Some aspects of the pharmacology of oral anticoagulants

The pharmacology of oral anticoagulants ls discussed with particular rejerence to data of value in the management of therapy. The importance of individual variability in response and drug interaction is stressed. Other effects of these agents which may have clinical utility are noted.

William W. Coon, M.D., and Park W. Willis 111, M.D., Ann Arbor, Mich. The Departments of Surgery (Section of General Surgery) and Medicine, University of Michigan Medical School

In the twenty-five years sinee the isola• dividual struetural features but by a com• tion of the hemorrhagie faetor in spoiled bination of several: molecular shape, in• sweet clever," the gradually inereasing creased aetivity with 6 membered hetero• utilization of oral antieoagulants for the eyclic rings with a substituent in position prevention and therapy of thromboembolie 8 and with a methoxyl rather than a free disease has made them one of the most hydroxl group. Also important is the dernon• widely used groups of pharmacologic stration that levorotatory warfarin is seven agents. This review is restrieted to as• times more aetive than its enantiomer.F" peets of the pharmaeology of these agents As Hunter and Shepherd'" have pointed whieh may be important to their proper out, the failure to obtain a precise cor• clinieal utilization. relation between strueture and antieoagu• lant aetivity is "not surprising in view of Relation of structure to function the influence of small struetural changes The oral antieoagulants have been di• on sueh variables as solubility, rate of ab• vided into four main groups on the basis sorption, ease of distribution, degree of of ehemieal strueture (Fig. 1). binding by tissues or plasma protein and Although a number of investigators have rate of detoxieation and excretion." attempted to define the struetural char• All eoumarin-type antieoagulants are 4• aeteristies neeessary for the produetion of hydroxyeoumarins. Mead and associates an antieoagulant effeet, eaeh theory has have shown that 3-, 5-, 6-, 7-, and 8-hy• been partially invalidated by the diseovery droxyeoumarins are phenolie in nature and of exeeptions. Arora and Mathur" have are metabolized in rabbits principally by reeently proposed that antieoagulant ac• direct eonjugation with glueuronic and tivity of eoumarins is governed not by in- sulfuric acids. However, 4-hydroxyeou• marin differs from its isomers in conju• Supported by grants from the Michigan Heart Asso• gating only with glucuronic acid. It forms ciation and Grant FR-üS383 from the National Institutes of Health. no ethereal sulfates since it is a relatively 312 Volume 11 Oral anticoagulants 313 Number3

1. Compounds with two coumarin rings: "Dicoumaro1s"

OH R OH Bishydroxycoumarin R=H I eH-CO"""I Ethylbiscoumacetate R=COOC2HS m~ 0"""·~O cf 0 "I- 2. 3-substituted 4-hydroxycoumarins: IMono-coumaro1s" CH2CH3 Phenprocoumon R=CH~ OH ~R ~O)~O

Warfarin

3. Cyclic acetals: "Cyclocoumarols"

Cyclocumarol

Rl-Q

R2 CH3

R 3 CH3 4. Indandiones Phenindione R=-Q Diphenadione R=-COC.'bD

Anisindione R=-o 0CH3

Chlorphenylindandione R=~Cl

Fig, 1. Four main groups of oral anticogulants on the basis of chemical structure.

strong acid with a pK of 5.8.98 This differ• Newer agents ence may have pharmacologic implica• A number of reports conceming new tions since almost all other naturally oc• oral anticoagulants have appeared in the curring derivatives of coumarin are either past several years. Most have been newly 7-hydroxy derivatives or 7-0-ethers, and synthesized derivatives of 4-hydroxycou• the 7-position may be more susceptible to marirr'" 48, 53, 67 or phenylindandione'": 113, biologic attack." 162 without unique properties or clinical 314 Coon and Willis Clinical Pharmacology and Therapeutics

utility. The isolation of a complex 4• tive or noncompetitive type. They propose phenylcoumarin with anticoagulant and that the action of an oral anticoagulant quinidine-like aetivity from an Indian me• depends upon the irreversible inhibition dicinal plant" is of interest chiefly because of transport of vitamin K1 to its intraceUu• of the rarity of naturally occurring 4-sub• lar site of action in the liver." With a stituted coumarins. much larger dose of vitamin K1 , however, New compounds of potential interest this inhibition can be surmounted, pos si• have recently been prepared by esterifica• bly because vitamin K can enter the cell tion of polyvinyl alcohol with the lactone by an aIternate mechanism which cannot of bis 4-hydroxy-3-coumaryl acetie acid; be inhibited by oral anticoagulants." As the product is a copolymer of vinyl alco• to its intracellular site of action, Olson-" hol and the vinyl ester of pelentanic acid. postulates that vitamin K may be necessary Fractions of varying molecular weight and for the derepression of a regulator gene degree of esterification have been ob• which controls the synthesis of elotting tained. Anticoagulant activity has been ob• factors and that an anticoagulant may in• served in rabbits after oral or intravenous terfere with the action of vitamin K on administration of a fraction of 30,000 the repressor substance. There is no evi• molecular weight; fractions of higher dence in support of any chemical altera• molecular weight were very toxic, After a tion of prothrombin (or other cIotting Iac• single dose, an anticoagulant effect was tors) or inhibition of its release or any observed for as long as 15 days; as with increased rate of utilization or degrada• other coumarin derivatives, onset of a tion." measurable anticoagulant effect took place None of the oral anticoagulants has a after a lag period of 20 to 24 hours. An signincant anticoagulant effect when added unexpected aspect of these studies was the to blood in vitro. When these agents are ad• discovery that this agent produced a pro• ministered to animals or man, the func• nounced increase in coagulation time of tional aetivities of several cIotting factors whole blood as weIl as prothrombin decrease. A decrease in activity of factor time.1 28 VII is followed sequentially by decreases in factors IX, X, and II (true prothrom• Mechanism of action bin). The rate of decrease in functional The keto isomer of 4-hydroxycoumarin activity of these coagulation factors ap• has a elose structural relationship to mena• pe ars to be related to the half-lives of the dione ( vitamin K~). Substitution of a individual proteins. After termination of methoxy group for the methyl in menadi• therapy, these elotting factors return to one (2-methyl-1,4 naphthoquinone) con• normal levels in the same order." All anti• verts this synthetic vitamin K into a com• coagulants produce the same effect. John• pound with anticoagulant activity.''" Cou• son," who proposes that purffied pro• marin and related anticoagulants are thrombin can be converted to factor VII thought to act by means of some antago• or factor IX by varying the activators, has nistic effect upon the action of vitamin K. suggested that the actions of oral antico• AIthough originally postulated to be com• agulants on these multiple elotting factors petitive inhibitors of vitamin K, Lowen• may be interrelated, possibly representing thaI and Macli'arlane'" have presented minor structural alterations of a single pro• data derived from experiments with the tein. simultaneous administration of warfarin Inhibition of thrombosis and moderate doses of vitamin K1 to rats which they have interpreted as indicating The therapeutic value of oral anticoagu• that the antagonism between these two lants in the prevention of thrombus forma• agents is neither of the elassical competi- tion or inhibition of propagation of pre- Valurne 11 Oral anticoagulants 315 Nurnber3

