Background Low-molecular-weight heparin is known to be safeand effective for the initial treatment of patients with proximaldeep-vein thrombosis. However, its application to patients withpulmonary embolism or previous episodes of thromboembolism hasnot been studied.
Methods We randomly assigned 1021 patients with symptomaticvenous thromboembolism to fixed-dose, subcutaneous low-molecular-weightheparin (reviparin sodium) or adjusted-dose, intravenous unfractionatedheparin. Oral anticoagulant therapy with a coumarin derivativewas started concomitantly and continued for 12 weeks. Approximatelyone third of the patients had associated pulmonary embolism.The outcome events studied over the 12 weeks were symptomaticrecurrent venous thromboembolism, major bleeding, and death.We sought to determine whether low-molecular-weight heparinis at least equivalent to unfractionated heparin in patientswith venous thromboembolism.
Results Twenty-seven of the 510 patients assigned to low-molecular-weightheparin (5.3 percent) had recurrent thromboembolic events, ascompared with 25 of the 511 patients assigned to unfractionatedheparin (4.9 percent). The difference of 0.4 percentage pointindicates that the two therapies have equivalent value accordingto our predetermined definition of equivalence. Sixteen patientsassigned to low-molecular-weight heparin (3.1 percent) and 12patients assigned to unfractionated heparin (2.3 percent) hadepisodes of major bleeding (P = 0.63), and the mortality ratesin the two groups were 7.1 percent and 7.6 percent, respectively(P = 0.89).
Conclusions Fixed-dose, subcutaneous low-molecular-weight heparinis as effective and safe as adjusted-dose, intravenous unfractionatedheparin for the initial management of venous thromboembolism,regardless of whether the patient has pulmonary embolism ora history of venous thromboembolism.
In Western countries, each year 2 to 4 persons per 1000 requireanticoagulant therapy for symptomatic deep-vein thrombosis orpulmonary embolism.1,2,3 Although deep-vein thrombosis and pulmonaryembolism were previously regarded as separate clinical entities,there is good evidence that they are expressions of a singledisease process — namely, venous thromboembolism.4,5,6
Until recently, the standard treatment of patients with venousthromboembolism was hospital admission, with unfractionatedheparin given by intravenous infusion for 5 to 10 days, followedby oral anticoagulant therapy for at least 3 months.7,8 Becausepatients vary widely in their anticoagulant response to unfractionatedheparin, frequent laboratory monitoring with appropriate doseadjustment is needed to keep their level of anticoagulationin the therapeutic range. In contrast, the longer half-lifeof low-molecular-weight heparins and the more predictable anticoagulantresponse make them suitable for subcutaneous administrationwithout laboratory monitoring.
Initial trials in hospitalized patients with proximal deep-veinthrombosis showed that low-molecular-weight heparin in a dosedetermined by body weight alone is at least as effective andsafe as unfractionated heparin.9,10 Two further recent trialshave had similar results when low-molecular-weight heparin wasgiven mainly on an outpatient basis to suitable patients withproximal deep-vein thrombosis.11,12 However, using due caution,these studies excluded patients with symptoms of pulmonary embolismand some patients with a history of venous thromboembolism,because such patients are thought to have more serious thromboembolicdisease. Before the widespread use of low-molecular-weight heparinis recommended, the effectiveness of these agents in treatingthe full spectrum of patients with venous thromboembolism mustbe confirmed.
We report the results of a large, open, international, randomizedclinical trial designed to determine whether fixed-dose, subcutaneouslow-molecular-weight heparin and adjusted-dose, continuous intravenousunfractionated heparin have at least equivalent efficacy inunselected patients with symptomatic venous thromboembolism.We studied the clinical outcomes of recurrent venous thromboembolism,hemorrhage, and death during 12 weeks of follow-up, with blindedvalidation of outcome events by a central adjudication committee.
