systemic thrombolytic therapy (preferably with alteplase or reteplase; tenecteplase is an alternative) is recommended in patients with hemodynamic compromise (shock, systolic BP <90 mmHg, or vasopressor requirement to maintain systolic BP >90 mmHg), as this patient group has a high mortality rate.[4][21][95][172][173][174][175][176] The ACCP recommends systemic thrombolytic therapy (unless contraindicated) using a peripheral vein for patients with acute PE associated with hypotension who do not have a high bleeding risk. The ACCP does not make specific recommendations on preferred agents due to lack of comparative data.[21]

Systemic thrombolytic therapy is associated with lower all-cause mortality than anticoagulation alone in patients with high-risk (massive) PE (acute PE with sustained hypotension [i.e., systolic BP <90 mmHg for at least 15 minutes]).[4][172][173][177]

Ideally, PE should be confirmed by imaging before thrombolytic therapy is administered.[95] However, if the patient is at risk of imminent cardiac arrest, treatment may be commenced on clinical grounds alone.[96]

Systemic thrombolytic therapy induces prompt clot dissolution and improves right ventricular function, pulmonary blood flow, and lung perfusion.[4][177] Thrombolysis plus heparin was associated with significantly reduced 30-day mortality compared with heparin alone (2.3% [24/1033] vs. 3.9% [40/1024], respectively; pooled odds ratio [OR] 0.59, 95% CI 0.36 to 0.96, P=0.03) in a meta-analysis of patients with acute PE.[177] Thrombolysis is, however, associated with a significantly increased risk of major and minor bleeding, including hemorrhagic stroke.[172][173][177] More patients receiving thrombolytic therapy plus heparin experienced a major bleeding episode compared with those taking an anticoagulant alone (9.9% [96/974] vs. 3.6% [35/961], respectively; OR 2.91, 95% CI 1.95 to 4.36).[177] The reported incidence of intracranial or fatal hemorrhage was 1.7% in the thrombolysis group and 0.3% in the anticoagulant group.[177]

Absolute contraindications to thrombolysis include: hemorrhagic stroke or stroke of unknown origin at any time; ischemic stroke in the preceding 6 months; central nervous system damage or neoplasms; recent major trauma/surgery/head injury (in the preceding 3 weeks); gastrointestinal bleeding within the last month; known bleeding risk.[4][178]

Relative contraindications to thrombolysis include: transient ischemic attack in the preceding 6 months; oral anticoagulant therapy; pregnancy, or within 1 week postpartum; traumatic resuscitation (in relation to this episode of PE); refractory hypertension (systolic BP >180 mmHg); advanced liver disease; infective endocarditis; active peptic ulcer.[4][178]

Thrombolytic therapy is not typically recommended for hemodynamically stable patients with acute PE.[4][21] In a randomized double-blind trial, primary reperfusion thrombolytic therapy plus heparin in normotensive patients with intermediate-risk PE (acute right ventricular dysfunction and myocardial injury without overt hemodynamic compromise) prevented hemodynamic decompensation compared with heparin alone, but increased the risk of major hemorrhage and stroke.[175]

Surgical embolectomy or catheter-directed therapy

Systemic thrombolytic therapy increases bleeding risk, including that of intracranial bleeding.[21][177] Surgical pulmonary embolectomy and catheter-directed therapy (which typically involves a combination of mechanical and pharmacotherapeutic thrombus fragmentation) likely have lower attendant bleeding risk than systemic therapy.[21][179][180][181]

Surgical pulmonary embolectomy is recommended for patients in whom systemic thrombolytic therapy has failed or is absolutely contraindicated.[4][181] Mortality rates following pulmonary embolectomy range from 4% to 27%.[182] In a small cohort of patients who underwent surgical pulmonary embolectomy for acute massive pulmonary thromboembolism, the 10-year survival rate was 84%.[183]

Catheter-directed therapy, which typically involves a combination of mechanical and pharmacotherapeutic thrombus fragmentation, may be considered for patients with acute PE associated with hypotension who also have a high bleeding risk, failed systemic thrombolysis, or shock that is likely to cause death before systemic thrombolysis can take effect (e.g., within hours), if appropriate expertise and resources are available.[21] Catheter-directed therapy uses a lower dose of thrombolytic drug (approximately one third of full-dose systemic thrombolytic therapy) and is believed to reduce the risks of bleeding at remote sites (e.g., intracranially or gastrointestinally).[21] A meta-analysis of nonrandomized trials of catheter-directed therapies reported a clinical success rate of 87% with an associated risk of major and minor complications of 2% and 8%, respectively.[184] Evidence is limited by small studies, study design (i.e., nonrandomized), and use of intermediate efficacy end points.[185]

Inferior vena cava filters

An inferior vena cava (IVC) filter can be placed in patients:[4][21][180]

With acute PE and an absolute contraindication to anticoagulant therapy, such as active major bleeding
With confirmed recurrent PE despite adequate anticoagulation.