existing thrombi has been attributed to stage prothrombin time, the less the inci• their effects in reducing activities of the dence of thrombosis. Thrombus formation above-mentioned clotting factors. In recent in rats is not reduced by bishydroxycou• years contradictory data have appeared marin unless prothrombin time is twice concerning a possible additional effect normal or greater; in fact, the incidence of upon platelet function. Platelets play an thrombosis in animals receiving a small important role in the initiation of throm• dose of drug is higher than that in con• bus formation, particularly in arteries. The trols." In experiments with "serum throm• true effect of oral anticoagulant therapy bosis," the antithrombotic effect of bishy• upon platelets is difficult to assess because droxycoumarin is demonstrable only if the of differences in experimental methods drug has been administered for one week (some in vitro, others in vivo) , different or more before thrombosis is produced animaI species, and measurement of differ• (unless very massive doses of drug are ing effects ( adhesiveness, aggregation, administered).178 This delay in demonstra• thrombus weight, etc.). In man, adequate tion of antithrombotic effect is not present doses of bishydroxycoumarin have been if thrombosis is produced by vascular in• reported to bring ab out a prolongation of jury. 77 platelet survival and a decrease in platelet If a comparable delay in appearance of turnover and platelet adhesiveness.vv v"• antithrombotic effect is present in human 161, 186 Inadequate dosage may have the beings with thrombotic disease, these find• opposite eflect." Platelet-rich plasma from ings may have implications for clinical anticoagulant-treated patients tested in vi• therapy. The thrombus produced by injec• tro in the Chandler apparatus shows a sig• tion of serum into an occluded venous seg• niflcant increase in time required for plate• ment is similar histologically, and probably let aggregation." However, when electri• in pathogenesis, to the "stasis" thrombus cally induced thrombi are produced in seen so frequently in the deep veins of hamster cheek pouches, oral anticoagulants the leg. Optimal therapy of patients with suppress formation of a fibrin thrombus deep venous thrombosis may require simul• but have no significant effect upon the taneous administration of heparin and an development of a platelet thrombus." oral anticoagulant until the maximum The data of greatest value to clinicians therapeutic effectiveness of the oral anti• in the assessment of the therapeutic utility coagulant has been achieved. of oral anticoagulants are those derived In animals the administration of oral from well-designed clinical trials. However, anticoagulants has produced an increase the effects of these agents on both initia• in the rate of recanalization of arterial?" tion and resolution of thrombi are difficult and venous thrombt-", this was not due to to study in man. Numerous investigations any demonstrable systemic fibrinolytic ac• of the antithrombogenic effect of antico• tivity. agulants have been conducted in experi• mental animals, but, since our knowledge Absorption of the pathogenesis of thrombosis is lim• Probably only a small fraction of orally ited, results obtained in animals may not administered drug is absorbed in the stom• be directly applicable to the management ach,' since, as organic acids, oral anti• of human disease. In general, heparin is coagulants are considerably more soluble more effective than oral anticoagulants in in alkaline solutions. The gastric content prevention of the formation of experimen• of free hydrochloric acid, however, does tal thrombi. Administration of an adequate not have a detectable influence upon rate dose of oral anticoagulant is critical for of onset of anticoagulant effect in man.s' the demonstration of an antithrombotic In general, rate and completeness of gas• effect; the greater the prolongation of one- trointestinal absorption are not important 316 Coon and W ilUs Clinical Pharmacology and Therapeutics

detenninants of rapidity of "prothrombin" devised by Axelrod and associates," These response, since differences in time of onset have been used, along with isotopically of effect vary little when oral and intra• labeled compounds, to study relations be• venous administration are compared, Drug tween plasma levels, tissue distribution, can usually be detected in plasma within and duration of anticoagulant effect. one to two hours after ingestion. Although The duration of anticoagulant effect cor• individual drugs are detectable in plasma relates reasonably weIl with the interval at essentially the same time, the peak con• in which the drug is retained in plasma174 centration of some agents (e.g., bishy• and in liver." On the basis of serial de• droxycoumarin, warfarin) is reached after terminations of plasma levels of individual aconsiderably Ionger interval than with drugs, Weiner174 has classifled oral anti• other agents (ethylbiscoumacetate, phenin• coagulants by rate of fall from the peak dione).176 plasma level as rapid (ethylbiscoumace• On the basis of stool content, absorption tate: 15 to 45 per cent per hour), inter• is usually complete, An exceptiön is an oc• mediate (acenocoumarin, phenindione: 4 casional report of poorabsorption of both to 15 per cent per hour), slow (bishy• coumarins and indandiones which appears droxycoumarin, cyclocumarol, warfarin, to be relatedchiefly to errors in eompound• phenprocoumon, anisindione, chlorphenin• ing or cdmpressi0n of tablets,123,176 al• dione: 15 to 20 per cent per day ), and though other factorsmay also be involved.' ultraslow (diphenadione: less than 15 per Response to two preparations of the same cent per day). Within moderate dosage anticoagulant may differ by as much as limits, the higher the initial dose the more 50 per cent.In Bishydroxycoumarin is more rapid the fall in "pro thrombin" activity. slowly and less completely absorbed when In general, the more rapid the fall in given as a tablet rather than as a solution blood level the more frequently a dose or powder. In vitro tests of the rate of dis• must be administered in order to maintain integration of tablets are not good predic• a stable therapeutic effect. tors of response in vivo.':" However, the peak in blood level of a Pretreatment of human subjects with given drug is not directly associated with heptabarbital appears to influence absorp• the maximum depression of "prothrombin" tion of bishydroxycoumarin. Increased ex• activity'" which may occur 12 hours to cretion of bishydroxycoumarin in the stool three or more days later. In addition, be• persists for several weeks after withdrawal cause of extensive individual variability, of the barbiturate.' Weiner-?" has not been able to correlate The solubility in water of a drug may depression of prothrombin activity with also influence its absorption, Warfarin the concentration of drug in plasma. Re• sodium is75,000 times more soluble than cently, however, Nagashima and col• bishydroxycoumarin in aqueous solutions; leagues-" have reported an essentially in contrast to bishydroxycoumarin, un• linear relationship between intensity of changed warfarin has not been recovered "prothrombinopenic" response and the from the stool.' Warfarin is the only "oral" logarithm of the dose of warfarin or its anticoagulant supplied in a form for in• concentration in human plasma. This ex• travenous or intramuscular administration. periment should be repeated with another oral anticoagulant, since warfarin may be Distribution and metabolism the only oral anticoagulant in which plasma Satisfactory and relatively simple meth• half-life is independent of dose.'> The ods are available for the determination of rates of disappearance of bishydroxycou• the majority of these drugs; most tech• marin and ethylbiscoumacetate from plas• niques are based on the original method ma decrease as the doses of drug in• for determination of bishydroxycoumarin orease.'"! Valurne 11 Oral anticoagulants 317 Number3

Protein binding may also influence rap• ly appear in the urine, presumably through idity of onset and duration of effect. The reabsorption from the intestinal tract after extent of protein binding (99 per cent for biliary excretion. The metabolie products bishydroxycoumarin, 97 per cent for war• of oral anticoagulants excreted in urine farin, 90 per cent for ethylbiscoumacetate) have not been fully identifled, The only roughly paralleIs the biologie half-life and anticoagulant excreted unaltered in the duration of prothrombinopenic effect. 123 urine in significant amounts is acenocou• Since at any given time less of the latter marin.':" Metabolites of several coumarin drug is bound, the considerably higher con• derivatives with hydroxyl groups in the centration of free drug may play a role in 6-, 7-, or 8-positions have been described. its comparatively rapid onset of effect. As 120, 130 The 6-, 7-, and 8-hydroxy metabolites will be discussed later, other agents which of warfarin are more polar and bind less alter protein binding have a significant in• weIl to albumin, probably determining their fluence upon anticoagulant effect. The absence in plasma and presence in urine.F" strongest and greatest percentage of bind• No metabolie product of a coumarin or ing is to albumin.!" O'Reilly and asso• indandione has been shown to have anti• ciates-"- 123 have proposed that the high coagulant activity. degree of nonelectrostatic binding of war• A metabolie product of phenindione im• farin to albumin and its nonpolar character parts a red color to alkaline human urine"; account for the sustained levels of this this color has resulted in mistaken diag• drug in plasma, the absence of urinary noses of hematuria. The red color in the loss, and its small volume of distribution. urine disappears when acid is added. Uptake of drug by erythrocytes is vari• Structurally related indandiones have been able, being about 20 per cent for bishy• used as industrial dyes. Diphenadione is droxycoumarin and phenindione (rabbit);" yellow in alkaline solution, thereby cre• 9 to 18 per cent for ethylbiscoumacetate ating no problems in misinterpretation of (rat),69 and less than 1 per cent for war" the color of the urine. farin (man).123 Warfarin is not detectable Administration of vitamin K does not in the cerebrospinal fluid (rabbit).73 Bis• alter metabolie transformation of bishy• hydroxycoumarin and other oral anticoagu• droxycoumarin but does appear to accele• lants cross the placenta, reaching con• rate the rate of disappearance of labeled centrations in the plasma of the fetus al• bishydroxycoumarin from the Iiver." most comparable to those of the mother.>" These agents appear in breast milk in Variability sufficient concentration to induce signifi• One of the major problems in the c1ear cant depression of prothrombin activity.l'" definition of the pharmacologic properties The majority of drug is distributed be• of oral anticoagulants is a marked vari• tween plasma and liver'": 30 with lesser ability in responsiveness: between species, amounts in kidney and intestinal tract. between individuals, and in the same indi• The rate of elimination follows the kinetics vidual under differing conditions, Species of a first-order reaction, probably reflect• differences are so marked that considerable ing the rate of metabolie transformation. caution is necessary in extrapolation of When C 1 4-labeled bishydroxycoumarin is effects in one or even several types of administered to rats," most of the radio• animals to man.'?" There are marked inter• activity is detectable in the feces within individual differences in the rate of me• five days. Only a small amount appears in tabolism of a given drug in man. More than the urine. However, if the bile duct is threefold differences in rates of disap• occ1uded, the major portion of radioactivity pearance of bishydroxycoumarin and war• appears in the urine. In other species'": 85, farin from plasma have been reported.'- 176, 106 greater amounts of radioactivity normal- 177 Daily maintenance doses may vary by 318 Coon and Willis Clinical Pharmacologu and Therapeutics

