Karl Link, Warfarin and the New Oral Anticoagulants

During the 1930's Karl Link was working to find out why cows were apparently dying from haemorrhage. He made the link between the bleeding problems and spoiled hay and in 1941 isolated an anticoagulant from the hay called dicumarol. This chemical reduced the clotting of blood and was highly toxic to rodents. Link assigned the patent on the chemical to the Wisconsin Alumni Research Foundation, which patented the substance in 1948 under the name “warfarin” and began to market the product as a commercial rodenticide.  Subsequently it started to be used to treat patients with heart problems to prevent blood clots. Although a number of warfarin like drugs were synthesized they are all vitamin K antagonists and for the last 60 years have been the only available oral anticoagulants.

Warfarin has always been a difficult drug to prescribe and use in clinical having multiple drug and food interactions, complex pharmacokinetics and the need for close monitoring. Dosing is complex since the tablet taken today doesn't affect blood clotting until 48-72h later. Many patients are anxious if warfarin is recommnended by their doctor and they are usually reluctant to take the drug. This usually requires a great deal of explanation from the prescribing physician. However when warfarin is used carefully it is a highly effective medicine invaluable for patients when used in conditions such as atrial fibrillation, pulmonary embolism and deep vein thrombosis. Warfarin also enabled valve replacement surgery to be performed with metallic valves which could never have otherwise occurred.

If you were a pharmaceutical company looking for a blockbuster drug then developing a replacement for warfarin would have been pretty high up your agenda. In 2004 Ximelagatran was launched as the first orally available anticoagulant and was shown to be non-inferior to warfarin in the SPORTIFF III trial published in the Lancet. Ximelagatran underwent an extensive clinical programme which unfortunately showed significant liver toxicity when used for more than 35 days and because of this it was withdrawn. However In the last 2 years three more new oral anti-coagulants (NOACs) have been launched.

Dabigatran is a direct thrombin inhibitor and rivaroxaban and apixaban are factor Xa inhibitors. Each drug has been investigated in a large clinical trial and compared against warfarin. In the trials it was shown that the NOACs were either more effective than warfarin (dabigatran at the 150mg dose) or non-inferior to warfarin (dabigatran at the 110mg dose, rivaroxaban 20mg and apixaban 5mg). The drugs are taken at a fixed dose and unlike warfarin do not need to be monitored with blood tests. Rivaroxaban is a once daily medicine whereas the others are twice daily. Dose adjustment is recommended in the elderly (>80 years) and the drugs are not suitable for people with severe kidney impairment but some can be used in moderate impairment. Clinical experience with these drugs is still limited and a number of questions remain. They do not affect the normal clotting tests undertaken in hospitals and so it is vital that patients inform medical staff if they are taking these medicines especially if they are admitted to hospital as an emergency.  There are issues of compliance since blood tests are not required to evaluate the anticoagulant effect and what it is now know how significant the omission of one or two doses would be. It may be more complex to manage patients who bleeding whilst taking NOACs since there are no antidotes are currently available. There are still unknowns such as whether it is safe to cardiovert a person from atrial fibrillation to sinus rhythm on a NOAC. There is data available from the RELY-AF trial subgroup and also recently a subgroup analysis from the ROCKET trial with rivaroxaban has been published but not trial has been done specifically to address this question.

We are entering a new era of anti-coagulant treatment. There will always be a role for warfarin but I think we will see it used less and less as clinical experience with the NOACs grows. Much of this is currently being driven by patient choice and apparent ease of prescribing but we need to be cautious whiclinical experience with these medicines grows.

RELY-AF Trial
ROCKET Trial
ARISTOTLE Trial
RELY-AF Trial: Cardioversion Substudy
ROCKET: Cardioversion Subgroup

---