الارتداد المعدي المريئي - الدكتور / وليد يوسف فرح استشاري امراض الجهاز الهضمي والكبد

مقدمة

المريء هو أنبوب عضلي ضيق يبلغ طوله حوالي 40 سنتيمتر . ويبدأ بعد اللسان وينتهي في المعدة يتألف من ثلاث طبقات ليفية من الخارج وعضلية في الوسط وغشاء مخاطي من الداخل .
التعريف
الارتداد المريئي هو أعراض مزمنة أو تخريب لمخاطية المريء ينتج عن رجوع زائد وغير طبيعي لحامض المعدة إلى المريء وهذا ما يطلق عليه الارتداد ، ويحدث نتيجة قصور في الوظيفة العضلية للمريء أو فشل في وسائل الحماية الأخرى.

الوبائيات
يعتبر الارتداد المريئي مرض شائع جداً يصيب 20 -40 % من الناس . وقد زادت نسبة حدوثه خلال العقود الماضية ويحدث الارتداد بالتساوي في كلا الجنسين أما التهاب المريء ( الناتج عن الارتداد ) فيحدث في الذكور ضعف الإناث كما يحدث الارتداد في كافة الأعمار وتزداد نسبة حدوثه بعد سن الأربعين .
آلية حدوث الارتداد المريئي
في الواقع إن البنية الأهم في الحماية من حدوث الارتداد المريئي هي طبقة عضلية في أسفل المريء عند اتصاله بالمعدة تسمى مصرة المريء السفلي حيث تفتح بعد البلع ليتمكن الطعام من الدخول إلى المعدة وتنغلق مباشرة بعد ذلك لمنع حدوث أي ارتداد لمحتويات المعدة ( بما فيها الحامض ) إلى المريء وتحافظ على وضعية الإغلاق حتى يتم البلع مرة أخرى .

الأعراض السريرية
• الحرقة : إحساس بالحرقة خلف عظمة القص ويحدث هذا الإحساس بإرتداد الحامض المعدي الذي تزيد كميته بعد تناول الوجبات وفي وضعية الاستلقاء .
• عسر البلع
• البلع المؤلم
• التجشوء
• التظاهرات خارج المريء وهى الأعراض التي تحدث في مناطق خارج المريء وتلاحظ كثيراً في المرضى المحولين من عيادات أخرى للإشتباه بوجود الارتداد المريئي لديهم ، وأ÷م هذه الأعراض .
- ألم الصدر غير المفسر
حيث يحضر المرضى إلى عيادات أمراض القلب إثر معاناتهم من ألم في الصدر والاشتباه بوجود أمراض نقص التروية القلبية من ذبحة صدرية وأحتشاء قلبي ولكن بعد إجراء جميع الفحوصات يتبين عدم وجود أي علامات لذلك وهنا يتم الأشتباه بوجود الارتداد المعدي المريئي كمسبب لألم الصدر .
- تظاهرات رئوية
هناك العديد من الأمراض الرئوية قد تظهر بسبب وجود الارتداد المريئي وأهمها
• الربو القصبي
• التهاب القصبات المزمن
• ذات الرئة الإستنشاقية
• انقطاع التنفس أثناء النوم
• انخماص الرئة
• التليف الرئوي

- تظاهرات أذنية
قد يراجع المرضى اختصاصي الأنف والأذن والحنجرة إثر شكواهم من أحد الأعراض التالية :
• السعال
• ألم الحلق
• بحة الصوت
• التهاب الجيوب الأنفية المزمن
• التهاب البلعوم الخلفي
• إحساس بوجود جسم غريب في الحلق

التشخيص
القصة المرضية مهمة جداً في تشخيص الارتداد المعدي المريئي ، وهناك أسئلة ذات أهمية تشخيصية عالية يوجهها الطبيب لمريضة وهى:
1- هل تعاني من إحساس عدم الارتياح منتشر للأعلى خلف القص ؟
2- هل يصاحب هذا الإحساس حرقة بأعلى البطن ؟
3- هل استعمال مضادات الحموضة تخفف الأعراض ؟
4- هل حدثت الأعراض لمدة أكثر من 4 أيام خلال الأسبوع المنصرم ؟
وقد وجد أن 85% من المرضى يجيبون بنعم على جميع الأسئلة .
وقد يلجأ الطبيب لإجراء الفحوصات الشعاعية ونعني هنا الوجبة الباريتية وهي مفيدة في المرضى الذين يعانون من عسر البلع حيث يمكن أن توضح مكان وجود التضيق إن وجد كما يمكن الاستدلال على وجود وشكل الفتق الحجابي لإذا كان مصاحباً
وفي كثير من الأحيان يُّجرى للمريض التنظير الهضمي العلوي بالمنظار حيث يتم التأكد من وجود التهاب المريء وتحديد درجة الالتهاب وإمكانية وجود داء باريت وينفي وجود أمراض أخرى مشابهة من ناحية الأعراض مثل القرحة الهضمية . وفي أكثر من نصف المرضى يكون التنظير طبيعياً بالرغم من وجود الارتداد .
ومن الفحوصات التي قد يلجأ إليها الطبيب مراقبة إفراز الحامض المعدي لمدة 24 ساعة . ويستطب إجراء هذا الفحص في المرضى ذوي التنظير الطبيعي ويعانون من أعراض الارتداد ولا يستجيبو للعلاج أو الذين يشكون من ألم صدر غير نوعي ومظاهر خارج المريء ( ربو ، بحة ، سعال مزمن ) ، وكذلك في المرضى ذوي التنظير المرضي ولا يستجيبو للعلاج أو المرضى الذين سيخضعوا للعلاج الجراحي .

التشخيص التفريقي
يمكن أن يختلط تشخيص الارتداد المريئي بالكثير من الأمراض التي تتشابه معه في الصورة السريرية نذكر منها :
• التهاب المعدة
• التهاب المريء الميكروبي
• التهاب المريء بالأدوية
• القرحة الهضمية
• عسر الهضم
• أمراض القنوات الصفراوية
• أمراض الشرايين التاجية القلبية
• اضطرابات المريء الحركية

المضاعفات
قد يترافق الارتداد المريئي بالعديد من المضاعفات ومنها
• التضيق
• داء باريت
• السرطان الغدي للمريء

العلاج
يهدف العلاج إلى إراحة المريض من الأعراض وشفاء التهاب المريء بالإضافة إلى تجنب حدوث المضاعفات ؟
والخطوة الأولى والأهم في علاج التهاب المريء تقع على كاهل المريض ذاته وذلك بإتباع النصائح والإرشادات التالية :
رفع رأس السرير من جهة الرأس وإتباع حمية صارمة لإنقاص الوزن وتناول وجبات خفيفة بفترات متقاربة بدلاً من الوجبات العادية والأهم عدم تناول الطعام قبل الذهاب إلى النوم بساعتين على الأقل .
كما يتوجب على المريض الامتناع عن التدخين والكحول والنعناع والشوكولاته والأطعمة الدسمة .
أما العلاج الدوائي فالهدف الأساسي منه هو إراحة المريض من الأعراض التي يشكو منها والحفاظ على درجة حموضة المعدة بمستوى 4 أو أكثر .
وكانت مضادات الحموضة حجر الزاوية في العلاج حتى السبعينات من القرن الماضي حيث تم استحضار مضادات مستقبلات الهستامين حيث بدأ استعمال السيميتيدين وحالياً يتوفر علاجات أخرى ضمن هذه المجموعة تعطي وظيفة ألإضل ومضاعفات أقل .
وفي عام 1988 بدأ استعمال مضادات البروتون والعلاج الأقدم في هذه المجموعة هو الأميبرازول وتلا ذلك استحضار علاجات أخرى ضمن هذه المجموعة والاحدث عقار إيسوميبرازول في عام 2000 م .
وتعطى هذه الأدوية بمعدل مرة إلى مرتين يومياً وقد يحتاج المرضى للمواظبة على العلاج لفترات طويلة . وفي بعض الحالات قد يلجأ الطبيب للتدخل الجراحي بإجراء عمليات الهدف منها منع حدوث ارتداد حامض المعدة إلى المريء ولا يتسع المقام هنا لتفصيلها .

