Royal College GIM Teaching

Royal College GIM Teaching

Bethan Myers

Haematology Consultant

Leicester Royal Infirmary

Lincoln County Hospital

Direct oral Anticoagulants (DOACs)

Direct oral anticoagulants (DOACs/NOACs)

•DOACS: effective, safer and more convenient than warfarin

•Becoming standard of care for a wide range of indications:

�Treatment and secondary prevention of VTE

�Prevention of stroke/systemic embolism in patients with non-valvular atrial fibrillation

The DOACs

RivaroxabanApixaban Edoxaban

(Betrixaban)

Dabigatran

Xa inhibitors

Thrombin (IIa) inhibitor

Apixaban

Mechanism of action

Direct factor Xa inhibitor

Oral bioavailability

~50%

Pro-drug No

Food effect No

Renal clearance

~27%

Mean half-life (t1/2)

12 h

Tmax 3–4 h

Clinical pharmacology of DOACs

Apixaban Rivaroxaban

Mechanism of action




~50% 80–100%

Pro-drug No No

Food effect No

Yes (20 mg and 15 mg doses

need to be taken with food)

Renal clearance

~27% ~33 %*


12 h5–9 h (young)

11–13 h (elderly)

Tmax 3–4 h 2–4 h


Apixaban Rivaroxaban Dabigatran

Mechanism of action



Direct thrombin inhibitor


~50% 80–100% ~6.5%

Pro-drug No No Yes

Food effect No



No

Renal clearance

~27% ~33 %* 85%


12 h5–9 h (young)

11–13 h (elderly)12–18 h

(patients)‡

Tmax 3–4 h 2–4 h 0.5–2 h


Apixaban Rivaroxaban Dabigatran Edoxaban

Mechanism of action



Direct thrombin inhibitor

Direct factor Xainhibitor


~50% 80–100% ~6.5% ~62%

Pro-drug No No Yes No

Food effect No



No No

Renal clearance

~27% ~33 % 85% 50%


12 h5–9 h (young)

11–13 h (elderly)12–18 h

(patients)‡ 10–14 h

Tmax 3–4 h 2–4 h 0.5–2 h 1–2 h


Thrombo-embolism & DOACS

Platelet-rich clot (platelets and coagulation)

Fibrin-rich clot (coagulation)

Case 1 -Lucy

*Patient is fictitious

Patient: Lucy*

Patient information

Age 82 years

Sex Female

Weight 65 kg

Blood pressure

125/85 mmHg

Creatinine clearance

35 ml/min

Patient case

Patient: Lucy*

Patient information

Age 82 years

Sex Female

Weight 65 kg

Blood pressure

125/85 mmHg


35 ml/min

Presentation

� Sudden onset pain and tenderness in left thigh 1

day after flying from London to Berlin (~3 hour

flight)

� Pitting oedema confined to the left leg

� No visible erythema and no signs or history of

trauma

Relevant medical history

�Hypertension

�Diabetes mellitus

�Osteoarthritis in both knees and right hip

�Moderate renal impairment

Current medications

�Atorvastatin 10 mg OD

�Enalapril 10 mg OD

�Metoprolol 100 mg BID

�Metformin 500 mg BID

� Ibuprofen PRN

Clinical probability of DVT: Wells score

Clinical characteristic Points Lucy’s score

Active cancer 1 0

Paralysis, paresis or recent plaster immobilisation of the lower extremities 1 0

Recently bedridden for 3 days or more, or major surgery within the previous 12 weeks

1 0

Localised tenderness along the distribution of the deep venous system 1 1

Entire leg swollen 1 0

Calf swelling at least 3 cm larger than that on the asymptomatic side 1 0

Pitting oedema confined to the symptomatic leg 1 1

Collateral superficial veins (non-varicose) 1 0

Previously documented DVT 1 0

Alternative diagnosis at least as likely as DVT −2 0

Clinical probability, two-level score

DVT likely ≥2 2

DVT unlikely <2

Created from Wells et al. 20031

•What investigations would you recommend next?

