RESUMO
BACKGROUND & AIMS: Cirrhosis frequently affects multiple components of hemostasis. Reversal of the coagulopathy of these patients is frequently required in case of bleeding episodes, or as prophylaxis before invasive procedures. Although 1-deamino-8-D-arginine vasopressin (DDAVP) is widely used as a pro-hemostatic agent in patients with cirrhosis, it is unclear whether DDAVP truly enhances hemostasis in these patients. Here we investigated the hemostatic effects of a single bolus of DDAVP in patients with cirrhosis. METHODS: Ten patients with cirrhosis (child B or C) and ten patients with mild haemophilia A received an intravenous single bolus of 0.3 microgram/kg DDAVP. Plasma was collected prior to and at 1, 3, 6, and 24 h after DDAVP administration. Levels of Von Willebrand factor (VWF), VWF propeptide, factor VIII (FVIII), and ADAMTS13 were measured in all plasma samples, whereas VWF multimers and functional VWF-dependent platelet adhesion were determined in the samples pre- and 1 h after DDAVP administration. RESULTS: Following DDAVP administration, VWF, FVIII, and VWF propeptide levels increased in patients with haemophilia, while patients with cirrhosis only showed an increase in VWF propeptide and FVIII levels. High molecular weight VWF multimers and VWF-dependent platelet adhesion increased in patients with haemophilia one hour after DDAVP administration, but did not change in the patients with cirrhosis. Levels of ADAMTS13 were unaffected in both patient groups after DDAVP. CONCLUSION: The lack of relevant effects of DDAVP on laboratory indices of primary hemostasis in patients with cirrhosis is in line with previous clinical study results in these patients.
Assuntos
Desamino Arginina Vasopressina/administração & dosagem , Hemofilia A/tratamento farmacológico , Hemostasia/efeitos dos fármacos , Hemostáticos/administração & dosagem , Cirrose Hepática/tratamento farmacológico , Proteínas ADAM/sangue , Proteína ADAMTS13 , Adulto , Biomarcadores/sangue , Fator VIII/metabolismo , Feminino , Hemofilia A/sangue , Hemofilia A/diagnóstico , Humanos , Infusões Intravenosas , Cirrose Hepática/sangue , Cirrose Hepática/diagnóstico , Masculino , Pessoa de Meia-Idade , Países Baixos , Fatores de Tempo , Resultado do Tratamento , Fator de von Willebrand/metabolismoRESUMO
We present a patient with no medical history admitted for jaundice and dark coloured urine. Further investigations revealed hepatitis A related acute liver failure while the patient had no travel history, nor contact with infected individuals. After admission, the patient deteriorated fulfilling the King's College criteria for acute liver failure. Two days after admission, he underwent liver transplantation and recovered. Careful investigation identified imported semi-dried tomatoes as the source of the hepatitis A infection. This patient was part of a foodborne hepatitis A outbreak in the Netherlands in 2010 affecting 13 patients. Virus sequence analysis of our patient's virus showed a strain commonly found in Turkey. Hepatitis A related acute liver failure is rare, but is associated with a poor prognosis. In developed countries, the incidence of hepatitis A is low, but foodborne outbreaks are emerging. Further, we review the literature on recent foodborne hepatitis A outbreaks in developed countries, hepatitis A related acute liver failure, and hepatitis A vaccine.
Assuntos
Doenças Transmitidas por Alimentos/diagnóstico , Doenças Transmitidas por Alimentos/patologia , Hepatite A/complicações , Hepatite A/diagnóstico , Falência Hepática Aguda/diagnóstico , Falência Hepática Aguda/patologia , Adulto , Análise por Conglomerados , Contaminação de Alimentos , Doenças Transmitidas por Alimentos/complicações , Genótipo , Vírus da Hepatite A/classificação , Vírus da Hepatite A/genética , Vírus da Hepatite A/isolamento & purificação , Humanos , Falência Hepática Aguda/cirurgia , Transplante de Fígado , Masculino , Dados de Sequência Molecular , Países Baixos , RNA Viral/genética , Análise de Sequência de DNA , Homologia de Sequência , Resultado do TratamentoRESUMO
Hepatopathy is the most common feature in the Congenital Disorders of Glycosylation (CDG). More than 70 subtypes have been identified in this growing group of inborn errors. Most defects present as multisystem disease, whereas phosphomannose isomerase deficiency (MPI-CDG) presents with exclusive hepato-intestinal phenotype. MPI-CDG has been considered as one of the very few treatable disorders of glycosylation; several patients showed significant improvement of their life-threatening protein-losing enteropathy and coagulation disorder on oral mannose supplementation therapy. However, patients who have MPI-CDG develop progressive liver insufficiency during a later course of disease. A patient who had MPI-CDG developed progressive liver fibrosis, despite oral mannose supplementation and repeated fractionated heparin therapy. She showed mannose therapy-associated hemolytic jaundice. She developed severe dyspnea and exercise intolerance owing to pulmonary involvement, necessitating liver transplant. After transplantation her physical exercise tolerance, pulmonary functions, and metabolic parameters became fully restored. She is still doing well 2 years after transplantation now. In conclusion, we here report on the first successful liver transplantation in CDG.
