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Venous Thromboembolism in Patients with Renal Insufficiency: Findings from the RIETE Registry

      Abstract

      Background

      Current guidelines make no specific recommendations for venous thromboembolism (VTE) treatment in patients with renal insufficiency, but some experts recommend some reduction in heparin dose.

      Methods

      Registro Informatizado de Enfermedad TromboEmbólica (RIETE) is an ongoing, prospective registry of consecutively enrolled patients with objectively confirmed, symptomatic, acute VTE. In this analysis we retrospectively analyzed the effect of renal insufficiency on the incidence of fatal pulmonary embolism (PE) and fatal bleeding within 15 days of diagnosis.

      Results

      Up to March 2005, 10,526 patients with acute VTE were enrolled in RIETE, of whom 9234 (88%) had a creatinine clearance (CrCl) greater than 60 mL/min, 704 (6.7%) had a CrCl 30 to 60 mL/min, and 588 (5.6%) had a CrCl less than 30 mL/min. The incidence of fatal PE during the study period was 1.0%, 2.6%, and 6.6%, respectively. Fatal bleeding occurred in 0.2%, 0.3%, and 1.2% of the patients, respectively. On multivariate analysis, patients with a CrCl less than 30 mL/min were independently associated with an increased risk for fatal PE and fatal bleeding. In addition, initial diagnosis of PE, immobility for 4 days or more, cancer, and initial therapy with unfractionated heparin were independent predictors of fatal PE; whereas immobility for 4 days or more and cancer were independent predictors of fatal bleeding.

      Conclusions

      Patients with VTE who have renal insufficiency had an increased incidence of both fatal PE and fatal bleeding, but the risk of fatal PE far exceeded that of fatal bleeding. Our data support the use of full-dose anticoagulant therapy, even in patients with a CrCl less than 30 mL/min.

      Keywords

      Treatment with anticoagulants improves outcomes in patients with venous thromboembolism (VTE).
      • Leizorovicz A.
      • Simonneau G.
      • Decousus H.
      • Boissel J.P.
      Comparison of efficacy and safety of low molecular weight heparins and unfractionated heparin in initial treatment of deep venous thrombosis: a meta-analysis.
      The Columbus Investigators
      Low-molecular-weight heparin in the treatment of patients with venous thromboembolism.
      • Merli G.
      • Spiro T.E.
      • Olsson C.G.
      • et al.
      Enoxaparin clinical trial group
      Subcutaneous enoxaparin once or twice daily compared with intravenous unfractionated heparin for treatment of venous thromboembolic disease.
      • Prandoni P.
      • Carnovali M.
      • Marchiori A.
      Galilei Investigators
      Subcutaneous adjusted-dose unfractionated heparin vs fixed-dose low-molecular-weight heparin in the initial treatment of venous thromboembolism.
      Current guidelines from the American College of Chest Physicians, based on evidence from clinical trials, recommend that patients with VTE be treated initially with either low-molecular-weight heparin (LMWH) or unfractionated heparin (UFH) for at least 5 days, followed by long-term treatment with a vitamin K antagonist.
      • Büller H.R.
      • Agnelli G.
      • Hull R.D.
      • Hyers T.M.
      • Prins M.H.
      • Raskob G.E.
      Antithrombotic therapy for venous thromboembolic disease The seventh ACCP conference on antithrombotic and thrombolytic therapy.
      However, patients with renal insufficiency are often excluded from clinical trials of anticoagulant therapy, which means that treatment regimens based on the results from clinical trials might not be suitable for all patients, such as those with renal insufficiency. Furthermore, the influence of renal insufficiency on the risk of bleeding complications, a factor that can lead physicians to withhold anticoagulant therapy, is not clear.
      • Patients with venous thromboembolism and severe renal insufficiency have an increased incidence of bleeding complications.
      • Their risk of fatal pulmonary embolism clearly exceeds that of fatal bleeding.
      • Our data support the use of full-dose heparin therapy, even in patients with severe renal insufficiency.
      Registro Informatizado de Enfermedad TromboEmbólica (RIETE) was initiated in March 2001 to record the current clinical management of VTE in Spanish hospitals and has now been expanded to include patients from other countries. It is an ongoing, multicenter, observational registry of consecutively enrolled patients, designed to gather data on treatment patterns and outcomes in patients with symptomatic, objectively confirmed, acute VTE.

