Influence of recent immobilization and recent surgery on mortality in patients with pulmonary embolism

Authors


Manuel Monreal, Servicio de Medicina Interna, Hospital Universitari Germans Trias i Pujol, Carretera del Canyet s/n, 08916 Badalona (Barcelona), Spain.
Tel.: +34 669675313; fax: +34 934978843.
E-mail: mmonreal.germanstrias@gencat.cat

Abstract

Summary.  Background:  The influence of recent immobilization or surgery on mortality in patients with pulmonary embolism (PE) is not well known.

Methods:  We used the Registro Informatizado de Enfermedad TromboEmbólica (RIETE) data to compare the 3-month mortality rate in patients with PE, with patients categorized according to the presence of recent immobilization, recent surgery, or neither.

Results:  Of 18 028 patients with PE, 4169 (23%) had recent immobilization, 2212 (12%) had recent surgery, and 11 647 (65%) had neither. The all-cause mortality was 10.0% (95% confidence interval [CI] 9.5–10.4), and the PE-related mortality was 2.6% (95% CI 2.4–2.9). One in every two patients who died from PE had recent immobilization (43%) or recent surgery (6.7%). Only 25% of patients with immobilization had received prophylaxis, as compared with 65% of the surgical patients. Fatal PE was more common in patients with recent immobilization (4.9%; 95% CI 4.3–5.6) than in those with surgery (1.4%; 95% CI 1.0–2.0) or those with neither (2.1%; 95% CI 1.8–2.3). On multivariate analysis, patients with immobilization were at increased risk for fatal PE (odds ratio 2.2; 95% CI 1.8–2.7), with no differences being seen between patients immobilized in hospital or in the community.

Conclusions:  Forty-three per cent of patients dying from PE had recent immobilization for ≥ 4 days. Many of these deaths could have been prevented.

Introduction

Venous thromboembolism (VTE) is a major health problem, with substantial morbidity and mortality. Reliance on prompt diagnosis and treatment may be inappropriate, because the diagnosis is often difficult, and massive pulmonary embolism (PE) may be the first clinical manifestation of the disease [1–3]. Hence, prevention is of paramount importance. Patients at risk of dying must be identified and given appropriate prophylaxis in order to reduce the incidence of VTE. However, the influence of recent surgery or recent immobilization on the incidence of fatal PE is not well known. Post-mortem studies have indicated that PE is associated with up to 10% of deaths in hospitalized patients, and only about one-quarter of these deaths occur following surgery [4]. Thus, about three-quarters of hospitalized patients who suffer a fatal PE are in fact medical (non-surgical) patients. However, most acutely ill patients do not require hospitalization, and many patients develop PE in the absence of prior surgery or immobilization [5,6].

The Registro Informatizado de Enfermedad TromboEmbólica (RIETE) is an ongoing, multicenter, international (Spain, Italy, France, Israel, Greece, Switzerland, Czech Republic, and Macedonia), observational registry of consecutive patients with symptomatic, objectively confirmed, acute VTE. It started in Spain in 2001, and 6 years later the database was translated into English with the aim of expanding RIETE to other countries, ultimately allowing physicians worldwide to use the database to select the most appropriate therapy for their patients. Data from this registry have been used to evaluate outcomes after acute VTE, such as the frequency of recurrent VTE, bleeding, and mortality, and risk factors for these outcomes [7–10]. The current analysis compared the severity of PE according to the presence or absence of recent immobilization for non-surgical reasons, recent surgery, or neither.

Patients and methods

Consecutive patients with symptomatic, acute deep vein thrombosis (DVT) or PE, confirmed by objective tests (compression ultrasonography or contrast venography for DVT; helical computed tomography [CT] scan or ventilation/perfusion lung scintigraphy for PE), were enrolled in RIETE. Patients were excluded if they were currently participating in a therapeutic clinical trial with blinded therapy. All patients (or their relatives) provided written or oral consent for participation in RIETE, in accordance with local ethics committee requirements. For this analysis, only patients with acute, symptomatic PE (with or without concomitant DVT) were considered.

