ABSTRACT
von Willebrand Disease (VWD) is associated with significant morbidity because of excessive bleeding. Early diagnosis and treatment are important to prevent and treat these symptoms. We systematically reviewed the accuracy of any von Willebrand factor (VWF) activity assay in the diagnosis and classification of patients for VWD. We searched Cochrane Central, MEDLINE, and EMBASE for eligible studies. The risk of bias was assessed using the Quality Assessment of Diagnostic Accuracy Studies (QUADAS)-2 and the certainty of evidence using the GRADE framework. We pooled estimates of sensitivity and specificity. The review included 77 studies that evaluated the use of newer tests of VWF platelet binding activity (VWF:GPIbR, VWF:GPIbM) and VWF:RCo for the diagnosis of VWD (13 studies), VWF propeptide to VWF:Ag ratio, and desmopressin trial for the diagnosis of type 1C VWD (5 studies), VWF multimer analysis and VWF:CB/VWF:Ag ratio for the classification of type 2 VWD (11 studies), genetic testing and ristocetin-induced platelet aggregation to diagnose type 2B VWD (14 studies), genetic testing and FVIII:VWF binding to diagnose type 2N VWD (17 studies). Based on available diagnostic test accuracy, there appear to be comparable test accuracy results between newer tests of platelet binding activity of VWF function and VWF:RCo. The findings of these reviews support VWF multimer analysis or VWF:CB/VWF:Ag to diagnose type 2 VWD. The desmopressin trial test with 1- and 4-hour postinfusion blood work is the test of choice to confirm increased VWF clearance in patients with suspected VWD type 1C. Additionally, genetic testing is most useful in diagnosing type 2B VWD and has a role in the diagnostic algorithm of suspected type 2N VWD.
Subject(s)
von Willebrand Disease, Type 2 , von Willebrand Diseases , Blood Coagulation Tests , Deamino Arginine Vasopressin/therapeutic use , Humans , von Willebrand Diseases/diagnosis , von Willebrand Diseases/drug therapy , von Willebrand Factor/metabolismABSTRACT
Autoimmune rheumatological disorders are known to have an increased risk for cardiovascular diseases including coronary artery disease (CAD), myocarditis, pericarditis, valvulopathy, and in consequence cardiogenic shock. Data on cardiogenic shock in rheumatological diseases are scarce; however, several reports have highlighted this specific entity. We sought to review the available literature and highlight major outcomes and the management approaches in each disease. Systematic literature search, including PubMed, Ovid/Medline, Cochrane Library, and Web of Science, was conducted between January 2000 and December 2009. We reviewed all cases reporting cardiogenic shock with rheumatologic conditions, including systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), Takayasu's arteritis (TA), granulomatosis with polyangiitis (GPA), giant cell arteritis (GCA), and antiphospholipid syndrome (APS). We selected 45 papers reporting a total of 48 cases. Mean age was 39 ± 7.3 years and 68.8% were females. Most common rheumatologic conditions associated with cardiogenic shock were SLE (31%), GPA (23%), TA (14.6%), APA (10.4%), and RA (8.3%). Cardiogenic shock was found to be caused by eosinophilic myocarditis in 58% of cases, CAD in 19% of cases, and valvulopathy in 6% of cases. Most patient required high-dose steroids and second immunosuppressant therapy. Mechanical circulatory supported was required in 23 cases, IABP in 16 cases, and ECMO in 12 cases. Complete recovery occurred in 37 patients while 9 patients died and 2 required heart transplant. Responsible for two-thirds of cases, eosinophilic myocarditis should be suspected in young cardiogenic shock patients with underlying rheumatologic conditions. Lupus and GPA are the two most common conditions.