Methods
Study Patients
Consecutive patients with acute, symptomatic deep-vein thrombosis,pulmonary embolism, or both who were considered to require antithrombotictherapy were eligible for the study. The symptomatic deep-veinthrombosis could be limited to the calf or could involve thepopliteal vein or a more proximal vein; the diagnosis had tobe documented by ultrasonography or venography. Clinically suspectedpulmonary embolism was confirmed by ventilation–perfusionlung scanning that showed a high probability of pulmonary embolismor by pulmonary angiography or, if lung scanning was nondiagnostic,by the demonstration of deep-vein thrombosis on compressionultrasonography or venography.5,6
Patients who met these criteria for inclusion were ineligiblefor the study if they had received therapeutic doses of low-molecular-weightheparin, unfractionated heparin, or oral anticoagulant therapyfor more than 24 hours; if anticoagulant therapy was contraindicated;if thrombolytic therapy was planned; if they had had gastrointestinalbleeding in the preceding 14 days; if they had undergone surgeryrequiring anesthesia within the previous 3 days; if they hadhad a stroke in the preceding 10 days; if the platelet countwas less than 100,000 per cubic millimeter; if they weighedless than 35 kg; if they were less than 18 years old; if theyhad a documented pregnancy or had childbearing potential butwere not using adequate contraception; or if they were in alocation that made follow-up difficult. Patients were enrolledwhether venous thromboembolism developed in the hospital orwhile the patients were outpatients. The feasibility of treatmentat home was not considered in assessing eligibility. After thepatient gave informed consent, randomization (stratified accordingto whether the patient presented with deep-vein thrombosis onlyor with pulmonary embolism, and also stratified according toclinical center) was performed with a computer algorithm andthe use of a central 24-hour telephone service that recordedinformation on the patient before the treatment assignment wasdisclosed. The study protocol was approved by the institutionalreview boards of all the clinical centers.
Treatment Regimens
The patients randomly assigned to low-molecular-weight heparinreceived reviparin sodium (Clivarin, Knoll, Ludwigshafen, Germany),administered subcutaneously in the following fixed doses: 6300anti–factor Xa units twice daily (according to the firstinternational standard for low-molecular-weight heparin), forpatients weighing more than 60 kg; 4200 units twice daily, forpatients weighing 46 to 60 kg; and 3500 units twice daily, forpatients weighing 35 to 45 kg. Patients could be treated athome, but the decision to do so was left to the treating physician.Patients who received some or all of their treatment at homewere instructed by a nurse in the method of self-injection.When self-administration was not feasible, the injections weregiven by a relative or a nurse.
The patients randomly assigned to unfractionated heparin weretreated in the hospital. They received an intravenous bolusinjection of 5000 IU (Liquemin, Roche, Basel, Switzerland),followed by a dose of 1250 IU per hour given by continuous intravenousinfusion and adjusted according to a nomogram.13 In practice,the clinical centers used an activated partial-thromboplastintime of 60 to 85 seconds as a target value or a fixed ratioof 1.5 to 2.5 times a control value.8 These tests were performed6 to 12 hours after the start of treatment or 6 to 12 hoursafter a subtherapeutic activated partial-thromboplastin timewas measured, and otherwise daily.
Oral anticoagulant treatment with a derivative of coumarin wasbegun on the first or second day and continued for a total of12 weeks. During treatment with the study drug, prothrombintimes were measured at least every other day, with the doseadjusted to achieve an international normalized ratio of 2.0to 3.0. The study drug was discontinued when the internationalnormalized ratio was maintained above 2.0 for two consecutivedays and the patient had received the study drug for at leastfive days.
Surveillance and Follow-Up
All the patients were contacted daily during the initial treatment,after 14 days, and after 12 weeks. At each visit, a checklistwas used to elicit information on symptoms and signs of recurrentvenous thromboembolism and bleeding. All the patients were instructedto report to the clinical center on an emergency basis if anynew symptoms developed that were suggestive of deep-vein thrombosisor pulmonary embolism. In cases of suspected deep-vein thrombosis(for example, when there was increased pain or swelling in theleg) or pulmonary embolism (for example, when there was dyspneaor chest pain), the patients underwent appropriate diagnostictests. The investigators were asked to report all clinicallyunusual episodes of bleeding.
During the initial treatment, platelet counts were obtainedevery third day. Hemoglobin and the hematocrit were measured,and platelet counts obtained, at base line and after 14 days.
Assessment of Clinical Outcomes
The principal outcome events were objectively confirmed symptomaticdeep-vein thrombosis or pulmonary embolism and major bleedingwithin 12 weeks of randomization. Information on all suspectedoutcome events and deaths was reviewed and classified by a centraladjudication committee whose members were unaware of the treatmentassignments. A training session was held at the start of thestudy concerning the techniques and interpretation of the diagnostictests used.
