Genetic Variation To Predict Initial Response To Warfarin Identified

[Rebecca]

Just found this good web site call Sciene Daily.

Found this at Sciene Daily: Genetic Variation To Predict Initial Response To Warfarin Identified

ScienceDaily (Mar. 8, 2008) — Scientists have identified which variations of a specific gene determine a patient's initial response to treatment with the blood-thinning (anticoagulant) drug warfarin. Researchers with the National Institutes of Health (NIH) Pharmacogenetics Research Network found that the gene VKORC1 plays a major role in determining a patient's initial sensitivity to warfarin treatment -- when dosage amounts are most critical to prevent clotting problems in patients. Researchers assessed CYP2C9 genotypes (CYP2C9 *1, *2, and *3) and VKORC1 haplotypes (designated A and nonA) in 297 patients starting warfarin therapy. They compared the participants' clinical characteristics and response to therapy, determined by international normalized ratio (INR) and bleeding events. Their findings confirm earlier research that the two genes, VKORC1 and CYP2C9, help predict how well a patient responds to warfarin. The new results take scientists' understanding a step further and indicate that although both genes significantly influence response to the drug after the first two weeks of therapy, only variations of VKORC1 predict response within the first week of therapy.

The blood clotting variations in VKORC1 help explain why certain patients require a lower or higher dose of warfarin to get its full benefits. The findings could ultimately help doctors determine a patient's optimal warfarin dose more quickly and precisely through genetic screening for the VKORC1 gene and could result in better warfarin dosing, thereby increasing the safety and effectiveness of treatment.

After the discovery of the two genes that play a role in warfarin responsiveness, the Food and Drug Administration (FDA) approved labeling changes in August 2007 instructing physicians to use genetic testing when determining initial dosage estimates for their patients. However, until now, information on genetic interactions with initial response to therapy was limited.

An estimated 2 million people in the United States take the anticoagulant drug warfarin to prevent harmful clotting after a heart attack, stroke, or major surgery. Despite its wide use, physicians find the drug challenging to prescribe because individuals' responses vary widely, and too high of a dose can result in excessive bleeding while too low a dose could allow dangerous blood clots to form.

The study was conducted by researchers at Vanderbilt University and funded by the National Heart, Lung, and Blood Institute (NHLBI) and the National Institute of General Medical Sciences (NIGMS), both part of NIH.

The article, "Genetic Determinants of Initial Warfarin Response," is published in the March 6, 2008, issue of the New England Journal of Medicine. An accompanying editorial written by NHLBI Director Elizabeth G. Nabel, M.D., and NHLBI Deputy Director Susan B. Shurin, M.D., on the role of pharmacogenomics is also in the NEJM.

Adapted from materials provided by NIH/National Heart, Lung and Blood Institute.

 

[Susan BAV]

It's so amazing when something dangerous has the potential for something good. But I wonder, who wanted to fiddle around with that dangerous stuff to see if anything good could come of it?

This reminds me too--a lot of the Indian reservation areas that burned around here, last October and four years previously, are full of wild castor bean plants (they are a really horrible noxious weed and difficult to get rid of--if your neighbor uphill plants them, those little pods can come up everywhere downhill or downwind) and so many people were ill for so long after the fires, I've wondered if those hundreds or thousands of bean plants that burned added to the problems.

[Edit - I guess I need to fill in the blank here and put my comment in proper context; ricin is made from castor beans. This comment I made here was because the original link in the thread was an article on ricin. I was wondering why I didn't see what was referenced about anticoagulation in the original link; I'm assuming it was changed because it was the incorrect link. Now the link in the first post of the thread is gone, the content is completely different, and at least one other followup post was deleted. I'm confused now so I'll just either leave this alone or delete it ...]

 

[witzkeyman]

It's so amazing when something dangerous has the potential for something good. But I wonder, who wanted to fiddle around with that dangerous stuff to see if anything good could come of it?

This reminds me too--a lot of the Indian reservation areas that burned around here, last October and four years previously, are full of wild castor bean plants (they are a really horrible noxious weed and difficult to get rid of--if your neighbor uphill plants them, those little pods can come up everywhere downhill or downwind) and so many people were ill for so long after the fires, I've wondered if those hundreds or thousands of bean plants that burned added to the problems.

it's kind of weird but used up grease from restaurants is being used as fuel, and rat poison is saving our lives.

