The management of coumarin‐induced over‐anticoagulation

Over the last decade there has been a dramatic increase in the use of oral anticoagulants. This is primarily as a result of the demonstration of their benefit in atrial fibrillation (Laupacis et al, 1998). It has been estimated that 2·3% of people older than 40 years and 5·9% of those older than 65 years suffer from atrial fibrillation (Feinberg et al, 1995). In Cambridge, UK, 0·5% of the population take warfarin (Baglin, 1998), while the Dutch Thrombosis Service monitors the anticoagulation of 270 000 persons annually (1·8% of a population of 15 million) (Breukink-Engbers, 1999). Three oral anticoagulant drugs are in widespread use. Warfarin is the anticoagulant most frequently prescribed in the UK and North America, while acenocoumarol and phenprocoumon are more commonly used elsewhere. The half-lives of these drugs differ and recommendations given below refer to anticoagulation with warfarin, except in the last section in which the specific problems associated with acenocoumarol and phenprocoumon are addressed. The coumarins act by inhibiting the post-ribosomal γ-carboxylation of glutamic acid residues in the N-terminal regions of the vitamin K-dependent factors (II, VII, IX and X) during synthesis in the liver. Carboxylation is dependent on the availability of vitamin K1 in its fully reduced hydroquinone form and results in its conversion to vitamin K epoxide. Under normal circumstances this is then reduced via epoxide reductase and quinone reductase to the hydroquinone form. Warfarin competitively inhibits these two enzymes and this leads to a deficiency of hydroquinone. The resultant vitamin K-dependent proteins are undercarboxylated, cannot bind calcium and, therefore, do not participate normally in the assembly of tenase and prothrombinase complexes. Thrombin generation is thus impaired. A further quinone reductase, which is NADH-dependent and is not inhibited by coumarins, provides the probable mechanism by which administration of vitamin K results in reversal of anticoagulation (Whitlon et al, 1978). Orally administered warfarin is rapidly absorbed, mostly albumin-bound in plasma and eliminated almost entirely by the liver. Interindividual variation in dose response is determined by race and genetic factors such as the hepatic cytochrome P-450 polymorphism (Aithal et al, 1999; Mannucci, 1999). Intraindividual variation occurs as a result of changes in diet, intercurrent illness and concurrent drug therapy. Warfarin has a half-life of 35 h, acenocoumarol 9 h and phenprocoumon 5·4 d. These differences have important implications for both initiation and resolution of the anticoagulant effect. The vitamin K-dependent clotting factors have different half-lives. The half-life of factor VII is shortest at 6 h and that of factor II is the longest at 50–80 h. The half-lives of factor IX and X are intermediate at 24 h and 25–60 h respectively (Saito, 1996). These differences may be relevant in consideration of the rate of reversal of warfarin therapy following administration of vitamin K and the duration of function in circulation following coagulation factor replacement. Warfarin therapy does not result in uniform reduction of the vitamin K-dependent factors (Paul et al, 1987). In studies of stable anticoagulated patients, factor II and X levels are most profoundly affected by warfarin with less reduction in factor VII and the least reduction in factor IX levels (Kumar et al, 1990). An identical relationship between the four factors has been observed in patients presenting with life-threatening bleeding (Makris et al, 1997). Many studies have reported the risks of haemorrhage in patients on oral anticoagulants and have investigated the factors associated with an increased bleeding risk. Most report bleeding in one of three categories, fatal, life-threatening or major, and minor. It is difficult to compare these studies, however, because of the lack of conformity in the classification of bleeding episodes. It is probable that most diagnoses of fatal haemorrhage are correct but, nevertheless, it is desirable that such events be objectively proven by overwhelming clinical evidence, imaging or post-mortem study. The classification of a bleed as major or life threatening is more problematic, primarily because of the lack of internationally agreed criteria. As a result, investigators apply their own definitions when reporting studies, often adopting subjective, non-reproducible criteria. While classification dependent on site of haemorrhage may be appropriate, there are no generally agreed criteria as to which sites of bleeding should be regarded as major except in the case of intracranial haemorrhage. In some studies, a low and arbitrary haemoglobin concentration is used to define major haemorrhage, while others even more subjectively classify bleeds as major if they trigger transfusion of the patient with red cell concentrate. Some studies include the need for surgical or endoscopic intervention to stem haemorrhage as criteria for major bleeding. While this can be criticised for being subjective, such treatment is not undertaken lightly and is clearly of major relevance to the patient. In our opinion, these criteria should be included in the definition of major haemorrhage. Finally, bleeding that results in shock is clearly