The criteria for the diagnosis of symptomatic deep-vein thrombosiswere as follows: an extension of an intraluminal filling defecton a venogram; a new intraluminal filling defect or an extensionof the nonvisualization of proximal veins in the presence ofa sudden cutoff defect on a venogram that was seen on at leasttwo projections; if no previous venogram was available for comparison,an intraluminal filling defect; if no venogram was available,abnormal results of compression ultrasonography in an area wherecompression had been normal or a substantial increase in thediameter of the thrombus during full compression at the poplitealor femoral vein11,12; or, if neither a venogram nor an ultrasonographicstudy was available, a change in the results of impedance plethysmographyfrom normal to abnormal. The criteria for the diagnosis of symptomaticpulmonary embolism were as follows: a new intraluminal fillingdefect, an extension of an existing defect, or the sudden cutoffof vessels more than 2.5 mm in diameter on a pulmonary angiogram;if no prior angiogram was available, an intraluminal fillingdefect or a sudden cutoff of vessels more than 2.5 mm in diameteron a pulmonary angiogram; or if no pulmonary angiogram was available,a defect of at least 75 percent of a segment on the perfusionscan, with normal ventilation. If the ventilation–perfusionscan was nondiagnostic (and no pulmonary angiogram was available),satisfaction of the criteria for deep-vein thrombosis was acceptable;or pulmonary embolism could be demonstrated at autopsy. Onlyif no adequate objective tests had been performed did the adjudicationcommittee base its final decision on the clinical informationprovided.
Bleeding was defined as major if it was clinically overt andassociated with a fall in the hemoglobin level of at least 2.0g per deciliter or a need for the transfusion of 2 or more unitsof red cells; if it was retroperitoneal or intracranial; orif it warranted the permanent discontinuation of treatment.Deaths were classified as due to pulmonary embolism (when therewas substantive evidence), sudden death, hemorrhage, or anothercause.
Statistical Analysis
On the basis of two recent studies comparing low-molecular-weightheparin with unfractionated heparin, we assumed a 7 percentincidence of recurrent venous thromboembolism with unfractionatedheparin and a 20 percent reduction in the relative risk of recurrentvenous thromboembolism associated with the use of low-molecular-weightheparin.11,12 On the basis of the previously observed absoluterisk reduction of 12 percentage points associated with the useof unfractionated heparin as compared with placebo,14 we tookan increase of 3 percentage points as the threshold value indicatingclinical equivalence. From these assumptions, a study of 1000patients would provide an 80 percent probability (power) ofrejecting, with a one-sided test at a significance level of0.05, the hypothesis that the rate of recurrence with low-molecular-weightheparin would be more than 3 percentage points higher than thatwith unfractionated heparin in the entire group of patientswith venous thromboembolism.
The rates of recurrent venous thromboembolism were comparedby the method of Blackwelder.15 This statistical test evaluateswhether the observed difference excludes the specified thresholdfor equivalence. For the comparisons of subgroups, the chi-squaretest (two-sided) was used.
Results
Study Patients
The recruitment of patients began in November 1994 and endedin October 1995. The follow-up of the patients was completedin February 1996. A total of 1745 consecutive patients met theeligibility criteria, among whom 424 (24 percent) met one ormore of the criteria for exclusion. The three most common reasonsfor the exclusion of patients were the use of therapeutic dosesof low-molecular-weight heparin, unfractionated heparin, ororal anticoagulant therapy for more than 24 hours (200 patients);contraindications to anticoagulant therapy (68 patients); anddifficulty with follow-up because of geographic location (59patients). Only 12 patients with pulmonary embolism were excludedfrom the study because thrombolytic therapy was planned. Ofthe 1321 eligible patients, 1021 (77 percent) gave informedconsent and were randomly assigned to low-molecular-weight heparin(510 patients) or unfractionated heparin (511). The base-linecharacteristics of the patients in the two treatment groupswere similar, as Table 1 shows.
Table 1. Base-Line Characteristics of the Study Patients.
Treatment and Follow-Up
Data on the initial treatment, hospitalization, and oral anticoagulationare shown in Table 2. The initial heparin treatment lasted approximatelysix days in both treatment groups, and the international normalizedratio was in the therapeutic range for similar proportions oftime in the two groups. The mean hospital stay was three daysless in the group assigned to low-molecular-weight heparin,mainly because 100 of the 372 patients with deep-vein thrombosisassigned to that group (27 percent) were not admitted to thehospital for treatment of their deep-vein thrombosis. Another56 of the patients with deep-vein thrombosis in that group (15percent) were discharged during the first three days of treatment.Compliance with treatment and with the study protocol was high,and no patient was lost to follow-up.
