A prospective study on cardiovascular events after acute pulmonary embolism

Cecilia Becattini1, Giancarlo Agnelli1,*, Paolo Prandoni2, Mauro Silingardi3, Rosamaria Salvi4, Maria Rita Taliani1, Renzo Poggio5, Davide Imberti6, Walter Ageno8, Enrico Pogliani7, Ferdinando Porro9 and Franco Casazza10

1Sezione di Medicina Interna e Cardiovascolare, Dipartimento di Medicina Interna, Università di Perugia, Via Enrico Dal Pozzo, 06126 Perugia, Italy
2Dipartimento di Scienze Mediche e Chirurgiche, Cattedra di Clinica Medica II, Università di Padova, Padua, Italy
3Divisione di Medicina Interna I, Arcispedale S. Maria Nuova, Reggio Emilia, Italy
4U.O. Medicina d'Urgenza, Ospedale di Cattinara, Trieste, Italy
5II Divisione Medicina Generale-Centro Trombosi, Ospedale Galliera, Genoa, Italy
6III Unità Operativa di Medicina Interna, Ospedale di Piacenza, Piacenza, Italy
7Divisione di Ematologia, Dipartimento di Medicina Interna, Università di Milano-Bicocca, Ospedale San Gerardo, Monza, Italy
8Dipartimento di Medicina Interna e Terapia Medica, Università dell'Insubria, Varese, Italy
9Medicina d'Urgenza, Ospedale Maggiore Policlinico, Milan, Italy
10Divisione di Cardiologia, Ospedale San Carlo Borromeo, Milan, Italy

Received April 17, 2004; revised August 4, 2004; accepted September 9, 2004 * Corresponding author. Tel: +39 075 572 2905 or 578 3395; fax: +39 075 573 3642 or 572 2011. E-mail address: agnellig{at}unipg.it

See page 3 for the editorial comment on this article (doi:10.1093/eurheartj/ehi041)


    Abstract
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Acknowledgements
 Appendix
 References
 
Aims To evaluate the incidence of cardiovascular events in the long-term clinical course of patients with a first episode of symptomatic, objectively confirmed pulmonary embolism.

Methods and results Three hundred and sixty patients with a first episode of pulmonary embolism were included in a prospective study: 209 with idiopathic pulmonary embolism and 151 with pulmonary embolism associated with transient risk factors. The study outcomes were cardiovascular events (recurrent venous thrombo-embolism, acute myocardial infarction, stroke, sudden otherwise unexplained death), cardiovascular death, and death due to any cause. The median follow-up was 38 months. Sixty-four patients had at least one cardiovascular event (5.5% patient-year). Recurrent venous thrombo-embolism occurred in 45 patients (3.9% patient-year), acute myocardial infarction in 12 patients (1.0% patient-year), stroke in six patients (0.5% patient-year), and sudden otherwise unexplained death in four patients (0.3% patient-year). A cardiovascular event occurred in 47 patients with idiopathic pulmonary embolism (7.5% patient-year) and in 17 patients with pulmonary embolism associated with transient risk factors (3.1% patient-year) (RR 2.0; 95% CI 1.20–3.34; P=0.006). Twenty patients with idiopathic pulmonary embolism (3.2% patient-year) and two patients with pulmonary embolism associated with transient risk factors (0.4% patient-year) presented an arterial cardiovascular event (RR 7.2; 95% CI 1.71–30.45; P=0.001). Thirty-three patients died (9.2%). Cardiovascular mortality and cancer mortality accounted for 42.4 and 21.2% of overall mortality, respectively. Idiopathic pulmonary embolism was an independent predictor of cardiovascular events after adjusting for age.

Conclusions Cardiovascular events are more common in patients with idiopathic pulmonary embolism than in patients with pulmonary embolism associated with transient risk factors. Cardiovascular events are the major cause of death in patients with idiopathic pulmonary embolism.

