Anticoagulation In Elderly :

Indications, Complications And

Its Management
Content :
 Classification of anticoagulants

 Indications and guidelines for use of anticoagulants

 Anticoagulants : complications and management

 Parenteral anticoagulants
 Vit-k antagonists
 Novel oral anticoagulants

 Anticoagulants : Who gets what…

FORMATION OF “BLOOD CLOT”
 Platelet adhesion
ANTIPLATELETS
 Platelet aggregation

 “Trap” of coagulation
factors
 Clot formation ANTICOAGULANTS

 Clot stabilisation
(Fibrin formation)
 Clot resolution THROMBOLYTICS
Indications of Anticoagulant Therapy

 Non-valvular atrial fibrillation

 Venous thromboembolic disease, including pulmonary embolism
and deep vein thrombosis
 Special conditions like post surgery, cancers…
 Cardio-embolic stroke
 Valvular heart disease and prosthetic heart valves
 Ischemic heart disease and Left ventricular dysfunction
 Peripheral artery disease
Anticoagualtion in atrial fibrillation
Atrial fibrillation is one of the most common
indication for starting anticoagulation therapy.

Anticoagulation therapy has a relative risk

reduction of 60-30% for prevention of ischemic
stroke in patients with A-fib.

Risk stratification before starting anticoagulation

therapy using the CHADVAS2 score.

 January CT, Wann LS, Alpert JS, Calkins H, Cigarroa JE, Cleveland JC, et al. 2014
AHA/ACC/HRS Guideline for the Management of Patients With Atrial Fibrillation A
Report of the American College of Cardiology/American Heart Association Task Force
on Practice Guidelines and the Heart Rhythm Society. Circulation. 2014 Dec 2
Deep Vein Thrombosis and
Pulmonary Embolism
 LMWH/fondaparinux > i.v./s.c. UFH as initial anticoagulants.
 suggest once- over twice-daily administration
 Those who receive oral warfarin as first-line long term anticoagulation
therapy should have warfarin overlapped with initial anticoagulation
therapy for a minimum of 5 days and until the INR is >2.0 for at least 24
hours, and then targeted to an INR of 2.0 to 3.0
 Newer oral anticoagulants are as safe and effective as warfarin for acute
VTE and does not require laboratory monitoring.

Kearon C, Akl EA, Comerota AJ, Prandoni P, Bounameaux H, Goldhaber SZ, et al. Antithrombotic therapy for VTE disease:
Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based
Clinical Practice Guidelines. Chest. 2012 Feb;141(2 Suppl):e419S – 94S.
Optimal Duration Of Anticoagulation
CLINICAL SETTING RECOMMENDATION

1st provoked PE/proximal leg DVT 3 to 6 months

1st provoked upper extremity DVT or isolated 3 months

calf DVT
2nd provoked VTE Uncertain
3rd VTE Indefinite duration

Cancer and VTE Consider indefinite duration or until cancer is

resolved
Unprovoked PE/proximal leg DVT Consider indefinite duration

1st unprovoked calf DVT 3 months

2nd unprovoked calf DVT Uncertain

Anticoagulation in surgical patient
 Provided there are no contraindications, start pharmacological VTE prophylaxis after
surgery. Choose any one of:
-Dabigatran (1–4 hours after surgery) - Fondaparinux (6 hours after surgery)
-LMWH (6–12 hours after surgery) - Rivaroxaban (6–10 hours after surgery)
-UFH (6–12 hours after surgery)
 Offer combined VTE prophylaxis with mechanical and pharmacological methods
1. elective hip/knee replacement surgery or hip fracture surgery.
2. major trauma/ spinal surgery.
 Extend pharmacological VTE prophylaxis to 28 days postoperatively for patients who
have had major cancer surgery in the abdomen or pelvis and patient undergoing
THR/TKR/HFS.