Subject(s)
Arthritis, Rheumatoid , Autoimmune Diseases , Rheumatic Diseases , Adult , Autoimmune Diseases/complications , Female , Humans , Middle Aged , Rheumatic Diseases/complications , Shock, Cardiogenic/epidemiology , Shock, Cardiogenic/etiology , Shock, Cardiogenic/therapy , Treatment OutcomeABSTRACT
von Willebrand disease (VWD) is the most common inherited bleeding disorder. The management of patients with VWD who are undergoing surgeries is crucial to prevent bleeding complications. We systematically summarized the evidence on the management of patients with VWD who are undergoing major and minor surgeries to support the development of practice guidelines. We searched Medline and EMBASE from inception through October 2019 for randomized clinical trials (RCTs), comparative observational studies, and case series that compared maintaining factor VIII (FVIII) levels or von Willebrand factor (VWF) levels at >0.50 IU/mL for at least 3 days in patients undergoing major surgery, and those with options for perioperative management of patients undergoing minor surgery. Two authors screened and abstracted data and assessed the risk of bias. We conducted meta-analyses when possible. We evaluated the certainty of the evidence using the Grading of Recommendations, Assessment, Development and Evaluations (GRADE) approach. We included 7 case series for major surgeries and 2 RCTs and 12 case series for minor surgeries. Very-low-certainty evidence showed that maintaining FVIII levels or VWF levels of >0.50 IU/mL for at least 3 consecutive days showed excellent hemostatic efficacy (as labeled by the researchers) after 74% to 100% of major surgeries. Low- to very-low-certainty evidence showed that prescribing tranexamic acid and increasing VWF levels to 0.50 IU/mL resulted in fewer bleeding complications after minor procedures compared with increasing VWF levels to 0.50 IU/mL alone. Given the low-quality evidence for guiding management decisions, a shared-decision model leading to individualized therapy plans will be important in patients with VWD who are undergoing surgical and invasive procedures.
Subject(s)
Tranexamic Acid , von Willebrand Diseases , Factor VIII/therapeutic use , Hemostasis , Humans , Tranexamic Acid/therapeutic use , von Willebrand Diseases/complications , von Willebrand Factor/therapeutic useABSTRACT
von Willebrand disease (VWD) is associated with significant morbidity as a result of excessive mucocutaneous bleeding. Early diagnosis and treatment are important to prevent and treat these symptoms. We systematically reviewed the accuracy of diagnostic tests using different cutoff values of von Willebrand factor antigen (VWF:Ag) and platelet-dependent von Willebrand factor (VWF) activity assays in the diagnosis of VWD. We searched Cochrane Central Register for Controlled Trials, MEDLINE, and Embase databases for eligible studies. We pooled estimates of sensitivity and specificity and reported patient-important outcomes when relevant. This review included 21 studies that evaluated VWD diagnosis. The results showed low certainty in the evidence for a net health benefit from reconsidering the diagnosis of VWD vs removing the disease diagnosis in patients with VWF levels that have normalized with age. For the diagnosis of type 1 VWD, VWF sequence variants were detected in 75% to 82% of patients with VWF:Ag < 0.30 IU/mL and in 44% to 60% of patients with VWF:Ag between 0.30 and 0.50 IU/mL. A sensitivity of 0.90 (95% confidence interval [CI], 0.83-0.94) and a specificity of 0.91 (95% CI, 0.76-0.97) were observed for a platelet-dependent VWF activity/VWF:Ag ratio < 0.7 in detecting type 2 VWD (moderate certainty in the test accuracy results). VWF:Ag and platelet-dependent activity are continuous variables that are associated with an increase in bleeding risk with decreasing levels. This systematic review shows that using a VWF activity/VWF:Ag ratio < 0.7 vs lower cutoff levels in patients with an abnormal initial VWD screen is more accurate for the diagnosis of type 2 VWD.
Subject(s)
von Willebrand Disease, Type 1 , von Willebrand Diseases , Blood Coagulation Tests , Hemorrhage/diagnosis , Hemorrhage/etiology , Humans , von Willebrand Disease, Type 1/diagnosis , von Willebrand Diseases/diagnosis , von Willebrand Factor/analysisABSTRACT
Von Willebrand disease (VWD) can be associated with significant morbidity. Patients with VWD can experience bruising, mucocutaneous bleeding, and bleeding after dental and surgical procedures. Early diagnosis and treatment are important to minimize the risk of these complications. Several bleeding assessment tools (BATs) have been used to quantify bleeding symptoms as a screening tool for VWD. We systematically reviewed diagnostic test accuracy results of BATs to screen patients for VWD. We searched Cochrane Central, MEDLINE, and EMBASE for eligible studies, reference lists of relevant reviews, registered trials, and relevant conference proceedings. Two investigators screened and abstracted data. Risk of bias was assessed using the revised tool for the quality assessment of diagnostic accuracy studies and certainty of evidence using the Grading of Recommendations Assessment, Development and Evaluation framework. We pooled estimates of sensitivity and specificity. The review included 7 cohort studies that evaluated the use of BATs to screen adult and pediatric patients for VWD. The pooled estimates for sensitivity and specificity were 75% (95% confidence interval, 66-83) and 54% (29-77), respectively. Certainty of evidence varied from moderate to high. This systematic review provides accuracy estimates for validated BATs as a screening modality for VWD. A BAT is a useful initial screening test to determine who needs specific blood testing. The pretest probability of VWD (often determined by the clinical setting/patient population), along with sensitivity and specificity estimates, will influence patient management.
