Fever and deep venous thrombosis. Findings from the RIETE registry ...

J Thromb Thrombolysis (2011) 32:288–292 DOI 10.1007/s11239-011-0604-7

Fever and deep venous thrombosis. Findings from the RIETE registry ´ ngeles Blanco-Molina • Raquel Barba • Pierpaolo Di Micco • A Cristina Delgado • Elena Cisneros • Jaume Villalta • Marıá V. Morales Alessandra Bura-Riviere • Philippe Debourdeau • Manuel Monreal

•

Published online: 24 June 2011 Ó Springer Science+Business Media, LLC 2011

Abstract Fever is a presenting sign in some patients with acute deep venous thrombosis (DVT), but its influence on outcome has not been thoroughly investigated. RIETE is an ongoing, international, observational registry of consecutive patients with symptomatic, objectively confirmed, acute venous thromboembolism. The aim of the present study was to assess the prevalence of fever in patients with acute DVT, and to compare their outcome during the first month of therapy, according to the presence or absence of fever. As of September 2009, 14,480 patients with symptomatic DVT have been enrolled in RIETE. Of these, 707

This study is conducted for the RIETE investigators. A full list of RIETE investigators is given in the Appendix.

(4.9%) had fever at presentation. During the 30-day study period, 448 patients (3.1%) died, 171 (1.2%) developed DVT recurrences, 376 (2.6%) had pulmonary embolism, and 384 (2.6%) had a major bleeding. Patients initially presenting with fever had a higher mortality (5.8% vs. 2.9%; odds ratio: 2.6; 95% CI 1.9–3.5) than those without fever. Among the causes of death, pulmonary embolism (0.7% vs. 0.1%) and infection (1.1% vs. 0.3%) were significantly more common in patients presenting with fever. Multivariate analysis confirmed that DVT patients with fever had an increased mortality (hazard ratio: 2.00; 95% CI 1.44–2.77) irrespectively of the patient’s age, body weight, and risk factors for VTE. Fever is not uncommon in patients with DVT, and carries a worse outcome.

R. Barba (&) Department of Internal Medicine, Fundacioń Hospital Alcorcoń, c/Budapest s/n, Madrid, Spain e-mail: [email protected]

J. Villalta Department of Internal Medicine, Hospital Clinic, Barcelona, Spain e-mail: [email protected]

P. Di Micco Department of Internal Medicine, Ospedale Buonconsiglio Fatebenefratelli, Naples, Italy e-mail: [email protected]

M. V. Morales Department of Internal Medicine, Hospital del Tajo, Aranjuez, Madrid, Spain e-mail: [email protected]

´ . Blanco-Molina A Department of Internal Medicine, Hospital Universitario Reina Sofıá, Co´rdoba, Spain e-mail: [email protected]

A. Bura-Riviere Department of Vascular Medicine, Hoˆpital de Rangueil, Toulouse, France e-mail: [email protected]

C. Delgado Department of Internal Medicine, Hospital Alto Gudalquivir, Andu´jar, Jaeń, Spain e-mail: [email protected]

P. Debourdeau Department of Internal Medicine, Hoˆpital Desgenettes, Lyon, France e-mail: [email protected]

E. Cisneros Department of Internal Medicine, Hospital Son Llatzer, Palma de Mallorca, Spain e-mail: [email protected]

M. Monreal Department of Internal Medicine, Hospital Universitari Germans Trias i Pujol, Badalona, Barcelona, Spain e-mail: [email protected]

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Fever and deep venous thrombosis

Keywords registry

Fever Deep venous thrombosis RIETE

289

DVT or PE was documented by repeat ultrasonography, venography, lung scanning, helical CT scan or pulmonary angiography.