ACCP guidelines recommend using an IVC filter only for patients with acute PE (e.g., diagnosed in the preceding 1 month) and an absolute contraindication to anticoagulant therapy (e.g., active major bleeding, severe thrombocytopenia, high bleeding risk, central nervous system lesion). The ACCP recommends against the use of IVC filters in addition to anticoagulation in patients with acute PE.[21] Other guidelines consider relative indications for IVC filter use to include massive PE with residual deep venous thrombus in a patient at risk for further PE, free-floating iliofemoral or IVC thrombus, and severe cardiopulmonary disease and DVT (e.g., cor pulmonale with pulmonary hypertension).[186]

Some centers insert IVC filters intraoperatively or immediately postoperatively in patients who undergo surgical pulmonary embolectomy.[187][188][189]

IVC filter placement should take place as early as possible if it is the only treatment that can be initiated. There is little evidence available to suggest the ideal time for placement. However, the highest risk of dying is within the first 2 hours of presentation, which might indicate that this is a reasonable timeframe for filter placement.[190] Observational studies suggest that insertion of a venous filter might reduce PE-related mortality rates in the acute phase but with an associated increase in the risk of filter-related VTE.[191][192]

Complications associated with permanent IVC filters are common, although they are rarely fatal.[192] Early complications (including insertion-site thrombosis) occur in approximately 10% of patients. Late complications are more frequent and include recurrent DVT (approximately 20% of patients) and post-thrombotic syndrome (up to 40% of patients).[193][194] Occlusion of the IVC affects approximately 22% of patients at 5 years and 33% at 9 years, regardless of the use and duration of anticoagulation.[194]

Post-filter anticoagulation should be considered on a case-by-case basis according to relative and absolute contraindications.[195] Anticoagulation should be initiated if the contraindication resolves or if a risk/benefit analysis suggests this to be a reasonable course.[21] When retrievable filters are used, they should be removed as soon as it is safe to use anticoagulants.[4]

Prognostic stratification of patients with confirmed PE without shock or hypotension: Pulmonary Embolism Severity Index

Patients with confirmed PE without shock or hypotension require further risk stratification, for example with the Pulmonary Embolism Severity Index (PESI) or the simplified Pulmonary Embolism Severity Index (sPESI).[4][95]

PESI classifies patients with confirmed PE without shock or hypotension into 1 of 5 risk categories associated with increasing 30-day mortality. PESI risk category is derived from the sum of points for 11 clinical criteria; sPESI has only 6 criteria, and reports risk stratification dichotomously (low [0 points] or high [≥1 point(s)] risk of 30-day mortality).

Studies indicate that PESI and sPESI predict short-term mortality with comparable accuracy, but the latter is easier to use.[196][197] One meta-analysis that evaluated the prognostic utility of PESI/sPESI for all-cause mortality reported pooled sensitivity and pooled specificity of 91% and 41%, respectively.[197]

PESI has been used to identify patients eligible for outpatient management in prospective studies.[198][199] Based upon social background and likely compliance with treatment, European Society of Cardiology guidelines suggest that low-risk patients (PESI class I or class II), and potentially those with a sPESI score of 0, can be considered for early discharge and outpatient management.[4][199]

[Figure caption and citation for the preceding image starts]: PESI criteria and risk stratificationCreated by BMJ Knowledge Centre [Citation ends]. com.bmj.content.model.Caption@4bf0a058 [Figure caption and citation for the preceding image starts]: sPESI criteria and risk stratificationCreated by BMJ Knowledge Centre [Citation ends].