Key Words: Pulmonary embolism • Venous thrombo-embolism • Stroke • Acute myocardial infarction • Anticoagulants


    Introduction
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Acknowledgements
 Appendix
 References
 
The long-term clinical course of patients with acute deep vein thrombosis (DVT) has been extensively evaluated,13 while limited information is available about the long-term clinical course of patients with a first episode of acute pulmonary embolism. Although pulmonary embolism and DVT are most commonly seen as a single disease, differences in the long-term clinical outcome of these two clinical manifestations have been observed.4

Currently available information on the long-term clinical course of patients with pulmonary embolism essentially derives from a study with 1 year follow-up.5 Patients with cancer at presentation and patients with previous venous thrombo-embolism were not excluded from this study. In this study, cancer was the most common long-term cause of death.

Idiopathic venous thrombo-embolism and atherosclerosis share a numbers of risk factors including obesity, cigarette smoking, and hypertension.6,7 A recent case–control study reported the association between atherosclerosis and venous thrombo-embolism.8 In this study, the prevalence of asymptomatic carotid plaques was higher in patients with idiopathic venous thrombo-embolism (47.1%) than in patients with venous thrombo-embolism associated with risk factors (27.4%) and in age- and sex-matched controls (32.0%). More recently, increased levels of lipoprotein(a) were shown to be an independent risk factor for idiopathic venous thrombo-embolism.9 Despite the biological plausibility of the association between atherosclerosis and venous thrombo-embolism, no studies have prospectively evaluated the incidence of cardiovascular events after an episode of acute venous thrombo-embolism.

In a prospective study, we evaluated the incidence of cardiovascular events [recurrent venous thrombo-embolism, acute myocardial infarction (AMI), stroke, and sudden otherwise unexplained death], cardiovascular death, and death due to any cause after a first episode of symptomatic, objectively confirmed pulmonary embolism treated with a standard anticoagulant treatment. The study included patients with idiopathic or unprovoked pulmonary embolism and patients with pulmonary embolism associated with transient risk factors.


    Methods
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Acknowledgements
 Appendix
 References
 
Study design
This study was a prospective, multi-centre trial with independent, blinded assessment of the outcome events. The study was aimed at evaluating the incidence of cardiovascular events, cardiovascular death, and death due to any cause in the long-term clinical course of patients with a first episode of symptomatic, objectively confirmed pulmonary embolism treated with a fixed anticoagulant regimen. The study was carried out in 19 Italian study centres.

Selection of patients
Consecutive patients ranging from 18 to 85 years of age with a first episode of symptomatic pulmonary embolism confirmed by pulmonary angiography, spiral computed tomography (CT), high probability lung scan, or by an intermediate probability lung scan associated with objectively diagnosed DVT were considered for inclusion in the study. Patients were included provided that they had completed 3 months of oral anticoagulant therapy without having a recurrence or bleeding. Patients with pulmonary embolism associated with permanent risk factors (known cancer, known thrombophilia) were excluded from the study. Patients were categorized as patients with idiopathic pulmonary embolism if this occurred in the absence of any transient risk factor for venous thrombo-embolism. Patients were categorized as patients with pulmonary embolism associated with transient risk factors if pulmonary embolism occurred after recent trauma with or without bone fracture, recent surgery or childbirth, prolonged immobilization (i.e. lasting more than 7 days), or during the use of oral contraceptives or pregnancy. Systematic screening for occult cancer or thrombophilia was not performed before patients were enrolled in the study. Patients who required prolonged anticoagulant therapy for reasons other than venous thrombo-embolism were excluded from the study, as were patients with major psychiatric disorders, patients with a life expectancy shorter than 2 years, those who could not return for the follow-up visits, and those who declined to participate. The study was approved by the institutional review boards of the participating hospitals; all patients gave informed consent to the study.

The majority of the patients we reported on in this study were included in the Wodit PE trial.10 The aim of that study was to compare the effect of two different durations of anticoagulant treatment on the incidence of recurrent venous thrombo-embolism after a follow-up of at least 1 year after discontinuation of oral anticoagulant treatment. The two anticoagulant regimens were equally effective and safe. In this study, we report the results of an extended prospective follow-up aimed at assessing the incidence of cardiovascular events, including arterial events.

