COMPARISON OF A NEW MICROCRYSTALLINE

Transcription

1 Br. J. cli. Pharmac. (1979), 8, COMPARISON OF A NEW MICROCRYSTALLINE DICOUMAROL PREPARATION WITH WARFARIN UNDER ROUTINETREATMENTCONDITIO D. LOCKNER & C. PAUL Departmet of Medicie, Thrombosis Uit, Huddige Uiversity Hospital, S Huddige, Swede 1 To determie whether two differet oral aticoagulats show differece uder routie cliical coditios, 71 patiets were radomized to treatmet with Apekumarol, a microcrystallie dicoumarol preparatio, ad 72 patiets to treatmet with warfari. 2 Durig the ipatiet phase of treatmet both drug groups remaied for about 94% of their treatmet time withi prothrombi value limits of 5-25% (Simplasti A). No statistically sigificat differece was foud betwee the drugs. 3 While uder outpatiet care, both drug groups remaied for about 80% of their treatmet time withi prothrombi value limits of 5-25%. No statistically sigificat differece was foud betwee the drugs. 4 The itesity of cotrol ad umber of prothrombi-determiatios did ot differ sigificatly betwee the groups. 5 Variatios i the daily dose did ot differ sigificatly betwee the groups. 6 The mea daily dose could ot be correlated to mea body weight. 7 The mea daily dose decreased with age for the male patiets takig warfari, ot for the female patiets. There was o such decrease for either male or female patiets takig ApekumarolE. A additioal 137 patiets who at the time of the trial were uder routie treatmet with warfari were also studied with regard to mea daily dose, age ad sex. I this additioal group the mea daily dose could be correlated with age i both males ad females. 8 No differece betwee Apekumarols ad warfari could be demostrated whe tested uder routie cliical coditios accordig to the desig of the preset study. Sesitivity for warfari, but ot for Apekumarol0, seems to icrease with age, this sesitivity has bee demostrated i both sexes. Itroductio Dicoumarol ad warfari are the two most frequetly used oral aticoagulats i Swede. Both drugs have certai disadvatages: Theabsorptio ofdicoumarol is ofte variable ad icomplete ad its breakdow is dose related, but this is ot the case with warfari (O'Reilly, Aggeler & Leog, 1964). Commercial warfari, however cosists of two racemic forms each havig a differet breakdow (Breckeridge, Orme, Wesselig, Lewis & Gibbos, 1974). These characteristics give warfari a advatage over covetioal dicoumarol ad this has resulted i warfari beig recommeded as the more suitable drug for cliical use (Blomback, Dieer, Forsberg, Hallbo6k, Hedlud, Locker, Lud & Reizestei, 1975). As theabsorptiocharacteristics ofdicoumarol seem maily to deped o the pharmaceutical preparatio of the drug (Lozisky, 1960; O'Reilly et al., 1964) a /79/ attempt was made to improve the absorptio of dicoumarol by producig the drug i microcrystallie form. This preparatio (Apekumarol0, AB Ferrosa, Swede) was show to be virtually completely absorbed at a more costat rate (Korsa-Begtsso, Holm, Kjallstrad & Korsa-Begtsso, 1978). It has bee show that ApekumarolO is 20% more effective i depressig prothrombi levels tha a covetioal dicoumarol preparatio (Korsa-Begtsso et al, 1978). The results of prelimiary studies with ApekumarolO i ma suggest that part of the earlier limitatios ofcovetioal dicoumarol have ow bee largely overcome with this ew microcrystallie dosage form ad that the pharmacokietic differeces betwee Apekumarols ad warfari may be of lesser cliical importace. We therefore udertook a radomized cliical study of warfari ad 0 Macmilla Jourals Ltd 1979

