Stolling en anesthesie 2 DS 2-VASc Score CHA 2 DS 2 risk factors C: Congestive heart failure 1 H: Arteral hypertension 1 A 2: Age ≥75 y 2 D: Diabetes mellitus 1 S 2: History of CVA/TIA

Stolling en anesthesie

Erik Vandermeulen MD, PhD – Dept. of Anesthesia

Preoperative use of anticoagulation

• Vitamin K-antagonists (VKA) – Fenprocoumon (Marcoumar®)

– Warfarin (Marevan®)

– Acenocoumarol (Sintrom®)

• Anti-Xa agents – Rivaroxaban

– Apixaban

• Direct thrombin inhibitors – Dabigatran

CHADS2-Score CHADS2 risk factors

C: Congestive heart failure 1

H: Arteral hypertension 1

A: Age >75y 1

D: Diabetes mellitus 1

S2: History of CVA/TIA 2

CHADS2

-score

Adjusted stroke rate

(%/Year)

0 0,8

1 2.2

2 4.5

3-6 9.6

(You JY et al. 9th ED ACCP Guidelines. Chest;141 (Suppl 2):e531S-e575S.)

CHA2DS2-VASc Score CHA2DS2 risk factors

C: Congestive heart failure 1

H: Arteral hypertension 1

A2: Age ≥75 y 2

D: Diabetes mellitus 1

S2: History of CVA/TIA 2

V: History of vascular disease 1

A: Age 65-74 y 1

Sc: Female Sex category 1

CHA2DS2-

Vasc score

Adjusted stroke

rate (%/Year)

0 0

1 1.3

2 2.2

3 3.2

4 4.0

5 6.7

6 9.8

7 9.6

8 6.7

9 15.2

(Lip GY et al. Chest. 2010; 137(2):263-72)

Annual thromboembolic risk without VKA

Thrombotic risk Valvular

prosthesis (VP)

Atrial fibrillation

(AF)

Thromboembolism

(TE)

High (>10%) Mitral VP

Older aortic VP

TIA or CVA (< 6m ago)

CHA2DS2-VASc score ≥5

TIA or CVA (<3 m ago)

Degenerative valvular

disease

Recent VTE (<3 m ago)

Severe thrombophilia (e.g.

homozygotic protein C- or

S-deficiency ...)

Intermediate (5-10%) ‘Bi-leaflet’ aortic VP with

additional risk factors:

congestive heart failure,

arterial hypertension,

age > 75 years,

diabetes mellitus,

history of TIA or CVA

CHA2DS2-VASc score 3 or

4

VTE 3-12 m ago

Mild trombophilia (e.g.

heterozygotic protein C- or

S-deficiency ...)

Multiple VTE

VTE + active cancer

Low (2-5%) ‘Bi-leaflet’ aortic VP

without additional risk

factors

CHA2DS2-VASc ≤2 (and

no history of TIA of CVA )

Single VTE > 12 m ago

and no thrombophilia

(From Douketis JD et al. 9th ACCP Guidelines. CHEST 2012; 141 (Suppl 2),e326S-e350S.)

VKA: ‘To bridge or not to bridge’

• Interruption of anticoagulation for diagnostic or therapeutic procedures In patients with AF who do not have mechanical valves,…, anticoagulation may be interrupted for a period of up to 1 week for surgical or diagnostic procedures without substituting heparin.

• In high-risk patients (particularly those with prior stroke, TIA, or systemic embolism), or when interruption of oral anticoagulant therapy for longer periods is required, … UFH or low-molecular-weight heparin may be administered.

(ACC/AHA/ESC 2006 Guidelines)

‘To bridge or not to bridge’

• In patients with a mechanical heart valve or atrial fibrillation or VTE at high risk for thromboembolism, we recommend bridging anticoagulation with therapeutic-dose SC LMWH or IV-UFH over no bridging during temporary interruption of VKA therapy (grade 1C). We suggest therapeutic-dose LMWH over IV UFH (grade 2C).