as much as tenfold. Many other elements other hemostatic abnormalities secondary such as nutritional state, vitamin K in• to the renal disease itself. take, age, sex, rate of hepatic synthesis of clotting factors, etc., may be of even Drug interaction: Effect on greater importance. Marked sensitivity or intraindividual variability in response resistance to oral anticoagulants appears, Tolerance to repeated doses of an anti- in rare instances, to be related to genetic coagulant does not occur except under cir• factors.' Whether less marked interindi• cumstances in which other pharmacologic vidual variability also has some genetic agents have brought ab out a change in determinants has not yet been defined. activity of drug-metabolizing enzymes or O'Reilly and Aggeler1 21 have described a some other form of drug interaction.':" family showing hereditary resistance to In recent years a multiplicity of agents warfarm. The average daily dose of war• having an effect on anticoagulant dosage farin to maintain prothrombin time in a have received attention because of the therapeutic range was 49 standard devia• significant effect they may have upon tions from the mean. The same subject management of therapy. The various needed only one-half to one-fifth the usual mechanisms through which drugs interact dose of vitamin K1 to reverse the antico• ineIude: altered intestinal absorption, agulant effect. Six of eight members of changes in transport (protein binding), the patient's family were also resistant altered metabolism of drug or its antago• to the effects of warfarin. nist, effects upon receptor site, altered Although the administration of a single excretion, and chelation. To date, no evi• dose of one of these drugs to a healthy dence for the latter two mechanisms in individual on separate occasions brings interactions of drugs with oral anticoagu• about a reproducible plasma concentration lants has been presented. of drug at a given interval, the presence The chief drug interaction inHuencing of certain diseases is associated with con• intestinal absorption is the indirect one in siderable intraindividual variation. The in• which various intestinal antibiotics may fluence of systemic disease upon dose influence synthesis or absorption of vita• requirements appears to be related chiefly min K1 , Iessening the continuous stimulus to changes in hepatic function which in• by vitamin K1 of production of eIotting fluence rates of synthesis of critical clotting factors and thus increasing the sensitivity factors. No major change in activity of of the individual to a given dose of oral drug-metabolizing enzymes'" or in the anticoagulant. metabolism of the anticoagulant" have Several drugs are thought to decrease been demonstrated under these circum• dosage requirements of anticoagulant by stances. Changes in gastrointestinal function displacing the anticoagulant from its bind• which bring about a decrease in intake ing site or by preventing initial binding to or absorption of vitamin K or of orally protein, thus increasing the concentration administered anticoagulant can also alter of free anticoagulant in plasma and the response to a given dose, Since, with the amount of drug present at its receptor exception of acenocoumarin, anticoagulants site. Phenylbutazone" appears to act are not excreted unaltered in sigmficant through competitive inhibition while eIo• amounts by the kidney, it is unlikely that fibrate functions by way of noncompetitive decreased renal excretion is responsible inhibition.116, 1 59 Salicylares mayaiso in• for the increased sensitivity of patients fluence anticoagulant dosage in this man• with ehrenie renal disease to these drugs. ner, although they have been shown to A more likely explanation for the increased have an intrinsic anticoagulant effect as incidence of hemorrhagic complications in well.": 33, 55, 152 Oxyphenbutazone'" and these patients is the presence of multiple phenyramidol"- 156 also decrease anticoagu- Va/urne 11 Oral anticoagulants 319 Number S

lant requirements, presumably by inhibi• coagulant has been reported in patients tion of activity of hepatic microsomal drug• receiving methylxanthines.v" metabolizing enzymes; oxyphenbutazone mayaIso have an effect upon protein bind• Side effects of oral anticoagulants ing of drug. Some of the additional effects of these Other drugs have been reported to po• agents may be related directly or indirect• tentiate the effect of oral anticoagulants, ly to their primary mechanism of action in but their mechanism of interaction has not suppression of synthesis of coagulation fac• been defined; these incIude n-thyroxine,':" tors, while other actions appear entirely androgens.v- 143 haloperidol,115 acetamino• unrelated. Several deserve considerable phen," methylphenidate.f quinidine;" and further investigation because of potential several monamine oxidase inhibitors therapeutic utility. (tranylcypromine and nialamide) .133 I pro• Martius and Nitz-Litzowv-?" have shown niazid has no enhancing effect, while the that very large doses of bishydroxycoumarin action of other monamine oxidase inhibi• inhibit oxidative phosphorylation. Phos• tors lies between these extremes. phorylation appears to be inhibited at every Many drugs bring about an increase step in electron transport.": 39, H Phenin• in the required dose of oral anticoagulant dione does not display this effect. Whether through induction of increased activity of this action is initiated through inhibition hepatic microsomal coumarin-metabolizing of ubiquinone function or by means of enzymes; those in which cIinical effects another mechanism is not yet cIear. No have been described incIude many barbital decrease in oxidative enzyme activity is derivatives": 45, 71, 135 (phenobarbital, hepta• demonstrable in the liver of anticoagulated barbital, amobarbital), glutethimide,40, 71 animals. chloral hydrate," and griseofulvin.28 Al• Coumarin derivatives display consider• though many other agents are known to able antibacterial activity in vitro'": 66, 83, produce drug tolerance by means of this 168-170 which is thought to be related to mechanism (sulfonylureas, meprobamate, uncoupling of oxidative phosphorylation.v" antihistamines, alcohol, caffeine), a cIinical However, if bishydroxycoumarin-treated effect upon anticoagulant requirements has rabbits are injected intracutaneously with not yet been described. hemolytic streptococci, infection is more On the other hand, several investigators extensive than that in controls.>" The have recently reported that coumarin de• absence of fibrin in tissues of anticoagu• rivatives can affect the action of other lated animals has been proposed as the drugs. Bishydroxycoumarin potentiates the factor contributing to increased spread of effect of diphenylhydantoin." Simultaneous infection. administration of bishydroxycoumarin and Fontaine and colleagues'" have reported tolbutamide may result in protracted hypo• that phenindione has an anti-inflammatory glycemia158; phenindione does not affect effect equivalent to that of phenylbutazone tolbutamide metabolism.82 in rats with edema secondary to carageenin Recently, Schrogie and associates':" have injections in the foot pad, Other anticoagu• reported that oral contraceptives, by in• lants are considerably less effective. A creasing vitamin K-dependent cIotting fac• similar effect can be demonstrated in ultra• tor activity, bring about an increase in violet-induced erythema in guinea pig skin. dosage of bishydroxycoumarin required for Of possible therapeutic potential is the desired anticoagulant effect. Administra• demonstration by a number of observers tion of multimethylated xanthines is fol• of the benefioial effects of anticoagulants lowed by a decrease in pro thrombin time in the reduction of spontaneous metastases in dogs receiving bishydroxycoumarin." from malignant neoplasms. The effect of The need for an increase in dose of anti- anticoagulants on this phenomenon ap- 320 Coon and Willis Clinical Pharmacology and Therapeutics

