1. Anticoagulation Update
David Lovinger, MD
Assistant Professor
Program in Hospital Medicine
University of Chicago
I have no financial conflicts to disclose

2. Objectives
To learn about new developments in anticoagulation therapy, monitoring and safety.
National Patient Safety Goal 3E
Pharmacogenetic dosing of warfarin
Use of very-low dose vitamin K to stabilize INR in hard to control patients
Duration of anticoagulation for patients with VTE

3. Introduction
In both its use and avoidance, anticoagulation is a risky therapy.
Warfarin is a very hard drug to dose properly.
There are many opportunities to improve the quality of care.

4. Risk of Adverse Events for Anticoagulated 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):

5. Anticoagulation Clinics
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

6. Key Ingredients to NPSG
“a defined anticoagulation management program”
“approved protocols”
Proper monitoring (baseline and follow-up INRs)
Education of patients and families about
Dietary restrictions
Monitoring/follow-up
Drug interactions
Outpatient and inpatient components*
Evaluation and monitoring of the program
* Not explicitly part of the NPSG, but UCMC has interpreted it to include an inpatient component.

7. Timetable
April 1, 2008: The organization’s leadership has assigned responsibility for oversight and coordination of the development, testing, and implementation of NPSG Requirement 3E.
July 1, 2008: An implementation work plan is in place that identifies adequate resources, assigned accountabilities, and a time line for full implementation by January 1, 2009.
October 1, 2008: Pilot testing in at least one clinical unit is under way.
January 1, 2009: The process is fully implemented across the organization.

8. Do Clinics Work?
In general, there is an increase in time spent in therapeutic range:
Time in therapeutic range – standard: 50-55%
Time in therapeutic range – clinic: 60-65%
Reduction in time spent in “alert” range (INR > 4.0 or < 1.4).1
Even self-testing is better than usual care.2
In studies of pharmacist managed AC clinic:
39% fewer anticoagulation-related complications.3
Pt INR’s were in therapeutic range 20% more often. 3
Reduction in hospitalizations.4
1 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.

9. Do Clinics Work? Yes, but:
The model is important: pharmacists are better studied than RN’s.
Standardization and continual evaluation are essential.
Centralization is likely NOT essential.
Small improvements in INR result in significant clinical outcomes.

10. Introduction to Warfarin Pharmacogenetics
Background on common genetic variants and how they affect warfarin dosing.
VKORC1 – affects vitamin K metabolism
CYP2C9 – affects warfarin metabolism
How these apply to clinical decisions.
Recent evidence regarding the use of warfarin dosing algorithms.

11. Warfarin Pharmacology
2 main components to the action of warfarin in the body:
Warfarin inhibits Vitamin K Epoxide Reductase (VKOR) which helps recycle Vit K.
Warfarin is metabolized via the cytochrome P450 system, specifically, CYP2C9.
CYP2C9---|
Hall, 2006

12. CYP2C9 Variant Alleles Impact Warfarin Metabolism
CYP2C9*2 has 30-50% activity of wt (CYO2C9*1.)
CYP2C9*3 has 10% activity of wt.
These variants account for 12% of the variation in warfarin dose.
Dervieux, 2005

13. CYP2C9 Allele Frequencies Vary Between Populations
CYP2C9*1 (WT)
CYP2C9*2
CYP2C9*3
Caucasian
78 – 84% %
5 – 10%
Asian
97.8% -
2.2%
African-American
93.0%
5.6%
1.4%
CYP2C9*2 reduces the rate of metabolism resulting in lower clearance (30-50% activity of WT).
CYP2C9*3 has more significantly reduced rate of metabolism and decreased enzyme efficiency (10% activity of WT).
Both result in lower need for warfarin and a lower dose
Non-WT patients have an increased risk of supratherapeutic INRs and bleeding (Higashi, et al, JAMA, 2002).

14. VKORC1 Variants Have Functional Consequences on Warfarin Dose
VKORC1 haplotype alone accounts for 21-25% of the variability in warfarin dose.
Hap A/A = 2.7±0.2 mg/day
Hap A/B = 4.9±0.2 mg/day
Hap B/B = 6.2±0.3 mg/day
Mechanism of action in these variants is unclear.
Variant VKORC1 haplotypes do not appear to have the same bleeding risk of CYP2C9 variants.
Reider, 2005

15. Frequencies of VKORC1 Variants
Form two distinct groups.
Hap A is associated with a lower warfarin maintenance dose.
Hap B is associated with a higher warfarin maintenance dose.
Population
Hap A
Hap B
European % %
African American % %
Asian % %
Peruvian
27%
71%
Mexican
38%
57%
African
23%
49%

16. Variables Known to Influence Warfarin Dose
Marsh (2006)

17. Algorithm for Dosing Daily dose of warfarin=
exp[( x VKOR3673G>A ) + ( x BSA) – ( x CYP2C9*3) – ( x age) – ( x CYP2C9*2) + ( x target INR) – ( x amiodarone) + ( x smokes) – ( x AA race) + ( x VTE)]
Difficult to use in clinical practice
Easier to use in clinical practice:
Does it work?

18. Randomized Trial of Genotype-Guided Versus Standard Warfarin Dosing in Patients Initiating Oral Anticoagulation
Anderson JL, Horne BD, Stevens SM, et al. Circulation, 2007;116:

19. Objective
To compare the effect of genotype-guided dosing on INR to standard, nomogram-based dosing.

20. Methods 206 inpatients in academic medical center.
Inclusions: patients with indication for AC (Goal INR 2-3)
Exclusions: rifampin, advanced age, renal or hepatic disease
Blinding: Unblinded
Randomized to PG-dosing or standard care based on 10 mg nomogram.
Primary endpoint was percentage of INR’s out of range.
Secondary endpoints include time to supratherapeutic INR, time in range, percentage of patients at goal by days 5 and 8, number of dosing changes.