• What investigations would you recommend next?

1. FBC;U&Es; LFTs; clotting

1. Imaging

• Doppler ultrasound

Duplex ultrasound

Patient: Lucy

Lucy’s chemistry profile

� Haemoglobin: 121 g/L

� Platelet count: 270 x 109/L

� AST: 21 U/L ALT: 28 U/L

� Serum creatinine: 164 μmol/L

� Normal baseline clotting screen

Age: 82 yearsWeight: 65 kg

• Lucy has a confirmed proximal DVT, which anticoagulant therapy would you initiate?

• What factors would you take into account in making your decision?

• Comorbidities – eg inflammatory bowel disease

• ? Interacting medications

• Renal (and liver) function, platelet count

• (frequent falls – use a DOAC with available reversal agent?)

Absorption and metabolism of the different direct oral anticoagulant drugs.

Hein Heidbuchel et al. Europace 2015;europace.euv309

ACCP Guidelines on antithrombotic therapy for DVT

ACCP: American College of Chest Physicians

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).1

Initial parenteral anticoagulation is given before dabigatran and edoxaban, is not given before rivaroxaban and apixaban, and is overlapped with VKA therapy.1

• You discuss the potential treatment options with Lucy and she expresses a preference for an oral treatment

If Lucy received apixaban – dosing recommendations1

The duration of overall therapy should be individualised after careful assessment of the treatment benefit against the risk of bleeding.*Short duration of treatment (≥3 months) should be based on transient risk factors (e.g. recent surgery, trauma, immobilisation).Apixaban should be used with caution in severe renal impairment (CrCl 15–29 mL/min). Not recommended in CrCl <15 mL/min or in patients undergoing dialysis.

1. Apixaban SmPC. Available at: www.ema.europa.eu

Moderate renal impairment

(Lucy’s CrCl: 35 mL/min)

No dose adjustment

Elderly

(Lucy’s age: 82 years)

No dose adjustment

Ongoing VTE treatment

Initial

VTE treatment Prevention of recurrent VTE

10 mg BID

Days 1–7

5 mg BID Day 8 onwards for at least 3

months*

2.5 mg BID Following completion of 6 months of treatment with apixaban 5 mg BID or

another oral anticoagulant

If Lucy received rivaroxaban – dosing recommendations1

The duration of overall therapy should be individualised after careful assessment of the treatment benefit against the risk of bleeding.*Short duration of treatment (≥3 months) should be based on transient risk factors (e.g. recent surgery, trauma, immobilisation); †Longer durations should be based on permanent risk factors or idiopathic DVT or PE; ‡The recommendation for the use of 15 mg is based on pharmacokinetic modelling and has not been studied in this clinical setting. Rivaroxaban should be used with caution in severe renal impairment. Not recommended in CrCl <15 mL/min.1

1. Rivaroxaban SmPC. Available at: www.ema.europa.eu

Moderate renal impairment

(Lucy’s CrCl: 35 mL/min)

Consider reduction from 20 mg OD to 15 mg OD (after

the initial 15 mg BID for 3 weeks) if patient’s assessed

bleeding risk outweighs risk for recurrent DVT and PE‡

Elderly

(Lucy’s age: 82 years)

No dose adjustment

Ongoing VTE treatment

Initial

VTE treatment Prevention of recurrent VTE

15 mg BID with foodDays 1–21

20 mg OD with foodDay 22 onwards for at least 3 months*†

Pharmacokinetics of DOACs

1. Eliquis (apixaban) SmPC. 2. Xarelto (rivaroxaban) SmPC. 3. Pradaxa (dabigatran) SmPC. 4. Lixiana (edoxaban) SmPC.

All available at www.medicines.org.uk.

inhibitor

*Please refer to the individual SmPCs for definitions of mild, moderate and severe renal impairment, and see the respective SmPCs for dosing considerations based on renalfunction. The information in this table is based on the SmPC for apixaban, rivaroxaban, dabigatran and edoxaban. Please refer to the SmPC for further information.†Reported as 1.4-, 1.5- and 1.6-fold, respectively, in the rivaroxaban SmPC.

