Rivaroxaban in Patients with Atrial Fibrillation and a Bioprosthetic Mitral Valve.

BACKGROUND: The effects of rivaroxaban in patients with atrial fibrillation and a bioprosthetic mitral valve remain uncertain. METHODS: In this randomized trial, we compared rivaroxaban (20 mg once daily) with dose-adjusted warfarin (target international normalized ratio, 2.0 to 3.0) in patients with atrial fibrillation and a bioprosthetic mitral valve. The primary outcome was a composite of death, major cardiovascular events (stroke, transient ischemic attack, systemic embolism, valve thrombosis, or hospitalization for heart failure), or major bleeding at 12 months. RESULTS: A total of 1005 patients were enrolled at 49 sites in Brazil. A primary-outcome event occurred at a mean of 347.5 days in the rivaroxaban group and 340.1 days in the warfarin group (difference calculated as restricted mean survival time, 7.4 days; 95% confidence interval [CI], -1.4 to 16.3; P<0.001 for noninferiority). Death from cardiovascular causes or thromboembolic events occurred in 17 patients (3.4%) in the rivaroxaban group and in 26 (5.1%) in the warfarin group (hazard ratio, 0.65; 95% CI, 0.35 to 1.20). The incidence of stroke was 0.6% in the rivaroxaban group and 2.4% in the warfarin group (hazard ratio, 0.25; 95% CI, 0.07 to 0.88). Major bleeding occurred in 7 patients (1.4%) in the rivaroxaban group and in 13 (2.6%) in the warfarin group (hazard ratio, 0.54; 95% CI, 0.21 to 1.35). The frequency of other serious adverse events was similar in the two groups. CONCLUSIONS: In patients with atrial fibrillation and a bioprosthetic mitral valve, rivaroxaban was noninferior to warfarin with respect to the mean time until the primary outcome of death, major cardiovascular events, or major bleeding at 12 months. (Funded by PROADI-SUS and Bayer; RIVER ClinicalTrials.gov number, NCT02303795.).

A randomized clinical trial to evaluate the efficacy and safety of rivaroxaban in patients with bioprosthetic mitral valve and atrial fibrillation or flutter: Rationale and design of the RIVER trial.

The efficacy and safety of rivaroxaban in patients with bioprosthetic mitral valves and atrial fibrillation or flutter remain uncertain. DESIGN: RIVER was an academic-led, multicenter, open-label, randomized, non-inferiority trial with blinded outcome adjudication that enrolled 1005 patients from 49 sites in Brazil. Patients with a bioprosthetic mitral valve and atrial fibrillation or flutter were randomly assigned (1:1) to rivaroxaban 20 mg once daily (15 mg in those with creatinine clearance <50 mL/min) or dose-adjusted warfarin (target international normalized ratio 2.0-30.); the follow-up period was 12 months. The primary outcome was a composite of all-cause mortality, stroke, transient ischemic attack, major bleeding, valve thrombosis, systemic embolism, or hospitalization for heart failure. Secondary outcomes included individual components of the primary composite outcome, bleeding events, and venous thromboembolism. SUMMARY: RIVER represents the largest trial specifically designed to assess the efficacy and safety of a direct oral anticoagulant in patients with bioprosthetic mitral valves and atrial fibrillation or flutter. The results of this trial can inform clinical practice and international guidelines.

Identification of environmental and genetic factors that influence warfarin time in therapeutic range.

Warfarin is an oral anticoagulant prescribed to prevent and treat thromboembolic disorders. It has a narrow therapeutic window and must have its effect controlled. Prothrombin test, expressed in INR value, is used for dose management. Time in therapeutic range (TTR) is an important outcome of quality control of anticoagulation therapy and is influenced by several factors. The aim of this study was to identify genetic, demographic, and clinical factors that can potentially influence TTR. In total,422 patients using warfarin were investigated. Glibenclamide co-medication and presence of CYP2C9*2 and/or *3 alleles were associated with higher TTR, while amiodarone, acetaminophen and verapamil co-medication were associated with lower TTR. Our data suggest that TTR is influenced by co-medication and genetic factors. Thus, individuals in use of glibenclamide may need a more careful monitoring and genetic testing (CYP2C9*2 and/or *3 alleles) may improve the anticoagulation management. In addition, in order to reach and maintain the INR in the target for a longer period, it is better to discuss dose adjustment in office instead of by telephone assessment. Other studies are needed to confirm these results and to find more variables that could contribute to this important parameter.

