Download Oral AntiCoagulants

Oral Anticoagulants
Dr JomyV Jose MBBS,MD
Attributes Of The Ideal Anticoagulant
Oral administration
Rapid onset of action/rapid offset of action
Wide therapeutic range
Predictable therapeutic effect with fixed or weight-based
dosing
No monitoring required (but the ability to monitor if
desired)
Well defined pharmacokinetics in presence of renal or
hepatic disease
Easily reversible
Cost effective
Oral Anticoagulants
 Vitamin K Antagonists ( Coumarins ) : Warfarin,
Acinocoumarol ( Acitrom )
 AntiThrombin Agents : Dabigatran
 Anti Xa Agents : Rivaroxaban, Apixaban,
Edoxaban, Betrixaban, Darexaban (Discontinued
from September 2011)
History of Oral Anticoagulation
 In 1921, Frank Schofield, a Canadian, observed that the cattle
were hemorrhaging to death on procedures like dehorning.
And that they were ingesting moldy fodder made from sweet
clover.
 Scientists at the University of Wisconsin identified it later to
be 4 hydroxycoumarin or Dicumarol.
 Further research on Coumarins lead to the discovery of Warfarin.
 The name "warfarin" stems from the acronym WARF, for Wisconsin
Alumni Research Foundation + the ending -arin indicating its link
with coumarin.
 Warfarin was first registered for use as a rodenticide in the US in
1948.
 In 1951, when a US Army Inductee, unsuccessfully attempted
suicide with multiple doses of warfarin as rodenticide and
recovered fully after presenting to a hospital, and being treated
with vitamin K (by then known as a specific antidote),studies
began in the use of warfarin as a therapeutic anticoagulant.
Savior
Dwight Eisenhower
&
Assassin
Joseph Stalin
Warfarin
 Most Commonly used oral anticoagulant.
 It is a water soluble Vitamin K antagonist.
 It interferes with the synthesis of Vitamin K
dependent clotting proteins which include Factors II,
VII, IX , X. It also impairs synthesis of Vitamin K
dependent anticoagulant proteins C and S.
Mechanism of Action of Warfarin
 All Vitamin K dependent clotting factors require a gamma
carboxylation of their glutamic acid residues. This is
catalyzed by reduced Vitamin K ( Vitamin K
hydroxyquinone).
 The Vitamin K hydroxyquinone is produced from vitamin K
epoxide by the enzyme Vitamin K epoxide reductase.
 Warfarin inhibits C1 subunit of Vitamin K Epoxide reductase
( VKORC1), thereby blocking the gamma carboxylation
process.
Pharmacokinetics
 Warfarin is a racemic mixture of R and S
Isomers.
 Rapid and almost complete absorption from gut.
 Blood levels peak after 90 minutes.
 Plasma half life of 36 to 42 hours.
 97% is bound to albumin. Only rest is
biologically active.
Pharmacokinetics Contd…
 The S enantiomer is more active and is metabolized by
CYP2C9.
 Variants are CYP2C9*2 and CYP2C9*3
 The patients with one variant allele require 20% to 30%
lower maintenance doses of warfarin.
 The R enantiomers are metabolized by CYP1A1, CYP1A2,
CYP3A4
VKORC1 Variations
 Polymorphisms in VKORC1 can also influence anticoagulant
response.
 Asians have maximum polymorphisms followed by whites
and blacks.
 They are designated as A haplotype and non A haplotypes.
 Warfarin dose requirements for subjects heterozygous or
homozygous for the A haplotype are 25% and 50% lower
than the dose required for non A/non A haplotype.
Dosing of Warfarin
 Usually started at 5 mg
 Check INR daily till in therapeutic range.
 Then check thrice weekly for upto 2 weeks.
 Lower doses are prescribed for:
1. Patients with CYP2C9 and VKORC1 polymorphisms.
2. Older patients (Response to Warfarin increases with age)
3. Increased risk of bleeding (prior Aspirin use)
4. Patients of Asian descent.
 Bridging with Parenteral Anticoagulant in patients with established
thrombosis or at high risk for thrombosis.
Dosing to be Reduced In:
 Congestive Heart Failure
 Liver Disease
 Renal Impairment
 Malnutrition
 Thyrotoxicosis
Dosing to be Increased In:
 Myxoedema
 Green vegetables such as broccoli
Monitoring Warfarin Effect
 Prothrombin time – Sensitive to reductions in levels of
Prothrombin, Factor VII and X
 Method : Addition of Thromboplastin ( Tissue factor,
Phospholipid and Calcium ) to citrated plasma. PT is time
until clot formation.
 Problems with PT: Thromboplastins vary in their sensitivity
to Vitamin K dependent clotting factors.
