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Original Investigation |

Symptomatic Pulmonary Embolism and the Risk of Recurrent Venous Thromboembolism FREE

Sabine Eichinger, MD; Ansgar Weltermann, MD; Erich Minar, MD; Milena Stain, MD; Verena Schönauer, MD; Barbara Schneider, PHD; Paul Alexander Kyrle, MD
[+] Author Affiliations

From the Division of Hematology and Hemostasis, Department of Internal Medicine I (Drs Eichinger, Weltermann, Stain, Schönauer, and Kyrle), Division of Angiology, Department of Internal Medicine II (Dr Minar), and Institute of Medical Statistics (Dr Schneider), University of Vienna, Vienna, Austria; and Ludwig-Boltzmann Institute for Thrombosis Research, Vienna (Dr Kyrle). The authors have no relevant financial interest in this article.


Arch Intern Med. 2004;164(1):92-96. doi:10.1001/archinte.164.1.92.
Text Size: A A A
Published online

Background  In patients with a first symptomatic pulmonary embolism (PE), the risk of recurrence is unknown. We therefore investigated the risk of recurrence among patients with spontaneous symptomatic PE and among those with deep vein thrombosis (DVT) without symptoms of PE.

Methods  After discontinuation of secondary thromboprophylaxis for a first venous thromboembolism (VTE), we prospectively observed 436 patients for an average of 30 months. Patients with secondary VTE, natural inhibitor deficiencies, lupus anticoagulant, cancer, long-term antithrombotic therapy, vena cava filters, or pregnancy were excluded. The study outcome was objectively documented recurrent symptomatic VTE.

Results  Recurrent VTE was seen among 28 (17.3%) of 162 patients with symptomatic PE and among 26 (9.5%) of 274 patients with DVT without symptoms of PE. Compared with patients with DVT, the relative risk of recurrent VTE among patients with symptomatic PE was 2.2 (95% confidence interval, 1.3-3.7; P = .005). The relative risk was not affected by age, sex, presence of factor V Leiden or prothrombin G20210A, hyperhomocysteinemia, or high factor VIII levels. Compared with patients with DVT without symptoms of PE, patients with symptomatic PE had an adjusted relative risk of PE at recurrence of 4.0 (95% confidence interval, 1.3-12.3; P = .03).

Conclusion  Patients with a first symptomatic PE not only have a higher risk of recurrent VTE than those with DVT without symptoms of PE, but are also at high risk of symptomatic PE at recurrence.

Figures in this Article

Pulmonary embolism (PE) is a frequent and potentially fatal disease with an incidence of 1 in 1000 persons per year.13 Approximately 10% of the patients die of heart failure and cardiac shock within hours.4 Twenty-five percent of the patients do not survive the first year,5,6 but many deaths during this time are related to underlying conditions, such as cancer or chronic heart disease, rather than to recurrent PE.7,8 The prognosis of patients with PE without a predisposing illness might be more favorable, but the risk of recurrent venous thromboembolism (VTE) among these patients has never been investigated, to our knowledge.

Recurrent VTE can be prevented by treatment with oral anticoagulants.9,10 Since these drugs may cause bleeding,1113 determining the optimal duration of anticoagulation entails balancing the risk of hemorrhage against the risk of recurrence. Pulmonary embolism is regarded as the consequence of deep vein thrombosis (DVT) rather than a separate clinical entity. Most trials on the risk of recurrent VTE therefore did not distinguish between patients with DVT and those with PE.9,10,14,15 Since the risk of recurrence is thus unknown in patients with PE, the decision as to how long these patients should receive anticoagulation is subject to individual preference rather than objective guidelines.

We observed 436 patients with a first spontaneous VTE and compared the risk of recurrence between patients with symptomatic PE and those with DVT without symptoms of PE.

PATIENT POPULATION

Between July 1, 1992, and June 30, 2002, 1056 consecutive patients (older than 18 years) with DVT of the leg and/or PE, who had been treated with oral anticoagulants for at least 3 months, were eligible. A total of 592 patients were excluded because of surgery, trauma, or pregnancy within the previous 3 months; previously recurrent VTE; deficiency of antithrombin, protein C, or protein S; presence of the lupus anticoagulant; cancer; requirement for long-term antithrombotic treatment; or a vena cava filter. All patients had been treated with unfractionated or low-molecular-weight heparin in therapeutic dosages. Twenty-one patients with PE had received thrombolytic therapy.