Physicians participating in RIETE ensured that eligible patients were consecutively enrolled. Data were recorded on a computer-based case report form at each participating hospital, and submitted to a centralized coordinating center through a secure website. The study coordinating center assigned patients a unique identification number to maintain patient confidentiality, and was responsible for all data management. Data quality was regularly monitored electronically, including checks to detect inconsistencies or errors, which were resolved by contacting the local coordinators. Data quality was also monitored by periodic visits to participating hospitals by contract research organizations that compared medical records with the submitted data.

Study outcomes

The major outcome for this study was the incidence of fatal PE within the first 90 days of diagnosis of acute PE. The secondary outcome was all-cause mortality. Immobilized patients were defined as non-surgical patients who had been confined to bed (i.e. total bed rest with bathroom privileges) for ≥ 4 days in the 2 months prior to PE diagnosis, in the absence of prior surgery. Surgical patients were defined as those who had undergone an operation in the 2 months prior to PE diagnosis. Fatal PE, in the absence of autopsy, was defined as any death occurring within 10 days of PE diagnosis, in the absence of any alternative cause of death. Fatal initial PE was defined as any fatal PE occurring within 10 days of initial PE diagnosis, in the absence of prior recurrent PE. Fatal recurrent PE was defined as any fatal PE occurring within 10 days of symptomatic (objectively proven) recurrent PE. Fatal bleeding was defined as any death occurring within 10 days of a major bleeding episode, in the absence of an alternative cause of death. Major bleeding was defined as an overt bleed that required a transfusion of two or more units of blood, was retroperitoneal, spinal or intracranial, or was fatal.

Baseline variables

The following parameters were recorded when the qualifying episode of PE was diagnosed: patient’s gender, age, body weight, and height; the presence of coexisting conditions such as chronic heart or lung disease; concomitant therapies; recent major bleeding; the presence of additional risk factors for PE, including active cancer (defined as newly diagnosed cancer or cancer that is being treated [i.e. surgery, chemotherapy, radiotherapy, hormonal, support therapy, or combined treatments]), hormonal therapy, pregnancy, puerperium, prior VTE, and recent travel; and laboratory data, including arterial oxyhemoglobin saturation levels and serum creatinine levels on admission.

Treatment and follow-up

Patients were managed according to the clinical practice of each participating hospital (that is, there was no standardization of treatment). The type, dose and duration of anticoagulant therapy were recorded. Patients were followed up for up to 3 months in the outpatient clinic. During each visit, any signs or symptoms suggesting PE recurrences or bleeding complications were noted. Each episode of clinically suspected recurrent PE was investigated by repeat lung scanning, helical CT scan, or pulmonary angiography, as appropriate. Most outcomes were classified as reported by the clinical centers. However, if staff at the coordinating center were uncertain how to classify a reported outcome, that event was reviewed by a central adjudicating committee (< 10% of events).

Statistical analysis

Student’s t-test and the Mann–Whitney test were used to compare continuous variables. Categorical variables were compared by ue of the Fisher exact test. The odds ratios (ORs) and 95% confidence intervals (CIs) were calculated. We used Kaplan–Meier plots to estimate the association of immobilization (and other risk factors) with the risk of dying from PE, adjusting for gender, age, body weight, recent surgery, recent immobilization, cancer, estrogen use, chronic lung disease, chronic heart failure, abnormal creatinine levels, recent major bleeding, antiplatelets, non-steroidal anti-inflammatory drugs, corticosteroids, systolic blood pressure levels of < 100 mm Hg at baseline, initial therapy, and insertion of a vena cava filter. In addition, the duration and site of immobilization were also entered in the multivariate analysis when only patients with recent immobilization were considered. Covariates entered in the multivariate analyses were selected by a significance level of P < 0.20 in univariate analysis, or by a well-known association reported in the literature. spss version 15 (SPSS, Chicago, IL, USA) was used for statistical management of the data. A two-sided P-value of < 0.05 was considered to be statistically significant.

Results

Up to July 2011, 18 028 patients with acute PE were enrolled in RIETE. Overall, 4169 (23%) had recent immobilization for ≥ 4 days, 2212 (12%) had recent surgery, and 11 647 (65%) had neither immobilization nor surgery. PE diagnosis was confirmed with a positive CT scan in 12 980 patients (72%), a high-probability ventilation/perfusion lung scan in 4146 patients (23%), angiography in 359 patients (2.0%), visualization of a thrombus on the echocardiogram in 130 patients (0.7%), and intermediate-probability lung scan plus evidence of DVT in the lower limbs in 413 patients (2.3%).