 So INR was introduced…
INR
 Calculated as ratio of patients PT to Mean normal PT
multiplied by International Sensitivity Index (ISI)
 ISI is an index of sensitivity of thromboplastin to reduction in
levels of Vitamin K dependent factors.
 Highly sensitive Thromboplastin have a ISI of 1.0
Issues With INR
 Unreliable reporting of ISI by Thromboplastin
manufacturers.
 Variations in reagent – coagulometer combinations.
 Every lab must establish mean normal PT with each new
batch of Thromboplastin reagent. To do this, PT of 20
healthy volunteers must be measured using same
coagulometer used for patients.
How Often to Check INR
 In patients with stable Warfarin dosing INR should be
checked every 3 weeks.
 More frequent INR testing will be required with addition of
new drugs due to interactions.
 Self monitored and self guided therapy is better for educated
patients.
Interactions
Side Effects : Bleeding & Skin Necrosis
 Bleeding may be mild as epistaxis or hematuria
 May be severe as retroperitoneal or GI Bleed.
 Causes : 1. Higher than Therapeutic INR
2. Within Therapeutic INR but bleeding
due to Peptic Ulcer or tumor.
Management of High INR & Bleeding
 Asymptomatic Patient : INR between 3.5 and 9 – Warfarin is
withheld till INR is in therapeutic range.
 If at high risk for bleeding:
INR 4.9 to 9 – 2.5 mg of Vitamin K 1(Oral)
INR > 9 – 2.5 to 5 mg of Vitamin K (Oral)
Higher doses of Vitamin K (5 – 10 mg )may be used for
rapid reversal of INR
Patients with Serious Bleeding
 Inj Vitamin K 10 mg slow IV infusion.
 Additional doses till INR is in Therapeutic range
 FFP to replace Vitamin K dependent clotting proteins.
 Prothrombin complex concenterates for life threatening
bleeding or if patients cannot tolerate volume load.
In Prosthetic Valve Patients
 In patients with prosthetic valves Inj Vitamin K should be
avoided because of the risk of valve thrombosis unless there is
a major intracranial bleed.
Skin Necrosis
 Rare complication
 Occurs in patients with congenital or acquired deficiencies of
Protein C and Protein S
 Occurs 2 to 5 days after initiation of therapy.
 Well demarcated erythematous lesions seen on buttocks, breasts,
thighs or toes.
 Skin biopsy from the borders reveal thrombi in the
microvasculature.
Mechanism of Skin Necrosis
 Initiation of warfarin therapy produces a fall in Protein C and
Protein S levels first as their half lives are……………
 Hence a prothrombotic state prevails before the
antithrombotic state takes effect.
 The procoagulant state triggers thrombosis in
microvasculature of fatty tissues.
 Treatment involves discontinuation of Warfarin and reversal
with Vitamin K if needed.
 Alternative anticoagulant UFH or LMWH should be given to
patients with thrombosis.
 Protein C concentrates in patients with Protein C deficiency
 FFP in patients with Protein S Deficiency.
Overlapping with Parenteral
Anticoagulant
 Hence in patients with known Protein C or Protein S
deficiency require overlapping treatment with a parenteral
anticoagulant.
 In these patients Warfarin should be started at low doses.
 Parenteral anticoagulant should be continued until the INR is
therapeutic for 2 to 3 days.
Contraindications
 Recent Stroke
 Hepatic Cirrhosis
 GI and Genitourinary Bleeding Points
 Uncontrolled Hypertension
 Renal impairment requires dose reduction. Eg. 25% dose
reduction for a mean Cr Clearance of 47 ml/min
 If anticoagulation is necessary always assess the risk benefit
ratio.
During Pregnancy
 Warfarin crosses the placenta but does not pass into breast
milk
 There is risk for embryopathy causing nasal hypoplasia and
stippled epiphyses especially in first trimester.
 CNS abnormalities occur with exposure to warfarin at any
time during pregnancy.
 Also creates a anticoagulant effect in foetus which can cause
intracranial hemorrhage during delivery.
Antiphospholipid Antibody Syndrome
 Usual Intensity Warfarin Therapy Versus High Intensity
Warfarin therapy
 If the Lupus Anticoagulant prolongs the baseline INR then
factor X levels can be used to monitor instead of INR.
Before Procedures
 No need to stop for procedures associated with low risk of
bleeding.
Eg: Dental Cleaning
Dental Extraction
Cataract Surgery
Skin Biopsy
 To stop Warfarin 5 days before procedures with moderate or
high risk for bleeding.
 Patients at high risk for thrombsis requires bridging with
LMWH.
How Good Is Acenocumarol…?
 Warfarin is employed more frequently than acenocoumarol
because of its longer half-life (36 h), theoretically providing
more stable anticoagulation, and avoiding factor VII
fluctuations that potentially occur during acenocoumarol
treatment (half-life 10 h).
