บทบาท ของ anti coagulan ใน cardio embolism

1. Anticoagulant in ischemic stroke
Pornwalai Boonmuang
Faculty of Pharmacy, Silpakorn University
กําหนดการอบรมความรูในการบริบาลทางเภสัชกรรมผูป,วยโรคหลอดเลือดสมอง • Introduction
• Classification of stroke
• Cause of cardioembolic ischemic stroke
• Anticoagulants in cardioembolic ischemic stroke
• Appropriate timing of start anticoagulants in cardioembolic ischemic stroke
• Anticoagulants for secondary prevention
• Role of pharmacist
2
Outline
Introduction
• Definition (WHO)
• Cerebrovascular disease or stroke
• Rapidly developing clinical symptoms and/or signs of focal, with symptoms lasting >
24 hours
This definition includes signs and symptoms suggestive of
• ischemic stroke
• hemorrhages (intracranial or subarachnoid)
World Health Organization Meeting on Community Control of Stroke and Hypertension. Control of stroke in the community: methodological considerations and protocol
of WHO stroke register. CVD/s/73.6 Geneva: WHO, 1973. 4
Stroke
Ischemic Stroke
Conceptual representation of ischemic stroke subtypes
Stroke 2021;52(7):e364-e467.

2. Conceptual representation of ischemic stroke subtypes
5
Non lacunar stroke
Cryptogenic stroke
Stroke 2021;52(7):e364-e467.
Conceptual representation of ischemic stroke subtypes
6
Non lacunar stroke
Cryptogenic stroke
Stroke 2021;52(7):e364-e467.
7
The subtypes of ischemic stroke
Journal of Stroke 2014;16(1):1-7.
Non-valvular AF
(45%)
Acute MI (15%) Other, less common
sources
(10%)
Prosthetic cardiac
valves (10%)
Rheumatic heart
Disease (10%)
Ventricular aneurysm
(10%)
8
Mechanical prosthetic valve
Atrial fibrillation or flutter
Left atrial or ventricular thrombus
Recent myocardial infarction (<4 week)
Dilated cardiomyopathy
Infective endocarditis
Regional left ventricular akinesis
Atrial myxoma
Rheumatic heart disease
Patent foramen ovale with thrombus in situ
High-risk sources of cardiac embolism
Circ Res. 2017;120:514-526.
European Heart Journal. 2020;42:373-498

3. 1 •Acute ischemic stroke
2 • Secondary prevention***
9
Management of ischemic stroke Optimal time to start anticoagulation after stroke
10
Hemorrhagic transformation (HT)
(median time: 6 days with a range of 1-27 days)
Optimal time to start anticoagulation after acute ischemic stroke : Unclear
Risk factors and predictors for HT
• Factors: Age, Race, and Gender
• HF
• Anticoagulation in AF and the timing of
initiation
• BP (esp. SBP)
• DM and hyperglycemia
• Size of Infarction
• NIHSS score
• Lipid Profile
• Fibrinolytic agents
International Journal of Vascular Medicine 2021: https://doi.org/10.1155/2021/4244267
• The optimal timing to start anticoagulant therapy after an ischemic stroke has
not yet been well defined by clinical trial evidence and should be based on
individual benefit/risk assessment
• Clinical circumstances
• Stroke severity
• Infarct size
• Imaging appearances
• Risk of hemorrhagic transformation
• Age
• Comorbidities
• Estimated stroke recurrence risk.
11
Timing of initiation of oral anticoagulant therapy following acute stroke
International Journal of Vascular Medicine 2021: https://doi.org/10.1155/2021/4244267
Initiation or re-initiation of anticoagulants for secondary prevention

4. Initiation or re-initiation of anticoagulants for secondary prevention
1-3-6-121-3-6-12
NIHSS score
Treatment options for secondary prevention of TIA or ischemic stroke
15
Antithrombotic Therapy To Prevent Stroke in Patients with Atrial Fibrillation:
A Meta-Analysis
Warfarin compared with aspirin
Ann Intern Med. 1999;131:492-501 16
Role of anticoagulant in stroke

