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Table 1. 
Baseline Characteristics of 424 Patients With Deep Venous Thrombosis or Pulmonary Embolism*
Baseline Characteristics of 424 Patients With Deep Venous Thrombosis or Pulmonary Embolism*
Table 2. 
Major Hemorrhage During Initial Unfractionated Heparin (UFH) Treatment of 17 Patients*
Major Hemorrhage During Initial Unfractionated Heparin (UFH) Treatment of 17 Patients*
Table 3. 
Causes of Death and Times of Occurrence in 19 Patients*
Causes of Death and Times of Occurrence in 19 Patients*
Table 4. 
APTT Prolongations in 3 Patients With Fatal Bleeding Complications and 5 With Pulmonary Embolism*
APTT Prolongations in 3 Patients With Fatal Bleeding Complications and 5 With Pulmonary Embolism*
1.
Salzman  EWDeykin  DShapiro  RM  et al.  Management of heparin therapy. N Engl J Med. 1975;2921046- 1050Article
2.
Glazier  RLCorwell  EB Randomized prospective trial of continuous versus intermittent heparin therapy. JAMA. 1976;2361365- 1367Article
3.
Mant  MJO'Brien  BDThong  KL  et al.  Haemorrhagic complications of heparin therapy. Lancet. 1977;11133- 1135Article
4.
Wilson  JRLampman  J Heparin therapy: a randomized prospective study. Am Heart J. 1979;97155- 158Article
5.
Fagher  BLundh  B Heparin treatment of deep vein thrombosis. Acta Med Scand. 1981;210357- 361Article
6.
Wilson  JEBynum  LJParkey  RW Heparin therapy in venous thromboembolism. Am J Med. 1981;70808- 816Article
7.
Bentley  PGKakkar  VVScully  MF  et al.  An objective study of alternative methods of heparin administration. Thromb Res. 1980;18177- 187Article
8.
Hull  RDRaskob  GEHirsh  J  et al.  Continuous intravenous heparin compared with intermittent subcutaneous heparin in the initial treatment of proximal-vein thrombosis. N Engl J Med. 1986;3151109- 1114Article
9.
Doyle  DJTurpie  AGHirsh  J  et al.  Adjusted subcutaneous heparin or continuous intravenous heparin in patients with acute deep vein thrombosis: a randomized trial. Ann Intern Med. 1987;107441- 445Article
10.
Walker  MGShaw  JWThomson  GJCumming  JGThomas  ML Subcutaneous calcium heparin versus intravenous sodium heparin in treatment of established acute deep vein thrombosis of the legs: a multicentre prospective randomised trial. Br Med J (Clin Res Ed). 1987;2941189- 1192Article
11.
Lopaciuk  SMeissner  AJCiesielski  LKorzycki  J Subcutaneous sodium heparin versus intravenous sodium heparin in the treatment of deep vein thrombosis.  Proceedings of the 6th International Meeting of the Danubian League Against Thrombosis and Haemorrhagic Disorders May 31 to June 3, 1989 Vienna, Austria
12.
Pini  MPattacini  CQuintavalla  R  et al.  Subcutaneous versus intravenous heparin in the treatment of deep venous thrombosis: a randomized controlled trial. Thromb Haemost. 1990;64222- 226
13.
Hommes  DWBura  AMazzaloi  L  et al.  Subcutaneous heparin compared with continuous intravenous heparin administration in the initial treatment of deep venous thrombosis: a meta-analysis. Ann Intern Med. 1992;116279- 284Article
14.
Levine  MNRaskob  GELandefeld  SHirsh  J Hemorrhagic complications of anticoagulant treatment. Chest. 1995;108277- 290Article
15.
Leizorovicz  A Comparison of the efficacy and safety of low molecular weight heparins and unfractionated heparin in the initial treatment of deep venous thrombosis: an updated meta-analysis. Drugs. 1996;52 Suppl730- 37Article
16.
Levine  MGent  MHirsh  J  et al.  A comparison of low-molecular-weight heparin administered primarily at home with unfractionated heparin administered in the hospital for proximal deep-vein thrombosis. N Engl J Med. 1996;334677- 681Article
17.
Koopman  MMWPrandoni  PPiovella  F  et al.  Treatment of venous thrombosis with intravenous unfractionated heparin administered in the hospital as compared with subcutaneous low-molecular-weight heparin administered at home. N Engl J Med. 1996;334682- 687Article
18.
Simonneau  GSors  HCharbonnier  B  et al.  A comparison of low-molecular-weight heparin with unfractionated heparin for acute pulmonary embolism. N Engl J Med. 1997;337663- 669Article
19.
The Columbus Investigators, Low-molecular-weight heparin in the treatment of patients with venous thromboembolism. N Engl J Med. 1997;337657- 662Article
20.
de Groot  MRBüller  HRten Cate  JWvan Marwijk Kooy  M Use of a heparin nomogram for treatment of patients with venous thromboembolism in a community hospital. Thromb Haemost. 1998;8070- 73
21.
Levine  MNRaskob  GELandefeld  SKearon  C Hemorraghic complications of anticoagulant treatment. Chest. 1998;114511S- 523SArticle
22.
Hull  RDRaskob  GEBrant  FR Relation between the time to achieve the lower limit of the APTT therapeutic range and recurrent venous thromboembolism during heparin treatment for deep-vein thrombosis. Arch Intern Med. 1997;1572562- 2568Article
23.
Hull  RDRaskob  GEBrant  RF  et al.  The importance of initial heparin treatment on long-term clinical outcomes of antithrombotic therapy: the emerging theme of delayed recurrence. Arch Intern Med. 1997;1572317- 2321Article
24.
Brandjes  DPMHeijboer  HBüller  HR  et al.  Acenocoumarol and heparin compared with acenocoumarol alone in the initial treatment of proximal vein thrombosis. N Engl J Med. 1992;3271485- 1489Article
25.
Graafsma  YPPrins  MHLensing  AWAde Haan  RJHuisman  MVBüller  HR Bleeding classification in clinical trials: observer variability and clinical relevance. Thromb Haemost. 1997;781189- 1192
Original Investigation
August 14/28, 2000

