Could genetics improve warfarin prescription?

A clinical trial is to be launched by researchers at Newcastle and Liverpool Universities to test if genetics could provide personalised medicine by optimising each patient's dose of the common blood-thinning drug, warfarin. One of the most widely prescribed drugs in the world, warfarin is used to prevent dangerous blood clots that can lead to heart attacks, strokes or even death.

One per cent of people in the UK are prescribed warfarin but doctors find the ideal dose for each person varies widely and is hard to predict, yet is crucial for the patient's safety.

Getting the wrong amount of warfarin can be dangerous - if the dose is too high, patients could bleed profusely, if it's too low, they could develop life-threatening clots.

Researchers know that two genes, CYP2C9 and VKORC1, which vary slightly among different individuals, can influence warfarin's effectiveness. Now, scientists want to work out whether information about these genes could improve decisions on the amount of warfarin given to a patient at the start of treatment.

Professor Farhad Kamali is leading the Newcastle University trial with his colleague Professor Ann Daly. Professor Kamali says, "The way different patients respond to warfarin is notoriously unpredictable, particularly at the very start of treatment. Now we know that certain genes can affect the way individual patients respond to warfarin then we can use this information to personalise therapy. This clinical trial will be able to demonstrate whether the gene-guided dosing can optimise the safety of anticoagulation therapy."

Using information from thousands of patients, an international team of researchers, including those at Liverpool and Newcastle Universities, have developed a mathematical formula using patient's genetic information that could help doctors better determine optimal warfarin doses. The results of the analysis are published in a paper titled "Warfarin Dosing Using Clinical and Pharmacogenetic Data" in today's issue (19th February) of The New England Journal of Medicine.

The scientists calculated warfarin dosages in three ways – (i) using the standard, clinical information, (ii) including additional information about individual patient variation in CYP2C9 and VKORC1, and (iii) using a fixed dose per day. They then checked how closely their computational predictions matched the actual, clinically derived stable warfarin dosage for each patient.

The results revealed that when genetic information was included, the predictions of ideal dosages were more accurate, especially for patients at the low or high ends of the dosing range. Nearly half of those on warfarin are at the extremes of the range, and these patients are typically at the greatest risk for excessive bleeding or clotting. By quickly optimizing dosages for these patients, doctors could minimize dangerous complications and improve the effectiveness and safety of warfarin treatment.

Professor Munir Pirmohamed who is leading the University of Liverpool trial says, "Warfarin is always amongst the top three drugs responsible for hospital-related adverse drug reactions. However, it is also highly beneficial in preventing thrombosis and strokes, and we need to develop methods that improve the benefits and minimize the harm associated with the use of warfarin. The crucial issue is to identify the correct dose for each patient."

An international research team involving 13 centres in seven European countries, including Newcastle and Liverpool Universities in the UK, will run a randomized clinical trial of 2,700 new patients on three anticoagulants (warfarin, acenocoumarol, phenprocoumon) to determine if the more precise, gene-based prescribing strategy is the best option for patients starting treatment.

Source: Newcastle University