5. 17
Development of Anticoagulants
• IV Anticoagulants
• Unfractionated heparin (UFH)
• Low molecular weight heparin (LMWH)
• Routine anticoagulant is not recommended in acute ischemic stroke (A)
• Not recommend in moderate-severe stroke (A)
• Not recommend within 24 hours in patient with alteplase
• Used only hemorrhage has been excluded by brain imaging
Intravenous anticoagulants
Contraindications
• Large infarction  risk to hemorrhagic transformation
• Uncontrollable arterial hypertension Europace 2021;23:1612–1676.
• First, they investigated whether bridging (defined as LMWH or heparin before introduction
of oral anticoagulants) compared with no bridging (no LMWH/heparin) before starting oral
anticoagulation after a recent ischemic stroke is beneficial.
• They found that bridging was associated with an increased risk of delayed
symptomatic intracranial hemorrhage (HR, 2.74 [95% CI, 1.01–7.42], P=0.047) but did
not reduce the risk of recurrent ischemic stroke.
• Second, they compared DOAC and VKA-therapy and found that DOAC treatment was
associated with a lower rate of recurrent ischemic events within 90 days (5.3% versus
10.0%; HR, 0.51 [95% CI, 0.29–0.87]; P=0.015) without a significant difference in rate of
symptomatic intracranial hemorrhage
• They thus conclude that DOACs without prior bridging therapy seem to have the most
favorable risk-benefit-profile in patients with ischemic stroke and AF.
19
Stroke 2020;51(9):2618-2619.
Intravenous anticoagulants
• First, they investigated whether bridging (defined as LMWH or heparin before introduction
of oral anticoagulants) compared with no bridging (no LMWH/heparin) before starting oral
anticoagulation after a recent ischemic stroke is beneficial.
• They found that bridging was associated with an increased risk of delayed
symptomatic intracranial hemorrhage (HR, 2.74 [95% CI, 1.01–7.42], P=0.047) but did
not reduce the risk of recurrent ischemic stroke.
• Second, they compared DOAC and VKA-therapy and found that DOAC treatment was
associated with a lower rate of recurrent ischemic events within 90 days (5.3% versus
10.0%; HR, 0.51 [95% CI, 0.29–0.87]; P=0.015) without a significant difference in rate of
symptomatic intracranial hemorrhage
• They thus conclude that DOACs without prior bridging therapy seem to have the most
favorable risk-benefit-profile in patients with ischemic stroke and AF.
20
Stroke 2020;51(9):2618-2619.
First, they investigated whether bridging (defined as LMWH or heparin before introduction
of oral anticoagulants) compared with no bridging (no LMWH/heparin) before starting oral
anticoagulation after a recent ischemic stroke is beneficial.
They found that bridging was associated with an increased risk of delayed symptomatic
intracranial hemorrhage (HR, 2.74 [95% CI, 1.01–7.42], P=0.047) but did not reduce the risk
of recurrent ischemic stroke.
Intravenous anticoagulants

6. 21
Warfarin: mechanism of action
Vitamin K dependent clotting factors
Warfarin ยับยั้งการสรางโปรตีนที่ทําหนาที่เกี่ยวกับการแข็งตัวของเลือด
21
Circulation. 2003;107:1692–1711.
Indication
Prevention thromboembolism in AF patient
Mechanical valve replacement with or without AF
LV thrombus
Anticoagulation/Avoid stroke in AF
Patient with AF
AF patients with prosthetic mechanical heart valve or moderate – severe mitral stenosis
VKAs; TTR≥70%
Yes
No
Step 1 identify low stroke risk patients
CHA2DS2VASc score: male=0, female=1
Yes
No
No antithrombotic
treatment
Re-evaluate 4 – 6 mo.
Step 2 consider stroke prevention in all patients with
CHA2DS2VASc score≥1 (male) or≥2 (female)
=1(male) or =2(female) ≥2(male) or ≥3(female)
OACs should be considered (IIa) OACs recommended (IA)
Step 3 begin OACs
NOACs generally recommended as first line therapy
TTR; time therapeutic range, OACs; oral anticoagulants,
VKA; vitamin K antagonist
European Heart Journal. 2020;42:373-498 22
Time in Therapeutic Range : TTR
European Heart Journal. 2020;00:1 -126
TTR: ช>วงเวลาที่ผูIปKวยมีค>า INR อยู>ในระดับเปWาหมาย ใชIในการประเมินประสิทธิภาพและความปลอดภัยของการรักษา
ดIวยยาวารbฟาริน
Recommendations for the prevention of
thromboembolic events in AF
European Heart Journal. 2020;00:1 -126