Frequency of Major Hemorrhage in Patients Treated With Unfractionated Intravenous Heparin for Deep Venous Thrombosis or Pulmonary EmbolismA Study in Routine Clinical Practice

Author Affiliations

From the Department of General Internal Medicine, Leiden University Medical Center (Mss Zidane, Schram, and Dr Huisman), the Departments of Internal Medicine, Diaconessenhuis Leiden (Dr Planken) and Rijnland Hospital, Leiderdorp (Dr Molendijk), and the Departments of Clinical Epidemiology (Dr Rosendaal) and Haematology (Drs Rosendaal and van der Meer), Leiden University Medical Center, Leiden, the Netherlands.

Arch Intern Med. 2000;160(15):2369-2373. doi:10.1001/archinte.160.15.2369
Abstract

Background  The rate of major hemorrhage during the initial treatment with unfractionated heparin (UFH) in patients with deep venous thrombosis (DVT) and pulmonary embolism (PE) in routine clinical practice is understudied. In recent clinical trials an overall average of 3.8% was reported. However, the incidence of this complication in routine patient care might be higher owing to less strict patient selection and lack of standardization in the administration of heparin. We have determined major bleeding rates during heparin treatment for DVT or PE in routine practice and compared these rates with data from clinical trials.

Methods  Data on the occurrence of major hemorrhage were retrieved according to strict criteria from the records of patients who had received continuous intravenous UFH therapy to treat objectively documented DVT or PE in 3 hospitals.

Results  After exclusion of 29 patients because of lack of objective diagnosis of DVT or PE and 25 patients because of initial treatment with low-molecular-weight heparin, 424 consecutive patients were available for detailed analysis. Among them, 17 patients (4.0%; 95% confidence interval, 2.1%-5.9%) experienced major hemorrhage during UFH treatment, which in most patients occurred at the end of planned heparin therapy; one of the hemorrhages was fatal. Six patients (1.4%; 95% confidence interval, 0.3%-2.5%) developed clinically suspected recurrent venous thromboembolism (fatal in 1 case) during UFH treatment or within 7 days' cessation.

Conclusions  Administration of continuous intravenous UFH in patients with DVT or PE in routine clinical practice leads to a major bleeding rate of 4.0%. This rate is comparable to the rate of major bleeding in patients who received UFH in clinical trials. Our findings are relevant to the discussion of major bleeding rates in patients with DVT and PE treated in daily clinical practice with subcutaneous low-molecular-weight heparin and newer antithrombotic drugs.