Subject(s)
von Willebrand Diseases , Adult , Bias , Child , Cohort Studies , Humans , Mass Screening , Sensitivity and Specificity , von Willebrand Diseases/diagnosisABSTRACT
PURPOSE: Intracardiac echocardiography (ICE) is increasingly common among periprocedural imaging modalities used during complex cardiac procedures. We sought to perform a meta-analysis comparing transesophageal echocardiography (TEE) and ICE in endocardial left atrial appendage occlusion (LAAO). METHODS: We searched PubMed and Google Scholar regarding abstracts and manuscripts using keywords: atrial fibrillation, left atrial appendage occlusion, Watchman, Amplatzer Cardiac Plug, Amulet, intracardiac echocardiography, and transesophageal echocardiography from their inception to July 12, 2019. Data extraction was performed using standard form for the following: title, year of publication, sample size, comorbid conditions, LAAO device, type of pre-procedural imaging, intraprocedural imaging, and clinical outcomes including the following: acute procedural success, fluoroscopy, and total procedure time and complications. RESULTS: A total of 42 relevant studies were screened resulting in inclusion of 8 observational studies comparing TEE and ICE in endocardial LAAO. Outcomes assessed including procedural success (RR 1.00, 95% CI (0.97-1.03, p = 0.98)), complications (RR 0.77, 95% CI (0.52 to 1.15, p = 0.20)), fluoroscopy time (mean difference - 0.40, 95% CI (-3.12-2.32, p = 0.77)), and procedural time (mean difference - 8.02, 95% CI (-22.81 to 6.76, p = 0.29)) were found to be similar between both groups. CONCLUSIONS: While TEE is the gold standard for perioperative imaging with LAAO, ICE is a feasible and safe alternative that reduces exposure to general anesthesia and associated potential risks.
Subject(s)
Atrial Appendage , Atrial Fibrillation , Echocardiography, Transesophageal , Atrial Appendage/diagnostic imaging , Atrial Appendage/surgery , Atrial Fibrillation/diagnostic imaging , Atrial Fibrillation/surgery , Cardiac Catheterization , Humans , Predictive Value of Tests , Treatment OutcomeABSTRACT
Hydralazine, an arterial vasodilator, is a widely used medication for the management of hypertension and heart failure, especially for patients who cannot tolerate the use of ACEIs or ARBs. It is generally well-tolerated and has a safe profile in pregnancy. However, hydralazine can induce immune-mediated side effects, such as hydralazine-induced lupus and less commonly hydralazine- induced ANCA vasculitis. The latter most commonly affects the kidneys with or without other organ involvement. There are several cases reported in the literature of hydralazine-induced ANCA associated vasculitis (AAV) that have pulmonary manifestations, also known as hydralazine- induced pulmonary-renal syndrome (PRS), a condition with a high risk of mortality. We are reporting a case of Hydralazine-induced ANCA associated glomerulonephritis with severe diffuse alveolar hemorrhage (DAH). In addition, we will review the current literature and discuss the importance of prompt diagnosis and early management to decrease mortality and morbidity associated with this serious condition.
