The influence of extreme body weight on clinical outcome of patients with venous thromboembolism: findings from a prospective registry (RIETE)

Authors


Manuel Monreal, Hospital Germans Trias i Pujol, Badalona, 08916 Spain. Tel.: 34 669675313; e-mail: mmonreal@ns.hugtip.scs.es

Abstract

Summary. Background: Data evaluating the safety of using weight-based dosing of low-molecular-weight heparin (LMWH) in either underweight or obese patients with venous thromboembolism (VTE) are limited. Thus, recommendations based on evidence from clinical trials might not be suitable for patients with extreme body weight. Patients and Methods: Patients with objectively confirmed, symptomatic acute VTE are consecutively enrolled into the Registro Informatizado de la Enfermedad TromboEmbólica (RIETE) registry. For this analysis, data from patients in the following ranges of body weight were examined: <50, 50–100, and >100 kg. Patient characteristics, underlying conditions, treatment schedules and clinical outcomes during the first 15 days of treatment were compared. Results: As of August 2004, 8845 patients with acute VTE were enrolled from 94 participating centers. Of these, 169 (1.9%) weighed <50 kg, 8382 (95%) weighed 50–100 kg and 294 (3.3%) weighed >100 kg. Patients weighing <50 kg were more commonly females, were taking non-steriodal antiinflammatory drugs (NSAIDs), and had severe underlying diseases more often than patients weighing 50–100 kg. Their incidence of overall bleeding complications was significantly higher than in patients weighing 50–100 kg (odds ratio 2.2; 95% CI: 1.2–4.0). Patients weighing >100 kg were younger, most commonly males, and had cancer less often than those weighing 50–100 kg. Incidences of recurrent VTE, fatal pulmonary embolism or major bleeding complications were similar in both groups. Conclusions: Patients with VTE weighing <50 kg have a significantly higher rate of bleeding complications. The clinical outcome of patients weighing over 100 kg was not significantly different from that in patients weighing 50–100 kg.

Introduction

Anticoagulant therapy is the treatment of choice for most patients with venous thromboembolism (VTE). Current guidelines from the American College of Chest Physicians, based on evidence from clinical trials, recommend that all patients with VTE be treated acutely with either activated partial thromboplastin time (APTT)-adjusted unfractionated heparin (UFH) or body weight-adjusted 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, in underweight or very obese patients, the typical dosage adapted to body weight may not be applicable because only few patients with extreme body weight are usually included in clinical trials.

The ‘Registro Informatizado de la Enfermedad TromboEmbólica’ (RIETE) was initiated in March 2001 to record current clinical management of VTE within Spanish hospitals. It is a multicenter, observational ongoing registry designed to gather and analyze data on treatment patterns and clinical outcomes in consecutive patients with symptomatic, objectively confirmed, acute VTE [3–5]. As of August 2004, data from 8845 patients with acute VTE have been collected from 94 participating centers.

The aim of the present observational study was to compare the clinical characteristics, treatment options and clinical outcomes during the first 15 days of therapy of three different body-weight groups of VTE patients included in the RIETE registry.

Patients and methods

Ninety-four Spanish hospitals participating in RIETE enrolled consecutive patients with symptomatic, acute deep vein thrombosis (DVT) or pulmonary embolism (PE), confirmed by objective tests (i.e. contrast venography, compression ultrasonography or impedance plethysmography, for suspected DVT; pulmonary angiography, lung scintigraphy or helical computed tomography scan, for suspected PE). Patients are not included if they are participating in a therapeutic clinical trial or if they are not available for a 3-month follow-up.

Study design

Patients were classified in three groups: <50, 50–100 and >100 kg. First, the clinical characteristics, underlying conditions, risk factors for VTE and treatment options were compared among the three weight groups. Then, the rate of VTE recurrences, bleeding complications and death at the end of the 15-day study period were calculated.

Clinical definitions

During the study period, special attention was paid to any sign or symptom suggesting either DVT or PE recurrences, or bleeding complications. Each episode of clinically suspected recurrent DVT or PE was documented by repeat ultrasonography, venography, lung scanning, helical-computed tomography scan or pulmonary angiography. Fatal PE, in the absence of autopsy, was defined as any death appearing shortly 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 or more, led to a transfusion of 2 units of blood or more, or were retroperitoneal or intracranial. Any other clinically relevant bleeding events were considered ‘minor’.