Patients entered the study at the time of discontinuation of oral anticoagulants and were then seen at 3-month intervals during the first year and every 6 months thereafter. They received written information on the symptoms of VTE and were instructed to report if such symptoms occurred.

The study was approved by the ethics committee of the Vienna University Hospital, Vienna, Austria, and all patients provided written informed consent before inclusion.

DIAGNOSIS OF VTE

The diagnosis of DVT was established by a positive finding on venography or color duplex sonography (in case of proximal DVT). To be considered positive, the venograms had to meet at least 1 of the following direct or indirect criteria: a constant filling defect seen on 2 views; an abrupt discontinuation of the contrast-filled vessel at a constant level of the vein; and the absence of filling in the entire deep vein system (without compression), with or without venous flow through collateral veins. With color duplex ultrasonography, at least 1 of the 2 following criteria for DVT had to be met: visualization of an intraluminal thrombus in a deep vein and incomplete compressibility or absence of compressibility.

A diagnosis of PE was considered if the patient had typical symptoms (chest pain, dyspnea, cough, hemoptysis, and/or syncope). The diagnosis of PE was then confirmed either by a positive finding on ventilation-perfusion scanning according to the criteria of the Prospective Investigation of Pulmonary Embolism Diagnosis16 or by spiral computed tomography demonstrating 1 or several low-attenuation areas that partly or completely filled the lumen of an opacified vessel.

STUDY END POINTS

The end point of the study was recurrent symptomatic DVT confirmed by venography or color duplex sonography (in case of proximal DVT of the contralateral leg) or recurrent symptomatic PE confirmed by ventilation-perfusion scanning and/or spiral computed tomography according to the aforementioned criteria. The DVT was considered to have recurred if the patient had a thrombus in the leg opposite from that affected by the previous thromboembolic event; a thrombus in another deep vein in the same leg as the previous event; or a thrombus in the same venous system as the previous event, with proximal extension of the thrombus (if the upper limit of the original thrombus had been visible) or with a constant filling defect surrounded by contrast medium (if the original thrombus had not been visible). The diagnosis was established by an adjudication committee consisting of independent clinicians and radiologists.

LABORATORY ANALYSIS

Blood was collected, after fasting, into 1:10 volume of 0.11mM trisodium citrate and immediately centrifuged for 20 minutes at 2000g. The plasma was stored at −80°C. Genomic DNA was isolated from leukocytes by standard methods.

Screening for factor V Leiden and for prothrombin G20210A was carried out as described.17,18 Determination of antithrombin, protein C, protein S, total homocysteine, and factor VIII was performed as previously reported.19 The diagnosis of a lupus anticoagulant was based on the criteria of the International Society of Thrombosis and Haemostasis.20 The technicians were unaware of the patient characteristics at all times.

STATISTICAL ANALYSIS

Times to recurrence (uncensored observations) or follow-up times in patients without recurrence (censored observations) were analyzed by survival time methods.21 The probability of recurrence was estimated according to Kaplan-Meier.22 To test for homogeneity between strata, we applied the log-rank and the generalized Wilcoxon test. The data were adjusted for age, sex, factor V Leiden, prothrombin G20210A, hyperhomocysteinemia (dichotomized at the 95th percentile of the reference range), and high factor VIII level (dichotomized at a plasma level of 234%). Categorical data were checked for homogeneity by means of contingency table analyses (χ2 test). Simple descriptive statistics were computed to provide a clear presentation of the data. For numerical operations, an SAS software package (SAS Institute Inc, Cary, NC) was used. Values are given as mean ± SD.

Of 464 patients, 162 patients had PE and 302 patients had DVT. Symptoms of PE were chest pain in 104 patients (64%), dyspnea in 116 patients (72%), cough or hemoptysis in 37 patients (23%), and syncope in 27 patients (17%). Twenty-eight patients with DVT were excluded because they had symptoms of PE but objective testing was not performed. The characteristics of the remaining 436 study patients (274 with DVT without symptoms of PE and 162 with symptomatic PE) are shown in Table 1. There was no significant difference between patients with symptomatic PE and patients with DVT without symptoms of PE with regard to age, sex distribution, the presence of factor V Leiden or prothrombin G20210A, hyperhomocysteinemia, or high factor VIII level. Patients with symptomatic PE had a shorter observation time and received anticoagulants significantly longer than patients with DVT.

