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By H. Elber. Henderson State Univerisity. 2018.

Performance also organized a roundtable with representatives from 9 purchase motilium 10mg line. ACSM and the US Department of Defense best 10 mg motilium, ACSM discount motilium 10 mg amex, NCAA, and content experts CHAMP summit on sickle cell trait: mitigating risks for from the ASH to examine strategies to mitigate risk associated with 9 warfighters and athletes. The best available evidence suggests that under extreme 2045-2056. Sickle-cell tion, SCT increases the relative risk of heat-related illness and trait as a risk factor for sudden death in physical training. Connes P, Reid H, Hardy-Dessources MD, Morrison E, Hue O. Plausible mechanisms have Physiological responses of sickle cell trait carriers during been proposed, but they are as yet untested6,11,28 and focused exercise. Data from new sources, including additional information regular physical activity on skeletal muscle structural, ener- from efforts by the military to mitigate heat-related risk; consistent getic, and microvascular properties in carriers of sickle cell comprehensive testing of athletes who experience severe myalgias trait. Exercise training blunts mandate on student-athletes are likely to make important contribu- oxidative stress in sickle cell trait carriers. Moderate endurance injuries and deaths and have no potential to harm may be the more exercise is not a risk for rhabdomyolysis or renal failure in prudent path. Effects of hydration and water Disclosures deprivation on blood viscosity during a soccer game in sickle Conflict-of-interest disclosure: The author has received research fund- cell trait carriers. Published online ahead of ing from Novartis, Glaxo Smith Kline, Eli Lilly, Amgen, and bluebird print June 9, 2012. Thompson, MD, MPH, Lurie Children’s Hospital Chi- 325-330. Exertional 312-227-4834; Fax: 312-227-9756; e-mail: [email protected] rhabdomyolysis: a clinical review with a focus on genetic northwestern. Natural history of exertional rhabdomy- to duty/return to play: conference proceedings. Jordan LB, Smith-Whitley K, Treadwell MJ, Telfair J, Grant 20. Update: exertional rhabdomyolysis, active AM, Ohene-Frempong K. Deuster PA, Contreras-Sesvold CL, O’Connor FG, et al. Committee on Bioethics, Committee on Genetics, The Genetic polymorphisms associated with exertional rhabdomyol- American College of Medical Genetics and Genomics So- ysis. Sambuughin N, Capacchione J, Blokhin A, Bayarsaikhan M, emy of Pediatrics. Policy statement: ethical and policy issues Bina S, Muldoon S. The ryanodine receptor type 1 gene in genetic testing and screening of children. Loosemore M, Walsh SB, Morris E, Stewart G, Porter JB, with sickle cell trait (SCT) without hemoglobin screening or Hb Montgomery H. Holcomb1 and Shibani Pati2 1Center for Translational Injury Research, Department of Surgery, and Texas Trauma Institute, University of Texas Medical School, Houston, TX; and 2Blood Systems Research Institute and Department of Laboratory Medicine, University of California, San Francisco, San Francisco, CA Over the past century, blood banking and transfusion practices have moved from whole blood therapy to components. In trauma patients, the shift to component therapy was achieved without clinically validating which patients needed which blood products. Over the past 4 decades, this lack of clinical validation has led to uncertainty on how to optimally use blood products and has likely resulted in both overuse and underuse in injured patients. However, recent data from both US military operations and civilian trauma centers have shown a survival advantage with a balanced transfusion ratio of RBCs, plasma, and platelets. This has been extended to include the prehospital arena, where thawed plasma, RBCs, and antifibrinolytics are becoming more widely used. The Texas Trauma Institute in Houston has followed this progression by putting RBCs and thawed plasma in the emergency department and liquid plasma and RBCs on helicopters, transfusing platelets earlier, and using thromboelastogram-guided approaches. These changes have not only resulted in improved outcomes, but have also decreased inflammatory complications, operations, and overall use of blood products. In addition, studies have shown that resuscitating with plasma (instead of crystalloid) repairs the “endotheliopathy of trauma,” or the systemic endothelial injury and dysfunction that lead to coagulation disturbances and inflammation. Data from the Trauma Outcomes Group, the Prospective Observational Multicenter Major Trauma Transfusion (PROMMTT) study, and the ongoing Pragmatic Randomized Optimal Platelet and Plasma Ratios (PROPPR) trial represent a decade-long effort to programmati- cally determine optimal resuscitation practices, balancing