7. 25
Interesting point of warfarin in acute ischemic stroke (AIS)
Acute ischemic stroke
กรณีที่มีขอบsงใชของยาละลายลิ่มเลือด
นอยกวsา 3 ชั่วโมง: PT มากกวsา 15 วินาที
หรือ INR มากกวsา 1.7: Exclusion criteria
3.0-4.5 ชั่วโมง: คsา INR เทsาไหรsก็ตาม:
relative exclusion criteria
Stroke 2020;51(9):2618-2619. 26
Documented AF plus ≥ 1 risk factors: age≥ 75 tears,
HTN, prior ischemic stroke/TIA, LVEF < 45%, PAD,
age 55-74 years plus CAD or DM
ACTIVE-W (6,500 patients)
Clopidogrel+ASA compared with
warfarin
ACTIVE-A (7,500 patients)
Clopidogrel+ASA compared with
ASA
Unsuitable for
warfarin use
The ACTIVE program
The Atrial Fibrillation Clopidogrel Trial with Irbesartan for Prevention of Vascular Events (ACTIVE) investigator
N Engl J Med 2009;360:2066-78.;
27
Cumulative risk of primary outcome;
Stroke, MI, embolism, vascular death
The ACTIVE-W
Lancet 2006;367(9526):1903-12. 28
Oral anticoagulation therapy is superior to clopidogrel plus aspirin for prevention of vascular events in patients
with atrial fibrillation at high risk of stroke, especially in those already taking oral anticoagulation therapy
Major bleeding
The ACTIVE-W
Lancet 2006;367(9526):1903-12.
Clopidogrel plus ASA
Warfarin

8. 29
Primary o/c: stroke, myocardial
infarction, non–central nervous system
systemic embolism, or death from
vascular cause
The ACTIVE-A
N Engl J Med 2009;360:2066-78. 30
The ACTIVE-A
N Engl J Med 2009;360:2066-78.
Therapeutic mornitoring
Adjusted odds ratios for ischaemic stroke
and intracranial bleeding in relation to INR
International normalized ratio
20
15
10
5
1
1.0 2.0 3.0 4.0 5.0 6.0 7.0 8.0
Ischemic stroke
Intracranial bleeding
Adapted from Hylek EM. N Engl J Med 1996;335:540-6
Target INR in AF: 2-3
Target INR in AF: 2-3 Mechanical AVR + additional risk factors for thromboembolic events (e.g. AF,
previous thromboembolism, LV dysfunction, or hypercoagulable conditions) or an
older generation mechanical AVR (such as ball-in-cage)
Target : 2.5-3.5
Therapeutic mornitoring
Starr-Edwards
Circulation. 2017;000:e000–e000.

9. Limitation of
warfarin therapy
Slow onset/offset
of action
Numerous food-drug or
herbs-drug interaction
Numerous drug-drug
interaction
Bleeding
complication
Unpredictable
response
Narrow therapeutic
index
Routine INR
monitoring
Difficult dose
adjustment
Limitation of warfarin therapy in AF
J Thromb Thrombolysis 2008;25:52-60
Intracerebral hemorrhage (ICH)
NOACs for stroke prevention in patients with AF
35
Nat Rev Drug Discov 2011;10:61-75.
Rivaroxaban
Apixaban
Edoxaban
Dabigatran
New/ Novel Oral Anticoagulants
Non-warfarin Oral Anticoagulants
Non-vitamin K antagonist Oral Anticoagulants
36
Initiation or re-initiation of anticoagulants for secondary prevention
Brain imaging
Clinical/NIHSS