Table Graphic Jump LocationTable 1. Baseline Characteristics of the 436 Patients

One hundred twenty-three patients left the study. Seven did so because they were given a diagnosis of cancer and 82 because they required antithrombotic therapy for reasons other than VTE. Twenty-eight patients (6%) were lost to follow-up. Six patients died, but recurrent VTE was the cause of death in none of them. The patients' data were censored at the time of exclusion or death.

Recurrent VTE (39 DVT without symptoms of PE, 15 symptomatic PE) occurred in 54 patients (12.4%). Thirty-nine patients with recurrence were male and 15 patients were female. The proportion of patients with high factor VIII levels was higher among patients with recurrence than among patients without recurrence (11 patients [20%] and 37 patients [9%], respectively; P = .01). There was no significant difference between patients with and without recurrence with regard to age (50 ± 16 years and 47 ± 18 years, respectively), the presence of factor V Leiden (16 patients [30%] and 135 patients [33%], respectively) or prothrombin G20210A (9 patients [17%] and 37 patients [9%], respectively), or the proportion of patients with hyperhomocysteinemia (16 patients [30%] and 107 patients [26%], respectively). In none of the patients was the episode of recurrent VTE fatal.

Recurrent VTE occurred in 28 (17.3%) of the 162 patients with symptomatic PE and in 26 (9.5%) of the 274 patients with DVT without symptoms of PE. A Kaplan-Meier analysis showed a significant divergence between the rate of recurrence among patients with symptomatic PE and among patients with DVT without symptoms of PE (Figure 1). At 24 months, the likelihood of recurrence was 19% (95% confidence interval, 12%-26%) among patients with symptomatic PE compared with 7% (95% confidence interval, 3%-11%) among patients with DVT (P = .004). A first symptomatic PE conferred a relative risk of recurrence of 2.2 (95% confidence interval, 1.3-3.7; P = .005) (Table 2) and remained an independent risk factor for recurrence after adjustment for age, sex, the presence of factor V Leiden or prothrombin G20210A, hyperhomocysteinemia, or high factor VIII level (relative risk, 2.2; 95% confidence interval, 1.3-3.7; P = .005).

Place holder to copy figure label and caption

Kaplan-Meier estimates of the risk of recurrent venous thromboembolism in patients with symptomatic pulmonary embolism (PE) or deep vein thrombosis (DVT) without symptoms of PE.

Graphic Jump Location
Table Graphic Jump LocationTable 2. Relative Risk of Recurrent Venous Thromboembolism

Patients with symptomatic PE had a high risk of a subsequent symptomatic PE. Compared with patients with DVT without symptoms of PE, the relative risk of PE at recurrence among patients with a first symptomatic PE was 4.0 (95% confidence interval, 1.3-12.3; P = .03) after adjustment for other potentially confounding thrombotic risk factors.

Our prospective study demonstrates that the risk of recurrent VTE is significantly higher among patients with symptomatic PE than among patients with DVT without symptoms of PE. In a prospective study of 436 patients, the risk of recurrence was more than twice as great among patients with a first spontaneous symptomatic PE as among those with DVT without symptoms of PE. Most important, patients with symptomatic PE had a 4-fold higher risk of symptomatic PE at recurrence than patients with DVT.

Our findings are in agreement with those of the Columbus Investigators, who compared the efficacy of low-molecular-weight and unfractionated heparin in patients with VTE.23 At 3 months, the rate of recurrence was higher among patients with PE (5.9%) than among patients with DVT (4.8%). That study, however, was neither intended nor powered to compare the rate of recurrence between patients with PE and DVT.

The observation of a high risk of PE at recurrence among patients with an incident symptomatic PE corroborates findings of 2 recent studies. In a meta-analysis, Douketis and coworkers24 found a higher rate of fatal recurrent PE in patients with PE (1.4%) than the rate of a fatal first PE after treatment for DVT (0.3%). In a retrospective cohort study, the initial clinical manifestation of VTE strongly predicted the same clinical presentation among patients rehospitalized for recurrent thromboembolism.25 Among patients with PE who developed recurrence, 70% were diagnosed as having PE and 30% were diagnosed as having venous thrombosis alone, whereas among patients with venous thrombosis and recurrence, only 15% were diagnosed as having PE and 85% had venous thrombosis.