THE MOST important adverse effect of initial intravenous unfractionated heparin (UFH) therapy of deep venous thrombosis (DVT) and pulmonary embolism (PE) is major hemorrhage. In a large number of randomized clinical trials, the efficacy and safety of intravenous continuous UFH treatment has been compared with intravenous intermittent UFH treatment,16 treatment with subcutaneously administered UFH,714 and low-molecular-weight-heparin (LMWH).15 The overall average of major hemorrhage rates in the continuous intravenous UFH groups in these studies was 3.8% (95% confidence interval [CI] 3.0%-4.6%) (widely varying between the studies from 0% to 20%).

However, in spite of the widespread application of UFH therapy, surprisingly little information is available on the incidence of bleeding complications in routine daily practice during the period that patients receive heparin administered in therapeutic doses. Moreover, it is unknown whether the bleeding rates found in clinical trials are applicable in routine clinical practice. The conditions of routine practice could affect the complication rate of heparin therapy because of selection criteria in trials and because the administration of heparin is often not standardized in routine practices. The current study was performed to accurately estimate the rate of major bleeding complications in patients treated with UFH in routine clinical practice for a thromboembolic event and to compare these data with those derived from clinical trials.

PATIENTS AND METHODS
STUDY POPULATION

All patients with a diagnosis of DVT or PE who had been hospitalized in 1995 and 1996 in the wards of internal medicine at the Academic University Medical Center in Leiden, at the Diaconessenhuis Leiden, or at the Rijnland Hospital in Leiderdorp, the Netherlands, were eligible. These hospitals provide immediate care for the whole region. The inclusion criterion was the use of unfractionated heparin for a least 2 days. Patients who had had surgery were included only if treatment for thrombosis had started at least 14 days after the day of surgery. The only exclusion criterion was initial treatment with LMWH. The medical ethical committees of all 3 participating hospitals approved the study.

TREATMENT REGIMENS

At the day of diagnosis, all patients received an intravenous bolus of 70 U/kg of body weight of UFH followed by a continuous infusion of UFH. The initial dose was 400 to 450 U/kg every 24 hours, resulting in a bolus of 5000 U and an initial dose of 35,000 U per 24 hours. The first activated partial thromboplastin time (APTT) was performed 4 to 6 hours after the bolus injection was given. The heparin dose was then adjusted to maintain the APTT at the therapeutic range of 1.5 to 2.0 times the control APTT in 2 of the 3 hospitals. In the third hospital, a range of 60 to 90 seconds was targeted, with a normal range of 25 to 35 seconds. Nomograms for heparin treatment were not used in any of the 3 hospitals. Oral coumarin treatment was begun on the first day of heparin treatment. The coumarin dose was adjusted to maintain the international normalized ratio (INR) between 2.5 and 3.5, according to national consensus of the Dutch Trombosis Services, The Hague, the Netherlands.

DATA COLLECTION

Data on baseline comorbidity, bleeding events that occurred during heparin treatment (including severity and treatment and recurrent thromboembolic events), and cause of death where applicable were obtained by review of medical records and by means of a standard questionnaire. In addition, the records of the blood transfusion services of all 3 hospitals were checked for every patient to see if transfusion had occurred during hospitalization.

The APTT values, INR, and administered doses of heparin were registered for all patients who met the criteria for major hemorrhage. A random sample (n = 50) of patients in whom major hemorrhage did not occur was taken, and the administered doses of heparin were registered for comparison with those of patients with a major hemorrhage.

In addition, APTT values were reviewed in the first 24 hours of heparin treatment as well as prior to the fatal event for those patients who experienced fatal hemorrhage or fatal pulmonary embolism. All patients had routine follow-up visits at the outpatient department after 3 months, during which a decision with respect to continuing anticoagulant treatment was made.

OUTCOME EVENTS

Prior to the start of the study, bleeding was defined as major if (1) it was associated with either a decrease in the hemoglobin level of at least 20 g/L or a transfusion was done of 2 or more units of blood, (2) the bleeding was intraperitoneal intracranial, or gastrointestinal, or (3) cessation of treatment was warranted, or it had led to death. Only major hemorrhagic events during initial UFH treatment or within 24 hours of stopping heparin treatment were considered a complication of the heparin treatment. Objectively demonstrated thromboembolism was defined by abnormal findings in compression ultrasonography or contrast venography for DVT and high probability perfusion ventilation lung scanning or by abnormal findings on pulmonary angiography.