Pacemaker or defibrillator surgery without interruption of anticoagulation.

BACKGROUND: Many patients requiring pacemaker or implantable cardioverter-defibrillator (ICD) surgery are taking warfarin. For patients at high risk for thromboembolic events, guidelines recommend bridging therapy with heparin; however, case series suggest that it may be safe to perform surgery without interrupting warfarin treatment. There have been few results from clinical trials to support the safety and efficacy of this approach. METHODS: We randomly assigned patients with an annual risk of thromboembolic events of 5% or more to continued warfarin treatment or to bridging therapy with heparin. The primary outcome was clinically significant device-pocket hematoma, which was defined as device-pocket hematoma that necessitated prolonged hospitalization, interruption of anticoagulation therapy, or further surgery (e.g., hematoma evacuation). RESULTS: The data and safety monitoring board recommended termination of the trial after the second prespecified interim analysis. Clinically significant device-pocket hematoma occurred in 12 of 343 patients (3.5%) in the continued-warfarin group, as compared with 54 of 338 (16.0%) in the heparin-bridging group (relative risk, 0.19; 95% confidence interval, 0.10 to 0.36; P<0.001). Major surgical and thromboembolic complications were rare and did not differ significantly between the study groups. They included one episode of cardiac tamponade and one myocardial infarction in the heparin-bridging group and one stroke and one transient ischemic attack in the continued-warfarin group. CONCLUSIONS: As compared with bridging therapy with heparin, a strategy of continued warfarin treatment at the time of pacemaker or ICD surgery markedly reduced the incidence of clinically significant device-pocket hematoma. (Funded by the Canadian Institutes of Health Research and the Ministry of Health and Long-Term Care of Ontario; BRUISE CONTROL ClinicalTrials.gov number, NCT00800137.).

PPARA gene and phenprocoumon: a new predictor of response variability.

Phenprocoumon is an anticoagulant used for thromboembolic disorder prophylaxis metabolized mainly by CYP3A4. However, polymorphisms in this gene did not explain the observed variability. PPARA (peroxisome proliferator-activated receptor-α) is a nuclear receptor that, among others, influences CYP3A4 gene expression. The aim of this study was to determine whether PPARA gene polymorphisms and the CYP3A4*22 allele are associated with phenprocoumon dose variability. A total of 198 patients on a stable dose of phenprocoumon were included in the study. Genotyping was performed by allele discrimination using standardized TaqMan assays. Differences between the average phenprocoumon dose and genotypes/haplotypes were assessed by analysis of variance and multiple linear regression analyses. Patients with the PPARA rs4253728A allele needed higher phenprocoumon doses. However, the effect size (3%) of this association was small. The CYP3A4*22 allele was not associated with the dose of phenprocoumon. As this is the first report of an association between PPARA gene polymorphisms and phenprocoumon dose, future studies are warranted to confirm these results.

Antithrombotic therapies in patients with prosthetic heart valves: guidelines translated for the clinician.

Patients with prosthetic heart valves require chronic oral anticoagulation. In this clinical scenario, physicians must be mindful of the thromboembolic and bleeding risks related to chronic anticoagulant therapy. Currently, only vitamin K antagonists are approved for this indication. This paper reviews the main heart valve guidelines focusing on the use of oral anticoagulation in these patients.

Comparison of surgical cut and sew versus radiofrequency pulmonary veins isolation for chronic permanent atrial fibrillation: a randomized study.