Acenocoumarol: A Review of Anticoagulant Efficacy and
Safety : JAPI Feb 2016
Overall Advantages Of Acenocumarol
 Rapid onset of action
 The effect lasts for 15-20 hours.
 Less dependence on CYP2C9 for metabolism compared to
warfarin
 Better anticoagulation stability than warfarin
 Rapid reversal of anticoagulant action with relatively small
amounts of vitamin K17
Switching
 The SPORTIF-III substudy has shown a good correlation
between doses of warfarin and acenocoumarol. The dose
ration of warfarin to acenocoumarol is 2.18±0.78.
 In another study the transition factor between
acenocoumarol and warfarin is shown to be 1.85. The
transition factor helps to calculate the maintenance dose
when patient is required to be switch from acenocoumarol to
warfarin.
What's Wrong With Warfarin?
Narrow therapeutic range
Slow onset of action
Slow offset of action (long duration of action, long
elimination half life)
Multiple drug and dietary interactions
Monitoring required to maintain in therapeutic range
Difficult to manage for invasive procedures
Impaired quality of life for the patient
Labor intensive for health care provider
Under-use of therapy due to fear of adverse events and
complexity of management
Efficacy is dependent upon infrastructure
Time in therapeutic range (TTR) is associated with
improved safety and efficacy
TTR is improved with AC management programs
TTR is greater in countries with more sophisticated health
care infrastructure
Newer Direct Oral Anticoagulants
 Rapid onset of Action
 Half lives that permit once or twice daily action.
 Given in fixed doses without routine monitoring of
coagulation.
 Antidotes now available for Induced bleeding.
Dabigatran
 Competitive direct thrombin inhibitor.
 Inhibits both free and clot bound thrombin as well as
thrombin induced platelet aggregation.
 Substrate of P glycoprotein but no significant drug
interactions.
 Half life is 12 – 17 hours.
 Bioavailability is 6.5% and 80% of drug is excreted by
the kidneys.
Dosing
 For prevention of Stroke in Non Valvular AF dose is 150 mg BD
 If Creatinine clearance is 15 – 30 ml/min, dose is reduced to 75
mg BD.
 Now approved for VTE also: Patients should initially receive a
minimum of 5 day course of parenteral anticoagulant before
starting Dabigatran at 150 mg BD.
 Qualitative assessment of anticoagulant activity is by APTT.
 Quantitative assessment by Dilute Thrombin clotting time.
RE – LY Study
 The RE-LY study demonstrated that compared to warfarin,
high-dose dabigatran reduces stroke risk without increasing
the risk of major bleeding among patients with atrial
fibrillation.
 Published in 2009, the Randomized Evaluation of Long-Term
Anticoagulation Therapy (RE-LY) trial was a non-inferiority
study randomizing 18,000 patients with nonvalvular AF and a
moderate-to-high risk of thromboembolic stroke to either
high- or low-dose dabigatran or to warfarin.
 At a median follow-up of 2 years, high-dose dabigatran
reduced the incidence of stroke (1.11% vs. 1.69%) without a
concomitant rise in major bleeding events (3.11% vs.
3.36%). Although the study was designed to test the noninferiority of either dose compared to warfarin, the final
analysis ultimately demonstrated superiority of high-dose
dabigatran over warfarin.
 Both high and low doses of Dabigatran were
associated with a statistically significant increase in
MI (0.74% and 0.72%, respectively, vs. 0.53% for
placebo).
ACC/AHA Guidelines 2014
 In patients with nonvalvular AF with prior stroke, TIA, or
CHA2DS2-VASc score ≥2, recommend oral anticoagulation
with:
 Warfarin, goal INR 2-3 (class I, level A)
 Dabigatran (class I, level B)
 Rivaroxaban (class I, level B)
 Apixaban (class I, level B)
 In patients with nonvalvular AF unable to maintain INR 2-3 with
warfarin, recommend dabigatran, rivaroxaban, or apixaban (class
I, level C)
 In patients with nonvalvular AF with moderate or severe CKD
with CHA2DS2-VASc score ≥2, consider treatment with reduced
doses of dabigatran, rivaroxaban, or apixaban, although safety has
not yet been clearly delineated (class IIb, level C)
 In patients with ESRD, dabigatran and rivaroxaban are untested
and are not recommended (class III, level C)
 In patients with a mechanical heart valve, do not use dabigatran
(class III, level B)
Side Effects of Dabigatran
 Risk of GI bleed is higher with Dabigatran and Rivaroxaban
compared to Warfarin.
 10 % of the patients have dyspepsia on Dabigatran.
 Contraindicated in Pregnancy
 In the RE - COVER and RE – COVER 2 studies, patients
with DVT and PE who had received initial parenteral
anticoagulation, such as intravenous heparin or a
subcutaneous low-molecular-weight heparin derivative, for
five to 10 days were randomized to warfarin or dabigatran.