 

[Susan BAV]

it's kind of weird but used up grease from restaurants is being used as fuel, and rat poison is saving our lives.

Good point! I don't know if I'll spell this correctly, but Thalydamide, which was prescribed for morning sickness during the fifties-sixties and caused horrific birth defects, is now a helpful med for multiple myeloma.

 

[lance]

Thanks to the FDA ..................

Thanks to the FDA ..................

thalidomide was not approved for use in the USA. My understanding is families of US military personnel stationed in Germany, where the drug was approved, gave birth to deformed babies.
One researcher in the US, a woman, would not approve the drug and was subject to a lot of criticism.
I remember when the story broke here in Canada when one of the "scandal" papers printed photos of the affected babies.
About 10 years ago I encountered what I think is a thalidomide baby doing very well showing her dog.
Correct me if I'm wrong but isn't ricin derived from the castor bean plant.

 

[Ross]

Aye this makes much more sense, thank you!

 

[Susan BAV]

thalidomide was not approved for use in the USA. My understanding is families of US military personnel stationed in Germany, where the drug was approved, gave birth to deformed babies.
One researcher in the US, a woman, would not approve the drug and was subject to a lot of criticism.
I remember when the story broke here in Canada when one of the "scandal" papers printed photos of the affected babies.
About 10 years ago I encountered what I think is a thalidomide baby doing very well showing her dog.
Correct me if I'm wrong but isn't ricin derived from the castor bean plant.

Sorry Lance. I don't know if you saw it but the original post in this thread must have had an incorrect link. It lead to an article about ricin. It's been changed now. Meanwhile, absolutely nothing about my posts makes any sense in this thread's context ! Oh well. I'll add to the confusion... I had a friend who recently died with multiple myeloma and during his treatment he found some relief from Thalydamide (sp?).

 

[Ross]

We could change them all, delete them or just leave and go on. I'm for the latter. Much less work.

 

[Bina]

Susan, you poor thing.......it's okay, we all know you have not gone nuts!

 

[Ross]

Despite its wide use, physicians find the drug challenging to prescribe because individuals' responses vary widely, and too high of a dose can result in excessive bleeding while too low a dose could allow dangerous blood clots to form.

The best thing would be to simply EDUCATE the Physician on it's use. You don't need fancy testing to tell you something that isn't hard to figure out if you know what your doing. The major problem was and is lack of education on the drug by the medical profession.

 

[Ross]

http://www.warfarinfo.com/geneticdosing.htm

Implications of Warfarin and Genetic Dosing

Charli J. Strebig

The world of medicine has vastly increased its knowledge of the factors that contribute to patient-warfarin variability. It is now accepted that there is a distinct relationship between genetic variations in CYP2C9 and VKORC genotypes and the warfarin dose required to therapeutically treat patients.10-11 Despite our current knowledge of pharmacogenomics and clinical factors that effect warfarin therapy, the source of more than 40% of the variability remains unclear.10 Additional genetic factors, such as genes that encode vitamin-K dependent clotting factors or multidrug resistance genes, may be responsible for the observed variability. Unfortunately, there is limited information on these genetic variants and their effect on warfarin dosing is still unclear.

However, information from genetic testing for the CYP2C9 and VKORC genotypes variants could still help optimize drug efficacy while minimizing adverse drug reactions.10 Several clinic trials have been conducted which have proposed dosing algorithms which integrate genetics into warfarin dosing. It is thought that the algorithms that incorporate genetic, demographic and clinical factors to estimate warfarin dosage could potentially minimize the risk of overdose during warfarin induction and improve the quality of warfarin dose management.10-11 An FDA advisory panel stated that genetic testing of warfarin could reduce adverse events and improve achievement of stable INR.12 The evidence that supports the relationship of certain genotypes (CYP2C9 and VKORC1) and warfarin dosing may warrant a re-labeling of warfarin to include genetic test information.12 It is believed by many scientists and health care professionals that the use of this testing will dramatically improve warfarin efficacy and safety and reduce the occurrence of adverse outcomes.12

A cost-benefit analysis of pre-prescription genotyping during warfarin treatment is still needed to determine the overall benefit of performing such genetic tests. Some feel it may not be cost effective to genotype a large population of patients to identify the small minority that may be at a markedly higher risk of adverse effects.10 On the other hand, even a small reduction in the risk of major bleeding during warfarin therapy induction could make genotyping of patients cost-effective.10 However, these benefits are still to be determined. Although the discovery of certain genotypes and their influence on warfarin therapy is very substantial, it may not be the most optimal method for managing patients.