BACKGROUND: Surgical pulmonary veins isolation (PVI) is done to restore sinus rhythm (SR) in patients with chronic permanent atrial fibrillation (CPAF) and mitral valve disease. Here we compare the efficacy of electrical block lines performed with radiofrequency (RF) compared with conventional surgery. METHODS: Randomized trial of 22 patients with CPAF and indication for mitral valve surgery. Ten patients underwent conventional surgery (SURG) and 12 RF. To prove the efficacy of the blockage lines, epicardial pacemaker wires were placed in the isolated pulmonary veins region (IPVR) and right atria (RA). RESULTS: There were no differences in the baseline data among the groups. All patients remained in SR during the immediate postoperative period. Block lines were tested in patients who remained in SR during the following days (eight in SURG and nine in RF). The median value of thresholds to conduct the stimulus of IPVR for the RA was 18 mA in SURG and 3 mA in RF (P < 0.022). Eight SURG patients and seven RF patients (P < 0.38) remained in SR at hospital discharge. Eleven RF patients and one SURG required amiodarone to maintain SR (P < 0.001). The incidence of recurrent atrial fibrillation (AF) in the follow-up was 10.7/100 patients/year in the SURG group versus 73.1/100 patients/year in the RF group (P = 0.009). CONCLUSIONS: PVI by SURG formed more effective block lines than RF. SR at hospital discharge was similar among the groups, but more amiodarone was used in RF. During follow-up, incidence of recurrent AF was higher in the RF group.

Concomitant anti-platelet therapy in warfarin-treated patients undergoing cardiac rhythm device implantation: A secondary analysis of the BRUISE CONTROL trial.

BACKGROUND: Anti-platelet therapy is commonly used in patients receiving oral anticoagulation and may increase bleeding risk among patients undergoing cardiac implantable electronic device (CIED) surgery. We sought to determine the proportion of anticoagulated patients who are concomitantly receiving anti-platelet therapy, the associated risk of clinically significant hematoma (CSH), and the proportion of patients in whom anti-platelet usage is guideline-indicated. METHODS: A secondary analysis of the Bridge or Continue Coumadin for Device Surgery Randomized Controlled Trial (BRUISE CONTROL). Patients who were receiving warfarin, had an annual predicted risk of thromboembolism of ≥5% and were scheduled to undergo non-emergent CIED surgery were randomized to continued warfarin versus heparin bridging. In the current analysis, patients were divided into those receiving anti-platelet therapy and those not receiving anti-platelet therapy. The incidence of CSH was compared in both groups. The proportion of patients on potentially inappropriate and potentially interruptible antiplatelet therapy was estimated. RESULTS: All 681 patients enrolled in BRUISE CONTROL were included, of whom 280 received and 401 did not receive anti-platelet therapy. Anti-platelet therapy increased the risk of CSH (relative risk, 1.72; 95% confidence interval (CI), 1.09 to 2.72; P = 0.02). Of the 280 patients receiving anti-platelet therapy, 97 (34.6%) had no guideline indication for concomitant anti-platelet therapy and an additional 146 (52.1%) were on anti-platelet therapy that could potentially have been interrupted around CIED surgery. CONCLUSIONS: Concomitant anti-platelet therapy in patients receiving anticoagulation is associated with a significant risk of CSH. The majority of concomitant anti-platelet therapy is potentially inappropriate or interruptible. TRIAL REGISTRATION: clinicaltrials.gov Identifier: (NCT00800137).

Effect of Direct Oral Anticoagulants, Warfarin, and Antiplatelet Agents on Risk of Device Pocket Hematoma: Combined Analysis of BRUISE CONTROL 1 and 2.

BACKGROUND: Oral anticoagulant use is common among patients undergoing pacemaker or defibrillator surgery. BRUISE CONTROL (Bridge or Continue Coumadin for Device Surgery Randomized Controlled Trial; NCT00800137) demonstrated that perioperative warfarin continuation reduced clinically significant hematomas (CSH) by 80% compared with heparin bridging (3.5% versus 16%). BRUISE-CONTROL-2 (NCT01675076) observed a similarly low risk of CSH when comparing continued versus interrupted direct oral anticoagulant (2.1% in both groups). Using patient level data from both trials, the current study aims to: (1) evaluate the effect of concomitant antiplatelet therapy on CSH, and (2) understand the relative risk of CSH in patients treated with direct oral anticoagulant versus continued warfarin. METHODS: We analyzed 1343 patients included in BRUISE-CONTROL-1 and BRUISE-CONTROL-2. The primary outcome for both trials was CSH. There were 408 patients identified as having continued either a single or dual antiplatelet agent at the time of device surgery. RESULTS: Antiplatelet use (versus nonuse) was associated with CSH in 9.8% versus 4.3% of patients (P<0.001), and remained a strong independent predictor after multivariable adjustment (odds ratio, 1.965; 95% CI, 1.202-3.213; P=0.0071). In multivariable analysis, adjusting for antiplatelet use, there was no significant difference in CSH observed between direct oral anticoagulant use compared with continued warfarin (odds ratio, 0.858; 95% CI, 0.375-1.963; P=0.717). CONCLUSIONS: Concomitant antiplatelet therapy doubled the risk of CSH during device surgery. No difference in CSH was found between direct oral anticoagulant versus continued warfarin. In anticoagulated patients undergoing elective or semi-urgent device surgery, the patient specific benefit/risk of holding an antiplatelet should be carefully considered. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifiers: NCT00800137, NCT01675076.

