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* From the Servicio de Neumología (Drs. Lobo and Zorilla) and Unidad de Investigación (Dr. Aizpuru), Hospital de Txagorritxu, Vitoria; Servicio de Neumología (Dr. Uresandi), Hospital de Cruces, Bilbao; Servicio de Medicina Interna (Dr. Garcia-Bragado), Hospital de Girona Dr. Josep Trueta, Girona; Servicio de Neumología (Dr. Conget), Hospital Clínico de Zaragoza, Zaragoza; and Servicio de Medicina Interna (Dr. Monreal), Hospital Universitari Germans Trias i Pujol, Badalona, Spain.
A complete list of RIETE investigators is given in the Appendix.
Correspondence to: Manuel Monreal, PhD, Servicio de Medicina Interna, Hospital Universitari Germans Trias i Pujol, 08916 Badalona (Barcelona), Spain; e-mail: mmonreal.germanstrias{at}gencat.net
Abstract
Introduction: The influence of the clinical syndromes of pulmonary embolism (PE) on clinical outcome has not been evaluated.
Patients and methods: The Registro Informatizado de la Enfermedad TromboEmbólica (RIETE) is an ongoing registry of consecutive patients with acute venous thromboembolism. In this study, all enrolled patients with acute PE without preexisting cardiac or pulmonary disease were classified into three clinical syndromes: pulmonary infarction, isolated dyspnea, or circulatory collapse. Their clinical characteristics, laboratory findings, and 3-month outcomes were compared.
Results: As of January 2005, 4,145 patients with acute, symptomatic, objectively confirmed PE have been enrolled in RIETE. Of them, 3,391 patients (82%) had no chronic lung disease or heart failure: 1,709 patients (50%) had pulmonary infarction, 1,083 patients (32%) had isolated dyspnea, and 599 patients (18%) had circulatory collapse. Overall, 149 patients (4.4%) died during the first 15 days of therapy: 2.5% with pulmonary infarction, 6.2% with isolated dyspnea (odds ratio [OR], 2.6; 95% confidence interval [CI], 1.7 to 3.8), and 6.5% with circulatory collapse (OR, 2.7; 95% CI, 1.7 to 4.2). From days 16 to 90, 31 patients had recurrent PE; 5 of 14 patients (36%) with pulmonary infarction died of their new PE, compared with 5 of 10 patients (50%) with isolated dyspnea, and all 7 patients (100%) with circulatory collapse.
Conclusions: PE patients with pulmonary infarction (50% of the whole series) had a significantly lower mortality rate both during initial therapy and after discharge.
Key Words: clinical syndromes • outcome • pulmonary embolism
Traditionally, the initial symptoms of pulmonary embolism (PE) in patients without underlying cardiopulmonary diseases have been grouped into three manifesting syndromes: pulmonary infarction, isolated dyspnea, and circulatory collapse.123 Patients with pulmonary infarction syndrome usually present with pleuritic pain and/or hemoptysis, and have the lowest severity as assessed by pulmonary angiography, which usually shows the emboli to be peripheral rather than central.3456 By contrast, those with isolated dyspnea are usually hypoxic, and thrombus is more likely to be central, while patients with circulatory collapse present with hypotension and/or syncope and have the most extensive vascular occlusion. However, the influence of these clinical syndromes on clinical outcome has not been evaluated.
The Registro Informatizado de la Enfermedad TromboEmbólica (RIETE) was initiated in March 2001 to record current clinical management of venous thromboembolism (VTE). RIETE is a multicenter, observational registry designed to gather and analyze data on treatment patterns and clinical outcome in consecutive patients with symptomatic, objectively confirmed, acute deep vein thrombosis (DVT) or PE.789101112 In this analysis, the clinical characteristics, laboratory findings, and 3-month outcomes of all enrolled patients with acute PE without underlying cardiopulmonary diseases were compared to determine whether these clinical syndromes are associated with clinical outcome.
Materials and Methods
Inclusion and Exclusion Criteria
Patients with symptomatic, acute DVT or PE confirmed by objective tests (ie, contrast venography, ultrasonography, or impedance plethysmography for suspected DVT; pulmonary angiography, lung scintigraphy, or helical CT scan for suspected PE) were consecutively enrolled in RIETE. Patients were excluded if they were participating in a therapeutic clinical trial or were unavailable for follow-up. All patients provided oral consent to their participation in the registry, in accordance with the requirements of the ethics committee within each hospital. For this analysis, only patients with PE and no coexisting chronic lung disease or chronic heart failure were considered.
Definitions
All patients had acute respiratory symptoms suggesting PE. The diagnosis was considered definitive if patients also had positive helical CT-scan results, high-probability ventilation/perfusion (
/
) lung scan results, positive pulmonary angiography findings, visualization of thrombus on the echocardiography, or indeterminate-probability lung scan results plus objective evidence of DVT in the lower limbs (by either compression ultrasonography or contrast venography).