Subject(s)
Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis , Glomerulonephritis , Hemorrhage , Hydralazine/adverse effects , Lung Diseases , Vasodilator Agents/adverse effects , Aged , Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis/chemically induced , Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis/diagnosis , Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis/pathology , Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis/therapy , Female , Glomerulonephritis/chemically induced , Glomerulonephritis/diagnosis , Glomerulonephritis/pathology , Glomerulonephritis/therapy , Heart Failure , Hemorrhage/chemically induced , Hemorrhage/diagnosis , Hemorrhage/pathology , Hemorrhage/therapy , Humans , Hydralazine/therapeutic use , Hypertension/drug therapy , Lung/diagnostic imaging , Lung/pathology , Lung Diseases/chemically induced , Lung Diseases/diagnosis , Lung Diseases/pathology , Lung Diseases/therapy , Vasodilator Agents/therapeutic useABSTRACT
PURPOSE: Phrenic and hypoglossal nerve pacing therapies have shown benefit in sleep apnea. We sought to analyze the role of pacing therapies in sleep apnea and their impact on heart failure. METHODS: A comprehensive literature search in PubMed and Google Scholar from inception to August 5, 2019, was performed. A meta-analysis was performed using fixed effects model to calculate mean difference (MD) with 95% confidence interval (CI). RESULTS: Six studies were eligible and included 626 patients, of whom 334 were in the control arm and 393 were in the experimental arm. Phrenic nerve pacing (MD - 23.20 events/h, 95% CI - 27.96 to - 18.44, p < 0.00001) and hypoglossal nerve pacing (MD - 20.24 events/h, 95% CI - 23.22 to - 17.27, p < 0.00001) were associated with improvements in apnea-hypopnea index (AHI). Phrenic nerve pacing was associated with a trend towards improvements in left ventricular ejection fraction (MD 3.95%, 95% CI - 0.04 to 7.94, p = 0.05). Hypoglossal and phrenic nerve pacing were associated with improvements in the quality of life as assessed by improvements in Epworth sleepiness scale (MD 3.71 points, 95% CI 2.89 to 4.54, p < 0.00001). CONCLUSIONS: Our analysis suggests that phrenic and hypoglossal nerve pacing improves AHI and quality of life with a trend towards improvement in left ventricular ejection fraction, especially in central sleep apnea. Complications were high but future refinement in technology will likely improve clinical outcomes and minimize complications.
Subject(s)
Sleep Apnea Syndromes , Sleep Apnea, Obstructive , Humans , Quality of Life , Sleep Apnea Syndromes/therapy , Sleep Apnea, Obstructive/therapy , Stroke Volume , Ventricular Function, LeftABSTRACT
BACKGROUND: Biliary pericardial tamponade (BPT) is a rare form of pericardial tamponade, characterized by yellowish-greenish pericardial fluid upon pericardiocentesis. Historically, BPT reported to occur in the setting of an associated pericardiobiliary fistula. However, BPT in the absence of a detectable fistula is extremely rare. LEARNING OBJECTIVE: A biliary pericardial tamponade is a rare form of tamponade warranting a prompt workup (e.g., MRCP or HIDA scan) for a potential fistula between the biliary system and the pericardial space. A pericardio-biliary fistula can be iatrogenic or traumatic. People with a history of chest wall trauma, abdominal surgery, or chest surgery are at increased risk. The use of HIDA scanning plays a salient role in effectively surveilling for the presence of a fistula - especially when MRCP is contraindicated. CASE PRESENTATION: A 75-year-old Hispanic male presenting with dyspnea and diagnosed with cardiac tamponade is the subject of the study. Subsequent pericardiocentesis revealed biliary pericardial fluid (bilirubin of 7.6 mg/dl). The patient underwent extensive workup to identify a potential fistula between the hepatobiliary system and the pericardial space, which was non-revealing. The mechanism of bile entry into the pericardial space remains to be unidentified. LITERATURE REVIEW: A total of six previously published BPT were identified: all were males, with a mean age of 53.3 years (range: 31-73). Mortality was reported in two out of the six cases. The underlying etiology for pericardial tamponade varied across the cases: incidental pericardio-biliary fistula, traumatic pericardial injury, and presence of associated malignancy. - Conclusion: Biliary pericardial tamponade is a rare form of tamponade that warrants a prompt workup (e.g., Hepatobiliary Iminodiacetic Acid - HIDA scan) for an iatrogenic vs. traumatic pericardio- biliary fistula. As a first case in the literature, our case exhibits a biliary tamponade in the absence of an identifiable fistula.