2 60 D. LOCKNER & C. PAUL ApekumarolS9 i order to determie whether patiets treated with Apekumarol* spet a loger-time withi therapeutic prothrombi limits tha patiets treated with warfari. Methods A total of 143 cosecutive patiets attedig the Thrombosis Uit of the Huddige Uiversity Hospital i whom the plaed duratio of oral aticoagulat treatmet was three moths or loger were radomized to either Apekumarol1 or warfari treatmet. Accordig to the priciple described by O'Reilly & Aggeler (1968) treatmet was started with a fixed dosage for each drug util prothrombi values had become lower tha 30% (ormal rage %), after which treatmet was cotiued with idividualized doses, these beig about 50% of the iitial dose. The iitial dosage of Apekumarol0 was 160 mg/day durig the first half of the study but this was icreased to 200 mg/day for the remaider. Warfari was give iitially at a dosage 15 mg/day. I most patiets treatmet was started with a ifusio of itraveous hepari, which was give parallel to the oral aticoagulats util the therapeutic values had bee maitaied for 2 to 3 days. Prothrombi levels were determied by the Simplasti A method. patiets were hospitalized durig the iitial phase of therapy. Durig this time daily prothrombi determiatios were performed util stable values had bee achieved. Thereafter, prothrombi determiatios were carried out while i hospital mostly o alterate days. After 1 to 2 weeks of therapy, uder hospital coditios, the patiets were usually allowed to6 leave -hospital to- cotiue their treatmet as outpatiets. The frequecy of prothrombi determiatios uder outpatiet coditios was determied idividually accordig to the stability ad the iveau of prothrombi values. Both drugs were always prescribed by the same physicia, but there were several chage-overs i the prescribig physicia as the study progressed. The aim was to keep the prothrombi values betwee 10 ad 15%, however values betwee 5 ad 25% were cosidered to be withi the therapeutic limits sice o major bleedig episodes or re-thromboses were observed withi these limits i our study. Measuremets were made of the time it took to achieve therapeutic prothrombi values after istitutio of the aticoagulat therapy ad of the time durig which the patiets were remaied withi therapeutic prothrombi limits, both as ipatiets ad as outpatiets. These latter measuremets were also related to the total treatmet time. testig was both age ad sex-adjusted by meas of variace aalysis. The statistical aalyses were performed accordig to Studet's t-test. Results ad discussio Sevety-oe patiets were radomized to Apekumarol* ad 72 to warfari. Of the 71 patiets radomized ito the Apekumarol(9 group, six could ot be evaluated; four ever started treatmet due to icorrect radomizatio, while two received the wrog drug. Nie further patiets were oly icluded i part of the evaluatio, seve because of icomplete data, oe because of trasfer to aother hospital ad oe due to death, the cause of which was urelated to the aticoagulat treatmet. Of the 72 patiets radomized ito the warfari group, 69 were treated. The remaiiig three patiets were icorrectly radomized ad ever started treatmet. Twety-two further patiets who received warfari were oly icluded i part of the study: I twelve of these patiets treatmet was stopped for various reasos, but ot because of side-effects. I eight patiets data were icomplete, ad two patiets died due to causes urelated to the aticoagulat treatmet. The mea age of the patiets i each group did ot differ statistically, ot eve whe the sexes were compared withi or betwee the groups (Table 1). The patiets alloted to the two treatmet groups were thus comparable with respect to age ad sex. I some of the smaller subgroups a degree of skew i the distributio was observed for which correctios were made whe makig the statistical calculatio by aalysis of variace. The meas ad the stadard deviatios i the tables are; however, uadjusted. It took a sigificatly shorter time to reach therapeutic prothrombi values whe warfari 15 