pears to parallel the depression of pro• the development of these colony-forming thrombin activity. Cancer cells contain an units; concurrent administration of vita• agent which induces fibrin formation.'!" min K1 restores to normal the number of The presence of a microthrombus around colony-forming units in the liver of mice embolie tumor cells appears to contribute treated with CCl4 and warfarin. The au• to adherence and penetration of these thors have questioned whether the estab• cells.!" In both transplanted and autoch• lishment of hematopoietic colony-forming thonous tumors in animals, adrninistra• units in "normal" sites of extramedullary tion of anticoagulants brings about a hematopoiesis, such as the spleen, might be significant decrease in number and fre• adversely affected by anticoagulants.l11 quency of spontaneous metastases."- 138, 139, Additional pharmacologic actions have 183 Since treatment with warfarin inhibits also been described. Warfarin sodium has the motility of cancer cells in vivo in bronchodilator activity, being about 50 rabbit ear chambers, Thomes and asso• per cent as active as aminophylline." On ciates>" have proposed that the uncoup• swine coronary arteries both bishydroxy• ling of oxidative prosphorylation might play coumarin and warfarin have vasodilator a role in the inhibition of motility; ad• activity comparable to that of nitroglyc• ministration of vitamin K1 restores can• erin.P Bishydroxycoumarin in high con• cer cell motility. In addition, bishydroxy• centration increases total coronary How in coumarin has a direct cytotoxic effect on the isolated perfused dog heart but also human cancer cells in vitro." Recently has adepressant effect upon cardiac con• Michaels'?" has reported a retrospective tractile force and increases total myocardial study of cancer inciderice and mortality oxygen consumption; no effect could be rate in a group of 540 patients receiving demonstrated with warfarin.F" long-term oral anticoagulants for preven• Phenindione has antithyroid activity in tion and treatment of thrombotic disease. rats, blocking uptake of p31 as effectively Incidence of cancer was comparable to as propylthiouracil.>" Other oral anticoagu• that predicted from statistics for that re• lants do not display this effect which, with gion. Eight deaths from cancer would phenindione, cannot be blocked by admin• have been expected during the 1,569 pa• istration of vitamin K1 • The 48 hour p31 up• tient-years of observation, while only one take was at or below normal in five patients was observed. Another patient who died receiving phenindione; uptake increased from an unrelated cause had hepatic after the drug was discontinued. metastases from an undetected neoplasm Both coumarin and indandione deriva• at autopsy. Although, as Michaels is aware, tives (bishydroxycoumarin, 51 ethylbiscou• the number of patients is too small for macetate.>" and phenindionev'") have a demonstration of valid statistical differ• uricosuric effect, producing reversible im• ences, this study should provide the pairment of urate reabsorption by renal tu• stimulus for future prospective investiga• bules. Acenocoumarin and anisindione tions. have no appreciable uricosuric action. Oral anticoagulants have also been used Recently, Sekhar':" has reported that as an.aid in the study of extramedullary diphenadione reduces serum cholesterol, erythropoiesis. After carbon tetrachloride• triglyceride and phospholipid levels, and induced hepatic injury, mitotically active aortic plaque formation in atherosclerotic hematopoietic cells of nonhepatic origin cockerels and pigeons. Simultaneous ad•

localize in the liver, presumably trapped ministration of vitamin K1 does not alter in the liver by a fibrin network, a mecha• this effect. George and associates'" have nism similar to that thought to bring about shown that phenylindandione and phen• hepatic metastases of malignant neoplasms. procoumon accelerate clearing of p31 trio• The administration of warfarin prevents lein from the bloodstream. Volume 11 Oral anticoagulants 321 Number 3

Tahle I. Oral anticoagulants

Usual loading dose Usual daily Interval to (mg. to 30% maintenance dose maximum effect Drug prothrombin activity) (mg.) (hours) Coumarins Bishydroxycoumarin 400- 700 25- 150 36-72 Ethyl biscoumacetate 1,800-3,000 200-1,200 18-36 Warfarin sodium 30- 60 3- 15 36-72 Cyclocumarol 150- 400 25- 175 24-48 Phenprocoumon 18- 30 1- 6 36-72 Acenocoumarin 30- 60 2- 16 24-36 Indandiones Phenindione 400- 700 25- 200 24-36 Diphenadione 30- 60 3- 15 60-84 Anisindione 250- 550 25- 200 24-48

Considerations in dinical management if these compounds are administered more Choice of drug; induction and main• frequently (e.g., a twice-daily dosage sched• tenance dosage. Tahle I lists some of the ule ), an impressive degree of stability can more commonly used oral anticoagulants be achieved." It has been proposed that with ranges for usual loading and main• more potent drugs which have a lower tenance doses and times required to plasma concentration might display less 175 achieve the desired increase in one-stage variation with respect to half-life ; how• prothromhin time, based upon our experi• ever, Solomon and Schrogiev" have not ence with these agents. Investigators, using been able to correlate marked differences other criteria, have reported values which in individual response to a fixed dose of differ from those in Table I. "Loading hishydroxycoumarin with differences in dose" refers to the total dose of drug re• half-life of drug in plasma. Weiner!" has quired to depress the Quick one-stage proposed that longer-acting drugs can be prothromhin activity to a value less than more readily managed if one gives a rela• 30 per cent. Time intervals are measured tively large intermittent maintenance dose to the peak effect rather than to the only after prothrombin activity increases first evidence of anticoagulant effect. following the maximum depression from Ranges have been used hecause of the the preceding dose. This presupposes that marked interindividual variahility in re• the greater fluctuation in prothrombin ac• sponse. tivity which is likely to occur with this ap• Although much has been written about proach does not contribute to a decrease in choice of drug, other than for exclusion of therapeutic effectiveness. drugs hecause of toxic effects upon hema• Recently, O'Reilly and associatesv- have topoiesis, no single agent has been shown suggested a different approach to the ini• to have characteristics which would justify tiation of therapy. Rather than utilizing a priority in clinical use. The most impor• relatively large loading dose of drug (e.g., tant consideration is the experience a clini• 50 mg. of warfarin), they suggest con• cian has had with the use of a particular tinued administration of a moderate-sized drug. From the point of view of cost, daily dose (e.g., 15 mg. of warfarin) until bishydroxycoumarin is one of the least prothrombin activity has reached the de• expensive. A greater Huctuation in day-to• sired level. As might be expected, this day level of prothrombin activity has been means a greater delay before "therapeutic" attributed to the shorter-acting drugs but, levels of prothrombin activity are achieved. 322 Coon and Willis Clinical Pharmacology and Therapeutics