Assuntos
Defeitos Congênitos da Glicosilação/cirurgia , Transplante de Fígado , Manose-6-Fosfato Isomerase/deficiência , Adulto , Pré-Escolar , Feminino , Seguimentos , Humanos , Indução de Remissão , Fatores de TempoRESUMO
BACKGROUND: Treatment and prevention of thrombotic complications is frequently required in patients with cirrhosis. However anticoagulant therapy is often withheld from these patients, because of the perceived bleeding diathesis. As a result of the limited clinical experience, the anticoagulant of choice for the various indications is still not known. OBJECTIVES: We evaluated the in vitro effect of clinically approved anticoagulant drugs in plasma from patients with cirrhosis. PATIENTS/METHODS: Thirty patients with cirrhosis and thirty healthy controls were studied. Thrombin generation assays were performed before and after addition of unfractionated heparin, low molecular weight heparin, fondaparinux, dabigatran, and rivaroxaban, to estimate anticoagulant potencies of these drugs. RESULTS: Addition of dabigatran led to a much more pronounced reduction in endogenous thrombin potential in patients compared to controls (72.6% reduction in patients vs. 12.8% reduction in controls, P<0.0001). The enhanced effect of dabigatran was proportional to the severity of disease. In contrast, only a slightly increased anticoagulant response to heparin and low molecular weight heparin and even a reduced response to fondaparinux and rivaroxaban was observed in plasma from cirrhotic patients as compared to control plasma. CONCLUSIONS: The anticoagulant potency of clinically approved drugs differs substantially between patients with cirrhosis and healthy individuals. Whereas dabigatran and, to a lesser extent, heparin and low molecular weight heparin are more potent in plasma from patients with cirrhosis, fondaparinux and rivaroxaban showed a decreased anticoagulant effect. These results may imply that in addition to dose adjustments based on altered pharmacokinetics, drug-specific dose adjustments based on altered anticoagulant potency may be required in patients with cirrhosis.
Assuntos
Anticoagulantes/uso terapêutico , Cirrose Hepática/metabolismo , Trombina/metabolismo , Benzimidazóis/uso terapêutico , Testes de Coagulação Sanguínea/métodos , Dabigatrana , Feminino , Fondaparinux , Heparina de Baixo Peso Molecular/uso terapêutico , Humanos , Masculino , Pessoa de Meia-Idade , Morfolinas/uso terapêutico , Polissacarídeos/uso terapêutico , Rivaroxabana , Tiofenos/uso terapêutico , beta-Alanina/análogos & derivados , beta-Alanina/uso terapêuticoRESUMO
There is increasing recognition that thrombotic complications may occur in patients with cirrhosis, and literature on antithrombotic treatment in these patients is rapidly emerging. Due to extensive haemostatic changes in patients with cirrhosis, careful monitoring of anticoagulant therapy may be required. Recent data suggest that plasma levels of low molecular weight heparin (LMWH) are substantially underestimated by the anti-activated factor X (anti-Xa) assay in patients with cirrhosis. We studied the in vitro recovery of antithrombin (AT)-dependent and -independent anticoagulant drugs in plasma from 26 patients with cirrhosis and 30 healthy controls and found substantially reduced anti-Xa levels when AT-dependent anticoagulant drugs were added to the plasma of patients with cirrhosis. LMWH (0·2 U/ml) had the poorest recovery in plasma from patients with cirrhosis (0·13 ± 0·06 U/ml, compared to 0·23 ± 0·03 U/ml in controls, P < 0·0001), followed by unfractionated heparin and fondaparinux. In contrast, the recovery of rivaroxaban and dabigatran was identical between patients and controls. These data suggest that the anti-Xa assay cannot be used to monitor AT-dependent anticoagulant drugs in patients with cirrhosis, as it substantially underestimates drug levels. The direct factor Xa and IIa inhibitors, however, may be monitored through the respective anti-Xa and anti-IIa assays in patients with cirrhosis.