serious. The development of shock as defined by hypotension with or without oliguria should, we feel, define a bleed as major. Adoption of a uniform classification of anticoagulant-related haemorrhage would allow accurate comparison of incidences of bleeding by category between studies. The main features of such a classification should be its simplicity, reproducibility, objectivity and clinical relevance. A proposed classification that we feel fulfils these criteria is illustrated in Table I. A review of observational studies in 1993 reported annual bleeding rates of fatal, major and minor bleeding of 0·8%, 4·9% and 15% (Landefeld Palareti et al, 1996; Beyth et al, 1998). Two factors probably explain these differences. Firstly, bleeding rates differ between cohorts depending on their composition. Secondly, these data reflect the non-conformity of classification of bleeding adopted. Despite this, it is clear that in the reported cohorts there are characteristics which are associated with a much increased haemorrhagic risk. Hypertension, history of gastrointestinal bleeding, previous cerebrovascular accident and recent initiation of anticoagulants have all been shown to be associated with a higher risk of haemorrhage (Table II). The two variables that are most consistently associated with bleeding risk are intensity of anticoagulation and age (Fig 1). In the Italian Study on Complications of oral Anticoagulant Therapy (ISCOAT), the risk of bleeding at an International Normalized Ratio (INR) of greater than 7 was 40 times the risk at an INR in the range 2–2·9 and 20 times the risk at an INR in the range 3–4·4 (Palareti et al, 1996). While there is also little doubt that bleeding is more common in older patients on anticoagulants, some authors suggest that age per se is not a risk factor when data are adjusted for other variables (Fihn et al, 1996). INR and bleeding risk. Rate of bleeding per 100 patient-years by INR level. ▪, all bleeding; ○, major bleeding. Adapted from Palareti et al, 1996. Panneerselvam et al (1998) reviewed those factors that are most commonly associated with over-anticoagulation. In a retrospective study, they demonstrated that recent intercurrent illness requiring alteration of medication (especially treatment with antibiotics) and a high target INR were the main risk factors. The importance of target INR was highlighted by a prospective study of patients with prosthetic heart valves treated to either a high INR target (3·5–4·5) or a lower INR target (2·5–3·5) with additional aspirin 100 mg/d. Those set a higher target INR had an increased risk of major haemorrhage (Meschengieser et al, 1997). Clearly, risk of haemorrhage is also determined by the duration of therapy (Fihn et al, 1993). Guidelines to the optimal duration and intensity of anticoagulation for different indications have been produced British Committee for Standards in Haematology, BCSH (Baglin American Association of Colleges of Pharmacy, AACP (Hyers et al, 2001); Scottish Intercollegiate Guidelines Network (SIGN, 1999) and the following principles should be adhered to: • When they are not the most appropriate method of oral anticoagulants should not be • When oral anticoagulation is the appropriate target INR should be • When oral anticoagulation is appropriate optimal of anticoagulation should be et al, et al, • anticoagulation for which there is no should be of these principles should the of patients presenting with bleeding to The of to the intensity of anticoagulation the category of or This is appropriate when a patient with haemorrhage even more with an INR to be associated with a increased bleeding risk. of bleeding risk however, A recent study that in clinical the of to risk of bleeding in a of patients was no than be by et al, 1998). This probably to lack of of the risk factors for bleeding in patients on This is important as it is clear as there are of patients are at increased risk of haemorrhage while on warfarin and this be in when levels of anticoagulation and need for reversal are Two are in in which the intensity of anticoagulation to be • of • of vitamin These may be or in with Warfarin of warfarin results in reversal of In a study of patients in warfarin was as the method of and to the range and h respectively et al in patients with an INR of had an INR and had an INR 24 h h had an INR et al, 1993). In patients the with a INR of in warfarin was the INR in an with a half-life of and a of h the of the 65 h the INR was and of patients were anticoagulated the INR was in of patients et al, 1995). are not of on the rate of of the INR following warfarin at greater than for patients, the to the range of therapy. with an INR in the range to reversal of a of h is the rate of of the INR Clearly, of warfarin is not intervention in in which of anticoagulation is of vitamin K The administration of vitamin K either or in with of warfarin is often for treatment of patients with minor bleeding or are to be at increased risk of bleeding (Baglin et al, The rate of reversal administration of vitamin K by the oral is reversal of anticoagulation can be 24 h using oral vitamin K et al, et al, some authors have the use of in patients with high INR et al, 1997). administration of vitamin K is more in North than and for its use have been et al, 1995). In a comparison between vitamin K administered