Venous thromboembolism

Case scenario

Margaret, a 67-year-old patient, is diagnosed with a pulmonary embolism (PE) after experiencing shortness of breath and chest heaviness. She has a history of heart disease, diabetes, osteoarthritis and systemic lupus erythematosus. She underwent knee replacement surgery 3 weeks ago. Her Wells score was 6 (moderate risk) and a CT pulmonary angiogram revealed a proximal PE. After confirming her renal function (creatinine clearance ~ 42 mL/min) and reviewing her blood results, her doctor prescribed apixaban 10 mg twice daily for 7 days then 5 mg twice daily.

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Introduction

Venous thromboembolism (VTE) is defined as a blood clot that starts in a vein. The term captures a broad spectrum of thromboembolic conditions including deep vein thrombosis (DVT) as well as its complication, pulmonary embolism (PE).¹ Diagnosis of VTE may be difficult but is assisted through careful clinical examination, use of validated prediction tools and diagnostic imaging.¹ Anticoagulation is the mainstay of treatment for active VTEs. Direct-acting anticoagulants (DOACs), apixaban or rivaroxaban, are the preferred therapeutic approaches for most adults with VTE.¹ Appropriate dosage, ongoing adherence and consideration of bleeding risk are important for the effective use of DOACs in this setting.¹ In the absence of data, or where safety concerns exist, certain clinical situations warrant anticoagulation using low molecular weight heparin (LMWH) or warfarin. Pharmacists have a critical role in the appropriate choice of therapy, dosing, adherence and ongoing monitoring of patients prescribed anticoagulation for the management of VTE.

Epidemiology

VTE is one of the leading causes of preventable death in Australia, accounting for almost 10% of all hospital deaths.² It is also associated with long-term complications such as recurrent thrombotic events, ongoing leg pain and swelling after DVT (post-phlebitic syndrome), as well as chronic pulmonary hypertension.³ Approximately 60% of patients with symptomatic VTE manifest as DVT alone, whereas approximately one-third manifest as PE.⁴ If left untreated, there is a 50% chance that patients with symptomatic proximal DVT will go on to develop symptomatic PE within 3 months.⁵ 

Aetiology and risk factors

Vascular injury, venous stasis or hypercoagulability increase risk of VTE.¹ Hospitalisation is strongly associated with VTE.⁶ Age, sex, ethnicity and presence of comorbidities are also contributing risk factors for VTE.⁷ See Table 1.

Clinical features and diagnosis

DVT is characterised by unilateral calf or thigh pain, tenderness, leg swelling or redness.³ Symptoms of a PE include chest pain, fatigue, shortness of breath, dry cough, tachycardia and, in extreme cases, loss of consciousness.⁸ At the other extreme, patients with PE involving only segmental or subsegmental pulmonary arteries may have minimal or no symptoms.³

Patients with suspected VTE should undergo a careful clinical examination, as accurate diagnosis can be difficult.¹ Diagnosis involves considering the signs and symptoms, risk factors for diagnosis, differential diagnoses and the need for diagnostic imaging studies. There are several clinical prediction tools that may assist the diagnostic process. The Wells criteria for DVT, Wells criteria for PE, and the revised Geneva score for PE are the most widely validated prediction tools in most situations (Geneva score only validated for outpatient population).^8–10 They are used to classify the likelihood of DVT and PE based on a patient’s symptoms and history.^8,9

An initial D-dimer blood test is useful in patients with low risk for VTE (pre-test probability). It is relatively inexpensive, results are returned quickly, and if negative, PE can be ruled out with no further testing required.⁹ If it is positive, further investigation is indicated noting that several scenarios can raise D-dimer levels (e.g. surgery and pregnancy).¹⁰

Imaging techniques such as computed tomography pulmonary angiography (CTPA) or ventilation perfusion isotope (V/Q) lung scan are used to investigate PE.¹ CTPA is the preferred diagnostic imaging test for PE when there is a preference to limiting radiation exposure.⁹

Prophylaxis

VTE prophylaxis is achievable via either pharmacological or mechanical strategies. Pharmacological prophylaxis is more effective than mechanical prophylaxis and is the preferred approach in most at-risk patients.¹ Mechanical prophylaxis includes intermittent compression devices such as pneumatic venous pumps or graduated compression stockings.