      Monreal M, Suárez C, González Fajardo JA, et al, and the RIETE investigators. Management of patients with acute venous thromboembolism: findings from the RIETE Registry. J Pathophysiol Haemost Thromb. 2003/2004;33:330-334.

      • Monreal M.
      • Kakkar A.K.
      • Caprini J.A.
      • et al.
      RIETE Investigators
      The outcome after treatment of venous thromboembolism is different in surgical and acutely ill medical patients Findings from the RIETE Registry.
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      • Perea-Milla E.
      • Jiménez-Puente A.
      • et al.
      RIETE Investigators
      Bed rest or ambulation in the initial treatment of patients with acute deep vein thrombosis or pulmonary embolism Findings from the RIETE Registry.
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      • Marchena P.J.
      • et al.
      RIETE investigators
      Clinical outcome of patients with venous thromboembolism and recent major bleeding: findings from a prospective registry (RIETE).
      • Barba R.
      • Marco J.
      • Martín-Alvarez H.
      • et al.
      RIETE investigators
      The influence of extreme body weight on clinical outcome of patients with venous thromboembolism: findings from a prospective Registry (RIETE).
      In this retrospective analysis of the registry, we compared the clinical characteristics and 15-day outcomes of patients with VTE with and without renal insufficiency.

      Patients and methods

      Inclusion and Exclusion Criteria

      Consecutive patients (both outpatients and inpatients) with symptomatic, acute deep vein thrombosis (DVT) or pulmonary embolism (PE) (confirmed by objective tests: contrast venography, ultrasonography, or impedance plethysmography for suspected DVT; pulmonary angiography, lung scintigraphy, or helical computed tomography scan for suspected PE) are enrolled in RIETE. Patients are excluded if they are participating in a therapeutic clinical trial or if they are not available for follow-up.

      Study Design

      Patients were classified according to their estimated creatinine clearance (CrCl) in 3 groups: less than 30 mL/min, 30 to 60 mL/min, and greater than 60 mL/min. CrCl was estimated with the Cockcroft and Gault formula.
      • Cockcroft D.W.
      • Gault M.H.
      Prediction of creatinine clearance from serum creatinine.
      The first creatinine measured after VTE diagnosis was the one used to calculate the CrCl. The clinical characteristics, treatment details, and clinical outcomes were compared among the 3 groups. The major outcomes were clinically recognized (and objectively confirmed) fatal PE and fatal bleeding during the first 15 days of therapy.

      Study Variables and Definitions

      The following parameters were recorded: patient’s baseline characteristics; clinical status including any coexisting or underlying conditions, such as chronic heart or lung disease; risk factors for VTE; the type and dose of treatment received on VTE diagnosis; and the outcome during the first 15 days of therapy. Immobilized patients are defined in this analysis as nonsurgical patients who had been immobilized (ie, total bed rest with bathroom privileges) for 4 days or more in the 2-month period before VTE diagnosis. Surgical patients are defined as those who had undergone an operation in the 2 months before VTE diagnosis. Fatal PE, in the absence of autopsy, was defined as death shortly after PE diagnosis in the absence of any alternative cause of death. Fatal bleeding was defined as any death occurring shortly after a major bleeding episode. Bleeding complications were classified as “major” if they were overt and associated with a decrease in the hemoglobin level of 2.0 g/dL (20 g/L) or more, required a transfusion of 2 units of blood or more, or were retroperitoneal or intracranial.

      Follow-up

      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.

      Data Collection

      All patients provided oral consent for their participation in the registry, in accordance with the requirements of the ethics committee within each hospital. Data are recorded in 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 coordinating center, which is responsible for all data management. Study outcomes are adjudicated by the attending physicians. Data quality is regularly monitored and documented electronically to detect inconsistencies or errors, which are resolved by the local 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 website. A full data audit is performed at periodic intervals.

