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Keywords:

  • anticoagulant therapy;
  • inferior vena cava filter;
  • major bleeding;
  • pulmonary embolism;
  • recurrences venous;
  • thromboembolism

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and methods
  5. Results
  6. Discussion
  7. Appendix
  8. Acknowledgements
  9. References

Summary. Background: Patients who have experienced a recent major bleeding episode are usually excluded from clinical studies of venous thromboembolism (VTE) treatment. Therefore, recommendations based on evidence from clinical trials may not be suitable for these patients. The Registro Informatizado de la Enfermedad TromboEmbólica (RIETE) is a multicenter, observational registry designed to gather and analyze data on VTE treatment practices and clinical outcomes in patients with acute VTE. Objectives: The aim of this analysis was to study outcomes of patients with VTE who had experienced recent major bleeding (< 30 days prior to VTE diagnosis). Methods: Patients with objectively confirmed symptomatic acute VTE are consecutively enrolled into the RIETE registry. Patient characteristics, details of antithrombotic therapy, and clinical outcomes at 3 months were recorded. Results: Of 6361 patients enrolled up to January 2004, 170 (2.7%) had experienced recent major bleeding: 69 (40.6%) gastrointestinal tract, 60 (35.3%) intracranial, 41 (24.1%) other. The incidences of major bleeding (4.1%) and recurrent pulmonary embolism (PE) (2.4%) were significantly higher in patients with recent major bleeding. Among them, patients with cancer had an increased incidence of major bleeding [odds ratio (OR) 10.0, 95% confidence interval (CI) 2.3, 50; P < 0.001] and fatal PE (OR 4.1, 95% CI 0.98, 17; P < 0.05). Conclusions: Patients with VTE and recent major bleeding prior to VTE diagnosis (2.7% of total enrolled patients) had poorer clinical outcomes compared with those who had not experienced recent major bleeding. In patients who had recent major bleeding prior to enrollment, those with cancer had a poorer clinical outcome than those without cancer.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and methods
  5. Results
  6. Discussion
  7. Appendix
  8. Acknowledgements
  9. References

Current guidelines from the American College of Chest Physicians, based on evidence from clinical trials, recommend that all patients with venous thromboembolism (VTE) be treated acutely with either unfractionated heparin (UFH) or low-molecular-weight heparin (LMWH) for at least 5 days' bridging to long-term therapy for at least 3 months with an oral anticoagulant [1,2]. However, patients who have experienced a recent major bleeding episode are usually excluded from clinical studies of VTE treatment. Therefore, guideline recommendations for VTE treatment may not be suitable for these patients.

The ‘Registro Informatizado de la Enfermedad TromboEmbólica’ (RIETE) was initiated in March 2001 to record current clinical management of VTE in Spanish hospitals. It is an ongoing, multicenter, observational registry of consecutively enrolled patients, designed to gather and analyze data on VTE treatment practices and outcomes in patients with symptomatic, objectively confirmed acute VTE [3–6]. The aim of the present analysis was to compare the clinical characteristics, treatment patterns and clinical outcomes of patients with VTE who had experienced recent major bleeding (< 30 days prior to VTE diagnosis) and those with VTE but without recent history of major bleedings.

Patients and methods

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and methods
  5. Results
  6. Discussion
  7. Appendix
  8. Acknowledgements
  9. References

Inclusion and exclusion criteria

Participating hospitals in the RIETE registry prospectively enroll consecutive patients with symptomatic, acute deep vein thrombosis (DVT) or pulmonary embolism (PE), confirmed by objective tests [i.e. contrast venography, ultrasonography or impedance plethysmography for suspected DVT; pulmonary angiography, lung scintigraphy or helical computed tomography (CT) scan, for suspected PE]. Patients are excluded if they are participating in a therapeutic clinical trial or if they will not be available for a 3-month follow-up.

