EEE Subcutaneous Adjusted-Dos e Unfractionated Heparin vs Fixed-Dose Low-Molecular-Weight Heparin in the Initial Treatment of Venous Thromboembolism Writing Commitice for the Galilei Investigators Background: Pew reports have addressed the value of unfractionated heparin (UPH) or low-molecular- ‘weight heparin in treating the fall spectrum of patients with venous thromboembolism (VTE), including reeur~ rent VIE and pulmonary embolism. ‘Methods: In an open, multicenter clinical tral, 720 con- secutive patients with acute symptomatic VTE, includ- ing 119 noncritically ill patients (16.5%) with pulmo- nary embolism and 102 (144.2%) with recurrent VTE, were randomly assigned to treatment with subcutaneous UPH with dose adjusted by activated partial thromboplastin time by means of a weight-based algorithm (preceded by an intravenous loading dose), or fixed-dose (adjusted only to body weight) subcutaneous nadroparin calcium. Oral anticoagulant therapy wasstarted concomitantly and con- lunued for atleast 3 months. We recorded the incidence ‘of major bleeding during the initial heparin treatment and that of recurrent VTE and death during 3 months of fol- low-up. Results: Fifteen (4.2%) of the 360 patients assigned to UFH had recurrent thromboembolic events, as com- pared with 14 (3.0%) ofthe 360 patients assigned to na- droparin (absolute difference between rates, 0.3%; 95% confidence interval, ~2.5% to 3.19%). Four patients as- signed to UFH (1.1%) and 3 patients assigned to nadro- parin (0.8%) had episodes of major bleeding (absolute difference between rates, 0.3%; 95% confidence inte val, =1.2% to 1.7%). Overall mortality was 3.3% in each ‘group. Conelusions: Subcutaneous UFH with dose adjusted by activated partial thromboplastin time by means of a weight-based algorithm is as effective and safe as fixed- dose nadroparin forthe initial treatment of patients with, VTE, including those with pulmonary embolism and re- ‘current VTE. Arch Intern Med. 2004;164:1077-1083 INCE THE DEMON! that heparin is necessary’ for the initial treatin nous thromboembolic (VIE) disorders, spective random *The Writing Commitee ‘numerous pro- clinical trials have STRATION doses capable of prolonging the activated partial thromboplastin time (APTT) within the targeted therapeutic range, either em- pirically oF according to appropriate no- mograms." Recently, Prandoni et al” showed that the use of a weight-based al- sent of ve- members for the Gallet Stay who had complete acces tothe rave data needed for this report ‘and who bear authorship responsibility for this report are Paolo Prandoni, MD, PHD: Marino Carmoval, MD; and Antonio Marchior, MD. The Writing Committe for this article has no relevant financial intrest in this article A-complet lis ofthe “afilations forthe Writing ‘Commitee appears in the Acknosledgments section. ‘complet is ofthe institutions and investigators participating in the Galles, ‘Study appeatson age 1082, (aepRayTeD) ARGHINTERN MEDVOL Toe MAYS SF Downloaded From: https: convincingly shown that fixed-dose low= molecular-weight heparins (LMWH) are at least as effective and safe as adjusted. dose unfractionated heparin (UFH) for the treatment of symptomatic VTE." Most of these studies were confined to patients ‘with symptomatic proximal deep venous thrombosis (DVT) of the lower extremi- ties, largely at their first episode of DVT Pew reports have compared the elficacy and safety of these agents in treating the full spectrum of patients with VTE, in- cluding calf vein thrombosis, recurrent VTE, and pulmonary embolism (PE). In all of the above-mentioned stud- ies but one,” UPH was administered in- travenously with the use ofa loading dose followed by the continuous infusion of gorithm allows the rapid achievement of correct anticoagulation in most patients treated with subcutaneous UFH alter an initial intravenous loading dose. As this strategy enables the early mobilization and discharge of suitable patients with DVT, the subcutaneous administration of UPH ‘might still represent a valuable ool for the iniUial treatment of thromboembolic dis- orders We performed an open, multicenter clinical tial in 720 consecutive patients with acute symptomatic VTE, of whom 119 (16.5%) had PE and 102 (14.2%) had recurrent VIE. They were randomly as- signed (o treatment with subcutancous UFH with dose adjusted by APT by means of a weight-based algorithm (pre- (©2004 American Medical Association, All rights reserved. jamanetwork.comy by Sun Yum on 05/10/2023hm for Adjustment of Subcutaneous