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Transcript of The Program in Hospital Medicine Anticoagulation Update David Lovinger, MD Assistant Professor...
The Program in Hospital Medicine
Anticoagulation UpdateAnticoagulation Update
David Lovinger, MDDavid Lovinger, MDAssistant ProfessorAssistant ProfessorProgram in Hospital Program in Hospital MedicineMedicineUniversity of ChicagoUniversity of ChicagoI have no financial conflicts to disclose
ObjectivesObjectives
To learn about new developments in To learn about new developments in anticoagulation therapy, monitoring anticoagulation therapy, monitoring and safety.and safety.• National Patient Safety Goal 3ENational Patient Safety Goal 3E• Pharmacogenetic dosing of warfarinPharmacogenetic dosing of warfarin• Use of very-low dose vitamin K to Use of very-low dose vitamin K to
stabilize INR in hard to control patientsstabilize INR in hard to control patients• Duration of anticoagulation for patients Duration of anticoagulation for patients
with VTEwith VTE
IntroductionIntroduction
In both its use and avoidance, In both its use and avoidance, anticoagulation is a risky anticoagulation is a risky therapy.therapy.
Warfarin is a very hard drug to Warfarin is a very hard drug to dose properly.dose properly.
There are many opportunities to There are many opportunities to improve the quality of care.improve the quality of care.
Risk of Adverse Events for Risk of Adverse Events for Anticoagulated PatientsAnticoagulated Patients
Adapted from Hylek EM et. al. An analysis of the lowest effective intensity of prophylactic anticoagulation for patients with nonrheumatic atrial fibrillation. NEJM 1996; 335(8):540-6 and Hylek EM and Singer DE. Risk factors for intracranial hemorrhage in outpatients taking warfarin. Ann Intern Med 1994; 120(11):897-902.
Anticoagulation ClinicsAnticoagulation Clinics
JCAHO Patient Safety Goal 3E:JCAHO Patient Safety Goal 3E:• Mandate:“Reduce the likelihood of patient
harm associated with the use of anticoagulation therapy.”
• Rationale: Anticoagulation is a high risk treatment, which commonly leads to adverse drug events due to the complexity of dosing these medications, monitoring their effects, and ensuring patient compliance with outpatient therapy. The use of standardized practices that include patient involvement can reduce the risk of adverse drug events associated with the use of heparin (unfractionated), low molecular weight heparin (LMWH), warfarin, and other anticoagulants
Key Ingredients to NPSGKey Ingredients to NPSG
““a defined anticoagulation management a defined anticoagulation management program”program”
““approved protocols”approved protocols” Proper monitoring (baseline and follow-up Proper monitoring (baseline and follow-up
INRs)INRs) Education of patients and families about Education of patients and families about
• Dietary restrictionsDietary restrictions• Monitoring/follow-up Monitoring/follow-up • Drug interactionsDrug interactions
Outpatient and inpatient components*Outpatient and inpatient components* Evaluation and monitoring of the programEvaluation and monitoring of the program
* Not explicitly part of the NPSG, but UCMC has interpreted it to include an inpatient component.
TimetableTimetable
1.1. April 1, 2008:April 1, 2008: The organization’s leadership The organization’s leadership has assigned responsibility for oversight and has assigned responsibility for oversight and coordination of the development, testing, coordination of the development, testing, and implementation of NPSG Requirement and implementation of NPSG Requirement 3E.3E.
2.2. July 1, 2008:July 1, 2008: An implementation work plan is An implementation work plan is in place that identifies adequate resources, in place that identifies adequate resources, assigned accountabilities, and a time line for assigned accountabilities, and a time line for full implementation by January 1, 2009. full implementation by January 1, 2009.
3.3. October 1, 2008:October 1, 2008: Pilot testing in at least one Pilot testing in at least one clinical unit is under way. clinical unit is under way.
4.4. January 1, 2009:January 1, 2009: The process is fully The process is fully implemented across the organization. implemented across the organization.