• In patients with a mechanical heart valve or atrial fibrillation or VTE at moderate risk for thromboembolism, we suggest bridging anticoagulation with therapeutic-dose SC LMWH, therapeutic-dose IV-UH, or low dose SC LMWH over no bridging during temporary interruption of VKA therapy (grade 2C). We suggest therapeutic-dose LMWH over other treatment options (grade 2C).

• In patients with a mechanical heart valve or atrial fibrillation or VTE at low risk for thromboembolism, we suggest bridging anticoagulation with low-dose SC LMWH or no bridging over bridging with therapeutic-dose SC LMWH or IV UFH (grade 2C).

(Douketis JD et al. 8th ACCP Guidelines. Chest 2008;133:299-339S)

‘To bridge or not to bridge’ - MkII

• In patients with a mechanical heart valve or atrial fibrillation or VTE at high risk for thromboembolism, we suggest bridging anticoagulation instead of no bridging during interruption of VKA therapy (grade 2C)

• In patients with a mechanical heart valve or atrial fibrillation or VTE at moderate risk for thromboembolism, the bridging or-no bridging aproach chosen is, as in the higher- and lower-risk patients, based on the assessment of individual patient- and surgery-related factors.

• In patients with a mechanical heart valve or atrial fibrillation or VTE at low risk for thromboembolism, we suggest NO bridging instead of bridging anticoagulation during interruption of VKA therapy (grade 2C).


VKA – when to interrupt?

• Fenprocoumon (Marcoumar®)

– 10 d (t1/2: 96-140 h)

• Warfarine (Marevan®)

– 5-7 d (t1/2: 36-42 h)

• Acenocoumarol (Sintrom®)

– 4d (t1/2: 8-11 h)


Bridging with LMWH – when to stop

before surgery?

• Therapeutic or intermediate dose

– 24 h before surgery

– Last preoperative dose on the morning of

the day before surgery should be halved (if

once daily dosing)

• Low (prophylactic dose)

– 12 h before surgery


http://www.thrombosisguidelinesgroup.be

Bridging with LMWH – when to restart

after surgery?

• Procedures with a low bleeding risk – Therapeutic or intermediate dose of LMWH

• 24 h after surgery

– Low (prophylactic) dose of LMWH • 6-8 h after surgery

• Procedures with a high bleeding risk – Therapeutic or intermediate dose of LMWH

• 48-72 h after surgery

– Low (profylactic) dose of LMWH • 24 h after sugery?


VKA – when to resume after surgery?

• Type of surgery, patients condition, bleeding risk, risk of reintervention, presence of drainage system – 12-24 h after surgery

• In patients who require temporary interruption of a VKA before surgery, we recommend resuming VKAs approximately 12-24 h after surgery (evening or the next morning) and when there is adequate hemostasis instead of later resumption of VKAs (Grade 2C)

• LMWH bridging to be maintained until therapeutic INR by VKA (≥ 2,5)


VKA: what are the options in case of

minor/non-invasive procedures • Minor dental procedures

– Root canal procedures, removal of caries • We suggest no interruption of VKA and coadminister a prohemostatic agent

(e.g. Tranexaminic acid orally or as mouthwash (Exacyl®)

OR

– Extraction of teeth • We suggest stopping VKAs 2-3 days before the procedure instead of

alternative procedures (Grade 2C)

• Titrate VKA to INR 2.0-2.5

• Minor dermatological procedures – Resection of nevi, basal or squamous cell carcinomas

• We suggest no interruption of VKA and optimizing local hemostasis instead of other strategies (Grade 2C)

• Cataract surgery – We suggest no interruption of VKA (Grade 2C)


VKA – what are the options in case of

emergency surgery

– INR ≤ 1.5 • INR > 1.5 – 24 h until surgery

• ≥ 2 mg Vitamin K1 orally

– 8-12 h until surgery • 10 mg Vitamine K1 slow IV

push

– Immediately before surgery • Prothrombine concentrate

(PPSB SD) 25-50 IU/kg IV – Factor II, VII or X < 30%

– Halflife < VKA

• FFP SD – Volume overload

– Halflife < VKA


Antiplatelet agents (AP)