risk versus benefits. With injury as the leading cause of death in patients age 1 to 44 years and hemorrhage the leading cause of potentially preventable death in this group, high-quality data must be obtained to provide superior care to the civilian and combat injured. Large-scale blood banking and transfusion originated during World transfusion practice mimicked the standard civilian approach, in War I, when blood transfusion was found to decrease mortality in which crystalloid was administered first, followed by RBCs, then bleeding and severely injured soldiers. By 2005, a change blood was the sole transfusion product. In the 1960s and 1970s, had already occurred, revealed in the publication by Borgman et al component therapy became predominant in the Western world, describing the survival advantage of the 1:1 plasma and RBC ratio, a albeit with little if any quality data documenting clinical superiority balanced transfusion concept described as “Damage Control Resus- or even equivalence. Over the ensuing 40 years, the practice of citation (DCR). In 1979, Counts et al admonished us to not used to guide resuscitation. However, what we have failed to 1:1:1 (plasma:platelet:RBC) ratio. This change was driven by by the use of components such as packed RBCs and crystalloid multiple studies describing a continued improvement in clinical resuscitation fluids. In the classic trauma textbook Trauma, the outcomes using the Joint Theater Trauma Registry. In a severely injured patient at risk of dying, plasma appears either on opinion or transfused products that are no longer available. The US military experience with transfusion has evolved dramati- At the Texas Trauma Institute in Houston, we admit more than 6500 cally over the past 12 years of the current war. Our current transfusion practice is very 656 American Society of Hematology similar to the military’s DCR approach. In 2010, we moved thawed endothelial injury after hemorrhagic shock. Infusion times of plasma are now within evolutionary pressure that conserves this response has existed for 3 minutes of patient arrival. Crystalloid use is severely limited; in millennia and is present across multiple species. Only in the past massively bleeding patients, only 3 to 4 L is infused in a 24-hour 100 years have medics placed IV catheters and forced crystalloid period. Platelets are transfused early in bleeding patients, within the fluid into the intravascular space while the endothelium is still first several units of RBCs. The infusion of crystalloid has shown to result in time, and international normalized ratio are not used on admission deleterious interstitial edema, ARDS, and multiple organ failure. The study by Borgman et al ignited the discussion of ratio Subsequently, we replaced the thawed plasma with liquid plasma. In short, we have changed almost every aspect of our blood from single and multicenter retrospective studies from around the product and coagulation management over the past 5 years. Most associated earlier and higher ratios of plasma and changes have resulted in decreases in the inflammatory consequences platelet use with improved outcomes.

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In particular purchase motilium 10mg with amex, for individuals with HLA- B*27 an epitope within Gag was defined which is responsible for viremic control order 10mg motilium free shipping. Mutations in this epitope are so devastating to the virus that it only leads to repli- cation competent viruses if a compensatory mutation arises far from this epitope Figure 7: Development of B and T lymphocytes 36 The Basics (Goulder 1997 discount 10mg motilium otc, Schneidewind 2008). It appears to be different for patients with the HLA-B*57 allele: there are epitopes which rapidly escape after infection. This leads to a restriction of the replicative capacity of the virus and to the consequent control of viremia (Leslie 2004). CD8 T cell responses exist in all HIV-infected patients and the variety of epitopes is immense (Addo 2003). From twins studies we know when the same virus hits the same immune system, the immune response is very similar (Draenert 2006). As a reaction to the immune pressure by a strong CD8 T cell response, viral variants with sequence changes arise, so-called escape mutations. This occurs most frequently in early HIV infection, which was shown nicely both in the monkey model and in humans (Allen 2000, O’Connor 2002, Allen 2005). Also, in late disease stages, there are CD8 T cell responses, sometimes broad and strong (Draenert 2004). However, these usually do not induce escape mutations, which is an indirect indication that these responses are no longer effective (Draenert 2004). Consequently, the CD8 T cell response was examined not only quantitatively but also qualitatively. It