Heparin Doses Dosage Athsinent nd Tm ole were Regine exter ‘Rint V Blas ard SCinjcton of heparin doses aj ob ‘wesght= Pat rst APTT afer ten proceed a fat 120 =5 ne sop up ‘ter 50.0 Same sp ‘tech 91-120 (One stap own tech >in Wits heparin eaten, pron APTT air, and proce as ‘olay <5 Same sp ‘ter 50.0 One stap down tech 91-120 To steps down tech >a Witte heparin ‘ter 3h ‘Aubrovatons: APT, acta partal ropa tine ravenous St, stbetaneoue “Doras waite than $0 kg, 4000 UW 12500 USC; 80-704, 000 UV 15000 USO more tan 704g, 000 UW 17300 Se 4 Steps: 10000, 2500, 1500, 1750071 250,75 00, nd 3000 ‘spon APTT in a als les than 10 esconde i band, thn at pac dosage according tthe scala ie or APTT get than ‘a saeons ceded by an intravenous loading dose), or to fixed-dose (adjusted only to body weight) subcutaneous LMWH (na- droparin calcium). Oral anticoagulant therapy witha cou- marin derivative was started concomitantly and contin- uted for atleast 3 months. We recorded the incidence of | major bleeding during the initial heparin treatment and that of recurrent VTE and death during 3 months of fol- low-up, with blinded validation of outcome events by a central adjudication committee —_iiom_@~___ STUDY PATIENTS Allconsecutve inpatients and outpatients refered to 19 alan Patcating centers from October 1, 1998, o April 30, 2001, fvth the clineal suspicion ofan acu (les than weeks ol} DV Tofthelowerestemiies andor PE were clighe forthe study, provided thatthe suspicion was objectively confirmed. A pos tveresul ofa east 1 the following tests was acceped for pa tent inclusion: ascending phlebography, compression ult sound ofthe proximal vein system, ceho color Bopper san of thecalf vein stem inthe case of clinica suspicion of DVT ven- tation perfusion scanning, spiral computed tomographic san- hing ard pulmonary anglograpy inthe case of clinkal suspi- Cow of PE" In the presence of normal results ofan ulttcound test ofthe lower extremities, the diagnose of PE was also ac- Cepeda perfusion lng scan vas compatible wih thigh prob Stliy of PE when compared withthe chest x14. Ceri for exclusion were ageless than 18 years, preg- nancy, containdications to anicongulant treatment fulldose anticoagulant treatment (ether heparin or oral alicoagu- Tans) for more than 24 hours, hemodynamic instability, pre vious (less than 1 yea eater) episode of VTE, le expecianc Ieesthan 3 months, poor compliance, and geographic maces tbl for follow-up (aepRnyTeD) ARGTINTERN MEDVOL Toe WAT All patents meeting the inclusion criteria were enrolled in the study provided they gave written informed consent. The study was approved by the ethical board of all partic paling centers ‘TREATMENT REGIMENS Randomization to UFH or LMWH treatment (strife accord ing to shether the patents presented with DVT ony or with PE, and also stratified according to clinical center) was per formed with a computer algorithm and the use of « 24-hour telephone servic that reconed patient information before dis closure ofthe treatment assigned Patents randomized to UFH were administered aninra- ‘enous bolus of heparin sodium (Rocke, Basel, switzerland) ndasubcataneous injection of heparin caicium (GentiumspA, Como, lly) in doses adjusted to body weight (4000 U intra ‘enowsly plus 12500 U subcutaneously inpatients weighing ies than 50 kg, 5000 U pls 13000 U respectively. in those ‘weighing 500 70 kg; and 6000 U plus 17500 U, respectively, inpatients weighing more than 70g. The fis APTT was me sured aller 6 hours, and subsequent dose adjustments daring the ira 48 hours were scheduled twice daly according othe lgoritim shown in Fable ¥, with the APT performed inthe Inidinterval. They were araigd in "steps te taken up of Alon according o APTI values, respective of body weight The targeted APTT range (0-90seconds) wascallbraed to cor respond toa plasa heparin level, as expressed by aXs activ iiyrof0.35 190.70 Ulm After the frst 48 hours, UFH adiin= istration was managed on the basis dally APTT determinations aliens randomized tol MWH received subeutancotsad- tunistration of nadroparin, 85 U/kg twice daly. al anticoagulant ueatment with warfarin sodium was started within the first 2 days and continued fora otal of 12 ‘weeks. During inal combined heparin and warfarin teat- ment, in both patiem groups, prothrombin ine was mea- ‘red at eat evry other day. it the dove adjusted toachieve international normalized ratio INR) of2.0 (030, by adopt- ingan identical approach, Heparin was discontinued when the INR was greater than 20 fr 2 consecative days and the