Do Clinics Work?Do Clinics Work? In general, there is an increase in time In general, there is an increase in time
spent in therapeutic range:spent in therapeutic range:• Time in therapeutic range – standard: 50-55%Time in therapeutic range – standard: 50-55%• Time in therapeutic range – clinic: 60-65%Time in therapeutic range – clinic: 60-65%• Reduction in time spent in “alert” range (INR Reduction in time spent in “alert” range (INR >>
4.0 or 4.0 or << 1.4). 1.4).11
Even self-testing is better than usual care.Even self-testing is better than usual care.22
In studies of pharmacist managed AC clinic:In studies of pharmacist managed AC clinic:• 39% fewer anticoagulation-related 39% fewer anticoagulation-related
complications.complications.33
• Pt INR’s were in therapeutic range 20% more Pt INR’s were in therapeutic range 20% more often. often. 33
• Reduction in hospitalizations.Reduction in hospitalizations.441 Personal communication, University of Utah, Chronic Anticoagulation Clinic.2 Connock M, et al, Health Technol Assess, 2007.3 Witt, et al, Chest, 2005.4 Locke, et al, Pharmacotherapy, 2005.
Do Clinics Work?Do Clinics Work?
Yes, but:Yes, but:• The model is important: pharmacists are The model is important: pharmacists are
better studied than RN’s.better studied than RN’s.• Standardization and continual Standardization and continual
evaluation are essential.evaluation are essential.• Centralization is likely Centralization is likely NOT NOT essential.essential.• Small improvements in INR result in Small improvements in INR result in
significant clinical outcomes.significant clinical outcomes.
Introduction to Warfarin Introduction to Warfarin PharmacogeneticsPharmacogenetics
Background on common genetic Background on common genetic variants and how they affect warfarin variants and how they affect warfarin dosing.dosing.• VKORC1 – affects vitamin K metabolismVKORC1 – affects vitamin K metabolism• CYP2C9 – affects warfarin metabolismCYP2C9 – affects warfarin metabolism
How these apply to clinical decisions.How these apply to clinical decisions. Recent evidence regarding the use of Recent evidence regarding the use of
warfarin dosing algorithms.warfarin dosing algorithms.
Warfarin PharmacologyWarfarin Pharmacology
2 main components to 2 main components to the action of warfarin the action of warfarin in the body:in the body:• Warfarin inhibits Warfarin inhibits
Vitamin K Epoxide Vitamin K Epoxide Reductase (VKOR) Reductase (VKOR) which helps recycle Vit which helps recycle Vit K.K.
• Warfarin is metabolized Warfarin is metabolized via the cytochrome via the cytochrome P450 system, P450 system, specifically, CYP2C9.specifically, CYP2C9.
Hall, 2006
CYP2C9---|
CYP2C9CYP2C9 Variant Alleles Variant Alleles Impact Warfarin MetabolismImpact Warfarin Metabolism
CYP2C9*2 has CYP2C9*2 has 30-50% activity 30-50% activity of wt of wt (CYO2C9*1.)(CYO2C9*1.)
CYP2C9*3 has CYP2C9*3 has 10% activity of 10% activity of wt.wt.
These variants These variants account for 12% account for 12% of the variation in of the variation in warfarin dose.warfarin dose.
Dervieux, 2005
PopulationPopulation CYP2C9*1 CYP2C9*1 (WT)(WT) CYP2C9*2CYP2C9*2 CYP2C9*3CYP2C9*3
CaucasianCaucasian 78 – 84%78 – 84% 10 - 12.5%10 - 12.5% 5 – 10%5 – 10%
AsianAsian 97.8%97.8% -- 2.2%2.2%
African-AmericanAfrican-American 93.0%93.0% 5.6%5.6% 1.4%1.4%
CYP2C9 Allele Frequencies Vary Between Populations
CYP2C9*2 reduces the rate of metabolism resulting in lower CYP2C9*2 reduces the rate of metabolism resulting in lower clearance (30-50% activity of WT).clearance (30-50% activity of WT).