Patients with recent immobilization were significantly older, were more likely to have chronic lung disease, chronic heart failure or renal insufficiency, more often received concomitant therapy with antiplatelet drugs or corticosteroids, and presented with more clinical signs of severity (hypotension, hypoxemia, and tachycardia) than those in the other two subgroups (Table 1). Patients with neither immobilization nor surgery were more likely to have had prior VTE or positive thrombophilia testing. Most patients (85%) in all three subgroups received initial therapy with low molecular weight heparin (LMWH), with no differences among subgroups in mean daily doses. Patients with neither recent immobilization nor surgery were more likely to have received thrombolytic therapy than those in the other subgroups. Seventy-three per cent received long-term therapy with anti-vitamin K drugs, and 22% continued on LMWH therapy.

Table 1.   Clinical characteristics of 18 028 patients with acute pulmonary embolism (PE), according to the presence or absence of recent immobilization or surgery
 Recent immobilizationRecent surgeryNeither
  1. IU, international units; LMWH, low molecular weight heparin; NSAID, non-steroidal anti-inflammatory drug; Sat O2, oxyhemoglobin saturation; SBP, systolic blood pressure; SD, standard deviation; VTE, venous thromboembolism. Comparisons between groups vs. recent immobility: *P < 0.05; †P < 0.01; ‡P < 0.001.

No. of patients4169221211 647
Clinical characteristics
 Mean age (years) ± SD71 ± 1663 ± 17‡67 ± 17‡
 Gender (males), n (%)1745 (42)1013 (46)†5558 (48)‡
 Body weight (kg) ± SD73 ± 1675 ± 1575 ± 15‡
 Inpatients, n (%)1382 (34)909 (42)‡2621 (23)‡
 Prior VTE, n (%)463 (11)189 (8.5)†2028 (17)‡
Underlying diseases, n (%)
 Cancer740 (18)589 (27)‡2605 (22)*
 Chronic lung disease734 (18)192 (8.7)‡1518 (13)†
 Chronic heart failure526 (13)113 (5.1)‡868 (7.5)‡
 Abnormal creatinine levels930 (22)205 (9.3)‡2027 (17)
 Recent major bleeding201 (4.8)96 (4.3)112 (1.0)‡
Concomitant therapies, n (%)
 NSAIDs276 (6.6)152 (6.9)420 (3.6)‡
 Antiplatelets800 (19)241 (11)‡1595 (14)‡
 Corticosteroids446 (11)97 (4.4)‡676 (5.8)‡
Clinical presentation, n (%)
 SBP < 100 mmHg454 (11)179 (8.1)‡761 (6.5)‡
 Sat O2 < 90% (N = 13 087)1380 (44)441 (30)‡2957 (35)‡
 Heart rate > 110 beats min–1819 (20)350 (17)‡1853 (16)‡
Thrombophilia testing, n (%)
 Tested patients715 (17)544 (25)‡3042 (26)‡
 Factor V Leiden33 (0.8)27 (1.2)248 (2.1)‡
 Prothrombin G20210A55 (1.3)44 (2.0)*221 (1.9)*
 Protein C deficiency10 (0.2)5 (0.2)73 (0.6)†
 Protein S deficiency30 (0.7)17 (0.8)107 (0.9)
 Antithrombin deficiency10 (0.2)8 (0.4)49 (0.4)
 Antiphospholipid syndrome53 (1.3)29 (1.3)233 (2.0)†
Initial therapy
 Thrombolytics, n (%)48 (1.2)27 (1.2)211 (1.8)†
 Unfractionated heparin, n (%)459 (11)295 (13)†1314 (11)
 LMWH, n (%)3599 (87)1854 (84)†9905 (85)
 Mean LMWH dose (IU kg–1) ±SD182 ± 41181 ± 37183 ± 36*
 Vena cava filter, n (%)112 (2.7)90 (4.1)†323 (2.8)
Long-term therapy
 Anti-vitamin K drugs, n (%)2692 (65)1598 (72)‡8856 (79)‡
 LMWH, n (%)1110 (27)535 (24)‡2247 (19)‡
 Mean LMWH dose (IU kg–1) ±SD149 ± 52149 ± 47151 ± 49
 90-day outcome, n (%)
  Recurrent PE63 (1.5)23 (1.0)152 (1.3)
  Fatal PE204 (4.9)32 (1.4)‡240 (2.1)‡
  Fatal, initial PE173 (4.1)25 (1.1)‡177 (1.5)‡
  Fatal, recurrent PE31 (0.7)7 (0.3)*63 (0.5)
  Major bleeding135 (3.2)64 (2.9)259 (2.2)‡
  Fatal bleeding30 (0.7)12 (0.5)61 (0.5)
  Overall death710 (17)144 (6.5)‡943 (8.1)‡

