Download Impediments to Anticoagulants

Anticoagulation in Cardiac Disorders
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Objectives
Be able to interpret and apply the CHEST guidelines for use of anticoagulants in cardiac conditions such
as atrial fibrillation and valves.
Recognize influences that make therapy with vitamin k antagonists difficult, and determine therapy
adjustments to account for them.
Understand the role of newer anticoagulants.
Develop a plan for educating patients.
Antithrombotic Therapy and Prevention of Thrombosis, 9th ed:
ACCP Evidence-Based Clinical Practice Guidelines
ACCP Guideline: GRADING SYSTEM
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These are the guidelines used in managing anticoagulation therapy in both cardiac disorders and venous
thromboembolism (VTE) including DVT and PE
These guidelines also now address ACS, CAD, and PAD.
The 1 recommendation is a very strong recommendation that should be followed.
The A,B, and C denotes the level of evidence involved in the recommendation.
• E.g. a Grade 1A recommendation is a very strong recommendation involving multiple placebocontrolled, double-blind, randomized trials with large populations.
• A C recommendation still is strong, but supporting literature is not as robust
The 2 recommendations are more opinionated, and not based on strong literature
• 2A recommendations are high quality evidence that suggest an outcome can go in either direction,
but their opinions are the recommendations within the guidelines
Interpreting the recommendations
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1A recommendation should be followed
1C recommendation should also be followed, but know the evidence is not as strong
2C recommendation is more of an opinion
DISCLAIMER:
• Guidelines are intended for general information
only, are not medical advice, and do not replace
professional medical care and physician advice,
which always should be sought for any specific
condition.
• No clinician, and body charged with evaluating a clinician’s actions, should attempt to apply our
recommendations in rote or blanket fashion.
Prevention of Thromboembolism with Valve Patients
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The main 2 valves that get replaced are the aortic and mitral valves in the left side of the heart
The mitral valve is a lower flow type of valve with the aortic valve having a higher flow/pressure
A valve of lower flow (mitral valve) would have a higher anticoagulation recommendation than a valve
of higher pressure (aortic valve) which would not produce clots as easily.
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Epidemiology/Etiology
• Incidence
• 70,000 replacements done each year in the US
• 60% of patients get mechanical heart valves
• 40% of patients get bioprosthetic heart valves
• Rheumatic heart disease
• Most common reason for valve replacement
• Typically affects mitral valve
• Congenital heart defects
• Typically affects the aortic valve
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Heart Valves
• Mechanical
• Caged Ball
• Tilting Disc (Monoleaflet)
• Bileaflet – only ones used NOW!
• Bioprosthetic
• Porcine
• Bovine
• Human
Caged Ball Valve
History
• First mechanical heart valve used and was designed by Charles Hufnagel.
• First used in 1960.
• Dominated for over a decade, but not used anymore
Problems
• Greatest risk of thromboembolism.
• The heart is forced to work harder.
• Damage to blood cells causing them to lyse
• Needed higher anticoagulation
Tilting Disc Valve
Introduced in 1977, and replaced the caged ball valve
• Benefits
• Improved hemodynamics and lower rate of thromboembolic (TE)
• Types
• BSCC (D/C), Medtronic Hall
• Open at a 60° angle, 70 bpm
• Angular opening reduces damage to blood cells
• Disadvantage
• Struts tend to fatigue or fracture over time
Tilting Disc Valve
• BSCC Valve:
• On the market from 1979 to 1986
• 82,000 valves implanted
• 500 cases of fracture
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• BSCC Failure:
• Outlet Strut Fracture (OSF)
• Over-rotation of the disc closing with 10x the force of the
disc opening.
Bileaflet Valve
Types
• St. Jude, CarboMedics
St. Jude
• First used in 1977
• Mitral valve prosthesis of choice in 1984.