Introduction

Variables and definitions

Although few studies have critically analyzed the association of fever with acute deep vein thrombosis (DVT) in the lower extremities, clinical wisdom has often suggested that fever may be a presenting sign of acute DVT [1–3]. Several studies have shown that some patients with acute DVT may have fever [4], but it is difficult to attribute fever to the DVT when there are a number of other clinical problems that might be the cause. The influence of age [5], weight [6], cancer [7] or risk factors on outcome in patients with DVT is well known, but the influence of fever on outcome in patients with DVT has not been thoroughly investigated. The Registro Informatizado de Enfermedad TromboEmbo´lica (RIETE) initiative is an ongoing, multicenter, international (Spain, France, Italy, Israel, Germany, Switzerland and Brazil) observational registry, designed to gather data on the clinical characteristics, treatment patterns and outcome in consecutive patients with symptomatic, objectively confirmed, acute venous thromboembolism [8–10]. The aim of the present study was to assess the prevalence of fever in patients with acute DVT, and to assess if its presence might be associated with a worse outcome during the first month of therapy.

The following parameters were recorded: patient’s baseline characteristics; clinical status including any coexisting or underlying conditions such as chronic heart or lung disease; risk factors for VTE; the type and dose of treatment received upon VTE diagnosis; and the outcome during the first 15 days and 1 month. Immobilized patients were defined in this analysis as non-surgical patients who had been immobilized (i.e., total bed rest with bathroom privileges) for C4 days in the 2-month period prior to VTE diagnosis. Surgical patients were defined as those who had undergone an operation in the 2 months prior to VTE diagnosis.

Patients and methods Study design The study population includes consecutive patients with symptomatic DVT, confirmed by objective tests (contrast venography or compression ultrasonography). Patients were excluded if they had a concomitant symptomatic pulmonary embolism (PE) or if they currently participating in a therapeutic clinical trial with a blinded medication. All patients provided oral consent to their participation in the registry, according to the requirements of the Ethics Committee within each hospital. The therapeutic approach was left to the decision of the attending physician. Patients were classified as having or not fever at baseline, and their outcomes within 30 days of DVT diagnosis were compared. Fever was defined as temperature of C38°C. The major outcome was overall mortality. The causes of death were assigned by their attending physicians. Secondary outcomes were recurrence VTE and bleeding. Each episode of clinically suspected recurrent

Data collection and monitoring in RIETE The attending physicians ensure that eligible patients were consecutively enrolled. Data are recorded on to a computer-based case report form at each participating hospital and submitted to a centralized coordinating center through a secure website. Encryption of data is used to enhance confidentiality and security. Data quality is regularly monitored and documented electronically to detect inconsistencies or errors, which are resolved by the local coordinators. Data quality is also monitored by periodic visits to participating hospitals, by contract research organizations, who compare the medical records with the data in the web. A data audit is performed at periodic intervals. Patient identities remain confidential because they are identified by a unique number assigned by the study coordinating center, which is responsible for all data management. Statistical analysis The v2 test was used for categorical variables with the correction of Yates and Fisher’s test for the dichotomous variables when the expected value of a cell was less than 5, and the Student’s t-test for the quantitative variables. A P-value \ 0.05 was considered statistically significant. First, the influence of a number of variables on the risk of death was tested by bivariate analysis using the v2 test. The characteristics of the variables of fever patients were compared with those of other without fever. Candidate variables were selected from clinical variables based on published literature. In order to measure predictors of outcome and the independence of the presence of fever, a multivariate analysis was carried out using a Cox proportional hazard regression analysis, and the corresponding

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survival curves were constructed (Fig. 1). All analyses were completed with the Statistical Package for Social Sciences (SPSS) program (version 16.0 for Windows, 2008. SPSS Inc. Chicago, IL, USA).