Rescue thrombolysis

Right ventricular function assessed by echocardiography and cardiac troponin testing should be considered in patients with PESI risk stratification ≥III or sPESI ≥1.[4][21] In patients with confirmed PE without shock or hypotension: right ventricular dysfunction is predictive of adverse outcome and enables further risk stratification; elevated troponin levels are associated with increased risk for short-term mortality, PE-related mortality, and serious adverse events.[130][131][132][200][201]

Intermediate high-risk patients

Patients with PESI risk stratification ≥III, or sPESI ≥1, with right ventricular dysfunction and a positive cardiac troponin test belong to an intermediate high-risk group.[4] Rescue thrombolysis may be indicated in intermediate high-risk patients, and in patients with other clinical features of cardiopulmonary impairment (e.g., elevated heart rate, respiratory rate, jugular venous pressure) who have started anticoagulant therapy, and:[4][21][180]

Are deteriorating (as seen by a decrease in systolic BP, increase in heart rate, worsening gas exchange, signs of inadequate perfusion, worsening RV function, or increasing cardiac biomarkers), but have not yet developed hypotension[21]
Are exhibiting signs of hemodynamic decompensation (e.g., systolic BP <90 mmHg for at least 15 minutes, or drop of systolic BP by at least 40 mmHg for at least 15 minutes with signs of end organ hypoperfusion).

Consideration of bleeding risk will inform choice of thrombolytic therapy.

Intermediate low-risk patients

Normotensive patients with PESI risk stratification ≥III, or sPESI ≥1, with normal echocardiogram and/or cardiac troponin test are considered to be intermediate low-risk.[4] Intermediate low-risk patients should be monitored if the cardiac troponin test is positive (even in the absence of right ventricular dysfunction); anticoagulant therapy should be maintained in all intermediate-low risk patients.[4]

Other prognostic indices

The RIETE (Registro Informatizado de la Enfermedad TromboEmbolica venosa) and HESTIA criteria may be helpful in selecting patients (with VTE at low risk of adverse clinical outcome) who could be managed as outpatients.[202][203][204]

Treatment-phase anticoagulant therapy

ACCP guidelines recommend that patients who do not have a contraindication are given a 3-month treatment phase of anticoagulation. Apixaban, dabigatran, edoxaban, or rivaroxaban are recommended over a VKA.[21]

Once the treatment phase is complete, all patients should be evaluated for extended-phase therapy.[21]

Extended-phase anticoagulant therapy

The goal for continuation of anticoagulant therapy into the extended phase (i.e., beyond the first 3 months and with no scheduled stop date) is secondary prevention of VTE.

ACCP guidelines recommend that the following patients are given extended-phase anticoagulation:[21]

Those with PE diagnosed in the absence of transient provocation (unprovoked PE or PE provoked by a persistent risk factor). These patients should be given a DOAC
Those with PE diagnosed in the absence of transient risk factor (unprovoked PE or PE provoked by a persistent risk factor) who cannot receive a DOAC. These patients should be given a VKA.

Extended-phase anticoagulation is not recommended in patients with PE diagnosed in the context of a major or a minor transient risk factor.[21]

The decision to start or continue extended therapy should be based on patient preference and the predicted risk of recurrent VTE or bleeding.[21]

Precise prediction of the risk for recurrent VTE after an initial event is challenging. The presence or absence of temporary provoking factors is the most potent predictor for recurrence. Patients with a major transient provocation (e.g., surgery) within the 3 months prior to the VTE event have the lowest risk for recurrence. Minor transient risk factors (e.g., medical hospitalization, estrogen use, long-haul travel) within 2 months of the diagnosis predict an intermediate risk for recurrence. Patients with no identifiable risk factor for VTE (i.e., unprovoked VTE) or a persisting provocation (e.g., cancer) are at high risk for recurrence.[20] Patients with recurrent unprovoked PE and proximal DVT are thought to be at an especially high risk for further recurrence.[174]

When assessing bleeding risk, the following factors should be considered: age >65 years (particularly >75 years), previous bleeding, cancer, renal failure, liver failure, thrombocytopenia, previous stroke, diabetes mellitus, anemia, antiplatelet therapy, poor anticoagulant control, comorbidity with reduced functional capacity, recent surgery, frequent falls, alcohol abuse, use of nonsteroidal anti-inflammatory drugs.[4] Patients with none of these risk factors are considered low risk; one risk factor renders a patient moderate risk; and two or more risk factors renders a patient high risk.

Several risk prediction models have attempted to identify patients with unprovoked and/or minor transient provocation who have a low risk of recurrent VTE. Of these, the HER-DOO2 model has been evaluated in a number of prospective clinical validation studies and has been used to identify a subpopulation of patients with a low risk of recurrence after stopping anticoagulation therapy (following completion of the treatment phase).[205]

Choice of agent

In patients who receive extended-phase anticoagulation therapy, there is usually no need to change the initial oral anticoagulant. ACCP guidelines recommend using reduced-dose apixaban or rivaroxaban for patients receiving apixaban or rivaroxaban; the choice of a particular drug and dose should take into account the patient’s body mass index, renal function, and expected adherence to the dosing regimen.[21]

