Urgent reversal of antithrombotic therapy module 1 answer explanations

Released21 October 2021     Expires: 21 October 2023      Programme:

Sponsorship Statement: This module has been sponsored by Alexion Pharmaceuticals UK Ltd.

1. A 65-year-old man who is taking warfarin attends the emergency department with a headache and is found to have a subdural haemorrhage. His INR is 2.5 and GCS is 11. The neurosurgeons are going to take him to theatre for an emergency decompressive craniotomy. What is the most appropriate treatment?

A. Vitamin K alone
B. Vitamin K and four factor prothrombin complex concentrate
C. Vitamin K and fresh frozen plasma
D. Vitamin K and three factor prothrombin complex concentrate
E. Vitamin K and activated charcoal

Answer:

B. Vitamin K and four factor prothrombin complex concentrate

This patient requires urgent reversal so vitamin K and four factor prothrombin complex concentrate is the treatment of choice. Studies suggest improved patient outcomes with PCC compared to FFP.

2. A 74-year-old woman who is taking apixaban for a previous deep vein thrombosis attends the emergency department with abdominal pain and guarding. CT scan of the abdomen shows a large bowel perforation due to a ruptured diverticulum. She requires an urgent laparotomy and the surgeons contact haematology for advice. She last took apixaban 6 hours ago. What is the most appropriate management of her anticoagulation?

A. Administer andexanet alfa
B. Administer four-factor prothrombin complex concentrate
C. Administer idarucizumab
D. Administer two units of platelets
E. Proceed with surgery and monitor for bleeding

Answer:

E. Proceed with surgery and monitor for bleeding

If a patient on an anti-FXa inhibitor requires emergency surgery, surgery should proceed cautiously and PCC administered only if coagulopathic bleeding is encountered. Idarucizumab may be used for patients taking dabigatran prior to surgery. Andexanet alfa is not licensed for this purpose.

3. A 67-year-old man with atrial fibrillation who recently had primary percutaneous coronary intervention for a STEMI is taking aspirin, clopidogrel and rivaroxaban is admitted to a hospital in London with a decreased consciousness and secondary to a spontaneous intracerebral haemorrhage. He last took all three medications 10 hours ago. His INR is 1.5. What is the most appropriate management?

A. Administer andexanet alfa
B. Administer andexanet alfa and two units of platelets
C. Administer four-factor prothrombin complex concentrate
D. Administer two units of platelets and four-factor prothrombin complex concentrate
E. Observe only

Answer:

C. Administer four-factor prothrombin complex concentrate

The INR of 1.5 is suggestive of current therapeutic rivaroxaban levels.

In Scotland, andexanet alfa could be given but it is not funded for intracerebral haemorrhage in England. Administration of PCC is therefore reasonable to try and restore factor Xa activity and thrombin generation that has been abrogated by the rivaroxaban.

Given the results of the PATCH study, platelets are probably best avoided3 (based on the best evidence that we have, although the patients in the PATCH study were not also receiving an anticoagulant).

4. A 73-year-old woman is taking edoxaban for secondary prevention after a DVT five years ago. She is admitted to the emergency department with haematemesis and melaena. Her blood pressure is 105/70, heart rate 95 beats per minute, and her haemoglobin is 115 g/l. She last took 60 mg edoxaban 20 hours ago. What is the most appropriate management?

A. Administer andexanet alfa
B. Administer prothrombin complex concentrate
C. Check INR and if elevated, administer andexanet alfa
D. Check INR and if elevated, administer four-factor prothrombin complex concentrate
E. Observe

Answer:

E. Observe

This patient does not need a reversal agent as she is not experiencing major bleeding at the moment. She also took the edoxaban 20 hours ago so one would expect its effect to be wearing off. To illustrate this point. In the ANNEXA-4 trial for andexanet alfa, patients were excluded if they were more than 18 hours post-dose and even then 25% of patients had subtherapeutic drug levels.18 If reversal is required for edoxaban, 4F-PCC is the drug of choice although some clinicians may choose to use andexanet alfa but it is not licensed for this purpose.