Assuntos
Anticoagulantes/sangue , Testes de Coagulação Sanguínea , Monitoramento de Medicamentos/métodos , Cirrose Hepática/sangue , Anticoagulantes/farmacologia , Antitrombinas/sangue , Antitrombinas/farmacologia , Benzimidazóis/sangue , Benzimidazóis/farmacologia , Benzimidazóis/uso terapêutico , Coagulação Sanguínea/efeitos dos fármacos , Dabigatrana , Testes Diagnósticos de Rotina , Inibidores do Fator Xa , Reações Falso-Negativas , Feminino , Fondaparinux , Heparina/sangue , Heparina/farmacologia , Heparina/uso terapêutico , Heparina de Baixo Peso Molecular/sangue , Heparina de Baixo Peso Molecular/farmacologia , Heparina de Baixo Peso Molecular/uso terapêutico , Humanos , Cirrose Hepática/complicações , Cirrose Hepática/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Morfolinas/sangue , Morfolinas/farmacologia , Morfolinas/uso terapêutico , Polissacarídeos/sangue , Polissacarídeos/farmacologia , Polissacarídeos/uso terapêutico , Protrombina/antagonistas & inibidores , Rivaroxabana , Sensibilidade e Especificidade , Tiofenos/sangue , Tiofenos/farmacologia , Tiofenos/uso terapêutico , Trombofilia/sangue , Trombofilia/etiologia , beta-Alanina/análogos & derivados , beta-Alanina/sangue , beta-Alanina/farmacologia , beta-Alanina/uso terapêuticoRESUMO
INTRODUCTION: Orthotopic liver transplantation (OLT) is accompanied by a significant postoperative infection risk. Immunosuppression to prevent rejection increases the susceptibility to infections, mainly by impairing the adaptive immune system. Genetic polymorphisms in the lectin complement pathway of the donor have recently been identified as important risk determinants of clinically significant bacterial infection (CSI) after OLT. Another genetic factor involved in innate immunity is NOD2, which was reported to be associated with increased risk of spontaneous bacterial peritonitis in cirrhotic patients. METHODS: We assessed association of three genetic NOD2 variants (R702W, G908R and 3020insC) with increased risk of CSI after OLT. 288 OLT recipient-donor pairs from two tertiary referral centers were genotyped for the three NOD2 variants. The probability of CSI in relation to NOD2 gene variants was determined with cumulative incidence curves and log-rank analysis. RESULTS: The R702W NOD2 variant in the recipient was associated with CSI after OLT. Eight out of 15 (53.3%) individuals with a mutated genotype compared to 80/273 (29.3%) with wild type genotype developed CSI (p=0.027, univariate cox regression), illustrated by a higher frequency of CSI after OLT over time (p=0.0003, log rank analysis). Multivariate analysis (including the donor lectin complement pathway profile) showed independence of this R702W NOD2 association from other risk factors (HR 2.0; p=0.04). The other NOD2 variants, G908R and 3020insC, in the recipient were not associated with CSI. There was no association with CSI after OLT for any of the NOD2 variants in the donor. CONCLUSION: The mutated NOD2 R702W genotype in the recipient is independently associated with an increased risk of bacterial infections after liver transplantation, indicating a predisposing role for this genetic factor impairing the recipient's innate immune system.