Study endpoints

The parameters recorded by the registry comprise details of each patient's baseline characteristics; clinical status including any coexisting or underlying conditions such as chronic heart disease or lung disease; recent bleeding complications; use of antiplatelet or corticosteroid drugs; the type, dose, and duration of treatment received upon VTE diagnosis; and the outcome during the first 3 months of therapy. The analysis endpoints are clinically recognized (and objectively confirmed) recurrences of VTE, bleeding complications, and death.

Follow-up

After hospital discharge, all patients were followed up for at least 3 months. Any signs or symptoms suggesting DVT or PE recurrences or bleeding complications were noted during each visit. Each episode of clinically suspected recurrent DVT or PE was documented by repeat compression ultrasonography, venography, lung scanning, helical CT scan, or pulmonary angiography. Fatal PE was defined as any death appearing during the first 48 h after PE diagnosis, in the absence of any alternative cause of death. Bleeding complications were classified as ‘major’ if they were overt and were either associated with a decrease in the hemoglobin level of 2.0 g dL−1 (20 g L−1) or more, required a transfusion of ≥ 2 U of blood, or were retroperitoneal or intracranial. Any other clinically relevant bleeding events were considered ‘minor’.

Data collection

All patients provided oral consent to their participation in the registry, according to the requirements of the ethics committee within each hospital. Data were recorded on to a computer-based case report form by a registry coordinator at each participating hospital and submitted to a centralized coordinating center through a secure website. The coordinators also ensured that eligible patients were consecutively enrolled. Patient identities remained confidential because they were identified by a unique number assigned by the study coordinator center, which was responsible for all data management. Study endpoints were adjudicated by the attending physicians. At regular intervals, data quality was monitored and documented electronically to detect inconsistencies or errors, which were resolved by the local coordinators. Data quality was also monitored by periodic visits to participating hospitals, by contract research organizations, who compared the medical records with the data in the web, as in the case of most clinical trials. In the event of substantial or unjustifiable inconsistencies, patients enrolled from that center were not included in the database. A full data audit was performed at periodic intervals.

Statistical analysis

Differences between groups were assessed by the Fischer exact test. Odds ratios and corresponding 95% confidence intervals (CI) were calculated using SPSS 11.5 software (SPSS Inc., Chicago, IL, USA), and a P-value < 0.05 was considered to be statistically significant.

Results

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and methods
  5. Results
  6. Discussion
  7. Appendix
  8. Acknowledgements
  9. References

By January 2004, 6361 patients with VTE had been enrolled at 94 participating hospitals in Spain and followed up for 3 months. Of them, 170 patients (2.7%) had experienced recent major bleeding: 69 (40%) in the gastrointestinal tract (28 of them had cancer); 60 (35%) intracranial bleeding (hemorrhagic stroke 39; trauma 12); 41 (24%) in other sites. More patients with recent major bleeding had cancer compared with those without recent major bleeding (Table 1). More patients who experienced recent major bleeding had undergone surgery < 2 months or had immobility > 3 days prior to diagnosis. During initial therapy 14% of patients with recent major bleeding received intravenous UFH; 46% received < 175 IU kg−1 daily of LMWH; and 38% received LMWH at > 175 IU kg−1 daily. An inferior vena cava (IVC) filter was inserted in 18% (Table 1). After discharge, 62% received long-term treatment with LMWH.

Table 1.   Clinical characteristics and treatment patterns in patients with and without a recent episode of major bleeding
 Recent major bleeding (N = 170)No recent major bleeding (N = 6191)Odds ratio (95% CI)P-value
  1. VTE, Venous thromboembolism; PE, pulmonary embolism; DVT, deep vein thrombosis; UFH, unfractionated heparin; LMWH, low-molecular-weight heparin; IVC filter, inferior vena cava filter; CI, confidence intervals; ns, not significant.