The incidence of fatal PE during the first 3 months of treatment was 2.6% (95% CI 2.4–2.9), and the all-cause mortality was 10.0% (95% CI 9.5–10.4). Of 476 patients who died from PE, 37 (7.8%) had confirmation by autopsy. Most patients with fatal PE (344, 72%) died during the first 7 days, and 25% died during the first 24 h (Fig. 1). The incidence of fatal PE was higher in patients with recent immobilization (4.9%; 95% CI 4.3–5.6) than in those with recent surgery (1.4%; 95% CI 1.0–2.0) or neither (2.1%; 95% CI 1.8–2.3). Among those with recent immobilization or recent surgery, three in every four patients with fatal PE died during the first 7 days of therapy (77% and 81%, respectively), as compared with 67% of those with no recent immobilization or surgery (Fig. 2). Interestingly, however, 65% of the surgical patients but only 25% of those with recent immobilization had received VTE prophylaxis. The all-cause mortality was also higher in patients with recent immobilization (17.0%; 95% CI 15.9–18.2) than in those with recent surgery (6.5%; 95% CI 5.5–7.6) or neither (8.1%; 95% CI 7.6–8.6). There were no significant differences between subgroups in the incidence of PE recurrence or fatal bleeding (Table 1).

Figure 1.

 Cumulative mortality in 18 028 patients with acute pulmonary embolism, according to the causes of death.

Figure 2.

 Cumulative incidence of fatal pulmonary embolism (PE), according to the different risk factors.

The most frequent reasons for immobilization were: trauma with no surgery (lower limb fracture, 189 patients; lower limb contusion, 159; sprained ankle, 146; other, 261), infections (respiratory, 193; pneumonia, 155; urinary, 79; other, 224), mental disorders, lower limb paralysis, and arthropathy (Table 2). The length and site of immobilization for each reason for immobility are shown in Table 3. Both the PE-related mortality and all-cause mortality progressively increased with the length of immobilization, and were similar for patients immobilized in hospital and those immobilized in the community. However, the use of VTE prophylaxis was higher in patients immobilized in hospital (57%) than in those immobilized in long-term-care centers (14%) or in the community (13%).

Table 2.   Clinical characteristics, use of venous thromboembolism (VTE) prophylaxis and 90-day outcome in 4169 immobilized patients with pulmonary embolism (PE)
  N 90-day fatal PE, n (%)90-day mortality, n (%)VTE prophylaxis, n (%)
All patients4169204 (4.9)710 (17)1054 (25)
Reason for immobilization
 Trauma75515 (2.0)48 (6.4)248 (33)
 Infection65119 (2.9)80 (12)232 (36)
 Mental disorders58950 (8.5)154 (26)31 (5.3)
 Lower limb paralysis30020 (6.7)58 (19)29 (9.7)
 Arthropathy2676 (2.2)21 (7.9)17 (6.4)
 Cancer22229 (13)141 (64)64 (29)
 Chronic lung disease2258 (3.6)38 (17)87 (39)
 Chronic heart failure19812 (6.1)43 (22)74 (37)
 Ischemic stroke15310 (6.5)29 (19)56 (37)
 Ischemic heart disease624 (6.5)9 (15)43 (69)
 Other74731 (4.1)89 (13)173 (23)
Length of immobilization
 < 7 days106243 (4.0)131 (12)281 (26)
 1–4 weeks182081 (4.5)296 (16)583 (32)
 > 4 weeks121777 (6.3)268 (22)168 (14)
 Unknown703 (4.3)15 (21)22 (31)
Sites of immobilization
 Hospital91332 (3.5)163 (18)523 (57)
 Long-term care centers23521 (8.9)64 (27)33 (14)
 Community199986 (4.3)318 (16)253 (13)
 Unknown102265 (6.4)165 (16)245 (24)
Table 3.   Length and sites of immobilization for patients with each reason for immobility*
  N Length of immobilization, n (%)Site of immobilization, n (%)
< 7 days1–4 weeks> 4 weeksHospitalLong-term-care centersCommunity
  1. *Some patients had missing data.