21. Risk of Adverse Events for Anticoagulated 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):

22. Results
With the exception of the number of dosing changes, there was no difference between the 2 groups.
A non-significant trend towards fewer INR’s and fewer supratherapeutic INR’s, but...
Small study
Trends are potentially significant
Bottom line: not ready for widespread use, but will likely be useful in the future.

23. Genetic Determinants of Response to Warfarin During Initial Anticoagulation
Schwarz UI, Ritchie MD, Bradford Y, et al. N Engl J Med 2008;358:

24. Objective
To compare the effect of genotype-guided dosing on INR and bleeding to standard, nomogram-based dosing.

25. Methods 328 inpatients in academic medical center.
Inclusions: patients with indication for AC (no specific goal)
Exclusions: active malignancy or alcoholism
Blinding: Unblinded
Randomized to PG-dosing or standard care based on 10 mg nomogram.
Primary endpoints were time to first INR in therapeutic range, time to first INR > 4.0 and time INR was supratherapeutic.
Secondary endpoints were average warfarin dose and bleeding events.

26. Results
Pts with VKORC1 A/A haplotype had a significantly faster time to a therapeutic INR and a faster time to supratherapeutic INR.
CYP2C9 genotype had no effect on time to first therapeutic INR, but...
Non-wt CYP2C9 genotypes had faster time to first supratherapeutic INR.

27. Genetic Testing: Summary
VKORC and CYP2C9 variants clearly influence warfarin dose.
The effects of genetic variation are seen during initiation of therapy, but the longer term effects are not as clear.
Clinical factors have roughly the same influence as genetic factors and standardization of the dosing process is beneficial regardless of the algorithm.
The proper role for genetic testing is not well defined and further investigation will be needed.

28. Daily Vitamin K Supplementation Improves Anticoagulant Stability
Rombouts EK, Rosendaal FR, van der Meer JM. J Thromb Haemost 2007;5:2043-8

29. Background
Fluctuations in INR are associated with low baseline vitamin K intake.
Small studies have shown value in stabilizing INRs when very low dose vitamin K is added to the diet.

30. Methods 200 patients enrolled in a Dutch anticoagulation clinic:
Inclusions: age 18-80, on AC for at least 1 year
Exclusions: Renal or hepatic disease, pregnancy, non-compliance.
Randomized to 100 mcg vitamin K daily or placebo.
Primary endpoint was time in therapeutic range.
Secondary endpoints was maximal stability (pts with INRs in therapeutic range for the entire study period.)

31. Results
Time in range was 89.5% for the vit K group and 85.5% for the placebo group 4% difference ( ).
43% of the vit K group vs. 24% of the placebo group had maximal stability, RR= 1.8 ( ).

32. Optimal Duration of Anticoagulation Therapy
Pts who have VTE in the setting of transient risk factors (immobility, surgery, trauma, etc) have a low risk of recurrence after appropriate anticoagulation – 3-6 months.
5 yr risk of recurrence after provoked VTE 8-12%
Pts who have VTE in the setting of long-term risk factors (hereditary thrombophilia, cancer, lupus anticoagulant, etc) have a high risk of recurrence after appropriate anticoagulation 6-12 months.
5 yr risk of recurrence after unprovoked VTE = 25%

33. Optimal Duration of Anticoagulation Therapy, cont’d
Pts who have unprovoked VTE also have an increased risk of recurrence.
Current guidelines for unprovoked VTE are for use of VKA for 6-12 months and to consider indefinite AC.
Does everyone with unprovoked VTE need indefinite AC?
Can we predict who needs indefinite AC?
How to determine length of therapy?

34. D-Dimer Testing 608 pts w/unprovoked VTE and at least 3 months AC.
223 w/abnormal D-dimer level 30 days after discontinuation of AC.
Half were restarted on AC, half were not.
Pts w/elevated D-dimer were more likely to have recurrence if not on AC.
Palateti G, Cosmi B, Legnani C, et al. N Engl J Med 2006;355:

35. Ultrasonography Cohort study of 313 pts in Italy. 3 months of AC.
80 thrombophilia
124 unprovoked
109 provoked
3 months of AC.
Serial U/S at 3, 6, 12, 24 and 36 months.
Pts w/residual clot on U/S were at much higher risk of recurrent VTE.
Prandoni P, Lensing AWA, Prins MH, et al. Ann Intern Med. 2002;137:

36. Recommendations
Provoked VTE: 3-6 months, depending on the severity of the event.
Unprovoked VTE: 6-12 months AC, followed by:
D-Dimer OR venous doppler
If negative, can discontinue AC
If positive, continue AC and reassess periodically
Chest, 2004 recommends lifelong AC as a reasonable alternative for unprovoked VTE.
Recurrent VTE: lifelong AC.

37. Recommendations, cont’d
VTE and Thrombophilia:
APLA, ATIII or Protein C + S def’cy: lifelong AC
Factor V Leiden AND Prothrombin Gene mutation 20210: lifelong AC or treat as unprovoked VTE.
Factor V Leiden homozygote: lifelong AC or treat as unprovoked VTE.
Factor V Leiden heterozygote OR Prothrombin Gene mutation 20210: treat as unprovoked VTE.

38. Conclusions
Anticoagulation clinics are likely to become more common as time goes on.
Standardization alone can bring significant improvements
Genetic testing is not ready for prime time.
Will likely be used in the near future
Effects likely seen in initiation of therapy
Low dose vitamin K can help stabilize hard to control patients.
Use D-dimer or venous ultrasonography to identify patients at high-risk for recurrent VTE and consider longer duration of AC therapy.