Management strategies and medication
All patients received an initial 3 month period of oral anticoagulation. Patients were then randomized to discontinue anticoagulant treatment or to continue it for an additional 3 months (pulmonary embolism associated with transient risk factors) or for an additional 9 months (idiopathic pulmonary embolism).10 The dose of warfarin or acenocumarol was adjusted to achieve a target international normalized ratio (INR) between 2.0 and 3.0. The therapy was monitored in anticoagulant clinics associated with the study centres.

Follow-up
Patients were instructed to return for follow-up visits at 3, 6, and 12 months from randomization and every 6 months thereafter. Patients were asked to return to the study centre immediately if symptoms developed that were suggestive of recurrent venous thrombo-embolism. For all patients who were readmitted to the hospital during the follow-up period, the cause for hospitalization and the diagnosis at discharge were both obtained.

Definition of clinical end-points
The study outcomes were cardiovascular events (recurrent venous thrombo-embolism, AMI, stroke, and sudden otherwise unexplained death); cardiovascular death and death due to any cause were also evaluated.

The criteria for diagnosis of recurrent pulmonary embolism were a new filling defect revealed by pulmonary angiography or spiral CT or a new high probability perfusion defect revealed by lung scan. The criteria for the diagnosis of DVT as a recurrent venous thrombo-embolism in patients without DVT at baseline were the presence of a non-compressible proximal vein at ultrasonography or an intraluminal filling defect at venography. In patients with DVT at baseline, the criteria for the diagnosis of recurrent DVT were: abnormal results at compression ultrasonography (proximal veins) or venography in the contralateral leg or, in the ipsilateral leg, an extension of an intraluminal filling defect at venography, a newly non-compressible venous segment or a 4 mm or more increase in the diameter of the thrombus (proximal veins) at ultrasonography.11

For adjudication purposes, non-fatal AMI was defined as the presence of two among the following criteria: (i) typical ischaemic chest pain; (ii) elevation of creatinine kinase (CK) enzyme or its MB fraction or troponin; (iii) new ECG changes which include new or persistent ST/T changes, new BBB or new Q-waves in at least two consecutive leads. Ischaemic stroke was defined as the presence of a new focal neurological deficit, lasting more than 24 h. CT scans or nuclear magnetic resonance images were required to exclude the non-ischaemic origin of the neurological event.

Cardiovascular death was defined as any death from pulmonary embolism, AMI, stroke, or sudden otherwise unexplained death. Deaths were classified as cardiovascular or due to cancer or other identifiable cause. For all patients who died during the follow-up period, the date and cause of death were recorded. We attempted to gain permission for autopsies of all patients in whom a pulmonary embolism could not be excluded as the cause of death.

All suspected outcome events (recurrent venous thrombo-embolism, AMI, and stroke) and all deaths were reviewed centrally by an independent external adjudication committee.

Statistical analysis
Duration of follow-up is reported as median and interquartile range (IQR, range from the 25th to the 75th percentile). All analyses were by intention to treat and based on two-sided significance tests with significance level stated at {alpha}=0.05. The cumulative hazard of cardiovascular events was calculated according to the Kaplan–Meier life-table method.12 Rates of outcome events in patients with idiopathic pulmonary embolism or with pulmonary embolism associated with transient risk factors were compared using the log-rank test.13 The distribution of risk factors for cardiovascular events (systemic arterial hypertension, diabetes, smoking, and hyperlipidaemia) was assessed in patients with idiopathic pulmonary embolism or with pulmonary embolism associated with transient risk factors. Age at inclusion in the study, gender, presence of DVT at baseline, nature of pulmonary embolism (idiopathic or associated with transient risk factors), duration of oral anticoagulant treatment, systemic arterial hypertension, diabetes, smoking, hyperlipidaemia, and a newly diagnosed cancer were evaluated in a univariate analysis. A Cox proportional hazard model was used to assess the influence of pre-specified clinical variables on the incidence of cardiovascular events. Baseline variables were considered for inclusion in the multivariable model if they were: (i) associated with high incidence of cardiovascular events at the univariate analyses; or (ii) known risk factors for cardiovascular events. Duration of oral anticoagulant treatment was also included in the multivariable analysis. The proportional hazards assumption was investigated by testing the constancy over time of the log hazard ratio for each model. We assessed the overall model fit using Cox–Snell residuals. Furthermore we tested the proportional hazard assumption for all covariates using Schoenfeld residuals. According to the tests, the proportional hazard assumption was not violated. SPSS version 11.1 was used for all analyses.