pa fents had recetved the study drug fora lest 3 days SURVEILLANCE AND FOLLOW-UP During the initial treatment with the study drugs, patients were ‘examined daly forsigns nd symptoms of reeurrentthrombo- ‘embolism, bleeding, or the accurrence of heparin-induced thrombocytopenia Follow-p visits were scheduled after 1 and 3 months. P tients were asked t return tothe study center if clinical mat Festations of recurrent thromboembolisi oceurred. Informs- tion on all suspected outcome events and deaths was reviewed and classified by «central adjudication committee blinded to lreatment assignment, CLINICAL OUTCOME ASSESSMENT \Weevaluated the rate of ecuren thromboembolism and mor- tality during heparin treatment and follow-up as well asthe tate of major being occuring during the period of heparin treatment and the subsequent 48 hours Reaurent DVT was diagnosed a follows: a new intalu- sual filling defect on a venogram tht wae seen om least 2 Projections abnormal results of compression ultrasound in an rea where compression had been normal, ora substantial in- ‘tease in the dameter of the thrombus during fall compres- Sonat the popliteal or femoral vein; ora new defect in the call ‘ein system on color Doppler testing, Recurrent PE was diag- (©2004 American Medical Association, All rights reserved. jamanetwork.comy by Sun Yum on 05/10/2023nosed as follows: new intraluminal filling defect om pulmo- nary angiography or computed tomographic scan; a new de- {ect of atleast 75% of a segment on the perfusion sean, with normal ventilation: or autopsy demonstration. bleeding was defined as major it was clinically overt and associated with a fall inthe hemoglobin level ofa least 2 g/dl. for anced for transfusion of 2 or more units of red blood cells: AH sas intracranial or retroperitoneal; or if it warranted the permanent discontinuation of treatment. Heparin-induced thrombocytopenia was defined as a platelet drop below 100% 10 ul and/or a fall greater than 50% below baseline Deaths were classified as due 1 PE, bleeding, another iden- liable cause, or unexplained. Awtopsy was intended for ll po- tients who died and in whom PE could not be excluded STUDY OUTCOMES AND ANALYSIS “The main aim of the study was to compare the eflicacy of the 2 treatment strategies by assessing the incidence of symptom- atic recurrent VTE during the 3-month study period. The sec- ‘ondary analysis dealt wth the incidence of major bleeding dur- {ng the inital LMWH treatment and additional 48 hours. Both analyses were perlormed on an intention-to-treat basis and in- ‘cluded all patients who were randomly assigned to either strat- tay. Restle were reported as a difference in incidence be- toveen treatment groups and the 95% confidence interval ‘On the basis of previous observations the incidence of re- ceurrent VTE during the 3-month period of follow-up was as sumed to be 4% to 5% in the LMWH group. To exclude a true increase of 3.5% or more in the incidence of recurrent VTE among the UFH-treated patiens, we ealculated a sample size of approximately 350 patients per group, allowing for a type | certor of0.05 (I sided) and a type Il eror of 0.20. For the com- parison of subgroups, the x test (2 sided) was used. The individual quality of warfarin anticoagulation was con- sidered satisfactory ifthe INR was within or above the thera- peutic range (INR, 2.0-3.0) in more than 70% of determina- —_ i dy STUDY PATIENTS Between October 1998 and April 2001, 845 patients were referred to the study centers with an episode of clinically symptomatic VIE, Ofthese patients, L12wereexcluded for the following reasons: full-dose anticoagulants formore than 2+hours (36 patients) geographic inaccessibility forfollow- up (8 patients); contraindications to anticoagulant treat- ment (16 patients); previous (within 1 year) episode of VTE (24 patients); life expectancy less than 3 months (13 pa- tients); poor compliance (6 patients); hemodynamic insta- bility (5 patients); pregnancy (3 patients);and ageless than 18 years (1 patient). Of the remaining 733 patients, 720 gave informed consent and were randomly assigned to receive UFH or LMWH (360 patients in each group). The baseline characteristics the patientsin the 2 treatment groups were similar (Fable 2). INITIAL TREATMENT AND FOLLOW-UP The median duration of heparin treatment was 6.5 days in each group (range, 5-12 days). all patients completed their initial treatment while remaining in the hospital (aepRnyTeD) ARGTINTERN MEDVOL Toe WAT ‘Table 2, Baseline Characteristics of the Study