10. • We investigated more practical optimal
timing of DOAC initiation according to
stroke severity.
• Patients were divided into transient
ischemic attack and 3 stroke
subgroups by the National Institutes
of Health Stroke Scale score:
mild (0–7), moderate (8–15), and
severe (≥16).
• Outcomes included a composite of
recurrent stroke or systemic
embolism, ischemic stroke, and severe
bleeding within 90 days.
Stroke. 2022;53:00–00. DOI: 10.1161/STROKEAHA.121.036695 Available on: https://www.ahajournals.org/doi/abs/10.1161/STROKEAHA.121.036695. Assessed on March 2022.
39
Interesting point of NOACs in AIS)
Acute ischemic stroke
ไมsควรใชยาละลายลิ่มเลือด หากรับประทาน
ยากลุsม NOACs มาภายใน 24-48 ชั่วโมง
Anticoagulation/Avoid stroke in AF
Patient with AF
AF patients with prosthetic mechanical heart valve or moderate – severe mitral stenosis
VKAs; TTR≥70%
Yes
No
Step 1 identify low stroke risk patients
CHA2DS2VASc score: male=0, female=1
Yes
No
No antithrombotic
treatment
Re-evaluate 4 – 6 mo.
Step 2 consider stroke prevention in all patients with
CHA2DS2VASc score≥1 (male) or≥2 (female)
=1(male) or =2(female) ≥2(male) or ≥3(female)
OACs should be considered (IIa) OACs recommended (IA)
Step 3 begin OACs
NOACs generally recommended as first line therapy
TTR; time therapeutic range, OACs; oral anticoagulants,
VKA; vitamin K antagonist
European Heart Journal. 2020;42:373-498 40

11. Selected indications and contraindications for NOAC therapy in AF patients
Europace 2021;23:1612–1676
Dabigatran
An oral prodrug, converted to dabigatran
High polar zwitterion ion molecule  not absorbed orally
Product available in Thailand: 75, 110, 150 mg
Pharmacokinetic:
Bioavailability: approximately 3-7%. (Tmax 0.5- 2 hours)
Protein binding = 35% (dialyzable)
Metabolism: conjugation and glucoronidation, substrate of p-gp
Excretion: 80% urine as unchanged (kidney)
Linear pharmacokinetic, half life 12-14 hours
Esterase
Br J Clin Pharmacol. 2007;64(3):292–303.
Circulation. 2011;123(13):1436-50.
Available on https://pubchem.ncbi.nlm.nih.gov/compound/Pradaxa#section=2D-Structure.
Accessed on March 2021
CrCl (ml/min) Dabigatran half life (hours)
> 80 ประมาณ 13
>50-80 ประมาณ 15
>30-<50 ประมาณ 18
< 30 ประมาณ 27
Dabigatran
Circulation. 2011;123(13):1436-50.
Europace 2016;18(11):1609-78.
JACC 2018;71(19):2162-75.
Dabigatran
Drug interaction
No participation with CYP450
 Dabigatran is a substrate of P-glycoprotein, an efflux pump
 Clarithromycin, potent P-gp inhibitor,  Cmax of dabigatran by 19%
 Amiodarone, P-gp inhibitor  Cmax of dabigatran by 50-60%
 Rifampicin, P-gp inducer  Cmax of dabigatran by 67%
 Contraindicated in patients taking systemic tacrolimus, cyclosporin, ketoconazole,
itraconazole
 ADR:
 Dyspepsia: co-administration with PPIs
 GI bleeding: 53% upper GI bleeding
Circulation. 2011;123(13):1436-50.

12. Dabigatran pellet structure
Crushing or breaking the capsule should be avoid, because pellet administration outside of the capsule
can increase bioavailability by up to 75%.
J Clin Pharmacol. 2012;52(2):243-50.
Pharmacokinetic
Bioavailability: 80-100% (10 mg), 66% (15-20 mg), Tmax 2-4
hours
Protein-bound: 92-95%
2/3 metabolized: excreted: 50% liver / 50% kidney
Hepatic enz. via CYPA3A4, CYP3A5, CYP2J2, substrate
P-gp
1/3 excreted unchanged via kidney
Half life 7-11 hours (mean 9 hours), 11-13 hours in elderly
Rivaroxaban
 Oral direct factor Xa inhibitors
 Product available in Thailand: 2.5, 15, 20 mg
Clin Pharmacol 2012;26:27-32
Rivaroxaban
> avoid
Dose 15-20 mg: 66% absorbed, food ↑AUC 39% (ควรรับประทานพรอม/หลัง
อาหารทันที)
Main absorption site: stomach.
Administer drug directly at proximal small bowel ↓AUC by 30% -> avoid
giving drug by feeding tube
JACC 2016;67(24):2888-99.
Rivaroxaban
 Avoid concomitant administration of rivaroxaban with
 P-gp and strong CYP3A4 inhibitors :
 Ketoconazole, itraconazole, tacrolimus, cyclosporine
 Lopinavir/ritonavir, ritonavir, indinavir/ritonavir
 Clarithromycin, erythromycin
 Increases in rivaroxaban exposure that may increase bleeding risk.
 P-gp and strong CYP3A4 inducers :
 Rifampicin, phenytoin
 ADR: bleeding
Drugs. 2013 May;73(7):715-39.

