Second look endoscopy in acute non-variceal upper gastrointestinal bleeding

Bleeding peptic ulcer remained an important cause of hospitalization worldwide. Primary endoscopic hemostasis achieved more than 90% of initial hemostasis for bleeding peptic ulcer. Recurrent bleeding amounted to 15% after therapeutic endoscopy, and rebleeding is an important risk factor to peptic ulcer related mortality. Routine second look endoscopy was one of the strategies targeted at prevention of rebleeding. The objective of second look endoscopy was to treat persistent stigmata of recent hemorrhage before rebleeding. Three meta-analyses showed that performance of routine second look endoscopy significantly reduced ulcer rebleeding especially when the endoscopic therapy was performed with thermal coagulation. Two cost-effectiveness analyses, however, demonstrated that selective instead of routine second look endoscopy is the most cost-effective approach to prevent ulcer rebleeding. While international consensus and guidelines did not recommend routine performance of second look endoscopy for prevention of ulcer rebleeding, further research should focus on identification of patients with high risk of rebleeding and investigate the effect of selective second look endoscopy in prevention of rebleeding among these patients.     

内镜治疗在急性非静脉曲张上消化道出血中的应用

急性非静脉曲张上消化道出血是临床常见的急危重症。内镜技术在急性非静脉曲张上消化道出血的治疗中有重要价值。近年此领域有了持续的新进展。本文即就内镜治疗对急性非静脉曲张上消化道出血的适宜治疗患者、治疗时机以及治疗方法和策略等方面给予简述。     

In-hospital mortality in non-variceal upper gastrointestinal bleeding Forrest 1 patients

Objective. Non-variceal upper gastrointestinal bleeding (NVUGIB) is recognized world-wide as a common cause of emergency hospitalization, and it often represents a life-threatening event. The purpose of this prospective study was to assess in-hospital mortality in NVUGIB Forrest 1 patients admitted to the emergency unit owing to active bleeding. Material and methods. We enrolled all patients consecutively admitted to the emergency unit for NVUGIB, acutely bleeding at endoscopy (spurting or oozing). Demographic characteristics, clinical and biochemical parameters, endoscopic findings and treatments were evaluated. Results. Of a total of 142 patients (98 M (69%), mean age±SD=66±14 years), spurting (16 (11.3%)) and oozing (126 (88.7%)) were identified. All patients received endoscopic treatment within 6 h of admission and were managed according to the guidelines. Seventeen (12%) patients suffered rebleeding, 4 patients (2.8%) required surgery to stop the bleeding, and 8 (5.6%) died during hospitalization (4 within 5 days and the remainder within 24 days of admission) – 3 as a consequence of bleeding (2.1%) and 5 of non-surgical complications (3.5%). Cox regression analysis showed that the lesions in more than one segment of the esophagogastroduodenal tract (p=0.008, hazard ratio (95% CI)=7.623 (1.680–34.600)) and the number of blood units transfused during the first 48 h of hospitalization (p=0.038, 2.075 (1.041–4.135)) were predictive of in-hospital death. Conclusions. In Forrest 1 patients given rapid endoscopic treatment, in-hospital mortality seems to be related to the contemporaneous presence of bleeding and non-bleeding lesions in more than one segment of the esophagogastroduodenal tract and the number of blood units transfused during the first 48 h of hospitalization.     

Prognostic factors in patients with active non-variceal upper gastrointestinal bleeding

Background and study aims

Acute upper gastrointestinal bleeding is one of the main causes of hospitalisation. The purpose of this study was to determine the prognostic factors in non-variceal upper gastrointestinal bleeding.

Assessing guideline adherence in patients with non-variceal upper gastrointestinal bleeding receiving antiplatelet and anticoagulant therapy

Abstract

Background & aims: Non-variceal upper gastrointestinal bleeding (NVUGIB) occurs frequently and is associated with a significant morbidity and mortality, especially in patients receiving antiplatelet or anticoagulant therapy (APT and ACT, respectively). We aimed to evaluate adherence to guideline recommendations published by European Society of Gastrointestinal Endoscopy (ESGE).

Methods: Retrospective analysis of patients with NVUGIB und prior exposition to APT or ACT at a single university hospital between 01 January 2016 and 31 December 2017.