Clinical characteristics
 Gender (males)76 (45%)3093 (50%)0.8 (0.6, 1.1)ns
 Age > 65 years110 (65%)3962 (64%)1.0 (0.7, 1.4)ns
 Creatinine levels > 1.2 mg dL−124 (14%)831 (13%)1.1 (0.7, 1.7)ns
Risk factors for VTE
 Cancer45 (26%)1262 (20%)1.4 (1.0, 2.0)0.05
 Surgery < 2 months48 (28%)856 (14%)2.4 (1.7, 3.5)< 0.001
 Immobility > 3 days98 (58%)1621 (26%)3.8 (2.8, 5.3)< 0.001
 Previous VTE17 (10%)1071 (17%)0.5 (0.3, 0.9)0.013
Clinical presentation
 Symptomatic PE76 (45%)2445 (39%)1.2 (0.9, 1.7)ns
 Symptomatic DVT94 (55%)3746 (61%)0.8 (0.6, 1.1)ns
Initial therapy
 UFH24 (14%)585 (9.4%)1.6 (1.0, 2.5)0.05
 LMWH, < 175 IU kg−1 day−179 (46%)1791 (29%)2.1 (1.6, 2.9)< 0.001
 LMWH, > 175 IU kg−1 day−164 (38%)3762 (61%)0.4 (0.3, 0.5)< 0.001
 IVC filter31 (18%)101 (1.6%)13 (8.5, 21)< 0.001
Long-term therapy
 Coumarin57 (38%)4424 (74%)0.2 (0.1, 0.3)< 0.001
 LMWH94 (62%)1557 (26%)4.7 (3.3, 6.7)< 0.001

Bleeding complications

During the 3-month study period 12 patients (7.1%) with recent major bleeding developed new major bleeding events: seven of them (58%) died. Major bleeding complications developed significantly more often in patients with recent major bleeding than in those without such antecedent (Table 2). The incidence of fatal bleeding was particularly high in patients who had previously bled in the gastrointestinal tract: seven of 69 such patients (10%) developed major bleeding during the study period, and six died of the bleeding event (Table 3). By contrast, none of the 60 patients with recent intracranial bleeding rebled. A univariate analysis including all patients with recent major bleeding revealed that patients with cancer had an increased risk to develop new major bleeding events (Table 4).

Table 2.   Clinical outcomes of VTE patients with and without a recent episode of major bleeding
Three-month outcomeRecent major bleeding (N = 170)No recent major bleeding (N = 6191)Odds ratio (95% CI)P-value
  1. PE, Pulmonary embolism; VTE, venous thromboembolism; CI, confidence intervals; ns, not significant.

Fatal bleeding7 (4.1%)41 (0.6%)6.4 (2.6, 15)< 0.001
Major bleeding12 (7.1%)146 (2.3%)3.1 (1.6, 5.9)0.001
Minor bleeding12 (7.1%)172 (2.8%)2.6 (1.4, 5.0)< 0.005
Fatal initial PE1 (0.6%)14 (0.2%)2.6 (0.2, 19)ns
Fatal recurrent PE4 (2.4%)33 (0.5%)4.5 (1.3, 14)< 0.05
Recurrent VTE8 (4.7%)184 (2.9%)1.6 (0.7, 3.4)ns
Overall mortality25 (15%)479 (7.7%)2.1 (1.3, 3.2)< 0.005
Table 3.   Clinical characteristics and outcomes of the 170 patients with a recent episode of major bleeding, according to the site of bleeding
 Brain N = 60GI tract N = 69Others N = 41
  1. VTE, Venous thromboembolism; PE, pulmonary embolism; DVT, deep vein thrombosis; UFH, unfractionated heparin; LMWH, low-molecular-weight heparin; IVC, inferior vena cava; GI, gastrointestinal.