Kearon C, Akl EA, Comerota AJ, Prandoni P, Bounameaux H, Goldhaber SZ, et al. Antithrombotic therapy for VTE disease: Antithrombotic Therapy
and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012 Feb.
Anticoagulation in STEMI
2013 ACCF/AHA Guideline for the Management of ST-Elevation
Myocardial Infarction:
Class I
1. Anticoagulant therapy with a vitamin K antagonist should be
provided to patients with STEMI and AF with CHADS2 score greater
than or equal to 2, mechanical heart valves, venous
thromboembolism, or hypercoagulable disorder. (Level of
Evidence: C)

2. The duration of triple antithrombotic therapy with a vitamin K

antagonist, aspirin, and a P2Y12 receptor inhibitor should be
minimized to the extent possible to limit the risk of bleeding. (Level
of Evidence: C)
Class IIa

1. Anticoagulant therapy with a vitamin K antagonist is a

reasonable for patients with STEMI and asymptomatic LV mural
thrombi. (Level of Evidence: C)
Duration of treatment is 3 months.

Class IIb

1. Anticoagulant therapy may be considered for patients with STEMI

and anterior apical akinesis or dyskinesis. (Level of Evidence: C)

2. Targeting vitamin K antagonist therapy to a lower international

normalized ratio (eg, 2.0 to 2.5) might be considered in patients with
STEMI who are receiving DAPT. (Level of Evidence: C)
Anticoagulation in Heart Valve Prostheses

Risk factors include AF, previous thromboembolism, LV dysfunction, hypercoagulable condition, and older-generation
mechanical AVR
 Reproduced from: Nishimura RA, Otto CM, Bonow RO, et al. 2014 AHA/ACC Guideline for the Management of Patients With
Valvular Heart Disease: A Report of the American College of Cardiology/American Heart Association Task Force on Practice
Guidelines. J Am Coll Cardiol 2014; 63:e57. Illustration used with the permission of Elsevier Inc. All rights reserved
Anticoagulation in Peripheral
Arterial Diseases
 Studies have demonstrated limited benefit of adding warfarin to
antiplatelet regimens in patients with PAD.
 A disproportionate increased risk of major or severe bleeding.
 Guidelines support the use of anticoagulants in only select PAD
populations – patients undergoing vein graft bypass.
 Studies are currently underway to evaluate the potential role of novel oral
anticoagulants for thrombotic prevention in patients with PAD.

Rooke TW, Hirsch AT, Misra S, et al. 2011 ACCF/AHA focused update of the guideline for the management of patients with peripheral artery disease
(updating the 2005 guideline): a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice
Guidelines. J Am Coll Cardiol 2011;58:2020-45. - See more at: http://www.acc.org/latest-in-cardiology/articles/2014/08/26/11/27/the-use-of-
anticoagulants-in-peripheral-arterial-disease#sthash.nhkYVDtw.dpuf
 Anticoagulation – VTE Prophylaxis In
Cancer Patient
 Four to seven times increased risk of VTE
among patients with cancer as among
persons without this disease.
 Highest risk in patient who have :
 Certain types of solid tumors and
hematologic cancers
 Are receiving chemotherapy or
radiotherapy,
 Undergone operative procedures,
 Who have metastatic disease,or
 Who have inherited thrombophilias

Connors JM. Prophylaxis against venous thromboembolism in

ambulatory patients with cancer. N Engl J Med. 2014 Jun
26;370(26):2515–9.
Anticoagulation in Cancer
Associated VTE
 Initial treatment of established VTE: low-molecular-weight heparin (LMWH) is recommended [1B];
fondaparinux and unfractionated heparin (UFH) can be also used [2D].

 For the early maintenance (10 days to 3 months) treatment of established VTE, LMWH for a minimum
of 3 months is preferred over vitamin K antagonists (VKA) [1A];

 After 3-6 months, LMWH or VKA continuation should be based on individual evaluation of the
benefit-risk ratio, tolerability, patient preference and cancer activity.

Farge D, Debourdeau P, Beckers M, Baglin C, Bauersachs RM, Brenner B, et al. International clinical practice guidelines for the treatment
and prophylaxis of venous thromboembolism in patients with cancer. J Thromb Haemost JTH. 2013 Jan;11(1):56–70.
Anticoagulation in Older Adults :
Increased Need
 AGE RELATED CHANGES IN HEMOSTASIS
 Increased plasma levels of fibrinogen, factor VII and factor VIII.
 An increased responsiveness to different aggregating stimuli, elevated levels of
beta-thromboglobulin and increased production of thromboxane-A2 in the
platelets of the elderly.
 Modifications of platelet membrane lipid composition, with possible related
changes in membrane fluidity.
 A decrease in the number of platelet prostacyclin and thromboxane-A2
receptors is observed with aging.
 Fibrinolytic activity is impaired, probably due to an increase in plasminogen
activator inhibitor 1.