turned out that “controllers” usually have a poly-functional CD8 T cell response, i. On the other hand “progressors” have CD8 cells that reply to an antigen stimulus with only one or two functions (Betts 2006). It has also been shown that effective CD8 cells of “controllers” proliferate well ex vivo, unlike those of “progressors” (Migueles 2002). This loss of effector func- tions is called immune exhaustion. In recent years, causes of immune exhaustion have been studied. It was shown that inhibitory signaling pathways, especially programmed death-1 (PD-1), play a major role in the development of immune exhaustion (Day 2006, Petrovas 2006, Trautmann 2006). By blocking PD-1, proliferation of CD8 T cells increased significantly (Day 2006). Other inhibitory molecules are Tim-3 and CD244 (2B4) (Jones 2008, Pacheco 2013). In addition, new cell types that suppress immune responses play a role. Recently it was demonstrated that myeloid-derived suppressor cells (MDSC), which inhibit immune responses in solid tumors, occur in increased number of HIV-infected persons and restrict the function of CD8 cells ex vivo (Vollbrecht 2012, Qin 2013). CD4 T cells T lymphocytes that keep the CD4 receptor during T cell development, undergo further maturation in the thymus. They are divided into various sub-groups, which differ in their phenotype and function. In the thymus, a clearly separated subgroup splits off: the regulatory T cells (Fig. What remains are the naïve CD4 T cells which can develop into four (and possibly more) cell lines, depending on the stimulus: Th1, Th2, Th17 and “follicular helper T cells” (TFH). The latter mediate B cell acti- vation in the B cell follicles of the secondary lymphoid organs (Papp 2014). Best known are the true CD4 helper cells, namely Th1 and Th2 cells, which differ in their cytokine profile and also have different functions: Th1 cells mainly produce inter- feron , lymphotoxin (LT ) and IL-2 and are considered crucial for fighting intra- cellular pathogens. Th2 cells on the other hand produce IL-4, IL-5, IL-9, IL-10, IL-13, IL-25 and amphiregulin. They aim at extracellular pathogens, including worms (Zhu 2008). CD4 T cells carry an T cell receptor as described for the CD8 T cells which interacts distinctly from HLA class II molecules. CD4 helper cells are important for the development of an effective CD8 T cell and B cell response. There are also directly acting antigen-specific CD4 cells. Since these cells are preferentially infected by HIV, it was not clear initially whether they func- tion properly in HIV infection. Today we know that virus-specific CD4 T cell responses (Th1) lose effector functions early in HIV infection, including, e. The function of HIV-specific CD4 cells of elite controllers is significantly better than in patients with progressive disease (Betts 2001, Younes 2003, Harari 2004, Pereyra 2008). However, it has been shown that the differences in function are at least partly the consequence and not the cause of the low viral load of elite controllers (Harari 2004, Potter 2007, Tilton 2007). For the CD4 T cell response, an important determinant is immune exhaustion as was already described for CD8 T cells. For CD4 T cells, the inhibitory molecule PD- 1 also plays an important role (D’Souza 2007). Several inhibitory synergistic signal- ing pathways are responsible for the loss of function of CD4 T cells, in particular, CTLA-4 and TIM-3 (Jones 2008, Kassu 2010). Cytokine IL-10 has been identified as a crucial mediator (Clerici 1994, Brockman 2009). Blockade of the IL-10 receptor by an antibody resulted in improved proliferation of CD4 T cells as well as to an increased secretion of IL-2 and interferon-. Regulatory T cells (Treg) Regulatory T cells are CD4 and CD25-positive T cells which mature within the thymus (Fig. They show a pronounced suppressive activity (suppressor cells), and inhibit the activation, proliferation, and function of a number of immune cells, including CD4 and CD8 T cells, NK cells, B cells and antigen-presenting cells such as dendritic cells and macrophages (Imamichi 2012, Josefowicz 2012). They protect the body against building harmful immune responses against self, foods or commensal (Josefowicz 2012), protecting against autoimmune diseases or allergies. The role of Treg in HIV infection is an area of intense research, as well as debate. There are conflicting data on the benefits or harm of Treg in the pathogenesis of HIV infection. There are studies describing increasing, comparable or decreasing Treg numbers in HIV infection in comparison to healthy individuals (Seddiki 2008). These inconsistencies can be explained by different phenotypic markers or methods of counting (percentage or absolute numbers). In addition the stage of HIV infection and the compartment in which cells are measured, play a role.