Simple surgical isolation of pulmonary veins for treating secondary atrial fibrillation in mitral valve disease.

BACKGROUND: Chronic atrial fibrillation (AF) due to mitral valve disease has been successfully treated by surgery. We performed a study to evaluate the effectiveness of a surgical method of simple pulmonary vein isolation (PVI) without radiofrequency or cryoablation in the restoration of sinus rhythm in a group of patients. METHODS: Fifteen patients were operated on for mitral valve disease and chronic AF. The technique consists basically of a circumferential incision excluding the pulmonary vein ostia from the left atrium. RESULTS: Sinus rhythm was achieved in 92.3% of the patients at 6-month follow-up. Echocardiograms 2 months after surgery showed a mean decrease of 1.1 cm in left atrial size. Effective atrial ejection was reestablished in all patients in whom sinus rhythm was achieved (mean LA ejection fraction 41% +/- 14%). Twenty-four hour Holter recordings did not show episodes of paroxysmal atrial fibrillation in any patients. Four patients had isolated episodes of ventricular ectopic beats. Stress electrocardiograms showed mean maximal ventricular response was 64% +/- 11% and 73% +/- 9% of predicted value at 2 and 6 months, respectively. All patients had improved NYHA functional class after surgery; 74% of patients were in NYHA functional class I at 6 months compared with 13.3% preoperatively. CONCLUSIONS: Pulmonary vein isolation without the use of radiofrequency or cryoablation is effective in restoring sinus rhythm in patients with chronic AF secondary to mitral valve disease. Based on simple surgical incisions, this technique is more advantageous than others requiring additional instrumentation.

Randomized study of surgery for patients with permanent atrial fibrillation as a result of mitral valve disease.

BACKGROUND: The Cox Maze procedure has been used to treat atrial fibrillation in patients with mitral valve disease. Recently, ectopic foci, originating in the pulmonary veins, were demonstrated in patients with atrial fibrillation, and the indication was that their arrhythmia could have a focal origin. In the light of this new evidence, a simplified surgical technique to isolate the pulmonary veins was developed to eliminate permanent atrial fibrillation in patients undergoing mitral valve surgery. This study compares three surgical procedures proposed to maintain sinus rhythm after mitral valve surgery. METHODS: A prospective clinical trial of 30 patients with mitral valve disease and permanent atrial fibrillation who had undergone mitral valve surgery were randomized in accordance with the type of surgery used on each: (1). associated en bloc isolation of pulmonary veins, (2). the Maze procedure, or (3). mitral valve correction alone. The preoperative clinical characteristics were similar in the three groups. RESULTS: The overall postoperative complications were similar in all three groups. The cardiopulmonary bypass time and the aortic cross-clamping time were shorter in the control group, but this factor bore no relation to increased morbidity in the intervention groups. The relative risk of atrial fibrillation after surgery was 0.08 in the group undergoing isolation of pulmonary veins (p = 0.010; 95% confidence interval, 0.01 to 0.71) and 0.20 in the Maze group (p = 0.044; 95% confidence interval, 0.04 to 1.02) compared with the control group. CONCLUSIONS: En bloc isolation of pulmonary veins associated with mitral valve surgery appears to be safe and just as effective as the Maze procedure in maintaining sinus rhythm in patients with permanent atrial fibrillation.

Isolation of the pulmonary veins in patients with permanent atrial fibrillation secondary to mitral valve disease.

