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The Program in Hospital Medicine Anticoagulation Update David Lovinger, MD Assistant Professor Program in Hospital Medicine University of Chicago I have.

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Presentation on theme: "The Program in Hospital Medicine Anticoagulation Update David Lovinger, MD Assistant Professor Program in Hospital Medicine University of Chicago I have."— Presentation transcript:

1 The Program in Hospital Medicine 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. To learn about new developments in anticoagulation therapy, monitoring 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 stabilize INR in hard to control patientsUse of very-low dose vitamin K to stabilize INR in hard to control patients Duration of anticoagulation for patients with VTEDuration of anticoagulation for patients with VTE

3 Introduction In both its use and avoidance, anticoagulation is a risky therapy. In both its use and avoidance, anticoagulation is a risky therapy. Warfarin is a very hard drug to dose properly. Warfarin is a very hard drug to dose properly. There are many opportunities to improve the quality of care. 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: 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 a defined anticoagulation management program approved protocols approved protocols Proper monitoring (baseline and follow-up INRs) Proper monitoring (baseline and follow-up INRs) Education of patients and families about Education of patients and families about Dietary restrictionsDietary restrictions Monitoring/follow-upMonitoring/follow-up Drug interactionsDrug interactions Outpatient and inpatient components* Outpatient and inpatient components* Evaluation and monitoring of the program Evaluation and monitoring of the program * Not explicitly part of the NPSG, but UCMC has interpreted it to include an inpatient component.

7 Timetable 1. April 1, 2008: The organizations leadership has assigned responsibility for oversight and coordination of the development, testing, and implementation of NPSG Requirement 3E. 2. 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, October 1, 2008: Pilot testing in at least one clinical unit is under way. 4. 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: In general, there is an increase in time 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 > 4.0 or 4.0 or < 1.4). 1 Even self-testing is better than usual care. 2 Even self-testing is better than usual care. 2 In studies of pharmacist managed AC clinic: In studies of pharmacist managed AC clinic: 39% fewer anticoagulation-related complications. 339% fewer anticoagulation-related complications. 3 Pt INRs were in therapeutic range 20% more often. 3Pt INRs were in therapeutic range 20% more often. 3 Reduction in hospitalizations. 4Reduction in hospitalizations. 4 1 Personal communication, University of Utah, Chronic Anticoagulation Clinic. 2 Connock M, et al, Health Technol Assess, Witt, et al, Chest, Locke, et al, Pharmacotherapy, 2005.

9 Do Clinics Work? Yes, but: Yes, but: The model is important: pharmacists are better studied than RNs.The model is important: pharmacists are better studied than RNs. Standardization and continual evaluation are essential.Standardization and continual evaluation are essential. Centralization is likely NOT essential.Centralization is likely NOT essential. Small improvements in INR result in significant clinical outcomes.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. Background on common genetic variants and how they affect warfarin 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 warfarin dosing algorithms. Recent evidence regarding the use of warfarin dosing algorithms.

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

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

13 Population CYP2C9*1 (WT) CYP2C9*2CYP2C9*3 Caucasian 78 – 84% % 5 – 10% Asian97.8%-2.2% African-American93.0%5.6%1.4% CYP2C9 Allele Frequencies Vary Between Populations CYP2C9*2 reduces the rate of metabolism resulting in lower clearance (30-50% activity of WT). 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). 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 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). 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. VKORC1 haplotype alone accounts for 21-25% of the variability in warfarin dose. Hap A/A = 2.7±0.2 mg/dayHap A/A = 2.7±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 these variants is unclear. Mechanism of action in these variants is unclear. Variant VKORC1 haplotypes do not appear to have the same bleeding risk of CYP2C9 variants. Variant VKORC1 haplotypes do not appear to have the same bleeding risk of CYP2C9 variants. Reider, 2005

15 Frequencies of VKORC1 Variants Population Hap A Hap B European % % African American % % Asian % % Peruvian27%71% Mexican38%57% African23%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.

16 Variables Known to Influence Warfarin Dose Marsh (2006)

17 Algorithm for Dosing Daily dose of warfarin= 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)] 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 Difficult to use in clinical practice Easier to use in clinical practice: Easier to use in clinical practice: Does it work? Does it work?

18 The Program in Hospital Medicine 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. To compare the effect of genotype-guided dosing on INR to standard, nomogram-based dosing.