The different rates of recurrence among patients with symptomatic PE and those with DVT without symptoms of PE do not result from an incidentally unbalanced distribution of thrombotic risk factors among the 2 groups. We have excluded patients with potent risk factors for recurrence, such as previous thrombosis, cancer, or the lupus anticoagulant, as well as low-risk patients with thrombosis related to surgery, trauma, or pregnancy. We excluded neither patients with high factor VIII level, who have a high risk of recurrence,19 nor carriers of factor V Leiden or prothrombin G20210A, in whom we reported a risk of recurrence similar to that in noncarriers of these mutations.26,27 However, the proportion of patients with either of these risk factors was not significantly different between patients with symptomatic PE and patients with DVT without symptoms of PE. Also, symptomatic PE remained an independent risk factor for recurrent VTE after adjustment for these risk factors in the multivariate analysis.

The duration of secondary thromboprophylaxis in patients with symptomatic PE was significantly longer than that in patients with DVT without symptoms of PE (11 vs 8 months on average, respectively). This difference can be explained by individual treatment preferences of the supervising physician. Since a longer duration of oral anticoagulation is associated with a lower rate of recurrence, the difference between the 2 groups with respect to the risk of recurrence might have been even greater in the case of a shorter duration of anticoagulation in the patients with PE.

In approximately 40% of the patients with proximal DVT, perfusion scan findings consistent with PE can be found in the absence of clinical symptoms.28 In our study, visualization techniques were not performed on a routine basis, but only in patients who presented with symptoms suggestive for PE. Therefore, some of our patients categorized as having DVT also had asymptomatic PE. Our patient classification would have affected our results only if asymptomatic PE would confer a lower risk of recurrence, which is very unlikely. Assuming that patients with asymptomatic PE have a higher risk of recurrence than patients with DVT without PE, the difference in the rate of recurrence between patients with PE (regardless of the presence or absence of symptoms) and patients with DVT without symptoms of PE would have been even greater. Nevertheless, the risk of recurrence among patients with asymptomatic PE ought to be investigated.

Our findings have 2 major clinical implications. To identify patients at high risk of recurrent VTE, a careful clinical examination of patients with DVT with regard to the presence of symptoms suggestive of PE is of utmost importance. Recurrent VTE is associated with serious clinical consequences: it is fatal in approximately 5% of the patients,24,29 and it is associated with the postthrombotic syndrome in one third of patients.30 Since the risk of recurrence and, thus, its complications can be reduced by treatment with anticoagulants, the results of our study indicate that prospective trials are warranted to investigate the optimal duration of secondary thromboprophylaxis in patients with PE.

Corresponding author and reprints: Sabine Eichinger, MD, Division of Hematology and Hemostasis, Department of Internal Medicine I, Waehringer Guertel 18-20, A-1090 Vienna, Austria (e-mail: sabine.eichinger@akh-wien.ac.at).

Accepted for publication February 21, 2003.

This study was supported by grant 1980 from the Medizinisch-Wissenschaftlicher Fonds des Bürgermeisters der Bundeshauptstadt Wien, Vienna, Austria.

