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Oral Anticoagulant Therapy and Its Limitations
Surgeon General's Workshop on Deep Vein Thrombosis
Oral Anticoagulant Therapy and Its Limitations
1 | 2 | 3 | 4 | 5 | 6 | 7 | 8 | 9 | 10 | 11 | 12 | 13 | 14 | 15 | 16 | 17 | 18
SLIDE 1: Oral Anticoagulant Therapy and Its Limitations The Importance of Expert Management
Oral Anticoagulant Therapy and Its Limitations The Importance of Expert Management
Jack Ansell, M.D.
Boston University School of Medicine
May 2006
SLIDE 2: Warfarin, 20th Most Prescribed Drug in the US
Hydrocodone w/APAP 92,720 Lipitor 69,766 Lisinopril 46,207 Atenolol 44,162 Synthroid 44,056 Amoxicillin 41,394 Hydrochlorothiazide 41,346 Zithromax 37,172 Furosemide 36,508 Norvasc 34,729 Toprol XL 32,795 Alprazolam 32,405 Albuterol 31,220 | Zoloft 29,878 Zocor 27,234 Metformin HCL 25,473 Ibuprofen 25,188 Triamterene w/HCTZ 24,616 Ambien 24,494 Warfarin 24,290 Cephalexin 23,665 Nexium 23,642 Prevacid 23,629 Lexapro 22,597 Prednisone 22,507 |
23.5 million scripts in 2000
2004 data from www.rxlist.com/top200.htm
SLIDE 3: Indications for Warfarin Therapy
- Prophylaxis and/or treatment of venous thrombosis and its extension, and pulmonary embolism.
- Prophylaxis and/or treatment of the thromboembolic complications associated with atrial fibrillation and/or cardiac valve replacement.
- To reduced the risk of death, recurrent myocardial infarction, and thromboembolic events such as stroke or systemic embolization after myocardial infarction.
SLIDE 4: Coagulation Cascade Vitamin K Dependent Factors
Graphic of Coagulation Cascade Vitamin K Dependent Factors:
Within the coagulation cascade, there are 4 coagulation factors that require vitamin K for their normal synthesis: factors II, VII, IX, and X. When vitamin K is absent (or interfered with by warfarin therapy), these normal functioning factors are degraded based on their normal metabolic half-lives (half-life in hours indicated next to the respective factor).
Graphic: Warfarin Pharmacology
The only oral anticoagulants available for clinical use are the coumarin and indandedione derivatives, collectively referred to as the vitamin K antagonists (VKA), since their mechanism of action is to interfere with vitamin K which is necessary for the synthesis of specific coagulation proteins (factors II, VII, IX, and X).
SLIDE 6: Drawbacks to Warfarin Therapy
- Delayed onset and offset of action.
- Frequent blood test monitoring required:
- the dose response is unpredictable,
- has a narrow therapeutic range above which or below which bleeding or thromboembolism can occur, and
- multiple factors (illness, drugs, diet, etc.) influence dose response.
- Monitoring assay has serious limitations.
- Reversibility of anticoagulant affect is slow.
- Requires labor-intensive follow up, expert dose management, and frequent patient communication.