For this analysis, PE patients were classified into three groups: pulmonary infarction (defined as patients with pleuritic pain or hemoptysis), isolated dyspnea (defined as dyspnea in the absence of hemoptysis, pleuritic pain, or circulatory collapse), or circulatory collapse (defined as loss of consciousness or systolic BP < 90 mm Hg), according to the criteria by Stein et al.1
Study Parameters
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; risk factors; clinical characteristics of the PE event; laboratory findings including data on the ECG, chest radiograph, echocardiogram, arterial blood gases, and other diagnostic tests; treatment received on PE diagnosis; and clinical outcome during the first 3 months of therapy. Data were obtained from medical records and recorded on case report forms by a study coordinator. Coexisting medical conditions or comorbidities were specified according to a prespecified list.
Follow-up
All patients were followed up for at least 3 months after hospital discharge. During each visit, any signs or symptoms suggesting recurrences of DVT or PE, or bleeding complications were noted. Each episode of clinically suspected recurrent DVT or PE was documented by repeat compression ultrasonography, venography, lung scanning, helical CT scan, or pulmonary angiography. Only confirmed recurrent events were accepted by the Adjudication Committee. Fatal PE was defined as death shortly after PE diagnosis and 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 (20 g/L), required a blood transfusion 2 U, or were retroperitoneal or intracranial.
Data Collection
Data were recorded on a computer-based case report form by a RIETE registry coordinator at each participating hospital and were submitted to a centralized coordinating center through a secure Web site. 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 end points 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 Web site, 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
Clinical characteristics, laboratory data, and outcomes during the first 3 months of PE patients with the different clinical syndromes were compared. A commercial software package (SPSS version 11.5; SPSS; Chicago, IL) was used to calculate odds ratios (ORs) and corresponding 95% confidence intervals (CIs), and a p value < 0.05 was considered to be statistically significant.
Results
As of January 2005, 4,145 patients with acute, symptomatic, objectively confirmed PE were enrolled in RIETE. Of them, 3,391 patients (82%) had no chronic lung disease or heart failure: 1,709 patients (50%) had pulmonary infarction, 1,083 patients (32%) had isolated dyspnea, and 599 patients (18%) had circulatory collapse. PE diagnosis was confirmed in 1,965 patients with positive CT scan results, 1,402 patients with high-probability / lung scan results, 12 patients with visualization of a thrombus on the echocardiogram, and 12 patients with an intermediate-probability lung scan result plus evidence of DVT in the lower limbs.
Compared to patients with pulmonary infarction, those with isolated dyspnea were significantly older, more commonly female, and had cancer, recent immobility for 4 days, abnormal creatinine levels, or used nonsteroidal antiinflammatory drugs more often (Table 1
). However, they had recent surgery less often. As for their clinical presentation, they had more often tachycardia, hypoxemia, ECG abnormalities, and cardiomegaly or vascular redistribution signs on chest radiography (Table 2
). Patients with circulatory collapse were also older than those with pulmonary infarction, more commonly female, and had immobility or abnormal creatinine levels more often, but recent surgery was less common. They presented more often with tachycardia, hypoxemia, ECG abnormalities, and cardiomegaly on chest radiography. By contrast, patients with pulmonary infarction had significantly more often pleural effusion, atelectasis, and pulmonary infiltrates on chest radiography (Table 2).
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The incidence of PE recurrences from days 16 to 90 was similar in the three groups: 0.8%, 0.9%, and 1.2%, respectively. However, the clinical relevance was different: 5 of 14 patients (36%) with pulmonary infarction died shortly (< 5 days) after the new PE, compared with 5 of 10 patients (50%) with isolated dyspnea, and all 7 patients (100%) with circulatory collapse. There were no differences in the rate of major bleeding complications. Finally, the 7.7% overall mortality from days 16 to 90 in patients with isolated dyspnea also was significantly higher than the 3.8% overall mortality in those with pulmonary infarction, or the 4.0% overall mortality in those with circulatory collapse (Table 3).
Discussion
Our data, obtained from a large prospective series of consecutive patients with acute, symptomatic PE, confirm that their clinical presentation on hospital admission may have prognostic value. Indeed, the 6.2% and 6.5% mortality rates during the first 15 days of therapy in patients who presented with isolated dyspnea or circulatory collapse, respectively, clearly outweighed the 2.5% mortality rate in those with pulmonary infarction, who represented 50% of the whole series. These differences may at least in part be explained because they are younger, have underlying diseases less often, and have a less severe clinical presentation, but adjustment for other important prognostic indicators confirmed the independent role of the clinical syndrome in the outcome.