13. Apixaban
Pharmacokinetic
 Bioavailability 58% (area of
absorption : 55% distal small bowel &
ascending colon
 Protein-bound 87%, Vd 21 L
 Metabolism: 25% by CYPA3A4
 Substrate of p-glycoprotein
 Apixaban is eliminated in both
urine and feces (t1/2~ 12 hours) JACC 2016;67(24):2888-99.
 Initial U.S. Approval: 2012
 Product available in Thailand: 2.5 mg และ 5 mg Film coated tablet
 Oral direct factor Xa inhibitors
 Initial U.S. Approval: 2015
 Product available in Thailand: 30 mg และ 60 mg
Pharmacokinetic
 Bioavailability 62%
 Protein-bound 55%
 Metabolism: liver by CYPA3A4, substrate of p-glycoprotein
 Elimination: terminal elimination half-life of edoxaban following oral administration is 10 - 14 hr
Edoxaban
50 Cardiol Ther 2016;5(1): 1–18.
Edoxaban
http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/.pdf
Renal clearance
Effect of CrCl on risk of Stroke/SEE
European Heart Journal 2018;39:1330–1393.
Indication:
 Reduce the risk of stroke/systemic embolism in patients with non-valvular AF.
 Limitation of use for NVAF: should not be used in patients with CrCL > 95 mL/min
because of increased risk of ischemic stroke compared to warfarin at the highest dose
studied (60 mg).
Use of NOACs in hepatic insufficiency
Europace 2021;00, 1–65.doi:10.1093/europace/euab065.
Close f/u

14. Use of NOACs according to renal function in AF patients
53
Europace 2021;00, 1–65.doi:10.1093/europace/euab065.
SmPCs=Summary of product characteristics
Use of NOACs according to renal function in AF patients
54
European Heart Journal 2018;39:1330–1393.
Dabigatran 75 mg in the US
JACC 2019;74(1):104-132.
For patients with AF who have a CHA2DS2-VASc score of 2 or greater in men or 3 or
greater in women and who have ESRD (CKD; [CrCl] < 15 mL/min) or are on dialysis, it might
be reasonable to prescribe warfarin (INR 2.0 to 3.0) or apixaban for oral anticoagulation
NOACs in patient with CKD
55
European Heart Journal. 2020;42:373-498, Circulation. 2019;140:e125–e151.
• The 2020 ESC guidelines recommend the
use of factor Xa inhibitors ‘with caution’ and
at reduced doses for patients with CrCl 15–
29 mL/min.
• The efficacy and safety of NOACs in
patients with end-stage renal dysfunction
and on dialysis is unclear.
• There are no data on the use of NOACs in
AF patients after kidney transplantation.
• For patients with AF and moderate-to-
severe CKD, treatment with reduced doses
of direct thrombin or factor Xa inhibitors
may be considered.
• For patients with AF and who have ESRD
or are on dialysis, it might be reasonable
to prescribe apixaban for oral
anticoagulation.
Dose selection criteria for apixaban
การทํางานของไต ขนาดยา
CrCl มากกวsาหรือเทsากับ 50 ml/min 5 mg วันละ 2 ครั้ง
CrCl 30-49 ml/min 5 mg วันละ 2 ครั้ง
CrCl 15-29 ml/min 2.5 mg วันละ 2 ครั้ง
CrCl นอยกวsา 15 ml/min และ/หรือ ไดรับการบําบัดทดแทนไต ไมsแนะนําใหใช
(1) European Heart Journal. 2020;42:373-498 (2) Eliquis (apixaban) prescribing information. (3) Circulation. 2019;140:e125–e151
• Dose reduction criteria(1,2):
In patients with any 2 of the following characteristics:
1) Age ≥80 years 2) BW ≤60 kg 3) SCr ≥1.5 mg/dL (133 µmol/L)
• Coadministered with drug that are strong CYP3A4 and P-gp inhibitors
หมายเหตุ: จากแนวทางการรักษาโรคหัวใจหองบนสั่นพลิ้วของประเทศสหรัฐอเมริกาป‡ พ.ศ. 2562(3) แนะนําใหใชยา apixaban 5 mg
วันละ 2 ครั้งในผูป,วยที่มี CrCl นอยกวsา 15 ml/min รวมถึงผูป,วยที่ไดรับการบําบัดทดแทนไต
56