All patients41691062 (25)1820 (44)1217 (29)913 (22)235 (5.6)1999 (48)
Reason for immobilization
 Trauma755176 (23)442 (59)125 (17)64 (8.5)26 (3.4)483 (64)
 Infection651311 (48)307 (47)25 (3.8)276 (42)10 (1.5)210 (32)
 Mental disorders58958 (9.8)119 (20)399 (68)32 (5.4)116 (20)320 (54)
 Lower limb paralysis3006 (2.0)53 (18)236 (79)16 (5.3)21 (7.0)162 (54)
 Arthropathy26754 (20)97 (36)109 (41)6 (2.2)10 (3.7)186 (70)
 Cancer22247 (21)115 (52)55 (25)63 (28)6 (2.7)119 (54)
 Chronic lung disease22564 (28)107 (48)53 (24)66 (29)7 (3.1)72 (32)
 Chronic heart failure19870 (35)90 (45)36 (18)70 (35)2 (1.0)58 (29)
 Ischemic stroke15328 (18)103 (67)19 (12)60 (39)13 (8.5)25 (16)
 Ischemic heart disease6229 (47)29 (47)3 (4.8)38 (61)1 (1.6)5 (8.1)
 Other747219 (29)358 (48)157 (21)222 (30)23 (3.1)359 (48)

The most frequent surgical interventions were: major joint surgery (elective knee arthroplasty, 170 patients; elective hip arthroplasty, 155; hip fracture, 159), other orthopedic surgery (lower limb fracture, 112; meniscal surgery, 92; upper limb fracture, 41; other, 74), and non-cancer abdominal surgery (hernia repair, 88; cholecystectomy, 77; bowel occlusion, 69; appendicectomy, 38; other, 31), as shown in Table 4. Most fatal PE events occurred in patients undergoing surgery for hip fracture (25%) or cancer (22%).

Table 4.   Clinical characteristics, use of venous thromboembolism (VTE) prophylaxis and 90-day outcome in 2212 surgical patients with pulmonary embolism (PE)
  N 90-day fatal PE, n (%)90-day mortality, n (%)VTE prophylaxis, n (%)
All patients221232 (1.4)144 (6.5)1441 (65)
Type of surgery
 Elective hip arthroplasty1551 (0.6)14 (9.0)146 (94)
 Elective knee arthroplasty1702 (1.2)3 (1.8)165 (97)
 Hip fracture1598 (5.0)28 (18)150 (94)
 Other orthopedic surgery3193 (0.9)8 (2.5)237 (74)
 Abdominal surgery3032 (0.7)15 (5.0)187 (62)
 Oncologic surgery2787 (2.5)34 (12)205 (74)
 Genitourinary surgery214010 (4.7)109 (51)
 Brain surgery1685 (3.0)11 (6.5)72 (43)
 Venous surgery7601 (1.3)26 (34)
 Arterial surgery503 (6.0)7 (14)31 (62)
 Other3201 (0.3)13 (4.1)113 (35)
Time from surgery to VTE
 < 7 days4568 (25)34 (24)279 (50)
 1–4 weeks105813 (41)61 (42)679 (64)
 > 4 weeks66611 (34)47 (33)468 (70)
 Unknown3202 (1.4)15 (47)

Among patients without immobilization or surgery, 22% had active cancer, 5.0% were using hormonal therapy, 2.9% had recently traveled, 0.7% were pregnant or postpartum, and 70% had none of the mentioned conditions (idiopathic PE). The 3-month incidence of fatal PE was significantly higher in patients with active cancer (4.4%; 95% CI 3.7–5.3) than in those with idiopathic PE (1.5%; 95% CI 1.2–1.8) or with other risk factors (Table 5).