      Statistical Analysis

      Odds ratios and corresponding 95% confidence intervals were calculated using Confidence Interval Analysis software (version 2.0.0; SPSS Inc., Chicago, Ill), and a P value less than .05 was considered to be statistically significant. The significance of a number of clinical variables on the risk of death from either PE or bleeding was tested by fitting bivariate proportional hazard models. Candidate variables were selected from clinical variables based on published literature and expert opinion. A logistic regression model was used to examine the individual relationship between each variable and the risk of death due to PE or bleeding. Multivariate analysis was performed with a multivariate logistic regression analysis to determine the independent nature of the variables, while adjusted for other characteristics. Both significance levels of P less than .05 and P greater than .10 were considered to include and exclude variables in the final multivariate model.
      Diagnoses of distal, proximal, and upper extremity DVT in patients were not included in the multivariate analysis because a number of patients with symptomatic PE did not undergo any objective tests to confirm the presence of proximal or distal DVT because they did not have signs of DVT. The long-term treatment received by the patients was not included in the multivariate analysis, because patients dying during initial therapy did not receive long-term therapy.

      Results

      As of March 2005, 10,526 patients with symptomatic, acute VTE were consecutively enrolled at 104 participating centers. Of these, 9234 (88%) had a CrCl greater than 60 mL/min; 704 (6.7%) had a CrCl 30 to 60 mL/min; and 588 (5.6%) had a CrCl less than 30 mL/min.