OBJECTIVE: To assess the efficacy of surgical isolation of the pulmonary veins for re-establishing sinus rhythm in patients with atrial fibrillation secondary to mitral valve disease. METHODS: Thirty-three (67% were women) patients with permanent atrial fibrillation and indication for surgical correction of the mitral valve underwent surgical isolation of the pulmonary veins. Their mean age was 56.3+/-10 years, preoperative NYHA functional class was 3.2+/-0.6, left atrial size was 5.5+/-0.9 cm, and ejection fraction was 61.3+/-13%. The surgical technique consisted of a circumferential incision surrounding the 4 pulmonary veins, excision of the left atrial appendage, and a perpendicular incision originating in the inferior margin of the circumferential incision isolating the pulmonary veins down to the mitral valve. Early arrhythmias were aggressively treated with cardioversion. RESULTS: The mean follow-up was 23.9+/-17 months, and 3 patients died in the postoperative period. Ten patients required electrical cardioversion in the postoperative period; 87% had sinus rhythm in the last medical visit, and 33% were using amiodarone. CONCLUSION: Isolation of the pulmonary veins associated with mitral valve surgery is an effective and safe technique for maintaining sinus rhythm in patients with permanent atrial fibrillation.

A new algorithm for weekly phenprocoumon dose variation in a southern Brazilian population: role for CYP2C9, CYP3A4/5 and VKORC1 genes polymorphisms.

Phenprocoumon is widely used in prophylaxis and treatment of thromboembolic disorders. However, its pharmacokinetics and pharmacodynamics vary according to several genetic and non-genetic factors. Phenprocoumon metabolism is mediated by CYP2C9 and CYP3A enzymes. Moreover, VKORC1 is phenprocoumon target of action. Therefore, the aim of this study was to evaluate the association of single nucleotide polymorphisms (SNPs) in VKORC1, CYP2C9, CYP3A4 and CYP3A5 genes with the variance of weekly phenprocoumon dose as well as to develop an algorithm for dose prediction based on genetic and environmental factors. A total of 198 patients with stable phenprocoumon dose, 81% of European ancestry, were investigated. Genotypes were determined by allelic discrimination with TaqMan assays. Polymorphisms -1639G>A and 1173C>T in VKORC1 and the presence of CYP2C9*2 and/or CYP2C9*3 are associated with lower doses. On the other hand, 3730G>A in VKORC1 gene is associated with higher doses. No association was found between CYP3A4*1B, CYP3A5*3 and CYP3A5*6 polymorphisms. Among non-genetic factors, gender, height, age and use of captopril, omeprazole, simvastatin and ß-blockers are associated with dose. Two algorithms were derived: one for the whole sample explained 42% of dose variation and one for patients of European ancestry only which explained 46% of phenprocoumon dose. The mean absolute difference between observed and predicted dose was low in both models (3.92 mg/week and 3.54 mg/week, for models 1 and 2, respectively). However, more studies with other genes and environmental factors are needed to test and to improve the algorithm.

Taquiarritmia fetal com conduçäo atrioventricular 1: 1. Infusäo em veia umbilical de adenosina como teste diagnóstico / Fetal tachyarrhythmia with 1: 1 atrioventricular conduction. Adenosine infusion in the umbilical vein as a diagnostic test

This is the report of a case of fetal tachyarrhythmia with 1:1 atrioventricular conduction detected by pre-natal echocardiography in a fetus at 25-weeks gestation. Adenosine infusion via cordocentesis was performed as a diagnostic test to differentiate between atrioventricular nodal reentrant supraventricular tachyarrhythmia and atrial flutter. After infusion, transient 2:1 atrioventricular dissociation was obtained and the diagnosis of atrial flutter was made. Transplacental therapy with digoxin and amiodarone was then successfully used.

Isolamento das veias pulmonares em pacientes com fibrilação atrial permanente secundária a valvopatia mitral / Isolation of the pulmonary veins in patients with permanent atrial fibrillation secondary to mitral valve disease

OBJETIVO: Analisar a eficácia do isolamento cirúrgico das veias pulmonares para restabelecer ritmo sinusal em pacientes com fibrilação atrial secundária à doença mitral. MÉTODOS: 33 pacientes com indicação de correção cirúrgica da valva mitral e com fibrilação atrial permanente, foram submetidos ao isolamento cirúrgico das veias pulmonares, sendo 67 por cento mulheres. Média de idade de 56,3±10 anos, classe funcional NYHA pré-operatória de 3,2±0,6, tamanho de átrio esquerdo de 5,5± 0,9 cm, fração de ejeção de 61,3±13 por cento. A técnica cirúrgica consistiu de incisão circunferencial ao redor das 4 veias pulmonares, excisão do apêndice atrial esquerdo e de incisão perpendicular desde a borda inferior da incisão, isolando as veias pulmonares, até o ânulo da valva mitral. Arritmias precoces foram tratadas, agressivamente, com cardioversão. RESULTADOS: O seguimento médio foi de 23,9±17 meses e ocorreram 3 óbitos no pós-operatório. Dez pacientes necessitaram de cardioversão elétrica no pós-operatório; 87 por cento apresentavam ritmo sinusal na última consulta e 33 por cento estavam em uso de amiodarona. CONCLUSAO: Isolamento das veias pulmonares associado à cirurgia da valva mitral é uma técnica efetiva e segura na manutenção de ritmo sinusal em pacientes com fribilação atrial permanente.