Table 5.   Clinical characteristics and outcome in 11 647 pulmonary embolism (PE) patients with no recent surgery or immobility
  N Mean age (years ± SD)90-day fatal PE, n (%)90-day mortality, n (%)
  1. *Some patients had more than one risk factor.

All patients11 647*67 ± 17240 (2.1)943 (8.1)
Cancer (%)2605 (22)70 ± 13115 (4.4)574 (22)
Site of cancer
 Lung45465 ± 1222 (4.8)157 (35)
 Breast36071 ± 1311 (3.1)40 (11)
 Colorectal31871 ± 1213 (4.1)52 (16)
 Prostate29577 ± 88 (2.7)28 (9.5)
 Hematologic19071 ± 137 (3.7)23 (12)
 Bladder13675 ± 96 (4.4)23 (17)
 Gastric10667 ± 136 (5.7)34 (32)
 Ovary8764 ± 133 (3.4)26 (30)
 Pancreas8470 ± 128 (9.5)51 (61)
 Uterus7569 ± 143 (4.0)15 (20)
 Kidney6370 ± 123 (4.8)8 (13)
 Cerebral6261 ± 142 (3.2)14 (23)
 Carcinoma of unknown origin4670 ± 149 (20)27 (59)
 Larynx4566 ± 111 (2.2)7 (16)
 Esophagus2765 ± 102 (7.4)8 (30)
 Other25769 ± 1411 (4.3)61 (24)
Estrogen use (%)579 (5.0)37 ± 164 (0.7)10 (1.7)
Pregnancy (%)53 (0.5)31 ± 600
 Puerperium (%)25 (0.2)34 ± 121 (4.0)1 (4.0)
 Recent travel (%)343 (2.9)58 ± 171 (0.3)7 (2.0)
 None of the above (idiopathic) (%)8187 (70)69 ± 17121 (1.5)363 (4.4)

On multivariate analysis, patients with recent immobilization were at an increased risk of dying from PE as compared with the remaining patients (OR 2.2; 95% CI 1.8–2.7), as shown in Table 6. Among patients with recent immobilization, those staying in long-term-care centers were at higher risk of dying from PE than those immobilized in hospital (OR 2.8; 95% CI 1.6–5.0), but there were no significant differences between patients immobilized in hospital and those immobilized in the community (Table 6). The length of immobility had no influence on the risk of fatal PE after multivariate analysis.

Table 6.   Multivariate analyses for fatal pulmonary embolism (PE) in all patients and in those with recent immobilization
 All patients, OR (95% CI)Patients with immobilization, OR (95% CI)
  1. CI, confidence interval; LMWH, low molecular weight heparin; OR, odds ratio; SBP, systolic blood pressure.

Clinical characteristics
 Age > 70 years1.8 (1.5–2.3)1.9 (1.2–2.9)
 Body weight < 70 kg1.5 (1.2–1.8)1.8 (1.2–2.5)
Underlying diseases
 Recent immobility ≥ 4 days2.2 (1.8–2.7)
 Cancer2.6 (2.2–3.2)2.4 (1.7–3.4)
 Abnormal creatinine levels2.1 (1.7–2.6)2.0 (1.4–2.9)
Concomitant therapies
 Antiplatelets1.4 (1.1–1.7)
 Corticosteroids1.8 (1.4–2.4)1.7 (1.1–2.7)
Clinical presentation
 SBP < 100 mmHg2.4 (1.9–3.1)2.4 (1.6–3.5)
Initial therapy
 LMWH0.6 (0.5–0.7)0.5 (0.3–0.8)
 Thrombolytics1.7 (1.02–2.9)
Sites of immobilization
 Hospital1 (Ref.)
 Long-term-care centers2.8 (1.6–5.0)
 Community1.4 (0.95–2.2)
Length of immobilization
 < 7 days1 (Ref.)
 1–4 weeks1.0 (0.6–1.5)
 > 4 weeks1.2 (0.8–1.9)

Discussion

This analysis showed that the risk of dying from PE in patients with recent immobilization was over twice as high as the risk in those without prior immobilization. This higher mortality was consistently found in patients immobilized in hospital or at home, and did not change with the length of immobility. Patients with recent immobilization were older, were more likely to have comorbid diseases and more frequently presented with clinical signs of severity than other patients with PE. This worse outcome persisted after multivariate adjustment. The worse outcome in patients with prior immobilization is an unexpected finding, which might not be explained only by these patients being more ill, because any difference in their baseline characteristics had probably disappeared after multivariate analysis.