      Baseline Clinical Characteristics

      Patients with a CrCl less than 30 mL/min were more often female and older than patients with a CrCl greater than 60 mL/min (Table 1). Recent immobility for 4 days or more and underlying chronic heart failure were also more frequent, whereas recent surgery was less common in patients with a CrCl less than 30 mL/min than in those with a CrCl greater than 60 mL/min.
      Table 1Clinical Characteristics, Treatment Details, and Clinical Outcomes of 10,526 Patients with Venous Thromboembolism, According to Their Creatinine Clearance
      Patients, n (%)>60 mL/min N = 923430-60 mL/min N = 704<30 mL/min N = 588OR (95% CI) 30-60 vs >60 mL/minOR (95% CI) <30 vs >60 mL/min
      Clinical characteristics
       Gender (males)4575 (50%)474 (67%)208 (35%)2.1 (1.8-2.5)
      P<.001.
      0.6 (0.5-0.7)
      P<.001.
       Age > 65 y5672 (61%)615 (87%)551 (94%)4.3 (3.5-5.4)
      P<.001.
      9.4 (6.7-13)
      P<.001.
       Outpatients6483 (70%)523 (74%)403 (69%)1.2 (1.0-1.5)
      P<.05;
      0.9 (0.7-1.1)
      Underlying conditions
       Chronic lung disease1016 (11%)107 (15%)59 (10%)1.4 (1.2-1.8)
      P<.001.
      0.9 (0.7-1.2)
       Chronic heart failure454 (4.9%)79 (11%)118 (20%)2.4 (1.9-3.1)
      P<.001.
      4.8 (3.9-6.1)
      P<.001.
      Risk factors for VTE
       Surgery1328 (14%)58 (8.2%)42 (7.1%)0.5 (0.4-0.7)
      P<.001.
      0.5 (0.3-0.6)
      P<.001.
       Immobility ≥ 4 d2170 (24%)198 (28%)241 (41%)1.3 (1.1-1.5)
      P<.01;
      2.3 (1.9-2.7)
      P<.001.
       Prior VTE1478 (16%)117 (17%)87 (15%)1.0 (0.9-1.3)0.9 (0.7-1.2)
       Cancer1817 (20%)176 (25%)131 (22%)1.4 (1.1-1.6)
      P<.01;
      1.2 (0.96-1.4)
      VTE characteristics
       Symptomatic PE3896 (42%)388 (55%)328 (56%)1.7 (1.4-2.0)
      P<.001.
      1.7 (1.5-2.0)
      P<.001.
      For patients with PE
       Heart rate > 100 beats/min3829 (28%)125 (32%)93 (28%)1.3 (1.0-1.6)
      P<.05;
      1.0 (0.8-1.3)
       Arterial Po2 < 60 mm Hg1423 (45%)171 (52%)151 (56%)1.3 (1.0-1.6)
      P<.05;
      1.5 (1.2-2.0)
      P<.01;
      For patients with DVT
       Proximal DVT4937 (82%)304 (90%)230 (95%)2.1 (1.4-3.0)
      P<.001.
      4.0 (2.3-7.0)
      P<.001.
      Initial therapy
       LMWH8622 (93%)637 (91%)525 (89%)0.7 (0.5-0.9)
      P<.01;
      0.6 (0.5-0.8)
      P<.001.
       Mean daily doses (IU/kg)180 ± 36176 ± 41179 ± 42P < .01P = NS
       LMWH < 175 IU/kg/d3010 (33%)257 (36%)186 (32%)1.2 (1.0-1.4)
      P<.05;
      1.0 (0.8-1.2)
       UFH562 (6.1%)60 (8.5%)52 (8.8%)1.4 (1.1-1.9)
      P<.01;
      1.5 (1.1-2.0)
      P<.01;
       Mean daily doses (IU/kg)384 ± 100377 ± 86389 ± 76P = NSP = NS
       Thrombolytics96 (1.0%)17 (2.4%)10 (1.7%)2.4 (1.4-4.0)
      P<.001.
      1.6 (0.9-3.2)
       IVC filter172 (1.9%)16 (2.3%)14 (2.4%)1.2 (0.7-2.1)1.3 (0.7-2.2)
      Long-term therapy
       AVK drugs6834 (74%)509 (72%)317 (54%)0.9 (0.8-1.1)0.4 (0.3-0.5)
      P<.001.
       LMWH2028 (22%)144 (21%)184 (31%)0.9 (0.8-1.1)1.6 (1.3-1.9)
      P<.001.
      15-d clinical outcomes
       Major bleeding94 (1.0%)28 (4.0%)32 (5.4%)4.0 (2.6-6.2)
      P<.001.
      5.6 (3.7-8.4)
      P<.001.
       Fatal bleeding17 (0.2%)2 (0.3%)7 (1.2%)1.5 (0.4-6.7)6.5 (2.7-16)
      P<.001.
       Recurrent VTE90 (1.0%)6 (0.9%)7 (1.2%)
       Fatal PE90 (1.0%)18 (2.6%)39 (6.6%)2.7 (1.6-4.4)
      P<.001.
      7.2 (4.9-11)
      P<.001.
       Overall death215 (2.3%)41 (5.8%)93 (16%)2.6 (1.8-3.7)
      P<.001.
      7.9 (6.1-10)
      P<.001.
      VTE = venous thromboembolism; PE = pulmonary embolism; DVT = deep vein thrombosis; LMWH = low-molecular-weight heparin; UFH = unfractionated heparin; IU = international unit; IVC = inferior vena cava; AVK = anti-vitamin K drugs; OR = odds ratio; CI = confidence interval; NS = nonsignificant.
      Comparisons between patients with a CrCl < 30 mL/min or 30 to 60 mL/min and patients with a CrCl > 60 mL/min:
      low asterisk P < .05;
      P < .01;
      P < .001.
      Patients with a CrCl less than 30 mL/min were more often enrolled with symptomatic PE than patients with a CrCl greater than 60 mL/min (Table 1). Among patients with PE, those with a CrCl less than 30 mL/min more commonly had a severe clinical presentation (ie, arterial Po2 < 60 mm Hg) than corresponding patients with a CrCl greater than 60 mL/min (Table 1). Patients with symptomatic DVT with a CrCl less than 30 mL/min were diagnosed with proximal DVT more often and with distal DVT less often.