Andersen  FA  JrWheeler  HBGoldbery  RJ  et al.  A population-based perspective of the hospital incidence and case-fatality rates of deep vein thrombosis and pulmonary embolism: the Worcester DVT Study. Arch Intern Med. 1991;151933- 938
PubMed Link to Article
Kniffin  WDBaron  JABarrett  JBirkmeyer  JDAnderson  FA  Jr The epidemiology of diagnosed pulmonary embolism and deep vein thrombosis in the elderly. Arch Intern Med. 1994;154861- 866
PubMed Link to Article
Silverstein  MDHeit  JAMohr  DNPetterson  TMO'Fallon  WMMelton III  LJ Trends in the incidence of deep vein thrombosis and pulmonary embolism: a 25-year population-based study. Arch Intern Med. 1998;158585- 593
PubMed Link to Article
Dalen  JEAlpert  JS Natural history of pulmonary embolism. Prog Cardiovasc Dis. 1975;17259- 270
PubMed Link to Article
Goldhaber  SZVisani  LDe Rosa  Mfor the International Cooperative Pulmonary Embolism Registry (ICOPR), Acute pulmonary embolism: clinical outcomes in the International Cooperative Pulmonary Embolism Registry. Lancet. 1999;3531386- 1389
PubMed Link to Article
Goldhaber  SZ Pulmonary embolism. N Engl J Med. 1998;33993- 110
PubMed Link to Article
Carson  JLKelly  MADuff  A  et al.  The clinical course of pulmonary embolism. N Engl J Med. 1992;3261240- 1245
PubMed Link to Article
Van Beek  EJRKuijer  PMMBüller  HRBrandjes  DPBossuyt  PMten Cate  JW The clinical course of patients with suspected pulmonary embolism. Arch Intern Med. 1997;1572593- 2598
PubMed Link to Article
Schulman  SRhedin  ASLindmarker  P  et al. Duration of Anticoagulation Trial Study Group, A comparison of six weeks with six months of oral anticoagulant therapy after a first episode of venous thromboembolism. N Engl J Med. 1995;3321661- 1665
PubMed Link to Article
Kearon  CGent  MHirsh  J  et al.  A comparison of three months of anticoagulation with extended anticoagulation for a first episode of idiopathic venous thromboembolism. N Engl J Med. 1999;340901- 907
PubMed Link to Article
Palareti  GLeali  NCoccheri  S  et al.  Bleeding complications of oral anticoagulant treatment: an inception-cohort, prospective collaborative study (ISCOAT): Italian Study on Complications of Oral Anticoagulant Therapy. Lancet. 1996;348423- 428
PubMed Link to Article
van der Meer  FJRosendaal  FRVandenbroucke  JPBriet  E Assessment of a bleeding risk index in two cohorts of patients treated with oral anticoagulants. Thromb Haemost. 1996;7612- 16
PubMed
Levine  MNRaskob  GLandefeld  SKearon  C Hemorrhagic complications of anticoagulant treatment. Chest. 2001;119(1, suppl)108S- 113S
PubMed Link to Article
Pinede  LNinet  JDuhaut  P  et al.  Comparison of 3 and 6 months of oral anticoagulant therapy after a first episode of proximal deep vein thrombosis or pulmonary embolism and comparison of 6 and 12 weeks of therapy after isolated calf deep vein thrombosis. Circulation. 2001;1032453- 2460
PubMed Link to Article
Agnelli  GPrandoni  PSantamaria  MG  et al.  Three months versus one year of oral anticoagulant therapy for idiopathic deep venous thrombosis. N Engl J Med. 2001;345165- 169
PubMed Link to Article
PIOPED Investigators, Value of the ventilation/perfusion scan in acute pulmonary embolism: results of the prospective investigation of pulmonary embolism diagnosis (PIOPED). JAMA. 1990;2632753- 2759
PubMed Link to Article
Bertina  RMKoeleman  BPKoster  T  et al.  Mutation in blood coagulation factor V associated with resistance to activated protein C. Nature. 1994;36964- 67
PubMed Link to Article
Poort  SRRosendaal  FRReitsma  PHBertina  RM A common genetic variation in the 3′-untranslated region of the prothrombin gene. Blood. 1996;883698- 3703
PubMed
Kyrle  PAMinar  EHirschl  M  et al.  High plasma levels of factor VIII and the risk of recurrent venous thromboembolism. N Engl J Med. 2000;343457- 462
PubMed Link to Article
Brandt  JTTriplett  DAAlving  BScharrer  Ifor the Subcommittee on Lupus Anticoagulant/Antiphospholipid Antibody of the Scientific and Standardisation Committee of the ISTH, Criteria for the diagnosis of lupus anticoagulants: an update. Thromb Haemost. 1995;741185- 1190
PubMed
Kalbfleisch  JDPrentice  RL The Statistical Analysis of Failure Time Data.  New York, NY John Wiley & Sons1980;
Kaplan  ELMeier  P Nonparametric estimation from incomplete observations. J Am Stat Assoc. 1958;53457- 481
Link to Article
Columbus Investigators, Low-molecular-weight heparin in the treatment of patients with venous thromboembolism. N Engl J Med. 1997;337657- 662
PubMed Link to Article
Douketis  JDKearon  CBates  SDuku  EKGinsberg  JS Risk of fatal pulmonary embolism in patients with treated venous thromboembolism. JAMA. 1998;279458- 462
PubMed Link to Article
Murin  SRomano  PSWhite  RH Comparison of outcomes after hospitalization for deep vein thrombosis or pulmonary embolism. Thromb Haemost. 2002;88407- 414
PubMed
Eichinger  SPabinger  IStümpflen  A  et al.  The risk of recurrent venous thromboembolism in patients with and without factor V Leiden. Thromb Haemost. 1997;77624- 628
PubMed
Eichinger  SMinar  EHirschl  M  et al.  The risk of early recurrent venous thromboembolism after oral anticoagulant therapy in patients with the G20210A transition in the prothrombin gene. Thromb Haemost. 1999;8114- 17
PubMed
Moser  KMFedullo  PFLitteJohn  JKCrawford  R Frequent asymptomatic pulmonary embolism in patients with deep vein thrombosis. JAMA. 1994;271223- 225
PubMed Link to Article
Prandoni  PLensing  AWACogo  A  et al.  The long-term clinical course of acute deep venous thrombosis. Ann Intern Med. 1996;1251- 7
PubMed Link to Article
Prandoni  PLensing  AWPrins  MR Long-term outcomes after deep venous thrombosis of the lower extremities. Vasc Med. 1998;357- 60
Link to Article