Most patients with fatal PE died shortly after arriving at the emergency ward (25% within 24 h; 72% during the first week), allowing a minimal time for effective therapy to be administered. During the first week of treatment, the risk of fatal PE was higher in patients with recent immobilization (77%) or surgery (81%) than in those with neither (67%). After the first week of treatment, the risk of fatal PE decreased in patients with recent immobilization or surgery. Differences in the intensity of anticoagulation did not appear to account for difference in mortality either, as LMWH doses and International Normalized Ratio (INR) results did not differ between subgroups. Thus, we hypothesize that improved treatment would probably have a minimal impact on the number of deaths caused by PE. However, this requires better recognition of at-risk patients and more widespread use of effective prophylaxis. Of course, the prescription of VTE prophylaxis may be associated with an increased risk of bleeding, and a balance should be made between prevention of thrombosis and causing bleeding.

In our series, one in every two patients dying of PE had recent immobilization (43%) or recent surgery (6.7%). Of 476 patients with fatal PE, 43 had recent immobilization for only < 7 days, 86 had been immobilized at home, and 15 had minor trauma (lower limb contusion, 3; sprained ankle, 1). Also, two patients died from PE after an elective knee arthroplasty, one after hip arthroplasty, and seven after cancer surgery. Interestingly, only 25% of PE patients with recent immobilization had received VTE prophylaxis, as compared with 65% of the surgical patients. This finding is consistent with previous reports in other series [10–13], and represents a significant underuse of VTE prophylaxis in patients with immobilization. A number of randomized clinical trials have consistently demonstrated the effectiveness of VTE prophylaxis in both surgical and medical patients [14–17], and current guidelines strongly recommend the use of prophylaxis in surgical and in acutely ill, hospitalized medical patients [18]. However, most acutely ill medical patients do not require hospital admission, and there is no evidence for the benefits of VTE prophylaxis in patients immobilized in the community, as these patients are usually excluded from clinical trials. In our series, only one in every four (23%) immobilized patients who subsequently died from PE had been in hospital: 62% were immobilized in the community, and 15% in long-term-care centers. In these latter subgroups, only 13% had received VTE prophylaxis.

The 2.6% PE-related mortality during the 3-month period and the 10% all-cause mortality that we observed are similar to the rates reported for several study cohorts [19,20], but are higher than those reported in randomized clinical trials [21–23]. We suspect that the higher incidence of fatal PE in the current analysis reflects the enrollment of consecutive unselected patients, including more older patients and patients with multiple comorbid diseases, who are often excluded from randomized trials. Studies that included only patients who were enrolled in randomized clinical trials may not have identified important risk factors, as the full clinical spectrum of disease was not represented.

The present study has several limitations. First, patients were not treated with a standardized anticoagulant regimen; treatment varied with local practice, and is likely to have been influenced by a physician’s assessment of a patient’s risk of bleeding. Second, data were not sufficient to enable us to assess the influence of INR control and type of vitamin K antagonist used on fatal PE. Third, in our study, patients with recent immobilization were older, were more likely to have comorbidities, and presented with more signs of severity. Thus, the different outcome in this study may reflect pre-existing, unrecognized diseases, even after careful exclusions. Hence, despite our efforts to control any bias resulting from underlying diseases, it is likely that we were unable to eliminate such bias completely. Thus, the increased incidence of fatal PE in patients with recent immobilization could have been a chance finding, and requires external validation. Fourth, to fulfill the definition of fatal PE in RIETE, patients must first experience an objectively confirmed PE event, followed by death within 10 days. Thus, all sudden unexplained deaths, which are usually considered as ‘likely’ fatal recurrent PE, are not considered in this analysis, and the rate of fatal PE may be underestimated, especially after hospital discharge. Fifth, although the higher risk of dying from PE in patients with recent immobility suggests that a substantial proportion of PE-related deaths might have been prevented if effective VTE prophylaxis had been prescribed, this suggestion is discordant with a recent meta-analysis showing that, in hospitalized medical patients, heparin prophylaxis had no significant effect on mortality, apart from a weak reduction in PE occurrence [24]. Finally, in RIETE, we cannot distinguish patients who were lost to follow-up from those who are still being followed up, and this may bias the results. The strengths of the current analysis include the facts that a large number of consecutive unselected patients were enrolled and that fatal PE is by far the most important outcome during treatment for acute PE.