      Treatment Details and 15-Day Clinical Outcomes

      Most patients in all 3 groups were initially treated for VTE with LMWH, but those with a CrCl less than 30 mL/min received UFH more often (8.8%) than those with a CrCl greater than 60 mL/min (6.1%) (Table 1). Mean initial daily doses of both LMWH and UFH were similar in the 3 patient groups. As for long-term therapy, the use of anti-vitamin K drugs was less common in patients with a CrCl less than 30 mL/min.
      The incidence of major bleeding was significantly higher in both subgroups with abnormal CrCl compared with patients with normal renal function, whereas the incidence of VTE recurrences (recurrent DVT or PE) was similar in all three subgroups (Table 1). Moreover, patients with a CrCl less than 30 mL/min had an increased incidence of fatal bleeding, fatal PE, and overall death compared with those with a CrCl greater than 60 mL/min. Patients with a CrCl of 30 to 60 mL/min had an increased rate of fatal PE and overall death, without significant differences in the fatal bleeding rate.
      The fatal PE rate was significantly higher in patients with severe renal insufficiency than in those with moderate or normal renal function. PE occurred in 1.0% of patients with a CrCl greater than 60 mL/min, in 2.6% of patients with a CrCl 30 to 60 mL/min, and in 6.6% of patients with a CrCl less than 30 mL/min. In addition, the use of UFH was associated with a significantly higher risk of fatal PE compared with LMWH (Table 2). On multivariate analysis in patients, those with an initial diagnosis of PE, decreasing CrCl, immobility for 4 days or more, cancer, or initial therapy with UFH were independently associated with an increased risk for fatal PE (Table 3).
      Table 2Univariate Analysis on the Risk of Developing Fatal Pulmonary Embolism
      Fatal PE N = 149No Fatal PE N = 10,449Odds Ratio (95% CI)P Value
      Clinical characteristics
       Gender (males)61 (41%)5237 (50%)0.7 (0.5-0.96).026
       Age > 65 y122 (82%)6779 (65%)2.4 (1.6-3.7)<.001
       Outpatients90 (62%)7343 (72%)0.6 (0.4-0.9).005
      Underlying conditions
       Chronic lung disease22 (15%)1168 (11%)1.4 (0.9-2.2).168
       Chronic heart failure25 (17%)638 (6.1%)3.1 (2.0-4.8)<.001
      Risk factors for VTE
       Surgery14 (9.4%)1418 (14%)0.7 (0.4-1.1).139
       Immobility ≥ 4 d71 (48%)2554 (24%)2.8 (2.0-3.9)<.001
       Prior VTE15 (10%)1682 (16%)0.6 (0.3-0.997).046
       Cancer42 (28%)2103 (20%)1.6 (1.1-2.2).015
      VTE characteristics
       Symptomatic PE140 (94%)4514 (43%)20 (10-40)<.001
      Renal function
       CrCL > 60 mL/min90 (61%)9144 (88%)0.2 (0.2-0.3)<.001
       CrCl 30-60 mL/min18 (12%)686 (6.6%)2.0 (1.2-3.2).007
       CrCl < 30 mL/min39 (27%)549 (5.3%)6.5 (4.4-9.4)<.001
      Initial therapy
       LMWH115 (77%)9734 (93%)0.2 (0.2-0.4)<.001
       LMWH < 175 IU/kg/d34 (30%)3443 (35%)0.8 (0.5-1.1).195
       UFH26 (17%)653 (6.2%)3.2 (2.1-4.9)<.001
       Other8 (5.4%)62 (0.6%)9.5 (4.5-20)<.001