CYP2C9*3 has more significantly reduced rate of CYP2C9*3 has more significantly reduced rate of metabolism and decreased enzyme efficiency (10% activity metabolism and decreased enzyme efficiency (10% activity of WT).of WT).
Both result in lower need for warfarin and a lower dose Both result in lower need for warfarin and a lower dose Non-WT patients have an increased risk of supratherapeutic Non-WT patients have an increased risk of supratherapeutic
INRs and bleeding (Higashi, et al, JAMA, 2002).INRs and bleeding (Higashi, et al, JAMA, 2002).
VKORC1VKORC1 Variants Have Functional Variants Have Functional Consequences on Warfarin DoseConsequences on Warfarin Dose
VKORC1VKORC1 haplotype alone haplotype alone accounts for 21-25% of accounts for 21-25% of the variability in warfarin the variability in warfarin dose.dose.• Hap A/A = 2.7Hap A/A = 2.7±0.2 mg/day±0.2 mg/day• Hap A/B = 4.9±0.2 mg/dayHap A/B = 4.9±0.2 mg/day• Hap B/B = 6.2±0.3 mg/dayHap B/B = 6.2±0.3 mg/day
Mechanism of action in Mechanism of action in these variants is unclear.these variants is unclear.
Variant VKORC1 Variant VKORC1 haplotypes do not haplotypes do not appear to have the same appear to have the same bleeding risk of CYP2C9 bleeding risk of CYP2C9 variants.variants.
Reider, 2005
Frequencies of Frequencies of VKORC1VKORC1 VariantsVariants
PopulationPopulation Hap AHap A Hap BHap B
EuropeanEuropean 37 - 42%37 - 42% 57 - 58%57 - 58%
African African AmericanAmerican 14 - 21%14 - 21% 49 - 58%49 - 58%
AsianAsian 85 - 89%85 - 89% 10 - 14%10 - 14%
PeruvianPeruvian 27%27% 71%71%
MexicanMexican 38%38% 57%57%
AfricanAfrican 23%23% 49%49%
Form two distinct groups.
Hap A is associated with a lower warfarin maintenance dose.
Hap B is associated with a higher warfarin maintenance dose.
Variables Known to Influence Variables Known to Influence Warfarin DoseWarfarin Dose
Marsh (2006)
Algorithm for DosingAlgorithm for Dosing
Daily dose of warfarin=Daily dose of warfarin= exp[(0.9751-0.3238 x VKOR3673G>A ) + exp[(0.9751-0.3238 x VKOR3673G>A ) +
(0.4317 x BSA) – (0.4008 x (0.4317 x BSA) – (0.4008 x CYP2C9*3CYP2C9*3) – ) – (0.00745 x age) – (0.2066 x (0.00745 x age) – (0.2066 x CYP2C9*2CYP2C9*2) + ) + (0.2029 x target INR) – (0.2538 x amiodarone) (0.2029 x target INR) – (0.2538 x amiodarone) + (0.0922 x smokes) – (0.0901 x AA race) + + (0.0922 x smokes) – (0.0901 x AA race) + (0.0664 x VTE)](0.0664 x VTE)]
Difficult to use in clinical practiceDifficult to use in clinical practice Easier to use in clinical practice: Easier to use in clinical practice:
http://www.warfarindosing.org/http://www.warfarindosing.org/ Does it work?Does it work?
The Program in Hospital Medicine
Randomized Trial of Genotype-Randomized Trial of Genotype-Guided Versus Standard Warfarin Guided Versus Standard Warfarin Dosing in Patients Initiating Oral Dosing in Patients Initiating Oral
AnticoagulationAnticoagulation
Anderson JL, Horne BD, Stevens Anderson JL, Horne BD, Stevens SM, et al. Circulation, SM, et al. Circulation, 2007;116:2563-25702007;116:2563-2570
ObjectiveObjective
To compare the effect of genotype-To compare the effect of genotype-guided dosing on INR to standard, guided dosing on INR to standard, nomogram-based dosing.nomogram-based dosing.
MethodsMethods 206 inpatients in academic medical center.206 inpatients in academic medical center.