mg/day was give tha whe Apekumarol4 160 mg/day was give as the iitial dosage (Table 2). Whe the iitial dosage of Apekumarol0 was icreased to 200 mg/day the therapeutic prothrombi values were reached equally fast i both groups (Table 2). This illustrates the poit that speed i depressig coagulatio factors with differet aticoagulats depeds to a great extet i providig a sufficiet dose (Aggeler & O'Reilly, 1966). It ca therefore be stated that 200 mg/day Apekumarol* ad 15 mg/day warfari are i this respect about equivalet doses. However, it should be poited out that the mea age of patiets i these subgroups differed sigificatly (P=0.039). The mea age for the Apekumarol0- subgroup was 64.5 years compared to 57.0 years i the warfari subgroup ad this may possibly have masked a differece betwee the two drugs. Iitial treatet with the respective aticoagulats was carried out o a ipatiet basis for a mea duratio of about twelve days. Durig this 'ipatiet'

3 COMPARISON OF MICROCRYSTALLINE DICOUMAROL WITH WARFARIN 61 phase of treatmet the patiets remaied for about 94% of their treatmet time withi the therapeutic prothrombi limits (Table 3). The total treatmet time did ot differ statistically betwee the drugs. There was o statistical differece i the time spet by the respective patiet groups withi therapeutic prothrombi limits or the percetage time spet withi therapeutic limits (Table 3). After beig discharged from hospital ipatiet care the treatmet was cotiued for a mea of about four moths as hospital outpatiets. Durig this 'outpatiet' phase of treatmet the patiets remaied for about 80% of their treatmet time withi therapeutic prothrombi limits. There was o statistical differece betwee the drugs tested (Table 4). The total time our i- ad outpatiets spet withi therapeutic prothrombi limits was loger tha that reported by other ivestigators (Borchgrevik, Table 1 Age ad sex of patiets studied (Mear s.d.) patiets Apekumarol@ = = ±16.1 = ±14.5 Warfari Warfari ~ = = =32 differece Apekumarols females/males: Warfari: females/males: Table 2 Time to reach therapeutic prothrombi values (Mea + s.d.) ApekumarolO 160mg days =30 Warfari 15mg days =33 (P=0.013 Apekumarols 200mg days =27 Warfari 15mg 2.6±0.6days =29 Table 3 Ipatiet results (mea ± s.d.) Treatmet time (days) Time withi thera- B/A peutic limits (days) (A) Apekumarol ± ± = 63 Warfari 11.2 ± = differece (B) Table 4 Outpatiet results (mea ± s.d.) Apekumarol0 Warfari differece Treatmet time (days) (A) 113.5± ± 84.1 Time withi therapeutic limits (days) (B) 87.4± ± 77.2 B/A = =53

4 62 D. LOCKNER & C. PAUL Bjerkelud, Abrahamse, Bay, Borge, Grade, Helle, Kjorstad, Peterse, Rorvik, Thorse & Odegaard, 1968; O'Malley, Steveso, Ward, Wood & Crooks, 1977) but this may, however be explaied at least i part, by the wider prothrombi limits set i our study (5-25%) compared with the Thrombotest limits of the authors cited, amely 5-15%. These fidigs idicate that uder the routie cliical coditios applied i this limited patiet material there appears to be o practical differeces betwee the drugs tested: Patiets o Apekumarol@ ad warfari maitaied their therapeutic prothrombi values to the same degree. These fidigs are i cotrast to those reported by Husted & Adrease (1976), who foud warfari to be superior to bishydroxycoumari ad pheprocoumo i maitaiig therapeutic prothrombi values. Their study, however, is limited by the fact that it was retrospective ad the results are based o a ihomogeous group of patiets. There is always the possibility of improvig prothrombi value stability i a give treatmet group by more frequet cotrols ad adjustmets i dosage, especially whe uder outpatiet care. I order to exclude such biasig iflueces i the preset study a compariso was made of the frequecy of prothrombi