      VTE = venous thromboembolism; PE = pulmonary embolism; CrCl = creatinine clearance; LMWH = low-molecular-weight heparin; IU = international unit; UFH = unfractionated heparin; CI = confidence interval.
      Table 3Multivariate Analysis on the Risk of Developing Fatal Pulmonary Embolism
      VariablesOdds Ratio (95% CI)P Value
      Symptomatic PE17 (8.8-34)<.001
      Renal function<.001
      CrCL > 60 mL/minReference-
      CrCl 30-60 mL/min2.0 (1.2-3.4).008
      CrCl < 30 mL/min5.2 (3.4-7.8)<.001
      Immobility ≥ 4 d2.4 (1.7-3.4)<.001
      Cancer2.0 (1.4-2.9)<.001
      Initial therapy, UFH1.9 (1.2-3.0)<.001
      Inpatients1.5 (1.0-2.1).027
      PE = pulmonary embolism; CrCl = creatinine clearance; UFH = unfractionated heparin; CI = confidence interval.
      Fatal bleeding occurred more frequently in patients with severe or moderate renal insufficiency: It occurred in 0.2% of patients with a CrCl greater than 60 mL/min, in 0.3% of patients with a CrCl 30 to 60 mL/min, and in 1.2% of patients with a CrCl less than 30 mL/min. The use of UFH was not associated with significant differences in the rate of fatal bleeding compared with LMWH (Table 4). Multivariate analysis confirmed that decreasing CrCl, cancer, and immobility for 4 days or more were independently associated with an increased risk for fatal bleeding (Table 5).
      Table 4Univariate Analysis on the Risk of Developing Fatal Bleeding
      Fatal Bleeding N = 27No Fatal Bleeding N = 10,571Odds Ratio (95% CI)P Value
      Clinical characteristics
       Gender (males)12 (44%)5286 (50%)0.8 (0.4-1.7).564
       Age > 65 y23 (85%)6878 (65%)3.1 (1.1-8.9).028
       Outpatients15 (56%)7418 (72%)0.5 (0.2-1.0).058
      Underlying conditions
       Chronic lung disease1 (3.7%)1189 (11%)0.3 (0.04-2.2).215
       Chronic heart failure3 (11%)660 (6.2%)1.9 (0.6-6.3).297
      Risk factors for VTE
       Surgery3 (11%)1429 (14%)0.8 (0.2-2.7).715
       Immobility ≥ 4 d15 (56%)2610 (25%)3.8 (1.8-8.2)<.001
       Prior VTE2 (7.4%)1695 (16%)0.4 (0.1-1.8).222
       Cancer10 (37%)2135 (20%)2.3 (1.1-5.1).030
      VTE characteristics
       Symptomatic PE13 (48%)4641 (44%)1.2 (0.6-2.5).657
      Renal function
       CrCL > 60 mL/min17 (65%)9217 (88%)0.3 (0.1-0.6).001
       CrCl 30-60 mL/min2 (7.7%)702 (6.7%)1.2 (0.3-4.9).837
       CrCl < 30 mL/min7 (27%)581 (5.5%)6.3 (2.6-15)<.001
      Initial therapy
       LMWH25 (93%)9824 (93%)1.0 (0.2-4.0).945
       LMWH < 175 IU/kg/d9 (36%)3468 (35%)1.0 (0.5-2.3).942
       UFH2 (7.4%)677 (6.4%)1.2 (0.3-4.9).832
       Other0 (0%)70 (0.7%)-.671
      VTE = venous thromboembolism; PE = pulmonary embolism; CrCl = creatinine clearance; LMWH = low-molecular-weight heparin; UFH = unfractionated heparin; CI = confidence interval.
      Table 5Multivariate Analysis on the Risk of Developing Fatal Bleeding
      VariablesOdds Ratio (95% CI)P Value
      Immobility ≥ 4 d3.3 (1.5-7.3).003
      Cancer2.7 (1.2-6.0).015
      Renal function,-.002
      CrCL > 60 mL/minReference-
      CrCl 30-60 mL/min1.4 (0.3-5.9).677
      CrCl < 30 mL/min5.0 (2.0-12)<.001
      CrCl = creatinine clearance; CI = confidence interval.

