# Presentation: 501766

## Oral Anticoagulant Therapy and Its Limitations

**Oral Anticoagulant Therapy and Its Limitations**
***The Importance of Expert Management***

**Jack Ansell, M.D.**
**Boston University School of Medicine**
**May 2006**

## 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

- <date/time>

**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**

- Warfarin, 20th Most
- Prescribed Drug in the US

**23.5 million scripts in 2000**
**2004 data from www.rxlist.com/top200.htm**

## Indications for Warfarin Therapy

- 1.  Prophylaxis and/or treatment of venous thrombosis
- 	 and its extension, and pulmonary embolism.
- 2.  Prophylaxis and/or treatment of the thromboembolic
- 	 complications associated with atrial fibrillation and/or
- 	 cardiac valve replacement.
- 3.  To reduced the risk of death, recurrent myocardial
- 	 infarction, and thromboembolic events such as stroke
- 	 or systemic embolization after myocardial infarction.

- Physicans Desk Reference, 2006 Thomson PDR,
- Montvale, NJ, page 933.

## Coagulation Cascade

- <date/time>

**Fibrin Clot**

**XII**

**Coagulation Cascade**
**Vitamin K Dependent Factors**

- Intrinsic

- Extrinsic

**XI**

**IX**

**VIII**

**VII**

**X**

**V**

**II**

**I**

**6 hr**

**36 hr**

**60 hr**

**24 hr**

- Tissue Factor

**PT / INR**

**aPTT**

## WARFARIN

**        ****O**
**H H  ||**
**N-C-C**
**     ****|**
**    ****CH****2**
**     ****|**
**    ****CH****2**
**     ****|**
**    ****COOH**

**Prothrombin **

**“****Carboxylase” ****CO****2**

**O****2**

**CO****2**

**Reduced Vitamin K**

**Oxidized Vitamin K**

**S-warfarin**

**R-warfarin**

- CYP1A1
- CYP1A2
- CYP3A4

**CYP2C9**

**Glutamic**
**Acid**

**-Carboxy-**
**Glutamic**
**Acid**

**               ****O**
**       ****H H  ||**
**       ****N-C-C**
**           ****|**
**          ****CH****2**
**           ****|**
**          ****CH**
**          ****/ \**
**HOOC  COOH**

**WARFARIN**

**Vitamin K Oxide Reductase**

- Adapted, B. Gage

## 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.

## WARFARIN

**        ****O**
**H H  ||**
**N-C-C**
**     ****|**
**    ****CH****2**
**     ****|**
**    ****CH****2**
**     ****|**
**    ****COOH**

**Prothrombin **

**“****Carboxylase” ****CO****2**

**O****2**

**CO****2**

**Reduced Vitamin K**

**Oxidized Vitamin K**

**S-warfarin**

**R-warfarin**

- CYP1A1
- CYP1A2
- CYP3A4

**CYP2C9**

**Glutamic**
**Acid**

**-Carboxy-**
**Glutamic**
**Acid**

**               ****O**
**       ****H H  ||**
**       ****N-C-C**
**           ****|**
**          ****CH****2**
**           ****|**
**          ****CH**
**          ****/ \**
**HOOC  COOH**

**WARFARIN**

**Vitamin K Oxide Reductase**

- Adapted, B. Gage

## Mutations in the CYP2C9 GeneLeading to Impaired Metabolism

- <date/time>

- Mutations in the CYP2C9 GeneLeading to Impaired Metabolism

- Two common CYP2C9 SNPs are associated with
- impaired metabolism of S-warfarin:
- 		A SNP in exon 3 (C	T) is denoted CYP2C9*2
- 		A SNP in exon 7 (A	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

## CYP2C9 Gene Variants & AC Outcomes

- <date/time>

- CYP2C9 Gene Variants & AC Outcomes

**	****	**** ****Exp / Actual****	****Mean****	****        Maj / Fatal**
_**Genotype**_**	****  **_**Prevalence**_**	**_**Dose**_**	****	****  **_**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 ****%****  **

- Higashi MK, et al, JAMA 2002; 287:1690-1698.  ©2002 American Medical Association