Assuntos
Infecções Bacterianas/genética , Predisposição Genética para Doença , Transplante de Fígado/efeitos adversos , Proteína Adaptadora de Sinalização NOD2/genética , Polimorfismo de Nucleotídeo Único/genética , Transplantados , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Fatores de Risco , Análise de Sobrevida , Doadores de TecidosRESUMO
Protein S acts as a cofactor for tissue factor pathway inhibitor (TFPI) in the down regulation of thrombin generation, and acquired and congenital protein S deficiencies are associated with a concomitant TFPI deficiency. In contrast, in patients with liver diseases, decreased protein S, but normal or increased levels of TFPI have been reported. We compared TFPI and protein S plasma levels between 26 patients with cirrhosis and 20 healthy controls and found that TFPI levels were comparable between patients (111 ± 38%) and controls (108 ± 27%), despite reduced protein S levels (74 ± 23% in patients vs. 98 ± 10% in controls). Subsequently, we quantified the activity of the TFPI-protein S system by measuring thrombin generation in the absence and presence of neutralizing antibodies to protein S or TFPI. Ratios of peak thrombin generation in the absence and presence of these antibodies were calculated. Both the protein S and the TFPI ratios were increased in patients with cirrhosis compared to controls. Protein S ratios were (0·62 [0·08-0·93] in patients vs. 0·32 [0·20-0·54] in controls; TFPI ratios were 0·50 [0·05-0·90] in patients vs. 0·18 [0·11-0·49] in controls). Thus, although the acquired protein S deficiency in patients with cirrhosis is not associated with decreased TFPI levels, the TFPI/protein S anticoagulant system is functionally impaired.
Assuntos
Lipoproteínas/sangue , Cirrose Hepática/sangue , Deficiência de Proteína S/sangue , Proteína S/metabolismo , Trombina/metabolismo , Estudos de Casos e Controles , Feminino , Humanos , Lipoproteínas/deficiência , Lipoproteínas/genética , Cirrose Hepática/genética , Masculino , Pessoa de Meia-IdadeRESUMO
BACKGROUND: Primary sclerosing cholangitis is a chronic cholestatic liver disease. An immune aetiology is suggested by associations between PSC and inflammatory bowel disease. Data on concomitant prevalence of other immune-mediated diseases is limited. AIM: To assess the prevalence of concomitant immune-mediated diseases and the impact on disease outcome in PSC. METHODS: We included 241 patients and retrospectively reviewed medical charts. RESULTS: Altogether 172 (71.4%) patients had concomitant immune-mediated disease, including IBD (149, 61.8%), autoimmune hepatitis (15, 6.2%) and other immune-mediated diseases (47, 19.5%). Thirty nine patients (22.7%) had more than one immune-mediated disease other than PSC. Most frequent extrahepatic non-IBD immune-mediated diseases were sarcoidosis, thyroid disease, and type I diabetes mellitus. Age at PSC diagnosis was lower in patients with IBD. In patients with other immune-mediated diseases than autoimmune hepatitis or IBD, age at PSC diagnosis was higher. Younger age at diagnosis and concomitant IBD related to longer survival till death or liver transplantation. CONCLUSIONS: In a large PSC population, a high prevalence of concomitant immune-mediated diseases was found. IBD occurred more often in early-acquired PSC, and the other immune-mediated diseases more often in later-acquired PSC. No effect on outcome was found for non-IBD immune mediated disease.
Assuntos
Colangite Esclerosante/complicações , Colangite Esclerosante/imunologia , Diabetes Mellitus Tipo 1/complicações , Hepatite Autoimune/complicações , Doenças Inflamatórias Intestinais/complicações , Sarcoidose/complicações , Doenças da Glândula Tireoide/complicações , Adolescente , Adulto , Fatores Etários , Idoso , Neoplasias dos Ductos Biliares/diagnóstico , Ductos Biliares Intra-Hepáticos , Criança , Pré-Escolar , Colangiocarcinoma/diagnóstico , Colangite Esclerosante/diagnóstico , Diabetes Mellitus Tipo 1/diagnóstico , Diabetes Mellitus Tipo 1/imunologia , Feminino , Humanos , Doenças Inflamatórias Intestinais/diagnóstico , Doenças Inflamatórias Intestinais/imunologia , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Estudos Retrospectivos , Sarcoidose/diagnóstico , Sarcoidose/imunologia , Doenças da Glândula Tireoide/diagnóstico , Doenças da Glândula Tireoide/imunologia , Adulto JovemRESUMO
Hepatitis E virus (HEV) infections are known to run a self-limiting course. Recently, chronic hepatitis E has been described in immunosuppressed patients after solid-organ transplantation. Besides the general recommendation to lower the immunosuppressive medication in these patients, there is currently no specific treatment. We here describe the successful use of pegylated interferon alpha-2b in the treatment of 2 liver transplant recipients who suffered a chronic HEV infection for 9 years (case A) or 9 months (case B). After 4 weeks of therapy, a 2-log decrease (case A) and a 3-log decrease (case B) in the viral load were observed. In case A, who received treatment for 1 year, serum viral RNA became undetectable from week 20 onward, and serum liver enzymes normalized completely. In case B, interferon was discontinued at week 16 because of a lack of a further decline in the viral load. However, 4 weeks after the cessation of therapy, viral RNA was no longer detectable in the serum, and this was probably related to a further decline in the immunosuppressive medication. Liver tests normalized completely. In both cases, no relapse has been noted so far. We conclude that pegylated interferon alpha-2b may be useful in the treatment of chronic HEV infections in patients in whom the reduction of the immunosuppressive medication alone is not sufficient.