The use of genetic information in the treatment and management of patients offers many potential clinical benefits, but may also provide many challenges. A warfarin-dosing regimen using clinical data and pharmacogenomic information could benefit many patients, however, further studies are still required before this type of testing will be incorporated into routine practice.1 Future research will also be needed to assess patient preferences and willingness to pay for these genetic tests.13 The balance between the benefits of using of genetic testing to determine warfarin dose and costs to use such technology also needs to be assessed in regards to providers, industry, insurers and government as well.13 The use of genetic testing is likely to have a positive impact on patients using warfarin therapy. However, like all new technologies, further investigation is needed to fully understand what the overall result may be.

©2007 Charli Strebig

References:

1. Lacy CF, Armstrong LL, Goldman MP, Lance LL. Drug Information Handbook, 16th ed. Hudson, Ohio, Lexi-Comp, Inc.; 2007: 1143-7.

2. Anderson JL, Horne BD, Stevens SM, Grove AS, Barton S, Nicholas ZP, et al. Randomized Trial of Genotype-Guided Versus Standard Warfarin Dosing in Patients Initiating Oral Anticoagulation. Journal of the American Heart Association 2007; 116: 1-8.

3. Warfarin Sensitivity DNA Test. Genetics and Health Web site. Available at: http://www.geneticsandhealth.com. Accessed November 15, 2007.

4. Warfarin (Coumadin) and DNA. Health and DNA Web site. Available at http://www.healthanddna.com/warfarin.html. Accessed November 15, 2007.

5. Higashi MK, Veenstra DL, Kondo LM, Wittkowsky AK, Srinouanprachanh SL, Farin FM, Rettie AE. Association between CYP2C9 genetic variants and anticoagulation-related outcomes during warfarin therapy. JAMA 2002; 287(13): 1690-1698.

6. Reider MJ, Reiner AP, Gage BF, Nickerson DA, Eby CS, McLeod HL, Blough DK, Thummel KE, Veenstra DL, Rettie AE. Effect of VKORC1 haplotypes on transcriptional regulation and warfarin dose. NEJM 2005;352:2285-2293.

7. Carlquist JF, Horne BD, Mublestein JB, Lappe DL, Whiting BM, Koleck MJ, Clarke JI, James BC and Anderson JL. Genotypes of the cytochrome p450 CYP2C9 and the vitamin K epoxide reductase complex subunit 1 conjointly determine stable warfarin dose: a prospective study. J Thromb Throbolysis 2006; 22:191-197.

8. Hillman MA, Wilke RA, Yale SH, Vidaillet HJ, Caldwell MD, Blurich I, Berg RL, Schmelzer J, Burmester JK. A prospective, randomized pilot trial of model-based warfarin dose initiation using CYP2C9 genotype and clinical data. Clinical Medicine and Research 2005; 3(3): 137-145.

9. Caraco Y, Blotnick S, Muszkat M. CYP2C9 genotype-guided warfarin prescribing enhances the efficacy and safety of anticoagulation: a prospective randomized controlled study. Clinical Pharmacology and Therapeutics. September 12, 2007. DOI:10.1038/sj.clpt.6100316. Available at: http://www.nature.com/clpt/journal.

10. Yin T, Miyata T. Warfarin dose and the pharmacogenomics of CYP2C9 and VKORC ? Rationale and perspectives. Thrombosis Research 2007; 120: 1-10.

11. Lippi G, Salvagno GL, Guidi GC. Genetic Analysis to prevent warfarin complications. CMAJ August 2007; 177(4): 377.

12. Warfarin (Coumadin) and DNA. Health and DNA Web site. Available at http://www.healthanddna.com/warfarin.html. Accessed November 19, 2007.

13. Phillips KA, Veenstra DL, Ramsey SD, Van Bebber SL, Sakowski J. Genetic Testing and Pharmacogenomics: Issues for Determining the Impact to Healthcare and Delivery Costs. American Journal of Managed Care July 2004; 10(7): 425-432.