**Gene variant group also required more time to achieve **
**stable dose and had increased risk of high INR**

**% per pt yr**

## WARFARIN

**        ****O**
**H H  ||**
**N-C-C**
**     ****|**
**    ****CH****2**
**     ****|**
**    ****CH****2**
**     ****|**
**    ****COOH**

**Prothrombin **

**“****Carboxylase” ****CO****2**

**O****2**

**CO****2**

**Reduced Vitamin K**

**Oxidized Vitamin K**

**S-warfarin**

**R-warfarin**

- CYP1A1
- CYP1A2
- CYP3A4

**CYP2C9**

**Glutamic**
**Acid**

**-Carboxy-**
**Glutamic**
**Acid**

**               ****O**
**       ****H H  ||**
**       ****N-C-C**
**           ****|**
**          ****CH****2**
**           ****|**
**          ****CH**
**          ****/ \**
**HOOC  COOH**

**WARFARIN**

**Vitamin K Oxide Reductase**

- Adapted, B. Gage

## VKORC1 Haplotype Frequency &Effect on Warfarin Dose Maintenance

- <date/time>

- VKORC1 Haplotype Frequency &Effect on Warfarin Dose Maintenance

- 				            Ave Maintenance
- _Haplotype_    	_# Patients (Freq)_     _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)

- Rieder et al. NEJM 2005;352:22

## Genetic Polymorphisms and Warfarin Therapy

- <date/time>

- Genetic Polymorphisms and Warfarin Therapy

- 	**	****	****	****	****CYP2C9 Polymorphisms****1**
**	****	****	****	**_**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%****	****   0.5% - 1.5%**
**Asians****	****	****95% - 98%****	****  0%****	****	****   1.7% - 5%**
**   **
**	****	****	****	****               ****VKORC1 Haplotypes****2**
**	****	****	****	****	****     **_**H1H2**_**	****	**_**H8H9**_
**Euro Americans****	****	****     37%****	****	****58%**
**African Americans****	****	****     14%****	****	****49%**
**Asian Americans****	****	****     89%****	****	****10%**

- 1Takahashi, et al. Clinical Pharmacokinetics 2001;40:587-603. © Lippincott Williams & Wilkins
- 2Rieder. NEJM 2005;352:2285

## High Quality Dose Management(ie, staying within therapeutic range)

- <date/time>

- 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

## Models of Anticoagulation Management

- <date/time>

- Models of Anticoagulation Management

-  Routine Medical Care (Usual Care)
-  Anticoagulation Clinic (ACC)
-  Patient Self-Testing (PST)
-  Patient Self-Management (PSM)

## Frequency of Hemorrhage 

- Frequency of Hemorrhage
- & TE with Usual Care vs ACC

**	****	****	****     ****	**** ****Pat            Major        Rec**
**   **_**Study**_** ****	****     ****	**** **_**Yrs**_**            **_**Hem**_**          **_**TE**_
- 7 UC Studies	  3,062	 5.5%	         2.7%
- 8 ACC Studies	17,644	 2.5%	         1.6%
**	**

**Usual Care Studies:**
- Landefeld 1989, Gitter 1995, Steffensen 1997, Beyth 1998,
- Cortelazzo 1995,Chiquette 1998, Matchar 2002

**Anticoagulation Clinic Studies:**
- Seabrook 1990, Fihn 1993, van der Meer 1993,
- Cortelazzo 1993, Cannegieter 1995, Palareti 1996,
- Chiquette 1998, Matchar 2002

## <footer>

- <date/time>

## PST & PSM vs UC or ACC

- _Study_	 	 _Comparators_	     _TTR_	   _Hem & TE_
- 1 Study	 **PST****ACC**** vs   UC****	****56****%****  vs  32****%****     ****14****%****  vs  25****%**
- 3 Studies	 **PST****ACC**** 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****%**

**PST Studies**
- Beyth2000 (RCT), White 1989 (RCT), Kaatz, Gadisseur2001 (RCT)

**PSM vs UC Studies**
- Horstkotte1996(RCT), Hasenkam1997(RCT), Sawicki1999(RCT), Koertke2001(RCT),
- Preiss2001(cohort).

**PSM vs ACC Studies**
- Ansell1995(case control), Watzke2000(RCT), Cromheecke2000(cross-over),
- Gadisseur2003(RCT), Menendez2005(RCT).

## 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

**- How to use (proper dose management)**