    Results
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Acknowledgements
 Appendix
 References
 
Patients
Overall, 360 patients were included in the study, 209 with idiopathic pulmonary embolism and 151 with pulmonary embolism associated with transient risk factors; 173 patients received 3 months of oral anticoagulation and 187 patients received extended oral anticoagulation, which was 1 year in 109 patients with idiopathic pulmonary embolism and 6 months in 78 patients with pulmonary embolism associated with transient risk factors.

The characteristics of patients at study inclusion are shown in Table 1. Patients with idiopathic pulmonary embolism were older than patients with pulmonary embolism associated with transient risk factors (67.0±12.3 vs. 56.2±17.7; P<0.001). Thrombolytic treatment was more commonly used in patients with idiopathic pulmonary embolism than in patients with pulmonary embolism associated with transient risk factors (17.7 vs. 9.2%; P=0.02). DVT was found in 243 patients (68%) at the time of diagnosis of pulmonary embolism. No differences were found for the distribution of common risk factors for cardiovascular events between the two groups of patients except for diabetes. Only 10 patients had diabetes at inclusion in the study (6.5%), and nine of them had idiopathic pulmonary embolism (P=0.02).


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Table 1 Patients' features at inclusion in the study
 
Outcome events
The median duration of the follow-up was 38 months (IQR 22–56). During this period, 64 patients (5.5% patient-year) experienced at least one cardiovascular event (Table 2). One recurrent venous thrombo-embolic event and one ischaemic stroke occurred while patients were on anticoagulant treatment, while all the other cardiovascular events occurred after withdrawal of anticoagulant treatment. Fourteen cardiovascular events (21.9%) were fatal.


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Table 2 Distribution of cardiovascular events in the overall study population and in the two groups of patients: patients with idiopathic pulmonary embolism and patients with pulmonary embolism associated with transient risk factors
 
Forty-five patients presented recurrent venous thrombo-embolism (3.9% patient-year), 12 patients an AMI (1.0% patient-year), six patients a stroke (0.5% patient-year) and four patients a sudden otherwise unexplained death (0.3% patient-year). Twenty-three recurrences of venous thrombo-embolism were pulmonary embolism (51.1%).

A cardiovascular event occurred in 47 patients with idiopathic pulmonary embolism (7.5% patient-year) and in 17 patients with pulmonary embolism associated with transient risk factors (3.1% patient-year) (RR 2.0; 95% CI 1.20–3.34; P=0.006) (Figure 1). Twenty-nine patients with idiopathic pulmonary embolism (4.6% patient-year) experienced a recurrent venous thrombo-embolism as compared with 16 patients with pulmonary embolism associated with transient risk factors (3.0% patient-year) (RR 1.31; 95% CI 0.74–2.32; P=0.35).



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Figure 1 Cumulative hazard of cardiovascular events (recurrence of venous thrombo-embolism, AMI, stroke, and sudden otherwise unexplained death) in patients with idiopathic pulmonary embolism and in patients with pulmonary embolism associated with transient risk factors. The rows running parallel to the time axis report the number of patients at risk in the two groups of patients.

 
None of the patients with pulmonary embolism associated with transient risk factors experienced an AMI while one patient had a stroke and one a sudden otherwise unexplained death. AMI, stroke, or sudden otherwise unexplained death occurred in 12, 5 and 4 patients with idiopathic pulmonary embolism, respectively. Overall, 20 patients with idiopathic pulmonary embolism (3.2% patient-year) and two patients with pulmonary embolism associated with transient risk factors (0.4% patient-year) presented at least one arterial cardiovascular event (AMI, stroke, and sudden otherwise unexplained death) (RR 7.2; 95% CI 1.71–30.45; P=0.001).