Data collection

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 or lung disease, recent bleeding complications, or abnormal creatinine levels (serum creatinine >1.2 mg dL−1), use of antiplatelet drugs; the type, dose, and duration of thromboprophylaxis received prior to enrollment; the type, dose, and duration of treatment received upon VTE diagnosis; and the outcome during the first 3 months of therapy. The analysis endpoints were clinically recognized (and objectively confirmed) recurrences of VTE, bleeding complications, and death.

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

Statistical analysis

Differences between groups were assessed by the Fisher's 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. The significance of a number of clinical variables on the risk of developing recurrent VTE or major bleeding during the first 15 days of therapy was tested by fitting bivariate proportional hazards models. Candidate variables were selected from the clinical variables and were based on published literature and on expert opinion. The variables were patient's baseline characteristics; clinical status including any coexisting conditions such as chronic heart or lung disease, abnormal creatinine levels, use of antiplatelet drugs, corticosteroids or non-steroidal antiinflammatory drugs (NSAID); the type, dose, and duration of treatment received upon VTE diagnosis; and the outcome during the first 15 days of therapy. A logistic regression model was used to examine the individual relationship between each variable and the risk of recurrent VTE or major bleeding. Those variables identified by the univariate analyses as potential risk factors and achieving a significance level of <0.05 were considered for inclusion in a multivariate logistic regression analysis.

Results

As of August 2004, 8845 patients were enrolled in RIETE: 169 patients (1.9%) weighed <50 kg; 8382 (95%) 50–100 kg; and 294 (3.3%) >100 kg. The clinical characteristics of these patients are depicted in Table 1. Their different treatment approaches appear in Table 2. During the 15-day study period, 118 patients (1.3%) had major bleeding (fatal bleeding in 20), 123 patients (1.4%) died of PE and 90 (1.0%) developed recurrent VTE.

Table 1.  Clinical characteristics of the 8845 patients, according to their body weight
 <50 kg50–100 kg>100 kg
n (%)Odds ratio (95% CI)n (%)Odds ratio (95% CI)
  1. Comparisons between patients weighing <50 or >100 kg and those weighing 50–100 kg: *P < 0.05; **P < 0.01; ***P < 0.001.

  2. NSAID, non-steroidal anti-inflammatory drugs; VTE, venous thromboembolism; DVT, deep vein thrombosis; PE, pulmonary embolism; LMWH, low-molecular-weight heparin; UFH, unfractionated heparin; CI, confidence intervals.

Patients (n)169 8382 294
 Body weight (kg)45 ± 3.2 73 ± 11 112 ± 11
 Body weight (range)30–49 50–100 101–160
Clinical characteristics
 Gender (males)30 (18)***0.2 (0.1–0.3)4202 (50)1.8 (1.4–2.2)188 (64)***
 Age (>65 years)110 (65)1.1 (0.8–1.5)5308 (63)0.2 (0.2–0.3)86 (29)***
 Outpatients107 (65)0.8 (0.6–1.1)5746 (71)1.2 (0.9–1.6)212 (74)
Underlying conditions
 Chronic lung disease31 (12)1.1 (0.7–1.8)944 (11)1.2 (0.8–1.7)38 (13)
 Chronic heart failure15 (8.9)1.4 (0.8–2.4)539 (6.4)1.1 (0.7–1.8)21 (7.1)
 NSAID intake17 (10)*1.8 (1.1–3.0)487 (5.8)0.9 (0.6–1.6)16 (5.4)
 Antiplatelet drugs15 (8.9)0.8 (0.5–1.4)874 (10)0.7 (0.4–1.1)22 (7.5)
 Corticosteroids19 (11)1.6 (0.96–2.5)631 (7.5)0.8 (0.5–1.2)17 (5.8)
 Creatinine (>1.2 mg dL−1)19 (14)1.0 (0.6–1.6)1144 (14)0.7 (0.5–1.0)29 (10)
Risk factors for VTE
 Cancer53 (21)***1.8 (1.3–2.5)1673 (20)0.5 (0.3–0.7)32 (11)***
 Surgery19 (11)0.8 (0.5–1.3)1160 (14)1.1 (0.8–1.5)43 (15)
 Immobility66 (39)***1.8 (1.3–2.4)2241 (27)0.9 (0.7–1.1)70 (24)
 Previous VTE19 (11)0.7 (0.4–1.1)1335 (16)1.6 (1.2–2.1)69 (24)**
VTE characteristics
 Symptomatic DVT110 (65)*1.4 (1.0–1.9)4782 (57)1.1 (0.9–1.4)174 (59)
 Symptomatic PE59 (35)*0.7 (0.5–0.98)3600 (43)0.9 (0.7–1.2)120 (41)
Treatment
 Initial therapy (LMWH)161 (95)*2.2 (1.1–4.5)7560 (90)0.5 (0.4–0.7)242 (82)***
 Initial therapy (UFH)8 (4.7)*0.5 (0.2–0.98)786 (9)2.0 (1.5–2.8)51 (17)***
 Long-term (coumarin)80 (47)***0.3 (0.2–0.4)6141 (73)1.4 (1.1–1.9)234 (80)*
 Long-term (LMWH)70 (41)***2.4 (1.8–3.3)1878 (22)0.7 (0.5–0.9)49 (18)*
Table 2.  Different doses of either LMWH or UFH, according to body weight (patients receiving thrombolytic therapy as initial therapy were not considered)
 <50 kg50–100 kg>100 kg
n (%)P-valuen (%)P-value
  1. IU, international units; LMWH, low-molecular-weight heparin; UFH, unfractionated heparin.