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Given these concerns generic 10mg motilium fast delivery, the use of independence and reduced risk of AML transformation or death discount 10 mg motilium overnight delivery, either romiplostim or eltrombopag should be avoided in patients whereas treatment-related thrombocytopenia has been associated with excess blasts cheap 10 mg motilium with mastercard. Presumptive use of granulocyte (or granulocyte macrophage) colony In anemic, lower-risk MDS patients who do not harbor the stimulating factors for MDS patients with neutropenia has never del(5q) lesion, a phase 2 study of lenalidomide similar in design been shown prospectively to reduce episodes of febrile neutropenia to the registration study enrolled 215 patients. Novel agents and combinations for MDS Agent(s) Mechanism of action Development stage Comments Lower-risk MDS Romiplostim Thrombopoietin receptor agonist Randomized phase 2 trial Romiplostim improved clinically significant (N 250) bleeding events and IWG platelet response rates; increase in myeloblasts in patients with baseline excess blasts. Eltrombopag Thrombopoietin receptor agonist Randomized phase 2 trial Eltrombopag improved platelet counts (still enrolling, N 17/171 and quality of life (preliminary). ARRY-614 p38 MAPK/Tie2 kinase inhibitor Phase 2 (N 62) 22% of patients with IWG hematologic improvement Ezatiostat Glutathione analog prodrug GSTP1–1 Phase 2 trial (N 38) 29% of patients with RBC transfusion inhibitor independence. Sotatercept Activin receptor type 2A IgG-Fc fusion Phase 2 (still enrolling, N? Although grade with lenalidomide showed a rate of AML evolution of 17% at 2 3 or 4 myelosuppression was approximately one-half of that seen years (with a median follow-up of 3 years), whereas another in the registration study, at 20%–25%, it also was not associated analysis of 381 untreated del(5q) MDS patients, with a median with subsequent attainment of a transfusion independence re- follow-up of 4 years, showed a rate of AML evolution of 17% at 5 sponse to therapy. Scio-469, a potent selective 84 American Society of Hematology Figure 2. Reprinted with permission from Sekeres and Cutler, 2014. These will be covered in ARRY-614, another p38 MAPK/Tie2 kinase inhibitor, was more detail in the section on therapies for higher-risk MDS. Of 54 evaluable lower-risk patients, IWG response rates appear to be 30%–40%. Ezatiostat, a glutathione analog prodrug glutathione S- of which (giving decitabine at a dose of 20 mg/m2 on 3 days per transferase P1-1 (GSTP1-1) inhibitor, was explored in the phase 28-day cycle) enrolled 65 lower-risk MDS patients, of whom 22% 2 setting in 38 lower-risk MDS patients, of whom 11 (29%) achieved an IWG response. Among the 32 enrolled MDS patients, 35% of previously treated and 60% of first-line-treated patients had an IWG response Treatment of multiple cytopenias excluding BM responses. Although, classically, these patients have also being studied as an oral formulation in lower-risk MDS. In common practice, this often takes the form of one of lower-risk MDS) were randomized to combined antithymocyte the hypomethylating agents, azacitidine or decitabine. The postu- globulin cyclosporine or to best supportive care. The TET2, IDH1 and IDH2, ASXL1, and others critical in DNA largest U. In a multivariate patients harboring these abnormalities. Hematology 2014 85 Azacitidine gained approval from the FDA based on a phase 3 trial overall survival was 13. Vorinostat, a small-molecule inhibitor of both class subsequent AZA-001 study, which was limited to higher-risk MDS I and II HDAC enzymes, promotes cell-cycle arrest and apoptosis of patients, when azacitidine was pitted against a predetermined cancer cells through regulation of gene expression. The outcomes of conventional care regiment (supportive care, low-dose cytarabine, 40 primarily higher-risk patients enrolled in a phase 2 trial testing or traditional, AML-like induction chemotherapy), it did result in an the combination of vorinostat and azacitidine highlight the potential overall survival advantage, with a median survival of 24. The median duration of response was 16 months and the median Likewise, decitabine gained regulatory approval in the United States overall survival was 21 months. Despite a large majority of patients based on a phase 3 trial in which it was compared with supportive with undetectable disease by morphology, analysis for the MDS care. The North American Intergroup randomized controlled trial in higher-risk MDS patients, with a MDS study (S1117, www. Why was a survival difference demonstrated for 1 hypomethylating Pracinostat is an oral pan-HDAC inhibitor that has also demon- agent but not the other when the 2 are structurally and biologically strated synergistic interactions with azacitidine in preclinical stud- so similar? Given the vast