All hospitalised patients should be assessed for their VTE risk and offered prophylaxis where appropriate.¹⁰

Overall, younger patients with no VTE risk factors may not require prophylaxis.¹² Moderate-risk patients (at least one risk factor for VTE) should be prescribed pharmacological prophylaxis, with or without mechanical prophylaxis.¹¹ High-risk patients (multiple risk factors for VTE) often require pharmacological and mechanical prophylaxis in combination.¹²

LMWH or fondaparinux is preferred over unfractionated heparin or a DOAC.¹² Monitoring of platelet counts should be undertaken to detect heparin-induced thrombocytopenia.

Some patients may have contraindications to pharmacological VTE prophylaxis. These include active or recent bleeding, a planned surgery in the next 6–12 hours, bleeding disorders or thrombocytopenia.¹¹

Travel and VTE

Long-distance travel is a well- recognised but weak risk factor for VTE, with risk increasing with increasing duration of travel.¹³

Generally, VTE may be attributable to travel if it occurs within 8 weeks of the journey. The incidence of symptomatic DVT in travellers with low VTE risk after 8 hours of travel is approximately 0.5%.¹⁴ The incidence of PE in all travellers is very low; approximately 1 in 2 million.¹³

A case-control study including participants who air travelled for more than 4 hours revealed a slightly lower VTE risk in passengers who were seated in business class compared to economy. People in window seats had double the risk of those in aisle seats.¹⁴

During a flight, travellers can be advised to maintain good hydration, minimise alcohol intake, undertake calf muscle exercises and regularly walk around. Wearing graduated compression stockings during a flight has been shown (in flights longer than 5 hours) to reduce DVT risk in a Cochrane review of 12 randomised trials.^15,16

Pharmacists can play an important role in educating patients on the appropriate use of compression stockings, particularly for travellers with risk factors for VTE.

Antiplatelets do not offer effective pharmacological prophylaxis against flight-related VTE in high-risk patients, and significantly increase the risk of bleeding.¹⁷ LMWHs should not be universally used for the prevention of travel-related VTE. They should be reserved for high-risk passengers undertaking a long-haul flight after careful consideration of the benefits and risks of treatment.¹⁸ If clinically appropriate, enoxaparin can be used subcutaneously at a dosage of 1 mg/kg administered 2–4 hours before departure to reduce VTE risk on a long-haul flight.¹⁷

Treatment of active VTE

The initial phase of treatment aims to prevent growth or embolism (travelling from primary site to a different location) of the thrombus. Anticoagulant therapy is recommended for the treatment of VTE, in most cases.¹⁹ See Table 2 and Table 3. The objectives of treatment are to prevent death and disability associated with PE (including pulmonary hypertension), prevent recurrence of VTE, and minimise risk of long-term adverse events. ²⁰

Before starting anticoagulant therapy, the following biochemistry measures should be reviewed: full blood count, activated partial thromboplastin time (APTT), international normalised ratio (INR), and kidney and liver function. ¹ Pregnancy should be ruled out in women of childbearing age.¹

Anticoagulant therapy is strongly recommended for upper-limb and lower-limb proximal DVT and PE.^1,19 Less evidence exists for anticoagulant use in isolated distal lower-limb DVT.¹⁹

In the 1970s and 1980s, unfractionated heparin followed by warfarin (a vitamin K antagonist) was the standard approach for treating VTEs. ²⁰ The approach to treatment has evolved significantly since then due to the introduction of DOACs.²¹

While having similar effectiveness, DOACs are preferred over warfarin for
the treatment of VTE in most cases.¹ No requirement for routine monitoring, no known food interactions and few drug interactions have made DOACs the agents of choice over warfarin.²²

Furthermore, apixaban or rivaroxaban are preferred over dabigatran or warfarin for the treatment of VTE as they do not require parenteral therapy at initiation.²²

When are DOACs not preferred?

There are several situations in which DOACs may not be recommended first-line for the treatment of VTE:

• Pregnancy and breastfeeding – LMWH is preferred, as safety data is lacking for DOACs, and warfarin may cause fetal harm.^1,19
• Cancer – LMWH is recommended for the management of VTE in people with active cancer.¹⁹ DOACs may be used in this setting; however, in people with a history of gastrointestinal or genitourinary malignancies, greater consideration is required, as increased bleeding rate has been demonstrated in these groups.²⁵
• Antiphospholipid syndrome – The weight of the evidence still supports the use of warfarin as the preferred modality of VTE management in these patients.²⁶
• Obesity – DOACs are not recommended in patients with a BMI >40 or weight >120 kg due to lack of data and the potential of a significant underdose.²⁷ 