Graphic: Warfarin Pharmacology
Recent new developments in warfarin pharmacology have uncovered major reasons for individual responses to therapy. These include mutations in the gene that codes for the major enzyme that metabolizes warfarin (called CYP2C9) and mutations in the gene that codes for the enzyme that is the target of warfarin's effect (called the vitamin K oxide reductase complex 1 or VKORC1)
SLIDE 8: Mutations in the CYP2C9 Gene Leading to Impaired Metabolism
Two common CYP2C9 SNPs are associated with impaired metabolism of S-warfarin:
- A SNP in exon 3 (C (right arrow) T) is denoted CYP2C9*2
- A SNP in exon 7 (A (right arrow) C) is denoted CYP2C9*3
(The wild type enzyme is denoted CYP2C9*1)
Both of these point mutations are associated with reduced warfarin requirements needed to achieve and maintain a therapeutic INR
SLIDE 9: CYP2C9 Gene Variants & AC Outcomes
| Genotype | Exp / Actual Prevalence | Mean Dose | Maj / Fatal Bleeds |
|---|---|---|---|
| 1/1 (127) | 65.7 / 68.6 | 5.6 MG | 5.6 % |
| 1/*2 (28) | 17.1 / 15.1 | 4.9 | 9.4 % |
| 1/*3 (18) | 13.6 / 9.7 | 3.3 | 12.5 % |
| *2/*2 (4) | 1.1 / 2.2 | 4.0 | 22.2 % |
| *2/*3 (3) | 1.8 / 1.6 | 2.3 | 100 % |
| *3/*3 (5) | 0.7 / 2.7 | 1.6 | 13.3 % |
Gene variant group also required more time to achieve stable dose and had increased risk of high INR
Graphic: Warfarin Pharmacology
Recent new developments in warfarin pharmacology have uncovered major reasons for individual responses to therapy. These include mutations in the gene that codes for the major enzyme that metabolizes warfarin (called CYP2C9) and mutations in the gene that codes for the enzyme that is the target of warfarin's effect (called the vitamin K oxide reductase complex 1 or VKORC1)
SLIDE 11: VKORC1 Haplotype Frequency & Effect on Warfarin Dose Maintenance
| Haplotype | # Patients (Freq) | Ave Maintenance Dose (Homozygous) |
|---|---|---|
| H1 | 43 (12%) | 2.9 (2.2-3.7) |
| H2 | 88 (24%) | 3.0 (2.5-3.6) |
| H7 | 132 (35%) | 6.0 (5.2-6.9) |
| H8 | 28 (8%) | 4.8 (3.4-6.7) |
| H9 | 77 (21%) | 5.5 (4.5-6.7) |
SLIDE 12: Genetic Polymorphisms and Warfarin Therapy
| CYP2C9 Polymorphisms | |||
|---|---|---|---|
| CYP2C9*1 | CYP2C9*2 | CYP2C9*3 | |
| Caucasians | 79% - 89% | 8% - 19% | 6% - 10% |
| Native Canadians | 91% | 3% | 6% |
| African Americans | 98% | 1.5% - 3.6% 0.05% - 1.5% | |
| Asians | 95% - 98% | 0% | 1.7% - 5% |
VKORC1 Haplotypes | ||
|---|---|---|
| H1H2 | H8H9 | |
| Euro Americans | 37% | 58% |
| African Americans | 14% | 49% |
| Asian American | 89% | 10% |
SLIDE 13: High Quality Dose Management (ie, staying within therapeutic range)
The best outcomes with warfarin therapy are achieved by knowing . . .
- When to use (proper indications)
- What intensity to use (proper therapeutic range)
- How to use (proper dose management)
Proper dose management requires . . .
- Dosing decisions and management of nontherapeutic INRs
- Peri-procedural dose management
- Follow-up & communication - Education
SLIDE 14: Models of Anticoagulation Management
- Routine Medical Care (Usual Care)
- Anticoagulation Clinic (ACC)
- Patient Self-Testing (PST)
- Patient Self-Management (PSM
SLIDE 15: Frequency of Hemorrhage & TE with Usual Care vs ACC
| Study | Pat Yrs | Major Hem | Rec TE |
|---|---|---|---|
| 7 UC Studies | 3,062 | 5.5% | 2.7% |
| 8 ACC Studies | 17,644 | 2.5% | 1.6% |
Four photos of blood testing devices.
SLIDE 17: PST & PSM vs UC or ACC
| Study | Comparators | TTR | Hem & TE |
|---|---|---|---|
| 1 Study | PSTACC vs UC | 56% vs 32% | 14% vs 25% |
| 3 Studies | PSTACC vs ACC | 73% vs 67% | no AEs |
| 5 Studies | PSM vs UC | 75% vs 54% | 3.2% vs 6.1% |
| 5 Studies | PSM vs ACC | 72% vs 64% | 1.4% vs 1.0% |
SLIDE 18: High Quality Dose Management (ie, staying within therapeutic range)
The best outcomes with warfarin therapy are achieved by knowing . . .
- When to use (proper indications)
- What intensity to use (proper therapeutic range)
Proper dose management requires . . .
- Dosing decisions and management of nontherapeutic INRs
- Peri-procedural dose management
- Follow-up & communication
- Education
