This case highlighted a number of issues in the management of VTE.
1) The investigation of a patient with newly diagnosed DVT
One of the most useful parts in the history taking is the identification of a provoking factor. We know that those with provoked DVT have relatively low risk of recurrence after an initial period of intensive anticoagulation. However frequently patients have ‘soft’ provoking factors or no provoking factors or relapsing-remitting provoking factors e.g. inflammatory bowel disease. Guidance from ISTH can help us decide on whether a provoking factor has occurred.
In those with a clearly provoked VTE e.g. following surgery or hospital admission then investigation into underlying causes may not be needed. A full history and examination should be performed in all patients.
In those with unprovoked VTE the addition of CT abdomen and pelvis was studied in addition to standard of care and in the SOME trial a routine CT scan did not offer any clinical benefit. Patients should have a systematic history and examination in addition to urinalysis, CXR and routine age-appropriate cancer screening. In addition to malignancy features of autoimmune disease should be asked about. Basic laboratory tests should be performed such as FBC, U&E, LFT and bone profile. Further investigations can be performed as guided by history, examination and blood tests. Tests such as autoimmune screening, immunoglobulins, thyroid function, inflammatory markers, ferritin and tumour markers are controversial but can be used on a case-by-case basis.
2) Deciding which anticoagulant to use
Various factors need to be considered and the final approach needs to be individualised to the patient after discussion with them. Factors that may need to be taken into account include:
- Presence of active cancer – LMWH generally better option if undergoing chemotherapy. DOACs are increasingly used in patients with malignancy.
- Need for reversal agent – currently warfarin and dabigatran have reversal agents but anti-Xa reversal agent Andexanet alfa has been approved by FDA for reversal of rivaroxaban and apixaban)
- Preferring oral vs parenteral
- Extremes of body weight – DOACS generally advised against over 120kg
- Ability to absorb – if absorption issues then parenteral anticoagulant or an anticoagulant that can be monitored reliably may be preferred
- Ability to monitor – warfarin and LMWH are easily monitored. DOAC levels can be checked but interpretation is not always straightforward and titration of dose is not generally possible
- Interacting medications
- Preference to take once daily – warfarin, LMWH and rivaroxaban are all once daily
- History or at risk of heavy menstrual bleeding – rivaroxaban has been associated with higher risk in non-randomised comparative studies
- Not wanting to take any injections – rivaroxaban and apixaban do not require any period of LMWH
- Ease of monitoring and facilities to do so (community vs hospital visits etc.)
- Presence of antiphospholipid syndrome – currently warfarin and LWMH are the preferred option here
- Local policies – this may dictate prescribing
- Cost – this may dictate prescribing
- Presence of renal failure – in the presence of severe renal failure warfarin is the best option for treatment of VTE although apixaban has been used for AF in dialysis-dependant patients. All other DOACs have limits and dose reductions depending on the degree of renal failure.
- Presence of liver disease and coagulopathy – LMWH may be the best option here
- Current or potential pregnancy – DOACs and warfarin are contraindicated in pregnancy but generally most are happy to become pregnant whilst on warfarin but to change to LMWH as soon as possible
- History of gastritis and GI bleed – dabigatran has more GI side effects and rivaroxaban has possibly more GI bleeding.
- Presence of coronary artery disease – dabigatran may have more cardiac side effects
Whatever anticoagulant is used patients should be counselled on the risks and benefits and expected side effects. They should be told what medicines to avoid and when next to have blood test monitoring if appropriate. They should be given advice on who to contact if any problems.
3) The use of compression hosiery
Again, another controversial issue with some people advocating its use and others avoiding. Generally use grade 2 stockings 30-40mmHg at ankle and change 3-6 monthly or after 100 washes. Patients should start wearing once the acute swelling has reduced – around two weeks post DVT and may need refitting if swelling reduced. The SOX trial in 2014 enrolled patients with a first DVT and they wore stockings at least three days a week and they were randomised against sham stockings. The incidence of post-thrombotic syndrome was 14.2% in stockings group versus 12.7% in sham stockings group.
However they can be useful to alleviate symptoms.
4) Diagnosis of recurrent DVT
There is no validated risk score and USS and d-dimer are also not validated. If the recurrence is in the contralateral leg then the diagnosis is usually straightforward. USS is operator dependant and some factors can be used to determine new clot vs old such as extent and appearances but this is not easy. In real life the clinical features, d-dimer and ultrasound findings need to be triangulated. A good review on recurrent DVT is here.
When someone has a recurrent thrombosis it is important to think about:
- Are levels required to assess compliance and efficacy?
- Check compliance with patient
- Check correct dose, weight, taking with food (if needed), timings
- Check no medications that may reduce effect
- On other medications e.g. chemotherapy or hormones that may increase hypercoagulability?