differences in median survival on the ies. After a successful single-agent study in myelofibrosis, a pilot control arms, which cannot be explained by the 30% of patients in phase 2 study of pracinostat combined with azacitidine has been the azacitidine study on the conventional care arm who received active conducted in 9 patients with advanced MDS, in whom the overall treatment, it is highly likely that different patient populations were response rate was 89% (7 achieved CR/CR with incomplete hematologic recovery). In addition, the median number of cycles of drug received was 9 for azacitidine and 4 for decitabine, which may have complete cytogenetic response. Invigorated by these results, a been inadequate to realize all responses; in addition, decitabine may randomized placebo-controlled phase 2 trial of the combination have been administered using a suboptimal schedule. Any attempts to study this retrospectively would likely be A cautionary tale in combination therapy is seen in the phase 2 corrupted by confounding and no prospective study has reported exploration of the HDAC inhibitor entinostat combined with “recovering” responses to adequate hypomethylating therapy upon azacitidine versus azacitidine monotherapy, which enrolled 136 higher-risk MDS and AML patients. Therefore, the survival were similar for those treated with monotherapy (on a standard is to continue a hypomethylating agent for as long as a 10-day schedule) and those treated with azacitidine combined with response persists and to avoid switching drugs. Azacitidine and lenalidomide have whereas AML can be cured with cytotoxic chemotherapy. The only complementary mechanisms of eliciting a response in patients with treatment modality that has resulted in long-term, maintenance-free MDS. The observation that patients with higher-risk MDS retain remission is allogeneic hematopoietic stem cell transplantation features similar to lower-risk disease—both microenvironment and (HSCT). Although HSCT for MDS is reviewed in detail elsewhere cell-regulatory mechanisms likely play a role in progression— in this publication, it is critical to mention here because HSCT and provided the impetus for combining these 2 agents. The combina- non-HSCT therapies are often integrated in a given patient’s care. Although (28%) experienced hematologic improvement for an overall re- several retrospective studies have explored various pre-HSCT sponse rate of 72%. Reprinted with permission from Gerds and Scott, 2012. Other lating therapy versus induction chemotherapy before HSCT is under agents being explored in this context include the nucleoside analog way (www. Further- sapacitabine, which had an overall response rate of 14% and median more, several preemptive and prophylactic strategies are being overall survival of 8. Because, on average, 9 somatic mutational events occur that lead to the MDS clinical phenotype, it is no wonder that a “magic bullet” drug Treatment after hypomethylating agent failure therapy has not yet been discovered. Nevertheless, several agents Only 3 drugs have received regulatory approval specifically for the directed at improving cytopenias without the cost of side effects are treatment of MDS, all with suboptimal response rates at 50% of being developed in lower-risk MDS and have the potential to limited durability, typically 1-2 years. Once these agents are no improve quality of life for patients with more indolent disease. Further- agent, are at the forefront of treatment for higher-risk disease and more, prognosis after hypomethylating agent failure is dismal, with are poised to make an immediate impact on the treatment landscape. Several resistance patients who have failed hypomethlylation agent therapy. A molecu- mechanisms are being targeted in an attempt to overcome the lar revolution is taking place that will undoubtedly redefine MDS limitations of current therapies. One such approach takes advantage of the relationship between Disclosures immune dysregulation and the development of MDS, which may Conflict-of-interest disclosures: M. Select MDS patients or an advisory committee for Celgene, Amgen, and Boehringer can experience a CR to immunosuppressive therapy, and self-tumor Ingelheim. Off-label drug antigens on the surface of the MDS cells within the niche may also use: Lenalidomide for non-del(5q) and higher-risk MDS; vorinostat induce the preferential proliferation of CD4 CD25 FOXP3 T- for higher-risk MDS. Recently, aberrant up-regulation of PD-1, PD-1L, and CTLA4 in MDS has been described, specifically PD-L1 protein Correspondence expression in CD34 MDS cells, whereas the stroma/nonblast Mikkael A. Sekeres, MD, MS, Leukemia Program Cleveland Clinic cellular compartment was positive for PD-1, the signaling of which Taussig Cancer Institute, Desk R35, 9500 Euclid Avenue, Cleve- may be specific to hypomethylating agent resistance.