Técnica cirúrgica simplificada pode ser eficaz no tratamento da fibrilação atrial crônica secundária a lesão valvar mitral? / Simplified surgical technique for the treatment of chronic atrial fibrillation in patients with mitral valve disease: could it work?

INTRODUÇÃO: Fibrilação atrial tem sido tratada pelo procedimento do Labirinto (Cox) e suas modificações. Há, no entanto, evidências de que o isolamento dos óstios das veias pulmonares ou exclusão do átrio esquerdo poderia ser eficaz para este fim. CASUÍSTICA E MÉTODOS: Avaliamos os resultados iniciais da técnica simplificada de isolamento cirúrgico dos óstios das veias pulmonares para tratar fibrilação atrial crônica em pacientes operados por lesão valvar mitral. Foram tratados 7 pacientes por esta técnica (grupo IVP) e comparados com série prévia de 57 casos submetidos a cirurgia do Labirinto (Cox 3). RESULTADOS: A idade média foi de 49 + ou - 8 anos vs 49 + ou -11 anos, (IVP vs. Cox3), sendo 71 por cento e 72 por cento (IVP vs. Cox 3) do sexo feminino. Dimensões do átrio esquerdo 5,5 + ou -0,7 cm vs. 6,0 + ou -1,1 cm (IVP vs. Cox 3). Fração de ejeção ventricular 63 + ou -10 por cento vs. 64 + ou -6 por cento (IVP vs. Cox 3). Tempo CEC 91 + ou -33 min vs. 104 + ou - 29 min (IVP vs. Cox 3). Tempo de isquemia 71 + ou - 23 min vs. 83 + ou - 26 min (IVP vs. Cox 3). Ritmo pós-operátório sinusal/atrial n(por cento): 6(86) vs. 46(80) (IVP vs. Cox 3). Ritmo marcapasso n(por cento):1 (14) vs. 4 (7) (IVP vs. Cox 3). Fibrilação atrial n( por cento): 0 vs. 7 (13) (IVP vs. Cox 3). CONCLUSÕES: Resultados iniciais mostram reversão a ritmo sinusal na maioria dos casos em ambos procedimentos e manutenção do ritmo a longo prazo. Foi iniciado estudo prospectivo randomizado para avaliar o IVP comparativamente ao procedimento Cox 3.

Sinusite fúngica: uma análise clínica em nosso meio / Fungal sinusitis: a clinical analysis

Objetivo: relatar achados microbiológicos, histopatológicos, radiológicos e endoscópicos associados às observações clínicas de pacinetes portadores de sinusite fúngica. Materiais e métodos: foi realizada análise prospectiva de 829 casos compatíveis com sinusopatia crônica, através de tomografia computadorizada e endoscopia nasal, análises clínicas, laboratoriais, microbiológicas e histopatológicas, chegou-se ao diagnóstico de sinusite fúngica em 33 pacientes, os quais foram enquadrados em uma das seguintes classificações_ bola fúngica, sinusite fúngica alérgica, sinusite invasiva aguda (fulminante) ou sinusite indolente ou lentamente invasiva...

Atualizaçäo em fibrilaçäo atrial / Atrial vibrilation: an update

Fibrilação atrial é uma arritmia cardíaca sustentada com expressiva prevalência na população. A ocorrência de fibrilação atrial aumenta de três a cinco vezes o risco de acidentes vasculares cerebrais isquêmicos e este risco é ainda maior quando existe concomitância de valvulopatia. O presente artigo faz uma atualização dos principais aspectos clínicos, epidemiológicos, fisiopatológicos e terapêuticos da doença