by the or the INR at 24 h was lower in The INR in the at 24 h the range for both and et al, 1999). from other factors such as patient availability and of administration need to be when the most appropriate of administration of vitamin the probably the most and reversal of it has been associated with the development of and is for use in and in the the other oral administration of vitamin K reversal of anticoagulation, there is a of data on the of oral vitamin a the of different and a lack of availability of dose of vitamin K In patients are not bleeding, the of vitamin K administration is to the INR the range more than warfarin without the patient to warfarin for a of that this can be by administration of of vitamin K et al, et al, et al, 1999; et al, administration of higher more commonly results in a In in which the of administration is it would that the appropriate dose is The data on oral administration of vitamin K are more difficult to studies have demonstrated that appropriate of the INR the range can be using a of vitamin K at low dose et al, et al, et al, there is no on the for oral own recent that there is a in of administered in the of anticoagulant reversal et al, 1999). is to the most appropriate dose and for this should be given vitamin The need for administration of vitamin K in is determined by the risk of bleeding. Guidelines in their recommendations most their proposed on the risk of bleeding associated with an INR et al, et al, the Secondly, of anticoagulation following of INR has not been shown to be associated with in recent studies in which patients were for et al, et al, 1998). the that the patient is by when this is the The that the bleeding risk for all with an INR of 7 the risk of associated with and, therefore, that these of the for anticoagulation, should have the INR using vitamin most in the INR range this does not of patients are at much increased risk of bleeding. Beyth et al (1998) have characteristics in patients that may be associated with a bleeding risk increased by as much as The previous history and (Table to this risk and should be this is to the it that some patients also have a bleeding risk which that of at an INR of and therefore, benefit from reversal of The does not take of further increased such as and is most to in which is on bleeding and probably reversal of It may be to an to treatment in which it is that of the bleeding and The of fatal anticoagulant-related bleeds are In a study, bleeds in on warfarin were the and associated with the of bleeds in patients not on anticoagulants et al, it is that intracranial on anticoagulants a greater for the following et al, 1995). feel that these a for and reversal of anticoagulation in the of major or life-threatening bleeding. are three that can be in the of life-threatening haemorrhage in a • • of vitamin • of coagulation factors. warfarin It is that warfarin should be at least the is dose has no in the because of the resolution of the anticoagulant effect. of K UK suggest that both oral or vitamin K are for use in patients with major bleeding on warfarin (Baglin et al, this the of in the of major bleeding. In our there is if for oral vitamin K to patients with life-threatening bleeding. of do not reversal of anticoagulation 24 h. studies of have not been we have a dose of given to be the most because it provides in the of of the and does not the patient to vitamin K of its of the INR h et al, 1999). factor In major or life-threatening anticoagulant-related bleeding, the clotting factors VII, IX and X should be as as This can be using plasma or The and of these are in Table In the UK and is more commonly used for this The dose for reversal is 15 (Baglin & Rose, 1998). are a of is not the optimal form of coagulation factor • The of for an is This is problematic, in may have of • has to be and the be • in It is in an a can be the and of and administered in less than h. • In the UK, most is a that has not been to a and a risk of of plasma can be produced as a by or as a using the additional do a benefit in of for use of UK plasma the risk of of This risk does not apply to plasma used in the of as UK are by following a by the Committee on of • The of is by of the factor The vitamin K-dependent factors are not in The and range of factors VII, IX and X in 20 of was and respectively (Makris et al, 1997). it can be that the administration of 15 provides the with of factor IX This would be to the by or When the INR on warfarin is the is often less than and may be less than (Makris et al, 1997). The of is not to correct the This has been by a study in which patients with of were given of The of factors VII, IX and X and were 6 and and 20 In this study, the administration of of to a concentration 20 for of the coagulation factors (Makris et al, 1997). It is that report that of the INR in most the INR was to anticoagulation in patients on coumarins and such as administration of coagulation factors may results more difficult to (Makris et al, 1997). The INR is not to changes in factor IX that may be important in the of anticoagulant-related bleeding. these in it is clear that are as in the INR following administration are in of the coagulation (Makris et al, 1997). These should be in when coagulation factor in anticoagulated would in INR in in these clinical A more and method to coagulation factors in