During the study period, 33 patients (2.8% patient-year) died (Table 3). In two patients, the cause of death was considered to be recurrent pulmonary embolism: in one of them the diagnosis was confirmed by autopsy. Four patients died due to AMI, four due to stroke, and four had a sudden otherwise unexplained death. Thus, cardiovascular death accounted for 42.4% of the overall mortality. Cancer accounted for 21.2% of the overall mortality (seven patients). Death occurred in 26 patients with idiopathic pulmonary embolism (12.4%) and in seven with pulmonary embolism associated with transient risk factors (4.6%) (RR 2.68; 95% CI 1.20–6.02; P=0.008). Only two patients with pulmonary embolism associated with transient risk factors (1.3%) died due to cardiovascular events compared with 12 patients with idiopathic pulmonary embolism (5.7%) (RR 4.33; 95% CI 0.98–19.09).


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Table 3 Causes of death in the overall population and in the two groups of patients
 
A new cancer was diagnosed in 27 patients (2.3% patient-year) during the follow-up period: 19 patients with idiopathic pulmonary embolism (2.8% patient-year) and eight patients with pulmonary embolism associated with transient risk factors (1.6% patient-year) (RR 1.72; 95% CI 0.77–3.82).

Predictors of cardiovascular events
Age over 60 years, idiopathic pulmonary embolism, and a new diagnosis of cancer were associated with an increased risk of cardiovascular events by univariate analysis while gender, the presence of systemic arterial hypertension, diabetes, smoking, hyperlipidaemia, the presence of DVT, and a shorter period of anticoagulant treatment (3 months) were not associated with an increased risk of cardiovascular events. The idiopathic nature of index pulmonary embolism remained an independent predictor of cardiovascular events after adjusting for age (Table 4).


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Table 4 Multivariable Cox regression analysis of potential predictors of cardiovascular events (recurrent venous thrombo-embolism, AMI, stroke, and sudden unexplained death) after adjusting for age
 

    Discussion
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Acknowledgements
 Appendix
 References
 
Patients with a first episode of pulmonary embolism have a high incidence of both venous and arterial events in the 3 years after the index episode. Cardiovascular events are more common in patients with idiopathic pulmonary embolism than in patients with pulmonary embolism associated with transient risk factors as is also the case for arterial events.

In our study, cardiovascular events were the most common cause of death in patients with pulmonary embolism. These results differ from those of the only other previous study on the long-term clinical course of pulmonary embolism, where cancer was the main cause of death.5 However, patients with known cancer were excluded from our study while they represented 18% of the patients in the previous study.

An original finding of our study is the high incidence of arterial events in patients with idiopathic pulmonary embolism. This observation is in keeping with recent findings of a high incidence of atherosclerotic lesions in patients with idiopathic DVT8 and is biologically plausible, given the common risk factors for arterial and venous diseases. It is difficult to define whether the incidence of arterial events we observed in patients with idiopathic pulmonary embolism is higher than that expected in a matched population without pulmonary embolism. A potential limitation of the study is that it did not include a control group. However, this incidence seems to be higher than that observed in untreated patients of similar age with at least one risk factor for cardiovascular diseases.14

Patients with idiopathic pulmonary embolism were older than patients with pulmonary embolism associated with transient risk factors. However, the idiopathic nature of pulmonary embolism was an independent risk factor for cardiovascular events after adjustment for age.