- Looking for malignancy
- Looking for pro-thrombotic state e.g. heparin-induced thrombocytopenia (if on heparin), paroxysmal nocturnal haemoglobinuria, myeloproliferative neoplasm and anti-phospholipid syndrome
- Looking for anatomical abnormality e.g. May Thurner
The treatment of recurrent DVT depends on the circumstance and some options are given:
- On warfarin but subtherapeutic? Give LWMH and once improving reintroduce warfarin with more intense monitoring and lower threshold for LMWH if subtherapeutic. Investigate why warfarin subtherapeutic. Could also increase target range to reduce likelihood of being subtherapeutic. A DOAC may be a better option here.
- On warfarin but therapeutic (ensure therapeutic leading up to event)? Give LWMH and once improving reintroduce warfarin with more intense monitoring and lower threshold for LMWH if subtherapeutic. Increase target INR range.
- On full dose DOAC? Give LWMH and once improving start warfarin.
- On half dose DOAC? Give full dose.
- On LWMH? Escalate dose by 20-25%
- If cancer – start LMWH
- If new MPN – use LWMH then warfarin and consider cytoreduction.
- If PNH – consider eculizumab
- If vascular abnormality refer to vascular surgeons
5) Duration of therapy
For provoked DVT generally 3-6 months anticoagulation is sufficient assuming the risk factors have gone. Patients should be counselled about risk in the future and symptoms to look out for. In unprovoked DVT treatment duration is less clear. Male sex, obesity and extent of DVT are all risk factors for recurrence. Consider long term anticoagulation in all unprovoked – reduces risk by 80-90%
- Distal do not need long term
- If don’t want need to way up risks and benefits
- Bleeding risk factors include: ETOH, hypertension, CKD, cirrhosis, previous bleed, over 65s, aspirin too)
- Options include
- Stop and no monitoring
- Stop and d-dimer monitoring e.g. DASH score (or similar)
- Stop and thromboprophylaxis during high risk events
- Extended anticoagulation with reduced dose
- Extended anticoagulation same dose
6) IVC filters
To prevent PE in patients who can’t be anticoagulated. Once inserted should start anticoagulation when no contraindication due to risk of recurrence and filter blocking, however no known benefit for starting anticoagulation for filter alone as patients with filter and anticoagulation still get VTE therefore decision to restart should be made on underlying condition not filter alone. Filter and anticoagulation reduces risk of PE but increases risk of DVT and no difference in overall survival. If anticoagulation fails – intensify first. Free-flowing thrombus is not an indication for filter. Remove filter in two months and definitely less than three months. Consider filter if:
- Pre op and VTE in last month where anticoagulation must be interrupted and surgery can’t be delayed
- Pregnant and contraindication to anticoagulation or within two weeks of delivery
- Chronic thromboembolic pulmonary hypertension pre pulmonary endarterectomy
- Platelets too low for treatment
- Recurrent DCT 20%
- IVC thrombus 10%
- Post thrombotic syndrome 15-40%
- Entrapment of guidewires
7) Cancer-associated VTE
LMWH has the most established use in this scenario having superiority to warfarin (CLOT trial). Edoxaban and rivaroxaban have been studied, however these may be less easier to manipulate during thrombocytopenia, interactions may not be easy to spot and during chemotherapy absorption may be altered and vomiting may occur. In the pilot data with use of rivaroxaban there was more bleeding in the rivaroxaban arm. The risks and benefits of oral agents should be discussed with patients and in those that find LMWH painful and difficult DOACs may be an option.
Our patient was diagnosed with an unprovoked DVT and was started on rivaroxaban. Whilst on treatment he had a recurrence which lead to the diagnosis of pancreatic malignancy. He was started on LMWH but needed urgent surgery (within two weeks of recurrence), so an IVC filter was inserted with instructions to stop LMWH 36 hours pre surgery and restart as soon as bleeding risk reduced (usually after 48-72 hours). At 48 hours prophylactic LWMH was introduced and then escalated to treatment dose BD until he was established on once a day. Once there was no bleeding and no further intervention planned the filter was removed three weeks later. He had a total of six months anticoagulation with LMWH and during repeat imaging he was declared cancer free. He had a monitoring scan two years later and remained cancer-free and off anticoagulation with no VTE recurrence. He was educated on the signs and symptoms to look out for and advised to be on prophylactic LMWH during times of risk.
Management of VTE is not straightforward. There are a number of debated issues:
- Treatment of isolated distal DVT
- Biomarkers for DVT diagnosis
- Treatment of recurrent DVT
- Investigations of the newly diagnosed patient
- Use of compression hosiery
- How long should patients be on treatment
- Risk factors: provoked vs unprovoked
- Incidental VTE
- Role of inherited thrombophilia screening
- Localised thrombolysis
The above issues may need to be discussed with patients and uncertainty acknowledged in order to promote shared decision making.