determiatios i both groups of outpatiets (Mea ± s.d. umber of prothrombi determiatios ApekumarolS group 9.1 ± 4.8, warfari group ). There was o statistical differece betwee the groups. Prothrombi levels were determied about every other week i our outpatiets. (Durig ipatiet treatmet the prothrombi levels were determied daily or every other day i both groups, thus there was much less risk of such bias durig ipatiet treatmet.) A aalysis of the daily drug treatmet data sheets was also carried out to determie whether the daily dose of oe drug had to be varied more frequetly tha that of the other i order to maitai the prothrombi values at the iteded level. For this purpose the mea daily aticoagulat dose for each patiet was calculated. To make the mea daily doses comparable, i order to overcome problems associated with differig amouts of active substaces i both preparatios, the stadard deviatio of this mea for each patiet was expressed as a percetage, thus providig a idicatio of the degree of variatio i the daily dose. The mea ( ± s.d.) values of this percetage for both groups were compared (40.5 ± 33.2, = 65 for Apekumarol* group; 41.6± 34.3, =69 for warfari group). The results idicate a wide variatio i the mea daily tablet dose for both groups of about 40%. No differece could be foud betwee the treatmet groups. The data were also aalysed to see whether a correlatio could be foud betwee the mea tablet dose ad mea body weight for patiets i the respective treatmet groups as a whole ad for males ad females withi the groups, separately (Table 5). No correlatio could be demostrated. Husted & Adrease (1977) foud that a therapeutic dose of bishydroxycoumari could be correlated to the bodyweight of the patiet but that such a correlatio could ot be foud for either pheprocoumo or warfari. To determiie the ifluece of age o therapeutic dosage requiremets, the mea daily tablet itake of each patiet was correlated to the patiets age (Table 6). A strog egative correlatio was foud for the warfari group. This idicates that with icreasig age the patiets eed sigificatly lower doses of warfari to achieve therapeutic prothrombi levels. No such correlatio could be foud for the Apekumarol0 group. A more detailed aalysis of the material revealed a sigificat correlatio betwee dose ad age for the Table 5 ApekumarolP Patiets weight ad its correlatio to mea tablet itake Warfari

5 COMPARISON OF MICROCRYSTALLINE DICOUMAROL WITH WARFARIN 63 males takig warfari but ot for the females (Table 6). Patiets i the Apekumarol@ group did ot show ay sex correlated variatio of the mea dose. The iability to fid a correlatio betwee dose ad age for the females i the warfari group could have bee due to the small umber of patiets i this subgroup (=32). The authors therefore ivestigated a additioal 137 patiets who were curretly uder treatmet with warfari at Huddige Uiversity Hospital. To obtai the mea tablet itake for each patiet a mea of 112 tablet igestios were aalyzed (rage ). The results of this study are preseted i Table 7. It ca be see that a statistically sigificat egative correlatio betwee mea tablet dose ad age was foud for the whole group, ad for both males ad females whe aalysed separately. Husted & Adrease (1977) have reported greater sesitivity for warfari with icreasig age ad i additio they also foud a coectio betwee age ad dose for bishydroxycoumari. This study was however ot cotrolled ad the patiet material was ihomogeous. Separate aalyses for the differet sexes were ot performed. I aother retrospective study (O'Malley et al., 1977) foud that elderly patiets eeded sigificatly lower warfari doses tha the youger adults. The mea warfari dose for the females did ot differ from that of the males. betwee dose ad age was however ot calculated