Table 2. Data on the Initial Heparin Treatment, Hospitalization, and Oral Anticoagulant Therapy.
Recurrent Venous Thromboembolism
Among the 510 patients treated with low-molecular-weight heparin,82 patients had a total of 98 episodes of clinically suspectedrecurrent venous thromboembolism. Of these episodes, 29 (in27 patients, or 5.3 percent of the total) met the criteria fordocumented recurrent venous thromboembolism. Among the 511 patientstreated with unfractionated heparin, 75 had a total of 88 suspectedepisodes that were adjudicated, and 30 episodes (in 25 patients,or 4.9 percent) met the criteria. The absolute difference of0.4 percentage point between these rates indicates equivalencebetween the treatments, since it rules out an increase of 2.7percentage points or more with low-molecular-weight heparinas compared with standard heparin at the 95 percent level ofconfidence (P = 0.030 for the comparison with the preset differenceof 3 percentage points).
The majority of the recurrent venous thromboembolic events occurredduring the first 14 days, and the risk of recurrence decreasedover time (Table 3). In 17 of the 27 patients assigned to low-molecular-weightheparin who had recurrences, the event was symptomatic deep-veinthrombosis; in the unfractionated-heparin group, the correspondingnumber was 13 of 25. In all patients except one, recurrent episodesof venous thromboembolism were documented by objective testsor at autopsy. Adjustment by logistic-regression analysis fordifferences in age and in the frequency of recent surgery atbase line did not alter the results of the study.
Table 3. Rates of Recurrent Venous Thromboembolism, Major Bleeding, and Death during the Study.
Bleeding Complications
Among the reported instances of clinically important bleeding,93 were confirmed by the central adjudication committee, and28 of them met the criteria for major bleeding. There were 46events among the patients treated with low-molecular-weightheparin and 47 among those treated with unfractionated heparin;16 and 12 of these, respectively, involved major bleeding. AsTable 3 shows, the majority of instances of bleeding occurredduring the first 14 days of the study.
Mortality
During the 12 weeks of follow-up, 75 patients (7.3 percent)died: 36 who were treated with low-molecular-weight heparin(7.1 percent) and 39 who were treated with unfractionated heparin(7.6 percent). The mortality rate remained fairly constant overtime (Table 3). Among the 36 deaths of patients treated withlow-molecular-weight heparin, 3 (on days 3, 4, and 35) wereclassified as due to pulmonary embolism and 3 (on days 18, 55,and 73) were considered sudden. There were no instances of fatalbleeding in this group. Among the 39 deaths in the unfractionated-heparingroup, there were 3 fatal episodes of pulmonary embolism (ondays 3, 24, and 64), 2 sudden deaths (on days 19 and 44), and2 instances of fatal bleeding (on days 4 and 5). All six fatalepisodes of pulmonary embolism occurred in patients who hadpulmonary embolism at presentation.
Additional Observations
Among the 271 patients with pulmonary embolism at presentation,16 had symptomatic recurrent venous thromboembolism (5.9 percent;8 patients in each treatment group), as compared with 36 ofthe 750 patients presenting with deep-vein thrombosis only (4.8percent; 19 patients treated with low-molecular-weight heparinand 17 treated with unfractionated heparin). Among the 16 patientspresenting with pulmonary embolism who had recurrent thromboembolism,11 (69 percent) had recurrences of pulmonary embolism, whereaspulmonary embolism occurred in only 11 of the 36 patients withdeep-vein thrombosis at presentation (31 percent, P = 0.023).Among the 232 patients with cancer at base line, 20 (8.6 percent)had symptomatic recurrent venous thromboembolism, as comparedwith only 32 (4.1 percent) of the remaining 789 patients (P= 0.009). Forty-seven of the patients with cancer (20.3 percent)died, as compared with 28 (3.5 percent) of those without cancer(P<0.001).
The relative effects of low-molecular-weight heparin and unfractionatedheparin with respect to the three major clinical outcomes weresimilar in all these subgroups. They were also similar in othersubgroups, such as patients with a history of venous thromboembolismand patients without such a history.