Recurrent thromboembolic events were defined as objective evidence of recurrent DVT as demonstrated by findings of repeated contrast venography or compression ultrasonography; (recurrent) pulmonary embolism was considered to have occurred if demonstrated by results of repeated perfusion lung scanning or repeated pulmonary angiography during heparin therapy or within 1 week after stopping treatment. Any APTT values prolonged 1.5 to 2.0 times the upper limit of the control value were considered adequate prolongations. Data on causes of death in patients who died during hospitalization were retrieved by reviewing the patients' medical records and, when available, autopsy reports.

STATISTICAL ANALYSIS

As effect measure, the frequency of the outcome events among the patients was calculated, ie, the proportion of patients with an outcome event. This may be viewed as a cumulative incidence, ie, the probability of an outcome event. Since the duration of treatment was short and fairly homogeneously distributed, the duration of treatment was not taken into account. The 95% CIs were calculated with the normal approximation to binomial distribution.

RESULTS

During 1995 and 1996, 478 patients with DVT or PE were identified in the 3 hospitals of the region. Fifty-four patients were not eligible for the analysis: 29 who did not receive UFH treatment because the diagnosis of DVT or PE could not be confirmed with objective methods, and 25 who initially received LMWH therapy. Thus 424 consecutive patients (Leiden University Medical Center, n = 117, Diaconessenhuis, n = 113, Rijnland Hospital, n = 194) were included. The patients' baseline characteristics are given in Table 1. These patient characteristics compare well with those observed in recent clinical trials.1619

BLEEDING COMPLICATIONS

Major hemorrhage during initial heparin treatment or within 24 hours of stopping the treatment occurred in 17 patients (4.0%; 95% CI, 2.1%-5.9%); in 1 patient it was fatal. Seven major bleeding complications occurred in patients with the diagnosis of DVT (3.1%) while 10 major hemorrhages occurred in patients with PE (6.2%). Major bleeding complications are given in Table 2.

The mean (SD) age of the patients who experienced a major bleeding complication (63.1 [21.1] years) did not significantly differ from the mean age of patients without a major bleeding complication (61.5 [19.3] years). In 5 of the 76 patients with disseminated malignancy, major hemorrhage occurred (relative risk, 1.91; 95% CI, 0.65-5.61).

Most major hemorrhages occurred near the end of the planned initial heparin treatment, when the INR was close to or in the desired range. In 1 patient (listed fifth in Table 2), the results of compression ultrasonography showed DVT, and anticoagulant treatment was planned. However, this patient was first operated on to treat a paravertebral abcess. Heparin treatment was started 2 days after the uneventful operation.

Five patients (1.2%) experienced a major bleeding complication during hospitalization but after UFH treatment had been stopped. In 3 of these patients, the bleeding complication was fatal. Minor hemorrhage occurred in 43 patients (10%).

RECURRENT VENOUS THROMBOEMBOLISM

Recurrent venous thromboembolism (VTE) within 12 weeks of UFH treatment occurred in 14 patients (3.3%; 95% CI, 1.6%-5.0). During heparin therapy or within 1 week of stopping therapy, 6 patients (1.4%; 95% CI, 0.3%-2.5%) had clinically suspected recurrent VTE, which was fatal in 1 patient. Abnormal compression ultrasonography findings confirmed the diagnosis of DVT in 1 patient who had been treated for DVT and in 1 patient who had been originally treated because of PE. In the other 4 patients, the diagnosis was not confirmed by objective testing.

After 1 week but within 12 weeks of cessation of initial heparin treatment, 8 patients (1.9%; 95% CI, 0.6%-3.2) experienced recurrent VTE. In 1 patient fatal PE occurred. Objective tests confirmed recurrent VTE in 6 of the 8 patients.

DEATHS

Deaths during hospitalization occurred in 19 patients (4.5%; 95% CI, 2.5%-6.5%). Causes of death and the time of occurrence are given in Table 3.