Abbate R, Prisco D, Rostagno C, Boddi M, Gensini GF. Age-related changes in the hemostatic system. Int J Clin Lab Res. 1993;23(1):1–
3.
Anticoagulation in Older Adults :
Increased Need
 Most of the common cardiovascular
disorders in older adults have a
relationship to thrombosis, requiring anti-
coagulation therapy, including
 Atrial Fibrillation,
 Stroke,
 Ischemic Heart Disease,
 Valvular Disease,
 Atherosclerotic Vascular Disease

 Increased incidence and prevalence

of cancers.
 Given that almost 10% of people over 80
years of age have atrial fibrillation, the
elderly population is clearly at high risk.
Anti-coagulation in elderly :
Increased risk of adverse events
 Age: a risk factor for bleeding

 Increased risk of fall

 Multiple co-morbidities

 Polypharmacy and drug-drug interaction

 Difficulty in monitoring and follow up

AN “IDEAL” ANTI COAGULANT

 ‘Fixed’ ‘oral’ dose

 No need for dose adjustment

 Wide therapeutic range

 Acceptable bleeding risks

 No need for monitoring

 Effective rapid antidote

PARENTERAL ANTICOAGUALANTS
Heparin

 A sulfated polysaccharide, Polymer of alternating d-glucuronic acid and N-

acetyl-d-glucosamine residues

 Activates antithrombin and accelerates the rate at which it inhibits clotting

enzymes, particularly thrombin and factor Xa

 Monitoring via aPTT

 Dose:
 Treatment of VTE- 80 U/kg bolus f/b 18 U/Kg/hr infusion(aPTT-2-2.5 times control)
 Prophylaxis of VTE- 5000 U SC BD/TDS
 Treatment of ACS- 60 U/kg f/b 12 U/kg/hr
Heparin
 Major side-effect :
 Bleeding - the most common side effect
 Thrombocytopenia
 Osteoporosis
 Elevated levels of transaminases.

 Management of severe bleeding

- Supportive and transfusion therapy
- Protamine
Low-Molecular-Weight Heparin

 Consists of smaller fragments of heparin

 The mean molecular weight of LMWH is about 5000, one third the mean
molecular weight of unfractionated heparin
 Shorter heparin chains bind less avidly to endothelial cells, macrophages,
and heparin-binding plasma proteins
 The clearance of LMWH is dose-independent and its plasma half-life is
longer
 Situations that may require LMWH monitoring include renal insufficiency ,
pregnancy and obesity
FONDAPARINUX

 A synthetic analogue of the antithrombin-binding pentasaccharide sequence

 Fondaparinux catalyzes factor Xa inhibition by antithrombin.
 Does not enhance the rate of thrombin inhibition

 Plasma t 1/2- 17 hours

 Subcutaneous once daily dosing
 Renal clearance
 Prophylactic dosing- 2.5 mg once daily
 Therapeutic dosing- 7.5 mg once daily
 H.I.T does not occur
 Bleeding risks equal to LMWH
Mechanism of action of heparin,
LMWH, and fondaparinux
Comparison of the Features of Heparin, Low-
Molecular-Weight Heparin, and Fondaparinux

FEATURE HEPARIN LMWH FONDAPARINUX

Source Biologic Biologic Synthetic

Molecular weight 15,000 5000 1728

Target Xa and IIa Xa and IIa Xa

Bioavailability (%) 30 90 100

Half-life (hr) 1 4 17

Renal excretion No Yes Yes

Antidote Complete Partial No

HIT <5% <1% Never

Advantages of Low-Molecular-Weight Heparin and
Fondaparinux over Heparin

ADVANTAGE CONSEQUENCE

Better bioavailability and longer Can be given subcutaneously once

half-life after subcutaneous or twice daily for both prophylaxis
injection and treatment
Dose-independent clearance Simplified dosing
Coagulation monitoring
Predictable anticoagulant response
unnecessary for most patients
Lower risk of heparin-induced Safer than heparin for short- or
thrombocytopenia long-term administration
Safer than heparin for long-term
Lower risk of osteoporosis
administration
Parenteral Direct Thrombin Inhibitors