Early endoscopic follow-up nets dysplasia in 9.5% of Barrett’s

CHICAGO (FRONTLINE MEDICAL NEWS) – Early endoscopic follow-up within 24 months detected dysplasia in nearly one in 10 patients with nondysplastic or low-grade Barrett’s esophagus in a retrospective study at the Mayo Clinic. Initial endoscopy missed four cases of high-grade dysplasia or esophageal adenocarcinoma (1.9%) and 16 cases of low-grade dysplasia (7.6%) for an overall miss-rate of 9.5%. Patients on proton pump inhibitors were less likely to have dysplasia missed than were those off PPIs (20% vs. 52.6%, P = .008). Those with long- versus short-segment Barrett’s esophagus were more likely to have dysplasia overlooked (85% vs. 53.6%; P = .008; mean 6 mm vs. 4 mm; P = .006), Dr. Kavel Visrodia said at the annual Digestive Disease Week. Current American College of Gastroenterology (ACG) guidelines recommend early repeat esophagogastroduodenoscopy (EGD) to exclude the presence of missed dysplasia in newly diagnosed nondysplastic Barrett’s esophagus (BE), while the ACG and American Society for Gastrointestinal Endoscopy call for repeat EGD within 6 months for those with low-grade dysplasia. The yield for repeat EGD has not been established, and only one study exists in the literature, said Dr. Visrodia of the department of medicine, Mayo Clinic, Rochester, Minn. That study (Dis. Esophagus 2012 Sept. 28. [doi:10.1111/j.1442-2050.2012.01431.x]) showed a miss-rate of 8.2% among 146 patients with newly diagnosed nondysplastic BE. Long-segment BE was the only significant predictor of dysplasia on follow-up (odds ratio, 9.18; P = .008). The cohort was relatively small and had no long-term follow-up, and with an interval to follow-up of 36 months, “it’s possible that some of these were actually incident cases of dysplasia and not prevalent cases,” he said. To address these gaps, Dr. Visrodia and his colleagues identified 488 BE cases from 1977 to 2011 in the Rochester Epidemiology Project in Olmsted County, Minn. A total of 278 patients were excluded because of high-grade dysplasia (HGD) or esophageal cancer on index endoscopy or repeat endoscopy after 24 months, leaving 181 patients with nondysplastic BE and 29 with low-grade dysplasia (LGD). Repeat endoscopy within 24 months revealed 2 cases of HGD or cancer and 16 cases of LGD in the nondysplastic BE group, and 2 cases of HGD or cancer in the LGD group, Dr. Visrodia said. Three of the four HGD/cancer cases were in patients with long-segment BE, defined as at least 3 cm of columnar mucosa. Biopsies were insufficient in 63% of patients with missed dysplasia, compared with 55% in the group without missed dysplasia. Biopsies were considered adequate if the number of biopsies divided by the BE length was at least 2, indicating that samples were taken every 2 cm in accordance with guidelines. This risk factor is noteworthy, although the difference between groups was not statistically significant, possibly because of the small sample size, he said. Finally, after a median of 6.8 years of follow-up, 30 asymptomatic, prevalent HGDs or cancers were detected within 24 months, compared with 22 incident cases detected after 24 months. This suggests that “a greater number of high-grade dysplasias and cancers were detected up front rather than during long-term careful surveillance,” Dr. Visrodia said. During a discussion of the study, one attendee asked whether the results make a better case for aggressive ablation up front rather than for surveillance, while others expressed surprise at the high miss rate at an institution such as the Mayo Clinic. Dr. Visrodia replied that the results do give them pause, and suggested that tighter early endoscopic surveillance may be warranted, particularly in those with long-segment BE.

Infliximab monitoring during remission limits IBD flare-ups

Trough infliximab concentrations were measured in patients who were in clinical remission at about 1 year on maintenance therapy. When trough concentrations fell below 5 mcg/mL, patients got a dose increase. The goal was to prevent secondary loss of response due to recurrence of symptoms or antibody-mediated side effects, such as infusion reactions, Dr. Byron P. Vaughn explained at the annual Digestive Disease Week. In a retrospective, nonrandomized proof-of-concept study, 48 inflammatory bowel disease patients in remission on infliximab were proactively monitored, and 78 matched controls were conventionally managed. The infliximab discontinuation rate during up to 5 years of follow-up was 10% in the proactively monitored group and 31% in the controls. Nearly 90% of treatment discontinuations in the control group were caused by loss of response or development of acute infusion reactions; in contrast, no one in the proactively monitored group stopped infliximab for those reasons. “We think this is exciting information. We now recommend dose optimization to a trough level of at least 3 mcg/mL, and our current clinical practice is to target a range of 5-10 mcg/mL,” said Dr. Vaughn, of Beth Israel Deaconess Medical Center and Harvard University, Boston. Of course, the findings certainly need to be validated in a prospective study, he added. For about the first year of infliximab therapy, the treatment continuation curves were similar for the two groups. After 1 year, the curves separated and the benefit of proactive trough monitoring could be seen. The main reasons for stopping infliximab in the control group were a flare of symptoms (15 patients) and acute infusion reactions (6 patients). Neither of these events occurred in the proactively monitored patients. The reasons for treatment discontinuation in the proactively monitored group included drug-induced lupus (1 patient), psoriasis (1 patient), a delayed infusion reaction (1 patient), and a reason unrelated to the medication (1 patient). Three-quarters of study participants had Crohn’s disease, and the rest had ulcerative colitis. Other investigators have previously shown that an undetectable serum infliximab trough concentration in the setting of Crohn’s disease often heralds a loss of response. Dr. Vaughn emphasized that fully one in four patients had an undetectable trough level at the first measurement, and nearly two-thirds had levels below 5 mcg/mL. The infliximab dose was increased in those patients. Patients with a trough level of 5-10 mcg/mL received no change in their regimen, while those with a level of more than 10 mcg/mL on two occasions got either a dose reduction or an increase in the interval between doses if they were on 5 mg/kg. In gastroenterology, serum infliximab concentrations are typically measured when patients stop responding or have side effects. So the costs of proactive infliximab monitoring and dose escalation are going to be an impediment to widespread implementation of this strategy under many health plans, at least until there is confirmatory data, he said. Proactive trough concentration monitoring and dose titration are typical in recipients of solid organ transplants receiving cyclosporine, mycophenolate mofetil, and mTOR (mammalian target of rapamycin) inhibitors, and are often performed in sepsis patients receiving vancomycin and gentamicin. When asked how often he recommends proactive infliximab trough testing, Dr. Vaughn replied, “I think when people are in a steady state – they’re not ill and they’re not flaring – you could probably check once every 6 months or maybe once a year. After a few stable troughs, that could be enough unless there’s been a major change like a big weight change, a change in other medications, or an illness.”