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Examination of baseline risk characteristics revealed that the pantoprazole 40 mg group had fewer patients taking anticoagulants (1% compared with 4%) purchase motilium 10mg without prescription, experiencing a change in nonsteroidal anti-inflammatory drug in the last month (6% compared with 9% or 10%) buy discount motilium 10mg on-line, and fewer with a history of endoscopically proven peptic ulcer (20% compared with 24% or 25%) buy discount motilium 10 mg online. These differences are small but may have biased the risk level in favor of the pantoprazole 40 mg group. Patients were censored from the analyses (considered lost to follow up) if they had low adherence to the nonsteroidal anti-inflammatory drug regimen, found to not meet inclusion after randomization, failed to adhere to the protocol, or withdrew from the study due to an adverse event not considered related to study drugs or due to “refusal to continue”. The numbers of patients censored for these reasons were greater in the omeprazole group (N=42) and lowest in the pantoprazole 40 mg group (N=29). With these issues in mind, we rate this trial as fair quality (rather than poor quality, as it does meet other aspects of internal validity) and suggest caution in interpreting the results. There was no statistically significant difference between the groups in remission rates based on either therapeutic failure or failure limited to endoscopic findings, with more than 90% of patients remaining in remission in all groups at 3 and 6 months. Indirect evidence One good-quality systematic review addressed the question of proton pump inhibitors for 159 treatment of nonsteroidal anti-inflammatory drug-induced ulcer. Its search for literature covered 1966 to 2000 (MEDLINE search from 1966 to January 2000, Current Contents for 6 months prior to January 2000, EMBASE to February 1999, and a search of the Cochrane Controlled Trials Register from 1973 to 1999). The review found 5 randomized trials that assessed omeprazole 20 mg with 40 mg in prevention of nonsteroidal anti-inflammatory drug- induced gastroduodenal toxicity. None of the studies were designed to evaluate the effectiveness of proton pump inhibitors in preventing serious complications of ulcers (hemorrhage, perforation, or death). The review showed that omeprazole is superior to the H2 receptor antagonists but provided no data on any other proton pump inhibitor. None of these studies was a head-to-head comparison and there were important differences in treatment regimens and follow-up, making comparisons across studies impossible. All the trials enrolled patients who were regular users of nonsteroidal anti- 165 inflammatory drugs, with 1 including COX-2 Inhibitors. Symptom assessment and reporting varied among these studies. After ulcers were healed and Helicobacter pylori were eradicated, patients continued with aspirin 100 mg and were randomized to lansoprazole 30 mg or placebo. In the last study of Helicobacter 163 pylori and prevention of nonsteroidal anti-inflammatory drug-induced ulcers, patients with Helicobacter pylori but without past or current ulcer were assigned to 1 of 4 treatment groups: Proton pump inhibitors Page 48 of 121 Final Report Update 5 Drug Effectiveness Review Project omeprazole 20 mg plus clarithromycin 500 mg and amoxicillin 1 gram for 1 week; placebo or omeprazole 20 mg daily for 4 weeks; omeprazole 20 mg once daily for 5 weeks; or placebo for 5 weeks. At 3 months, the gastric ulcer rate (failure rate) was 7% for misoprostol, 20% for lansoprazole 15 mg, and 18% for lansoprazole 30 mg, with no significant difference between lansoprazole doses. However, when adverse effects were included as failures, the failure rate for all 3 treatment groups was 31%. A post hoc subgroup analysis of patients taking nonsteroidal anti-inflammatory drugs and low dose aspirin found no significant 166 difference among treatments at 12 weeks. Symptoms (antacid use and day and nighttime abdominal pain) were assessed by patient diary and were found to be significantly better in the lansoprazole groups than the misoprostol group, but comparisons between the 2 lansoprazole 160 doses were not made. In the study of Helicobacter pylori positive patients with ulcer complications (bleeding, 162 perforation, or obstruction), the primary endpoint was prevention of ulcer complications and the secondary endpoint was recurrence. The rate of recurrence of ulcer complications at a median follow-up of 12 months was 1. Two patients in the placebo group (N=61) were also taking nonsteroidal anti- inflammatory drugs. In patients with Helicobacter pylori but no history of ulcer, all 3 active treatment regimens were better than placebo in reducing the occurrence of ulcer and dyspeptic