• Inclusions: patients with indication for AC (Goal INR Inclusions: patients with indication for AC (Goal INR 2-3)2-3)
• Exclusions: rifampin, advanced age, renal or hepatic Exclusions: rifampin, advanced age, renal or hepatic diseasedisease
• Blinding: UnblindedBlinding: Unblinded Randomized to PG-dosing or standard care Randomized to PG-dosing or standard care
based on 10 mg nomogram.based on 10 mg nomogram. Primary endpoint was percentage of INR’s out Primary endpoint was percentage of INR’s out
of range.of range. Secondary endpoints include time to Secondary endpoints include time to
supratherapeutic INR, time in range, supratherapeutic INR, time in range, percentage of patients at goal by days 5 and 8, percentage of patients at goal by days 5 and 8, number of dosing changes.number of dosing changes.
Risk of Adverse Events for Risk of Adverse Events for Anticoagulated PatientsAnticoagulated Patients
Adapted from Hylek EM et. al. An analysis of the lowest effective intensity of prophylactic anticoagulation for patients with nonrheumatic atrial fibrillation. NEJM 1996; 335(8):540-6 and Hylek EM and Singer DE. Risk factors for intracranial hemorrhage in outpatients taking warfarin. Ann Intern Med 1994; 120(11):897-902.
ResultsResults With the exception of With the exception of
the number of dosing the number of dosing changes, there was no changes, there was no difference between the 2 difference between the 2 groups. groups.
A non-significant trend A non-significant trend towards fewer INR’s and towards fewer INR’s and fewer supratherapeutic fewer supratherapeutic INR’s, but...INR’s, but...• Small studySmall study• Trends are potentially Trends are potentially
significantsignificant Bottom line: not ready Bottom line: not ready
for widespread use, but for widespread use, but will likely be useful in the will likely be useful in the future.future.
The Program in Hospital Medicine
Genetic Determinants of Genetic Determinants of Response to Warfarin During Response to Warfarin During
Initial AnticoagulationInitial Anticoagulation
Schwarz UI, Ritchie MD, Bradford Schwarz UI, Ritchie MD, Bradford Y, et al. N Engl J Med Y, et al. N Engl J Med 2008;358:999-1008.2008;358:999-1008.
ObjectiveObjective
To compare the effect of genotype-To compare the effect of genotype-guided dosing on INR and bleeding to guided dosing on INR and bleeding to standard, nomogram-based dosing.standard, nomogram-based dosing.
MethodsMethods 328 inpatients in academic medical center.328 inpatients in academic medical center.
• Inclusions: patients with indication for AC (no Inclusions: patients with indication for AC (no specific goal)specific goal)
• Exclusions: active malignancy or alcoholismExclusions: active malignancy or alcoholism• Blinding: UnblindedBlinding: Unblinded
Randomized to PG-dosing or standard care Randomized to PG-dosing or standard care based on 10 mg nomogram.based on 10 mg nomogram.
Primary endpoints were time to first INR in Primary endpoints were time to first INR in therapeutic range, time to first INR > 4.0 therapeutic range, time to first INR > 4.0 and time INR was supratherapeutic.and time INR was supratherapeutic.
Secondary endpoints were average Secondary endpoints were average warfarin dose and bleeding events.warfarin dose and bleeding events.
ResultsResults Pts with VKORC1 A/A Pts with VKORC1 A/A
haplotype had a haplotype had a significantly faster significantly faster time to a therapeutic time to a therapeutic INR INR and and a faster time a faster time to supratherapeutic to supratherapeutic INR. INR.
CYP2C9 genotype CYP2C9 genotype had no effect on time had no effect on time to first therapeutic to first therapeutic INR, but...INR, but...
Non-wt CYP2C9 Non-wt CYP2C9 genotypes had faster genotypes had faster time to first time to first supratherapeutic INR.supratherapeutic INR.
Genetic Testing: SummaryGenetic Testing: Summary
VKORC and CYP2C9 variants clearly influence VKORC and CYP2C9 variants clearly influence warfarin dose.warfarin dose.