Fecal transplant falls short in UC, but may not be the end

CHICAGO (FRONTLINE MEDICAL NEWS) – Results were negative from the first randomized placebo-controlled trial of fecal microbiota transplant in ulcerative colitis, but enthusiasm remains for this newly regulated and trendy therapy. “We need to get more data and we need to understand how better to use this approach, but I don’t think this study is telling us we should stop exploring. I still think it is an interesting avenue that we need to evaluate,” study author Dr. Paul Moayyedi said during a late-breaking abstract session at Digestive Disease Week. Part of the enthusiasm for what was described as “the new kid on the block for altering gut flora,” has been fueled by a roughly 90% success rate for fecal transplant in treating Clostridium difficile infection. Dr. Moayyedi also showcased a success story from the trial that “typifies a few patients in this study.” The patient had ulcerative colitis for almost 20 years that was unresponsive to steroids and 5-aminosalicylic acid for 2 years before the study and so severe it caused bloody diarrhea 10-20 times per day. No improvement was seen after 6 weeks of placebo therapy and his Mayo Clinic score was “about as bad as it can be” at 12. After crossing over to 6 weeks of open-label fecal microbiota transplantation (FMT), symptoms were much improved and his Mayo score dropped to 5. After 20 weeks, mucosa healed throughout the colon, his Mayo score reached 0, and he was “fine” on no medication. “What we’re finding is that 6 weeks is usually not enough and that if you continue longer, you can get remission in some patients,” said Dr. Moayyedi, the Richard Hunt-Astra Zeneca Chair in Gastroenterology, McMaster University, Hamilton, Ontario. He went on to say, “I’m a very big proponent of evidenced-based medicine, but cases like these make you think something must be going on in some patients, but we don’t have the funding to do the 500-patient trial you need to get that signal.” Dr. Moayyedi and his associates enrolled ambulatory patients with active ulcerative colitis, defined as a Mayo score of at least 4 and an endoscopic Mayo score of at least 1, who tested negative for the C. difficile gene. Patients could be on ulcerative colitis medications, if doses were stable for at least 12 weeks but had to be off antibiotics for 30 days. Patients were randomly assigned to receive a 50-mL retention enema containing fecal microbiota from an anonymous donor or water, once per week for 6 weeks. The primary outcome was remission of ulcerative colitis, defined as a Mayo score of 2 or less and an endoscopic Mayo score of 0 at week 7. Patients, clinicians, and investigators were blinded to therapy. The 31 FMT and 30 placebo patients were well matched at baseline, except for significantly more pancolitis in the FMT group (64% vs. 36%). Remission was achieved by seven FMT patients (23%) and two placebo patients (7%), which was not significantly different (P = .15), Dr. Moayyedi said. There also were no differences between the FMT and placebo groups in any of the secondary outcomes: 6-week Mayo score (6.36 vs. 6.30; P = .95), 6-week Inflammatory Bowel Disease Questionnaire (148.4 vs. 146.4; P = .85), and 6-week EQ-5D health questionnaire (61.0 vs. 66.2; P = .34). Based on these findings, the study is being stopped for futility, he said. There were no major adverse events, although the diagnosis changed to Crohn’s colitis for two patients given FMT and one on placebo. This was “much bigger than you’d expect,��� Dr. Moayyedi said. “We’re not sure why, and of course the worry is that FMT may change the phenotype, which would not be good.” If FMT is to succeed in ulcerative colitis, he suggested more data will be needed on the fecal microbiome and the best approach to administer FMT, including donor selection, timing, preparation, and duration of treatment. The group has not done an analysis of enema dwell time and response, and no signal was seen that FMT is more effective in left-sided disease. More detailed microbiome analyses of the patient highlighted during the talk, however, revealed the man had a “very diverse and unstable” microbiome at baseline that gradually became more stable, “with a loss of Ruminococcus that seems to be a feature of improvement and a movement toward the phenotype of the donor,” Dr. Moayyedi said. During a discussion of the results, some audience members expressed concern that FMT might change the phenotype, while others were more enthusiastic about the therapy. Dr. Scott Harris, a gastroenterologist and professor of medicine, Georgetown University Medical Center, Washington, said the trial was likely underpowered, and that by including patients with less severe disease, it may have been more difficult to see a treatment effect. Other trials have also shown that 6 weeks of therapy may not be enough for refractory patients. “I’m very optimistic, I wouldn’t stop at this point,” he said. Session cochair Dr. John M. Inadomi, professor of medicine and head of gastroenterology, University of Washington School of Medicine, Seattle, agreed that the length of treatment as well as the study’s use of anonymous donors could have affected results. One of the big questions is whether the donor feces actually grafted and thus affected the recipient. “If you use the wrong donor stool, if the stool didn’t graft, these kinds of things can obviously make a negative result, even if the concept is potentially fine,” he said in an interview. Last year, the Food and Drug Administration moved to require an investigational new drug permit to treat C. difficile with fecal microbiota, but changed course within weeks citing public pressure. While researchers are studying the potential to deliver feces via capsule, Dr. Moayyedi observed that some enthusiasts are offering Internet advice on how to mix your own FMT at home.

Gut microbiota may play a role in the development of alcoholic liver disease

London, UK, Saturday 12 April 2014: Exciting new data presented today at the International Liver Congress™ 2014 shows that the gut microbiota has a potential role in the development of alcoholic liver disease (ALD). Though an early stage animal model, the French study highlights the possibility of preventing ALD with faecal microbiota transplantation – the engrafting of new microbiota, usually through administering human faecal material from a healthy donor into the colon of a recipient. In the study, two groups of germ-free mice received gut microbiota transplants from human representatives; one set from a patient with severe alcoholic hepatitis, the other from a patient with a history of alcohol abuse but without alcoholic hepatitis. The two sets of germ-free mice were then fed a liquid alcoholic diet. The group that received microbiota from the patient with severe alcoholic hepatitis developed a more severe liver injury and a higher disruption of the intestinal mucosa in direct comparison to the group that received microbiota from the patient without severe alcoholic hepatitis. The study also identified two Clostridium bacteria that were able to produce ethanol in vitro and that were systematically associated with intestinal microbiota associated liver injury. EASL Scientific Committee Member Prof. Frank Lammert commented: “Among heavy drinkers, the severity of alcoholic liver disease does not strictly correlate with the amount of alcohol intake, meaning that other factors must be influencing its development.” “These findings provide first evidence for a causal role of gut microbiota in alcohol-induced inflammation, and open up new avenues for the treatment of alcoholic liver disease with potentially better patient outcomes.” At present, intestinal microbiota is considered to constitute a “microbial organ”: one that has pivotal roles in the body’s metabolism as well as immune function. Therefore transplantation aims to restore gut functionality and re-establish the homoestasis of intestinal flora. The study was developed by an INRA-Micalis and INSERM/Paris-South University/Antoine-Béclère hospital