separately for both sexes. Several reasos for the coectio betwee age ad dose have bee proposed: Chages i the lea body mass (Forbes & Reia, 1970), chaged sesitivity to vitami K or warfari (Hasel & Baloch, 1970), the rate of iactivatio of warfari beig possibly decreased with age (O'Malley et al., 1977, Husted & Adrease, 1977) lower albumi values i the aged, a chage of the affiity of the receptor site ad a icreased degradatio rate of coagulatio factors (Husted & Adrease, 1977). Shepherd, Hewick, Morelad & Steveso (1977) showed that vitami K depedet clottig factors were more effectively ihibited by warfari i the elderly. Clottig factor degradatio, however, did ot chage with age, either did the pharmacokietics of warfari. The authors cocluded that the age related chages are caused by a icreased sesitivity to warfari with age. I summary it ca be stated that, o differece betwee Apekumarol0 ad warfari could be demostrated whe tested uder routie cliical Table 6 Mea daily tablet itake correlated to the patiets age Apekumarol'5 Warfari P> >P> P > P> P> > P> Table 7 Daily tablet itake correlated to the patiets age (mea ± s.d.) i a separate group of patiets curretly uder treatmet with warfari Age (years) differece Mea umber of tablets/day differece P< > P> >P> ± 1.20

6 64 D. LOCKNER & C. PAUL coditios accordig to the desig of the preset study. Sesitivity for warfari, but ot for ApekumarolO, seems to icrease with age ad this sesitivity has bee demostrated i both sexes. Refereces AGGELER, P.M., & O'REILLY, R.A. (1966). Pharmacological basis of oral aticoagulat therapy. Thromb. Diath. Haemorrh. (suppl. 21), BLOMBACK, M., DIENER, L., FORSBERG, K., HALLBOOK, T., HEDLUND, P.O., LOCKNER, D., LUND, F. & REIZETEIN, P. (1975). Frekves, diagostik, profylax och behadlig av vetrombos. Ldckartidige, 72, BORCHGREVINK, C.F., BJERKELUND, C., ABRAHAMSEN, A.M., BAY, G., BORGEN, P., GRANDE, B., HELLE, I., KJORSTAD, H., PETERSEN, A.M., RORVIK, T., THORSEN, R. & ODEGAARD, A. (1968). Log term aticoagulat therapy after myocardial ifarctio i wome. Br. med. J., 3, BRECKENRIDGE, A., ORME, M., WESSELING, H., LEWIS, RJ. & GIBBO, R. (1974). Pharmacokietics ad pharmacodyamics of the eatiomers of warfari i ma. Cli. Pharmac. Ther., 15, FORBES, G.B. & REINA, J.C. (1970). Adult lea body mass declies with age: some logitudial observatios. Metabolism, 19, HASEL, K. & BALOCH, K.H. (1970). Vitami K deficiecy i the elderly. Gerot. Cli., 12, HUSTED, S. & ANDREASEN, F. (1976). Problems ecoutered i log-term treatmet with aticoagulats. Acta med. Scad., 200, HUSTED, S. & ANDREASEN, F. (1977). The ifluece of age The techical assistace of Asa Lidgre ad Helge Locker is gratefully ackowledged. Our thaks are due to AB Ferrosa, Swede, for kidly supplyig us with Apekumarol0. o the respose to aticoagulats. Br. J. cli. Pharmac., 4, KORSAN-BENGTSSON, B.M., HOLM, G., KJALLSTRAND, G. & KORSAN-BENGTSSON, K. (1978). A log term cross over study comparig the cliical usefuless of a ew dicumarol preparatio with warfari. Eur. J. cli. Pharmac. (i press). LOZIKI, E. (1960). Physiological availability of dicumarol. Ca. med. Ass. J., 83, O'MALLEY, K., STEVEON, I.H., WARD, C.A., WOOD, AJJ. & CROOKS, J. (1977). Determiats of aticoagulat cotrol i patiets receivig warfari. Br. J. cli. Pharmac., 4, O'REILLY, R.A., AGGELER, P.M. & LEONG, L.S. (1964). Studies o the coumari aticoagulat drugs: a compariso of the pharmacodyamics of dicoumarol ad warfari i ma. Thromb. Diath. Haemorrh., 11, O'REILLY, R.A. & AGGELER, PM. (1968). Studies o coumari aticoagulat drugs. Iitiatio of warfari therapy without a loadig dose. Circulatio, 38, SHEPHERD, A.M.M., HEWICK, D.S., MORELAND, T.A. & STEVEON, I.H. (1977). Age as a determiat of sesitivity to warfari. Br. J. cli. Pharmac., 4, (Received August 31, 1978)