The effects of genetic variation are seen The effects of genetic variation are seen during initiation of therapy, but the longer during initiation of therapy, but the longer term effects are not as clear.term effects are not as clear.
Clinical factors have roughly the same Clinical factors have roughly the same influence as genetic factors and influence as genetic factors and standardization of the dosing process is standardization of the dosing process is beneficial regardless of the algorithm.beneficial regardless of the algorithm.
The proper role for genetic testing is not well The proper role for genetic testing is not well defined and further investigation will be defined and further investigation will be needed.needed.
The Program in Hospital Medicine
Daily Vitamin K Daily Vitamin K Supplementation Improves Supplementation Improves
Anticoagulant StabilityAnticoagulant Stability
Rombouts EK, Rosendaal FR, van Rombouts EK, Rosendaal FR, van der Meer JM. J Thromb Haemost der Meer JM. J Thromb Haemost
2007;5:2043-82007;5:2043-8
BackgroundBackground
Fluctuations in INR are associated Fluctuations in INR are associated with low baseline vitamin K intake.with low baseline vitamin K intake.
Small studies have shown value in Small studies have shown value in stabilizing INRs when very low dose stabilizing INRs when very low dose vitamin K is added to the diet.vitamin K is added to the diet.
MethodsMethods
200 patients enrolled in a Dutch 200 patients enrolled in a Dutch anticoagulation clinic:anticoagulation clinic:• Inclusions: age 18-80, on AC for at least 1 yearInclusions: age 18-80, on AC for at least 1 year• Exclusions: Renal or hepatic disease, pregnancy, Exclusions: Renal or hepatic disease, pregnancy,
non-compliance.non-compliance. Randomized to 100 mcg vitamin K daily or Randomized to 100 mcg vitamin K daily or
placebo.placebo. Primary endpoint was time in therapeutic Primary endpoint was time in therapeutic
range.range. Secondary endpoints was maximal stability Secondary endpoints was maximal stability
(pts with INRs in therapeutic range for the (pts with INRs in therapeutic range for the entire study period.)entire study period.)
ResultsResults Time in range Time in range
was 89.5% for the was 89.5% for the vit K group and vit K group and 85.5% for the 85.5% for the placebo group 4% placebo group 4% difference (-0.3 - difference (-0.3 - 8.0).8.0).
43% of the vit K 43% of the vit K group vs. 24% of group vs. 24% of the placebo group the placebo group had maximal had maximal stability, RR= 1.8 stability, RR= 1.8 (1.1-2.7).(1.1-2.7).
Optimal Duration of Optimal Duration of Anticoagulation TherapyAnticoagulation Therapy
Pts who have VTE in the setting of transient Pts who have VTE in the setting of transient risk factors (immobility, surgery, trauma, risk factors (immobility, surgery, trauma, etc) have a low risk of recurrence after etc) have a low risk of recurrence after appropriate anticoagulation – 3-6 months.appropriate anticoagulation – 3-6 months.• 5 yr risk of recurrence after 5 yr risk of recurrence after provokedprovoked VTE 8- VTE 8-
12%12% Pts who have VTE in the setting of long-Pts who have VTE in the setting of long-
term risk factors (hereditary thrombophilia, term risk factors (hereditary thrombophilia, cancer, lupus anticoagulant, etc) have a cancer, lupus anticoagulant, etc) have a high risk of recurrence after appropriate high risk of recurrence after appropriate anticoagulation 6-12 months.anticoagulation 6-12 months.• 5 yr risk of recurrence after 5 yr risk of recurrence after unprovokedunprovoked VTE = VTE =
25%25%
Optimal Duration of Optimal Duration of Anticoagulation Therapy, cont’dAnticoagulation Therapy, cont’d
Pts who have unprovoked VTE also Pts who have unprovoked VTE also have an increased risk of recurrence. have an increased risk of recurrence.