New Chinese herbal medicine has significant potential in treating Hepatitis C

London, UK, Saturday 12 April 2014: Data from a late-breaking abstract presented at the International Liver CongressTM 2014 identifies a new compound, SBEL1, that has the ability to inhibit hepatitis C virus (HCV) activity in cells at several points in the virus’ lifecycle. SBEL1 is a compound isolated from Chinese herbal medicines that was found to inhibit HCV activity by approximately 90%. SBEL1 is extracted from a herb found in certain regions of Taiwan and Southern China. In Chinese medicine, it is used to treat sore throats and inflammations. The function of SBEL1 within the plant is unknown and its role and origins are currently being investigated. Scientists pre-treated human liver cells in vitro with SBEL1 prior to HCV infection and found that SBEL1 pre-treated cells contained 23 percent less HCV protein than the control, suggesting that SBEL1 blocks virus entry. The liver cells transfected with an HCV internal ribosome entry site (IRES)-driven luciferase reporter that were treated with SBEL1 reduced reporter activity by 50% compared to control. This suggests that that SBEL1 inhibits IRES-mediated translation, a critical process for viral protein production. In addition, the HCV ribonucleic acid (RNA) levels were significantly reduced by 78 percent in HCV infected cells treated with SBEL1 compared to the control group. This demonstrates that SBEL1 may also affect the viral RNA replication process. Prof. Markus Peck-Radosavljevic, Secretary-General of the European Association for the Study of the Liver and Associate Professor of Medicine, University of Vienna, Austria, commented: “People infected with hepatitis C are at risk of developing severe liver damage including liver cancer and cirrhosis. In the past, less than 20 percent of all HCV patients were treated because the available treatments were unsuitable due to poor efficacy and high toxicity. Recent advances means that we can now virtually cure HCV without unpleasant side effects. However, the different virus genotypes coupled with the complexity of the disease means there is still a major unmet need to improve options for all populations.” Professor Peck-Radosavljevic continued: “SBEL1 has demonstrated significant inhibition of HCV at multiple stages of the viral lifecycle, which is an exciting discovery because it allows us to gain a deeper understanding of the virus and its interactions with other compounds. Ultimately this adds to our library of knowledge that may bring us closer to improving future treatment outcomes.” HCV invades cells in the body by binding to specific receptors on the cell, enabling the virus to enter it.2 Once inside, HCV hijacks functions of the cell known as transcription, translation and replication, which enables HCV to make copies of its viral genome and proteins, allowing the virus to spread to other sites of the body.2 When HCV enters the host cell, it releases viral (+)RNA that is transcribed by viral RNA replicase into viral (-)RNA, which can be used as a template for viral genome replication to produce more (+) RNA or for viral protein synthesis. Once the viral RNA is transcribed, HCV initiates a process known as IRES-mediated translation, which allows the viral RNA to be translated into proteins by bypassing certain protein translation checkpoints that would normally be required by the host cell to start protein translation. Viral RNA is the genetic material that gives HCV its particular characteristics. This process enables the virus to take advantage of the host cell’s protein translation machinery for its own purposes. There are an estimated 150 million to 200 million people living with chronic HCV and more than 350,000 people die annually from HCV-related diseases. HCV is transmitted through blood contact between an infected individual and someone who is not infected. This can occur through needlestick injuries or sharing of equipment used to inject drugs. Disclaimer: the data referenced in this release is based on the submitted abstract. More recent data may be presented at the International Liver Congress™ 2014.

High rate of ED visits for insulin-related hypoglycemia

ST LOUIS - Insulin-related hypoglycemia and errors (IHEs) account for close to 100,000 emergency department (ED) visits per year in the United States, according to a study published online by JAMA Internal Medicine. The researchers sought to estimate the burden, rates, and characteristics of ED visits for IHEs, including identification of high-risk groups and precipitating factors. The analysis included National Electronic Injury Surveillance System-Cooperative Adverse Drug Event Surveillance project data from 1997 through 2011, along with a national household survey of insulin use. The lead author was Dr Andrew I. Geller of the Centers for Disease Control and Prevention. Based on 8,100 cases identified from the adverse drug event surveillance database, the annual number of ED visits for IHEs was estimated at 97,648. Of these, 29.4% led to hospitalization and 60.6% were associated with severe neurologic sequelae. Blood glucose levels of 50 mg/dL or less were recorded in 53.4% of events. Patients aged 80 years older were at highest risk of ED visits for IHEs, rate ratio 2.5; and at highest risk for hospitalization, rate ratio 4.9 (compared to patients aged 45 to 64). The main precipitating factors were inadequate food intake and taking the wrong type of insulin. Recent reports have drawn attention to the potential for harmful effects of tight glycemic control with insulin in patients with type 2 diabetes. One important risk is insulin-related hypoglycemia, particularly in groups of patients who are less likely to benefit from tight control. This study identifies IHEs as an important cause of ED visits and hospitalizations, especially in diabetic patients aged 80 years and older. Of the nearly 100,000 annual ED visits for IHEs, 60,000 lead to severe neurologic sequelae and almost 30 000 to hospitalization. Efforts to reduce this risk should focus on the precipitating factors identified, such as "meal-related misadventures and insulin product mix-ups."

Distinct Presentation of Autoimmune Hepatitis in the Elderly

Distinct Presentation of Autoimmune Hepatitis in the Elderly

Dual-vaccine therapy prolonged survival in pancreatic cancer

SAN FRANCISCO (FRONTLINE MEDICAL NEWS) – Serial administration of two vaccines that stimulate the immune response to pancreatic cancer antigens prolonged survival of metastatic disease by about 2 months, according to Dr. Dung T. Le. A team led by Dr. Le of the Johns Hopkins University Sidney Kimmel Comprehensive Cancer Center in Baltimore tested the vaccines – GVAX Pancreas and CRS-207 – in 90 patients. The interim results of the phase II trial showed that overall survival was about 4 months with GVAX alone but was 6 months with GVAX followed by CRS-207, Dr. Le reported in a press briefing held before the annual Gastrointestinal Cancers Symposium. The symposium was sponsored by the American Society of Clinical Oncology. In fact, the efficacy data met the criteria for an early halt to the trial, and patients in the single-vaccine arm are now receiving both vaccines. “This is the first randomized study of immunotherapy in metastatic pancreatic cancer demonstrating an improvement in survival,” commented press briefing moderator Dr. Smitha Krishnamurthi of Case Western Reserve University in Cleveland. “Patients who received at least one dose of the CRS-207 vaccine had a doubling of 1-year survival, and this was accomplished without the side effects of chemotherapy.” Safety results suggested that the vaccines were well tolerated. Local reactions of erythema, warmth, and swelling after intradermal administration of GVAX, as well as transient fevers and chills after infusion of CRS-207, were generally mild and transient. “Additional clinical study of the combination treatment is underway in a three-arm study testing the combination, CRS-207 alone, and chemotherapy alone,” Dr. Le noted. GVAX is an allogeneic whole-cell vaccine. Its genetically modified pancreatic cancer cells secrete granulocyte macrophage colony-stimulating factor, which attracts dendritic cells to the vaccine site, Dr. Le explained. It is given after low-dose cyclophosphamide to inhibit a regulatory T-cell response. CRS-207 consists of live-attenuated Listeria monocytogenes virus vaccine that expresses mesothelin. The vaccine stimulates innate and adaptive immunity to mesothelin, which is highly expressed in pancreatic cancer cells. The investigators tested the vaccines serially in part because GVAX induces a response to a wide variety of tumor-associated antigens, and CRS-207 then boosts the response to mesothelin. Patients in the trial, sponsored by Aduro BioTech, had declined or had experienced a failure of prior chemotherapy. They were randomized 2:1 to receive either two doses of GVAX followed by four doses of CRS-207 or to receive six doses of GVAX therapy alone, with all doses spaced 3 weeks apart. Repeated courses were allowed as long as patients were medically stable. With a median follow-up of 7.8 months, median overall survival among all patients who received at least one dose of vaccine was longer by nearly 2 months with dual-vaccine therapy compared with single-vaccine therapy (6.1 vs. 3.9 months; hazard ratio 0.59; P = .03). The 1-year probability of survival was doubled with dual versus single therapy (24% vs. 12%), according to Dr. Le. In a per-protocol analysis restricted to patients who received at least three doses of vaccine, dual therapy had a greater 5-month overall survival benefit (9.7 vs. 4.6 months; hazard ratio 0.53; P = .03).