‡Reported as 2.7-fold and 6 times higher, respectively, in the dabigatran SmPC.

Apixaban1

Mechanism of actionDirect factor Xa

inhibitor

% active drug renally excreted 27%

Renal impairment and drug exposure

(AUC increase or decrease)

Mild* (50–≤ 80 mL/min) ↑ 16%

Moderate* (30–49) ↑ 29%

Severe* (15–29) ↑ 44%

AUC, area under the curve




inhibitor



Apixaban1 Rivaroxaban2


inhibitor

Direct factor Xa

inhibitor

% active drug renally excreted 27% 35% %



Mild* (50–≤ 80 mL/min) ↑ 16% ↑ 40%†

Moderate* (30–49) ↑ 29% ↑ 50%†

Severe* (15–29) ↑ 44% ↑ 60%†





inhibitor



Apixaban1 Rivaroxaban2 Dabigatran3


inhibitor

Direct factor Xa

inhibitor

Direct thrombin

inhibitor

% active drug renally excreted 27% 35% 85% %



Mild* (50–≤ 80 mL/min) ↑ 16% ↑ 40%† Not reported in SmPC

Moderate* (30–49) ↑ 29% ↑ 50%† ↑ 170%‡

Severe* (15–29) ↑ 44% ↑ 60%† ↑ 500%‡





inhibitor



Apixaban1 Rivaroxaban2 Dabigatran3 Edoxaban4


inhibitor

Direct factor Xa

inhibitor

Direct thrombin

inhibitor

Direct thrombin

inhibitor

% active drug renally excreted 27% 35% 85% 50%



Mild* (50–≤ 80 mL/min) ↑ 16% ↑ 40%† Not reported in SmPC ↑ 32%

Moderate* (30–49) ↑ 29% ↑ 50%† ↑ 170%‡ ↑ 74%

Severe* (15–29) ↑ 44% ↑ 60%† ↑ 500%‡ ↑ 72%


Lucy has now been receiving a DOAC for 3 months for the acute treatment of her DVT

• Would you consider there to be any factors that might have provoked Lucy’s DVT?

• Is a 3-hour flight a significant enough antecedent?

• Following Lucy’s unprovoked proximal DVT, would you consider continuing anticoagulation beyond 3 months?

• What factors would you take into consideration in your decision?

Estimated risk of VTE recurrence after stoppinganticoagulant therapy based on patient subgroup

*The risk of recurrence rates are based mainly on data from VKA studies.†Recurrence at 5 years not estimated because of high mortality from cancer.

1. Kearon C, et al. Chest 2016;149:315–352.

Subgroup of VTE patient Risk of recurrence*

Provoked by surgery 3% recurrence at 5 years

Provoked by non-surgical transient

risk factor, including:

�Oestrogen therapy

�Pregnancy

�Leg injury

�Flight >8 hours

15% recurrence at 5 years

Unprovoked 30% recurrence at 5 years

Cancer-associated thrombosis15% annualised risk of

recurrence†

Annual event rates of recurrent VTE

Kaatz S et al. Cleve Clin J Med 2011;78(9):609–18.

Duration of follow-up

Provoked bysurgery

Provoked bynonsurgical factor

Unprovoked(idiopathic)

12 months 1.0%/yr 5.8%/yr 7.9%/yr

24 months 0.7%/yr 4.2%/yr 7.4%/yr

Data from Iorio A, Kearon C, Filippucci E, et al. Risk of recurrence after a first

episode of symptomatic venous thromboembolism provoked by a transient

risk factor: a systematic review. Arch Intern Med. 2010;170:1710–1716.