However, they argue that this longer in• agulant may have to be increased several terval reHects changes in the rate of de• fold to maintain a constant effect. pression of factor VII activity while factors Combined use of heparin. As has been II, IX, and X fall just as rapidly as with a mentioned, the maximum depression of all larger induction dose. They suggest that, of the four clotting factors known to be since these latter clotting factors may play affected by oral anticoagulants may not a greater role in stimulating propagation of be achieved until five to seven days after thrombus than does factor VII, the slower the initial dose of drug. Although the rela• depression of prothrombin activity by this tive influence of each factor in the promo• approach may be as satisfactory in pre• tion of thrombus propagation in man is not venting further thromboembolism as the known, on the basis of experiments in ani• more rapid depression achieved by the use mals, factors IX and X may be of particu• of larger initial doses. In our opinion, these lar importance. An increasing number of suppositions may be valid provided that clinicians have been extending the initial treatment with an oral anticoagulant is period of combined therapy with both accompanied by immediate and adequate heparin and an oral anticoagulant to a heparin therapy for at least five to seven minimum period of five to ten days. If days while factors 11, IX, and X are slowly only short-term therapy (seven to ten decreasing. days) is planned, many are recommending In no other area of pharmacotherapy is the use of heparin alone. individualization more important than in When both heparin and oral anticoagu• the administration of oral anticoagulants. lants are administered, blood for estima• Some of the numerous variables which tion of one-stage prothrombin time must may affect individual dosage requirement be obtained at a time when residual have been discussed. We and many others plasma heparin content has reached a low have noted as much as a tenfold interin• level. Otherwise, the heparin in plasma dividual variation in dose of drug required will bring about prolongation of prothrom• for maintenance of a stable depression of bin time and thus prevent proper interpre• prothrombin activity in patients being tation of the effect of the oral anticoagu• treated for thrombotic disease. Other than lant on clotting factor activity. This prob• fundamental genetic differences in rates of lem is a significant one when heparin is drug metabolism, age, sex, "body content' given by subcutaneous injection. The most of vitamin K, the presence of debilitating practical method for simultaneous use of disease which may affect hepatie function, these agents is the intermittent intravenous and intake of other "interacting" drugs ap• injection of heparin at four- to eight-hour pear to be the most common factors inHu• intervals, the blood for determination of encing this variability. In addition, oc• prothrombin time being obtained just prior casional patients with extensive thrombotic to the next dose of heparin, disease may be unusually resistant. Laboratory control. All of the early and Experience has shown that, regardless many of the recent assessments of the of cause, many patients with pretreatment clinical efficacy of anticoagulants in the prothrombin activity of less than 70 per treatment of thrombotic disease in the cent will display increased sensitivity to United States have been based upon labo• oral anticoagulants. Smaller loading and ratory control by the one-stage prothrom• maintenance doses of drug should be bin time of QUick.1 32 However, numerous utilized for these patients. On the other modifications of this procedure have been hand, as the usually sensitive seriously ill devised and advocated as being "more ef• .patient responds to therapy of his primary fective" in control of anticoagulant ther• disease (e.g., congestive heart failure), apy, particularly in the reduction of daily maintenance doses of oral antico- hemorrhagic complications. Some of the Volumell Oral anticoagulants 323 Number3

modifications which are most frequently Although these tests are simple, con• utilized include: (1) the Quick test with tinued supervision of personnel and the use of a BaS04-adsorbed plasma in standardization of reagents are necessary place of saline for determining dilution to assure reproducibility of results.':" The curves-'"; (2) several modifications of the tissue "thromboplastin" extracts show con• Quick method determined on diluted siderable lability and variability and must plasma'": 153; (3) the prothrombin and be carefully selected and repeatedly proconvertin (P & P) test and its modi• checked. An understanding by the physi• fications-'", (4) "thrornbotest'T"; (5) par• cian of the nature of the procedure and tial thromboplastin times." methods of reporting results are critical to Each of these procedures has been pro• proper interpretation and management of moted with claims of greater sensitivity, the level of anticoagulant therapy. Results easier reproducibility, better standardiza• have been reported as: tion, etc., but what has frequently been 1. Prothrombin time. The time for clot• ignored is that a given result by one ting of anormal "control" plasma is re• method is in no way comparable to the ported for comparison with that of the result obtained when another technique is patient's plasma. used. The lack of equivalence of these 2. Percentage prothrombin activity. tests has been pointed out by a number These percentage values are derived from of observers.t'": 136, 137, 163. 181 a curve made by testing various dilutions Obviously, the optimal laboratory con• of normal plasma with saline or BaS04• trol of anticoagulant therapy should be adsorbed plasma. The dilution curve ob• determined by that regimen which pro• tained with saline differs from that ob• vides maximum protection against throrn• tained with adsorbed plasma containing boembolism while minimizing serious additional factor V and fibrinogen. What hemorrhagic complications. While the many physicians who administer antico• definitive answer to this problem has not agulants in their daily practice have failed yet been provided, the best available data to understand is that this reported per• have been derived from studies utilizing centage value cannot be linearly related on the one-stage Quick prothrombin time. a percentage basis to the magnitude of The optimal range, as will be discussed anticoagulant effect. The dilution curve is later, appears to be a prolongation of hyperbolic in shape, a prolongation of a Quick prothrombin time of between two few seconds in prothrombin time will be and three times the control value. This reported as a large difference in percen• range by the Quick method represents tage, while in the therapeutic range, where more intensive anticoagulant therapy than the slope of the curve changes, a con• that recommended by the advocates of siderable increase in prothrombin time will either the P & P or thrombotest techniques. be reported as a very small change in per• As Miale':" points out, a prothrombin time centage (Fig. 2). In managing therapy ( Quick) of two and one-half times the one must know whether saline or adsorbed normal is equivalent to a value of 1 per plasma was used in preparing the dilution cent by the P & P method and 0.6 per cent curve; because of differing slopes of the by the thrombotest. To date, there is no curve, a pro thrombin activity of 15 per evidence that any of the proposed modifi• cent with adsorbed plasma is equivalent to cations of the Quick procedure are superior an activity of approximately 25 per cent in the clinical management of patients as with the saline dilution curve. assessed by the combined criteria of pre• 3. Prothrombin index. This percentage is vention of thromboembolic and hemor• derived by dividing the control prothrom• rhagic complications of therapy at equiva• bin time in seconds by patient's prothrom• lent levels of anticoagulation. bin time and multiplying by 100. A pro- 324 Coon and Willis Clinical Pharmacology and Therapeuttee

40...------,

IJ) 0 z 30 0 U 1LI IJ)

Z

1LI ~ I- 20 elz I- I- 0 ...J U

10

O+----r--,...---.---,;----r--...... ,.---r----r-~ 10 20 40 50 60 70 80 90 100 PERCENT PROTHROMBIN "ACTIVITY" (PERCENT DILUTION OF NORMAL PLASMA) Fig. 2. Curve for Quick one-stage prothrombin activity (constructed from determinations of "accelerated clotting time" of dilutions of normal plasma with saline). thrombin index of 50 per cent is equivalent thrombin activity, Quick) as opposed to to a prothrombin activity of approximately those patients with less intensive treat• 20 per cent. The hazard is that misinter• ment.l'" In arecent randomized prospee• pretation of the prothrombin index as pro• tive study, patients with pulmonary em• thrombin aetivity may lead the physician bolism alloeated to a group treated in the to underestimate the oral anticoagulant 10 to 29 per eent range of prothrombin effeet and to administer more of the agent, aetivity had a signifieantly lower ineidenee placing the patient in jeopardy of serious of thromboembolie complieations during hemorrhage. therapy than those treated in a range of Intensity and duration of therapy. Al• 30 to 49 per eent prothrombin activity though information comparing thrombo• (Quick}." Sevitt and Innes,"!' in studying embolie eomplieation rates in patients incidenee at autopsy of thrombosis and managed at differing levels of intensity of embolism in a group of injured patients therapy is searce, what information is avail• reeeiving prophylactie anticoagulants, able is in support of more intensive ther• found a higher frequeney of thromboem• apy. In the antieoagulant treatment of bolie sequelae in those patients with a aeute myoeardial infaretion, the frequeney Quick prothrombin time maintained at less of thromboembolie eomplieations was re• than twiee normal (prothrombin activity dueed by about 40 per eent in those subjects of 24 per cent in their laboratory ). with prothrombin times maintained at or Duration of antieoagulant treatment above 25 seconds (about 23 per eent pro- must be related to type and severity of Valume 11 Oral anticoagulants 325 Number3

