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Will Genetic Testing help?

For patients taking warfarin (Coumadin) the only Vitamin K antagonist (VKAs) available in the US, keeping within ones INR range lessens the chance of an adverse reaction (bleeding) and increases the VKAs prevention of dangerous blood clots: (see Figure from Cannegieter et al, NEJM Vol 333, No 1, page 14 Copyright © 1995 Massachusetts Medical Society. All rights reserved.) 

For many patients keeping the INR within range is difficult.  It is most difficult when a physician first begins warfarin usually in the hospital after the diagnosis of a serious medical problem or heart surgery.  In many studies 1/3 of complications happen during the early dose-adjusting phase (within the first 3-6 months).  Genetic testing from Blood/Saliva may make it easier for physicians to prescribe the correct dose of warfarin and decrease hospitalizations from adverse events.

In a study released March 16, 2010, the Medco-Mayo Warfarin Effectiveness Study (MM-WES) found that a simple test for two genes (CYP2C9 and VKORC1) done shortly after starting warfarin "can be used to more accurately predict the best warfarin dose early on."  For example, a patient might be classified as having a high sensitivity to warfarin based on genotype. In this case, the physician would be advised to reduce the warfarin dose and monitor blood tests more frequently. If a patient were found to have a low sensitivity to warfarin, the report would recommend an increase in warfarin dose.

For the study, researchers recruited 896 patients who were beginning warfarin therapy. The researchers found that, during the first six months of warfarin therapy, patients who underwent genetic testing had a 33 percent lower risk of all-cause hospitalization and a 43 percent lower risk of hospitalization for bleeding or blood clots (thromboembolism) when compared to an historical control group that did not undergo genetic testing.

The cost of genetic testing is approximately US$250 to $400, depending on the laboratory.

This information is from a press release at the American College of Cardiology annual scientific session. This study has not been published in a peer reviewed medical journal.  It is limited because it compares patients who had genetic studies done with "historical" controls rather than with a group of patients occurring in the same period of time. It is not hard to imagine that INR testing may have been done more frequently during the study than it was in "usual clinical practice" before the study began.  If this were true, one could not be sure whether the observed improvement in outcomes were due to genetic testing or the increased INR monitoring. Fortunately studies of genetic testing with properly randomized control patients are underway.  If these studies confirm the MM-WES results genetic testing at the onset of therapy will decrease the risks of warfarin therapy. 

Michael Schwartz MD (retired)

Swannanoa, NC 28778 USA (July 2nd, 2010)

Guideline for implementation of patient self-testing and patient self-management of oral anticoagulation

International consensus guidelines prepared by International Self-Monitoring Association for oral Anticoagulation (ISMAA).


Living with Oral Anticoagulants

Education, Training, and Self-Management not only for Seniors

Patient education and training is a substantial part being anticoagulated in order to know how to deal properly with Oral Anticoagulants.


The Importance of Pharmacogenetics

Utilizing the correct intensity of a vitamin K antagonist (VKA) and maintaining the patient in the therapeutic range are two of the most important determinants of its effectiveness and safety.  Therapeutic efficacy can be influenced by physiologic and pharmacologic factors such as drugs or illnesses that affect the pharmacokinetics or pharmacodynamics of the VKA, dietary or GI factors that affect the availability of vitamin K1, physiologic factors that affect the synthetic or metabolic fate of the vitamin K-dependent coagulation factors, and the ability of the health-care provider to make appropriate dosage and follow-up decisions....


Modern life with anticoagulants

Oral anticoagulant therapy (OAT) with warfarin has been used for more than 60 years to prevent blood from clotting inside the heart or in blood vessels. In spite of a wide spectrum of newer drugs available on the market, scientific studies with warfarin has repeatedly proven this drug as most effective for several applications and it has also been verified as a drug with remarkably few side effects. ...