Table 1 Clinical characteristics of 14,480 patients with acute DVT, according to the presence or absence of fever Patients, N

Fever 707

No fever 13773

P value

Clinical characteristics

Results As of September 2009, 28,137 patients had been enrolled in RIETE. Of these, 14,814 had symptomatic DVT with no signs or symptoms of PE. Fever was present in 707 patients (4.9%), and in 334 (2.3%) patients this information was not recorded. The study population includes 6,929 women and 7,551 men, aged 14–103 years (mean, 64.1 years). Their clinical characteristics are depicted in Table 1. Patients with fever were 2 years younger, weighed less and more likely had chronic lung disease, recent bleeding, recent surgery or immobility than those with no fever. However, patients with fever less likely had chronic heart disease. As for the initial presentation, patients with fever more likely presented with upper-extremity DVT than those without fever. Most patients in both groups were initially treated with low-molecular-weight heparin (92% and 96%, respectively), at similar dosages (Table 2), although a higher proportion of patients with fever received unfractionated heparin (5.5% vs. 2.7%) During the 30-day study period, 448 patients (3.1%) died, 171 (1.2%) developed DVT recurrences, 376 (2.6%) had PE recurrences, and 384 (2.6%) had a major bleeding complication. Patients initially presenting with fever had a higher mortality (5.8% vs. 2.9%; odds ratio: 2.6; 95% CI 1.9–3.5) and an increased incidence of DVT recurrences 1,000

Fever yes No

0,995

378 (53%)

7173 (52%)

0.487

Age (years ± SD) Body weight (kg ± SD)

62.0 ± 19.8 72.8 ± 14.5

64.3 ± 17.6 74.1 ± 14.8

0.001 0.027

Inpatients

340 (48%)

6760 (49%)

0.001

Underlying conditions Chronic lung disease

61 (8.6%)

509 (3.7%)

Chronic heart disease

32 (4.5%)

1061(7.7%)

0.002

Recent major bleeding

39 (5.5%)

314 (2.3%)

0.001

Abnormal creatinine levels

96 (13%)

1692 (12%)

0.290

Risk factors for VTE Surgery

117 (17%)

1557 (11%)

0.001

Immobility C4 days

239 (34%)

3435 (25%)

0.001

Immobility due infection

45 (19%)

448 (14%)

0.001

Cancer

166 (23%)

2911 (21%)

0.143

Disseminated cancer

75 (11%)

1277 (9.3%)

0.233

Pregnancy

4 (0.6%)

138 (1.0%)

0.250

Estrogen therapy Long-travel

21 (3.0%) 11 (1.6%)

548 (4.0%) 308 (2.3%)

0.172 0.155

None of the above (idiopathic)

149 (27%)

4876 (35%)

0.02

Prior VTE

103 (15%)

2254 (16%)

0.230

Bilateral

31 (4.4%)

424 (3.1%)

0.083

Proximal

512 (84%)

10419 (83%)

Upper-extremity DVT

66 (9.6%)

807 (5.9%)

LMWH

653 (92%)

13257 (96%)

0.002

Mean LMWH dose (IU/kg/day)

178 ± 40

176 ± 38

0.174

Unfractionated heparin

39 (5.5%)

376 (2.7%)

0.003

Anti-vitamin K drugs

445 (66%)

9349 (70%)

0.03

LMWH

215 (32%)

3904 (29%)

0.126

Mean LMWH dose (IU/kg/day)

147 ± 49

144 ± 48

0.399

DVT characteristics 0.512 \0.001

Initial therapy

Long-term therapy

0,990

Cum Survival

Gender (males)

0,985

VTE venous thromboembolism, SD standard deviation, PE pulmonary embolism, DVT deep vein thrombosis 0,980

0,975

0,970 0

5

10

15

20

25

time (days)

Fig. 1 Cox-model survival curves for 1-month mortality

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(2.1% vs. 1.1%; odds ratio: 1.9; 95% CI 1.1–3.2), but the incidence of PE recurrences and major bleeding events was similar (Table 2). Interestingly, pulmonary embolism (0.7% vs. 0.1%) and infection (1.1% vs. 0.3%) were significantly more common causes of death in patients presenting with fever than in those with no fever (Table 2). There were no differences in the remaining causes of death On multivariate analysis, patients with fever had an independently increased mortality (hazard ratio: 2.00; 95%

Fever and deep venous thrombosis

291

Table 2 Thirty-day outcome of 14,480 patients with acute DVT, according to the presence or absence of fever Patients, N