Low hospital readmission rates apply across diagnoses

ST LOUIS (MD Consult) - Hospitals with lower 30-day readmission rates have a lower number of readmissions across a wide range of diagnoses and throughout the post-discharge period, reports a study in the January 11, 2014, British Medical Journal. The researchers analyzed data on Medicare beneficiaries aged 65 or older who were readmitted within 30 days after admission for heart failure, acute myocardial infarction, or pneumonia from 2007 to 2009. Readmission diagnoses were classified using a modified version of the Centers for Medicare and Medicaid Services' condition categories, and the timing of readmission was classified by day since discharge. Based on 30-day risk-standardized readmission rates over the 3 years studied, hospitals were classified as having high, average, or low readmission performance for each condition. The range of readmission diagnoses and median times to readmission were compared for high-, average-, and low-performing hospitals. The lead author was Kumar Dharmarajan of Columbia University Medical Center. The analysis included about 320,000 readmissions after 1.3 million admissions for heart failure at 4,041 hospitals, 103,000 readmissions after 516,000 admissions for acute myocardial infarction at 2,378 hospitals, and 208,000 readmissions after 1.1 million admissions for pneumonia at 4,328 hospitals. For all 3 index conditions, the range of readmission diagnoses was similar at hospitals with high, average, and low readmission rates. For heart failure and acute myocardial infarction, median time to readmission was similar across the 3 hospital performance groups. For pneumonia, median time to readmission was 1.4 days longer among high-performing hospitals, compared to low-performing hospitals. The patterns were similar after adjustment for additional hospital factors potentially affecting readmission rates. Thirty-day readmission rates vary substantially among U.S. hospitals. There are few data on how hospital readmission rates are related to the diagnoses and timing of readmissions. This information could have implications for identifying the effective strategies followed by the best-performing hospitals. For the 3 index diagnoses studied, hospitals with low 30-day readmission rates have proportionately fewer readmissions, with similar readmission diagnoses and timing. The results may help to explain why studies evaluating "broad based and longitudinal" interventions for lowering readmissions have higher reported higher success rates, compared to "disease specific or time limited interventions."

Never exceed dose of constipation drugs containing sodium phosphate, FDA warns

ST LOUIS (MD Consult) - On January 8, 2014, the US Food and Drug Administration (FDA) issued an alert concerning the use of over-the-counter (OTC) sodium phosphate drugs to treat constipation. The agency is warning that using more than 1 dose in 24 hours of such drugs can cause rare but serious harm to the kidneys and heart, and even death. These drug products include oral solutions and enemas. They are marketed under the brand-name Fleet, and as store brands and generic products. They are available as single-ingredient drug products, containing either sodium biphosphate or sodium phosphate, and as combination drug products containing both ingredients. The FDA reviewed the Adverse Event Reporting System database from 1969 through 2012 and the medical literature from 1957 through August 2013 for cases describing serious adverse events associated with the of over-the-counter (OTC) sodium phosphate drug products used to treat constipation. The agency identified 54 cases describing serious adverse events in 25 adults and in 29 children. These reports described severe dehydration and changes in serum electrolytes levels associated with taking more than the recommended dose of OTC sodium phosphate products, resulting in serious adverse effects on organs (eg, kidneys and heart) and in some cases resulting in death. These serum electrolytes include calcium, sodium, and phosphate. According to the reports, most cases of serious harm occurred with a single dose of sodium phosphate that was larger than recommended or with more than 1 dose in a day. Some persons may be at higher risk for potential adverse events when the recommended dose of OTC sodium phosphate is exceeded. This includes young children, persons older than 55 years, patients with dehydration, kidney disease, bowel obstruction, or bowel inflammation, and patients who receive medications that may affect kidney function. These medications include diuretics, angiotensin converting enzyme inhibitors, and angiotensin receptor blockers used to treat hypertension, as well as nonsteroidal anti-inflammatory drugs such as aspirin, ibuprofen, and naproxen. Health care professionals should use caution when recommending an oral dose of these products for children 5 years and younger. The rectal form of these products should never be given to children younger than 2 years.

Resecting residual gastrointestinal stromal tumors improved survival

SAN FRANCISCO (IMNG)– Surgically removing residual gastrointestinal stromal tumors in patients who respond to imatinib therapy significantly increased time to tumor progression to 88 months, compared with 43 months using imatinib alone, based on findings from a retrospective study of 134 patients. After controlling for the effects of other risk factors, the surgery decreased threefold the likelihood of disease progression and decreased fivefold the risk of death, Dr. Seong Joon Park reported in a press briefing sponsored by the American Society of Clinical Oncology (ASCO). The press conference was held in advance of at a meeting on gastrointestinal cancers sponsored by ASCO and three other cancer organizations. The findings support the widely adopted practice of removing residual tumors in these patients, despite the retrospective and observational design of the study, Dr. Park said. A prospective European study of similar design to this one terminated early due to poor patient enrollment. “It’s really hard to conduct a prospective study of this design,” said Dr. Park of Asan Medical Center, Seoul, South Korea. He and his associates reviewed the records of patients who showed at least 6 months of disease stabilization or response to imatinib (Gleevec) treatment, 92 of whom got the drug treatment alone and 42 of whom underwent surgery to remove residual tumors after a median of 19 months of imatinib therapy. The imatinib therapy was restarted after surgery. Median follow-up for the cohort as a whole was 59 months. “This treatment strategy is worth trying as a clinical practice if the medical center is large enough to have an experienced multidisciplinary team and to have low morbidity and mortality associated with surgery,” he said. Each year, approximately 5,000 new cases of gastrointestinal stromal tumors are diagnosed in the United States, most often in the stomach and small intestine, though they can occur anywhere in or near the GI tract. Imatinib typically is first-line therapy, and 80%-85% of patients will respond to the treatment, he said. A majority of patients who respond to imatinib will have residual tumors, however, which are believed to contribute to the development of drug resistance, leading to the hypothesis that removing the residual tumors would improve survival. In general, one-third of patients are candidates for surgical removal of residual lesions, depending on the tumor size and other tumor and patient characteristics, Dr. Park said. The two patient groups in the study were similar except that the surgery group was significantly younger (51 vs. 58 years) and was less likely to have metastases in the peritoneum (41% in the surgery group vs. 61% in the control group). As it is an aggressive and difficult treatment, surgery is more likely to be considered and recommended to younger patients who have a good performance status and, thus, less likely to be recommended in patients with multiple peritoneal metastases. Factors associated with longer progression-free and overall survival included surgery and having an initial tumor size less than 150 mm, multivariate analyses showed. Female sex and having the KIT exon 11 mutation also were associated with longer progression-free survival. The researchers used propensity scores and inverse-probability-weighting adjustments to account for the effects of factors other than surgery.