Results: 270 patients were identified (70.4% male, median age 72?years). 6/17 (35.3%) patients receiving APT for primary cardiovascular prophylaxis, 39/71 (54.9%) and 35 (49.3%) patients receiving APT for secondary cardiovascular prophylaxis (using strict and liberal definition, respectively) and 13/25 (52%) patients receiving dual antiplatelet therapy (DAPT) were not managed according to current recommendations. Management of ACT for secondary thromboembolic prophylaxis did not follow guideline recommendations in 59/93 (63.4%) and 34/93 (36.6%) patients (using strict and liberal definition, respectively). 23.7% of patients with NVUGIB were exposed to combined APT and ACT for whom no guideline recommendations exist. Mortality for any reason was twice as high in patients who were not managed according to guideline recommendations (18.8% vs. 8% using strict definition, 20.5% vs. 10.2% using liberal definition), which did not remain significant after adjusting for comorbidities, whereas cardiovascular events were observed at similar rates.

Conclusion: A significant number of patients with NVUGIB receiving APT or ACT is not managed according to current ESGE guideline recommendations. Strategies to implement these guidelines into daily practice need to be developed.     

Treatment with proton pump inhibitors in acute non-variceal upper gastrointestinal bleeding: a meta-analysis

Medical therapy is an attractive adjuvant to endoscopic treatment in upper gastrointestinal (UGI) bleeding. This review aims to assess the treatment effects of proton pump inhibitor (PPI) therapy in acute non-variceal UGI bleeding. Outcome measures evaluated were further bleeding, surgery, all-cause deaths, ulcer deaths and non-ulcer deaths. We searched MEDLINE (1966-2002) and EMBASE (1974-2002) using the terms 'gastrointestinal hemorrhage', 'peptic ulcer hemorrhage', 'proton pump inhibitor', 'omeprazole', 'pantoprazole', 'lansoprazole', 'rabeprazole' and 'esomeprazole'. The search was extended to the Cochrane controlled trials registry database, published abstracts from five international gastroenterology conferences, manufacturers of PPI, known contacts and bibliographies from each full-length published report. We included trials published in English and non-English languages. Eligible studies were randomized controlled trials that compared the treatment effects of PPI therapy with placebo or H2 receptor antagonists in patients with acute non-variceal UGI bleeding. Of the 175 articles screened, 26 controlled trials including 4670 subjects (2317 in treatment arm and 2353 in control arm) were analyzed. The methodology, population, intervention, and outcomes of each selected trial were evaluated using duplicate independent review. Disagreements were resolved by consensus. PPI therapy significantly reduced rates of further bleeding (odds ratio [OR], 0.48; 95% confidence interval [CI], 0.40-0.57) and surgery (OR, 0.61; 95% CI, 0.48-0.76). All-cause deaths were unaffected (OR, 1.02; 95% CI, 0.76-1.37). Ulcer deaths showed a significant reduction (OR, 0.58; 95% CI, 0.35-0.96), while non-ulcer deaths showed a significant increase (OR, 1.60; 95% CI, 1.06-2.41) in the PPI therapy group. Sensitivity analysis of 22 trials published in peer-reviewed journals, 10 trials with double-blind design and 19 trials with high quality score and 22 trials using omeprazole in the treatment group showed results similar to those seen in the analysis of all 26 trials, confirming the stability of the conclusions. Subgroup analysis revealed that summary outcome measures were not influenced by control group therapy (placebo vs H2 receptor antagonists) or the use of prior endoscopic treatment to achieve hemostasis (given vs not given). However, the summary treatment effects for further bleeding and need for surgery were significant in only those trials enrolling patients with peptic ulcers having high risk for rebleeding and not in those trials enrolling patients with all causes of UGI bleeding. The summary treatment effects for further bleeding and need for surgery were significant in trials using intravenous as well as oral PPI. However, summary OR for all-cause deaths and non-ulcer deaths in trials using intravenous PPI were higher in the treatment group and not in trials using oral PPI. This raised the possibility of intravenous PPI-therapy-associated non-ulcer deaths in high-risk patients. PPI therapy in acute non-variceal UGI bleeding reduced rates of further bleeding, surgery and deaths caused by ulcer complications. However, non-ulcer deaths were increased. The overall mortality was unaffected. PPI therapy is useful only in a selected group of patients with acute non-variceal UGI bleeding, namely those with peptic ulcers having endoscopic high-risk stigmata for rebleeding.     