PARAMETER HIRUDIN BIVALIRUDIN ARGATROBAN

Molecular mass 7000 1980 527

Site(s) of interaction Active site and Active site and

Active site
with thrombin exosite 1 exosite 1

Renal clearance Yes No No

Hepatic metabolism No No Yes

Plasma half-life
60 25 45
(min)
Heparin-induced thrombocytopenia (HIT)
 Heparin-induced thrombocytopenia (HIT) is an antibody-mediated process
triggered by antibodies against neoantigens on PF4 that are exposed when
heparin binds to this protein

FEATURE DETAILS

Platelet count of 100,000/µL or less or decrease in platelet count of

Thrombocytopenia
50% or more from baseline

Timing Platelet count falls 5-10 days after starting heparin

Type of heparin More common with unfractionated heparin than with LMWH

More common in surgical patients than medical patients; more

Type of patient
common in women than in men

Thrombosis Venous thrombosis more common than arterial thrombosis

 Lo GK, Juhl D, Warkentin TE, Sigouin CS, Eichler P, Greinacher A. Evaluation of pretest clinical score (4 T’s) for the diagnosis of
heparin-induced thrombocytopenia in two clinical settings. J Thromb Haemost 2006; 4: 759-65.
H.I.T Syndromes : Management

Withdraw heparin immediately and initiate one of the following:

 Fondaparinux
 Lepirudin – preferred over Argatroban in hepatic diseases
 Argatroban - preferred over lepirudin and fondaparinux in renal
diseases

“Warfarin NOT TO BE USED IMMEDIATELY post HMWH/LMWH”

Oral ANTICOAGULANTS
Warfarin

 In 1940 Karl Link and his student

Harold Campbell in Wisconsin first
discovered that the anticoagulant
in sweet clover, causing
hemorrhagic disease in cattle, was
3,3′methylenebis (4-hydroxy
coumarin).

 Further work by Link led in 1948 to

the synthesis of warfarin, which was
initially approved as a rodenticide
in the USA in 1952, and then for
human use in 1954.
Warfarin

 The name “WARFARIN” is derived from WARF (Wisconsin Alumni

research Foundation) and –arin from coumarin.

 More than 70 years later and despite all its problems, warfarin still
remains the most commonly used anti coagulant.
MECHANISM OF ACTION: Warfarin inhibits the vitamin K cycle
Warfarin
Epoxide
Reductase CYP2C9

Inactivation

 -Carboxylase
(GGCX)

Post translational modification

Vitamin K-dependent clotting factors

(FII, FVII, FIX, FX, Protein C/S/Z)
PLASMA HALF-LIVES OF VITAMIN K-DEPENDENT PROTEINS

Peak anticoagulant effect may be delayed by 72 to 96 hours

WARFARIN : PHARMACOLOGY
 Recemic mixture of R and S isomers (S more active)
 Rapidly and completely absorbed from GI tract
 Blood level peaks about 90 min of administration
 90% of circulating warfarin is bound to albumin
 Plasma t1/2 is 36-42 hrs
 Only small fraction of unbound warfarin is biologically active
 Warfarin is accumulates in liver, where it undergoes CYP2C9 mediated
oxidative metabolism.
 Inactive metabolites are excreted in urine and stools.
EFFECT OF CYP2C9 GENOTYPE ON ANTICOAGULATION

• CYP2C9 SNPs alter warfarin metabolism:

 CYP2C9*1 (WT) – normal activity
 CYP2C9*2 (Arg144Cys) - low/intermediate activity
 CYP2C9*3 (Ile359Leu) - low activity

• Approximately 25% of whites have at least one variant allele of CYP2C9*2 or

CYP2C9*3, whereas these variant alleles are less common in blacks and Asians

• Warfarin dose reduction requires as follow:

• Heterozygosity for CYP2C9*2 or CYP2C9*3 allele : 20%-30%
• Homozygosity for the CYP2C9*2 or CYP2C9*3 allele : 50%-70%
VKORC1: New Target Protein for Warfarin

Epoxide
Reductase

(VKORC1)

 -Carboxylase
(GGCX)