Current guidelines for unprovoked Current guidelines for unprovoked VTE are for use of VKA for 6-12 VTE are for use of VKA for 6-12 months and to consider indefinite AC.months and to consider indefinite AC.• Does everyone with unprovoked VTE Does everyone with unprovoked VTE
need indefinite AC?need indefinite AC?• Can we predict who needs indefinite AC?Can we predict who needs indefinite AC?• How to determine length of therapy?How to determine length of therapy?
D-Dimer TestingD-Dimer Testing
608 pts w/unprovoked 608 pts w/unprovoked VTE and at least 3 VTE and at least 3 months AC.months AC.
223 w/abnormal D-223 w/abnormal D-dimer level 30 days dimer level 30 days after discontinuation after discontinuation of AC.of AC.
Half were restarted on Half were restarted on AC, half were not.AC, half were not.
Pts w/elevated D-Pts w/elevated D-dimer were more likely dimer were more likely to have recurrence if to have recurrence if not on AC.not on AC.
Palateti G, Cosmi B, Legnani C, et al. N Engl J Palateti G, Cosmi B, Legnani C, et al. N Engl J Med 2006;355:1780-9.Med 2006;355:1780-9.
UltrasonographyUltrasonography Cohort study of Cohort study of
313 pts in Italy.313 pts in Italy.• 80 thrombophilia80 thrombophilia• 124 unprovoked124 unprovoked• 109 provoked109 provoked
3 months of AC.3 months of AC. Serial U/S at 3, 6, Serial U/S at 3, 6,
12, 24 and 36 12, 24 and 36 months.months.
Pts w/residual Pts w/residual clot on U/S were clot on U/S were at much higher at much higher risk of recurrent risk of recurrent VTE.VTE. Prandoni P, Lensing AWA, Prins MH, et al. Ann Intern
Med. 2002;137:955-560
RecommendationsRecommendations Provoked VTE:Provoked VTE: 3-6 months, depending on 3-6 months, depending on
the severity of the event.the severity of the event. Unprovoked VTE: Unprovoked VTE: 6-12 months AC, 6-12 months AC,
followed by:followed by:• D-Dimer D-Dimer OROR venous doppler venous doppler• If negative, can discontinue ACIf negative, can discontinue AC• If positive, continue AC and reassess If positive, continue AC and reassess
periodicallyperiodically Chest, 2004 recommends lifelong AC as a Chest, 2004 recommends lifelong AC as a
reasonable alternative for unprovoked reasonable alternative for unprovoked VTE.VTE.
Recurrent VTE:Recurrent VTE: lifelong AC. lifelong AC.
Recommendations, cont’dRecommendations, cont’d
VTE and Thrombophilia: VTE and Thrombophilia: • APLA, ATIII or Protein C + S def’cy: APLA, ATIII or Protein C + S def’cy:
lifelong AClifelong AC• Factor V Leiden Factor V Leiden ANDAND Prothrombin Gene Prothrombin Gene
mutation 20210: lifelong AC or treat as mutation 20210: lifelong AC or treat as unprovoked VTE.unprovoked VTE.
• Factor V Leiden homozygote: lifelong AC Factor V Leiden homozygote: lifelong AC or treat as unprovoked VTE.or treat as unprovoked VTE.
• Factor V Leiden heterozygote Factor V Leiden heterozygote OROR Prothrombin Gene mutation 20210: Prothrombin Gene mutation 20210: treat as unprovoked VTE.treat as unprovoked VTE.
ConclusionsConclusions Anticoagulation clinics are likely to become Anticoagulation clinics are likely to become
more common as time goes on.more common as time goes on.• Standardization alone can bring significant Standardization alone can bring significant
improvementsimprovements Genetic testing is not ready for prime time.Genetic testing is not ready for prime time.
• Will likely be used in the near futureWill likely be used in the near future• Effects likely seen in initiation of therapyEffects likely seen in initiation of therapy
Low dose vitamin K can help stabilize hard Low dose vitamin K can help stabilize hard to control patients.to control patients.
Use D-dimer or venous ultrasonography to Use D-dimer or venous ultrasonography to identify patients at high-risk for recurrent identify patients at high-risk for recurrent VTE and consider longer duration of AC VTE and consider longer duration of AC therapy.therapy.