• Inhibitors of platelet activation – Dipyridamole – Acetyl-salicylic acid (ASA) – Thienopyridines (TNP)

• Ticlopidin • Clopidogrel (CLOP) • Prasugrel (PRA) • Ticagrelor

– SSRIs • Inhibitors of platelet aggregation

– Glycoprotein IIb-IIIa receptor antagonists • Abciximab • Eptifibatide • Tirofiban


Antiplatelet agents – Non-cardiac surgery

• In patients who are receiving ASA for the secondary prevention of cardiovascular disease and are having minor dental or dermatologic procedures or cataract surgery, we suggest continuing ASA around the time of the procedure instead of stopping ASA 7 to 10 days before the procedure (Grade 2C)

• In patients at moderate to high risk for cardiovascular events who are receiving ASA therapy and require non-cardiac surgery, we suggest continuing ASA around the time of surgery instead of stopping ASA 7 to 10 days before surgery (Grade 2C)

• In patients at low risk for cardiovascular events who are receiving ASA therapy, we suggest stopping ASA 7 to 10 days before surgery instead of continuation of ASA (Grade 2C)


Antiplatelet agents – Cardiac surgery

• In patients who are receiving ASA and require CABG surgery, we suggest continuing ASA around the time of surgery instead of stopping 7 to 10 days before surgery (Grade 2C)

• In patients who are receiving dual antiplatelet therapy and require CABG surgery, we suggest continuing ASA around the time of surgery and stopping clopidogrel/prasugrel 5 days before surgery instead of continuing dual antiplatelet therapy around the time of surgery (Grade 2C)


Antiplatelet agents – Coronary stents

• In patients with a coronary stent who have interruption of antiplatelet therapy before surgery, we suggest AGAINST the use of bridging therapy with UFH, LMWH, direct thrombin inhibitors, or glycoprotein IIb/IIIa inhibitors” (Grade 2C)

• In patients with a coronary stent who are receiving dual antiplatelet therapy and require surgery, we recommend deferring surgery for at least 6 weeks after placement of a bare-metal stent and for at least 6 months after placement of a drug-eluting stent instead of undertaking surgery within these time periods (Grade 1C)

• In patients who require surgery within 6 weeks after placement of a bare-metal stent or within 6 months after placement of a drug-eluting stent, we suggest continuing dual antiplatelet therapy around the time of surgery instead of stopping dual antiplatelet therapy 7 to 10 days before surgery (Grade 2C)


Antiplatelet agents

• When to restart?

– As soon as possible (≤24 u) • Type of surgery, condition of patient, bleeding risk,

risk of re-intervention, presence of a drainage system

– Loading dose • ASA: preoperative dose

• Clopidogrel: 150-300 mg, thereafter 75 mg/d

• Prasugrel: 30-60 mg, thereafter 10 mg/d (5 mg/d if ≥ 75 y)

Anti Xa agents

• Rivaroxaban (Xarelto®) in

high dose

– 20 mg once daily

• t1/2 =11-13 h

• 66% liver metabolism,

33% renal metabolism

• Strong correlation between

plasma concentrations and

aXa-activity and PT

prolongation

• PT, anti- Xa assay for

specific agent (under

development)

• Apixaban (Eliquis®) in

high dose

– 5 mg twice daily

• t1/2 =10-15 h

• 75% liver metabolism,

25% renal metabolism

• Strong correlation between

plasma concentrations and

aXa-activity and PT

prolongation

• PT, anti- Xa assay for

specific agent (under

development)

Anti Xa agents


(From Kubitza D et al. Eur J Clin Pharmacol 2005; 61,873-880. )

Anti Xa agents - PT


(From Douxfils J et al. Thrombosis Research 2012; 130 (Suppl 2),956-966.)