Misdiagnosis, noncompliance often culprits in refractory celiac disease

Refractory celiac disease is often the result of patients having either received an incorrect diagnosis, or their noncompliance, according to Dr. Joseph Murray of the Mayo Clinic in Rochester, Minn. “When faced with such a patient, it’s important to reconfirm the original diagnosis,” said Dr. Murray, who made his remarks during a clinical track presentation at a conference on inflammatory bowel. In cases in which the diagnosis can be confirmed and the patient is compliant, discovering if there are other conditions, and whether to intervene and how, are the important next steps, according to Dr. Murray. When patients present with symptoms of nonresponsive celiac disease, besides taking the patient’s history, which should include whether the patient has any first-degree family members with “true” celiac disease, not just family members who have chosen to stop eating gluten, “I will always ask for the original biopsies,” said Dr. Murray. In addition, original serology tests, if they were done, can confirm whether there are celiac-specific antibodies. “Gliadin antibodies are not celiac specific,” said Dr. Murray. “You can get gliadin antibodies in virtually every other disorder that affects the intestines, so they are pretty much worthless.” Better specificity comes from tissue transglutaminase or endomysial antibodies, he said at the meeting diseases sponsored by the Crohn’s & Colitis Foundation of America. Human leukocyte antigen genotyping, and whether the patient had a clinically obvious response to a gluten-free diet also will help the clinician puzzle out if the original diagnosis was correct, according to Dr. Murray. Worth noting is whether the patient has dermatitis herpetiformis, “That’s pathognomonic for celiac disease,” said Dr. Murray. For example, in the case of a 90-year-old woman whose biopsy 10 years before had been interpreted as presumptive celiac disease and who had had an initial response to a gluten-free diet, had symptoms that persisted for a decade because she’d contracted tropical sprue from annual visits to Indonesia that were not noted in her original patient history. Treated properly, her symptoms abated entirely, according to Dr. Murray. “She wasn’t exactly happy about her 10 years of living gluten free,” he said. Dangers of noncompliance As for patients who claim to follow a gluten-free diet, “That’s not true most of the time,” said Dr. Murray. “A positive serology test in a patient who’s been following a gluten-free diet for a year or more means they’re not just getting a little gluten. They’re getting a lot of gluten.” It can either be advertent or inadvertently, he said. However, serology is insensitive for lower levels of gluten contamination, but a gram of gluten, roughly one-half a slice of bread per day, can be detected, according to Dr. Murray. If noncompliance is the reason for the refractory condition, patients are at greater risk for increased mortality, osteoporosis, lymphomas, and other cancers, and psychological effects such as depression. “Eliminating the gluten may take time. Often we have to use behavioral counselors to help,” said Dr. Murray. Also key is to stay in touch with the patient. “Follow-up in patients with celiac disease is abysmal,” Dr. Murray said, “It’s almost like once the disease is diagnosed, it’s forgotten about medically.” “The complicating thing about celiac disease can be that autoimmune disorders and like disorders hang out together,” said Dr. Murray. “Complications of celiac disease also can occur in multiples.” Bacterial overgrowth, microscopic colitis, lymphoma, and systemic sclerosis associated–dysmotility are all concurrent conditions Dr. Murray reported seeing in his own practice when treating refractory celiac disease. Because lactose intolerance is also common in celiac disease, Dr. Murray said he will often advises patients to avoid dairy for a year, and then gradually add that back into the diet with good results. “Often, that will work, so I don’t even test for lactose intolerance initially,” he said. Despite all the possible etiologies for nonresponsive celiac disease, gluten exposure was found in more than a third of cases, while “true refractory celiac disease really makes up only about 10% or 11% of these nonresponsive patients,” said Dr. Murray, referring to a study on the topic (Clin. Gastroenterol. Hepatol. 2007;5:445-50). Patients with celiac disease also can have multifocal strictures in the proximal duodenum that reach the jejunum, “but rarely affect the ileum,” according to Dr. Murray. Possible lymphomas “The first thing that I think about when I see a really sick patient previously diagnosed with celiac disease several years before is, ‘Does the patient have lymphoma?’” said Dr. Murray. Ulcerative jejunoileitis typically indicates that lymphoma is imminent, although shallower ulcers are often linked to the use of NSAIDs, he said. Giant cavitating lymphadenopathy, while rare, is also a consideration, according to Dr. Murray. “A premalignant type of disorder, sometimes will respond to immunosuppressives, but often can presage the development of lymphoma,” he said. True refractory celiac disease involves symptomatic malabsorption, severe enteropathy, and a primary or secondary nonresponse to a gluten-free diet. “By definition, there should be no lymphoma,” said Dr. Murray. Refractory celiac disease is either characterized as type 1, which has a normal T-cell population and responds well to immunosuppression, or as type 2 with clonal T cells. Dr. Murray said he often uses topical budesonide to treat type 1 patients, with good results, since there is about a 90% recovery rate in this patient population. Type 2 is the most pernicious, with nearly half of patients dying within 5 years of diagnosis, either from malignant or infectious complications, according to Dr. Murray. “Type 2 refractory disease is not a trivial disease,” he said. Although most adults with celiac disease don’t heal, many are asymptomatic; however, this does not mean a patient’s risk of mortality from the disease has improved. Patients are also at greater risk for malignant complications. (Am. J. Gastroenterol. 2010;105:1412-20 [doi:10.1038/ajg.2010.10]). “We really don’t know what we should do about those asymptomatic patients,” said Dr. Murray. He noted that, “Failure to heal is not entirely benign, but it’s not refractory celiac disease,” said Dr. Murray.

Thrombosis precautions in IBD not met in two-thirds of high-risk cases

HOLLYWOOD, FLA. (FRONTLINE MEDICAL NEWS) – The relative risk of thromboembolic events is greater in inpatient inflammatory bowel disease patients than in the general population, but prophylactic treatment is still not standard, according to a speaker at a conference on inflammatory bowel diseases. “It’s a relatively rare problem, only about 1 to 1.5 percent,” said Dr. Athos Bousvaros, of Boston Children’s Hospital. “So, why worry about it so much? Because it really is a major source of morbidity in the IBD population. It usually happens in the sick patients, the ones at risk for strokes; and it usually happens at the worst time, when you’re thinking about colectomy.” However, Dr. Bousvaros said only about a third of IBD patients at risk for a thromboembolic event are given prophylactic treatment in the inpatient setting, especially in severe colitis, and it is generally recommended. Although pharmacologic prophylaxis is included in the American College of Gastroenterology guidelines, Dr. Bousvaros cited a recent study that found only 35% of gastroenterologists in the United States actually do so (J. Clin. Gastroenterol. 2013;47:e1-e6). “In the inpatient setting, especially in severe colitis, [prophylaxis] is generally recommended,” Dr. Bousvaros said. “It is included in the AGA [American Gastroenterological Association] physician performance measure set.” In the outpatient setting, data do not support it, he said. Relative risk high While the absolute risk is low, the relative risk of a venous thromboembolic event is six times greater in IBD, particularly in patients aged 20 years or less, said Dr. Bousvaros, citing a cohort study that used Danish administrative data (Gut 2011;60:937-43). “It’s mainly patients with flares, and mainly those with colitis, either Crohn’s or severe ulcerative colitis,” Dr. Bousvaros said. In a prospective study of about 2,800 IBD patients (mean age, 42 years) recruited over 2.5 years, matched with non-IBD controls, and followed for several years, about 4% developed de novo venous thromboembolism (Gastroenterol. 2010;139:779-787.e1). Dr. Bousvaros emphasized that IBD was an independent risk factor for VTE recurrence in the study. “They were typically treated with long-standing prophylaxis. And if any anticoagulation was involved, the risk of recurrence was high,” he said at the meeting, which was sponsored by the Crohn’s & Colitis Foundation of America. High-risk criteria Overall, the relative risk for VTE was found by a just-published meta-analysis of more than 200,000 IBD patients to be 2.4 for deep vein thrombosis, 2.5 for pulmonary embolism, 1.3 for ischemic heart disease, and 3.4 for mesenteric ischemia (J. Crohns Colitis 2013 Oct 29 [doi: 10.1016/j.crohns.2013.09.021]). Dr. Bousvaros said the investigators did not find an increased risk for arterial thromboembolic events in IBD, but that VTEs “were highly significant in this population.” Patients with IBD should be considered high risk for VTE if they are being treated in hospital for severe colitis and have a personal or family history of thrombosis, have known thrombophilia, have been taking oral contraceptives, have a history of smoking, are obese, or have had a PICC line. “Any of those makes you a particularly high-risk patient,” Dr. Bousvaros said.