The Importance of stable therapeutic INR in oral anticaogulation

Valve thrombosis, thromboembolism and bleeding together account for approximately 75% of the complications experienced by patients with prosthetic heart valves. Not all are prosthesis-related, as there is a ‘background incidence’ of stroke/TIA and major bleeding in the general population, rising gradually with age. Nevertheless, despite published guidelines on anticoagulation management, many events occur as the result of under-anticoagulation, over-anticoagulation or very variable anticoagulation.


Frequent monitoring of Atrial Fibrillation patients key to optimal outcomes when treated with anticoagulants

Latest opinion confirms overwhelming evidence of the benefits of risk-adjusted oral anticoagulation on stroke reduction in patients with atrial fibrillation 

International experts have warned that the burden of cardiovascular disease (CVD) will continue to increase if diagnostics is not accepted as a significant part of the management of the condition. Speaking at a media conference, being held alongside the first Roche Asia Pacific Cardiology Forum, Dr Marcel Levi, Professor of Medicine, University of Amsterdam said that the management of Atrial Fibrillation (AF) is much improved if frequent monitoring is central to the treatment.

Atrial Fibrillation is one of the most common heart rhythm disorders, affecting 8% of the population over 80 years of age[i]. It is considered one of the major risk factors for stroke, as well as a significant contributor to hospitalization of elderly patients, with a 66 percent increase in hospitalization over the last 20 years.[ii] Worldwide the impact of AF is enormous, with an estimated 5.6 million people suffer from AF in the US[iii], 4.5 million in Europe[iv] up to 8 million in China alone[v].

Importantly, stroke and mortality rates for patients with AF are at least twice as high for patients without AFi and a stroke caused by AF is much more lethal than other strokes[vi].

The most effective treatment for AF is anticoagulation therapy which has been shown to reduce stroke risks by at least two thirds (68%)[vii]. Alarmingly, despite the compelling evidence for its effectiveness, particularly in reducing stroke risk, it is still underused in high risk patients. Worldwide an average of only 30 percent of patients with AF are treated with oral anticoagulation[viii], whereas it is estimated that 60-70 percent of AF patients should be using this treatmentii.

“One of the main reasons that physicians do not prescribe anticoagulation therapy is that they fear excessive bleeds. However, if frequent monitoring of INR levels is considered central to the overall patient management, the risk of adverse events can be controlled,” said Dr M. Levi.

Dr Levi’s remarks come on the back of a new consensus paper developed by a multidisciplinary expert group which recommends improvements in the management of anticoagulant treatment in patients with AF. A key conclusion of the consensus statement is that when monitored frequently the benefit of stroke reduction outweighs the risk of bleeding associated with treatment with anticoagulation therapy in high risk patients[ix].

There are a number of different models when it comes to monitoring anticoagulation and the choice of care is a major aspect contributing to patient outcomes. This ranges from Usual Care (UC), where patients are cared for by a physician and have their INR levels tested by IV blood tests; Alternate Site Testing (AST – mainly used in Warfarin Clinics) where patients INR levels are tested in the clinic via portable monitoring devices such as CoaguChek, requiring only a finger prick; and Patient Self Testing (PST) where a patient monitors their own levels at home using the same portable monitoring device.

Recent evidence has shown that patients who test themselves have a 39 percent lower risk of death and a 90 percent lower risk of suffering from complications than patients undergoing Usual Care.[x]

“The more involved a patient is in their own management, the greater reduction there is in complications from clots, excessive bleeding and even death,” said Dr M. Levi. “Frequent monitoring – that is, at least once a month if not once a week – can contribute to better patient outcomes. Warfarin Clinics with AST setup provide patients with a more convenient way of monitoring, which encourages and facilitates frequent monitoring. Patient self testing provides even better outcomes.”

Also presenting at the media conference is Mr Christian Schaefer, President of the International Self Monitoring Association of oral Anticoagulated Patients and a strong proponent of PST.“I test myself at home on a weekly basis, which accounts for more than 1,200 times over the past 23 years and I urge other patients around the world to do the same. Managing my condition in partnership with my doctor means that I am able to have control over my life and take into account changes in my daily activities so that we can adjust my warfarin dose accordingly,” said Mr Schaefer. “It’s my condition and my health, so I want to make sure I play an active part.”