Discussion
Previous randomized trials have shown that subcutaneous, low-molecular-weightheparin is likely to be at least as effective and safe as unfractionatedheparin in treating patients with uncomplicated deep-vein thrombosis.16,17,18However, because these trials did not include patients withpulmonary embolism and because some patients with a historyof venous thromboembolism were excluded, clinicians may legitimatelybe concerned that the findings may not translate directly totheir own clinical practice.19
We studied a broad range of patients, including a large subgroupwith pulmonary embolism, in many hospitals in several countries.Unmonitored, subcutaneous low-molecular-weight heparin was shownto be an effective and safe treatment for patients with venousthromboembolism. We observed similar treatment effects in eachof various sizable subgroups — patients with pulmonaryembolism, cancer, or previous thromboembolism and those withouteach of these conditions. We also included patients with symptomaticcalf-vein thrombosis, who would normally receive anticoagulanttherapy, since it has been documented that such patients areat risk for recurrent venous thromboembolism if left untreated.20Our predetermined criterion for equivalence between the treatmentswas an absolute increase in the recurrence rate of no more than3 percentage points with low-molecular-weight heparin. Sinceour findings showed that there was no such difference, one mayconclude that the treatments are equivalent for patients withvenous thromboembolism. It should be understood that the studydid not have the power to detect differences among subgroupsof patients.
Thus, in terms of safety and efficacy, low-molecular-weightheparin offers an appropriate alternative to unfractionatedheparin in patients with venous thromboembolism. In addition,low-molecular-weight heparin has several practical advantages.Since there is no need for laboratory monitoring or infusion,suitable patients can be treated at home, either throughouttheir care or after early discharge from the hospital.11,12Those requiring hospital admission also benefit because theyavoid the inconvenience and hazards of intravenous lines.
Because this was an open trial, care was taken to minimize thepotential for bias. We included consecutive patients, used centralrandomization by telephone, and ensured that follow-up was completefor all randomized patients. Furthermore, all clinically suspectedoutcome events were assessed by an independent, blinded centraladjudication committee on the basis of predetermined criteria.
Meta-analyses of early trials of low-molecular-weight heparinsfor the treatment of deep-vein thrombosis have suggested that,as compared with unfractionated heparin, these agents may beassociated with reductions as large as 50 percent in the relativerisk of recurrent thrombosis.16,17,18 Our findings are inconsistentwith a reduction of this magnitude. Explanations for the apparentdiscrepancy, other than that it occurred by chance, includethe possibility that low-molecular-weight heparins are associatedwith a more modest reduction, if any. This possibility is supportedby two recent studies.11,12 It is noteworthy that the ratesof recurrent venous thromboembolism with low-molecular-weightheparins in the various treatment trials are consistent, around4 to 5 percent, whereas the rates among the groups treated withunfractionated heparin vary more widely; the latter variationmay be due in part to differences in the regimens of unfractionatedheparin in the different trials.9,10,11,12,21,22,23,24 The incidenceof major bleeding reported for both groups in this study isconsistent with that reported previously.16,17,18
Overall, the rates of recurrence we observed were low, whetherpatients were treated with low-molecular-weight heparin or withunfractionated heparin. In patients with cancer, however, therecurrence rate was doubled in both treatment groups, suggestingthat anticoagulant therapy in these patients needs further improvement.
We conclude that low-molecular-weight heparin and unfractionatedheparin are equally effective and safe in unselected patientswith confirmed deep-vein thrombosis, with or without associatedpulmonary embolism. In addition, low-molecular-weight heparinpermits treatment regimens to be simplified so that hospitalstays can be shortened and suitable patients can be treatedoutside the hospital.
Supported by a grant from Knoll AG, Ludwigshafen, Germany.
* The institutions and investigators participating in the studyare listed in the Appendix.
Source Information
The Writing Committee of the Columbus Study (H.R. Büller, M. Gent, A.S. Gallus, J. Ginsberg, M.H. Prins, and R. Baildon) takes responsibility for the content of this article.
Address reprint requests to Professor J.W. ten Cate, Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam Zuid-oost, the Netherlands.