Figures

Place holder to copy figure label and caption

Kaplan-Meier estimates of the risk of recurrent venous thromboembolism in patients with symptomatic pulmonary embolism (PE) or deep vein thrombosis (DVT) without symptoms of PE.

Graphic Jump Location

Tables

Table Graphic Jump LocationTable 1. Baseline Characteristics of the 436 Patients
Table Graphic Jump LocationTable 2. Relative Risk of Recurrent Venous Thromboembolism

References

Andersen  FA  JrWheeler  HBGoldbery  RJ  et al.  A population-based perspective of the hospital incidence and case-fatality rates of deep vein thrombosis and pulmonary embolism: the Worcester DVT Study. Arch Intern Med. 1991;151933- 938
PubMed Link to Article
Kniffin  WDBaron  JABarrett  JBirkmeyer  JDAnderson  FA  Jr The epidemiology of diagnosed pulmonary embolism and deep vein thrombosis in the elderly. Arch Intern Med. 1994;154861- 866
PubMed Link to Article
Silverstein  MDHeit  JAMohr  DNPetterson  TMO'Fallon  WMMelton III  LJ Trends in the incidence of deep vein thrombosis and pulmonary embolism: a 25-year population-based study. Arch Intern Med. 1998;158585- 593
PubMed Link to Article
Dalen  JEAlpert  JS Natural history of pulmonary embolism. Prog Cardiovasc Dis. 1975;17259- 270
PubMed Link to Article
Goldhaber  SZVisani  LDe Rosa  Mfor the International Cooperative Pulmonary Embolism Registry (ICOPR), Acute pulmonary embolism: clinical outcomes in the International Cooperative Pulmonary Embolism Registry. Lancet. 1999;3531386- 1389
PubMed Link to Article
Goldhaber  SZ Pulmonary embolism. N Engl J Med. 1998;33993- 110
PubMed Link to Article
Carson  JLKelly  MADuff  A  et al.  The clinical course of pulmonary embolism. N Engl J Med. 1992;3261240- 1245
PubMed Link to Article
Van Beek  EJRKuijer  PMMBüller  HRBrandjes  DPBossuyt  PMten Cate  JW The clinical course of patients with suspected pulmonary embolism. Arch Intern Med. 1997;1572593- 2598
PubMed Link to Article
Schulman  SRhedin  ASLindmarker  P  et al. Duration of Anticoagulation Trial Study Group, A comparison of six weeks with six months of oral anticoagulant therapy after a first episode of venous thromboembolism. N Engl J Med. 1995;3321661- 1665
PubMed Link to Article
Kearon  CGent  MHirsh  J  et al.  A comparison of three months of anticoagulation with extended anticoagulation for a first episode of idiopathic venous thromboembolism. N Engl J Med. 1999;340901- 907
PubMed Link to Article
Palareti  GLeali  NCoccheri  S  et al.  Bleeding complications of oral anticoagulant treatment: an inception-cohort, prospective collaborative study (ISCOAT): Italian Study on Complications of Oral Anticoagulant Therapy. Lancet. 1996;348423- 428
PubMed Link to Article
van der Meer  FJRosendaal  FRVandenbroucke  JPBriet  E Assessment of a bleeding risk index in two cohorts of patients treated with oral anticoagulants. Thromb Haemost. 1996;7612- 16
PubMed
Levine  MNRaskob  GLandefeld  SKearon  C Hemorrhagic complications of anticoagulant treatment. Chest. 2001;119(1, suppl)108S- 113S
PubMed Link to Article
Pinede  LNinet  JDuhaut  P  et al.  Comparison of 3 and 6 months of oral anticoagulant therapy after a first episode of proximal deep vein thrombosis or pulmonary embolism and comparison of 6 and 12 weeks of therapy after isolated calf deep vein thrombosis. Circulation. 2001;1032453- 2460