Lower doses of both apixaban and rivaroxaban are similarly effective for extended-phase anticoagulant therapy, and are associated with a modest reduction in non-major bleeding compared with treatment doses.[21][206][207]

Evidence from studies of ≥6 months' duration suggests that there are no differences between direct oral anticoagulants and conventional anticoagulation for the management of PE.[208][209] [ ] [Evidence B]

The continued use of extended-phase anticoagulation should be reassessed at least annually, and at any time there is a significant change in the patient’s clinical status.[21] The evidence to continue extended therapy beyond 4 years is uncertain. ACCP guidelines recommend shared decision-making, taking into account the patient values and preferences.[21] Patients should be periodically reassessed for bleeding risk, burdens of therapy, and any change in values and preferences.

If the decision is to stop extended-phase anticoagulation, ACCP guidelines recommend giving aspirin (unless contraindicated) to prevent recurrent VTE.[21] The benefits of using aspirin should be balanced against risk of bleeding and inconvenience of use. Aspirin should not be considered a reasonable alternative for patients who are willing to undergo extended anticoagulation therapy, as aspirin is much less effective. The use of aspirin should always be reassessed when a patient stops anticoagulant therapy (because aspirin might have been stopped when anticoagulant therapy was started).[21]

Active cancer

For patients with active cancer, ACCP guidelines recommend apixaban, edoxaban, or rivaroxaban over LMWH for extended-phase anticoagulation.[21] DOACs (particularly edoxaban and rivaxobaran) are associated with a higher risk of gastrointestinal bleeding than LMWH. In patients with luminal gastrointestinal cancer, the ACCP recommends apixaban or LMWH as preferred agents.[21] [ ] ASH recommends using DOACs or LMWH for the extended phase; ASH acknowledges that this recommendation is conditional based on very low-certainty evidence.[166]

Extended-phase anticoagulant therapy is recommended in these patients (i.e., no scheduled stop date) while cancer remains active.[4][21][166]

Pregnancy

Anticoagulant therapy should be administered for at least 6 weeks postpartum in women at high risk for postpartum VTE, and for a minimum overall treatment duration of 3 months from initial PE diagnosis.[4][169] LMWH is used during the antepartum as other anticoagulants, including VKAs, may cross the placenta with attendant risk of fetal adverse effects.[4][21]

Continued LMWH or VKAs are an option for breast-feeding mothers. DOACs are not recommended for breast-feeding mothers because they are excreted in breast milk, and safety to the nursing baby has not been established.[4]

Severe renal impairment

The ACCP recommends a VKA for patients with severe renal impairment (i.e., creatinine clearance <30 mL/minute).[21] Apixaban is also suitable for use in patients with severe renal dysfunction or end-stage renal disease, though evidence for use in this patient population is limited.[165]

Hepatic impairment and coagulopathy

ACCP guidelines recommend LMWH in this patient population.[21] Health professionals should refer to the label and/or local formularies before prescribing a direct oral anticoagulant for a patient with hepatic impairment.

Antiphospholipid syndrome

In patients with antiphospholipid syndrome, the ACCP and the International Society on Thrombosis and Haemostasis guidelines recommend a VKA as the preferred agent.[21][210]

Evidence from randomized controlled trials suggests that DOACs may not be as effective as VKAs for the treatment of thrombosis among patients with antiphospholipid syndrome. Therefore, ACCP guidelines recommend avoiding DOACs in these patients.[21]

Patients with recurrent VTE on anticoagulant therapy

Recurrent VTE is unusual among patients receiving therapeutic-dose anticoagulant therapy, with the exception of cancer (7% to 9% on-therapy recurrence with LMWH).[4][21][211] In addition to definitively establishing the presence of recurrent PE, consideration should be given to compliance with anticoagulant therapy or the presence of underlying malignancy.[21]

ACCP guidelines recommend a temporary switch to LMWH (for at least 1 month) for patients with recurrent PE who are thought to be compliant with a non-LMWH anticoagulant (or within the therapeutic range if receiving VKA therapy).[21] An increased dose of LMWH (one quarter to one third) is appropriate for patients with recurrent PE who have been receiving LMWH.[21]

Recurrent VTE following discontinuation of anticoagulant therapy

For patients who are no longer receiving anticoagulant therapy and experience a second PE with no identifiable risk factor (i.e., unprovoked), guidelines recommend the following anticoagulant treatment durations:[4][21]

Low or moderate bleeding risk: extended anticoagulant therapy with periodic reassessment to review risk-benefit ratio
High bleeding risk: stop anticoagulation after 3 months.

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