Assuntos
Hepatite E/terapia , Interferon-alfa/uso terapêutico , Hepatopatias/terapia , Transplante de Fígado/métodos , Polietilenoglicóis/uso terapêutico , Adulto , Doença Crônica , Feminino , Hepatite E/complicações , Humanos , Terapia de Imunossupressão/efeitos adversos , Imunossupressores/uso terapêutico , Interferon alfa-2 , Transplante de Fígado/efeitos adversos , Masculino , Pessoa de Meia-Idade , Proteínas Recombinantes , Resultado do Tratamento , Carga ViralRESUMO
Hepatitis E virus (HEV) infection is known to run a self-limited course. Recently, chronic hepatitis E has been described in several immunosuppressed patients after solid organ transplantation. The prevalence of HEV infection after transplantation, however, is unknown. We studied HEV parameters [HEV RNA, HEV immunoglobulin M (IgM), and HEV immunoglobulin G (IgG) by enzyme-linked immunosorbent assay and confirmatory immunoblotting] in a cohort of 285 adult liver transplant recipients. The most recent freeze-stored sera were investigated, and if they were positive, a retrospective analysis was performed. Samples from 274 patients (96.1%) tested negative for all HEV parameters. This included a patient described earlier as having experienced an episode of chronic HEV hepatitis in the past. One patient was found positive for HEV RNA without HEV antibodies. She presently suffers from chronic HEV hepatitis and has also been described before. Sera from 9 patients tested positive for HEV IgG without HEV IgM or HEV RNA. Six of these 9 patients (2.1% of the total) were found to have HEV IgG antibodies in retrospect related to an HEV infection at some time pre-transplant as they also tested positive in a pretransplant serum sample. One of these 9 patients suffered in retrospect from a chronic HEV infection with mild hepatitis between 2 and 5 years after liver transplantation on the basis of the course of HEV RNA, IgM, and IgG, aminotransferases, and liver histology. Overall, the prevalence of acquired HEV hepatitis after liver transplantation was 1% in this cohort. We conclude that liver transplant recipients have a risk for chronic HEV infection, but the prevalence is low.
Assuntos
Vírus da Hepatite E/metabolismo , Hepatite E/complicações , Hepatite E/epidemiologia , Hepatopatias/complicações , Hepatopatias/epidemiologia , Transplante de Fígado/métodos , Adulto , Idoso , Estudos de Coortes , Ensaio de Imunoadsorção Enzimática/métodos , Feminino , Hepatite E/virologia , Humanos , Imunoglobulina G/metabolismo , Imunoglobulina M/metabolismo , Hepatopatias/virologia , Masculino , Pessoa de Meia-Idade , Prevalência , RNA Viral/metabolismo , Estudos Retrospectivos , RiscoRESUMO
BACKGROUND: The model of end-stage liver disease (MELD) score is nowadays widely used to prioritize patients for liver transplantation. AIMS: To assess the contribution of the individual components of the MELD score in interlaboratory variability. METHODS: We sent 15 samples from patients listed for liver transplantation to seven different European laboratories who were asked to measure all three variables. In addition, 10 samples from patients on oral anticoagulant treatment were sent to the same labs for the international normalised ratio (INR) measurement. RESULTS AND CONCLUSIONS: In all 15 samples, a substantial and clinically relevant variation in the calculated MELD score was observed between laboratories. The mean difference in the MELD score between the highest- and the lowest-scoring laboratory was 4.8. The variation in creatinine measurements resulted in differences of up to three MELD points in a single patient when comparing the highest and the lowest scoring lab. The variation in bilirubin measurements only accounted for a difference of one point between the highest- and the lowest-scoring laboratory, but the variation in INRs resulted in differences of 2 to 12 MELD points. MELD scores or INR values were not substantially different in laboratories that used the Owren instead of the more widely used Quick methodology for INR measurements. The variability in the INR in patients on oral anticoagulants was substantially less as compared with the variability in patients with liver disease. In conclusion, we observed a large interlaboratory variation in the MELD score. This variation in the MELD score is primarily caused by the INR.