Provoked and unprovoked VTE

ACCP guidelines recommend at least 3 months’ VKA therapy after provoked VTE or longer after unprovoked (idiopathic) VTE

Provoked VTE

Unprovoked (idiopathic)

VTE

Transient/reversible factors

e.g. surgery or hospitalisation

Continuing/ irreversible factors

e.g. cancer

No identifiable

cause

Risk factors for bleeding with anticoagulant therapy and categorisation of risk of bleeding (ACCP Guidelines)

• Patient’s risk of bleeding on anticoagulant therapy categorised as:1

• Low (no bleeding risk factors; 0.8% annualised risk of major bleeding)

• Moderate (one bleeding risk factor;1.6% annualised risk of major bleeding)

• High (two or more bleeding risk factors; ≥6.5% annualised risk of major bleeding)

*Most studies assessed risk factors for bleeding in patients who were on VKA therapy. The risk of bleeding with different anticoagulants is not addressed in this table.

Created from Kearon et al. 20161

Risk factors*

Age >65 years Diabetes

Age >75 years Anaemia

Previous bleeding Antiplatelet therapy

Cancer Poor anticoagulant control

Metastatic cancer Comorbidity and reduced

functional capacity

Renal failure Recent surgery†

Liver failure Frequent falls

Thrombocytopenia Alcohol abuse

Previous stroke Non-steroidal anti-inflammatory

drug

PP-ELI-GBR-0032 Date of preparation: May 2016

Pooled NOAC

(n/N)

Pooled VKA

(n/N)

Risk ratio (95%

CI)

P value ARR

(95% CI)

Intracranial

bleeding

15/13477

(0.1%)

43/13481

(0.3%)

0.37

(0.21-0.68)

0.001 -0.17%

(-0.30% to -0.03%)

Fatal

bleeding

7/13477

(0.1%)

22/13481

(0.2%)

0.35

(0.15-0.84)

0.02 -0.08%

(-0.16% to -0.01%)

Major GI bleeding 63/13477

(0.5%)

76/13481

(0.6%)

0.78

(0.47-1.31)

0.35 -0.12%

(-0.37% to 0.13%)

CRNM bleeding 854/13477

(6.3%)

1103/13481

(8.0%)

0.73

(0.58-0.93)

0.01 -1.88%

(-3.24% to -0.52%)

Safety analysis of pooled DOAC data vs VKA in VTE treatment

1. Van Es et al. Blood. 2014:1968–1975.

Intracranial, major gastrointestinal, fatal and clinically relevant non-major bleeding

100.1Favours VKAFavours NOAC

1Adapted from Van Es et al. 2014.1

DOACs – Management of bleeding

Clinical Strategies Available to Stop/ Reduce Bleeding when Patients Are on DOACs

Supportive measures:

• Mechanical compression

• Endoscopic haemostasis if GI

bleed

• Surgical haemostasis

• Fluid replacement +/-RBCs

Fresh–frozen plasma (as

plasma expander)

• Platelet substitution (if platelet

count ≤60×109/l)

For dabigatran:adequate

diuresis; idarucizumab

• Delay or discontinue next

dose

• Reconsider concomitant

medication

Consider:• PCC 50 U/kg; +25 U/kg if

indicated

• aPCC (Feiba®) 50 U/kg;

max 200 U/kg/day

• (rFVIla (NovoSeven®) 90

U/kg: no data about

additional benefit)

• For dabigatran-treated

patients: idarucizumab 5

g i.v.

Mild bleeding Moderate severe bleeding

Life-threatening bleeding

+ +

• Inquire about last DOAC intake

• Blood sample to determine creatinine clearance, haemoglobin and WBC

• Inquire to lab about possibility of rapid coagulation assessment

Clinical Strategies Available to Stop/ Reduce Bleeding when Patients Are on DOACs

Supportive measures:

• Mechanical compression

• Endoscopic haemostasis if GI

bleed

• Surgical haemostasis

• Fluid replacement +/-RBCs

Fresh–frozen plasma (as

plasma expander)

• Platelet substitution (if platelet

count ≤60×109/l)

For dabigatran:adequate

diuresis; idarucizumab

• Delay or discontinue next

dose

• Reconsider concomitant

medication • PCC 50 U/kg;

• For dabigatran-treated patients: idarucizumab 5 g i.v.