Fever 707

No fever 13773

Recurrent PE Major bleeding Overall death

15 (2.1%) 16 (2.3%) 1 (6.3%) 51 (5.8%)

156 (1.1%) 360 (2.6%) 17 (4.7%) 397 (2.9%)

Lower

Upper

P value

\0.0001

1.028

1.020

1.036

0.029

Gender (female)

0.841

0.683

1.036

0.103

0.705 0.746

Weight (each kilo)

0.966

0.958

0.974

\0.0001

Fever

2.001

1.444

2.773

\0.0001

Recent bleeding

2.564

1.767

3.722

\0.0001

Co-morbidity

2.017

1.518

2.679

\0.0001

Cancer Previous surgery

5.397 0.705

4.374 0.506

6.660 0.984

\0.0001 0.040

Immobility C4 days due to infection

2.063

1.438

2.958

\0.0001

Previous VTE

0.459

0.316

0.666

\0.0001

\0.001

5 (0.7%)

18 (0.1%)

Dyspnea

3 (0.4%)

20 (0.1%)

Sudden, unexpected

0

Bleeding

2 (0.3%)

57 (0.4%)

0.654

Malignancy

8 (1.1%)

108 (0.8%)

0.320

Infection

8 (1.1%)

47 (0.3%)

0.006

Heart failure

2 (0.3%)

33 (0.2%)

0.758

Ischemic stroke

0

24 (0.2%)

0.301

Myocardial infarction

0

12 (0.09%)

0.548

Renal insufficiency

1 (0.1%)

6 (0.04%)

0.338

6 (0.04%)

95% CI for EXP(B)

Age (each year)

Causes of death Pulmonary embolism

OR

P value

30-day outcome Recurrent DVT

Table 3 Multivariate analysis on the risk to die in 30 days

0.005 0.125 0.741

Unknown

10 (1.4%)

97 (0.7%)

0.051

Other

2 (0.3%)

19 (0.1%)

0.354

LMWH low-molecular-weight heparin, IU international units, DVT deep vein thrombosis, PE pulmonary embolism

CI 1.44–2.77) irrespectively of the patient’s age, gender, body weight, previous bleeding, comorbidities (chronic lung disease or/and chronic heart disease), immobility due infection, previous surgery, active cancer or prior VTE, as shown in Table 3.

Discussion Fever is relatively common in patients presenting with acute DVT (one in every 20 such patients in our series had fever), but its influence on outcome has not been thoroughly studied so far. Our data, obtained from a large prospective series of consecutive patients in the RIETE Registry, reveal that DVT patients presenting with fever have an up to 2-fold higher mortality during the first 30 days compared with those with no fever. This worse outcome persisted after multivariate adjustment, and was mostly due to an increased incidence of fatal PE or infection. Previous studies have shown that fever accompanies VTE in a wide range of patients [11–13]. Fever associated to VTE has been reported as usually low grade, but in some patients a higher temperature has also been observed. These studies were unable to identify any specific characteristics of VTE in patients with fever. Several series reported the temperature was higher in patients presenting

VTE venous thromboembolism, OR odds ratio, CI confidence intervals

with acute PE, but whether the fever was caused by the PE or an associated disease was no clarified. In some studies [12, 13], more the one-half of patients with PE and fever had signs and symptoms of associated DVT. Even more, some series reported DVT as cause of fever of unknown origin [1]. The pathogenesis of DVT associated fever has not been clarified. The potential pyogenic mechanism includes infection and tissue necrosis, haemorrhage and local vascular irritation or inflammation [12]. In this study, selection bias was avoided by including consecutive patients with objectively confirmed VTE, but it has potential limitations that should be addressed. First, in our study, patients with fever were 2 years younger, and less likely had chronic heart disease than those without fever. Second, in RIETE we do not gather information on other potential risk factors for fever, such as concomitant infection, and we have not information about antibiotic treatment, both situations would likely influence the results. Despite our efforts to control any bias from underlying diseases, it is likely that we were unable to eliminate such bias completely. Thus, the worse outcome associated with fever in this study may reflect pre-existing, unrecognized, diseases process, or the coexistence of an infection. Finally, as the RIETE-registry includes all patients with VTE and not only those with DVT, the present study may represent a sort of subgroup analysis of the RIETE-registry. The RIETE registry provides insights into the natural history of VTE without unselected patient population, in contrast to the controlled conditions of randomized clinical studies. It can help to identify factors associated with worse outcomes, and provide feedback from real-world clinical situations. Thus, the worse outcome associated with fever in this study may reflect pre-existing, unrecognized,