Clotting Factors
5 kb - chr 16 (FII, FVII, FIX, FX, Protein C/S/Z)
Rost et al. & Li, et al., Nature (2004)
EFFECT OF VKORC1 GENOTYPE ON
ANTICOAGULATION
 Three polymorphic variants of VKORC1
 Non-A,Non-A : wild type – Requiring more warfarin dose
 Non-A/A : Heterozygous – Requiring 25% dose reduction
 A/A : Homozygous - Requiring 50% dose reduction

 Asians have the highest prevalence of VKORC1 variants, followed by whites and
blacks

 VKORC1 variants are more prevalent than variants of CYP2C9

Genotype Freq in Asians (%) Dose reduction

Non-A,Non-A : wild type 7 --
Non-A/A : Heterozygous 30 26
A/A : Homozygous 63 50
DOSING
 Usual dose is 5 mg/day (1-20 mg)
 Lower doses require in
 Elderly
 Pt on increased risk of bleeding eg. Pt on aspirin
 Heart failure
 Liver disease
 Renal impairment
 Malnutrition
 Thyrotoxicosis (Opposite in Myxedema)
 Asian patients: Explained by genetic variation in hepatic enzymes (CYP3C9 &
VKORC1 Polymorphism)
 High intake dietary Vit-K (green vegetables e.g. broccoli) reduces the efficacy of
Warfarin.
 It is okay to eat food with different levels of vitamin K, it is more important to eat the
same amount from day to day.
Warfarin : Initiation Of Therapy And
Monitoring
Side Effects Of Warfarin

 Bleeding
 Skin necrosis
 Purple toe syndrome
 Teratogenicity
 Osteoporosis
 Others: Agranulocytosis, leukopenia, diarrhoea,
nausea, anorexia.
Managing Deranged INR And Bleeding
WARFARIN : SKIN NECROSIS

 Rare but very serious complication of warfarin

(prevalence of 0.01-0.1 %)
 Occurs 2 to 5 days after initiation of warfarin
 Usually occurs after high dose of warfarin

 Typical presentation is :
Well-demarcated erythematous lesions
form on the thighs, buttocks, breasts, or toes.
Typically, the center of the lesion becomes
progressively necrotic. Examination of skin
biopsies taken from the borders of these
lesions reveals thrombi in the microvasculature
WARFARIN : SKIN NECROSIS
 Mechanism : Not well understood but a precipitous fall in plasma protein C or S
levels (natural anticoagulants) before warfarin exert anticoagulant effect, results
in procoagulant state triggering thrombosis of adipose tissue microvasculatures.
 Prevention :
 Start with low dose warfarin in pts with known Protein C or S deficiency
 Overlapping with a parenteral anticoagulant when initiating warfarin therapy

 Treatment :
 Discontinuation of warfarin and reversal with vitamin K, if needed
 An alternative anticoagulant, such as heparin or LMWH, should be given to patients with
thrombosis
 Protein C concentrates or recombinant activated protein C may accelerate healing of the
skin lesions in protein C deficient patients
 Frozen plasma may be useful for those with protein S deficiency
 Occasionally, skin grafting is necessary when there is extensive skin loss.
Warfarin : Drug-Drug Interaction
ACENOCOUMAROL (acitrom)

 Same as warfarin with following differences:

 Shorter half life 10-16 hrs
 More rapid onset of action on PT
 Shorter duration of action (2 days)
 Less drug interactions

 Causes GI disturbances, oral ulcerations and dermatitis

 4 mg on day one, 4-8 mg on the day 2nd then maintenance dose 1-8 mg
according to response by PT test
 A comparative study on the quality of oral anticoagulant
therapy (warfarin versus acenocoumarol).
72%

The overall quality of treatment

was significantly better in patients
treated with warfarin (72% of 72%

% Responders
controls within the therapeutic
range versus 67% on
70% 67%
acenocoumarol, p < 0.001). 68%
Also the individual quality of 66%
therapy, which was assessed as the
percentage of patients with 75% or 64%
more assays in range, was in favour
of warfarin (50.7% vs 34.5%, p <
0.05). Warfarin Acenocoumarol

Pattacini C, Manotti C, Pini M, Quintavalla R, Dettori AG. A comparative study on the quality of oral
anticoagulant therapy (warfarin versus acenocoumarol). Thromb Haemost. 1994 Feb;71(2):188–91.
 NEWER ORAL ANTICOAGULANTS :

