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Abstract
Background:
Many strategies are used to prevent nonsteroidal anti-inflammatory drug (NSAID)-associated gastrointestinal toxicity, but the comparative effectiveness remains unclear.
Aim:
To evaluate the comparative effectiveness of clinical strategies for preventing gastrointestinal toxicity induced by NSAIDs.
Methods:
MEDLINE, EMBASE and the Cochrane Library (from their inception to May 2015) were searched for randomised controlled trials comparing the risk of gastrointestinal adverse events in patients taking nonselective NSAIDs, selective cyclooxygenase(COX)-2 inhibitors or nonselective NSAIDs/COX-2 inhibitors plus gastroprotective agents [proton pump inhibitors (PPIs), histamine-2 receptor antagonists, misoprostol]. Both pairwise meta-analysis and Bayesian network meta-analysis were performed.
Results:
Analyses were based on 82 trials including 125 053 participants. Network meta-analysis demonstrated that selective COX-2 inhibitors + PPIs [Risk ratio (RR), 95% Credible Interval (CrI): ulcer complications 0.07, 0.02-0.18], selective COX-2 inhibitors (RR, 95% CrI: ulcer complications 0.25, 0.15- 0.38; symptomatic ulcer 0.12, 0.04-0.30), nonselective NSAIDs + PPIs (RR, 95% CrI: ulcer complications 0.28, 0.18-0.41; symptomatic ulcer 0.11, 0.04-0.23), nonselective NSAIDs + misoprostol (RR, 95% CrI: ulcer complications 0.47, 0.24-0.81; symptomatic ulcer 0.41, 0.13-1.00) were associated with significantly lower risk of clinical gastrointestinal events compared with nonselective NSAIDs. For all effectiveness endpoints, selective COX-2 inhibitors + PPIs was associated with the lowest absolute event probability and the highest rank, followed by selective COX-2 inhibitors and thirdly by nonselective NSAIDs + PPIs.
Conclusion:
The combination of selective COX-2 inhibitors plus PPIs provides the best gastrointestinal protection, followed by selective COX-2 inhibitors, and thirdly by nonselective NSAIDs plus PPIs.
... Notably, the model predicted a percent relative effect of 41.1% (p-value < 0.05) for the interaction involving meloxicam and esomeprazole, which is a known CYP 3A4 inhibitor and not recorded in Twosides. Furthermore, combination use of proton pump inhibitors (esomeprazole) with NSAIDs (meloxicam) to allay potential GI bleeding is common practice [211] and so the clinical relevance of this interaction is high. . Philip Payne for their valuable guidance and feedback. ...
... Generally, the co-prescribed drug may not drive the recorded hepatotoxic outcome, but instead can be used during treatments that involve either NSAID administration or the alleviation of hepatotoxic conditions. As an example of the former, co-administration of a proton pump inhibitor, such as esomeprazole, can help to prevent NSAID-associated lesions and damage of the upper gastrointestinal tract [132,211]. With regards to the latter, lidocaine (Table 3.2) is a local anesthetic used widely for minor surgeries or invasive procedures. ...
... Rx+ and Rx-designate whether meloxicam is prescribed or not.. Notably, the model predicted a percent relative effect of 41.1% (p-value < 0.05) for the interaction involving meloxicam and esomeprazole, which is a known CYP 3A4 inhibitor and not recorded in Twosides. Furthermore, combination use of proton pump inhibitors (esomeprazole) with NSAIDs (meloxicam) to allay potential GI bleeding is common practice[211] and so the clinical relevance of this interaction is high.Of the 6 CYP 3A4 inhibitors analyzed, 5 of them have some clinical basis in Twosides that links them to DILI outcomes when co-prescribed with meloxicam. The model predicted a percent dependent relative effect of 41.1% (p-value < 0.05) for the interaction involving meloxicam and esomeprazole, a known CYP 3A4 inhibitor and not recorded in Twosides ...