Role of multidetector computed tomography angiography in non-variceal upper gastrointestinal bleeding: A comprehensive review

Non-variceal upper gastrointestinal bleeding (NVUGIB) is a common gastroenterological emergency associated with significant morbidity and mortality. Upper gastrointestinal endoscopy is currently recommended as the gold standard modality for both diagnosis and treatment, with computed tomography traditionally playing a limited role in the diagnosis of acute NVUGIB. Following the introduction of multidetector computed tomography (MDCT), this modality is emerging as a promising tool in the diagnosis of NVUGIB. However, to date, evidence concerning the role of MDCT in the NVUGIB diagnosis is still lacking. The aim of our study was to review the current evidence concerning the role of MDCT in the diagnosis of acute NVUGIB.     

Epidemiology of acute upper gastrointestinal bleeding

Acute upper gastrointestinal bleeding is an important emergency situation. Population-based epidemiology data are important to get insight in the actual healthcare problem. There are only few recent epidemiological surveys regarding acute upper gastrointestinal bleeding. Several surveys focusing on peptic ulcer disease showed a significant decrease in admission and mortality of peptic ulcer disease. Several more recent epidemiological surveys show a decrease in incidence of all cause upper gastrointestinal bleeding. The incidence of peptic ulcer bleeding remained stable. Peptic ulcer bleeding is the most common cause of upper gastrointestinal bleeding, responsible for about 50% of all cases, followed by oesophagitis and erosive disease. Variceal bleeding is the cause of bleeding in cirrhotic patients in 50-60%. Rebleeding in upper gastrointestinal bleeding occurs in 7-16%, despite endoscopic therapy. Rebleeding is especially high in variceal bleeding and peptic ulcer bleeding. Mortality ranges between 3 and 14% and did not change in the past 10 years. Mortality is increasing with increasing age and is significantly higher in patients who are already admitted in hospital for co-morbidity. Risk factors for peptic ulcer bleeding are NSAIDs use and H. pylori infection. In patients at risk for gastrointestinal bleeding and using NSAIDs, a protective drug was only used in 10%. COX-2 selective inhibitors do cause less gastroduodenal ulcers compared to non-selective NSAIDs, however, more cardiovascular adverse events are reported. H. pylori infection is found in about 50% of peptic ulcer bleeding patients. H. pylori should be tested for in all ulcer patients and eradication should be given.     

Upper gastrointestinal bleeding etiology score for predicting variceal and non-variceal bleeding

AIM： To identify clinical parameters, and develop an Upper Gastrointesinal Bleeding （UGIB） Etiology Score for predicting the types of UGIB and validate the score. METHODS： Patients with UGIB who underwent endoscopy within 72 h were enrolled. Clinical and basic laboratory parameters were prospectively collected. Predictive factors for the types of UGIB were identified by univariate and multivariate analyses and were used to generate the UGIB Etiology Score. The best cutoff of the score was defined from the receiver operating curve and prospectively validated in another set of patients with UGIB. RESULTS： Among 261 patients with UGIB, 47 （18%） had variceal and 214 （82%） had non-variceal bleeding. Univariate analysis identified 27 distinct parameters significantly associated with the types of UGIB. Logistic regression analysis identified only 3 independent factors for predicting variceal bleeding; previous diagnosis of cirrhosis or signs of chronic liver disease （OR 22.4, 95% CI 8.3-60.4, P 〈 0.001）, red vomitus （OR 4.6, 95% CI 1.8-11.9, P = 0.02）, and red nasogastric （NG） aspirate （OR 3.3, 95% CI 1.3-8.3, P = 0.011）. The UGIB Etiology Score was calculated from （3.1× previous diagnosis of cirrhosis or signs of chronic liver disease） ＋ （1.5× red vomitus） ＋ （1.2× red NG aspirate）, when 1 and 0 are used for the presence and absence of each factor, respectively. Using a cutoff ≥ 3.1, the sensitivity, specificity, accuracy, positive predictive value （PPV）, and negative predictive value （NPV） in predicting variceal bleeding were 85%, 81%, 82%, 50%, and 96%, respectively. The score was prospectively validated in cases （46 variceal and 149 another set of 195 UGIB non-variceal bleeding）. The PPV and NPV of a score ≥ 3.1 for variceal bleeding were 79% and 97%, respectively. CONCLUSION： The UGIB Etiology Score, composed of 3 parameters, using a cutoff ≥ 3.1 accurately predicted variceal bleeding and may help to guide the choice of initial therapy for UGIB before endoscopy.     