Anti Xa agents - PT

• No data available that associate PT changes with bleeding risk

• No data suggesting that PT is a valid marker for the anticoagulant efficacy

• In emergency situations in patients on rivaroxaban, a prolonged PT therefore may at most suggest the recent intake of the drug; prolonged PT would suggest the likely intake of rivaroxaban in the last 7 hours. Conversely, a non-delayed PT will only suggest that rivaroxaban was likely taken more than approximately 7 hours ago.

• The planning of an urgent surgical/invasive procedure based on the results of the PT/aPTT (as for VKAs and unfractionated heparin) is not a validated strategy and cannot be recommended at the current time


Anti Xa agents - Measuring aXa

(From Douxfils J et al. Thrombosis Research 2012; 130 (Suppl 2),956-966.)

Anti Xa agents


Rivaroxaban: A Practical Guide V1.0 – 6 July 2012

31

*Thromboprophylaxis with rivaroxaban low dose (10mg OD) only recommended in case of THR and TKR

surgery9.

Figure 14: Interrupting rivaroxaban for interventions with a bleeding risk

6.2. Urgent surgical interventions

In an emergency situation, clinical judgment by the attending physician will be required to

assess the relative risk of deferring the procedure versus an increased risk of bleeding if the

procedure/surgery is performed in a patient with recent intake of rivaroxaban.

If the procedure can be postponed, it is recommended to defer until 24 hours after the last

intake of rivaroxaban. Caution is required if this is not possible. In case of an (anticipated)

serious bleeding, the bleeding management described in section 6.1 should be taken into

consideration.

When the timing of the last intake of rivaroxaban is not known, a sensitive PT can provide

semi-quantitative information with respect to rivaroxaban intake. It needs to be reminded

though that a non-delayed PT will only suggest that rivaroxaban was likely taken more than

approximately 7 hours ago (see also section 2). Due to this limitation, the planning of a

surgical/invasive procedure based on the results of the PT/aPTT (as for VKAs and

unfractionated heparin) is not a validated strategy and cannot be recommended at the

current time.

Anti Xa agents – Stopping before surgery


• No bridging therapy with LMWH is required

Anti Xa agents - Reversal

(From Eerenberg ES et al. Thrombosis Research 2011; 124,1573-1579.)


(From Marlu R et al. Thromb Haemost 2012; 108,217-224.)


Rivaroxaban: A Practical Guide V1.0 – 6 July 2012

27

Currently, there is no specific antidote available for rivaroxaban. The antidotes available for

LMWH and VKA, protamine sulfate and vitamin K respectively, do not impact the

anticoagulation activity of rivaroxaban. Amongst the non-specific pro-coagulants, thus far

only Prothrombin Complex Concentrate (PCC) has shown a potential to reverse the

anticoagulant effects of rivaroxaban as assessed with thrombin generation assay (TGA) and

PT in a phase I clinical trial with 12 healthy volunteers15, 16.

Patients presenting with bleeding complications while on rivaroxaban should receive

individualized care based on the dose regimen, time of intake, drug compliance, possible

changes in co-morbidity impacting the plasma levels (e.g. overdose, renal or hepatic

function, drug-drug interactions) and the severity, source and location of the bleeding.

Regardless of the time of intake, the patient with a (suspected) bleeding should delay the

next administration. It is also possible that the treatment needs to be interrupted after

appropriate evaluation of the patient. The patient needs to be evaluated for associated

factors that increase the bleeding risk including a potential overdose, concomitant use of

antiplatelet or other antithrombotic agents, the use of non-steroidal anti-inflammatory

drugs (NSAIDs), co-existing bleeding disorders, renal or hepatic impairment.

There is insufficient (pre)clinical experience on the management of severe bleedings and the

guidance provided in table 8 and figure 13 is based on expert consensus and are not

clinically validated.