Initial therapy – LMWHn = 161 n = 7559 n = 242
 Mean daily dose (IU)9282 ± 2240<0.00113112 ± 3007<0.00116373 ± 3967
 Mean daily dose (IU kg−1)208 ± 51<0.001181 ± 36<0.001148 ± 36
 Daily dose (<175 IU kg−1)36 (22)0.0012516 (33)<0.001178 (74)
 Daily dose (175–200 IU kg−1)38 (24)<0.0013492 (46)<0.00162 (26)
 Daily dose (>200 IU kg−1)87 (54)<0.0011551 (21)<0.0012 (0.8)
Initial therapy – UFHn = 8 n = 760 n = 51
 Mean daily dose (IU)20113 ± 64370.01526 489 ± 7399<0.00137 337 ± 13 035
 Mean daily dose (IU kg−1)442 ± 1490.062372 ± 1050.001321 ± 101

Patients weighing less than 50 kg

Patients weighing <50 kg were more commonly females, were taking NSAIDs, and had severe underlying diseases (i.e. cancer, immobility) more often than those weighing 50–100 kg (Table 1). Eight of these 169 patients (4.7%) received UFH as initial therapy, and the remaining 161 were treated with LMWH. Mean daily doses of both, UFH and LMWH were significantly lower in patients weighing <50 kg than in those weighing 50–100 kg (Table 2). However, 54% of those treated with LMWH received >200 UI kg−1 day−1, compared with only 21% of patients weighing 50–100 kg (odds ratio 4.6; 95% CI 3.3–6.3).

Patients weighing <50 kg had an increased rate of overall bleeding complications: five patients (3.0%) developed major bleeding and nine patients (5.3%) had minor bleeding, when compared with 1.3% and 2.6%, respectively, in patients weighing 50–100 kg (odds ratio 2.2; 95% CI 1.2–4.0; Table 3). One of the five patients weighing <50 kg who developed major bleeding had received UFH therapy, and three patients received >200 IU kg−1 day−1 of LMWH. Two patients (1.2%) developed recurrent VTE: one of them had cancer and received initial therapy with suboptimal doses of LMWH (121 IU kg−1 day−1) because of the presence of brain metastases. The overall mortality rate was also significantly higher in this weight group (Table 3).

Table 3.  Clinical outcomes of the patients during the first 15 days of antithrombotic therapy
 <50 kg50–100 kg>100 kg
n (%)Odds ratio (95% CI)n (%)Odds ratio (95% CI)
  1. Comparisons between patients weighing <50 or >100 kg and those with 50–100 kg: *P < 0.05; **P < 0.01.

  2. VTE, venous thromboembolism; PE, pulmonary embolism; CI, confidence intervals.

Patients (n)169 8382 294
 Fatal bleeding1 (0.6)2.6 (0.3–20)19 (0.2)0
 Major bleeding5 (3.0)2.3 (0.9–5.7)110 (1.3)0.8 (0.2–2.5)3 (1.0)
 Minor bleeding9 (5.3)*2.1 (1.1–4.1)218 (2.6)0.5 (0.2–1.4)4 (1.4)
 Total bleeding14 (8.3)**2.2 (1.2–4.0)328 (3.9)0.6 (0.3–1.3)7 (2.4)
 Fatal PE1 (0.6)0.4 (0.1–2.9)121 (1.4)0.2 (0.03–1.7)1 (0.3)
 Recurrent VTE2 (1.2)1.2 (0.3–4.7)86 (1.0)0.7 (0.2–2.7)2 (0.7)
 Overall death13 (7.7)**2.7 (1.5–4.7)255 (3.0)0.2 (0.1–0.9)2 (0.7)*