5. A 33-year-old woman taking therapeutic low molecular weight heparin for DVT is 36 weeks pregnant and arrives at the emergency department following a road traffic collision. She has a splenic laceration and is haemodynamically unstable. She last took her 15,000 units of dalteparin 6 hours ago. The team decide that reversal is required. What is the most appropriate dose of protamine sulfate?

A. Protamine sulfate 25 mg
B. Protamine sulfate 50 mg
C. Protamine sulfate 75 mg
D. Protamine sulfate 100 mg
E. Protamine sulfate 150 mg

Answer:

B. Protamine sulfate 50 mg

She had her last dose within the last 8 hours. so the recommended dosing is 1 mg/100 units. 15,000 / 100 = 150 mg. However, the dose should be capped at 50 mg.

6.Normal standard tests of coagulation do not rule out therapeutic drug levels of DOACs except:

A. Apixaban, activated partial thromboplastin time (aPTT)
B. Dabigatran, thrombin time (TT)
C. Edoxaban, prothrombin time (PT/INR)
D. Rivaroxaban, prothrombin time (PT/INR)

Answer:

B. Dabigatran, thrombin time (TT)

Dabigatran is the only DOAC where therapeutic drug levels can be ruled out by a normal thrombin time. However, dabigatran levels do not affect the thrombin time in a linear manner so other tests need to be used to accurately quantify the levels (dilute thrombin time or Ecarin clotting time). A normal aPTT may also suggest non-therapeutic dabigatran levels although this is somewhat unreliable so best avoided.

7. An 83-year old woman on apixaban 5 mg BD for atrial fibrillation is admitted with haematemesis and malaena requiring resuscitation with 2 units of packed red cells and 3,000 IU of prothrombin complex concentrate. Gastroscopy revealed severe erosive oesophagitis and gastritis. She was started on high dose proton-pump inhibitor and made a good recovery. The ward doctor calls you 2 weeks later as they are thinking of discharging her and ask for advice regarding her anticoagulation. She weighs 65 kg and her creatinine is 76 μmol/l.

What would you advise for her anticoagulation from today going forwards?

A. Do not restart anticoagulation
B. Restart apixaban at a lower dose of 2.5 mg twice daily
C. Restart apixaban 5 mg twice daily
D. Switch to edoxaban 60 mg once daily
E. Switch to therapeutic dose low molecular weight heparin

Answer:

C. Restart apixaban 5 mg twice daily

There is a clear evidence of benefit to restarting anticoagulation following upper GI bleed. A large, Danish registry study followed up 4,602 patients with AF (excluding those with recent orthopaedic surgery, recent VTE, and valvular heart disease) who had presented with upper GI bleeding. They found that resuming anticoagulation reduced recurrent VTE and all-cause mortality by 2.5 times. There was a 37% increased risk of major bleeding compared with not restarting anticoagulation.51

The timing of restarting anticoagulation is debatable and was not investigated in the Danish registry study. Data from several other studies that looked at resumption of warfarin following GI bleed, suggests that the optimal timing is about 2 weeks after the bleed. This balances the risk of mortality from bleeding versus the risk from thromboembolism and is summarised Daniel Witt’s review which is highly recommended.55

LMWH heparin is an option but this lady requires long-term anticoagulation so daily injections are not ideal. Additionally, there is no evidence that LMWH in this setting would be any better.
Again, changing to edoxaban is an option but there is no evidence of benefit doing this. Perhaps if she were on rivaroxaban, one might argue that there is a decreased risk of bleeding if switched to apixaban but again this is contentious.

Decreasing the dose to 2.5 mg BD is not advised as this is not the licensed dose for someone with normal renal function and a weight of 60 kg.