the dose to fully correct anticoagulation is as is produced by the of The coagulation factor of the on the Most factors VII, IX and X in some little factor were used for the treatment of for more than 20 to the of and factor are in form as a which is with to The is at least years and of factor can be in a of 20 It is to and rapidly the coagulation factor deficiency the are of two studies the use of in life-threatening bleeding, both In patients with life-threatening bleeding, the administration of reduced the INR from a of to 15 The levels of factors VII, IX and X increased from and to and respectively (Makris et al, 1997). et al reported patients with objectively proven intracranial haemorrhage to anticoagulation or was a benefit in of and rate of in of patients treated with less clinical with these studies were retrospective and and, in not compare of coagulation factor they of can be warfarin reversal in the h with bleeding. retrospective study of patients also demonstrated the of anticoagulation with et al, 1998). The optimal dose of or to correct warfarin and bleeding is This is to a lack of of the importance of the clotting factors for and lack of data on the of coagulation factor levels on In in which there is a relationship between coagulation factor levels and bleeding, most with a patient with life-threatening bleeding would to the by the appropriate dose of concentrate. on this and from the levels of stable anticoagulated patients, we the following of for patients with an INR of for an INR of 35 and for an INR of the because the half-life of the is 6 h, it is to vitamin The main are the to and and the risk of of both and have been reported to their use in and warfarin It that the risk of is higher when are used in clinical such as lower and in in which is used at high and for In the it was demonstrated that these were associated with more problems in patients with there have been a of of in patients to over-anticoagulation. et al (1998) reported the development of h the administration of to a patient with gastrointestinal bleeding following a warfarin In fatal of coagulation and probably associated with the use a of have been the had risk factors for that included and and et al, 1998). It be that almost all treated with warfarin by have a to of administration of of and need to be in are the they have in of a risk these are not they are to this In of by a were reported in its use in patients While and are important they have to be the risks of bleeding and of treatment that be if is not is in using these and they should be for patients with major life-threatening haemorrhage. and are to the use of commonly while the INR is the In the study, of all and of major bleeds while the INR was the of fatal intracranial bleeding, in which an INR at the of the was at an INR of (Palareti et al, 1996). The principles of of these patients the as bleeding, a reduction in the INR with oral or vitamin K is while for life-threatening bleeding, treatment with clotting factor and vitamin K is The use of oral anticoagulants is on an of and bleeding risk. is The risk of is In a retrospective study, of anticoagulated patients had a year (Fihn et al, 1993). et al a rate of in patients had their warfarin a life-threatening in atrial aspirin may a and should be in patients with prosthetic heart valves have as their risk & (1998) reported their of patients with heart valves had had a while their anticoagulant was in the of bleeding and it was to all of with Over a of one patient had a haemorrhage and three patients While warfarin is used almost for oral anticoagulation in the UK and North America, acenocoumarol and phenprocoumon are In for of the patients on anticoagulants of its patients on acenocoumarol often need of one or more when their INR is while they can be as for patients on warfarin if they are bleeding. In because of its patients on phenprocoumon may of vitamin et al (1998) patients on acenocoumarol with an INR of either vitamin K with a that had their anticoagulants the vitamin K had a greater in a of patients in a INR 24 h. In a study from the patients on phenprocoumon of oral vitamin K when their INR was and were the INR at h, most patients to have an INR of and this increased the that the dose used was and also that a dose of vitamin K may be et al, 1999). Most of the data in the on anticoagulant reversal to warfarin and there is an need for studies to the optimal of of patients on other oral anticoagulants. the risk factors for and anticoagulant-related haemorrhage are the lack of a uniform classification of bleeding comparison of reported rates of bleeding these we feel that a uniform such as that would be an In the of life-threatening haemorrhage, there is a for and reversal of there are we feel that this is probably by and vitamin K in appropriate In of minor bleeding or of the reversal of anticoagulation the range can be in 24 h using vitamin K given by or of of vitamin K correct while administration of a dose probably the patient oral vitamin K also there may be a in between and further studies to optimal dose and are A more to the of is for anticoagulation, patient age and as as need to be when which patients should vitamin K for this such as the use of and of treatment to the of anticoagulant therapy. It is important that appropriate to and bleeding are in in with these