Patients weighing more than 100 kg

These patients were younger, most commonly males, and had cancer less often than those weighing 50–100 kg (Table 1). Fifty-one of them (17%) received UFH therapy, 242 received LMWH therapy and one patient was initially treated with thrombolytics (Table 2). When considering patients receiving LMWH, 74% of them received <175 UI kg−1 day−1 when compared with 33% of patients weighing 50–100 kg (odds ratio 5.6; 95% CI 4.1–7.5) (Table 2).

Three patients in this group (1.0%) had major bleeding complications and four patients (1.4%) had minor bleeding (Table 3). The total bleeding rate in patients weighing >100 kg was significantly lower than in those weighing <50 kg (odds ratio 0.3; 95% CI 0.1–0.7; P = 0.003). Furthermore, one patient weighing >100 kg (0.3%) died of his initial PE, and two patients (0.7%) developed VTE recurrences during the 15-day study period: all three patients received initial therapy with UFH.

Clinical outcomes

In the univariate analysis, age >65 years, chronic heart disease, corticosteroid intake, renal insufficiency, cancer, immobility, and symptomatic PE were all associated to a significantly higher risk to develop major bleeding during the 15-day follow-up period (Table 4). By contrast, outpatient status and initial therapy with LMWH were associated with a significantly lower risk for major bleeding. Body weight was not associated with a significantly higher risk for major bleeding. Multivariate analysis confirmed that corticosteroids intake, renal insufficiency, cancer, and immobility were associated with an increased risk for major bleeding; while outpatient status, and initial therapy with LMWH were independently associated with a lower risk to develop major bleeding (Table 5).

Table 4.  Univariate analysis of the risk to develop major bleeding complications during the first 15 days of therapy
 Major bleeding (n = 118) (%)No major bleeding (n = 8727) (%)Odds ratio (95% CI)P-value
  1. NSAID, non-steroidal anti-inflammatory drugs; VTE, venous thromboembolism; DVT, deep vein thrombosis; PE, pulmonary embolism; LMWH, low-molecular-weight heparin; UFH, unfractionated heparin; CI, confidence intervals.

Body weight (kg)
 <50 kg5 (4.2)164 (1.9)2.3 (0.9–5.7)0.075
 50–100 kg110 (93)8727 (95)0.8 (0.4–1.6)0.404
 >100 kg3 (2.5)291 (3.3)0.8 (0.2–2.4)0.634
Clinical characteristics
 Gender (males)52 (44)4368 (50)0.8 (0.5–1.1)0.228
 Age (>65 years)92 (78)5412 (62)2.2 (1.4–3.3)<0.001
 Outpatients69 (59)5996 (71)0.6 (0.4–0.9)0.008
Underlying conditions
 Chronic lung disease15 (13)988 (11)1.1 (0.7–2.0)0.660
 Chronic heart failure15 (13)560 (6.4)2.1 (1.2–3.7)0.012
 NSAID intake11 (9.3)509 (5.8)1.7 (0.9–3.1)0.113
 Antiplatelet drugs17 (14)894 (10)1.5 (0.9–2.5)0.167
 Corticosteroids17 (14)650 (7.4)2.1 (1.2–3.5)0.008
 Creatinine (>1.2 mg dL−1)49 (42)1147 (13)4.7 (3.2–6.8)<0.001
Risk factors for VTE
 Cancer40 (34)1718 (20)2.1 (1.4–3.1)<0.001
 Surgery15 (13)1207 (14)0.9 (0.5–1.6)0.893
 Immobility48 (41)2329 (27)1.9 (1.3–2.7)0.001
 Previous VTE12 (10)1411 (16)0.6 (0.3–1.1)0.100
VTE characteristics
 Symptomatic DVT51 (43)5015 (58)0.6 (0.4–0.8)0.003
 Symptomatic PE67 (57)3712 (42)1.8 (1.2–2.6)0.003
Treatment
 Initial therapy (LMWH)97 (82)7866 (90)0.5 (0.3–0.8)0.008
 Initial therapy (UFH)21 (17)824 (9.4)2.1 (1.3–3.3)0.004
Table 5.  Multivariate analysis of the risk to develop major bleeding complications during the first 15 days of therapy
 Odds ratio (95% CI)P-value
  1. VTE, venous thromboembolism; PE, pulmonary embolism; LMWH, low-molecular-weight heparin; CI, confidence intervals.