Patients charactors Damopapievaabis| “oe. ean 20. y es72156 670.148 So No. AE ‘sun 16108 ck cars for trombos, No.) Proves tronboanboism (>ty)S4(150) 48 (183) Case moa) 76.213) cet rumatcturs S169) 634175) ect sugary S606) 46(128) Prolnge immobilization 55(182) 61169) Estrogen therapy Bey 1283) oun tromBophia mes 2364) Dagnsisat presentation, No. (3) Deep vrais hominy anvyere) —a0,@23) Provial «dial Eo 25 lenlted dt a 5 Puirorary embasm sates) 60(167) ‘Associad with dogpcintrombosis 16 7 -Abrvatns WH, lou-ncecula-weight opr UFHunacsonatad hepa The mean 4 SD hepatin dose administered during the first and the second days in patients allocated to the UPH [group was 365005300 U and 305002 10800 U, respec Lively. The proportion of patients who reached the thera- peutic APTT threshold (=50 seconds) was 73.1% (263/ 360) and 88.1% (317/360) after 24 and 48 hours, respectively. During the course of initial UPH treatment, ‘only 23 patients (6.4%) required no dosing changes, while the remaining 337 required at least 1 change (1 change in 35 patients, 2 changes in 58, and more than 2 dosing ‘changes in the remaining 244). On average, 3 dosing, ‘changes were needed to monitor heparin in patients allo- ceated to the UFH group. ‘Compliance with treatment and with the study pro- tocol was high, and no patients were lost to Follow-up. The quality of oral anticoagulant treatment was similar inboth groups, an INR within or above the targeted thera- peutic range (INR, 2.0-3.0) on at least 70% of measur ‘ments was reached in 72.7% of UPH and 70.0% of LMWH recipients. RECURRENT VTE Among the 360 patients treated with UFH, 15 (4.2%) de- veloped an episode of objectively confirmed recurrent VTE. Among the 360 patients treated with LMWH, ar ‘current VTE was recorded in 14 (3.0%; absolute diffe cence between rates, 0.3%; 05% confidence interval, -2.5% to 3.1%) (able 3). Recurrent thromboembolic events involved the int- Uially affected leg in 4 patients in the UPH group and in 3 of the LMWH recipients (all proximal DVT); they in- volved the contralateral leg in 5 and 5, respectively (iso- lated calf DVT in 1 patient per group); and they pre- sented as PE in 6 patients in each group (with a fatal ‘outcome in 3 and 4, respectively). Recurrent thromboembolic events were similarly dis. tributed throughout the study period. In the UFH group, (©2004 American Medical Association, All rights reserved. jamanetwork.comy by Sun Yum on 05/10/2023Table 3. Primary Study Results ne) (m=300) (v= 380) Facarent ramboembalen™ Ipsatal thrombosis 4 a Conrata trombosis 5 5 Pumonaryemtoism 6 6 relat 19142) 1409) sor beeing acu) 3108) -Abbreatons: LMWH, low-meleular-weight heparin; UFH, untactinatod bat "Ding th intial eatmen an allow. uring he tal eaten 5 episodes occurred in the initial 2 weeks, 4 in the fol- owing month, and 6 in the remaining 6 weeks; the cor- responding figures in the LMWH recipients were 4 5, and 5, respectively. Among the 119 patients with PE, 3 had symptom- atic recurrent VTE (1 in the group of 59 patients allo- cated to UFH and 2 in the group of €0 LMWH recipients) BLEEDING COMPLICATIONS Among the 360 patients treated with UPH, 4 (1.19%) de- veloped a major bleeding complication during the ini- tial treatment, which was fatal in 1. A major bleeding event ‘was also recorded in 3 (0.8%) of the 360 patients treated, with LMWH (absolute difference between rates, 0.3%: 95% confidence interval, ~1.2 %to 1.7%) (Table 3) During the subsequent period, 5 additional pa- tients developed major bleeding while receiving warla- rin (fatal in 1 patient); 1 was in the UPH group, and the remaining 4 were initially allocated to LMWH. MORTALITY During the 12 weeks of follow-up, 24 patients died, 12 (6.3%) in each group. Among the 12 deaths of patients treated with UFH, 3 were classified as due to PE and 1 to major bleeding: the respective figures in the LMWEL ‘group were 4 and none. ADDITIONAL OBSERVATIONS (Overall, recurrent thromboembolism was more frequent among patients with proximal than isolated calf DVT (25/ +469 [5.3%] vs 1/132 [0.8%]; P=.02), and among patients with cancer than those free of malignancy (11/156 [7-1%] vs 17/564 [3.0%]; P=.03), whereas the rate of recurrent events did not differ between patients witha history of pre vious thromboembolism and those with a first episode of thrombosis (5/102 [4.0%] vs 24/618 [3.0%]: P=.63). Sub- ‘group analysis failed to display differences between UPH and LMWH recipients in this regard Among patients allocated to UPH, recurrent throm- bboembolism occurred