thrombotie disease. However, as far as patients. The great majority of these epi• venous thromboembolism is eoneerned, sodes are minor and can be managed our reeent experience with extending the without termination of treatment. Deaths period of therapy by continuing treatment are rare. The apparent causes of hemor• on an outpatient basis has brought about rhage are multiple and complex. Same of a significant reduction in rates of reeurrent the variables whieh may influence the thromboembolism in those patients receiv• development of bleeding include: (1) ing more prolonged treatment.37 Since anti• inordinate depression of clotting factor coagulant therapy in outpatients must of activity; (2) a possible taxie effect upon necessity be regulated with less frequent capillary walls; and (3) changes in plate• laboratory measurements than those pro• let function. Since multiple coagulation vided in ahospital environment,main• factars are depressed by oral anticoagu• tenance of prothrombin activity between lants, efforts have been made to correlate 30 and 50 per cent is usually reeommended bleeding with selective depression of in• to lessen the frequency of hemorrhagic dividual factars. Many conflicting reports complications. have appeared. Since after five to seven Same elinicians have proposed that, days of treatment levels of activity of fac• when anticoagulant treatment is to be tors II, VII, IX, and X are markedly terminated, the drug dosage be gradually decreased, the incrimination of any single reduced to lessen the hazard of "rebound factor is difficult. Baugh13 has reported thromboembolism." The validity of this that the levels of these factars are no approach has never been doeumented. In different in patients who are bleeding than fact, the little re1iable data which are avail• in those who are not. able da not support this premise.v? When very excessive or lethai doses Toxicity. In addition to hemorrhagic of anticoagulant have been ingested by complications, several eoumarin derivatives animals'"- 95 or man,180 widespread dila• have been shown to be associated on rare tation of small blood vessels has been oceasions with other side effects.':" Tran• noted. With one known exception.t'" no sient alopecia, severe dermatitis.t" skin ne• histologie changes in the vessel wall it• crosis, and generalized urticaria have been self have been detectable. An "increased reported after ingestion of warfarin and vascular fragility" has been postulated.w• other coumarins. Ulcerations of the mouth 182 The petechiae which have been noted have appeared after administration of in patients with coumarin overdosage acenocoumarin. Gastrointestinal distur• could be seeondary to the possible effects bances (nausea, vomiting, diarrhea) ap• of these agents on platelet adhesiveness pear rarely in association with bishydroxy• rather than to any structural alteration of coumarin or ethylbiscoumacetate therapy." the vascular wall itself. The only evidence Taxie side effects have been reported for an alteration in vascular integrity is more frequently in association with use the demonstration by Nelson'P that bis• of phenindione. These include agranulo• hydroxycoumarin increases the rate of cytosis, renallesions (albuminuria, poly• lass of T1824-labeled protein from the uria, renal failure), dermatitis (including bloodstream of rabbits. exfoliative dermatitis), diarrhea and steator• Aseries of studies which may con• rhea, paralysis of accommodation and tribute to our understanding of the patho• blurring of vision, anemia, and hepatitis."'" genesis of bleeding are those performed Bleeding. Same form of hemorrhage ap• by Jaques74 in rabbits and rats. The inci• pears in approximate1y 10 per cent of dence of spontaneaus hemorrhage in an i• hospitalized patients receiving oral anti• mals receiving large doses of anticoagu• coagulants and in almost one in three indi• lant alone is very low, However, if one viduals receiving lang-term therapy as out- superimposes any other measure which 326 Coon and Willis Clinical Pharmacology and Therapeutics

4 0 affects another phase of hemostasis (plate• drugs , 43 and may last for as long as lets, the vessel wall), the frequency of six weeks after therapy has been dis• lethai hemorrhage increases markedly. contlnued.v" The other forms of drug inter• Some of these other measures include ad• action act more directly to increase sensi• ministration of p32, reserpine, steroids, or tivity to anticoagulants. production of "stress" (electric or insulin In arecent survey of our experience shock, injection of formalin, sham opera• with anticoagulant therapy in 2,468 epi• tion, frostbite, etc.). Mortality rate from sodes of thromboembolism, bleeding oc• hemorrhage increases with the increase in curred in 7.9 per cent of the courses of hypocoagulability produced by the anti• treatment. Major bleeding which was de• coagulant and with the increase in in• fined as hemorrhage of such magnitude as tensity of the measure affecting another to require termination of anticoagulant phase of hemostasis. Unfortunately, since therapy appeared in 2.4 per cent; greater so many factors may influence hemostasis than one half of these hemorrhagic events in anticoagulant-treated patients, the va• were gastrointestinal in origin, followed lidity of this thesis is extremely difficult in order of frequency by vaginal bleeding, to document in man, particularly the pos• hemorrhage from an operative wound, and sible effects of "stress" upon the vascular severe epistaxis, Minor bleeding, requiring phase of hemostasis. an adjustment in drug dosage without Since developments are relatively re• termination of therapy, was present in the cent, the quantitative role of drug inter• remaining 5.5 per cent with the predomi• action in the etiology of anticoagulant-in• nant source being the genitourinary tract duced bleeding in man has also not yet (hematuria) followed by epistaxis, minor been adequately investigated. It appears, bleeding from a wound, vagina or gastro• however, that this factor may contribute intestinal tract, ecchymoses, etc. About one to an appreciable proportion of hemor• third of these episodes appeared to be rhagic episodes. MacDonald and Robin• primarily related to associated heparin son'" have recently reported that in 14 therapy rather than to the oral anticoagu• of 67 episodes of bleeding, enzyme in• lant. Less frequently, bleeding may oc• duction was a contributing faetor; two cur in brain and spinal cord, wall of the patients died. Forty of 52 patients with intestine, pericardium, ovary, adrenal myocardial infarction receiving anticoagu• glands, and other areas.P" lants were also treated with barbiturates; Bleeding usually occurs at values for they required higher doses of anticoagu• prothrombin activity by the Quick pro• lants and therapy was more difficult to cedure of 15 per cent or below.v" Very control. Since barbiturates and other seda• frequently, and particularly at higher pro• tives (chloral hydrate, glutethimide) are thrombin activity, bleeding is related to administered so frequently, the majority of the presence of a pre-existing organic lesion, reports of bleeding brought about by this On many occasions such lesions, especially mechanism have been related to these in the gastrointestinal tract, have been drugs. Enzyme induction by these seda• previously unrecognized. Organic lesions tives brings about an increased rate of responsible for hemorrhage can be identi• metabolism of the anticoagulant and fied in at least one half of patients bleed• necessitates an increase in the dose re• ing at levels of prothrombin activity of 15 quired to maintain the desired effect; per cent or above."" if the sedative is then discontinued the Reversal of anticoagulant effect. Vita• prothrombin time will increase markedly min K1 (2-methyl-3-phytyl-1,4-naphtho• and bleeding may occur. Microsomal en• quinone) corrects the abnormalities in zyme induction may appear within two coagulation produced by oral anticoagu• to seven days after administration of these lants. An equimolar amount of vitamin Valume 11 Oral anticoagulants 327 Number 3

K3 (2-methyl-l,4-naphthoquinone) is con• or ulcerative lesions of the gastrointestinal, siderably less effective, probably because respiratory, or genitourinary systems (e~­ of its much more rapid conjugation and pecially prostate gland). Of equal impor• excretion.?" When isotopically labeled vita• tance in contributing to an increased risk

min K1 is administered to anticoagulant• of bleeding are an uncooperative patient, treated rats, there is a positive corre1ation inadequate laboratory control, and un• between shortening of prothrombin time informed or casual medical supervision.

and hepatic content of vitamin K1 . Since Other entities which contribute to a higher

vitamin K1 is metabolized very slowly, the risk include severe hypertension, subacute minimum effective dose of this agent bacterial endocarditis, pericarditis, severe should be utilized if further oral anti• hepatic disease, and certain nutritional coagulant therapy is contemplated; other• problems (particularly deflciencies of vita• wise, considerable resistance to the effect mins C and K). Many of these and other of subsequent administration of anticoagu• contraindications which have been pro• lant may be encountered, in same instances posed are relative rather than absolute. In for periods of several weeks or more. Ad• many instances anticoagulants can be ad• ministration of doses of vitamin K1 of 2.5 ministered with relative safety (the risk of to 5 mg., either orally or intravenously, serious bleeding being less than the hazard can have an appreciable effect in shorten• of fatal thromboembolism) if dosage is ing a prolonged prothrombin time within carefully managed and laboratory control four to eight hours.?' Since recent studies is rigidly supervised. have shown a considerable interindividual Some indications for therapy. Only the variability in response of prothrombin more important indications and a few of times of warfarin-treated patients to small the clinical trials will be noted. By far, the doses of vitamin K1 (5 mg. or less),190 in most important indication for anticoagu• instances of life-threatening hemorrhage, lant therapy, in terms of both numbers of doses of 50 mg. will produce a more pre• patients and value, is the prevention and dictable response.v" Bleeding produced by treatment of deep venous thrombosis and excessive dosage of anticoagulant is usu• pulmonary embolism. Since numerous stud• ally treated with a larger dose of vitamin ies have pointed out the extreme difficulty