In conclusion, our data indicate that PE patients with recent immobilization are at higher risk of dying from PE than those with no immobilization. In our series, 43% of patients who died from PE had recent immobilization. These findings may help in the design of more effective measures to reduce the burden of fatal PE.

Acknowledgements

We thank the Registry Coordinating Center, S & H Medical Science Service, for its quality control, logistic and administrative support, and S. Ortiz, Universidad Autónoma de Madrid and Statistical Advisor S& H Medical Science Service for the statistical analysis of the data presented in this article.

Disclosure of Conflict of Interests

We express our gratitude to Sanofi-Aventis Spain for supporting this Registry with an unrestricted educational grant. We also express our gratitude to Bayer Pharma AG for supporting this Registry. Bayer Pharma AG’s support was limited to the part of RIETE outside Spain, which accounts for 15.22% of the total patients included in RIETE. This project has been partially supported by the Plan Nacional de I+D+I 2008–2011 and the ISCIII-Subdirección General de Evaluación y Fomento de la Investigación (Reference number: PI080902).

Appendices

Appendix

The members of the RIETE group are as follows.

Spain: J. I. Arcelus, M. P. Arcos, A. Ballaz, R. Barba, M. Barrón, B. Barrón-Andrés, A. Blanco-Molina, J. Bosco, E. Chaves, F. Campano, I. Cañas, I. Casado, E. Cisneros, F. Conget, C. Delgado, J. de Miguel, R. del Campo, J. del Toro, C. Falgá, C. Fernández-Capitán, F. Gabriel, P. Gallego, F. García-Bragado, O. Gavín, V. Gómez, J. González, V. Gracia, J. Gutiérrez, L. Hernández, D. Hernández-Huerta, M. J. Jaras, D. Jiménez, S. Jiménez, M. Jiménez-Gil, J. L. Lobo, R. Lecumberri, L. López-Jiménez, A. Lorenzo, J. M. Luque, M. Macià, O. Madridano, A. Maestre, P. J. Marchena, M. Martín, J. J. Martín-Villasclaras, M. Monreal, M. Morales, L. P. Morán, M. D. Nauffal, J. A. Nieto, M. J. Núñez, J. L. Ogea, R. Otero, J. M. Pedrajas, A. Riera-Mestre, M. A. Rodríguez-Dávila, P. Román, B. Román-Bernal, V. Roldán, V. Rosa, C. Royo, J. Ruíz, A. Ruiz-Gamietea, N. Ruiz-Giménez, J. C. Sahuquillo, A. L. Samperiz, R. Sánchez, J. F. Sánchez Muñoz-Torrero, S. Soler, M. J. Soto, G. Tiberio, J. A. Todolí, C. Tolosa, J. Trujillo, F. Uresandi, M. Valdés, R. Valle, J. Vela, G. Vidal, J. Villalta, V. Zorrilla. France: L. Bertoletti, A. Bura-Riviere, P. Debourdeau, I. Mahe, I. Quere. Greece: D. Babalis, M. Papadakis. Israel: B. Brenner. Italy: G. Barillari, M. Ciammaichella, P. Di Micco, F. Dalla Valle, R. Duce, R. Maida, S. Pasca, C. Piovella, R. Poggio, P. Prandoni, R. Quintavalla, L. Rota, A. Schenone. Republic of Macedonia: M. Bosevski. Switzerland: H. Bounameaux. Czech Republic: R. Malý, T. Tomko.

Coordinator of RIETE: M. Monreal (Spain). RIETE Steering Committee Members: H. Decousus (France); P. Prandoni (Italy); B. Brenner (Israel). RIETE National Coordinators: R. Barba (Spain); P. Di Micco (Italy); L. Bertoletti (France); M. Papadakis (Greece); M. Bosevski (Republic of Macedonia); H. Bounameaux (Switzerland); R. Malý (Czech Republic). RIETE Coordinating Center: S & H Medical Science Service.

Ancillary