★ Most common prosthetic valve
Advantages:
• Best central flow (leaflets open completely)
• Very little resistance. (minimize blood cell damage)
Disadvantages:
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Allow some back-flow (Design flaw)
Activated platelets from the lysed red blood cells
Bioprosthetic Valves
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Advantages:
• Only require temporary anticoagulation
Disadvantages:
• Lifespan of only 10-15 years
- The patient’s then start to get the symptoms they had before the valve was replaced
• Typically only used in elderly
Types
• Porcine, Bovine, OR
• Human
- Allograph (donor)
- Autograph (self)
ACCP Recommendations: Antithrombotic Therapy - Valves
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Warfarin is the only anticoagulant approved for these mechanical valves
Valve Type
Recommendation
Grade
MITRAL Bileaflet, tilting disk, caged ball or caged disk
INR 3.0 (2.5 - 3.5)
2C
AORTIC Bileaflet or Medtronic Hall tilting disk in NSR
with normal left atrium size
INR 2.5 (2.0 - 3.0)
2C
AORTIC Caged ball or caged disk
INR 3.0 (2.5 - 3.5)
2C
Mechanical valve with low bleeding risk
+ ASA 50 - 100 mg daily (new)
2C
AORTIC Bioprosthetic – warfarin not necessary
ASA 50 - 100 mg daily
2C
MITRAL Bioprosthetic – start with warfarin then go to
aspirin
INR 2.5 (2.5 - 3.5) x3 months then
ASA
2C
Stroke Prevention in Atrial Fibrillation
Most common heart condition involving anticoagulation
Pathophysiology of Stroke in Atrial fibrillation (AF)
• Previously believed to be a relatively simplistic mechanism: loss of organized mechanical contraction
leads to pooling of blood → mural thrombi → breaks away and travels up carotid to brain → STROKE!
Now several other mechanisms have been proposed utilizing Virchow’s Triad theory:
• Abnormal blood stasis (70-90%) cause a clot which leads to a stroke
• Endothelial/Endocardial injury; myocyte hypertrophy/necrosis
• Hypercoagulable state (prothrombin factors, D-dimer, vWF, C-reactive protein (CRP), IL-6, VEGF)
Estimating Stroke Risk in A. Fib
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Retrospective Findings:
• Prior Stroke or TIA = 2.5 – 2.9 relative risk (RR) of having a stroke
• Age = 1.6 – 1.8 RR/decade of life
• Hypertension = 1.6 – 2.0 RR (SBP > 160 = 2.3 RR)
• Female Gender* = 1.6 RR
• Diabetes Mellitus* = 1.7 RR
• LV Dysfunction = 2.5 RR
• Coronary Artery Disease = Increased Risk
• EtOH > 14 Drinks/Wk. = 0.4 RR (Better than ASA)
• *Not a significant factor in some methods of analysis
CHADS2 Risk score
Score to Estimate Stroke Risk in Atrial Fibrillation
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Congestive Heart Failure (1 point)
Hypertension (1 point)
Age > 75 years (1 point)
Diabetes (1 point)
Stroke (2 points)
CHA2DS2-VASc Risk score
Patients of low risk with a CHADS2 (score 1.9 - 2.8) then use the CHA2DS2-VASc score
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CHF/LV dysfunction (1 point)
Hypertension (1 point)
Age ≥75 (2 points)
Diabetes (1 point)
Stroke (2 points)
Vascular disease* (1 point)
Age 65-74 years (1 point)
Sex category (female) (1 point)
*Prior MI, PAD, or aortic plaque
ACCP Recommendations: Stoke Prevention in Afib, PAF
Risk Factor
No risk factor
Therapy
No therapy, OR
ASA 75-325mg daily
Grade
2B
2B
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Risk Factor
Therapy
Grade
1 risk factor
OAC* OR If unable for reasons other than bleeding
ASA + clopidogrel
1B
2B
2 risk factors
OAC* OR If unable for reasons other than bleeding
ASA + clopidogrel
1A
1B
Mitral stenosis or prosthetic
valve
Warfarin INR 2.5 OR
ASA + clopidogrel
1B
1B
With stable CAD
Warfarin alone (new)
2C
* Suggest dabigatran 150 mg BID over VKA warfarin
WARFARIN
MOA: Vitamin K Antagonist (VKA)