      Discussion

      A number of studies have shown that patients with VTE who have renal insufficiency have an increased incidence of bleeding complications with therapeutic doses of heparin therapy.
      • Gerlach A.T.
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      • Antman E.M.
      Safety and efficacy of unfractionated heparin versus enoxaparin in patients who are obese and patients with severe renal impairment: analysis from the ESSENCE and TIMI 11B studies.
      • Thorevska N.
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      Anticoagulation in hospitalized patients with renal insufficiency A comparison of bleeding rates with unfractionated heparin vs enoxaparin.
      • Farooq V.
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      • et al.
      Serious adverse incidents with the usage of low molecular weight heparins in patients with chronic kidney disease.
      The data in this analysis, obtained from a large prospective series of consecutively enrolled patients in the RIETE registry, confirm this increased incidence of bleeding complications in patients with renal insufficiency. Indeed, the 5.4% incidence of major bleeding clearly outweighs the 1.2% incidence of recurrent VTE in patients with a CrCl less than 30 mL/min. However, their 6.6% incidence of fatal PE also exceeded their 1.2% rate of fatal bleeding. In fact, the fatal PE rate is more than 5-fold higher than that of fatal bleeding in all 3 groups, but patients with a CrCl less than 30 mL/min have a 6 to 7 times greater mortality as the result of PE or bleeding than those with normal function.
      Some 39% of patients with VTE who died of PE in our series had some degree of renal insufficiency. The increased incidence of fatal PE in these patients may be partly attributable to the more severe presentation of VTE compared with patients with normal renal function. However, it is also likely to be partly attributable to the older age, the more frequent occurrence of coexisting underlying conditions (eg, immobility and congestive heart failure), or associated therapies in these patients. Comorbid conditions such as these are predictive of poor survival in patients with VTE.
      • Gitter M.J.
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      • Petterson T.M.
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      • Silverstein M.D.
      Bleeding and thromboembolism during anticoagulant therapy: a population-based study in Rochester, Minnesota.
      • Fihn S.D.
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      • Martin D.
      Risk factors for complications of chronic anticoagulation: a multicenter study.
      • Anderson F.A.
      • Wheeler H.B.
      • Goldberg R.J.
      • et al.
      A population based perspective of the hospital incidence and case-facility rates of deep-vein thrombosis and pulmonary embolism The Worcester DVT Study.
      Thus, a more severe presentation of VTE, combined with a less favorable prognosis because of concomitant disease, could contribute to the higher fatal PE rate seen in patients with renal insufficiency. More evidence is needed to ascertain whether it is the renal insufficiency rather than the more symptomatic PE or underlying comorbidities that contribute to the greater mortality.
      We report that LMWH use is associated with a significantly lower rate of fatal PE when compared with UFH, and that this benefit was found irrespective of renal function. We failed to find any increase in the fatal bleeding rate among patients with VTE and renal insufficiency who were receiving initial therapy with LMWH compared with those receiving UFH. The use of LMWH in patients with renal insufficiency traditionally has been considered hazardous given its impaired metabolism in renal failure, eventually leading to unwanted “overdose” and bleeding complications. Indeed, the current guidelines from the American College of Chest Physicians suggest (grade 2C of evidence) the use of intravenous UFH rather than LMWH in patients with severe renal insufficiency.
      • Leizorovicz A.
      • Simonneau G.
      • Decousus H.
      • Boissel J.P.
      Comparison of efficacy and safety of low molecular weight heparins and unfractionated heparin in initial treatment of deep venous thrombosis: a meta-analysis.
      • Hirsh J.
      • Raschke R.
      Heparin and low-molecular-weight heparin The Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy.
      Our findings do not support this recommendation. The benefit of LMWH over UFH in patients with renal insufficiency has been reported in patients with acute coronary syndrome,
      • Collet J.P.
      • Montalescot G.
      • Agnelli G.
      • et al.
      Grace Investigators
      Non-ST-segment elevation acute coronary syndrome in patients with renal dysfunction benefit of low-molecular-weight heparin alone or with glycoprotein IIb/IIIa inhibitors on outcomes: The Global Registry of Acute Coronary Events.
      • Petersen J.L.
      • Mahaffey K.W.
      • Hasselblad V.
      • et al.
      Efficacy and bleeding complications among patients randomized to enoxaparin or unfractionated heparin for antithrombin therapy in non-ST-segment elevation acute coronary syndromes: a systematic overview.
      but not thus far in patients with VTE. Unfortunately, there is no information on the anti-Xa levels in the Registry.
      Finally, our data confirm that renal insufficiency is an independent predictor of fatal bleeding in patients with acute VTE. This is the reason why many authors suggest that heparin dosing should be reduced for these patients.
      • Thorevska N.
      • Amoateng-Adjepong Y.
      • Sabahi R.
      • et al.
      Anticoagulation in hospitalized patients with renal insufficiency A comparison of bleeding rates with unfractionated heparin vs enoxaparin.
      • Hulot J.S.
      • Montalescot G.
      • Lechat P.
      • Collet J.P.
      • Ankri A.
      • Urien S.
      Dosing strategy in patients with renal failure receiving enoxaparin for the treatment of non-ST-segment elevation acute coronary syndrome.
      However, because renal insufficiency is consistently used as an exclusion criterion in randomized trials evaluating antithrombotic drugs, there is no clinical evidence to support this view. In our series, patients with renal insufficiency received similar doses of heparin therapy as those with normal function, and the rate of fatal PE in these patients (as in those with normal renal function) remained more than fivefold higher than their fatal bleeding rate. Thus, our findings do not support the use of a change in dosing rate when treating VTE in patients with renal insufficiency.
      The main limitation of our study lies in its design. In contrast with randomized, controlled trials, no experimental intervention is imposed in RIETE; treatment 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. In addition, selection bias was avoided by including consecutive patients with objectively confirmed, symptomatic, acute VTE who were referred to study centers. Enrolled patients were treated according to standard practice, and prospective follow-up was completed for all patients. Objective criteria were strictly applied for the diagnosis of initial and recurrent VTE, along with quality control and audit measures.
      Another limitation is the likely underestimated incidence rate of fatal PE. Certainly, the deaths of some patients may have been caused by PE, but these would not have been included because the Adjudication Committee accepts only VTE events that have been objectively confirmed. However, because the overall death rate also was significantly higher in patients with renal insufficiency, it seems unlikely that our findings would have been different if a better knowledge of the cause of death had been obtained. Finally, the Crockcroft Gault calculation overestimates the CrCl in obese patients, rendering some of these patients inappropriately categorized.

