One of the significant secondary side effects resulting from of our advanced prostate cancer treatments can be blood clots. Blood clots are potentially dangerous as they can lead to heart attacks, strokes and death. Warfarin is one of the drugs commonly prescribed to prevent these dangerous blood clots from ever forming. However, dosing of Warfarin is very difficult for doctors because each person’s ideal dose varies widely and is hard to predict, yet it is crucial for our safety.

Getting the wrong dose of warfarin can be dangerous—if the dose is too high, we can bleed profusely; and out of control, if it is too low, we could still develop the life-threatening blood clots. Doctors know that each person responds differently to warfarin. The problem is that one person may need 10 times more of the drug than another may, so it is challenging to figure out where to start the dosage levels. Typically, doctors are forced to start the initial dose based on standard clinical factors—such as age, weight and gender. They then are required to fine-tune the dosage over a few weeks in response to periodic tests of the blood’s ability to clot, possibly leaving us in danger of either bleeding out or developing blood clots.

In an attempt to get better information about proper dosing a study was conducted which evaluated information from thousands of genetically and geographically diverse patients. The international research team was able to develop a way to use an individual’s personal genetic information that could help determine optimal warfarin dosing. The results of the analysis are published in the Feb. 19 issue of The New England Journal of Medicine.

To investigate this issue, researchers from more than 20 teams in nine countries on four continents formed the International Warfarin Pharmacogenetics Consortium (IWPC).
They pooled their data so they were able to evaluate the data from about 5,700 people on stable dosages of warfarin. For each patient, the data included demographic information like age, gender and race; CYP2C9 and VKORC1 variants; and initial, as well as optimized, warfarin dosages.

Warfarin dosages was calculated in three ways—one that relied on the standard, clinical information, one that included additional information about individual patient variation in CYP2C9 and VKORC1, and one that used a fixed dose per day. Then they 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. This is meaningful because 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.

The National Cancer Institute (NIH), in response to this study, is launching a large prospective, multi-center, randomized clinical trial in the United States to test whether a gene-based strategy for prescribing the initial warfarin dose will improve patient outcomes. The clinical trial will use a dosing strategy similar to that developed in the international study. The trial will enroll 1,200 participants of diverse backgrounds and ethnicities at twelve clinical sites, and is scheduled to begin next month.

“In these investigations, NIH-funded basic research and clinical trials are working hand in hand to improve the care of the millions of patients on warfarin therapy,” said Raynard S. Kington, M.D., Ph.D., acting NIH director. “More broadly, these efforts showcase NIH’s firm commitment to building a future of personalized medicine—a future in which doctors will be able to prescribe the optimal dosage of medicine for each patient right from the start.”

In 2007, the FDA required that the makers of warfarin include on the product label a citation that a patient’s genetic makeup may affect how he or she responds to the drug.
Researchers know that two genes, CYP2C9 and VKORC1, which vary slightly among different individuals, can influence warfarin’s effectiveness. Researchers now need to find out whether information about these genes can improve optimal dosage predictions.

Most physicians do not use genetic information about their patients when determining initial warfarin dosing, but they should. The technology is available, so if you are facing the need to start warfarin to prevent blood clots insist that the doctor also perform a genetic screen to more quickly determine your personal dosing requirements. You need to take control of your health care, so make sure your doctor uses current knowledge and technology.

Journal references:

1. The International Warfarin Pharmacogenetics Consortium. Estimation of the Warfarin Dose with Clinical and Pharmacogenetic Data. N Engl J Med, 2009; 360: 753-764

[link] 2. Janet Woodcock, Lawrence J. Lesko. Pharmacogenetics — Tailoring Treatment for the Outliers. N Engl J Med, 2009; 360: 811-813

Joel T Nowak MA, MSW