Treatment of upper gastrointestinal bleeding in 2020: New techniques and outcomes

The clinical outcome of upper gastrointestinal bleeding has improved due to advances in endoscopic therapy and standardized peri‐endoscopy care. Apart from validating clinical scores, artificial intelligence‐assisted machine learning models may play an important role in risk stratification. While standard endoscopic treatments remain irreplaceable, novel endoscopic modalities have changed the landscape of management. Over‐the‐scope clips have high success rates as rescue or even first‐line treatments in difficult‐to‐treat cases. Hemostatic powder is safe and easy to use, which can be useful as temporary control with its high immediate hemostatic ability. After endoscopic hemostasis, Doppler endoscopic probe can offer an objective measure to guide the treatment endpoint. In refractory bleeding, angiographic embolization should be considered before salvage surgery. In variceal hemorrhage, banding ligation and glue injection are first‐line treatment options. Endoscopic ultrasound‐guided therapy is gaining popularity due to its capability of precise localization for treatment targets. A self‐expandable metal stent may be considered as an alternative option to balloon tamponade in refractory bleeding. Transjugular intrahepatic portosystemic shunting should be reserved as salvage therapy. In this article, we aim to provide an evidence‐based comprehensive review of the major advancements in endoscopic hemostatic techniques and clinical outcomes.     

Are repeat upper gastrointestinal endoscopy and colonoscopy necessary within six months of capsule endoscopy in patients with obscure gastrointestinal bleeding?

Background and Aim: Medicare reimbursement for capsule endoscopy for the investigation of obscure gastrointestinal bleeding in Australia requires endoscopy and colonoscopy to have been performed within 6 months. This study aims to determine the diagnostic yield of repeating these procedures when they had been non‐diagnostic more than 6 months earlier. Methods: Of 198 consecutive patients who were referred for the investigation of obscure gastrointestinal bleeding, 50 underwent repeat endoscopy and colonoscopy solely to enable reimbursement (35 females and 15 males; mean age 59.4 [range: 21–82] years). The average duration of obscure bleeding was 50.16 (range: 9–214) months. The mean number of prior endoscopies was 3 (median: 2) and 2.8 colonoscopies (median: 2). The most recent endoscopy had been performed 18.9 (median: 14; range: 7–56) months, and for colonoscopy, 19.1 (median 14; range 8‐51) months earlier. Results: A probable cause of bleeding was found at endoscopy in two patients: gastric antral vascular ectasia (1) and benign gastric ulcer (1). Colonoscopy did not reveal a source of bleeding in any patient. Capsule endoscopy was performed in 47 patients. Twenty four (51%) had a probable bleeding source identified, and another five (11%) a possible source. These included angioectasia (17 patients), mass lesion (2), non‐steroidal anti‐inflammatory drug enteropathy (2), Cameron's erosions (2), and Crohn's disease (1). Four patients undergoing repeat capsule endoscopy had a probable bleeding source detected. Conclusion: The yield of repeat endoscopy and colonoscopy immediately prior to capsule endoscopy is low when these procedures have previously been non‐diagnostic. Such an approach is also not cost‐effective.     

四种非静脉曲张上消化道出血危险性评分系统的对比分析

目的探讨四种非静脉曲张性上消化道出血的危险性评分系统(Rockall再出血危险积分、Cedars-Sinai Medical Center预后指数、Blatchford入院危险性计分、The Baylor出血积分)对于已确定的非静脉曲张性上消化道出血的病人中再出血情况的预测能力。方法选取2002年-2007年消化内科收治的消化道出血病人753例,以四种危险性评分系统分别评分后,行卡方拟和优度检验检测数据分布的合理性,后计算受试者工作特性曲线(ROC曲线)下面积。结果四种评分系统的ROC曲线下面积分别为:Rockall再出血危险积分0.681(P0.01,95%CI:0.638-0.723),Cedars-Sinai Medical Center预后指数0.685(P0.01,95%CI:0.639-0.731),Blatchford入院危险性计分0.886(P0.01,95%CI:0.857-0.916),The Baylor出血积分0.737(P0.01,95%CI:0.95-0.779)。结论①四种评分系统均对再出血有预测性。②Blatchford入院危险性计分更适用于门诊及急诊。     