Assuntos
Erros de Diagnóstico/estatística & dados numéricos , Laboratórios/normas , Falência Hepática Aguda/classificação , Falência Hepática Aguda/diagnóstico , Transplante de Fígado/normas , Índice de Gravidade de Doença , Bilirrubina/sangue , Creatinina/sangue , Europa (Continente) , Humanos , Coeficiente Internacional Normatizado/estatística & dados numéricos , Reprodutibilidade dos TestesRESUMO
Hepatitis E virus (HEV) infection is known to run a self-limiting course. Sporadic cases of acute hepatitis due to infection with HEV genotype 3, present in pig populations, are increasingly recognized. Zoonotic transmission seems infrequent. The entity of unexplained chronic hepatitis after liver transplantation has been recognized. Detection of HEV in 2 liver transplant recipients triggered a review of these cases. Freeze-stored sera were available for retrospective analysis. HEV antibodies were determined. For virus detection and identification, a fragment of the gene encoding the major capsid protein (open reading frame 2) was amplified by reverse-transcription polymerase chain reaction and sequenced to identify the genotype. Two months after liver transplantation, case A developed unexplained chronic hepatitis, which developed into cirrhosis. Retransplantation followed 7 years later, after which chronic hepatitis recurred. In retrospect, HEV RNA was present in serum 3 weeks after the first transplantation and remained present afterwards. HEV RNA was also present in retransplant liver tissue. HEV antibodies appeared late after retransplantation. Case B developed unexplained chronic hepatitis 7 years after transplantation. Retransplantation was needed 5 years later, after which no signs of hepatitis recurred. In retrospect, the period of chronic hepatitis up to the retransplantation coincided with HEV RNA in serum. In case B, antibodies developed, the viral load was much lower than in case A, and the virus seemed to be cleared after retransplantation. Genotyping in both cases revealed 2 unique strains of genotype 3. In conclusion, chronic HEV infection may develop in immunosuppressed patients, who may then serve as long-term carriers of the virus. We hypothesize that HEV may be the cause of chronic hepatitis in liver transplant recipients.
Assuntos
Vírus da Hepatite E/isolamento & purificação , Hepatite E/epidemiologia , Transplante de Fígado/estatística & dados numéricos , Adulto , Doença Crônica , Feminino , Liofilização , Hepatite B/cirurgia , Degeneração Hepatolenticular/cirurgia , Humanos , Testes de Função Hepática , Estudos RetrospectivosRESUMO
Long-term follow-up studies on the impact of vascular events (VE) and risk factors of liver transplant recipients are scarce. In this study, 311 recipients of a first isolated liver transplant who survived at least 1 year were followed up from 1979 to 2002. The median follow-up duration was 6.2 (range1-22.7) years. Overall median survival was 18.7 [95% confidence interval (CI): 15.5-20.1] years and this was significantly lower compared with age- and sex-matched controls. Eleven (21%) of the patients had a vascular cause of death and VE were the third cause of death. VE occurred later compared with other causes of death (mean 10.3 years vs. 4.5 years, P < 0.0001, 95% CI: 2.7-8.9). Systolic hypertension, systolic blood pressure, smoking, renal failure, age, hypertriglyceridemia, serum total cholesterol levels and hypercholesterolemia at the 1-year follow-up visit were associated with the occurrence of VE, but renal failure and age at 1 year after transplantation were the only independent risk factors for vascular death (hazard ratio 0.06, 95% CI: 0.01-0.41 and hazard ratio 1.17, 95% CI: 1.02-1.34, respectively). Finally, it was shown that the adequate treatment of hypertension was associated with a significant reduced risk of vascular death. Therefore, vascular risk factors should be treated aggressively to prevent VE in the long term.