15. Choosing of NOACs
Circulation. 2019;140:e125–e151., Europace. 2021;00:1–65.
Evaluation:
• Pharmacokinetic
• Absorption
• Distribution
• Hepatic function
• Renal function
• Compliance
• Crushed/via NG
• Thromboembolism / Bleeding risk
• Drug–drug interaction
57
Administration of NOACs through enteral feeding tubes
NOACs Formulation Able to Crush and
Administer via
NG/G Tube
Directions for Administration Notes
Dabigatran Capsule containing
drug coated pellets
No Capsule must be swallowed whole 75% increase in bioavailability if
the capsule is opened
Rivaroxaban Film-coated tablet Yes • Stable in 50 mL of sterile water,
applesauce, and juice
• Flushing tubing prior to and after
administration is preferable
• 15 mg and 20 mg tablets
should be taken with nutrition
for consistent bioavailability
• Absorption not altered by PPIs,
H2 antagonists, or antacids
• Drug compatible with tubing
• Avoid administering distal to
the stomach
• Solution may be given orally
Journal of Pharmacy Technology2016;32(5):196 –200.
Administration of NOACs through enteral feeding tubes
NOACs Formulation Able to Crush and
Administer via NG/G Tube
Directions for Administration Notes
Apixaban Film-coated tablet Yes • Suspend in 60 mL of D5W
• Suspension should be
immediately delivered through
NG tube
• Flushing tubing is preferable
• If crushed and administered
care should be taken to
avoid taking in conjunction
with food
• Drug compatible with
tubing
• Solution may be given
orally
Edoxaban Film-coated tablet Yes No data to support recommendation Needs acidic environment to
be absorbed
Journal of Pharmacy Technology2016;32(5):196 –200.
Landmark trials of NOACs in AF
Dabigatran (RE-LY)(1) Rivaroxaban (ROCKET-AF)(2) Apixaban (ARISTOTLE)(3) Edoxaban (ENGAGE AF-TIMI 48)(4)
Age 71 years, female 37%,
CHADS2 2.1, TTR 64%
Age 73 years, female 39%, CHADS2
3.5, TTR 55%
Age 70 years, female 35%,
CHADS2 2.1, TTR 62%
Age 72 years, female 37%, CHADS2
2.8, TTR 68%
Dabigatran 150 mg bid (n=6,076),
110 mg bid (n=6,015)
Rivaroxaban (n=7,131) Apixaban (n=9,120)
Edoxaban 60 mg OD (n=7,035),
Edoxaban 30 mg OD (n=7,034)
Warfarin (n=6,022) Warfarin (n=7,133) Warfarin (n=9,081) Warfarin (n=7,036)
- Stroke or systemic embolism:
D 150 mg 1.11% p/y (P<0.001 for
superiority); D 110 mg 1.53% p/y
(P<0.001 for noninferiority);
W 1.69% p/y
- GI bleeding: D 150 mg HR 1.49
(95%CI 1.21-1.84; P<0.001); D 110
mg HR 1.09 (95%CI 0.87-1.36;
P=0.44)
- Stroke or systemic embolism:
Rivaroxaban 2.1% p/y (P<0.001 for
noninferiority); W 2.4% p/y
- GI bleeding: Rivaroxaban 2.2% vs W
3.2% (P<0.001)
- Stroke or systemic embolism:
Apixaban 5 mg bid 1.27% p/y
(P=0.01 for superiority); W 1.60%
p/y
- GI bleeding: Apixaban HR 0.89
(95%CI 0.7-1.15; P=0.37)
- Stroke or systemic embolism:
E 60 mg 1.18% p/y (P<0.001 for
noninferiority); E 30 mg 1.61% p/y
(P=0.005 for noninferiority); W 1.5%
p/y
- GI bleeding: E 60 mg HR 1.23
(95%CI 1.02-1.50; P=0.03); E 30 mg
HR 0.67 (95%CI 0.53-0.83; P<0.001)
(1) N Engl J Med 2009; 361:1139-1151. (2) N Engl J Med 2011; 365:883-891. (3) N Engl J Med 2011; 365:981-992. (4) N Engl J Med 2013; 369:2093-2104.
60