Clinical characteristics
 Age (>65 years)1.5 (0.98–2.4)0.064
 Outpatients0.6 (0.4–0.9)0.022
Underlying conditions
 Chronic heart failure1.3 (0.7–2.3)0.348
 Corticosteroids1.8 (1.0–3.0)0.036
 Creatinine (>1.2 mg dL−1)3.6 (2.4–5.3)<0.001
Risk factors for VTE
 Cancer2.1 (1.4–3.1)<0.001
 Immobility1.6 (1.1–2.4)0.014
VTE characteristics
 Symptomatic PE1.4 (0.95–2.1)0.090
Treatment
 Initial therapy (LMWH)0.6 (0.4–0.98)0.043

Age over 65 years and initial therapy with LMWH were associated in the univariate analysis with a significantly lower risk to develop VTE recurrences (Table 6). By contrast, NSAIDs and cancer were associated with a significantly higher risk of recurrences. Multivariate analysis confirmed these findings (Table 7). Moreover, body weight had no impact on the risk for recurrent VTE.

Table 6.  Univariate analysis of the risk to develop recurrent VTE during the first 15 days of therapy
 Recurrent VTE (n = 90) (%)No Recurrent VTE (n = 8755) (%)Odds ratio (95% CI)P-value
  1. NSAID, non-steroidal anti-inflammatory drugs; VTE, venous thromboembolism; DVT, deep vein thrombosis; PE, pulmonary embolism; LMWH, low-molecular-weight heparin; UFH, unfractionated heparin; CI, confidence intervals.

Body weight (kg)
 <50 kg2 (2.2)167 (1.9)1.2 (0.3–4.8)0.691
 50–100 kg86 (96)8292 (95)1.2 (0.4–3.3)0.735
 >100 kg2 (2.2)292 (3.3)0.7 (0.2–2.7)0.771
Clinical characteristics
 Gender (males)54 (60)4366 (50)1.5 (0.98–2.3)0.057
 Age (>65 years)45 (50)5459 (62)0.6 (0.4–0.9)0.021
 Outpatients61 (69)6004 (71)0.9 (0.7–1.4)0.641
Underlying conditions
 Chronic lung disease14 (16)989 (11)1.4 (0.8–2.6)0.239
 Chronic heart failure4 (4.4)571 (6.5)0.7 (0.2–1.8)0.664
 NSAID intake14 (16)506 (5.8)3.0 (1.7–5.3)0.001
 Antiplatelet drugs11 (12)900 (10)1.2 (0.6–2.3)0.488
 Corticosteroids10 (11)657 (7.5)1.5 (0.8–3.0)0.223
 Creatinine (>1.2 mg dL−1)8 (8.9)1188 (14)0.6 (0.3–1.3)0.276
Risk factors for VTE
 Cancer39 (43)1719 (20)3.1 (2.1–4.8)<0.001
 Surgery17 (19)1205 (14)1.5 (0.9–2.5)0.166
 Immobility26 (29)2151 (27)1.1 (0.7–1.8)0.635
 Previous VTE17 (19)1406 (16)1.2 (0.7–2.1)0.470
VTE characteristics
 Symptomatic DVT51 (57)5015 (57)1.0 (0.6–1.5)0.915
 Symptomatic PE39 (43)3740 (43)1.0 (0.7–1.6)0.915
Treatment
 Initial therapy (LMWH)75 (83)7888 (90)0.5 (0.3–0.96)0.049
 Initial therapy (UFH)14 (16)831 (9.6)1.8 (0.99–3.1)0.052
Table 7.  Multivariate analysis of the risk to develop recurrent VTE during the first 15 days of therapy
 Odds ratio (95% CI)P-value
  1. NSAID, non-steroidal anti-inflammatory drugs; VTE, venous thromboembolism; LMWH, low-molecular-weight heparin; CI, confidence intervals.

Clinical characteristics
 Age (>65 years)0.6 (0.4–0.9)0.027
Underlying conditions
 NSAID intake3.0 (1.7–5.4)<0.001
Risk factors for VTE
 Cancer3.2 (2.1–4.8)<0.001
Treatment
 Initial therapy (LMWH)0.5 (0.3–0.9)0.014

Discussion

Our data, obtained from a large prospective series of consecutive patients with VTE reveal that there are no significant differences in major bleeding or VTE recurrences among patients weighing <50, 50–100 or >100 kg during the first 15 days of therapy. The increased rate of overall bleeding complications in patients weighing <50 kg may be explained by the more frequent presence of underlying diseases in this patient group. Comorbid conditions such as cancer and immobility have been reported to be associated with an increased risk of both recurrences and bleeding during VTE treatment, while the presence of renal insufficiency and the use of anti-inflammatory drugs had been associated with an increased risk of bleeding [6–9]. The use of high doses of LMWH (>200 IU kg−1 day−1) in over 50% of patients in this group may also have contributed to this significant increase in the overall bleeding rate.