Machine learning has demonstrated potential in analyzing large, complex datasets and has become ubiquitous across many fields of scientific research. As machine learning is actively deployed in many complex and critical domains, it is essential for machine learning to engage with domain expertise to aid in knowledge discovery as well as address challenges in predictive modeling in complex domains. Domain expertise represents an essential and elaborate collection of knowledge that is often under-utilized when applying machine learning in complex domains. In this dissertation, I have addressed existing challenges regarding knowledge discovery in complex domains via engagement with domain expertise, particularly in the context of medicine and healthcare, as well as developing neural network-based algorithms that improve predictive modeling in challenging scenarios such as class imbalance and under-representation. First, a domain expertise guided machine learning framework has been developed that is capable of identifying potential interventions for clinical outcomes. Domain experts were looped in the model building process to mitigate the pitfalls of confounding and data-leaking variables. Second, a simple machine learning approach has been presented to study drug-drug interactions that lead to adverse events of clinical significance. Identifying unknown interventions for clinical outcomes and adverse drug interactions lead to novel knowledge discovery in a complex domain such as in medicine and healthcare. Third, the problems of class imbalance and under-representation have been studied. Novel neural network architectures have been presented that simultaneously improve classification and calibration performances across under-represented sub-populations in class imbalanced datasets.
... 12 endoscopically confirmed ulcers may develop in 15%-30% of people who are long-term users of nsaiDs and complications may occur in 2%-4% of ulcers. 15 inhibition of cyclo-oxygenase 1 enzyme (cOX-1) is thought to be the main mechanism by which nsaiDs cause gastrointestinal damage, and selective cOX-2 inhibitors were developed to reduce the risk of this complication. however, research has suggested that the relationship between the cOX isoforms and gastrointestinal damage is more complex. ...
... a recent systematic review of randomised controlled trials (82 trials, 125 053 participants) compared the effectiveness of strategies for preventing nsaiD-induced gastrointestinal toxicity. 15 The review's authors conducted a network meta-analysis for non-selective nsaiDs alone, non-selective nsaiDs plus ppi, nonselective nsaiDs plus h 2 -receptor antagonist, non-selective nsaiDs plus misoprostol, selective cOX-2 inhibitors alone, selective cOX-2 inhibitors plus ppi and selective cOX-2 inhibitors plus misoprostol. The primary outcomes were ulcer complications (bleeding, perforation and obstruction) and symptomatic ulcers. ...
... The strategy with the lowest absolute risk of an ulcer complication (49 studies, 64 421 participants; moderate-quality to very low-quality evidence) was the combination of a selective cOX-2 inhibitor plus ppi (see table 1). 15 The estimated absolute risk reductions from using a cOX-2 inhibitor plus ppi instead of a cOX-2 inhibitor alone or a non-selective nsaiD plus ppi were 0.09% and 0.11%, respectively. The difference in ulcer complications between a non-selective nsaiD plus h 2 -receptor antagonist and a nonselective NSAID alone was not statistically significant. ...
Topics for DTB review articles are selected by DTB’s editorial board to provide concise overviews of medicines and other treatments to help patients get the best care. Articles include a summary of key points and a brief overview for patients. Articles may also have a series of multiple choice CME questions.
... They compared the risk for gastrointestinal adverse events in nsNSAID or selective COX-2 inhibitor users that received gastroprotection with a PPI, H2RA, or misoprostol. 95 For all of the efficacy evaluation criteria, the concomitant prescription of a selective COX-2 inhibitor + PPI was associated with the least absolute probability of an adverse event and the highest safety range, followed by selective COX-2 inhibitors alone, and in third place, nsN-SAIDs plus PPIs. 95 28.-In patients at high risk for a gastroduodenal event and low risk for a cardiovascular event, the best strategy for preventing NSAID-associated damage is the combination of a selective COX-2 inhibitor and PPI. ...
... 95 For all of the efficacy evaluation criteria, the concomitant prescription of a selective COX-2 inhibitor + PPI was associated with the least absolute probability of an adverse event and the highest safety range, followed by selective COX-2 inhibitors alone, and in third place, nsN-SAIDs plus PPIs. 95 28.-In patients at high risk for a gastroduodenal event and low risk for a cardiovascular event, the best strategy for preventing NSAID-associated damage is the combination of a selective COX-2 inhibitor and PPI. ...
... Naproxen, at a dose of 500 mg every 12 h, was not associated with an increased cardiovascular risk, unlike ibuprofen and diclofenac, the most widely studied nsNSAIDs. 95 A particular case is that of patients that take ASA. It must be kept in mind that NSAIDs, such as naproxen, and especially ibuprofen, interfere with the antiplatelet activity of ASA. ...