Moreover, we found the initial clinical presentation also to be associated with the clinical severity of the PE recurrences later on. There were no differences among groups in the frequency of recurrent symptomatic PE from days 16 to 90, but when occurring the death rate greatly differed: 36% of patients with pulmonary infarction died after the new PE, compared to 50% in those with isolated dyspnea, and 100% with circulatory collapse. Most of these patients died shortly after symptom onset, allowing minimal time for effective therapy to be administered, probably because they were sicker and more likely to die from recurrence. These findings may be considered as hypothesis generating; perhaps these patients should receive longer injected anticoagulant therapy, or longer hospitalization, or maybe closer follow-up with repeated imaging to examine for clot improvement. Hence, while improved treatment might have a minimal impact on the number of deaths, more effective prevention of recurrent PE would represent the greatest opportunity to prevent fatal recurrent PE.
Identifying clinical characteristics that put PE patients at increased risk of death is important if their outcomes are to be improved. So far, two models for risk stratification have been proposed.1314151617 However, none of them identifies the cause of death. Our most striking finding was that the classification of PE patients according to their clinical syndromes may identify those at an increased risk to die of PE (either the initial episode or a new PE). In our series, the recurrence rate was similar in all three groups, but since the mortality of the new PEs varied according to the initial presentation, we hypothesize that the dosage and the duration of therapy might be tailored accordingly.
The RIETE provides insights into the natural history of PE with an unselected patient population, in contrast to the rigorously controlled conditions of randomized clinical studies. It can, therefore, help to identify factors associated with better or worse patient outcomes, and provide feedback from real-world clinical situations, which may be valuable when designing new randomized clinical studies. Selection bias was avoided by including consecutive patients with objectively confirmed, symptomatic, acute PE who were referred to study centers. Objective criteria were strictly applied for the diagnosis of initial and recurrent PE, including pulmonary angiography if indicated. The main limitation of the present study lies on the likely underestimated incidence of fatal PE after discharge. Certainly, the death of some PE patients after discharge may have been due to PE, but these would not have been included, as the Adjudication Committee only accepts PE events that have been objectively confirmed. Another limitation is that in clinical practice, PE may present with an enormous variety of clinical findings, thus making it hard to categorize patients as belonging to one or the other of the predefined clinical syndromes. Finally, patients with circulatory collapse in our series had a rather good prognosis (fatal PE, 4.3%, vs 1.3% and 3.3% for the infarction and dyspnea groups, respectively) compared to the studies of Stein et al.123 This may be explained by the fact that only 19% of patients in the circulatory collapse group had a systolic BP < 90 mm Hg, syncope being the only inclusion criterion for 81% of patients in this group. And the definition of syncope may have been vague, so that any malaise could have been reported as a syncope.
In summary, significant differences exist in clinical outcomes of PE patients without underlying cardiopulmonary diseases according to their initial clinical presentation. These data may help identify which patients may benefit most from more effective or longer therapy.
Appendix
Members of the RIETE Group
Spain: Arcelus J.I.; Barba R.; Barrón M.; Beato J.L.; Blanco A.; Bugés J.; Cabezudo M.A.; Casado I.; Conget F.; De las Heras G.; Falgá C.; Fernández-Capitán C.; Gallego P.; García-Bargado F.; Grau E.; Guijarro R.; Guil M.; Gutiérrez J.; Hernández L.; Jiménez D.; Laserna E.; Lecumberri R.; Lobo J.L..; López F.; López L.; López I.; Maestre A.; Martín J.J.; Monreal M.; Montes J.; Naufall M.D.; Nieto J.A.; Núñez M.J.; Orue M.T.; Otero R.; Pedrajas J.M.; Portillo J.; Rabuñal R.; Raguer E.; Raventós A.; Román P.; Romero C.; Rosa V. Ruiz-Giménez N.; Sampériz A.L.; Sánchez R.; Sánchez J.F.; Soler S.; Soto M.J.; Tiberio G.; Tirado R.; Toda M.R.; Todolí J.A.; Tolosa C.; Trujillo J.; Uresandi F.; Valle R.; Vasco B.; and Llobet X (Medical Department, Sanofi-Aventis); France: Mismetti P.; Rivron-Guillot K.; Argentina: Bottaro F; Adjudication Committee: Monreal M.; Barba R.; Uresandi F.
Acknowledgements
We express our gratitude to the Registry Coordinating Center, S & H Medical Science Service, for their logistic and administrative support.
Footnotes
Abbreviations: CI = confidence interval; DVT = deep vein thrombosis; LMWH = low-molecular-weight heparin; OR = odds ratio; PE = pulmonary embolism; RIETE = Registro Informatizado de la Enfermedad TromboEmbólica; / = ventilation/perfusion; VTE = venous thromboembolism
This project has been partially supported by Red Respira, Instituto Carlos III (RedRespira-ISCiii-RTIC-03/11).
RIETE was supported by an unrestricted educational grant from Sanofi-Aventis.
Drs. Lobo, Zorrilla, Aizpuru, Uresandi, Conget, Garcia-Bragado, and Monreal have reported to the ACCP that no significant conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.
Received for publication April 3, 2006. Accepted for publication June 1, 2006.
References
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