Duration of treatment

After completion of the treatment and maintenance phases, a decision must be made on whether anticoagulation is continued for ongoing prevention. If the decision to cease anticoagulation is made, an ultrasound with documentation of residual thrombi should be undertaken.²⁸

Several factors influence the duration of anticoagulant treatment, including the location of the thrombus, the presence of provoking factors, and the risk factors for recurrence. An unprovoked VTE is defined as one not associated with a major provoking factor in the 3 months prior to diagnosis (e.g. surgery).¹

Most proximal DVTs or PEs are treated with therapeutic anticoagulation for 3–6 months. ²² Distal DVTs caused by a transient provoking factor (e.g. estrogen-containing therapy), no longer present, are generally treated with anticoagulation for 6 weeks.¹

Extended therapeutic anticoagulation is considered for patients with recurrent unprovoked VTEs, or recurrent and provoked by active cancer or antiphospholipid syndrome.²²

Bleeding risk

The largest predictor of bleeding associated with an anticoagulant is active or recent bleeding.²⁹ Patients with a history of bleeding, gastric lesions (e.g. ulcers), recent surgery or severe kidney disease are at higher risk of bleeding when prescribed an anticoagulant.

Bleeding risk should be evaluated regularly, beginning at the time of diagnosis and continuing through the decision-making process for extending anticoagulation beyond 3 months.³⁰ Anticoagulation should be avoided in patients with absolute contraindications such as active intracranial bleeding.³⁰

A meta-analysis showed the incidence of major bleeding associated with DOAC therapy was 1.12 (95% CI: 0.72–1.62) per 100 person-years compared to 1.74 (95%
CI: 1.34–2.20) with warfarin therapy.³¹

A patient’s preferences and concerns should be at the forefront of clinical decision-making related to managing an active VTE or preventing recurrence. Risks should be explained in an easy-to-understand format, and the patient should receive comprehensive education on their anticoagulant therapy, including how to triage acute adverse effects.²⁸

Knowledge to practice

Adherence is critical for the effective treatment of VTE using anticoagulant therapy.³² Pharmacists should support adherence and shared patient decision-making in their day-to-day practice. Pharmacists should review anticoagulant therapy for the appropriate dose and duration, and screen for any drug-drug interactions.³²

Bleeding risk should be assessed throughout a patient’s journey, from the point of diagnosis, through to maintenance management and follow-up.³⁰

Pharmacists can play an important role in the assessment of bleeding risk in patients prescribed anticoagulant therapy.³² 

Conclusion

VTE, including DVT and PE, is a common cardiovascular condition that impacts an estimated 10 million people annually worldwide.³³ Diagnosis may be difficult and involves considering the signs and symptoms, the risk factors for diagnosis, and the results of diagnostic imaging studies. DOACs have revolutionised the way that VTEs are managed, providing more safe and convenient modalities for treatment and prevention.

It remains important to correctly dose, monitor and potentially extend the use of DOACs for the treatment of VTEs, particularly considering a patient’s kidney function. Warfarin and/or parenteral LMWH are still the preferred choices in certain clinical situations, including obesity and pregnancy.

Pharmacists have a critical role to play in supporting the quality use of therapeutic anticoagulation for the management of VTEs, helping to facilitate safe and personalised care for individual patients. 

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Key points

• Venous thromboembolism (VTE), including deep vein thrombosis (DVT) and pulmonary embolism (PE), is common, and can be diagnosed through careful clinical examination, clinical prediction tools and diagnostic imaging.
• Anticoagulant therapy is recommended for the treatment of VTE in most cases, with apixaban or rivaroxaban the preferred agents of choice.
• Low molecular weight heparin (LMWH) or a combination of LMWH and warfarin is preferred for pregnant women, people with active cancer, obesity or severe kidney disease.
• Adherence to therapy and bleeding risk should be monitored regularly throughout the course of treatment to ensure effective management of VTE and prevention of recurrence.

References

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Our author

Natalie Raffoul BPharm (Hons), GradCertPharmMed, MHM is a clinical cardiology pharmacist by background and is currently working as the Senior Manager for Healthcare Programs and Clinical Strategy at the National Heart Foundation of Australia.

Our reviewer

Hana Numan (she/her) BPharm (NZ), PGDipClinPharm (NZ), MPS (NZ)