TARGET SPECIFIC ORAL ANTICOAGULANTS

Newer Oral Anticoagulants
Dabigatran etexilate

 PRADAXA  trade name

 Contraindications
- Active pathological bleeding
- H/o serious HS reaction
- Mechanical prosthetic heart valve
Dabigatran

 Adverse effects
 Bleeding – increases with age
 GI events
 Dyspepsia (12%)
 Abdominal pain
 Gastritis including GERD, esophagitis, erosive gastritis, gastric hemorrhage
and GI ulcers
 Hypersensitivity reaction (<0.1%)
 An unexplained increase in acute myocardial infarction in the
dabigatran group versus warfarin
(~0.2% increased risk for a AMI re-ly trial)
Dabigartan : FDA Status
RIVAROXABAN
 Contraindications
- Active pathological bleeding
- Severe HS reaction
 NOT RECOMMENDED in patients- PROSTHETIC heart valves
 Avoid in patients with Child-Pugh B and C hepatic impairment
and any hepatic d/s associated with coagulopathy

 A/E- Bleeding

Reference: Xarelto medication guide (FDA) Feb 2014. Accessed at

URL:http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/022406s009lbl.pdf,Last accessed on
22/09/2014.
RIVAROXABAN : FDA Status

Reference: Xarelto medication guide (FDA) Feb 2014. Accessed at

URL:http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/022406s009lbl.pdf,Last accessed on
22/09/2014.
APIXABAN

 Contraindication
- Active pathological bleeding
- Severe HS
 NOT recommended in PROSTHETIC heart valves
 Severe hepatic impairment- not recommended
- Mild: no modification
- Moderate: Data not available
 A/E- Bleeding

Medication Guide FDA,August 2014, accessed at

URL:http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/202155s009lbl.pdf, Last
accessed on 22/9/14
APIXABAN : FDA Status

 FDA approval for

- Reduce risk of stroke or systemic embolism in patients with NVAF
- Prophylaxis of DVT->PE
- Treatment of DVT and Pulmonary embolism
- Reduction in risk of recurrence of DVT and PE
 Doses: 2.5 mg and 5 mg BD

Medication Guide FDA,August 2014, accessed at

URL:http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/202155s009lbl.pdf, Last accessed on
22/9/14
Edoxaban: FDA Status

 Lixiana trade name

 For the prevention of DVT/PE after orthopedic surgery:

 No FDA approval yet
 Edoxaban approved in Japan

 For the prevention of stroke in patients with atrial fibrillation or

treatment and prevention of recurrence of DVT and PE
 No approvals yet

 Doses: 60/30 mg OD

- 30 mg: CrCl-30-50 ml/min, Body wt <=60 Kg

Potential Drug Interactions
 Dabigatran: affected by pGP inhibitors or inducers

 Not excluded from clinical trials

 Quinidine contraindicated;
 Use caution with:
 strong inhibitors “like verapamil, clarithomycin and others”
 strong inducers (rifampin, St. John’s wort) reduced effect

 May be impacted by degree of renal insufficiency

Potential Drug Interactions
 Rivaroxaban and Apixaban : affected by combined pGP and
CYP3A4

 Decrease dose of by 50% when coadministered with strong dual

inhibitors of CYP3A4 and P-gp (e.g., ketoconazole, itraconazole,
ritonavir, clarithromycin)
 Avoid concomitant use of strong dual inducers of CYP3A4 and P-
gp (e.g., rifampin, carbamazepine, phenytoin, St. John’s wort)

 May be impacted by degree of renal insufficiency

Potential Drug Interactions
 pGP + CYP3A4 inhibitors:
 itraconazole, ketoconzole, clarithromycin, azithromycin
 cyclosporin, dronedarone
 verapamil, diltiazem,
 lopinavir/ritonavir, conivaptan
 amiodarone, captopril, carvedilol, felodipine, quinidine
 pGP inducers:
 carbamazepine, phenytoin,
 rifampin, tipranavir/ritonavir,
 St. John’s wort
 CYP3A inhibitors: voriconazole (strong), cimetidine (weak)
New Oral Anticoagulants:
Measurement ≠ Monitoring
 Common assays (aPTT, prothombin time) insensitive and inconsistently affected
 INR is a lab parameter created ONLY for warfarin