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Lowest Effective Intensity for Warfarin Therapy for Stroke Prevention in AFib
Studies going back to 1996 showed that the lower the INR the higher the rate of clot
Patients with atrial fibrillation have the highest risk of clots with an INR of 1
Clot risk are significantly reduced with an INR of 2 (odds ratio 1.0) or above
Studies consistently show an INR below 1.8 increase the risk of stroke
Treating a patient with warfarin as the OAC the INR needs to be > 2
Age Related Trends in AF
A focus on use of anticoagulation and risk of stroke
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With each decade of life our stroke risk increases
Warfarin use in patients approximately 70 years old decreases
These patients are at increased risk of stroke as they age, but the use of warfarin declines
Research has tried to discover the reason for this, and have found impediments to anticoagulants
Impediments to Anticoagulants
Survey of Cardiologists, Neurologists, and Primary-Care Physicians
Reason
Mean Rank (1–8)
Risk of hemorrhage
2.0
Risk of embolism too low
3.4
Patient refusal
3.6
Inconvenience of monitoring
5.1
Impairs quality of life
5.2
Aspirin is better
5.2
Cost to patient
5.6
Doubt effectiveness
6.8
Risk of Bleeding
Risk of Intracranial Hemorrhage in Outpatients
• The bleeding risk is fairly low with an INR between 1.9 – 2.3
• As the INR approaches 3.8 the bleeding risk starts to increase
• As the INR approaches 5 – 8 the increase of bleeding is even greater, and elderly patients (>75 yo) this
increased risk increases even more significantly
• There is a safety margin at the top of our target range (INR 2-3) ending at an INR of 3.5
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Bleeding risk starts to significantly increase at an INR > 4 - 5
Warfarin: Major Adverse Effect — Hemorrhage
Factors that may influence bleeding risk:
• Intensity of anticoagulation (INR > 4.0)
• Concomitant clinical disorders (i.e. cerebrovascular disease, G.I. bleed, age)
• Concomitant use of other medications
• Use of other medications such as clopidogrel, aspirin, or NSAIDs
• Quality of management – Frequency of visits to the clinic for monitoring.
HEMMORR2HAGES Bleeding Risk
H epatic or Renal disease
E thanol abuse Score Bleed Rate
M alignancy
O lder (age > 75 years)
R educed platelets
R2 ebleeding risk
H ypertension (uncontrolled)
A nemia
G enetic factors (CYP2C9)
E xcessive fall risk
S troke
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HAS–BLED Score is a newer scoring
system that is not presently in use
Special Considerations in the Elderly
Bleeding
Increased age associated with increased
sensitivity at usual doses
Comorbidity
Increased drug interactions
Possible increased bleeding risk independent of the above
Bleeding During Anticoagulation
Cumulative Rates of Major Bleeding Italian Study of Complications of Anticoagulant Therapy (ISCOAT)
• Patients greater than 75 years of age whether they have an injury or not have a bleeding risk 5 times
greater than that of the average patient
• Research has shown caution should be taken in patients > the age of 75
Warfarin Dosing in Elderly Patient
• Finding the Proper Therapeutic Range for INR: INR Values at the Time of Stroke or Intracranial Bleed
• Gurwitz, et al, 1992 and James, et al, 1992
• These 2 studies showed increasing age has been associated with an increased response to the effects of
warfarin. Most often elderly patients greater than the age of 75 need a lower dose of warfarin.
★ These studies showed doses in patients that were < 50 years old compared to those in their 70s. The
younger patients had dosage requirements that were twice that of their older counterparts.