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Appendix
In addition to the members of the Writing Committee, the followinginstitutions and investigators participated in the study. ExecutiveCommittee: J.W. ten Cate, H.R. Büller, M. Gent, J. Hirsh,M.H. Prins, and R. Baildon; Adjudication Committee: A.W.A. Lensing,D.R. Anderson, and E.J.R. van Beek; Safety Committee: J.N. Fiesingerand J.G.P. Tijssen; Coordination and Data Management Centers:Academic Medical Center, University of Amsterdam, Amsterdam— A. van Barneveld, L.T. Eimers, Y.P. Graafsma, R. Hettiarachchi,B. Hutten, and K. Redekop; Hamilton Civic Hospitals ResearchCenter, Hamilton, Ont., Canada — S. Haley, L. Liberale,T. Finch, S. Whittaker, and L. Wilkinson; Participating Centers(the number of patients contributed by the center follows thename of the center): Institute of Medical Semiotics, Padua,Italy (96) — P. Prandoni, S. Villalta, B. Girolami, P.Bagatella, L. Rossi, and A. Girolami; Medicina Interna e OncologiaMedica, Policlinico "San Matteo," Pavia, Italy (81) —F. Piovella, M. Barone, C. Beltrametti, S. Serafini, S. Siragusa,and E. Ascari; Victoria Hospital and University of Western Ontario,London, Ont., Canada (75) — M.J. Kovacs, B. Morrow, andJ. Kovacs; Academic Medical Center, University of Amsterdam,Amsterdam (71) — P.M.M. Kuijer, M.M.W. Koopman, and H.Jagt; Hamilton Civic Hospitals, Henderson General Division,Hamilton, Ont., Canada (53) — J. Weitz, C. Kearon, andL. Biagioni; Krankenhaus Bogenhaussen–Medizinische Poliklinik,Munich, Germany (52) — S. Haas, F. Lössner, F.A.Spengel, and M. Berger; Hôpital du Saint-Sacrement, Quebec,Que., Canada (51) — C. Demers and J. Poulin; UniversityHospital Groningen, Groningen, the Netherlands (41) —J. van der Meer, G.T.H. Que, and W.M. Smid; Victoria GeneralHospital, Halifax, N.S., Canada (38) — D.R. Anderson,K.S. Robinson, and E. Boyle; Montreal General Hospital, Montreal(35) — J.R. Leclerc, B. St. Jacques, and S. Finkenbine;Flinders Medical Centre, Adelaide, Australia (33) — A.S.Gallus, D. Cohlan, and C. Rich; Slotervaart Hospital, Amsterdam(33) — D.P.M. Brandjes, C.A. Hoefnagel, M. de Rijk, andF. Turkstra; Centre Hospitalier de l'Université Laval,Quebec, Que., Canada (30) — L. Desjardins, J. Cote-Desjardins,L. Couture, M. Ruel, and J. Villeneuve; Sunnybrook Health ScienceCentre, Toronto (29) — W.H. Geerts, R.M. Jay, and K.I.Code; Hamilton Civic Hospitals, Hamilton General Division, Hamilton,Ont., Canada (29) — A.G.G. Turpie and J. Johnson; HôtelDieu, Montreal (28) — P. Nguyen, J.R. Cusson, and S. Roy;Ottawa Civic Hospital, Ottawa, Ont., Canada (28) — P.S.Wells, J. Bormanis, and D. Goudie; University Hospital, London,Ont., Canada (26) — M. Cruickshank and M. von Lewinski;Hospital Germans Trias i Pujol, Barcelona, Spain (24) —M. Monreal, J.C. Sahuquillo, and E. Lafoz; Hôpital AntoineBéclère, Clamart, France (20) — G. Simonneau,F. Parent, and J. Jagot; St. Joseph's Hospital, Hamilton, Ont.,Canada (19) — J.D. Douketis and K. Kinnon; McMaster UniversityMedical Centre, Hamilton, Ont., Canada (19) — J.S. Ginsberg,P. Brill-Edwards, and D. Donovan; Auckland Hospital, Auckland,New Zealand (18) — P.A. Ockelford; Hôpital Maisonneuve-Rosemount,Montreal (18) — J. Kassis and S. Bornais; Centre HospitalierUniversitaire Hôtel Dieu, Nantes, France (17) —B. Planchon, D. El Kouri, and M.A. Pistorius; Hospital de 12Octubre, Madrid (13) — M. Escribano and G. Garrido; Princeof Wales Hospital, Sydney, Australia (13) — C.N. Chesterman,B.H. Chong, and S. Pritchard; Royal Melbourne Hospital, Melbourne,Australia (10) — J.F. Cade, T. Bynon, and J. Stanford;St. Joseph's Health Centre, London, Ont., Canada (9) —W.M. Brien and B. Palmer; Clinique Saint Vincent, Besançon,France (9) — R. Faivre and P.Y. Petiteau; Hemophilia andThrombosis Center A. Bianchi Bonomi, Maggiore Hospital, Milan,Italy (5) — P.M. Manucci, M. Moia, and P. Bucciarelli.
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