APTT PROLONGATION AND HEPARIN DOSES

In 8 of the 17 patients who had a major hemorrhage during UFH treatment, the APTT prolongation was supratherapeutic within 24 hours of the bleeding complication (Table 2). None of the patients who experienced a recurrent VTE during initial UFH treatment or within 7 days after this treatment had been stopped had a subtherapeutic APTT prolongation in the first 24 hours of UFH treatment. Of the 3 patients who died, possibly of PE, during heparin treatment, only 1 had a subtherapeutic APTT prolongation in the first 48 hours of initial UFH treatment (Table 4). Finally, the mean amount of UFH given did not differ significantly between patients with major bleeding complications (28,764 U/d; n = 17) and the randomly selected patients (29,819 U/d; n = 50).

COMMENT

In this large retrospective study of 424 patients treated for VTE with UFH in routine daily practice, 17 patients (4.0%; 95% CI, 2.1%-5.9%) experienced a major bleeding event during initial treatment. One patient experienced fatal major hemorrhage. The overall average reported in clinical trials was 3.8%.115 This rate is comparable to our observed rate of 4.0%. Our prior expectation was that the rate of major hemorrhage in daily practice would be higher than in controlled studies. In all the trials evaluating treatment with LMWH, patients with a high risk of bleeding (eg, those with active malignancies or kidney or liver function diseases) were excluded.15 Specific nomograms for UFH treatment regimens were often implemented in these patients.20

By assessing the APTT prolongation the day before a major bleeding complication or the suspected thromboembolic event, we checked whether patients received adequate heparin doses. Eight of the 17 patients (47%) who experienced a major hemorrhage during UFH treatment had a supratherapeutic APTT prolongation within 24 hours of their hemorrhagic complication, which is in agreement with other studies.21 None of the 6 patients who experienced a recurrent VTE during UFH treatment or within 7 days of treatment cessation had subtherapeutic APTT prolongation, (<1.5 × control), which is in disagreement with studies that have found a clear association between subtherapeutic APTT results at 24 to 48 hours and recurrent VTE.8,2224

A strength of our study is that we included consecutive patients by comparing the information as provided by the hospitals' documentation departments and regional thrombosis service. This thrombosis service holds records of all anticoagulated patients in the Leiden region with attached indications for anticoagulation.

A study design such as ours may result in underreporting or inconsistent reporting of bleeding events. We have tried to obviate this by looking only at major hemorrhages and by predefining the criteria for major hemorrhage before studying the patients' records. We also checked patient charts and records of the transfusion services of all 3 hospitals. It seems unlikely, using this method, that we would have missed any major hemorrhage. The consistency of reporting major bleeding complications was assessed in a recent study.25

Another potential weakness of our study is related to the reporting of recurrent VTEs. To obtain a true estimate of the rate of recurrent VTE, we predefined the criteria for objective recurrent VTE, and we evaluated the records of every patient for a clinical suspicion of recurrence as well as whether any objective test had been performed to ascertain the diagnosis. All of these precautions strengthen the generalizability of our results to other hospitals.

Our data on bleeding rates during UFH therapy may form the background against which the complication of major bleeding during subcutaneous LMWH therapy in patients with DVT and PE can be evaluated in general community hospitals in daily clinical practice. Such studies of daily practice are needed before the use of LMWH is routinely applied in an out-of-hospital setting.

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Article Information

Accepted for publication March 30, 2000.

We acknowledge M. H. Prins, MD, PhD, for his assistance in the preparation of this article.

Reprints: Menno V. Huisman, MD, PhD, Department of General Internal Medicine, Room B3-Q84, Leiden University Medical Center, PO Box 9600, 2300 RC, Leiden, the Netherlands (e-mail: m.v.huisman@lumc.nl).