Overt gastrointestinal bleeding in patients with acute myocardial infarction: retrospective analysis of risks and outcomes

Overt gastrointestinal bleeding (GIB) is one of the noncardiac complications in patients with acute myocardial infarction (AMI).Identification of patients at increased risk of overt GIB could aid in targeting more aggressive treatment,and lead to improved outcomes.The aim of this study is to determine the frequency,risk factors,and prognostic significance of overt GIB in patients with AMI.Methods A retrospective review of the medical records of 1443 patients admitted to the Chinese PLA General Hospital with AMI was conducted.Charts were reviewed for clinical characteristics,possible precipitating factors and complications.Patients were categorized as having or not having overt GIB(GIB associated with hemodynamic changes or the need for transfusions).Results Twenty nine (2.0%) patients developed overt GIB within 30 days after AMI.Patients with overt GIB had higher 30-day mortality rate than those without (44.8% vs.9.9%,P ＜ 0.001).Multivariate logistic regression analysis showed major determinants of in-hospital overt GIB secondary to AMI were gender of female (odds ratio 2.41,95% confidence interval [CI] 1.08 to 5.37),age=75 years (odds ratio 1.58,95% CI 1.13 to 2.20),prior history of AMI (odds ratio 2.28,95% CI 1.17 to 4.88),pneumonia (odds ratio 3.47,95% CI 1.50 to 8.03) and anemia at admission (odds ratio 2.37,95% CI 1.04 to 5.37).Conclusions In patients with AMI,overt GIB is associated with higher in-hospital mortality,and female sex,older age,prior AMI,pneumonia and anemia at admission are predictors of overt GIB during hospitalization.(J Geriatr Cardiol 2008;5:195-198)     

老年急性非食管静脉曲张性上消化道出血的临床特征分析

目的 分析老年人急性非食管静脉曲张性上消化道出血的临床特征.方法 对本院2009年6月至2012年12月间收治的急性非食管静脉曲张性上消化道出血患者172例进行回顾性分析,其中老年患者56例作为研究组,中青年患者116例作为对照组.详细分析两组病因、临床特征、实验室及内镜检查结果等.结果 两组患者出血首要原因均为消化性溃疡,分别为62.5％和67.2％;研究组癌症占30.4％ （17/56）,显著高于对照组6.0％ （7/116）,差异有统计学意义（x2=18.609,P=0.000）;研究组使用非甾体抗炎药物占21.4％（12/56）,显著高于对照组7.8％（9/116）,差异有统计学意义（x2=6.584,P=0.01）;研究组患者幽门螺杆菌感染占83.9％ （47/56）,对照组患者幽门螺杆菌感染占81.0％（94/116）,两者比较差异无统计学意义（x2=0.214,P＞0.05）.治疗期间研究组发生低血压或休克者占19.6％（11/56）,显著高于对照组7.8％（9/116）,差异有统计学意义（x2=5.191,P＜0.05）;研究组输血量、止血时间均显著高于对照组（t=4.573,=5.027,P＜0.01）.结论 老年人急性非食管静脉曲张性上消化道出血病情较非老年人重,治疗更为复杂,临床医生应给予足够重视,提高治疗效果.     

Endoscopic advances in the management of non-variceal upper gastrointestinal bleeding:A review

Upper gastrointestinal bleeding is defined as the bleeding originating from the esophagus to the ligament of Treitz and further classified into variceal and nonvariceal gastrointestinal bleeding.Non-variceal upper gastrointestinal bleeding remains a common clinical problem globally.It is associated with high mortality,morbidity,and cost of the health care system.Despite the continuous improvement of therapeutic endoscopy,the 30-d readmission rate secondary to rebleeding and associated mortality is an ongoing issue.Available Food and Drug Administration approved traditional or conventional therapeutic endoscopic modalities includes epinephrine injection,argon plasma coagulation,heater probe,and placement of through the scope clip,which can be used alone or in combination to decrease the risk of rebleeding.Recently,more attention has been paid to the novel advanced endoscopic devices for primary treatment of the bleeding lesion and as a secondary measure when conventional therapies fail to achieve hemostasis.This review highlights emerging endoscopic modalities used in the management of non-variceal upper gastrointestinal related bleeding such as over-the-scope clip,Coagrasper,hemostatic sprays,radiofrequency ablation,cryotherapy,endoscopic suturing devices,and endoscopic ultrasound-guided angiotherapy.In this review article,we will also discuss the technical aspects of the common procedures,outcomes in terms of safety and efficacy,and their advantages and limitations in the setting of non-variceal upper gastrointestinal bleeding.     