Bariatric surgery benefits in type 2 diabetes linked to disease duration

MELBOURNE (FRONTLINE MEDICAL NEWS) – The benefits of bariatric surgery in people with type 2 diabetes are significantly reduced with longer disease duration at the time of surgery and with time since surgery, a long-running, prospective, controlled study has found. The Swedish Obese Subjects study showed that 72% of surgery patients achieved remission at 2 years after treatment, compared with 16% of control patients. Furthermore, 15 years after surgery, 31% of the surgery patients remained in remission, compared to 7% of control patients, according to data presented at the International Diabetes Federation world congress. When stratified by disease duration at baseline, newly diagnosed patients maintained significantly higher remission rates at 2, 10 and 15 years’ follow-up (roughly 94%, 60%, and 47%, respectively) than did those who had had diabetes for more than 3 years at baseline (about 39%, 12%, and 9%). These data came from the SOS (Swedish Obese Subjects) study, a nonrandomized, prospective, observational study involving 2,010 obese subjects who underwent bariatric surgery in 1987-2001, when they were 37-60 years old. A total of 68% of the bariatric surgery recipients had vertical band gastroplasty, 19% underwent gastric banding, and 13% had a Roux en-Y gastric bypass. They were extensively matched by 18 variables to 2,037 obese controls. The SOS study is being conducted at 25 surgical departments and 480 primary care clinics across Sweden. Follow-up is ongoing. There were 343 individuals with type 2 diabetes in the surgical group and 260 in the control group, enabling a secondary analysis of the impact of bariatric surgery in type 2 diabetes. Presenter Markku Peltonen said that although bariatric surgery achieves impressive results in the short-term, there is considerable relapse in the longer term. “It’s typical of bariatric surgery that you achieve the greatest weight loss initially, after 2 years, then there is a slow regain again and this was observed in this study,” said Dr. Peltonen, director of the department of chronic disease prevention at the National Institute for Health and Welfare, Helsinki. “Even in the long term, they are doing much better than the controls who were treated with traditional weight management means,” he said in an interview. This also extended to the microvascular and macrovascular complications of diabetes, with the study showing a significant 47% lower incidence of complications in the surgery group, compared with the control group. However, these benefits were also attenuated by disease duration. Patients who had had diabetes for more than 3 years and were treated with surgery showed no significant differences in diabetes complication rates, compared with the patients given medical care only. Dr. Peltonen said he was surprised by the degree of impact that disease duration had on the outcomes of surgery. “Somehow the expectation would be that we would see an effect even in those people with long diabetes duration, because they have a serious, advanced disease but it looks like, based on our results, that maybe it’s so that the disease has advanced for so long that bariatric surgery cannot reverse that development.” Session chair John Dixon said the SOS study represented the pinnacle of long-term data for bariatric surgery, and offered impressive insights. “The fact that 31% of these patients are still in remission from diabetes some 15 years down the track is extraordinary, because we know the deterioration of beta cells is significant and this group has held it off for a long time,” said Dr. Dixon, head of clinical obesity research at the Baker IDI Heart and Diabetes Institute in Melbourne. Dr. Dixon said the finding that patients treated early fared better and had a reduction in long-term complications was also a very important clinical finding, suggesting that bariatric surgery should be considered earlier in obese patients not getting good control with conventional therapy. SOS was supported by the Swedish Research Council, the Swedish Foundation for Strategic Research, and the Swedish government. Some study investigators authors had received paid lectureships, held stock in, or were on the advisory boards for pharmaceutical companies.

DOs and DON’Ts in Managing GERD ( GastroEsophageal Reflux Disease ) :

DO eat a healthy diet, rich in fruits, vegetables, and low-fat dairy products. Lower your intake of saturated and total fats. DO raise the head of your bed 6 to 8 inches with wooden blocks. DO maintain a healthy body weight. DO take medicines recommended by your doctor. DON’T eat refl ux-inducing foods, such as citrus fruits and juices, coffee, peppermint, chocolate, and spicy foods. DON’T eat large meals. DON’T eat meals late in the day. DON’T lie down just after eating. DON’T wear tight-fi tting clothing. DON’T smoke or use tobacco products.

Restrictions on use of diabetes drug rosiglitazone lifted after FDA re-examines cardiovascular risk data

ST LOUIS - On November 25, 2013, the US Food and Drug Administration (FDA) issued a safety alert stating that it is requiring the removal of certain restrictions on prescribing and use of Avandia (rosiglitazone), a drug used in the treatment of diabetes. This new label information concerns cardiovascular risk. The FDA is also requiring the same modifications be made to the labels for any other drugs that contain rosiglitazone. The decision to remove the previous prescribing and dispensing restrictions for rosiglitazone-containing medicines was made on the basis of results from the FDA's review of data of a large, long-term clinical trial. Moreover, the decision to change the restrictions was supported by a comprehensive, outside, expert re-evaluation of the data conducted by the Duke Clinical Research Institute. In 2010, in response to data from a meta-analysis of placebo-controlled randomized trials that suggested an elevated risk of cardiovascular events in association with rosiglitazone use, the FDA announced it would restrict the drug to use in patients with type 2 diabetes who could not manage their disease with other medications. The FDA also required GlaxoSmithKline, the manufacturer of Avandia, to convene an independent group of scientists to readjudicate key aspects of the trial known as Rosiglitazone Evaluated for Cardiac Outcomes and Regulation of Glycemia in Diabetes (RECORD). This trial evaluated the cardiovascular safety of Avandia compared with standard diabetes drugs. The original evaluation of data from RECORD suggested an increase in myocardial infarctions (MIs) and decreases in the rates of death and stroke in patients treated with rosiglitazone. These results were not statistically significant. During the course of the FDA's original 2010 review of the RECORD trial, important questions had arisen about potential bias in the identification of cardiovascular events. The readjudicated results could not dismiss an increased risk of MI with rosiglitazone versus placebo, because the trial did not use a placebo. However, the readjudicated results did assess rosiglitazone versus the standard-of-care diabetes drugs metformin and sulfonylurea and confirmed the original RECORD finding that did not show an increased risk of MI associated with the use of rosiglitazone. In the trial, patients treated with rosiglitazone experienced fewer deaths from a cardiovascular cause, from a stroke, and from an MI; fewer nonfatal strokes; and fewer deaths from any cause compared with patients treated with metformin and sulfonylurea. Patients treated with metformin and sulfonylurea experienced fewer nonfatal MIs compared with patients treated with rosiglitazone. However, none of these results were statistically significant. On the basis of the results from the readjudicated RECORD trial, the FDA is requiring modifications to the rosiglitazone Risk Evaluation and Mitigation Strategy (REMS) program to remove the requirements for restricted distribution. After the changes to the REMS are finalized, health care professionals, pharmacists, and patients will no longer be required to enroll in the rosiglitazone REMS program to prescribe, dispense, or receive rosiglitazone medicines. Patients will also be able to receive rosiglitazone through regular retail pharmacies and mail order pharmacies.