The large majority of cardiovascular events occur after the discontinuation of treatment with oral anticoagulants, thus confirming the results of previous studies.10,1518 This finding suggests that patients with pulmonary embolism could benefit from an extended anti-thrombotic treatment given beyond the recommended period of oral anticoagulant treatment. This is particularly the case in patients with idiopathic pulmonary embolism. However, long-term oral anticoagulant treatment is associated with an increased risk of bleeding complications and is inconvenient as it must be monitored.19 The high incidence of arterial events in patients with idiopathic pulmonary embolism may influence future research on the optimal long-term management of venous thrombo-embolism. Anticoagulant agents active on both coagulation and platelet aggregation, such as the anti-thrombin agents, could be preferred. Furthermore, the observed high incidence of arterial events could open the case on the clinical value of anti-platelet agents after initial oral anticoagulant treatment.

In this study, ~50% of the recurrences of venous thrombo-embolism occurred as a second episode of pulmonary embolism. In contrast, in patients presenting with DVT, only 18% of the recurrences of venous thrombo-embolism were pulmonary embolism.17

Thrombolysis was used more commonly in patients affected by idiopathic pulmonary embolism than in patients with pulmonary embolism associated with transient risk factors including surgery and trauma. In these patients, the fear of bleeding complications probably reduced the use of thrombolysis. We did not find an association between administration of thrombolysis and cardiovascular events. However, only a minority of the patients included in our study received thrombolysis (14%). Previous studies on the long-term course of patients with pulmonary embolism who received thrombolysis showed a low incidence of cardiovascular events.20,21 However, none of these studies specifically assessed the incidence of cardiovascular events, thus whether thrombolytic treatment could reduce the incidence of cardiovascular events is still undefined.

In conclusion, patients with a first episode of idiopathic pulmonary embolism have a substantial risk of cardiovascular events, particularly a second pulmonary embolism, after discontinuation of oral anticoagulant therapy. In these patients, cardiovascular events are by far the most common cause of death. Patients with idiopathic pulmonary embolism are at risk for arterial events. Hence, future trials on the long-term management of venous thrombo-embolism should also consider arterial cardiovascular events.


    Acknowledgements
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Acknowledgements
 Appendix
 References
 
This study was presented in part at the 21st Congress of the International Society of Thrombosis and Haemostasis, Birmingham, 15 July 2003. We are indebted to Eva Tikotin for her editorial assistance and to the nursing and laboratory staff of the participating centres for their enthusiastic co-operation; and to the patients included in the study for their trust and support. This study was performed without any external financial support.


    Appendix
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 Acknowledgements
 Appendix
 References
 
List of participating centres: Divisione di Chirurgia Vascolare, Ospedale S. Chiara, Trento (A. Bertoldi); Divisione di Medicina, Ospedale Civile, Bolzano (C. Tomasi); Divisione di Cardiologia, Ospedale S. Maria della Misericordia, Rovigo (P. Zonzin, S. Aggio, K. D'Elia); Emostasi ed Angiologia Medica, Ospedale Sacro Cuore di Gesù, Gallipoli (L. Ria); Centro Emofilia e Trombosi, IRCCS Ospedale Maggiore, Milan (M. Moia); Divisione Medica I, Ospedale S. Giovanni e Paolo, Venice (G.B. Ambrosio, R. Parisi); IRCCS Policlinico San Matteo, Università di Pavia, Pavia (F. Piovella); Patologia Generale ed Oncologica, Università di Napoli, Naples (D. De Lucia); Università di Firenze, Azienda Ospedaliera Careggi, Florence (F. Pieralli); Dipartimento di Scienze Mediche e Chirurgiche, Cattedra di Clinica Medica II, Università di Padova, Padua (P. Bagatella); Medicina d'Urgenza, Ospedale Maggiore, Trieste (M. Miccio); Divisione di Ematologia, Dipartimento di Medicina Interna, Università di Milano-Bicocca, Ospedale San Gerardo, Monza (A. Carrer); II Divisione Medicina Generale—Centro Trombosi, Ospedale Galliera, Genoa (A. Schenone, P.A. Pittaluga); Divisione di Cardiologia, Ospedale San Carlo Borromeo, Milan (A. Bongarzoni); Dipartimento di Medicina Interna e Terapia Medica, Università dell'Insubria, Varese (L. Steidl, A. Squizzato).


    References
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 Acknowledgements
 Appendix
 References
 

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