Mild bleeding Moderate severe bleeding

Life-threatening bleeding

+ +

• Inquire about last DOAC intake

• Blood sample to determine creatinine clearance, haemoglobin and WBC

• Inquire to lab about possibility of rapid coagulation assessment

Antidote infusion: Idarucizumab(Praxbind)

• Immediate, complete, and sustained reversal of dabigatran anticoagulation

• Mean clotting times were reversed to baseline immediately after end of antidote infusion

• The effect was sustained for the 2 g and 4 g antidote doses

DABIGATRAN RIVAROXABAN-APIXABAN

CrCl

(ml/min)

Low bleeding

risk

High bleeding

risk

Low

bleeding risk

High

bleeding risk

≥ 80 ml/min Omit 24 hr Omit 48-72 hr Omit 24 hr Omit 48 hr

50-79ml/min

Omit 36 -48 hr Omit 72-96 hr Omit 24 hr Omit 48-72 hr

30-49

ml/min

Omit 48 hr Omit 96 hr Omit 24 hr

Omit 72-96 hr

15-29ml/min

NA NA Omit 48 hr Omit 96-120hr

What if Lucy was 22 instead of 82 yrs?

Patient: Lucy*

Patient information

Age 22 years

Sex Female

Weight 65 kg

Blood pressure

125/85 mmHg


>90 ml/min

Presentation

Presenting with acute pleuritic chest pain and dyspnoea

Major PE diagnosed on CTPA, as first VTE event, no leg pain/swelling

Previously well, no comorbiditiesNo recent trauma, operations, travel

Relevant medical history

�Nil

Current medications

�Nil

• Diagnosis: Unprovoked major VTE

• Risk factors: nil

• Treatment: Rivaroxaban 20mg od

• Counselling:

importance of compliance/adherence;

importance of avoiding pregnancy

consider long-term anticoagulation

Review at 3 months:

Clinically improving, but

c/o heavy, prolonged menstrual & fatigue++

Hb 92g/L; ferritin <5

• Options:

Try alternative anticoagulant

Reduce dose for first few days menstruation

Omit dose for first 1-2 days menstruation

(Review contraceptive method)

Particular issues in women of reproductive years

• Many patients on oral anticoagulation for VTE are in reproductive years

• Many DVT clinics give a DOAC first – line

• Heavy Menstrual Bleeding (HMB)

• DOACs and risk of Pregnancy

DOACs and Pregnancy

• Potential for reproductive toxicity of DOACs in humans unknown

• No adequate data on the use of DOACs in pregnant women via maternal or paternal exposure.

• DOAC SPCs recommend against their use in pregnancy and during breastfeeding

• National/international guidance from RCOG (2015); ACCP (2012)

• However, patients may unintentionally become pregnant while on DOAC therapy.

FAQ for DOACS• My patient has AF and a prosthetic heart valve - is he eligible

for a NOAC? No

• My patient has a nasogastric tube. Are any of the NOACs suitable for nasogastric administration? Rivaroxaban or Apixaban

• Can I use a DOAC in obese and low weight patients? Not recommended >120Kg; use with caution <50Kg

• Can I use a DOAC if patient has an unusual site clot? • Not advised

• Which DOAC for which patient?• Elderly with↓renal function? Apix 2.5mgbd or riva 15mgod

• Patients at high risk of bleeding? Apix 5mgbd; dabig 110mg bd

• AF patient at high risk of stroke? Dabig150mgbd; Apix 5mgbd;Riva20mgod

Thrombophilia Thrombophilia Thrombophilia Thrombophilia testingtestingtestingtesting

How useful is it?