 Other measures may better reflect drugs

 Ecarin clotting time (ECT): dabigatran
 Chromogenic factor Xa actvity level : rivaroxaban, apixaban

 Even if drug effect can be measured, not the same as what results correlated with
outcomes in the studies
Conversion of anti-coagulants

 Warfarin to pradaxa
- Discontinue warfarin and start pradaxa when INR <2

 Pradaxa to warfarin
- CrCl ≥50 :start warfarin 3 days before D/C pradaxa
- CrCl 30-50 :start warfarin 2 days before D/C pradaxa.
- CrCl 15-30 :start warfarin 1 day before D/C pradaxa
- CrCl <15 :no recommendations
Cont...
 Warfarin to Xarelto
- D/C warfarin and start Xarelto when INR<3
 Xarelto to warfarin
- D/C xarelto and give both parenteral anti-coagulant and warfarin at
next recommended dose (bridging)

 Warfarin to Eliquis
- Stop warfarin and start Eliquis ,INR <2
 Eliquis to warfarin
- Stop Eliquis and start both parenteral anti-coagulant and warfarin at same
time at next scheduled dose time
New OACs: Interruption of Therapy
 Dabigatran
 If CrCl>50 ml/min, hold 1-2 days
 If CrCl<50 ml/min, hold 3-4 days
Ecarin clotting time may be a marker of activity
aPTT “approximates” activity (??), INR unreliable
 Rivaroxaban
 Hold for at least 24 hours
 Apixaban
 Hold for at least 24 hours, 48 for interventions with higher bleeding risk

o Restart- after surgery once hemostasis is achieved

Reversal of New OACs
 Fix the HOLE that’s bleeding

 Decrease quantity of drug

 Activated charcoal if thought to still be in stomach
 Dabigatran may be dialyzed

 Bypass the drug effect

 Prothrombin complex (PCC), factor VIIa concentrates anecdotally successful
 Recent study suggested aPCC may work best for anti-Xa (rivaroxaban) but not anti-
thrombin (dabigatran)

DeLoughery, Am J Hem 86:586, 2011

Eerenberg, Circulation 124:1508, 2011
Sardar, J Am Geriat Soc 62:857, 2014
Specific Antidote For The Noacs

1.ARIPAZINE 2.ANDEXANET 3. IDARUCIZUMAB

(PER977; ciraparantag) (PRT064445) (BI 655075)

Molecule A synthetic molecule A modified A monoclonal

recombinant antibody
derivative of (fXa)
Mechanism Binds to the Higher affinity to the Binds to dabigatran
anticoagulation agents fXa inhibitor than and its metabolites
via covalent bonds, natural fXa, it binds to with higher affinity
rendering them inactive. the inhibitor and than the binding
prevent its binding to affinity of dabigatran
fXa. to thrombin.

Action against UFH, LWMH, Dabigartan, Factor Xa inhibitors Dabigatran

Factor Xa inhibitors
Phase Phase 2 clinical trials Phase 2 clinical trial FDA approved
IDARUCIZUMAB

 In this prospective cohort study, the capacity of idarucizumab to reverse the

anticoagulant effects of dabigatran was studied.
 Group A : patients who had serious bleeding
 Group B : patient who required an urgent procedure
 Primary end point : maximum percentage reversal of the anticoagulant effect of
dabigatran within 4 hours of administration of idarucizumab, by determination of the
dilute thrombin time or ecarin clotting time.
 RESULTS: Idarucizumab normalized the test results in 88 to 98% of the patients within
minutes. Concentrations of unbound dabigatran remained below 20 ng per milliliter
at 24 hours in 79% of the patients.
ANDEXANET

 In this study, Healthy older volunteers were given 5 mg of apixaban twice

daily or 20 mg of rivaroxaban daily.
 For each factor Xa inhibitor, a two-part randomized placebo-controlled
study was conducted to evaluate andexanet administered as a bolus or as
a bolus plus a 2-hour infusion.
 The primary outcome was the mean percent change in anti-factor Xa
activity, which is a measure of factor Xa inhibition by the anticoagulant.
>Among the apixaban-treated
participants, anti-factor Xa activity
was reduced by 94% among those
who received an andexanet bolus ,
as compared with 21% among those
who received placebo (P<0.001).
>Thrombin generation was fully
restored in 100% versus 11% of the
participants (P<0.001) within 2 to 5
minutes.