8. A 73-year-old man who is taking apixaban 5 mg BD for treatment of a DVT is admitted to hospital in Glasgow with right=sided weakness and a decreased level of consciousness (GCS 10). A CT scan shows an acute left frontal intracerebral haemorrhage. He last took apixaban 6 hours ago and his INR is 1.1.

What is the most appropriate management?

A. Andexanet alfa 400 mg bolus then 480 mg infusion over 120 minutes
B. Andexanet alfa 800 mg bolus then 960 mg infusion over 120 minutes
C. Four factor prothrombin complex concentrate 25 units/kg
D. Four factor prothrombin complex concentrate 50 units/kg
E. Observation

Answer:

A. Andexanet alfa 400 mg bolus then 480 mg infusion over 120 minutes

Andexanet alfa is licensed for this indication (unlike PCC) and is funded for intracerebral haemorrhage in Scotland (but not in England). Patients on apixaban at most treatment doses require low dose andexanet alfa with high dose only required for those on high doses such as the 10mg BD dose in the first 7 days of treatment for VTE.

Therefore, the correct dose is a 400 mg bolus then a 480 mg infusion over 120 minutes.

Remember, that the normal INR does not rule out therapeutic drug levels of apixaban.

Table 6. Decision tool for determining whether andexanet alfa should be administered at low dose or high dose based on drug dose and time elapsed since most recent administration

Last drug and dose Time elapsed since last dose Reversal dose required
Apixaban Rivaroxaban
≤ 5 mg ≤10 mg Any Low dose
> 5 mg / unknown >10 mg / unknown ≥ 8 hours Low dose
< 8 hours / unknown High dose

Table 7. Dosing of andexanet alfa according to whether low dose or high dose is indicated

Initial intravenous bolus Continuous intravenous infusion
Low dose 400 mg at a target rate of 30 mg/min 4 mg/min for 120 minutes (480 mg)
High dose 800 mg at a target rate of 30 mg/min 8 mg/min for 120 minutes (960 mg)

9. A 69-year-old woman is taking rivaroxaban 20 mg daily for atrial fibrillation and she last took a dose 7 hours ago. She is admitted to hospital in Leeds after having two episodes of malaena. On admission she is tachycardic and hypotensive and a point of care haemoglobin is 63 g/l. She is transfused two units of red cells but has a further three episodes of malaena. What is the most appropriate treatment?

A. Andexanet alfa 400 mg bolus then 480 mg infusion over 120 minutes
B. Andexanet alfa 400 mg bolus then 960 mg infusion over 120 minutes
C. Andexanet alfa 800 mg bolus then 960 mg infusion over 120 minutes
D. Four factor prothrombin complex concentrate 25 units/kg
E. Four factor prothrombin complex concentrate 50 units/kg

Answer:

C. Andexanet alfa 800 mg bolus then 960 mg infusion over 120 minutes

Andexanet alfa is the licensed treatment for this situation and is approved by NICE for major GI haemorrhage. As this patient is on rivaroxaban 20 mg and last took a dose <8 hours ago, she should receive the high dose regimen which is 800 mg as a bolus then a 960 mg infusion over 120 minutes.

Table 6. Decision tool for determining whether andexanet alfa should be administered at low dose or high dose based on drug dose and time elapsed since most recent administration

Last drug and dose Time elapsed since last dose Reversal dose required
Apixaban Rivaroxaban
≤ 5 mg ≤10 mg Any Low dose
> 5 mg / unknown >10 mg / unknown ≥ 8 hours Low dose
< 8 hours / unknown High dose

Table 7. Dosing of andexanet alfa according to whether low dose or high dose is indicated

Initial intravenous bolus Continuous intravenous infusion
Low dose 400 mg at a target rate of 30 mg/min 4 mg/min for 120 minutes (480 mg)
High dose 800 mg at a target rate of 30 mg/min 8 mg/min for 120 minutes (960 mg)

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