K1 than is bleeding secondary to unusual in clinical recognition of venous throm• sensitivity to an "ordinary" dose of drug. boembolism, prophylaxis will be superior In addition, the more prolonged the pro• to therapy of established disease in the thrombin time, the larger the dose of vita• prevention of morbidity and death. The min K1 needed for prompt reversal of ef• many diseases associated with an increased fect. In the rare instance of very serious risk for development of secondary throm• massive bleeding, correction of coagulative boembolic disease and the case for much abnormalities can also be brought about more extensive use of prophylactic anti• by administration of whole blood or coagulants in patients confined to bed with plasma. these conditions have been repeatedly Contraindications to anticoagulant ther• emphasized."- 35, 148 A number of trials apy. The decision to administer anticoagu• have shown that anticoagulants can bring lants must be made by balancing the risk about a reduction of up to tenfold in the of serious or lethai hemorrhage against the incidence of thromboembolism in high-risk potential for equally morbid or fatal patients with obstetrical and surgical prob• thromboembolic disease. The hazard of lems."- 49, 141, 149 A signiBcant decrease in bleeding is especially great in patients lethai thromboembolism is also achieved with other hemostatic abnormalities, recent when anticoagulants are administered to cerebral hemorrhage, recent operations patients with congestive heart failure.' upon the central nervous system or eye, Numerous trials of anticoagulants in the 328 Coon and Willis Clinical Pharmacology and Therapeutics

treatment of clinically established venous the long-term use of anticoagulants (one thrombosis and pulmonary embolism have year or more) in lowering the incidence of provided data which, when compared by recurrent myocardial infarction,"- 100, 173 a retrospective analysis with prior series of well-controlled recent investigation>" has patients treated by bed rest alone, sub• not provided support for their use; in that stantiate the significant contribution of study, however, the prothrombin and pro• anticoagulants to the reduction of mor• convertin (P & P) test was utilized and bidity and death from this disease. How• the intensity of treatment was moderate ever, it was not until 1960 that the first (only 13 per cent of P & P values below adequately designed randomized prospec• 30 per cent, about 50 per cent by the Quick tive clinical trial of anticoagulants in the method ). As Loeliger and associates'" treatment of pulmonary embolism was re• have recently demonstrated, the intensity ported by Barritt and Jordan.1 2 By the of anticoagulant treatment may be the crit• time 19 patients had been followed in the ical factor in achieving a significant reduc• control group (bed rest alone) and 16 in tion in morbidity and death; in a double• the treated group, five control subjects had blind clinical trial, rigorously controlled died from pulmonary embolism and five anticoagulant therapy brought about a sig• others had developed nonfatal pulmonary nificant reduction in incidence of cardio• emboli, while none of the treated patients vascular deaths. had any evidence of recurrent disease (p The validity of anticoagulant therapy in < 0.001). A comparable controlled trial the management of severe angina pectoris of treatment of deep venous thrombosis and "impending myocardial infarction" is alone has not yet been performed, but also difficult to assess. True randomization morbidity and death in anticoagulant• of patients has not been carried out. Sever• treated patients is so low as to leave little al groups have reported an appreciable doubt regarding its value." reduction in frequency of myocardial in• The value of anticoagulants in the treat• farction particularly within the first few ment of acute myocardial infarction is months of initiation of therapy.v» 185 much more controversiaI. Despite alI the One point of general agreement has been recent debate concerning selection of pa• reached concerning the use of anticoagu• tients and the influence of multiple other lants in cerebrovascular disease. Antico• variables, the summary by Douglas-? of agulants have no place in the treatment the more important clinical trials indicates of acute completed strokes and may actu• a 50 per cent over-all reduction in mortal• ally be harmful by increasing the risk of ity rate for treated patients as compared fatal cerebral hemorrhage. In addition, to that for control patients. With the ad• there is no unequivocal evidence that long• vent of coronary care units, the current term anticoagulant therapy favorably in• aggressive attitude toward prevention and fluences the incidence of recurrent cerebral treatment of arrhythmias and earlier mo• infarction although McDevitt and Mc• bilization of the patient, the reduction in Dowell'" have recently reported that anti• mortality rate brought about by antico• coagulant-treated patients had a lesser agulants may be considerably less in fu• morbidity and mortality rate within the ture trials. Many investigators believe that first year after a completed stroke. Al• whatever reduction in mortality rate is though the data are by no me ans defini• achieved may be related less to a decrease tive, several trials provide some evidence in deaths from extension of the myocardial that antieoagulants may be of value in re• infarct or recurrent infarction than to a ducing the extent of neurologie deficit in decrease in incidence of fatal pulmonary patients with "stroke in evolution.T'?- 26 As• embolism. sessment of the value of these drugs in Although many studies have supported "transient ischemic attaeks" is partieularly Volurne 11 Oral anticoagulants 329 Nurnber3

difficult because of problems of aecurate 4. Anderson, G. M., and Hull, E.: The effect of diagnosis and the variability in frequency Dicumarol upon the mortality and incidence and severity of attacks. Nevertheless, a of thromboembolic complications in conges• tive heart failure, Amer. Heart J. 39:697-702, number of observers,": 56, 155 including a 1950. large cooperative study," have reported a 5. Antlitz, A. M., Mead, J. A., Jr., and Tolen• reduction in frequency of attacks in pa• tino, M. A.: Potentiation of oral anticoagu• tients receiving anticoagulants. lant therapy by acetaminophen, Curr. Ther, Although no controlled prospective tri• Res. 10:501-507, 1968. 6. Arora, R. B., and Mathur, C. N.: Relation• als have yet been condueted, long-term ship between structure and anticoagulant anticoagulant therapy appears to be of activity of coumarin derivatives, Brit. J. benefit in patients at risk from arterial em• Pharmacol. 20:29-35, 1963. bolism, including cerebral embolism. The 7. Arora, R. B., Mathur, C. N., and Seth, S. D. subjects at particular risk are those with S.: Anticoagulant and cardiovascular actions of calophyllolide, an indigenous complex cou• mitral stenosis and atrial fibrillation seeon• marin, Arch. Int. Pharmacodyn. 139:75-84, dary to rheumatie heart disease. Several 1962. observers have reported a reduetion in fre• 8. Axelrod, J., Cooper, J. R., and Brodie, B. B.: queney of arterial embolism of the order of Estimation of Dicumarol, 3,3'-methylenebis tenfold during periods of antieoagulant (4-hydroxycoumarin) in biological fluids, Proc, Soc. Exp. Bio!. Med. 70:693-695, 1949. treatrnent.v- 96, 126 A delay of several days 9. Baker, R. N.: An evaluation of anticoagulant or more before initiation of antieoagulants therapy in the treatment of cerebrovascular in patients with reeent cerebral emboli disease: Report of the Veterans Administra• may be prudent in order to reduee the risk tion Cooperative Study of Atherosclerosis, of hemorrhage into an infarcted area. Neurology Section, Neurology 11:132-138, 1961. Similarly, the prophylaetie value of anti• 10. Baker, R. N., Broward, J. A., Fang, H. G, eoagulant therapy in patients undergoing Fisher, C. M., Groch, S. N., Heyman, A., eardioversion and in those with prosthetie Karp, H. R., McDevitt, E., Scheinberg, P., heart valves is difficult to assess but seems Schwartz, W., and Toole, J. F.: Anticoagu• established.v " In the former group there lant therapy in cerebral infarction: Report on cooperative study, Neurology 12:823-835, is a statistically valid deerease in the fre• 1962. queney of embolie episodes oeeurring be• 11. Barker, N. W., Nygaard, K. K., Walters, W., tween six hours and six days after eon• and Priestley, J. T.: A statistical study of version.?" postoperative venous thrombosis and pulmo• The use of anticoagulants has been ad• nary embolism. 11. Predisposing factors, Mayo Clin. Proc. 16:1-5, 1941. voeated in the management of athero• 12. Barritt, D. W., and Jordan, S. C.: Antico• sclerotie peripheral arterial disease and in agulant drugs in the treatment of pulmonary retinal arterial and venous thrombosis, but embolism: A controlled trial, Lancet 1:1309• no clear evidenee of benefit has yet been 1312, 1960. presented. 13. Baugh, C. W.: An investigation of the hemor• rhagic diathesis in patients receiving cou• References marin and indanedione anticoagulants, Canad. Med. Ass. J. 92:116-120, 1965. 1. Aggeler, P. M., and O'Reilly, R. A.: The 14. Berman, H. J.: Anticoagulant-induced altera• pharmacological basis of oral anticoagulant tions in haemostasis, platelet thrombosis, and therapy, Thromb. Diath. Haemorrh. 21 vascular fragility in the peripheral vessels of (Suppl.) :227-256, 1966. the hamster cheek pouch, in MacMillian, R. 2. Aggeler, P. M., O'Reilly, R. A., Leong, L., L., and Mustard, J. F., editors: International and Kowitz, P. E.: Potentiation of anti• Symposium Anticoagulants and Fibrinolysins, coagulant effect of warfarin by phenylbuta• Philadelphia, 1961, Lea & Febiger, Pub• zone, New Eng. J. Med. 276:496-501, 1967. lishers, pp. 95-107. 3. Akbarian, M., Austen, W. G., Yurchak, P. 15. Bingham, J. B., Meyer, O. 0., and Pohle, M., and Scannell, J. G.: Thromboembolic F. J.: Studies on the hemorrhagic agent 3,3'• complications of prosthetic cardiac valves, methylenebis (4-hydroxycoumarin). I. Its Circulation 37:826-831, 1968. effect on the prothrombin and coagulation 330 Coon and Willis Clinical Pharmacology and Therapeutics