Increased mortality of acute upper gastrointestinal bleeding in patients with chronic obstructive pulmonary disease

The etiology, clinical presentation, and mortality of acute upper gastrointestinal bleeding in patients with chronic obstructive pulmonary disease (COPD) were analyzed in a case-controlled study of 53 consecutive patients admitted from 1985 through 1990 to a university teaching hospital. The primary controls were 40 consecutive patients with acute upper gastrointestinal bleeding and without COPD admitted from June through November 1990 to the same hospital. COPD patients had a significantly increased mortality from gastrointestinal bleeding as compared to controls with gastrointestinal bleeding and without COPD (mortality in COPD=32%, controls=10%, odds ratio=4.3, confidence interval of odds ratio=1.22–14.8,P<0.01, fisher's=" exact=" test)=" and=" as=" compared=" to=" a=" second=" control=" group=" of=" 53=" consecutive=" copd=" patients=" without=" gastrointestinal=" bleeding=" (mortality=" in=" second=" controls="11%," odds=" ratio="3.7," confidence=" interval=" of=" odds=" ratio=">P<0.02, chi=" square).=" the=" study=" copd=" patients=" had=" a=" significantly=" greater=" likelihood=" of=" being=" older,=" smokers,=" alcoholics,=" and=" taking=" corticosteroids=" than=" the=" primary=" controls.=" however,=" an=" increased=" mortality=" was=" still=" present=" when=" controlling=" for=" these=" differences=" by=" population=" stratification=" (eg,=" mortality=" in=" patients=">60 years old: COPD=36%, controls=13%, odds ratio=4.6,P<0.05). the=" two=" groups=" had=" similar=" mean=" values=" of=" parameters=" of=" bleeding=" severity,=" such=" as=" lowest=" hematocrit=" and=" units=" of=" packed=" erythrocytes=" transfused.=" the=" increased=" mortality=" was=" correlated=" with=" copd=" severity=" (eg,=" four=" of=" five=" patients=" with=" prior=" endotracheal=" intubation=" for=" copd=" died,=" 13=" of=" 48=" copd=" patients=" without=" prior=" intubation=" died,=" odds=" ratio=">P<0.04, fisher's=" exact=" test).=" we=" conclude=" that=" copd=" patients=" have=" increased=" mortality=" associated=" with=" gastrointestinal=" bleeding=" not=" accounted=" for=" solely=" by=" their=" unusual=" demographic=" features.=" this=" finding=" of=" a=" poor=" prognosis=" suggests=" that=" copd=" patients=" with=" acute=" gastrointestinal=" bleeding=" should=" be=" evaluated=" early=" for=" possible=" intensive=" care=" unit=" admission,=" emergency=" endoscopy,=" and=" therapeutic=" endoscopy=" or=" interventional=">Presented at the 1994 annual meeting of the American Gastro-enterology Association.     

Management of acute nonvariceal upper gastrointestinal bleeding: current policies and future perspectives

Acute upper gastrointestinal bleeding (UGIB) is a gastroenterological emergency with a mortality of 6%-13%. The vast majority of these bleeds are due to peptic ulcers. Nonsteroidal anti-inflammatory drugs and Helicobacter pylori are the main risk factors for peptic ulcer disease. Endoscopy has become the mainstay for diagnosis and treatment of acute UGIB, and is recommended within 24 h of presentation. Proton pump inhibitor (PPI) administration before endoscopy can downstage the bleeding lesion and reduce the need for endoscopic therapy, but has no effect on rebleeding, mortality and need for surgery. Endoscopic therapy should be undertaken for ulcers with high-risk stigmata, to reduce the risk of rebleeding. This can be done with a variety of modalities. High-dose PPI administration after endoscopy can prevent rebleeding and reduce the need for further intervention and mortality, particularly in patients with high-risk stigmata.