PubMed Link to Article
Agnelli  GPrandoni  PSantamaria  MG  et al.  Three months versus one year of oral anticoagulant therapy for idiopathic deep venous thrombosis. N Engl J Med. 2001;345165- 169
PubMed Link to Article
PIOPED Investigators, Value of the ventilation/perfusion scan in acute pulmonary embolism: results of the prospective investigation of pulmonary embolism diagnosis (PIOPED). JAMA. 1990;2632753- 2759
PubMed Link to Article
Bertina  RMKoeleman  BPKoster  T  et al.  Mutation in blood coagulation factor V associated with resistance to activated protein C. Nature. 1994;36964- 67
PubMed Link to Article
Poort  SRRosendaal  FRReitsma  PHBertina  RM A common genetic variation in the 3′-untranslated region of the prothrombin gene. Blood. 1996;883698- 3703
PubMed
Kyrle  PAMinar  EHirschl  M  et al.  High plasma levels of factor VIII and the risk of recurrent venous thromboembolism. N Engl J Med. 2000;343457- 462
PubMed Link to Article
Brandt  JTTriplett  DAAlving  BScharrer  Ifor the Subcommittee on Lupus Anticoagulant/Antiphospholipid Antibody of the Scientific and Standardisation Committee of the ISTH, Criteria for the diagnosis of lupus anticoagulants: an update. Thromb Haemost. 1995;741185- 1190
PubMed
Kalbfleisch  JDPrentice  RL The Statistical Analysis of Failure Time Data.  New York, NY John Wiley & Sons1980;
Kaplan  ELMeier  P Nonparametric estimation from incomplete observations. J Am Stat Assoc. 1958;53457- 481
Link to Article
Columbus Investigators, Low-molecular-weight heparin in the treatment of patients with venous thromboembolism. N Engl J Med. 1997;337657- 662
PubMed Link to Article
Douketis  JDKearon  CBates  SDuku  EKGinsberg  JS Risk of fatal pulmonary embolism in patients with treated venous thromboembolism. JAMA. 1998;279458- 462
PubMed Link to Article
Murin  SRomano  PSWhite  RH Comparison of outcomes after hospitalization for deep vein thrombosis or pulmonary embolism. Thromb Haemost. 2002;88407- 414
PubMed
Eichinger  SPabinger  IStümpflen  A  et al.  The risk of recurrent venous thromboembolism in patients with and without factor V Leiden. Thromb Haemost. 1997;77624- 628
PubMed
Eichinger  SMinar  EHirschl  M  et al.  The risk of early recurrent venous thromboembolism after oral anticoagulant therapy in patients with the G20210A transition in the prothrombin gene. Thromb Haemost. 1999;8114- 17
PubMed
Moser  KMFedullo  PFLitteJohn  JKCrawford  R Frequent asymptomatic pulmonary embolism in patients with deep vein thrombosis. JAMA. 1994;271223- 225
PubMed Link to Article
Prandoni  PLensing  AWACogo  A  et al.  The long-term clinical course of acute deep venous thrombosis. Ann Intern Med. 1996;1251- 7
PubMed Link to Article
Prandoni  PLensing  AWPrins  MR Long-term outcomes after deep venous thrombosis of the lower extremities. Vasc Med. 1998;357- 60
Link to Article

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For CME Course: A Proposed Model for Initial Assessment and Management of Acute Heart Failure Syndromes
Indicate what changes(s) you will implement in your practice, if any, based on this CME course.
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