Clinical characteristics
 Gender (males)28 (47%)31 (45%)17 (41%)
 Age > 65 years36 (60%)50 (72%)24 (59%)
 Creatinine levels > 1.2 mg dL−15 (8.3%)13 (19%)6 (15%)
Risk factors for VTE
 Cancer5 (8.3%)28 (32%)12 (29%)
 Surgery < 2 months19 (32%)18 (26%) 11 (27%)
 Immobility > 3 days49 (82%)33 (48%)16 (39%)
Clinical presentation
 Symptomatic PE26 (43%)30 (43%)19 (46%)
 Symptomatic DVT34 (57%)39 (57%)22 (54%)
Initial therapy
 UFH2 (3.3%)13 (19%)9 (22%)
 LMWH, < 175 IU kg−1 day−139 (65%)25 (36%)15 (37%)
 LMWH, > 175 IU kg−1 day−117 (28%)30 (43%)17 (41%)
 IVC filter15 (25%)14 (20%)2 (4.9%)
Long-term therapy
 Coumarin14 (23%)23 (33%)20 (50%)
 LMWH44 (73%)32 (46%)20 (50%)
3-month outcome
 Minor bleeding3 (5%)6 (8.6%)3 (7.3%)
 Major bleeding07 (10%)5 (12%)
 Fatal bleeding06 (8.6%)1 (2.4%)
 Recurrent VTE3 (5%)3 (4.3%)2 (4.9%)
 Fatal PE1 (1.6%)2 (2.8%)1 (2.4%)
 Overall mortality3 (5%)16 (23%)6 (15%)
Site of new bleeding
 Brain000
 GI tract1 (1.6%)12 (17%)0
 Others2 (3.3%)1 (1.4%)8 (19%)
Table 4.   Univariate analysis of the variables associated with new episodes of major bleeding, among patients with a recent episode of major bleeding (N = 170)
 New bleeding (N = 12)No new bleeding (N = 158) Odds ratio (95% CI)P-value
  1. VTE, Venous thromboembolism; PE, pulmonary embolism; DVT, deep vein thrombosis; UFH, unfractionated heparin; LMWH, low-molecular-weight heparin; IVC filter, inferior vena cava filter; CI, confidence intervals; ns, not significant.

Clinical characteristics
 Gender (males)8 (66%)68 (43%)2.7 (0.7, 11)ns
 Age > 65 years11 (92%)99 (62%)6.6 (0.9, 41)ns
 Creatinine levels > 1.2 mg dL−14 (33%)21 (13%)3.3 (0.7, 14)ns
Risk factors for VTE
 Cancer9 (75%)36 (23%)10 (2.3, 50)< 0.001
 Surgery < 2 months1 (8.3%)47 (30%)0.2 (0.1, 1.7)ns
 Immobility > 3 days7 (58%)91 (58%)1.0 (0.3, 3.9)ns
 Previous VTE017 (11%)ns
Clinical presentation
 Symptomatic PE7 (58%)69 (44%)1.8 (0.5, 6.9)ns
 Symptomatic DVT5 (42%)89 (56%)0.6 (0.2, 2.0)ns
Site of previous bleeding
 Gastrointestinal7 (58%)62 (39%)2.2 (0.6, 8.3)ns
 Brain060 (38%)
 Others5 (42%)36 (23%)1.8 (0.5, 6.1)ns
Initial therapy
 UFH2 (16%)22 (14%)1.2 (0.3, 6.7)ns
 LMWH, < 175 IU kg−1 day−17 (58%)52 (33%)2.9 (0.8, 11)ns
 LMWH, > 175 IU kg−1 day−13 (25%)82 (52%)0.3 (0.1, 1.3)ns
 IVC filter2 (17%)29 (18%)0.9 (0.2, 4.7)ns

As for the development of minor bleeding complications, their incidence was also significantly higher in patients with a recent episode of major bleeding (Table 2). The most common sites of minor bleeding were the gastrointestinal tract (six patients) and the urinary system (five patients).

Fatal PE and recurrent VTE

Eight patients (4.7%) with recent major bleeding developed VTE recurrences during the 3-month study period: four had recurrent DVT, and four had PE (Table 2). All four patients with recurrent PE in this group died shortly after the event. In addition, one patient initially presenting with PE died of PE. The recurrence rate was independent of the site of previous bleeding (Table 3). A univariate analysis including all patients with recent major bleeding revealed that cancer and IVC filter insertion were associated with an increased risk of recurrences (Table 5). Four of the 31 patients (13%) in whom an IVC filter was inserted developed recurrences: recurrent DVT in three patients, recurrent PE in one patient.