Finding the proper therapeutic range for INR:
INR values at the time of stroke or intracranial bleed
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Safe INR target range of warfarin is between 2 – 3
Intracranial bleed increased significantly with an INR > 4
Underdosing
Avoid the temptation to under dose as:
• No good quality evidence that it reduces bleeding risk with an INR between 1.5 - 2.0
• Good quality evidence that it increases thrombosis risk
• Bleeding risk increases after an INR of 4.0
• Follow-up with patient on a regular basis (usually every 4-6 weeks)
Variable INRs
Defined as > 3 dose changes or > 3 INRs outside of range over 6 months
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When educating patients on eating foods that have a high content of vitamin K (brussels sprouts,
broccoli, spinach, romaine lettuce, etc.) tell them to eat some of these foods on a regular basis so that the
warfarin has vitamin K to anchor too.
Patients who avoid vitamin K foods have greater chance of variability of their INRs when vitamin K
foods are ingested
• Study showed 74% in range with diet strategy versus. 58% managed conventionally
• Tampa VA Study: Effects of phytonadione to decrease variability of INR for patients on warfarin.
Daily vitamin k versus. Conventional (currently ongoing, expecting 350 patients).
Pharmacogenomics and warfarin
There is a wide variability in the R and S isomers of warfarin
New guidelines suggest against routine use of genetic testing
Genetic Variations
Definition
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Possible Effects
VKORC1
• Vitamin K Epoxide Reductase, subunit C1
• Enzyme responsible for reducing vitamin K
• Polymorphisms of the VKOR gene
can lead to a varied warfarin response
CYP2C9
• CYP2C9 isoenzyme of CYP450 system is
responsible for warfarin S-isomer metabolism
• Genetic variations in 2C9 can alter
warfarin metabolism
Pharmacogenetics with warfarin
Pharmacogenetic model explained more than half of the variance in the therapeutic warfarin dose
R2 = 53.1% and without genetic factors explained only 21.5%
Dosing: www.warfarindosing.org
Use of pharmacogenetic and clinical factors to better predict the therapeutic dose of warfarin
Knowing these genetic factors can increase predictability of warfarin starting dose
Oral Anticoagulant Monitoring
Why is monitoring necessary?
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Narrow therapeutic window
• Bleeding risk at an INR > 4.0
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• Loss of efficacy at an INR < 1.8
Variable anticoagulant response due to:
• Pharmacokinetics of warfarin AND clotting factors (with different half-lives)
• Age
• Compliance
• Drug interactions (mostly related to CYP450)
• Diet (vitamin k, alcohol)
• Genetic factors
Because of these many influences there is a NEED to monitor approximately every 4 to 6 weeks if INR
is stable
More frequently if unstable, started on new medications, etc.
New guidelines suggest monitoring every 12 weeks if stable. (probably need more evidence to
implement 12 week monitoring)
New/Promising Oral Anticoagulation Agents
Current Use of Anticoagulants: Acute versus Chronic Therapy
Acute Phase
Chronic Phase
Inpatient IV heparin
Oral Vitamin K analog (warfarin)
Inpatient SC LMWH
SC LMWH
Outpatient SC LMWH
SC factor Xa inh (fondaparinux)
Inpatient SC factor Xa inh (fondaparinux)
Oral DTI (Dabigatran)
Inpatient Parenteral DTIs
Oral factor Xa inh (Rivaroxaban)
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Mechanistically this is where the medications work
Unfractionated heparin works at ATIII (antithrombin III)
LMWH (enoxaparin, and dalteparin) work and Factor X and Factor II
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Warfarin works at 4 of the clotting factors (II, VII, IX, and X)
The oral and injectable direct thrombin inhibitors work at Factor II
Pentasaccharide Xa Inhibitors (oral and injectable) work at Factor X
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Dabigatran
MOA: Direct thrombin inhibitor
Dabigatran etexilate (Pradaxa®), Boehringer Ingelheim
Pharmacology
• Prodrug of dabigatran
• Specific, competitive, reversible thrombin inhibitor
• Rapidly absorbed
• Half life ~8 hours after a single dose and 14-17 hours after multiple doses
Indications evaluated
• Stroke and systemic embolism prevention in nonvalvular atrial fibrillation (RE-LY trial) **FDA
Approved**
• Prevention and treatment of VTE (RE-NOVATE trial)
RE-LY Trial
Dabigatran versus warfarin in Afib
N= 18,113 patients (mean CHADS2 score = 2.1), Blinded dabigatran versus. unblinded warfarin
Time-in-Range for warfarin = 66%, Median follow-up = 2 years
Results:
• Dabigatran 150 mg is superior to warfarin
• Dabigatran 110 mg is non-inferior to warfarin
• Bleeding rates higher at the 150 mg dose and with age over 80 years
Dabigatran Dosing and Monitoring
Dose: 150 mg BID w/o regard to meals
Renal dosing (CrCl 15-30mg/min): 75 mg BID
Must remain in original packaging for the whole day.