Hemostatic agent Recommendations

PCC: 4 factor concentrate

PPSB S.D.®

(flacon 20 ml - FIX ≥ 40 0I E ) Confidex

®

(flacon 20 ml - FIX 500IE) Octaplex

®

(flacon 20 ml - FIX 400 à 620IE)

The administration of Prothrombin Complex Concentrate (PCC) is suggested in case of life-threatening bleeding. After an initial administration of 25U/kg of the available PCC we recommend to clinically re-evaluate the need for a repeat administration of PCCs*.

Desmopressin

Minirin®

Amp (4 µg/ml) for iv. use

Desmopressin can be considered in case of associated coagulopathy or

thrombopathy**.

A standard dose scheme for bleeding disorders is 0,03 µg/kg with a maximum of

20 µg.

Tranexamic Acid

Exacyl®

Tranexamic acid associated to direct anti-Xa (antithrombin-independent) oral anticoagulants was effective in reducing postoperative blood loss, improving hemoglobinemia at 5 days and reducing transfusion rates.

21

aPCC: activated prothrombin concentrate (Feiba S-Tim 4®)

This writing group does not recommend the use of Feiba S-Tim 4® for life-threatening bleedings in patients treated with rivaroxaban.

recombinant human FVIIa (Novoseven®)

There is no clinical experience with rhFVIIa in rivaroxaban treated subjects. Due to the short half-life of rhFVIIa, a repeat dose may be needed. This writing group does not recommend the use of Novoseven® for life-threatening bleedings in patients treated with rivaroxaban.

Table 8: Recommended a-specific pro-hemostatic agents



Anti Xa agents

Direct thrombin inhibitors

• Dabigatran (Pradaxa®) in high dose

– 220-300 mg once daily

• t1/2 =12-17 h

• Mainly renal metabolism

• aPTT, TT, dTT (calibrated diluted Thrombin

Time) , Ecarin Clotting Time (ECT)


Direct thrombin inhibitors - APTT

• Only approximate indication of the anticoagulation intensity

• Useful to determine an excess of anticoagulant activity in patients who are bleeding or at risk of bleeding

• Limited sensitivity and not suitable for precise quantification of the anticoagulant effect, especially at high plasma concentrations of dabigatran.


(From Douxfils J et al. Thromb Haemost 2012; 107,985-997.)

Direct thrombin inhibitors – (d)TT

• Result of TT test depends on the coagulometer and the thrombin lot

• A calibrated diluted thrombin time (dTT) with dabigatran standards to calculate the dabigatran plasma concentration is necessary

• Linear relationship between dabigatran concentration and the dTT, which is therefore suitable for the precise quantitative assessment of dabigatran concentrations

• Normal TT measurement indicates no clinically relevant anticoagulant effect of dabigatran



Direct thrombin inhibitors – ECT &

PT • ECT provides a direct

measure of the activity

of direct thrombin

inhibitors

• PT/INR is unreliable in

patients on dabigatran



6

Supplementary Figures:

Figure 6: I nfluence of dabigatran on prothrombin time (PT ). PT showed a concentration-

dependent prolongation of clotting time. Innovin® was characterised by the best sensitivity

with a 2 x CT of 175 ng/ml. The box in blue and red represents the therapeutic range in the

orthopaedic indication and in AF patients, respectively. Cut-off at Ctrough of 67 ng/ml and 200

ng/ml are defined for the orthopaedic indication (220 mg qd) and for the twice daily dosing in

AF patients (150mg bid), respectively (4).

ECT

PT

Direct thrombin inhibitors - Reversal

(From Eerenberg ES et al. Thrombosis Research 2011; 124,1573-1579.)

Direct thrombin inhibitors - Reversal

(From Marlu R et al. Thromb Haemost 2012; 108,217-224.)

