Features December 2011 Issue

Warfarin Alternatives Provide Doctors and Their Patients with More Options

The commonly used anticoagulant warfarin isn’t for everybody, and newer drugs may help make sure more people are protected against dangerous blood clots.

Warfarin (Coumadin) is a life-saving drug for people who have had heart attacks or who have had a blood clot in the legs (deep veing thrombosis or DVT) or lungs (pulmonary embolism or PE), or who have certain arrhythmias or heart valve disease. The widely used anticoagulant, or “blood thinner,” however, can be a serious risk to patients with a tendency to bleed, and requires frequent monitoring to ensure that patients are getting the proper dose.

But several new anticoagulants recently have been or are on their way to getting approval by the U.S. Food and Drug Administration (FDA). For example, dabigatran (Pradaxa) was approved for atrial fibrillation (Afib) patients a year ago by the FDA in two doses: a 150 mg dose to be taken twice a day; and a 75 mg dose, also for twice-daily consumption, for patients with renal disease or insufficiency.

In July, rivaroxaban (Xarelto) was approved to help prevent deep vein thrombosis (DVT) in patients undergoing knee or hip replacement surgery. And apixaban (Eliquis) has shown great promise in clinical trials as a warfarin alternative, but it has yet to get FDA approval.

While the rise of alternatives might signal the beginning of the end for warfarin Cleveland Clinic vascular medicine specialist John Bartholomew, MD, predicts that warfarin will continue to have a place among the newer medications for some time.

“I do not see warfarin disappearing completely,” he says. “It is inexpensive and generic. The newer drugs cannot be used in patients with severe kidney disease (who are on dialysis) and must be used with caution in patients who have marginal kidney function. There is no approved indication for the newer medications in patients with DVT or PE (except prophylaxis), mechanical heart valves, pregnancy, breast feeding and pediatric patients.”

New Drug Risks
And what is perhaps most concerning about the new drugs, aside from their cost, which is several times that of warfarin, is that there is no antidote in case of bleeding complications. A patient who develops a bleeding problem after taking warfarin can be treated with vitamin K. Warfarin is slower acting than the new medications, which start working in a few hours, but that can be a benefit if bleeding starts.

“Warfarin inhibits certain blood clotting factors including II, VII, IX and X,” Dr. Bartholomew says. “It takes 4 or 5 days to become effective and if bleeding develops it can be reversed with fresh frozen plasma or vitamin K. The new anticoagulants are not reversible although there is ongoing work looking for antidotes.”

Trade-Offs
While warfarin complications may be more treatable than the new anticoagulants on the scene, dosing warfarin can be an ongoing challenge. Patients on warfarin must have their international normalized ratio (INR) checked at a lab on a regular basis – anywhere from twice a week to every month or so, depending on their health and what their blood work shows.

INR is essentially a measure of how quickly your blood clots. If it’s too fast, you run the risk of a dangerous clot forming in your body. If it takes too long to clot, your blood may be too thin and you run the risk of bleeding. Based on the results of your blood test, your warfarin dose will be adjusted to get the INR in a safe and healthy range.

The newer drugs do not require INR testing or any monitoring. In addition, the newer anticoagulants appear to have fewer food-drug and drug-drug interactions than warfarin. For instance, because vitamin K can counteract the effectiveness of warfarin, foods high in vitamin K, such as dark, leafy green vegetables should be eaten in moderation.

In addition, common drugs such as ibuprofen can result in bleeding complications in patients taking warfarin.
Dr. Bartholomew says that while some of the newer anticoagulants don’t have those restrictions, he acknowledges that doctors are still learning about all the risks and benefits of the medications.

“As with all new drugs, I am sure we will find out more about their side effects,” he says. “The new drugs do not interact with foods and other drugs like warfarin does. With warfarin, you have to watch what you eat and also must be careful about drug-drug interactions. Some drugs prolong the INR if they are taken with warfarin leading to an increased risk of bleeding if their blood gets too thin. Other drugs affect warfarin in the opposite way, causing the blood to get too thick and a potential for clotting.”

The other trade-off, which is not insignificant, is that warfarin remains a single-dose daily medication. Some of  the others require two doses per day, and Dr. Bartholomew says that the warfarin alternatives are not recommended for the non-compliant patient. Doctors need to believe their patients will faithfully take two doses daily before they will prescribe a drug such as dabigatran.

Changes Ahead
Dr. Bartholomew says that because we have so many years of experience with warfarin, many doctors are comfortable and confident prescribing it to their patients, and are less comfortable with the newer drugs.

And given the disparity in costs, many physicians and patients may opt for warfarin until the alternative medications drop in price.

“I do expect the cost of the new drugs to come down, but not immediately,” he says. “Rivaroxaban is indicated for deep vein thrombosis prophylaxis in patients who need hip and or knee surgery, while dabigatran is approved for patients with atrial fibrillation. So these two drugs are not yet in direct competition for the same patient population.”