in 7 2.7%) of the 263 patients who reached the APTT therapeutic threshold within 24 hours, as compared with 8 (8.2%) of the 97 patients who did (aepRnyTeD) ARGTINTERN MEDVOL Toe WAT not (P=.02); and in 13 (4.1%) of the 317 patients who reached the APTT therapeutic threshold within 48 hours, as compared with 2 (4.7%) of the 43 patients who did not (P=.86) During the study period, immune heparin-induced thrombocytopenia was observed in 1 patient in each ‘group. Two patients per group developed a malignancy that was not apparent at the lime of inclusion into the ‘current investigation, ee Despite the increasing availability of LMWHs, UFH still represents a widely used antithrombotic drug forthe ini- tial management of venous thromboembolic disorders, ‘especially in the United States.'°"* In clinical practice, UFH is commonly adminis tered intravenously, either empirically or with the use ‘of nomograms, which allows the prompt achievement ‘of adequate levels of anticoagulation in most patients” However, the continuous intravenous administration requires costly facilities, makes early mobilization and discharge of patients with venous thrombosis prob- lematic, and generally is not well tolerated by either patients or hospital staff, The subcutaneous adminis- tration of adjusted-dose UFH has the potential to shorten the duration of patients’ hospitalization as ‘compared with the intravenous route." The results of ‘our randomized clinical tial clearly show that subeu- taneous administration of UPH with the use of APTT- adjusted doses according to a weight-based algorithm that has recently been validated at our institution” is as effective and safe as fixed-dose nadroparin for the ini tial treatment of patients with VTE. The equivalence between the 2 drugs was seen in all categories of cenrolled patients, including those with noneritical PE. and recurrent VIE. The distribution of recurrent thromboembolic events during the study period was similar, as was the mode of presentation of recurrent events and the case-fatality rate, The rate of major bleeding during the initial treatment and subsequent 48 hours was similarly low, as was the mortality due to reasons other than recurrent thromboembolism and bleeding, Our results are consistent with those obtained in a study of similar characteristics where patients treated with UFH received intravenous administration ‘of heparin, and suggest that whenever UFH is constd- ‘ered for the intial treatment of VTE disorders, subcuta- neous heparin is an attractive alternative The Fate of outcome events obtained with subeuta- neous heparin in the present investigation is among the lowest reported so far in clinical studies dealing with the treatment of symptomatic patients with UFH."A few el- ‘ements suggest the possibility that the route of admint tration might be relevant to the isste of heparin elficacy. Bentley et al” randomized 100 patients with calf vein thrombosis, as shown by phlebography, to receive either subcutaneous or intravenous heparin for 7 days, and noted, 44 489% rate of thrombus resolution in the subcutaneous ‘group compared with 18% in the intravenous group, stg ‘gesting an effect of heparin that was related to the route of administration. A meta-analysis of 8 trials comparing (©2004 American Medical Association, All rights reserved. jamanetwork.comy by Sun Yum on 05/10/2023subcutaneous with intravenous administration in pa tients with DVT concluded that both thrombus propaga- tion and symptomatic recurrences were less likely in pa~ tients receiving subcutaneous therapy." In addition, in the only available comparative study between subcutaneous adjusted-dose UFH and fixed-dose LMWH in patients with DVT, the 2 strategies were associated with a similar re- duction of the thrombotic burden, as shown by repeated phlebography,’ which contrasts with the distinet advan- tage of LMWH over intravenous UPH consistently shown inall comparative studies between the strategies" Ae- cording to the results of recent investigations, continu ‘ous intravenous heparin might deplete stores of intravas- ceular tissue factor pathway inhibitor and reduce levels of the natural anticoagulant antithrombin It wa greater ex- tent than subeutaneous UFH.""