Subject(s)
Biliary Tract Diseases , Cardiac Tamponade , Adult , Aged , Dyspnea , Female , Humans , Male , Middle Aged , PericardiocentesisABSTRACT
Right atrial thrombus can originate from distal venous sources or can be iatrogenic, secondary to the placement of central venous catheters, atrial devices, or surgeries. One of the most common complications of Central Venous Catheters (CVCs) is thromboembolism, which can be either fixed to the right atrium or can be free-floating. Device-related Right Atrial Thrombosis (RAT) can result in catheter occlusion, vascular occlusion, infection, and pulmonary embolism. The true incidence of these complications is unknown because the diagnosis may not be considered in asymptomatic patients, and it might be missed by Transthoracic Echocardiography (TTE). In this literature review, we discuss iatrogenic etiologies of RAT that is complicated by pulmonary embolism. We highlight the importance of maintaining a high index of suspicion of iatrogenic RAT, possible complications, and its management.
Subject(s)
Heart Diseases , Pulmonary Embolism , Heart Atria/diagnostic imaging , Heart Diseases/diagnostic imaging , Heart Diseases/etiology , Humans , Iatrogenic Disease , Pulmonary Embolism/diagnostic imaging , Pulmonary Embolism/etiology , Pulmonary Embolism/therapy , Thromboembolism , Thrombosis/diagnostic imaging , Thrombosis/etiologyABSTRACT
Heart failure (HF) affects an increasing number of geriatric patients. The condition is classified according to whether the left ventricular ejection fraction (EF) is reduced or preserved. Many patients have heart failure with preserved ejection fraction (HFpEF) and face a shortage of effective therapeutic strategies. However, an emerging mechanical strategy for treatment is gaining momentum. Interatrial septal connection devices, i.e. V-wave device and Interatrial septal device, are new devices for patients with heart failure with preserved ejection fraction. We review the function of these systems and the data from the recent clinical trials. Interatrial septal connection device therapy provided favorable efficacy and safety profile applicable to a wide range of patients with HFpEF. However, the long-term effects of these devices on morbidity.
Subject(s)
Heart Failure , Aged , Atrial Pressure , Cardiac Catheterization , Heart Failure/therapy , Humans , Stroke Volume , Treatment Outcome , Ventricular Function, LeftABSTRACT
BACKGROUND: Systemic Mastocytosis (SM) is a disorder of excessive mast cell infiltration in multiple organ tissues. Atherosclerosis is a major risk factor for developing acute coronary syndrome. In addition to lipid accumulation in the arterial wall, inflammation plays an important role in the pathogenesis of plaque rupture and activating the thrombosis cascade. The Mast cells contribution to plaque destabilization has been well established in multiple animal and human studies. In a recent study, SM has been proven to be associated with a higher incidence of acute coronary syndrome even with lower plasma lipids levels. The study showed that 20% of patients with SM had cardiovascular events compared to only 6% in the control group with adjustment to all cardiac risk factors. CASE: We presented a patient with no risk factors for heart disease other than old age and history of SM who developed acute myocardial infarction. CONCLUSION: SM can be life-threatening and can result in ACS, anaphylactic reaction, syncope, or cardiac arrest. Clinicians should have a high index of suspicion of acute coronary syndrome (ACS) occurrence in the setting of inflammatory conditions, such as SM and KS, and vice versa, where SM should be considered or ruled out in patients who suffer from anaphylaxis and cardiac arrest or myocardial infarction.
Subject(s)
Acute Coronary Syndrome/etiology , Mastocytosis, Systemic/complications , Myocardial Infarction/etiology , Acute Disease , Aged , Female , Humans , Risk FactorsABSTRACT
Coronary Artery Fistulas (CAF) are inappropriate connections between a coronary artery and a major vessel or a cardiac chamber. These fistulas may or may not present with symptoms, but they need to be detected as early as possible in order to decide the most appropriate treatment methodology (i.e. surgery vs. conservative management). We report the case of a 67-year-old female with no modifiable cardiovascular risk factors who had an unwitnessed sudden death at home during her ongoing evaluation of a fistula detected incidentally between the Left Anterior Descending Artery (LAD) and the Pulmonary Artery (PA). This case highlights that early diagnosis and treatment of symptomatic CAF are crucial to minimize the risk of sudden cardiac death. Although the symptomatic fistula of LAD to PA has been reported in the literature multiple times, it has been rarely reported that this fistula can result in sudden cardiac death.