16. Baseline Characteristics
61
N Engl J Med 2009;361:1139–51; N Engl J Med 2010;363:1875–6; N Engl J Med 2011;365:883–91; N Engl J Med 2011;365:981–92.
All NOACs; stroke or systemic embolic events
Lancet.2014;383:955-62.
63
All NOACs; Major Bleeding
Relative ratio (95% CI)
Lancet.2014;383:955-62.
Safety outcomes of NOACs vs warfarin: Data from RE-LY, ROCKET AF,
ARISTOTLE, and ENGAGE trials
Dabigatran 110 mg Dabigatran 150 mg Rivaroxaban 20 mg Apixaban 5 mg Edoxaban 60 mg
Major bleeding Decreased Equally Equally Decreased Decreased
ICH Decreased Decreased Decreased Decreased Decreased
Life threatening
bleeding
Decreased Decreased NA Decreased Decreased
GI bleeding Equally Increased Increased Equally Increased
Total bleeding Decreased Decreased Equally Decreased Decreased
64
NA=not available; * Includes major and non major clinically relevant bleeding events only Based on an indirect
comparison, where dabigatran , rivaroxaban and apixaban were all compared against the reference drug warfarin
(target INR 2-3).
N Engl J Med 2009;361:1139–51; N Engl J Med 2010;363:1875–6; N Engl J Med 2011;365:883–91; N Engl J Med 2011;365:981–92; N Engl J Med 2013; 369:2093-2104.

17. Switching between NOACs and other anticoagulants
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From VKA to NOACs
From NOACs to VKA
Monitoring parameter of apixaban
• Stroke or systemic embolism symptoms
• Bleeding symptoms
• Renal function
• Liver function
• Hemoglobin / hematocrit
European Heart Journal 2018;39:1330–1393.
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Measuring the anticoagulant effect of NOACs
67
Dabigatran Apixaban Edoxaban Rivaroxaban
European Heart Journal 2018;39: 1330–1393. 68
Dabigatran Apixaban Edoxaban Rivaroxaban
Measuring the anticoagulant effect of NOACs
European Heart Journal 2018;39: 1330–1393.

18. Checklist during follow-up of AF patients on NOACs
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Checklist during follow-up of AF patients on NOACs
Adherence
Each visit Inspect remaining medication Re-educate on importance of adherence Inform about
compliance aids (boxes, smartphone apps, etc)
Thromboembolism Each visit Systemic circulation (TIA, stroke, peripheral), Pulmonary circulation
Bleeding
Each visit ‘Nuisance’ bleeding: prevention possible? (proton pump inhibitor [PPI], haemorrhoidectomy,
etc.). Motivate patient to diligently continue anticoagulation Bleeding with risk or impact on
QoL – prevention possible? Need to revise dose?
Other side effect
Each visit Continuation? Temporary cessation with bridging? Change of anticoagulant drug?
Co-medications
Each visit Prescription or over-the-counter drugs (especially aspirin/NSAIDs)? Even temporary use
can be risky
Blood sampling
Yearly 6-
monthly x-
monthly on
indication
Haemoglobin, renal, liver function Age 75–80 years (especially dabigatran or edoxaban) or
frail If renal function ≤60 ml/min: recheck interval = CrCL/10 (in months). If intercurrent
condition may impact renal or hepatic function
European Heart Journal 2018;39:1330–1393.
Role of pharmacist
 Patient education
• Compliance
• Sign of stroke or systemic embolism
• Sign of bleeding
• Drug-Drug interaction, drug-dietary supplement interaction
 Monitor efficacy and safety
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