When should we request screening?

Thrombophilias BCSH guidance:

• Initiation and intensity of anticoagulant therapy following a diagnosis of acute VTE should be the same in patients with and without heritable thrombophilia



• Indiscriminate testing for heritable thrombophilias in unselected patients presenting with a first episode of venous thrombosis is not indicated



• Indiscriminate testing for heritable thrombophilias in unselected patients presenting with a first episode of venous thrombosis is not indicated

• Decisions regarding duration of anticoagulation (lifelong or not) in unselected patients should be made with reference to whether or not a first episode of venous thrombosis was provoked or not, other risk factors, and risk of anticoagulant therapy-related bleeding, regardless of whether a heritable thrombophilia is known

Thrombophilias: BCSH guidance

• Case finding of asymptomatic relatives with low risk thrombophilia, such as factor V Leiden or F2G20210A, is not indicated

• Case finding of asymptomatic relatives with high risk thrombophilia, (antithrombin, protein C or protein S deficincies) should only be considered in selected thrombosis-prone families.

Thrombophilias: BCSH guidance

• Case finding of asymptomatic relatives with low risk thrombophilia, such as factor V Leiden or F2G20210A, is not indicated

• Case finding of asymptomatic relatives with high risk thrombophilia, (antithrombin, protein C or protein S deficincies) should only be considered in selected thrombosis-prone families.

• If testing is performed, the risks, benefits and limitations of testing should be discussed in the context of explained inheritance and disease risk.

• Testing for heritable thrombophilia is not indicated in patients with arterial thrombosis

NICE guidance on thrombophilia testing

• Do not offer thrombophilia testing to patients who are continuing anticoagulation treatment.

• Consider testing for antiphospholipid antibodies in patients who have had unprovoked DVT or PE if it is planned to stop anticoagulation treatment.

NICE guidance on thrombophilia testing

• Do not offer thrombophilia testing to patients who are continuing anticoagulation treatment.

• Consider testing for antiphospholipid antibodies in patients who have had unprovoked DVT or PE if it is planned to stop anticoagulation treatment.

• Consider testing for hereditary thrombophilia in patients who have had unprovoked DVT or PE and who have a first-degree relative who has had DVT or PE if it is planned to stop anticoagulation treatment.

• Do not offer thrombophilia testing to patients who have had provoked DVT or PE.

• Do not routinely offer thrombophilia testing to first-degree relatives of people with a history of DVT or PE and thrombophilia.

Testing for thrombophilia does not reduce recurrence of venous thrombosis

Coppens et al JTH

• Large case-control study (5051); 197 patients had a recurrence during follow-up

• Comparison incidence of thrombophilia testing and control cohort of 324

• Thrombophilia tests were performed in 35% cases and 30% controls; OR recurrence was 1.2 for tested vs non-tested

• Corrected for: age, sex, family history, presence of clinical risk factors, year of first VTE

• Conclusion: Presence of inherited thrombophilia is only a weak predictor of recurrence, and does not reduce the incidence of recurrence in clinical practice

Haemostasis on-call

Haemostatic screening tests

• Using Prothrombin Time (PT) and Activated Partial Thromboplastin Time (APTT) to determine risk of bleeding can be misleading.

• Can be normal even in those with significant derangements of haemostasis - in vitro tests and may not reflect the underlying haemostatic mechanism.

• most important screening ‘test’ in haemostasis is the patient’s personal bleeding history, their medication history and whether any family history suggestive of an inherited bleeding diathesis

• 60 yr old man

• On warfarin for metallic heart valve

• Admitted with headache after a fall

• CT head demonstrates subdural haemorrhage

• INR >8

• Action?

• Concerns over thrombosis of metal valve if reverse anticoagulation, BUT

• Intracranial bleeding requires immediate reversal with prothrombin complex (factors II, VII, IX, X) and vitamin K

• (<0.2% over 7 day period – Cannegieter et al 1994)

Any questions?

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