      Conclusions

      We confirm that patients with VTE who have severe renal insufficiency demonstrate an increased incidence of bleeding complications, but that their risk of fatal PE clearly exceeds that of fatal bleeding. Thus, our data support the use of full-dose heparin therapy, even in patients with severe renal insufficiency. As for the use of UFH rather than LMWH in this patient population, our data do not confirm any benefit for those receiving UFH. We suggest not avoiding LMWH in these patients, probably with anti-Xa monitoring. We propose to prospectively study this issue.

      Acknowledgments

      All of the authors had full access to the data in the study and take responsibility for the integrity of the data and accuracy of the data analysis. 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 article.

      APPENDIX.

      Members of the RIETE Group
      J. C. Alvárez , R. Otero (Sevilla), J. I. Arcelus, I. Casado (Granada), M. Barrón (La Rioja), J. L. Beato (Albacete), J. Bugés, F. Epelde, C. Falgá, M. Monreal, E. Raguer, A. Raventós, C. Tolosa (Barcelona), R. Barba, J. del Toro, C. Fernández-Capitán, J. Gutiérrez, D. Jiménez, J. M. Pedrajas, N. Ruíz-Giménez (Madrid), A. Blanco, L. López, R. Tirado (Córdoba), J. Bosco, P. Gallego, M. J. Soto (Cádiz), M. A. Cabezudo, I. López (Asturias), F. Conget (Zaragoza), J. L. Pérez-Burkhardt (Tenerife), F. Gabriel, E. Grau, F. López, M. D. Naufall, P. Román, J. A. Todolí (Valencia), F. García Bragado, S. Soler (Girona), R. Guijarro, M. Guil, J. J. Martín (Málaga), L. Hernández, A. Maestre, R. Sánchez (Alicante), R. Lecumberri, M. T. Orue, A.L. Sampériz, G. Tiberio (Navarra), S. Herrera, M. A. Page, J. Trujillo (Murcia), J. L. Lobo (Vitoria), J. Montes, M. J. Núñez (Vigo), J. A. Nieto (Cuenca), J. Portillo (Ciudad Real), R. Rabuñal (Lugo), J. F. Sánchez (Cáceres), J. A. Torre (A Coruña), F. Uresandi (Bilbao), R. Valle (Cantabria), and X. Llobet (Medical Department, Sanofi-Aventis).
      A full list of RIETE investigators is given in the Appendix.

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