20 Methods 206 inpatients in academic medical center. 206 inpatients in academic medical center. Inclusions: patients with indication for AC (Goal INR 2-3)Inclusions: patients with indication for AC (Goal INR 2-3) Exclusions: rifampin, advanced age, renal or hepatic diseaseExclusions: rifampin, advanced age, renal or hepatic disease Blinding: UnblindedBlinding: Unblinded Randomized to PG-dosing or standard care based on 10 mg nomogram. Randomized to PG-dosing or standard care based on 10 mg nomogram. Primary endpoint was percentage of INRs out of range. Primary endpoint was percentage of INRs 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. 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. With the exception of the number of dosing changes, there was no difference between the 2 groups. A non-significant trend towards fewer INRs and fewer supratherapeutic INRs, but... A non-significant trend towards fewer INRs and fewer supratherapeutic INRs, but... Small studySmall study Trends are potentially significantTrends are potentially significant Bottom line: not ready for widespread use, but will likely be useful in the future. Bottom line: not ready for widespread use, but will likely be useful in the future.

23 The Program in Hospital Medicine 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. 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. 328 inpatients in academic medical center. Inclusions: patients with indication for AC (no specific goal)Inclusions: patients with indication for AC (no specific goal) Exclusions: active malignancy or alcoholismExclusions: active malignancy or alcoholism Blinding: UnblindedBlinding: Unblinded Randomized to PG-dosing or standard care based on 10 mg nomogram. 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. 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. 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. 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... CYP2C9 genotype had no effect on time to first therapeutic INR, but... Non-wt CYP2C9 genotypes had faster time to first supratherapeutic INR. Non-wt CYP2C9 genotypes had faster time to first supratherapeutic INR.

27 Genetic Testing: Summary VKORC and CYP2C9 variants clearly influence warfarin dose. 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. 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. 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. The proper role for genetic testing is not well defined and further investigation will be needed.

28 The Program in Hospital Medicine 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. 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. 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: 200 patients enrolled in a Dutch 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, non- compliance.Exclusions: Renal or hepatic disease, pregnancy, non- compliance. Randomized to 100 mcg vitamin K daily or placebo. Randomized to 100 mcg vitamin K daily or placebo. Primary endpoint was time in therapeutic range. Primary endpoint was time in therapeutic range. Secondary endpoints was maximal stability (pts with INRs in therapeutic range for the entire study period.) 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 ( ). 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 ( ). 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. 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%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. 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%5 yr risk of recurrence after unprovoked VTE = 25%

33 Optimal Duration of Anticoagulation Therapy, contd Pts who have unprovoked VTE also have an increased risk of recurrence. 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. 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?Does everyone with unprovoked VTE 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?

34 D-Dimer Testing 608 pts w/unprovoked VTE and at least 3 months AC. 608 pts w/unprovoked VTE and at least 3 months AC. 223 w/abnormal D- dimer level 30 days after discontinuation of AC. 223 w/abnormal D- dimer level 30 days after discontinuation of AC. Half were restarted on AC, half were not. Half were restarted on AC, half were not. Pts w/elevated D-dimer were more likely to have recurrence if not on AC. 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. Cohort study of 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, 12, 24 and 36 months. 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. 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. Provoked VTE: 3-6 months, depending on the severity of the event. Unprovoked VTE: 6-12 months AC, followed by: Unprovoked VTE: 6-12 months AC, followed by: D-Dimer OR venous dopplerD-Dimer OR venous doppler If negative, can discontinue ACIf negative, can discontinue AC If positive, continue AC and reassess periodicallyIf positive, continue AC and reassess periodically Chest, 2004 recommends lifelong AC as a reasonable alternative for unprovoked VTE. Chest, 2004 recommends lifelong AC as a reasonable alternative for unprovoked VTE. Recurrent VTE: lifelong AC. Recurrent VTE: lifelong AC.

37 Recommendations, contd VTE and Thrombophilia: VTE and Thrombophilia: APLA, ATIII or Protein C + S defcy: lifelong ACAPLA, ATIII or Protein C + S defcy: lifelong AC Factor V Leiden AND Prothrombin Gene mutation 20210: lifelong AC or treat as unprovoked VTE.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 homozygote: lifelong AC or treat as unprovoked VTE. Factor V Leiden heterozygote OR Prothrombin Gene mutation 20210: 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. Anticoagulation clinics are likely to become more common as time goes on. Standardization alone can bring significant improvementsStandardization alone can bring significant improvements 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 to control patients. 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. Use D-dimer or venous ultrasonography to identify patients at high-risk for recurrent VTE and consider longer duration of AC therapy.


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