Discard if not used after 120 days
Very important that patient is COMPLIANT with this medication because of it’s short half-life
Monitor for:
• Adherence, Signs and symptoms of bleeding, Stroke, GI and other ADRs
• Labs: CBC, SCR, LFTs initially and prn
Interruption for surgery: 24-48 hours prior
Rivaroxaban
MOA: Factor Xa inhibitor
Name: Xarelto, Johnson & Johnson
Pharmacology
• Reversible, factor Xa inhibitor
• Half life: healthy 5-9 hrs, elderly 9-13 hours
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Indications evaluated
• Stroke and systemic embolism prevention in nonvalvular atrial fibrillation (ROCKET-AF) ** FDA
Approved **
• Prevention of DVT/PE following knee or hip surgery ** FDA Approved **
• Prevention and treatment of VTE (EINSTEIN trial)
ROCKET-AF
Rivaroxaban versus warfarin in Afib
• N= 14, 264 (86% with CHADS2 score above 3)
• Blinded rivaroxaban versus unblinded warfarin
• Time-in-Range for warfarin = 57.8%
• Median follow-up = 19 months
• Results:
• Rivaroxaban 20 mg is similar in stroke prevention
• Rivaroxaban major bleeding rate similar; fatal bleeding rates were less; GI bleeds were more
Rivaroxaban Dosing & Monitoring
• Dose: 20 mg q24 hours taken with evening meal
• Renal dosing: 15 mg q24 hours
• Very important that patient is COMPLIANT with this medication because of it’s short half-life
• Monitor for:
• Adherence, Signs and symptoms of bleeding, Stroke, GI and other ADRs
• Labs: – CBC, SCR, LFTs prn
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Opportunities for New Agents
Rapid onset of action unlike warfarin, and no need to bridge with LMWH
• Possible elimination of initial use of parenteral agents
Less diet, Alcohol, drug interactions
Advantage in long-term anticoagulation
• Fixed dosing
• Coagulation monitoring not needed
May have increased safety over warfarin
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Potential Drawbacks of New Agents
Lack of a specific antidote for new agents
Unknown mechanism for increase in hepatic enzymes with oral agents
Effect of oral agents on PT/INR
Lack of anticoagulation monitoring
Difficult to assess compliance
Cost
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Choosing agents
Personal choice
• If patient therapeutic and doing fine on warfarin and with good compliance monitoring (stay with
warfarin)
• Patients with wildly fluctuating INRs not caused by compliance OR on multiple drugs that interact
with warfarin might be a reason to switch
Long term safety, efficacy, and tolerability
Similar ADRs: rivaroxaban and warfarin
More dyspepsia and possibly MIs with dabigatran over warfarin
Daily dosing, problem with reversing effect?
Warfarin monitoring, reinforcing compliance
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