Bejing, China, 16 June 2010

[i] Fuster V et al. Guidelines for the Management of Patients With Atrial Fibrillation. Executive Summary. Rev Esp Cardiol. 2006; 59(12): 1329.


[ii] Fuster V et al. American College of Cardiology/American Heart Association Task Force on Practice Guidelines; European Society of Cardiology Committee for Practice Guidelines; European Heart Rhythm Association; Heart Rhythm Society. ACC/AHA/ESC 2006 Guidelines for the Management of Patients with Atrial Fibrillation: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the European Society of Cardiology Committee for Practice Guidelines (Writing Committee to Revise the 2001 Guidelines for the Management of Patients With Atrial Fibrillation): developed in collaboration with the European Heart Rhythm Association and the Heart Rhythm Society. Circulation. 2006; 114(7): e257-354.


[iii] Bajpai A et al. Epidemiology and economic burden of atrial fibrillation. US Cardiovascular Disease. 2007; 14-17.


[iv] Kannel WB, Benjamin EJ. Status of the epidemiology of atrial fibrillation. Med Clin North Am 2008;92:17-40


[v] Hur D, Sun Y. Epidemiology, Risk Factors for Stroke, and Management of Atrial Fibrillation in China. JACC Vol. 52, No. 10, 2008:865–8


[vi] Nieuwlaat R et al. European Heart Survey Investigators. Atrial fibrillation management: a prospective survey in ESC member countries: the Euro Heart Survey on Atrial Fibrillation. Eur Heart J. 2005; 26(22): 2422-34.


[vii] Atrial fibrillation investigators. Risk factors for stroke and efficacy of antithrombotic therapy in atrial fibrillation. Analysis of pooled data from five randomized controlled trials. Arch Intern Med. 1994; 154(13): 1449-57.


[viii] Ang SY et al. Review of antithrombotic drug usage in atrial fibrillation. J Clin Pharm Ther. 1998; 23(2): 97-106.


[ix] Levi M et al. Improving antithrombotic management in patients with atrial fibrillation: current status and perspectives. Semin Thromb Hemost 2009;35:527-542.


[x] Heneghan C et al. Self-monitoring of oral anticoagulation: a systematic review and metaanalysis. Lancet. 2006; 367 (9508): 404-411.


Optimal management of anticoagulation with atrial fibrillation

It is projected that 7.5 million individuals will have atrial fibrillation by the year 2020 in the United States alone.  The prevalence of atrial fibrillation increases with age as does the risk of stroke.  In a meta-analysis of the early trials in atrial fibrillation, vitamin K antagonists were shown to reduce the risk of stroke by 68%.


Efficacy and Safety of Vitamin K Antagonists in Elderly Patients with Atrial Fibrillation


INR Self-Management: A promising tool to achieve low complication rates after mechanical heart valve replacement

During recent decades, heart valve replacement has become a frequent intervention in cardiovascular medicine. Mechanical heart valves account for approximately 70 % and biological heart valves for approximately 30 % of totally implanted heart valves. Because biological heart valves are durable for only 8 to 12 years in the aortic position and only 6 to 8 years in the mitral position, these implants are restricted to elderly patients.


Self-management of oral anticoagulation therapy improves long-term survival in patients with mechanical heart valve replacement


Quality of life and self-monitoring: CVD prevention in practice

Engaged patients with a good knowledge of their own disease are open to prevention and are also active in managing their own disease.


Self-management of oral anticoagulation in the elderly:

Rationale, design, baselines and oral anticoagulation control after one year of follow-up


Low-dose oral anticoagulation in patients with mechanical heart valve prostheses: Final report from the early self-management anticoagulation trial II (ESCAT II)