Subject(s)
Coronary Vessel Anomalies/complications , Death, Sudden, Cardiac/etiology , Fistula/diagnosis , Aged , Death, Sudden, Cardiac/pathology , Female , HumansABSTRACT
BACKGROUND: Austrian syndrome, which is also known as Osler's triad, is a rare aggressive pathology consisting of pneumonia, endocarditis, and meningitis caused by Streptococcus pneumoniae and carries drastic complications. CASE PRESENTATION: A case of a 68-year-old female with a past medical history of hypertension and had a recent viral influenza is presented. She developed bacterial pneumonia, endocarditis with mitral and aortic vegetations and perforation, meningitis, and right sternoclavicular septic arthritis. Two prior case reports have described sternoclavicular septic arthritis as part of Austrian syndrome. Our case is the third case; however, it is the first case to have this tetrad in an immunocompetent patient with no risk factors, i.e., males, chronic alcoholism, immunosuppression, and splenectomy. CONCLUSIONS: Clinicians should maintain a high index of suspicion for the possibility of sternoclavicular joint septic arthritis as a complication of Austrian syndrome in immunocompetent patients.
ABSTRACT
Endocardial LAAO has been increasingly utilized in atrial fibrillation (AF) patients who are not suitable for long term oral anticoagulation. While overall procedural complications have decreased, rare complications like contiguous vessel and valve injury may be more frequently seen in the future with increase in the procedure volume. We performed a systematic search using predefined terms which reviewed all cases published in literature of contiguous vessel (pulmonary artery, pulmonary vein and left circumflex artery) and mitral valve injury caused by LAAO devices. Our results showed that Amplatzer Cardiac Plug (ACP) and Amplatzer Amulet devices were the most commonly used devices. Pulmonary artery perforation was the most commonly seen collateral vessel injury associated with LAAO. Close proximity of left atrial appendage to pulmonary artery was noted in all cases of pulmonary artery injury. Pulmonary artery injury commonly manifests as pericardial tamponade with hemodynamic collapse and is often fatal. Most common denominator of all the reviewed cases was the presence of an oversized LAAO device. In conclusion, collateral vessels and valve injury can be seen after LAAO mostly with double lobe devices such as ACP or Amulet. Increased awareness by the operators along with proper imaging and investigations could potentially mitigate such rare complications associated with LAAO.
ABSTRACT
BACKGROUND: Manufacturer/federal drug administration (FDA) recommends inpatient initiation of dofetilide with the manufacturer providing an initiation algorithm. The outcomes of algorithm deviation have not been reported outside of clinical trials. OBJECTIVE: We sought to perform a chart review of all the patients admitted for inpatient initiation of dofetilide to report on the incidence of protocol deviations and their implications. METHODS: We performed a retrospective review of all patients over a 15-month periodwho were initiated on dofetilide for the very first time or reinitiated on dofetilide after a break of three months or more at our institution. We assessed data about patients who were given dofetilide without adherence to the protocol (i.e. protocol deviation). RESULTS: A total of 189 patients were included in the study with a median age of 66 ± 9 years. Mean baseline QTc interval was 436 ± 32 msec, and 61% (116/189) were in atrial fibrillation (AF) at the time of dofetilide initiation. In 9% (17/189) of patients, the drug was discontinued due to intolerance or inefficacy. Therapy in 49% (93/189) of patients was noted to deviate from manufacturer recommended protocol with deviations more than once in some patients during the same hospitalization. Baseline QTc exceeding 440 msec(>500msec in conduction abnormalities) was the most frequent deviation (25%; 47/189).Ventricular tachyarrhythmia occurred in 4% (7/189) of patients, did not differ between patients, and occurred with and without protocol deviations (5% vs 2%; p = 0.27). CONCLUSIONS: In our retrospective study, there were frequent deviations from the manufacturer-recommended algorithm guidelines for dofetilideinitation, primarily due to prolonged baseline QTc interval. The impact of these protocol deviations on drug discontinuation was uncertain; however, significant adverse events were higher in the deviation group compared to the group that fully adhered to the protocol. Further multicenter studies are warranted to clarify our findings.