* Prescribing an intravenous loading dose was cho- sen because of the poor bioavailability of subcutaneous heparin, and weight-adjusted heparin doses were used because body weight isthe single best predictor of indi- vidual heparin requirements." Owing to the use of APTT-adjusted doses according to a weight-based algo- rithm, an adequate level of anticoagulation was reached within 24 hours in 73% of patients and within 48 hours i889, Not surprisingly, these rates were slightly lower than those (87% and 99%, respectively) observed in the primary clinical study performed a few years ago with the aim of identifying and validating this algorithm. Miti- gation of benefit is likely to occur whenever guidelines are moved from the realm of efficacy research into clini- cal practice." Nevertheless, the weight-based algorithm ‘was well accepted by all clinicians participating in this trial, eading to a more aggressive heparin dosage than that used in the single institutions, and most likely ac- counts forthe lavorable outcome achieved by UPH in this clinical wil Whether the adequacy of anticoagulation, as ex- pressed by an APTT level above the lower limit of the therapeutic range within the first 24 to 48 hours, is an important component of the success of UPH therapy is controversial" In the present investigation, failure to promptly achieve a therapeutic APTT level in patients treated with UPH was associated with a statistically sig- nificant and elinically important increase in the risk of subsequent recurrent thromboembolism. The rate of re- eurrence was indeed 3 times lower in patients who did achieve the therapeutic APTT threshold within the first 24 hours of therapy than in those who did not. The re- sults of our study are fully consistent with those ob- tained by Hull and coworkers?" and suggest that, irre- speetive of administration route, prompt achievement of therapeutic APTT level considerably improves the long-term clinical outcome of patients treated with UPH Despite the large number of patients treated with both heparin compounds, immune thrombocytopenia was observed inonly’1 patient in each group during the study period. Asthe duration of intial heparin treatment isthe main determinant of this threatening complication that especially affects patients treated with UPH."'*" we think that the low rate of heparin-induced thrombocytopenia throughout the whole study period is likely to be ex- (aepRayED) ARCHINTERN MEDVOL Toe MAVEN SF plained by the early overlap with coumarin derivatives adopted in the present investigation and the conse- {quent short duration of heparin treatment (on average, 65 days) In keeping with findings from other investiga- tions irrespective ofthe stidy arm, recurrent throm bhocmbolisin was considerably more frequent among pa- Lents with proximal than isolated calf DVT. Fustheemore, patients with cancer exhibited a significantly higher risk ‘of recurrent events than did cancer-free patients. This ob- servation is fully consistent with that reported by oth- crs" and suggests that anticoagulant therapy needs further improvement in cancer patients with theombo- [A few methodologle aspects deserve proper com- ment. Becatise of the need for laboratory monitoring of patients treated with UFH, no attempt was made to blind the treatment. Since this was an open trial, care was taken to minimize the potential for bia. We included consecu- Live patents, used central randomization by telephone, and ensured that follow-up was complete forall random. ized patients, Furthermore, a clinically suspected out- ‘come events were assessed by an independent, blinded ‘central adjudication committee on the basis of predeter- mined criteria. Because the rate of eligible patients who ‘were actually excluded from the current investigation was negligible, our results are likely to be applicable to the ‘ast majority of patients with VTE We conclude that treatment with subcutaneous UPH with dose adjusted by APTT by means of aweight- Ipased algorithm is as elfective and sale as fixed-dose {adjusted only for body weight) nadroparin forthe int tial treatment of patients with VTE, including those ‘with PE and recurrent VIE. The use of LMWHs for VTE treatment has clear advantages over UFH, as they do not require laboratory monitoring, are associated with a lower incidence of immune thrombocytopenia, and make home treatment of selected patients fea. sible." IF for any reason (such as mode of elinical pr sentation, drug availability, anticipated prolonged hos- pitalization for comorbidities other than VTE, oF patient's choice) UFH is deemed to be the proper choice, the subcutaneous administration of this drug is an altracive option, Accepted for publication June 30, 2003. From the Department of Medical and Surgical Sei- ‘ences, Universita di Padova, Padova (Drs Prandoni