>Among the rivaroxaban-treated

participants, anti-factor Xa activity
was reduced by 92% among those
who received an andexanet bolus,
as compared with 18% among
those who received placebo
(P<0.001).
>Thrombin generation was fully
restored in 96% versus 7% of the
participants (P<0.001).
CIRAPARANTAG (PER977)

 In this double-blind, placebo-controlled trial involving 80 healthy persons, effects of

escalating, single intravenous doses of PER977 (5 to 300 mg) administered after a 60-mg
oral dose of edoxaban were studied.
 Whole-blood clotting time was used to measure the anticoagulant effect of edoxaban
and its reversal by PER977.
 Result : In patients receiving a single intravenous dose of PER977 (100 to 300 mg) 3 hours
after the administration of edoxaban, the whole-blood clotting time decreased to within
10% above the baseline value in 10 minutes or less, which was much longer
(approximately 12 to 15 hours) in the placebo group.
 The whole-blood clotting time remained within 10% above or below the baseline value for
24 hours after the administration of a single dose of PER977.
New OACs: “Like drinking your LMWH”
LMWH
 Inhibit activated factors
 No vitamin K impact
 Weight-adjusted dose
 Dependent on renal
clearance
 No medication interactions
 No monitoring needed
 Irreversible
 Injections (ouch)
 Very expensive
NEW ORAL AGENTS
 Inhibit activated factors
 No vitamin K impact
 Fixed dose
 Dependent on renal clearance
(not apixaban)
 Few medication interactions
 No monitoring needed (can’t)
 Irreversible
 Oral
 5-10x cheaper than LMWH
New OACs: Different than Warfarin
WARFARIN
 Production of dysfunctional factors
 Changes the body
 Effect through vitamin K
 Multiple medication interactions
 Dose adjusted
 Can/must be monitored
 Reversible
 Can be used in renal failure
NEW ORAL AGENTS
 Inhibition of activated factors
 No effect unless factors active
 No vitamin K (diet) impact
 Few medication interactions
 Fixed dose
 No monitoring (can’t)
 Irreversible*
 Dependent on renal clearance (not
apixaban)
• Asian population, despite having low prevalence AF compared to white
population, are at increased risk of stroke and stroke related mortality.

• Asian with AF are at particularly high risk of hemorrhagic stroke. Various

associated factor include
• increase prevalence of cerebral micro-bleeds,
• genetic susceptibly to bleeding with warfarin (VKORC1 gene variation), and
• poor monitoring, low TTR.

• Recent meta-analysis have found that the new anticoagulants are associated
with decreased incidence of hemorrhagic stroke compared to warfarin.

• This association is even more significant in the Asian population.

Sabir I, Khavandi K, Brownrigg J, Camm AJ. Oral anticoagulants for Asian patients with atrial fibrillation. Nat Rev Cardiol. 2014 May;11(5):290–303.
Agent Selection – Who Gets What?
 New OACs Instead of LMWH

 Basically similar properties – irreversible, unmonitored -

except new agents require:
 Better (e.g. >60 ml/min) renal function, probably
 Awareness of potentially interacting meds
 Ability to take p.o. medication

 Arguably, new agents are at least as efficacious and safe,

easier to administer and cheaper
Agent Selection – Who Get’s What?

 New OACs Instead of Warfarin

 Normal renal function; low risk for rapid progression to renal
insufficiency
 Low bleeding risk: unlikely to need reversal
 Patients with unstable INRs: new agents likely cost-effective in
addition to safety/efficacy advantage
 Adherence: missed dose will be missed!
 However, immediate return to adequate anticoagulation once
dosing resumed…
 Drug monitoring not “needed” to assess adherence, interpret clinical
events
 Not on potentially interacting drugs
Agent Selection – Who Gets What?

 Warfarin Instead of New Anticoagulants:

 Renal insufficiency (GFR<60? <30?), ESRD
 High bleeding risk: most easily reversed
 Patients with stable INR: most cost-effective
 Difficulty with adherence: least harm with missed dose
 History of multiple events (bleeding or clotting)
 Can measure INR to assess degree of anticoagulation relative
to event (INR too high or too low)
THANK YOU