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warfarin-v'C to human albumin, Biochem. 171. Varon, M. L., and Cole, L. J.: Hemopoietic Pharmacol, 16:1219-1226, 1967. colony-forming units in regenerating mouse 160. Sougin-Mibashan, R., and Horwitz, M.: The Iiver: Suppression by anticoagulants, Science uricosuric action of ethyl biscoumacetate, 153:643-644, 1966. Lancet 1:1191-1197, 1955. 172. Venho, E. V.: Pharmakologische Untersuch• 161. Spooner, M., and Meyer, O. 0.: The effect ungen über die Toxizität und die Antago• of Dicumarol (3,3'-methylenebis 4-hydroxy• nisten der synthetischen Antikoagulantien, coumarin) on platelet adhesiveness, Amer, Ann, Med. Exp. Fenn. 37:(Suppl. 6), 1959. J. Physiol. 142:279-283, 1944. 173. Veterans Administration Cooperative Study: 162. StolI, W. G., and Litvan, F.: Der Einfluss Long-term anticoagulant therapy after myo• der Substitution in 4-0xycumarin-Derivaten cardial infarction: A study of 747 patients aus die Gerinnungsvalenz des Blutes, in Kol• in 15 hospitals, J. A. M. A. 193:929-934, ler, T., and Merz, W. R., editors: Thrombo• 1965. sis and emboIism: Proceedings of the first 174. Weiner, M.: Pharmacological considerations international Conference Basel 1954, Basel, of antithrombotic therapy, Advances Phar• 1955, Benno Schwabe & Co., pp. 244-250. macol. 1:277-307, 1962. 163. Tat, R. J., and Lewis, A. E.: Levels of 175. Weiner, M.: The significance of the physio• equivalence for various measurements of cou• logie disposition of drugs in anticoagulant marin activity, J. A. M. A. 180:744-746, therapy, Seminars Hemat. 1:345-374, 1964. 1962. 176. Weiner, M., Brodie, B. B., and Burns, J. 164. Thompson, G. R., Mikkelsen, W. M., and J.: A comparative study of hypoprothrombin• Willis, P. W., III: The uricosuric effect of emic agents. The physiologie disposition and certain oral anticoagulant drugs, Arthritis chemieal pharmacology of coumarin and Rheum. 2:383-388, 1959. indandione compounds, in Koller, T., and 165. Thornes, R. D., Edlow, D. W., and Wood, Merz, W. R., editors: Thrombosis and em• S., Jr.: Inhibition of locomotion of cancer boIism: Proceeclings of the first international cells in vivo by anticoagulant therapy. I. Conference Basel 1954, Basel, 1955, Benno Effects of sodium warfarin on V2 cancer Schwabe & Co., pp. 181-193. cells, granulocytes, lymphocytes and macro• 177. Weiner, M., Shapiro, S., Axelrod, J., Cooper, phages in rabbits, BuH. Hopkins Hosp. 123: J. R., and Brodie, B. B.: The physiological 305-316, 1968. disposition of Dicumarol in man, J. Pharma• 166. Thurer, G. R., and Angevine, D. M.: In• col. Exp. Ther. 99:409-420, 1950. fluence of Dicumarol on streptococcic in• 178. Wessier, S., Reimer, S. M., and Sheps, M. feetion in rabbits, Arch, Path. 48:274-277, C.: Biologie assay of a thrombosis-inducing 1949. activity in human serum, J. Appl. Physiol. 14: 167. Ukita, T., and Ejima, A.: Mode of anti• 943-946, 1959. bacterial activity of 3-acetyl-4-hydroxycou• 179. West, B. D., Preis, S., Schroeder, C. H., and marin and dehydroacetic acid. I, J. Pharm. Link, K. P.: Studies on the 4-hydroxycou• Soc. Jap. 82:1625-1630, 1962. marins. XVII. The resolution and absolute 168. Ukita, T., Mizuno, D. 1., Tamura, T., Yama• configuration of warfarin, J. Amer. Chem. kawa, T., and Nojima, S.: The antibacterial Soc. 83:2676-2679, 1961. properties of compounds containing the 180. Williams, E. D., and Doniach, I.: The anti• tricarbonylmethane group. II. III. Antibac• thyroid activity of the anticoagulant phenyl• terial properties of 3.alkylated or 3-acylated indanedione, J. Endocr. 21:421-431, 1961. 4-hydroxycoumarins and of a related pyrone, 181. Willis, P. W., III, Coon, W. W., and Duff, J. Pharm. Soc. [ap. 71:234-243, 1951. I. F.: The management of anticoagulant 169. Ukita, T., Nojima, S., and Matsumoto, M.: therapy, Postgrad. Med. 27:85-93, 1960. The antibacterial properties of compounds 182. Wood, J. C., and Conn, H. L., Jr.: Pre• containing the tricarbonylmethane group. IV. vention of systemic arterial emboIism in Syntheses of 3-alkylated or 3-acylated 4• chronic rheumatic heart disease by means hydroxycoumarins and of a related pyrone, of protracted anticoagulant therapy, Circu• J. Amer. Chem, Soc. 72:5143-5144, 1950. lation 10:517-523, 1954. 170. Ukita, T., Tamura, T., Matsuda, R., and 183. Wood, J. S., Jr., Holyoke, E. D., and Yard• Kashiwabara, E.: Antibacterial properties of ley, J. H.: An experimental study of the compounds having tricarbonylmethane group influence of adrenal steroids, growth hor• in their structure. I. Antibacterial properties mone, and anticoagulants on pulmonary of 1,I-climethyl-4-acyl-cydohexanediones-3,5, metastasis formation in miee, Proc. Amer. dehydracetic acid and 3-acyl-4-hydroxy• Ass. Cancer Res. 2:157-158, 1956. (Abst.) coumarins, Jap. J. Exp. Med. 20:109-115, 184. Wood, J. S., Jr., Holyoke, E. D., and Yard• 1949. ley, J. H.: Mechanisms of metastasis pro- 336 Coon and Willis Clinical Pharmacology and Therapeutics

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