symptoms requiring therapy. There were no significant differences between the treatment groups. The pantoprazole group had 17% fewer ulcers at 4 weeks and 27% at 12 weeks. Patients who dropped out due to adverse events were included in the 4 week data as treatment failures. The methods or scales used to assess symptoms 161 were not described but reported just “symptoms. At 4 and 12 weeks presence of gastrointestinal symptoms improved in the pantoprazole group (to 17% and 20%, respectively), while in the placebo group remained stable (20% and 19%, respectively). The only evidence on prevention of ulcers related to COX-2 inhibitors came from a combined report of 2 similar fair quality trials that enrolled patients who were regularly taking a nonselective nonsteroidal anti-inflammatory drug or a COX-2 inhibitor and were at risk of peptic 165 ulcer (age > 60 years or documented peptic ulcer in last 5 years). Combined, the studies randomized 1429 patients to esomeprazole 20 mg, esomeprazole 40 mg, or placebo daily for 6 months. Using pooled and separate life-table analyses, the overall analysis indicated that both esomeprazole groups prevented peptic ulcer statistically significantly more often than placebo for all nonsteroidal anti-inflammatory drugs. While no statistical analyses were undertaken comparing the 2 doses of esomeprazole, the rates of ulcer development were very similar (5. The rates of ulcer development among the subgroup taking a COX-2 inhibitor were also statistically significantly lower with either dose of esomeprazole compared to placebo (16. The separate study analyses of the subgroup taking nonselective nonsteroidal anti-inflammatory drugs indicated that esomeprazole was superior to placebo in one Proton pump inhibitors Page 49 of 121 Final Report Update 5 Drug Effectiveness Review Project trial (N=844) but not in the other (N=585), while the pooled analysis indicated statistically significant benefit with either dose of esomeprazole compared to placebo. What is the comparative effectiveness of different proton pump inhibitors in eradicating Helicobacter pylori infection? Summary • The evidence on comparative effectiveness of various proton pump inhibitors was fair, despite 5 systematic reviews and 29 head-to-head trials. The significant heterogeneity in design, participants, and method of measuring outcomes among studies lessen the strength of the evidence. Neither trial found the addition of lansoprazole to result in higher eradication rates than antibiotic therapy alone. Detailed Assessment Direct evidence Five systematic reviews have evaluated the efficacy of proton pump inhibitors in eradication of Helicobacter pylori, however because these reviews focused on comparisons to H2 receptor antagonists, were out of date (literature searches conducted prior to 2001), or included non- randomized studies or studies published only as abstracts, they were not sufficient to evaluate 47, 167-171 this question. Twenty-nine studies directly compared one proton pump inhibitor with another, in 98, 104, combination with the same antibiotic(s), and reported Helicobacter pylori eradication rates. Several studies 187, 104, 178, 183, 190, 198, 200 included antibiotic regimens that are no longer standard. Of these, 23 trials compared proton pump inhibitors using identical regimens of antibiotics (within study) and reported eradication rates in a way that allowed statistical pooling (Table 11). While most of these trials used a 7 day proton pump inhibitor regimen in combination with 2 antibiotics, 3 trials used 190, 202 175 longer proton pump inhibitor regimens, a 14 day and a 30 day regimen. Interestingly, these regimens resulted in lower eradication rates at follow-up. Overall, eradication rates ranged from 67% in a trial of lansoprazole 60 mg daily for 30 days to 100% in a trial of pantoprazole 40 mg daily for 7 days. Pooled rates of eradication from these trials vary (see Table 11 below), but pooled relative risks of these rates did not identify statistically significant differences between groups when stratified by number of days of treatment and dose comparison (Table 11 below). Several trials examined different dose levels (high compared to usual and low compared to usual) of proton pump inhibitors without finding statistically significant differences in eradication rates. Proton pump inhibitors Page 50 of 121 Final Report Update 5 Drug Effectiveness Review Project In 1 additional study, patients who had failed a 1 week regimen of amoxicillin, clarithromycin, and a proton pump inhibitor were randomized to rabeprazole 20 mg, 188 lansoprazole 60 mg, or omeprazole 40 mg daily each plus amoxicillin and metronidazole. No differences were found among the proton pump inhibitors in eradication rates, with 91% eradication in each group.