and Mar- chiori), and Area Strategica di Patologia Vascolare, Osped- ale di Rho-Passirana, Milan (Dr Carnevali), laly This study was supported by a grant from Gentium SpA, Come, Hay. This study was presented as an interim report at the sth Congress of the International Society of Thrombosis ‘and Haemostasis; July 10, 2001; Paris, France. Corresponding author and reprints: Paola Prandoni, MD, PhD, Department of Medical and Surgical Sciences, Sec~ ‘ond Chair of Internal Medicine, University of Padua, Via Ospedale Civile, 105, 33128 Padua, Italy (e-mail: paoloprandoni@in i). (©2004 American Medical Association, All rights reserved. jamanetwork.comy by Sun Yum on 05/10/2023Inadtion tothe members of the Writing Commitee, the following institutions and investigators participated in the study Executive Committe” A Gitolami, MD, PPrandont, MD, PRD (Clinica Medical, Univer Padova, Padova Hal), M acabll, MD (Gent Spa, Como Hal. External Safety Committe: A.W. A Lensng, MD, MH. Prins, MD (Academic Medical Center, University of Amster dam, rsterda, the Netherton) “Adjudication Committee E- Berardi, MD, P. Sion, MID (Clinica Medica, Universita Padova, F. Velo, MD, 6. Camporese, MD, GM. Anrosss, MD (Servizi di Angiiogi,Azionla Ospedale di Padova) ‘Coordination and Data Management Centers: Universi ci Padova (Prandont, MD, A. Machi MD, P. Bagatla, Mb); Ospedale dr Rho-Pasiana ian aly (M. Carmona, MD}; Gentium SpA, Como (N.laobll, MD, G. Clerc MD) Paripating Centers al nly th order of numberof patients contributed tthe ty) linia Medic, Univer sa di Padova (PProndont MD, A. Marchor, MD, P.agtellg MD, P.Pecil, MD, D. Tormene, MD. L. Nosena, MD, Xt Fla, MD, D. Sart MD, A. Girolas, MD): Unita Opertva di Tromboembolismo Venoso, Dipartimento Area Medica, ‘Arcapeale “Santa Mara Nuova” Reggio Emilia (A Ghiradusci, MD, M.Slngard, MD, Mera, MD): Divisione dk Me dicina Generale, Asin Ospedalier ch Padova (B. Girolam, MD, P. Fedele, MD, A. Lombard, MD, C. Foss, MD, A. Dent MD, 6. Bagg, kD) Medicina dUrgenca, Astenda OspedalieraS: Maria degh Angel,” Pordenone (PF Tropeano, MD, M Seremin, Mb, $.Cal, MD, G.Cerpeggian MD. 1. De Sant, MD, P. 1. Papin M,C. tefanon, MD, W. . Mercant, DY: Area Stratepca ci Patologia Vascolare, Oxpedale dt Rho-Passrana, Aziends Ospedalera“G. Salvi -Carbagnate Milan (M Carova MD, A. Alar, MD, M. Avert, MD, M. Bonzant, MB, E Cres, MD, R Scarell, MD, MSommariv, MD, S.To- nolo MD, C. Vecchi, MD); Sezione d Patologia Vascolaec delaCoagelasione UO. Medicina intema, Malate Metabol- Chee Vascolar, Azienda Onpedalirs dk Patna (R.Quintvala, MD). Divisione dh Medina Interna, Onpele Maggiore dk Bologes (F Accor, MD, G.Astorin, MD, [Aug MD, V. Arent, MD); Cento Emilia ¢ Tombos "A. Blanc Bono IRCES Ospedale Maggiore “Policlinico, Milan (Nota, MD, P Buccarel, MD); U.O, Medicinal, Ospedale Regionale Cx Foncello, Treviso (G Scannapico, MD, V.Pagiara, MD, M, Ros, MD); Repario ds Medicina, Casa di Cura “Villa Bric,” Vicenza (A. cago, MD); UO Medicina I, Onpedale Regionale Cx Foncello, Trevis (S, Vilalta, MD, F- Zenesin, MD, G Foscolo, MD) UO. Angilogia, Ospedale "S. Camilo,” Rome (A R. Toni, MD, ML Pala, MD); Disnione dh Medicina, ‘Asienda Onpedaliens"Waazi” Lecce (F Parenle, MD, . Catrignano, MD, A. Valea MD, . Forse, MD, M. Campobasso MD, R. Pot, MD); Divisione Medic I, Ospedale Piacenea(D. Inert, MD, C. Prat MD, P.Cavalat, MD); Dipartimento Ai tiedicina Interna eVanclare, Universita di Perugia (G. Agrell, MD, R. Ros, MD); Dipartimento di Oncologia ed Ema. tologiaEmatlogin, Ospedale Csi d Nose, Venesa(D, Sartori: MD, O, Vina, MD); Dipartimento dk Medicina ed On- Cologia, Ospedale i Adin, Rovgo(S. Capp MD, G.Vescon, MD); U.O. Medicina Generale, Ospedale dh Corona, Ares=0 (R Miglae, MD); Unita Autonoma di Medicina, Ospedale dt Avago, Vicenza (F. Cor, MD) 11. His J Waki TE Shaughnessy 86, eal. Hepa an ow-meeular- —_ =a ‘weight epi: mecurisms ato, pharmacokinetics, dosing, mentaing ‘ear, a say. Chest 200111, sup 645- 9, 1. anit OW, Jordan $6 Anicoagulr deags inte estmet of uimonayem- 12 HiSeh DR Lee TH, Moron BE, Cron W,Gulchabsr 2 Shared has als: corre ia Lane 16011901512 ‘aketon by mns fasta dose subeuanasshpun o deperas 2 Sande DPM, Hos, Bl, de ik gt, at J, Aan tosis Am Hear J 1095181: 276280. ural an hepa conte wih acenoaurarl done the inal wea 13. Bey PG, Klar W, Sul ME tal. An objet fata mat ‘net of prea hobo Engl Med 1992527151480, of epari adnan. Trond Res. 1801817187 4, Daven UR, Ginsberg J. Doukets J Holbeck AM, Cvah 6. A meta 4 Hommes DW, ua A zzol Bile tn Cala J. Subcatneos hp