Direct thrombin inhibitors – Reversal


Practical guide dabigatran version 2.0

January 1, 2013

Page 12

trial11. In a mouse ICH (intracranial haemorrhage) model, PCC prevented excess intracerebral haematoma expansion associated with dabigatran and reversed the prolonged bleeding time in a dose-dependent manner12. Recombinant activated factor VII (rFVIIa) reversed the prolonged aPTT and the prolonged bleeding time in rats treated with a high dose of dabigatran13. Activated prothrombin complex concentrate reversed the prolonged bleeding time but not the prolonged aPTT in rats treated with a high dose of dabigatran13.

At this time, there is insufficient (pre)clinical experience on the administration of hemostatic agents in patients bleeding on dabigatran; the guidance provided in table 5 is based on expert consensus and is not clinically validated. Table 5: Recommended a-specific pro-hemostatic agents

Hemostatic agent Recommendations

PCC: 4 factor concentrate PPSB S.D. ®

(vial 20 ml – FIX ≥ 400IE)

Confidex® (vial 20 ml – FIX 500IE)

Octaplex® (vial 20 ml – FIX 400 to 620IE)

The administration of Prothrombin Complex Concentrate (PCC) is suggested in case of life-threatening bleeding.

After an initial administration of 25U/kg of the available

PCC we recommend to clinically re-evaluate the need for a repeat administration of PCCs.

Desmopressin Minirin®

Amp (4μg/ml) for I

V

us e

Desmopressin can be considered in case of associated coagulopathy or thrombopathy.

A standard dose scheme for bleeding disorders is 0,03μg/kg

with a maximum of 20μg

aPCC: activated prothrombin

concentrate Feiba S-Tim4®

There is some experimental evidence to support the role of

aPCC in reversing the anticoagulant effect of dabigatran, but data on its usefulness in clinical settings and also on

the possible risk of rebound thromboembolism is very limited4.

In view of the limited availability in Belgium, this writing

group does currently not recommend the use of Feiba S-Tim4® for life-threatening bleeding in patients treated with

dabigatran.

Recombinant human FVIIa

Novoseven®

There is some experimental evidence to support the role of

rhFVIIa in reversing the anticoagulant effect of dabigatran, but data on its usefulness in clinical settings and also on

the possible risk of rebound thromboembolism is very

limited4.

This writing group does therefore not recommend the use

of Novoseven® for life-threatening bleeding in patients treated with dabigatran.

Direct thrombin inhibitors – Reversal

• Hemodialyis can be considered


(From Stangier J et al. Thromb Haemost 2010; 49,259-268.)

Direct thrombin inhibitors


Renal function

(CrCl ml/min)

Estimated

half-life (h)

Stop dabigatran before elective surgery

High risk of bleeding or

major surgery

Standard risk

≥ 80 ≅ 13 2 days 24 hours

≥ 50 - <80 ≅ 15 2-3 days 1-2 days

≥ 30-< 50 ≅ 18 4 days 2-3 days

(>48 hours)

Resume after elective surgery

High risk of bleeding or

major surgery

Standard risk

48 hours 24 hours

• No bridging therapy with LMWH is required

Platelet aggregation inhibitors - Prasugrel

(From Wiviott SD et al. NEJM 2007; 357,2001-2015.)


(From Wiviott SD et al. NEJM 2007; 357,2001-2015.)


(From Farid NA et al. Drug Metab Disp 2007; 35,1096-1104.)

• Stop 7 days before surgery

• Resume >6 – 24h after surgery

Platelet aggregation inhibitors - Ticagrelor

(From Wallentin L et al. NEJM 2009; 361,1045-1057.)

Platelet aggregation inhibitors – Ticagrelor

(From Wallentin L et al. NEJM 2009; 361,1045-1057.)

Platelet aggregation inhibitors – Ticagrelor

(From Gurbel PA et al. Circulation 2009; 120,2577-2585.)

• Stop 5 days before surgery

• Resume >6 – 24h after surgery

Documents

Stolling en anesthesie 2 DS 2-VASc Score CHA 2 DS 2 risk factors C: Congestive heart failure 1 H: Arteral hypertension 1 A 2: Age ≥75 y 2 D: Diabetes mellitus 1 S 2: History of CVA/TIA