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disease processes, be secondary to a malignancy, or the coexistence of an infection. In summary, our findings support the hypothesis of an association between fever and mortality in patients with DVT. We suggest that DVT patients presenting with fever should be closely monitored. Acknowledgments We express our gratitude to Sanofi-Aventis Spain for supporting this Registry with an unrestricted educational grant. We also express our gratitude to Bayer Schering Pharma for supporting this Registry. Bayer Schering Pharma’s support was limited to the part of RIETE outside Spain, which accounts for a 13.49% of the total patients included in the RIETE Registry. We also thank the Registry Coordinating Center, S & H Medical Science Service, for their quality control, logistic and administrative support.

Appendix Coordinator of the RIETE Registry Dr. Manuel Monreal (Spain) RIETE Steering Committee Members Dr. Herve` Decousus (France) Dr. Paolo Prandoni (Italy) Dr. Benjamin Brenner (Israel) RIETE National Coordinators Dr. Raquel Barba (Spain) Dr. Pierpaolo Di Micco (Italy) Dr. Laurent Bertoletti (France) Dr. Manolis Papadakis (Greece) Dr. Marijan Bosevski (R. Macedonia) Dr. Henri Bounameaux (Switzerland) RIETE Registry Coordinating Center S & H Medical Science Service Members of the RIETE group SPAIN: Arcelus JI, Arcos MP, Barba R, Barroń M, BlancoMolina A, Bosco J, Boix L, Ca´mara T, Casado I, Casas JM, Cisneros E, Chaves E, Conget F, del Campo R. Delgado C, del Toro J, Durań M, Falga´ C, Fernańdez-Capitań C, Ferreiro M, Font C, Gabriel F, Gallego P, Garcıá-Bragado F, Guil M, Gutie´rrez J, Hernańdez L, Hernańdez-Huerta D, Hernańdez-Toboso F, Jaras MJ, Jimeńez D, Jimeńez S, Jimeńez P, Jimeńez-Gil M, Lecumberri R, Lobo JL, Lo´pezJimeńez L, Lorenzo A, Luque JM, Llado´ M, Madridano O, Maestre A, Marchena PJ, Martıń-Villasclaras JJ, Monreal M, Montes J, Morales M, Munõz S, Nauffal MD, Nieto JA, Ogea JL, Oribe M, Otero R, Pedrajas JM, Rabunãl R, Riera-Mestre A, Roldań V, Rodrı´guez-Da´vila MA, Romań P, Romań-Bernal B, Rosa V, Royo C, Rubio S, Ruı´z J, Ruiz-

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Gamietea A, Ruiz-Gimeńez N, Sahuquillo JC, Samperiz A, Sańchez R, Sańchez Munõz-Torrero JF, Soler S, Soto MJ, Tiberio G, Tolodı´ JA, Tolosa C, Torres MI, Trujillo J, Uresandi F, Valde´s M, Valde´s V, Valle R, Vidal G, Villalta J. Zorrilla V. FRANCE : Bertoletti L, Bura-Riviere A, Debourdeau P, Mahe I, Rivron-Guillot K, GREECE: Papadakis, M, Babalis D, Tzinieris I. ISRAEL: Brenner B ITALY: Barillari A, Barillari G, Ciammaichella M, Di Micco P, Dalla Valle F, Duce R, Maida R, Pasca S, Piovella C, Poggio R, Prandoni P, Quintavalla R, Schenone A, Tiraferri E, Visona` A, REPUBLIC OF MACEDONIA: Bosevski M. SWITZERLAND: Bounameaux H,

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