The absence of significant differences in clinical outcomes in VTE patients weighing over 100 kg is consistent with the findings of a meta-analysis including data on 921 overweight patients with ischemic heart disease [10]. The lower incidence of cancer and the younger age of most patients weighing over 100 kg may explain their better clinical outcome. Interestingly, both the patient who died of PE and the two patients who developed VTE recurrences in this group had received UFH therapy.

The pharmacodynamic rationale for weight-adjusted LMWH therapy dosing was established in healthy subjects [11–13]. Accordingly, most of the studies with LMWH in patients with acute VTE have been performed using body weight-adjusted dosages [14]. However, dose-finding trials have not been carried out in special populations, such as patients with renal insufficiency or extreme body weight, and the most appropriate way to administer LMWH therapy remains uncertain in these patient groups. In some countries, approved dosing recommendations place a dosing ‘cap’ at a maximum absolute allowable LMWH dose, despite patient body weight. This may be the reason why 74% of patients weighing over 100 kg in our series received low (<175 IU kg−1 day−1) doses of LMWH. Surprisingly, none of these patients developed either fatal PE or VTE recurrences.

An interesting debate on the necessity of laboratory monitoring of LMWH therapy has been recently published in this Journal [15–21]. As there is no immediate prospect of resolving uncertainty about the optimum treatment of patients with extreme body weight in a randomized trial, prospective data derived in unselected patients may be useful to identify the efficacy and safety of heparin therapy in different weight groups. The goal of RIETE (http://www.riete.org) is to provide online information to help physicians evaluate treatment options, particularly for those patient groups that are not included in clinical trials, thereby aiding patient management and disseminating information on good clinical practice. In contrast to a randomized controlled trial, no experimental intervention is imposed: management is determined entirely by the treating physicians. Although this limits the nature of the conclusions that can be drawn, data captured and reported in the registry reflect ‘real-world’ practices and outcomes in the treatment of VTE.

The main limitation of the present study is its design, as it is an observational study and contains several sources of potential bias. First, patients were not randomly allocated, but received the drug of their doctor's choice. Secondly, in some patients, the doses of heparin therapy varied widely from day to day, making it impossible to compare different treatment patterns. In any case, our registry is a prospective cohort study involving a large series of consecutive patients with acute, symptomatic, objectively confirmed VTE. Our data reveal that VTE patients weighing <50 kg have an increased rate of overall bleeding complications, probably because of the clinical characteristics of these patients. But we also found that in real life, many underweight patients receive high doses of LMWH therapy, thus contributing to their increased bleeding rate. By contrast, the clinical outcome of VTE patients weighing >100 kg is not different to that in patients weighing 50–100 kg, although we cannot know what could have happened if patients weighing >100 kg would have received higher doses of LMWH. As to the use of UFH therapy in these patients, our experience does not support this indication.

Acknowledgements

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 (RedRespira-ISCiii-RTIC-03/11).

We would like to thank Prof. Salvador Ortíz, Universidad Autónoma de Madrid and Statistical Advisor S & H Medical Science Service for the statistical analysis of the data presented in this paper.

Declaration of conflicts of interest

The authors declare they have no conflicts of interest regarding this study.

Appendix

Members of the RIETE Group:

M. Barrón (La Rioja), J. Bugés, C. Falgá, M. Monreal, E. Raguer, A. Raventós, C. Tolosa (Barcelona), J.I. Arcelus, I. Casado (Granada), R. Barba, C. Fernández-Capitán, J. Gutiérrez, D. Jiménez, P. Rondón, C. Suárez (Madrid), J.L. Beato (Albacete), A. Blanco, 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, A.L. Sampériz, G. Tiberio (Navarra), J.L. Lobo (Vitoria), I. López (Asturias), J. Montes (Vigo), J.A. Nieto (Cuenca), M.A. Page (Murcia), J.L. Pérez-Burkhardt (Tenerife), J. Portillo (Ciudad Real), 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).

Ancillary