 These two trials showed that Dabigatran was noninferior to
warfarin in reducing DVT and PE and was associated with
lower bleeding rates.
Management of Bleeding
 Stop Drug
 Activated Charcoal if last dose in 4 – 6 hours.
 Prothrombin complex concentrate or Factor VIIa can be
administered.
 In patients with renal failure Dialysis removes Dabigatran from the
circulation.
 Idarucizumab : Specific antidote
Humanized Monoclonal Antibody Fragment
Infused as 5g IV
Rivaroxaban
 Oral inhibitor of factor Xa
 Once daily dosing
 Absolute bioavailability is about 100%
 Plasma protein binding is 92 – 95 %
 For Non Valvular AF dose is 20 mg once daily with a
reduction to 15 mg once daily in patients with Creatinine
clearance 15 – 49 ml/min.
 For VTE dose is 15 mg BD for 3 weeks and then reduced to
20 mg OD
 For VTE prophylaxis dose is 10 mg once daily.
Rivaroxaban contd…
 For qualitative assessment of anticoagulant activity Prothrombin
time can be used.
 Quantitative assessment using Chromogenic anti factor Xa assays.
 For bleeding on Rivaroxaban:
Stop Drug
Procoagulant PCC
Antidote : Andexanet Alpha
Rocket AF
 Among patients with nonvalvular atrial fibrillation,
rivaroxaban is noninferior to warfarin in preventing stroke
and systemic thromboembolism.
 ROCKET AF randomized 14,264 patients with nonvalvular
atrial fibrillation and at least a moderate risk of stroke (mean
CHADS2 score 3.5) to rivaroxaban or warfarin. At a mean
follow-up of 2 years, rivaroxaban was noninferior to warfarin
for the composite endpoint of stroke or systemic embolism,
without increasing the bleeding rates.
ATLAS ACS 2 – TIMI 51
 ATLAS ACS-2, TIMI 51 (2012) randomized 15,342 patients with
recent ACS to either twice-daily doses of either 2.5mg or 5mg of
rivaroxaban (an oral factor Xa inhibitor) vs. placebo.
 93% received dual antiplatelet therapy with aspirin and either
clopidogrel or ticlopidine.
 At a mean follow-up of 13.1 months, both dosages of rivaroxaban
decreased the rate of the primary composite outcome of CV
mortality, MI, or stroke (8.9% vs. 10.7%; HR 0.84), as well as the
rate of stent thrombosis.
 Low-dose rivaroxaban reduced CV mortality and all-cause
mortality, but this was not observed with the higher dose. The
benefits of rivaroxaban were offset by an increased rate of nonfatal bleeding, including ICH, but there was no increase in fatal
bleeding.
 In May 2012, the FDA rejected rivaroxaban in ACS patients
because of concerns regarding missing data;
Apixaban
 Direct factor Xa inhibitor
 Bioavailability is 50 % for a 10 mg dose.
 Half life is 8 – 15 hours.
 Liver metabolism is by CYP3A4 dependent and independent
mechanisms.
 Not recommended in patients receiving strong inhibitos of
both CYP3A4 and P – Gp such as azole antimycotics and HIV
protease inhibitors.
 Dosing for Non Valvular AF is 5 mg BD
 But 2.5 mg BD is recommended for patients with two or
more of the following criteria:
1. Age more than 80 years
2. Body weight < 60 kg
3. Serum Creatinine > 1.5 mg / dl
ARISTOTLE
 Apixaban for Reduction in Stroke and Other
Thromboembolic Events in Atrial Fibrillation (ARISTOTLE)
trial randomized 18,201 patients with nonvalvular AF and ≥1
stroke risk factor to apixaban or warfarin. With a median
follow-up of 1.8 years, apixaban was superior to warfarin in
rates of stroke or systemic embolism (annual incidence
1.27% vs. 1.60%). It was also associated with less major
bleeding (annual incidence 2.13% vs. 3.09%).
 In patients with nonvalvular atrial fibrillation and at ≥1 risk
factor, apixaban is associated with a greater reduction in rates
of stroke or systemic embolism while having a lower rate of
bleeding than warfarin.
APPRAISE - 2
 APPRAISE-2 (2011) randomized patients with ACS to
Apixaban or placebo. However, this was terminated early
secondary to increased rate of major bleeding in the apixaban
arm without reductions in CV death, MI or ischemic stroke.
 We should carefully explain to the patients the potential
benefits and some adverse reactions, such as dyspepsia with
dabigatran, associated with these new oral agents and the
importance of absolute compliance. Patients should be
warned that reduced adherence or nonadherence to the
treatment regimen could be fatal.
 It may be rational to monitor these drugs frequently, even if
monitoring is not needed, to make sure that the patient is
compliant.