Drug interaction with coumarin derivative anticoagulants. Standing Advisory Committee for Haematology of the Royal College of Pathologists.

The use oforal anticoagulants in the form ofcoumarin derivatives in the treatment of thrombosis continues to carry the risk of inducing abnormal bleeding. While the laboratory control of such treatment has been improved considerably by the introduction of standardisation (ICSH)' and the use of British comparative reagents (ACP broadsheet),' the increasing number of drugs that interact with these anticoagulant agents has enhanced the number of such often life-threatening events.3-10 These drugs may potentiate or antagonise the coumarin activity by affecting the binding of the anticoagulant drugs to plasma proteins or by affecting microsomal enzymes in the liver. This potentiating or inhibiting interaction varies with the drug used and there is also variation from patient to patient. It is not the purpose of this communication to describe each interaction in detail but to draw the attention of all doctors to the increasing number of drugs that can influence this form of treatment. Further, the introduction ofnew drugs in preliminary clinical trials in man, before the granting of licence, can also produce unexpected effects. Drugs and physical states that potentiate the response may require a reduction of the dose of oral anticoagulants or, conversely, the dose may have to be increased to maintain an effective anticoagulant effect once the drug is withdrawn. Those drugs that inhibit the effect of anticoagulant drugs may make effective treatment impossible. If it is possible to maintain an effective low level of the K dependent factors (II, III, X) by giving a large dose the withdrawal of the inhibiting drugs may result in a precipitate fall of the II, VII, and X levels with consequent danger of spontaneous bleeding. The concomitant use of a definitely potentiating or antagonising drug along with oral anticoagulants should be avoided, but if the clinical state necessitates the risk then frequent laboratory surveillance is essential. When drugs with a less definite effect are used, careful control is also required until a "steady state" is established. It is not the purpose of this paper to recommend the dose of oral anticoagulant drugs or to didactically lay down suitable laboratory methods for control of the "effective" and "safe" levels of anticoagulant treatment in any given patient. It has, however, been recommended that the one-stage prothrombin time be prolonged by a ratio of 2-0-4-0 of the normal control time (BCR), the degree of prolongation depending on the clinical condition of the patient.11 12 When a potentiating drug is administered with an oral anticoagulant, the dose of coumarin should be reduced by about a third and the prothrombin time/ BCR checked in two to three days' time. Weekly testing may be necessary to attain dosage stability. Similar control testing will be required after withdrawal of an antagonising drug and also with change in the clinical stage of the patient.