Table 5.   Univariate analysis of variables associated with recurrent VTE, among patients with a recent episode of major bleeding (N = 170)
 Recurrent VTE (N = 8)No recurrences (N = 162) Odds ratio (95% CI)P-value
  1. VTE, Venous thromboembolism; PE, pulmonary embolism; DVT, deep vein thrombosis; UFH, unfractionated heparin; LMWH, low-molecular-weight heparin; IVC filter, inferior vena cava filter; CI, confidence intervals; ns, not significant.

Clinical characteristics
 Gender (males)6 (75%)70 (43%)3.9 (0.7, 18)ns
 Age > 65 years6 (75%)104 (64%)1.7 (0.3, 8.5)ns
 Creatinine levels > 1.2 mg dL−12 (25%)22 (14%)2.1 (0.4, 13)ns
Risk factors for VTE
 Cancer5 (63%)40 (25%)5.1 (1.0, 28)< 0.05
 Surgery < 2 months2 (25%)46 (28%)0.8 (0.2, 4.9)ns
 Immobility > 3 days5 (63%)93 (57%)1.2 (0.2, 6.8)ns
 Previous VTE017 (10%)ns
Clinical presentation
 Symptomatic PE5 (63%)71 (44%)2.1 (0.4, 12)ns
 Symptomatic DVT3 (37%)91 (56%)0.5 (0.1, 2.4)ns
Site of previous bleeding
 Gastrointestinal3 (38%)66 (41%)0.9 (0.2, 4.4)ns
 Brain3 (38%)57 (35%)1.1 (0.2, 5.6)ns
 Others2 (26%)39 (24%)1.1 (0.1, 6.1)ns
Initial therapy
 UFH1 (13%)23 (14%)0.9 (0.1, 7.6)ns
 LMWH, < 175 IU kg−1 day−14 (50%)75 (46%)1.2 (0.2, 5.8)ns
 LMWH, > 175 IU kg−1 day−12 (25%)61 (38%)0.6 (0.1, 3.2)ns
 IVC filter4 (50%)27 (17%)5.0 (0.97, 26)< 0.05

Clinical outcomes and cancer

Nine of the 45 cancer patients (20%) developed new major bleeding events (fatal bleeding in six). Patients initially treated with suboptimal doses (< 175 IU kg−1 day−1) of LMWH had a similar bleeding rate to those receiving full (> 175 IU kg−1 day−1) doses (Table 6). Six patients with cancer (13%) had recurrent VTE: four of them died of PE. In addition, one further patient died of his initial PE. Again, patients on suboptimal doses of LMWH had a similar recurrence rate to those with full doses (Table 6).

Table 6.   Clinical outcomes in 170 VTE patients with recent major bleeding, according to initial therapy and the presence or absence of cancer
VariablesPatients, NFatal bleedingMajor bleedingFatal PERecurrent VTE
  1. UFH, Unfractionated heparin; LMWH, low-molecular-weight heparin; IVC filter, inferior vena cava filter; VTE, venous thromboembolism; PE, pulmonary embolism.

With cancer
 UFH  31 (33%)2 (67%)00
 LMWH at < 175 IU kg−1 day−1 214 (19%)5 (24%)2 (9.5%)2 (9.5%)
 LMWH at > 175 IU kg−1 day−1 201 (5.0%)2 (10%)2 (10%)2 (10%)
 IVC filter 111 (9.1%)1 (9.1%)1 (9.1%)2 (18%)
 All 456 (13%)9 (20%)5 (11%)5 (9.0%)
Without cancer
 UFH 210001 (4.8%)
 LMWH at < 175 IU kg−1 day−1 581 (1.7%)2 (3.4%)02 (3.4%)
 LMWH at > 175 IU kg−1 day−1 4301 (2.3%)00
 IVC filter 201 (5.0%)1 (5.0%)02 (10%)
 All1251 (0.8%)3 (2.4%)03 (2.4%)
All patients1707 (4.1%)12 (7.1%)5 (2.9%)8 (4.7%)

Three of the 125 patients (2.4%) without cancer developed major bleeding (fatal bleeding in one). Three further patients (2.4%) recurred, but none of them died. The rates of major bleeding and recurrent VTE in these 125 patients were similar to the corresponding rates in the cohort of VTE patients without recent major bleeding (2.3% and 2.9%, respectively), as shown in Table 2.

Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and methods
  5. Results
  6. Discussion
  7. Appendix
  8. Acknowledgements
  9. References

Patients with major bleeding who subsequently develop clinically apparent VTE present a particularly difficult therapeutic dilemma because they are perceived to be at substantial risk of recurrent fatal PE in the absence of treatment and of recurrent hemorrhage if treated with anticoagulants. Erosive, friable endobronchial, gastrointestinal or genitourinary lesions are more prone to bleed during anticoagulation than at baseline. Treatment decisions in these patients are currently made on an empiric individual basis and entail evaluating the following factors: the expected morbidity and mortality in patients with VTE that is left untreated, the expected effectiveness of treatment with anticoagulation or IVC filter insertion, and the expected morbidity and mortality associated with any treatment option [7–12]. Since there is no immediate prospect of resolving uncertainty about the optimum treatment of these patients in a randomized trial, prospective data derived in unselected patients may be useful to identify the short- and long-term safety and effectiveness of each therapeutic strategy.

Our findings, extracted from a large series of consecutive patients with VTE, demonstrate three important findings. First, VTE patients with recent major bleeding have an increased rate of both fatal bleeding and fatal PE compared with those without such antecedent. Second, these patients can be stratified into higher and lower risk categories according to the presence or absence of cancer. One in every four patients with cancer in our series died of either PE (11%) or bleeding (13%). By contrast, the clinical outcome in patients with recent major bleeding but without cancer was similar to that in VTE patients without recent major bleeding. Third, a surprisingly high percentage of patients with a recent history of major bleeding in our series received anticoagulation instead of the insertion of an IVC filter at the time of diagnosis of VTE. Current guidelines from the American College of Chest Physicians, based on evidence from clinical trials, recommend the placement of an IVC filter in VTE patients with contraindications for anticoagulant therapy [1]. The higher incidence of hemorrhagic and/or embolic events in our series, when compared with VTE patients without recent major bleeding, might originate from a too limited enforcement of the above-mentioned clinical recommendations.

Cancer patients with VTE are more likely to develop major bleeding and recurrent VTE during anticoagulant therapy than those without malignancy. In a recent study, Prandoni et al. found the risk for recurrent VTE to be increased 4-fold, and the risk of bleeding to be twice as high in cancer patients, during both initial heparin therapy and subsequent oral anticoagulation [13]. This increased risk was not due to different therapeutic intensities, but to the extension of cancer. The potential risks of anticoagulation and the ready availability of IVC filters have led some authors to recommend filters in these patients. However, only a small number of unrandomized reports exist to support these recommendations [14–16]. In fact, in our series IVC filter insertion was associated with a significantly higher recurrence rate. Thus, any clinical management decision will continue to be individualized, since the most appropriate treatment has to be more thoroughly investigated. In the meantime, careful dosing and frequent therapeutic monitoring are imperative.

The clinical outcome in VTE patients with recent major bleeding but no cancer was similar to that in the cohort of patients without recent major bleeding. Interestingly, 60 patients in our series developed VTE shortly after intracranial bleeding, and none of them rebled while on anticoagulant therapy. Most physicians would be hesitant to use anticoagulants in this setting. In fact, two-thirds of these patients in our series were treated with suboptimal doses of LMWH, and then most of them did not switch to coumarin. However, the absence of major bleeding complications in the cohort of patients treated with full-dose anticoagulant therapy suggests that anticoagulation is safe in these patients. These findings agree with some reports on patients with either primary intracerebral hemorrhage [17] or brain tumors [18,19].