FDA warns of risk of myocardial infarction and death with use of certain cardiac stress test drugs

On November 20, 2013, the US Food and Drug Administration (FDA) issued a warning concerning the rare risk of myocardial infarction (MI) and death with use of the cardiac nuclear stress test agents Lexiscan (regadenoson) and Adenoscan (adenosine). The FDA has approved changes to the drug labels to reflect these serious events and has updated its recommendations for use of these agents. The FDA has reviewed the FDA Adverse Event Reporting System (FAERS) database and the medical literature for cases of MI and death from all causes associated with the use of Lexiscan and Adenoscan. Information about Lexiscan included that dating from June 24, 2008, to April 10, 2013, and for Adenoscan, from May 18, 1995, to April 10, 2013. The beginning dates correlated with the start of marketing for each drug. The FAERS database contained 26 MI cases and 29 cases of death occurring after Lexiscan administration, and 6 cases of MI and 27 cases of death after Adenoscan administration. Reports did not always specify when deaths or MIs occurred. When reported, these adverse events tended to occur within 6 hours after Lexican or Adenoscan administration. A few deaths occurred when Lexiscan or Adenoscan was administered with exercise stress testing, which is not an FDA approved use of the drugs. With Lexiscan, the most common adverse events associated with death were cardiac arrest, MI, loss of consciousness, respiratory arrest, electrocardiography ST-segment depression, pulmonary edema, and ventricular fibrillation. With Adenoscan, the most common adverse events associated with death were cardiorespiratory arrest, dyspnea, cardiac arrest, respiratory arrest, and ventricular tachycardia. A review of the medical literature also identified 2 case reports of MI associated with Lexiscan use. However, published studies from the medical literature have not documented an increased incidence of cardiovascular adverse events with Lexiscan compared with Adenoscan. Lexiscan and Adenoscan are FDA approved for use during cardiac nuclear stress tests in patients who cannot exercise adequately. Both products help identify coronary artery disease by dilating these arteries and increasing blood flow to help identify obstructions. Lexiscan and Adenoscan cause blood to flow preferentially to the healthier, unblocked, or unobstructed arteries, which can reduce blood flow in obstructed arteries. In some cases, this reduced blood flow can lead to an MI, which can be fatal. The use of both drugs should be avoided in patients with signs or symptoms of unstable angina or cardiovascular instability because these patients may be at greater risk for serious cardiovascular adverse reactions. Cardiac resuscitation equipment and trained staff should be readily available before administering Lexiscan or Adenoscan.

High schoolers smoking more cigars, pipes, e-cigarettes

BY RICHARD FRANKI Overall use of tobacco among high school students decreased from 2011 to 2012, but cigar and pipe smoking went up, as did the use of some nonconventional products, the Centers for Disease Control and Prevention reported. In 2012, 23.3% of high school students surveyed reported current tobacco use, compared with 24.3% in 2011. Use of cigars, driven largely by a significant increase among non-Hispanic black students, went from 11.6% in 2011 to 12.6% in 2012, and pipe use rose from 4.0% to 4.5%, according to data from the National Youth Tobacco Survey. “Youths are known to have higher rates of cigar use than adults, which might be related to the lower price of some cigars (e.g., cigarillos and ‘little cigars’) relative to cigarettes, or the marketing of flavored cigars that might appeal to youths,” the report said (MMWR 2013;62;893-7). Significant increases in use were seen for electronic cigarettes (1.5% in 2011 to 2.8% in 2012) and hookahs (4.1% to 5.4%), but the use of other nonconventional products such as bidis (small brown cigarettes wrapped in a leaf), kreteks (clove cigarettes), and snus declined, the CDC noted.

Gastric bypass induces diabetes remission in obese patients

WASHINGTON (IMNG) – Gastric bypass surgery resulted in significantly more weight loss and also improved measures of glycemic control significantly more than did other forms of bariatric surgery, Dr. John Morton reported at the annual clinical congress of the American College of Surgeons.

However, he noted, while remission did correlate with weight loss in patients who had gastric banding or sleeving, it appeared to be independent of weight loss in those who had the bypass surgery. While he didn’t speculate on the reasons for this finding, he did affirm his belief that gastric bypass is the best option for most obese patients with comorbid diabetes.

“I feel very comfortable recommending it” for these patients, said Dr. Morton of the Stanford (Calif.) University. “There are, of course, other clinical conditions to consider when deciding [among] bypass, banding, and sleeve, but if the only consideration is around diabetes, I’m 100% comfortable in recommending it for obese diabetics.”

He presented the 1-year follow-up data on 1,792 obese patients who underwent bariatric surgery. Of these, 1,364 had a Roux-en-Y bypass; 264 had a sleeve gastrectomy; and 164 had adjustable gastric banding.

The patients were a mean of about 46 years old. Body mass index was statistically, but not clinically, different between the groups (bypass 47 kg/m2; band 44 kg/m2; sleeve 44 kg/m2). Waist circumference ranged from 51 to 53 inches. About 75% of the group was female and more than half, white.

Overall, about one-third of each group had type 2 diabetes. Most were taking only oral medications. About 5% took only insulin, and about a quarter took both oral agents and insulin. At baseline, the mean HbA_1c was more than 7% in each group. The mean fasting insulin was 36 microU/mL in the bypass group, 28 microU/mL in the band group, and 32 microU/mL in the sleeve group.

By 12 months after surgery, patients with diabetes who had bypass had lost the most weight – a mean of 71% of their excess body weight, compared with 38% in the banding group and 50% in the sleeve group.

Those who had the bypass surgery also experienced the biggest change in their HbA_1c – dropping almost 16% to a mean of 5.8%. Patients in the other two groups experienced a mean drop of 10%, resulting in HbA_1c levels of right around 6%.

Fasting insulin levels also improved significantly more in the bypass group, falling from a baseline mean of 56 microU/mL to 7.8 microU/mL – a decrease of 68%. In the band group, the level fell from 28 microU/mL to 12 microU/mL – a 52% decrease. In the sleeve group, levels fell from 32 microU/mL to 10 microU/mL – a 61% decrease.

“Fasting insulin is also considered an independent marker of cardiac risk,” Dr. Morton added, indicating that the risk of cardiovascular problems would fall along with insulin levels.

Blood glucose improved significantly more in the bypass group, falling from a baseline mean of 149 mg/dL to 101 mg/dL – a 22% change. In the band group, the level fell from 140 mg/dL to 125 mg/dL (8%) and in the sleeve group, from 130 mg/dL to 118 mg/dL (5.6%).

A multivariate analysis controlled for surgery type, sex, body mass index, race, age, and insurance status. Of these factors, surgery type was the strongest predictor, with bypass patients three times more likely to achieve that goal than those undergoing banding or sleeve placement.

Dr. Morton did not present his complication data. However, during the discussion period, he said the three procedures were similarly safe. The gastric sleeve group had a higher leak rate than did the other groups, but that remained less than 1%. Readmission rates were comparable, he said, but he did not provide that number.

“Any time you consider this, it has to be a risk/benefit analysis,” he said. “It’s our philosophy that for obese patients with severe diabetes, we approach them first with the bypass because it has the most proven track record over time.”

Dr. Morton has up to 7 years of data on some of the patients, and said he is now analyzing that. But when questioned about durability, he agreed that diabetes can recur in the rather common scenario of a patient regaining weight. “At the end of the day, though, what’s important is that the obese patient with diabetes gets treatment. All three surgeries demonstrated some improvement, and I believe that any surgery is better than no surgery at all.”

Dr. Morton has received research support from Covidien.