References
1.
Salzman  EWDeykin  DShapiro  RM  et al.  Management of heparin therapy. N Engl J Med. 1975;2921046- 1050Article
2.
Glazier  RLCorwell  EB Randomized prospective trial of continuous versus intermittent heparin therapy. JAMA. 1976;2361365- 1367Article
3.
Mant  MJO'Brien  BDThong  KL  et al.  Haemorrhagic complications of heparin therapy. Lancet. 1977;11133- 1135Article
4.
Wilson  JRLampman  J Heparin therapy: a randomized prospective study. Am Heart J. 1979;97155- 158Article
5.
Fagher  BLundh  B Heparin treatment of deep vein thrombosis. Acta Med Scand. 1981;210357- 361Article
6.
Wilson  JEBynum  LJParkey  RW Heparin therapy in venous thromboembolism. Am J Med. 1981;70808- 816Article
7.
Bentley  PGKakkar  VVScully  MF  et al.  An objective study of alternative methods of heparin administration. Thromb Res. 1980;18177- 187Article
8.
Hull  RDRaskob  GEHirsh  J  et al.  Continuous intravenous heparin compared with intermittent subcutaneous heparin in the initial treatment of proximal-vein thrombosis. N Engl J Med. 1986;3151109- 1114Article
9.
Doyle  DJTurpie  AGHirsh  J  et al.  Adjusted subcutaneous heparin or continuous intravenous heparin in patients with acute deep vein thrombosis: a randomized trial. Ann Intern Med. 1987;107441- 445Article
10.
Walker  MGShaw  JWThomson  GJCumming  JGThomas  ML Subcutaneous calcium heparin versus intravenous sodium heparin in treatment of established acute deep vein thrombosis of the legs: a multicentre prospective randomised trial. Br Med J (Clin Res Ed). 1987;2941189- 1192Article
11.
Lopaciuk  SMeissner  AJCiesielski  LKorzycki  J Subcutaneous sodium heparin versus intravenous sodium heparin in the treatment of deep vein thrombosis.  Proceedings of the 6th International Meeting of the Danubian League Against Thrombosis and Haemorrhagic Disorders May 31 to June 3, 1989 Vienna, Austria
12.
Pini  MPattacini  CQuintavalla  R  et al.  Subcutaneous versus intravenous heparin in the treatment of deep venous thrombosis: a randomized controlled trial. Thromb Haemost. 1990;64222- 226
13.
Hommes  DWBura  AMazzaloi  L  et al.  Subcutaneous heparin compared with continuous intravenous heparin administration in the initial treatment of deep venous thrombosis: a meta-analysis. Ann Intern Med. 1992;116279- 284Article
14.
Levine  MNRaskob  GELandefeld  SHirsh  J Hemorrhagic complications of anticoagulant treatment. Chest. 1995;108277- 290Article
15.
Leizorovicz  A Comparison of the efficacy and safety of low molecular weight heparins and unfractionated heparin in the initial treatment of deep venous thrombosis: an updated meta-analysis. Drugs. 1996;52 Suppl730- 37Article
16.
Levine  MGent  MHirsh  J  et al.  A comparison of low-molecular-weight heparin administered primarily at home with unfractionated heparin administered in the hospital for proximal deep-vein thrombosis. N Engl J Med. 1996;334677- 681Article
17.
Koopman  MMWPrandoni  PPiovella  F  et al.  Treatment of venous thrombosis with intravenous unfractionated heparin administered in the hospital as compared with subcutaneous low-molecular-weight heparin administered at home. N Engl J Med. 1996;334682- 687Article
18.
Simonneau  GSors  HCharbonnier  B  et al.  A comparison of low-molecular-weight heparin with unfractionated heparin for acute pulmonary embolism. N Engl J Med. 1997;337663- 669Article
19.
The Columbus Investigators, Low-molecular-weight heparin in the treatment of patients with venous thromboembolism. N Engl J Med. 1997;337657- 662Article
20.
de Groot  MRBüller  HRten Cate  JWvan Marwijk Kooy  M Use of a heparin nomogram for treatment of patients with venous thromboembolism in a community hospital. Thromb Haemost. 1998;8070- 73
21.
Levine  MNRaskob  GELandefeld  SKearon  C Hemorraghic complications of anticoagulant treatment. Chest. 1998;114511S- 523SArticle
22.
Hull  RDRaskob  GEBrant  FR Relation between the time to achieve the lower limit of the APTT therapeutic range and recurrent venous thromboembolism during heparin treatment for deep-vein thrombosis. Arch Intern Med. 1997;1572562- 2568Article
23.
Hull  RDRaskob  GEBrant  RF  et al.  The importance of initial heparin treatment on long-term clinical outcomes of antithrombotic therapy: the emerging theme of delayed recurrence. Arch Intern Med. 1997;1572317- 2321Article
24.
Brandjes  DPMHeijboer  HBüller  HR  et al.  Acenocoumarol and heparin compared with acenocoumarol alone in the initial treatment of proximal vein thrombosis. N Engl J Med. 1992;3271485- 1489Article
25.
Graafsma  YPPrins  MHLensing  AWAde Haan  RJHuisman  MVBüller  HR Bleeding classification in clinical trials: observer variability and clinical relevance. Thromb Haemost. 1997;781189- 1192
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