The main limitation of the present study is its design, which contains several sources of potential bias. First, RIETE is a registry; the data reported are not from a prospective, randomized, controlled trial. As in most registries, patients were not randomly allocated, but received the drug of their doctor's choice. Second, in many patients with recent major bleeding the doses of heparin therapy varied widely from day to day, making it impossible to compare different treatment patterns. However, the strength of this report is the prospective collection of data from actual practice, from a very large number of consecutive patients with objectively confirmed VTE, and by strictly applying objective criteria for diagnosis of recurrent VTE. The goal of RIETE (http://www.riete.org) is to improve the treatment of VTE patients through a better understanding of demographics, management, and in-hospital and postdischarge outcomes. Starting as a Spanish initiative in March 2001, currently it has been open to other countries, thus becoming an international registry. In contrast to a randomized controlled trial, there is no imposed experimental intervention: management is determined solely by physicians. Data captured and reported in the registry will therefore reflect ‘real-world’ approaches and outcomes in the treatment of VTE. Although patient numbers for many subsets within the RIETE database are currently small, numerical differences in outcomes such as those reported in the current paper suggest the possibility of clinically relevant treatment differences. As the RIETE database grows, these apparent treatment differences will be clarified, providing physicians with outcomes data based on ‘real-world’ data, rather than results of highly controlled clinical trials with restricted study populations.

In summary, VTE patients with recent major bleeding and cancer have an increased risk of both fatal bleeding and fatal PE. These patients warrant further studies. However, for patients with recent major bleeding but without cancer, since their clinical outcome is similar to that in the general VTE population, no specific strategies seem to be warranted.

Appendix

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and methods
  5. Results
  6. Discussion
  7. Appendix
  8. Acknowledgements
  9. References
Members of the RIETE Group

M. Barrón (La Rioja), J. Bugés, I. Cañas, C. Falgá, M. Monreal, E. Raguer, A. Raventós, C. Tolosa (Barcelona), J. I. Arcelus, I. Casado (Granada), R. Barba, I. Candel, J. del Toro, C. Fernández-Capitán, J. Gutiérrez, P. Rondón, C. Suárez (Madrid), J. L. Beato (Albacete), A. Blanco, M. D. García, L. López, R. Tirado (Córdoba), J. Bosco, P. Gallego, M. J. Soto (Cádiz), J. M. Calvo (Badajoz), F. Conget (Zaragoza), M. C. del Río (Zamora), F. Gabriel, E. Grau, P. Román, J. A. Todolí (Valencia), F. García-Bragado, A. Grau, S. Soler (Girona), M. R. Gutiérrez, R. Otero (Sevilla), J. A. González-Fajardo (Valladolid), R. Guijarro, J. J. Martín, J. Trujillo (Málaga), L. Hernández (Alicante), R. Lecumberri, M. Rivero, A. L. Sampériz, G. Tiberio (Navarra), J. L. Lobo (Vitoria), I. López (Asturias), A. Maestre (Alicante), J. Montes (Vigo), J. A. Nieto (Cuenca), M. A. Page (Murcia), J. L. Pérez-Burkhardt (Tenerife), J. Portillo (Ciudad Real), R. Rabuñal (Lugo), J. F. Sánchez (Cáceres), A. Sánchez (Salamanca), J. A. Torre (A Coruña), F. Uresandi (Bilbao), R. Valle (Cantabria), and F. Pajuelo (Medical Department, Aventis Pharma, Madrid).

Acknowledgements

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and methods
  5. Results
  6. Discussion
  7. Appendix
  8. Acknowledgements
  9. References

We express our gratitude to Aventis Pharma for supporting this Registry with an unrestricted educational grant and ‘S & H Medical Science Service’ for their logistic and administrative support. The project has been partially supported by Red Respira from the Instituto Carlos III (Red Respira-ISCiii-RTIC-03/11). We thank Salvador Ortíz (Prof. Universidad Autónoma de Madrid and Statistical Advisor S & H Medical Science Service) for the statistical analysis of the data presented in this paper.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and methods
  5. Results
  6. Discussion
  7. Appendix
  8. Acknowledgements
  9. References
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