ni compting on leigh apie th nace psn ‘2 compre ith caninousiraenous heparin aintraian te etal inthetratmantl venous trombuemboism Ach tn Mad 200601 ‘tame of spain tomboss mea ant Ann In Med 10216 8 aes 4, Gaui 1K, Dbz AD, Doyle RL, Haste TU, Gabe AM, Lovleut- 18 ColubortiveEopesn Nuticone Sui. Aanonisad al of subcutaneous ‘rh epi compre wien earn exe act ep low malclar weight apn (CY 216 compared wih incaenausunacton ‘nous thrombosis orancorzed corre te. An tn ‘ied heparan th veamar of ep-vntronbesi Tam Heanos 10 on 40080, east, 5. Cohinbue Invi, Low-nlaala-nsight heparin inte tementatp- 16. Pando, Lasng AWA, Ber Ht Comparison sbcutznens ‘ems with enous tvarboombalsm. Eng Me 107 35757 52 rales pan wih inoue snr haan posal 6 Simomen 6, Sos Chrbonier Beta THESEE(Teuaparin ou Hepaine ‘trombos ane 1025861 5 ‘Standart: Enlatons ans EnbalePulnoni) Sty Group Acorprien 17. HaenbagSchnt Kopenagenk, Tole Human Ber. Ft forall epi th raced pari or ase pono oss, body wigh-indpenrsueuznonus MUM aus std dose ‘ay els Eng 197207 63-58, ‘rented nvaous heparin nial eaten roxma venus 7 Lopack &. Meisner lige, et a. Seutangou low maleaar hosts. Tuamb Hoanast 20083882656 ‘eit heprinvsu sukedaneous uactostd heparin the tsimant 18, Bein Hach Wunder, Meov , Kar. fats alone ‘cep van trams: Posh mula Tram Hasos 192 88 wight heparin tvonbus ogession ad eere tyomoenbasm sp wie tt eh depen thambost WV Enid 200744 626-651 8. Bomar E, Picci A Oban, Zu, Glam A, PanonP.Nomayams 18, Hansen J, Sandet PL irri aspes ow mou weight hepa ‘arte administration of untae heparin in teeta weanet fete ‘ad nacional haprn an crcutg es antivombin an ssa thronboenbossn:anovrie. Thromb Heomst 2000242226, ‘or pathway itor possale mechan fr dnc in terapuie f 9, Pando Sap Sarar tal Uso an alr for admiring (2ef Trane Res 100891177181 Subcutaneous heparin in the weamar cap veces tonbasis. Amt 20. EgermajerP. Thetis at heparin andor anicaaglanonronbus prop Hon 120 200202, gion a prevenson othe os yarome 2 eral ea oe 1. yr onl Gl RO, a. Avot therapy fr egw thon (sae, Pag Cardone Ds 20074489 20 boomboic see. Chet 20111 0ep.76 10, 21 Rose RA, Rey BU, Guy J, Frtana J, Sis 8. The weighs (aepRnTED) ARCHINTERN MEDIVOL Toe MAVEN Soot WWWARCHINTERNNED CON (©2004 American Medical Association, All rights reserved. Downloaded From: https:/jamanetwork.com/ by Sun Yum on 05/10/2023heparin sig nomograconpaeé wth stand car namogram2a- hain onl tal Aon nr Med 108 1874881 (Gal Sete RNa, Zaske DE, Has E Heparin kis: vate [tetas an dosage. i Pharmac! Te 198 2037-39 Whe RH Zou MurglD Efecto wey, ox, ap, clincal agai, and ‘hronbaplast magnon steaystinravencs para equa Ach ler Me 1997.57. 2468-272 cla, Glare, Pare 1c. Te estan otimplnenting te wih based haar amegram asa races gudel, Ach ner Med 195156 tes-640, ul Raho GE, Grae RF, Po GF, Vane KA. The impor ‘ial heparin weston lng-tem cincal outcomes of antithrombotic thera: th arin heme of eyed recuence. Ach Med 097, rai. 200 Hu RD, Raha GE, ran, Peo GF, Vein KA, Ratton been he ine ‘ahi te loner lit ote APTT rapa ange an rcurent vnaus ‘hronboerboism ug hapa wean ep en tvomsosis Ach fern Md 07 57250-2988 Anan, Ginsberg, ere 0, Gant ish Th ation beeen he ae ‘td paral tvrbonastntimeresponee and acarencin pants whe ‘nou tomo wth contaustrvenus pati, Ach nm Me fe 5617-168. Anand 35, Babs 5, shag, tal Recent weoous orbs ep (ngpRa\ TED) XRCHINTERN WEDIVOL 16h MAYIN D00P a 2 a herp an eluant iparancealy sted pari trombe basi mes. Ac ire Me, 1980 1592020-2002 Giralon Prndo. Stan PU tl Teint heparin tro ozytapena i espalaed mail pte ened wih subanous wc Aone heart rpc coke sty, lod 208-101 2008 2050 ehuinan$, Rh AS Ldn, ealAeamarsonct sx west thsi onto al anioaglan hap ater ais piste of vereus tobe enol, 1 EJ Med. 165332 66-165 Prods, Nests Duka, sal Comparson of 3 and 6 mons a wal an ‘xan thaay ater fist epsoe pound deep ain varios pul tnaryembotsm and conparsn of6ané 12 ess of trap arte ca deep en tombos revi 2011062468 2880, Hanson PO, SutEntson H ecuret nau iomboenbalematr deep ‘en thrombosis: ane and nk ats rch tr Me, 200-160 79 m7 PradniP Lansing AWA, Cog Ata Thelongse cin couse fete ep enous tonbosis Aan nro Med 19512517 Dou JO, Foster GA, Cover MA, Pn MH. Ginsberg JS inl ik ‘orang fren arou ramamlam rng ial ert sf enna herp. Arch ne Med, 200 160481 S46, Panda’, Lng AWA Peco tal Recut vonoustonboombals ‘nde camplaons during anicaaguln ene patets wih a ‘aan venous ombose, lod 2002 124 488 (©2004 American Medical Association, All rights reserved. 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