More than 30 million persons worldwide take nonsteroidal anti-inflammatory drugs (NSAIDs) on a daily basis, and annual consumption is increasing. In addition to their analgesic and anti-inflammatory properties, NSAIDs also produce well-known gastrointestinal adverse events. There is no consensus in Mexico on the diagnosis, treatment, and prevention of NSAID-induced gastropathy and enteropathy, and so the Asociación Mexicana de Gastroenterología brought together a group of experts to establish useful recommendations for the medical community. Thirty-three recommendations were formulated in the present consensus, highlighting the fact that the risk for NSAID-induced gastrointestinal toxicity varies according to the drug employed and its pharmacokinetics, which should be taken into account at the time of prescription. The risk factors for gastroduodenal complications due to NSAIDs are: a history of peptic ulcer, age above 65 years, high doses of NSAIDs, Helicobacter pylori infection, and the presence of severe comorbidities. The symptoms and gastroduodenal damage induced by NSAIDs vary, ranging from an asymptomatic course to the presentation of iron-deficiency anemia, bleeding, stricture, and perforation. Capsule endoscopy and enteroscopy are direct diagnostic methods in NSAID enteropathy. Regarding prevention, the minimum dose of an NSAID needed to achieve the desired effect, administered for the shortest period of time, is the recommendation. Finally, proton pump inhibitors are the gold standard for the prophylaxis and treatment of gastroduodenal effects, but they are not useful in enteropathy.
... This was followed by the use of selective COX-2 inhibitors alone, and then nonselective NSAIDs with PPIs. Nonselective NSAIDs with H2RAs ranked the lowest in terms of effectiveness (Fig. 4, Ref. [79]). Additionally, another meta-analysis indicated that H2RAs were found to be less effective in pre-venting GIB and ulcer formation associated with LDA use, suggesting the preferential usage of PPIs in cases of intolerance [80]. ...
... NSAIDs [79]. COX, Cyclo-oxygenase; H2RAs, H2 receptor antagonists. ...
... Following endoscopy, patients were randomized and received either celecoxib (200mg bid), naproxen (500mg bid), nabumetone (1,000mg bid) or placebo. Follow up endoscopies were performed after 5 days of drug and then at 3 day intervals until complete re epithelialization (primary outcome variable) of all lesions or a total of four weeks passed (days 0, 6,9,12,15,18,21,24,27, and 30). The NSAID was continued throughout this period. ...
... Even though they were able to show a difference between selective COX-2 inhibitors and traditional NSAIDs, both resulted in unacceptably high rates of rebleeding. Those data suggest that for chronic ulcers, at least in the immediate post healing stage, neither traditional, nor selective COX-2 inhibitors are safe even when given with relatively high dose PPI (30mg omeprazole equivalent) [23,24]. ...
Background: Nonsteroidal anti-inflammatory drugs impair gastrointestinal ulcers healing. This study evaluated the role of cyclooxygenase isozymes COX- 1 and COX-2 in the healing of acute gastric ulcers in humans. Methods: This was an open-label, endoscopist-blind, parallel-group study, age and sex matched at baseline in normal volunteers. At endoscopy, we took four large jumbo forceps gastric mucosal biopsies (2 from each of the antrum and corpus). Subjects received celecoxib 200mg bid), naproxen 500mg bid), nabumetone 1000mg bid or placebo until end of study. Endoscopies were performed after 5 days and every 3 days until complete re-epithelialization of all lesions or 30 days. Survival analysis was used to compare time-to-healing defined as the day with complete re-epithelialization of all ulcers. Results: Fifty-two subjects completed the study, each received four biopsyinduced gastric ulcers (204 total ulcers; the majority included the muscularis mucosa). The mean time-to-healing was 9.4 ± 0.4 days with placebo, 10.5 ± 0.4 with celecoxib, 11.1 ± 0.6 with naproxen, and 12.3 ± 0.9 with nabumetone. The time to healing of each ulcer or all ulcers was significantly delayed compared to placebo with naproxen (p=0.01) and nabumetone (p=0.002) but not with celecoxib (p=0.07). Conclusion: The COX-1 preferential inhibitor naproxen and the balanced COX-1/COX-2 inhibitor nabumetone significantly delayed the healing of ulcers. With the COX-2 specific inhibitor celecoxib, healing was delayed but not significantly. Synthesis of COX-1 derived prostaglandins appears to be important in the healing of gastric ulcers in humans.
... Generally, the co-prescribed drug may not drive the recorded hepatotoxic outcome, but instead can be used during treatments that involve either NSAID administration or the alleviation of hepatotoxic conditions. As an example of the former, co-administration of a proton pump inhibitor, such as esomeprazole, can help to prevent NSAID-associated lesions and damage of the upper gastrointestinal tract [64,65]. With regards to the latter, lidocaine (Table 2) is a local anesthetic used widely for minor surgeries or invasive procedures. ...
... The model predicted a percent dependent relative effect of 41.1% (p-value < 0.05) for the interaction involving meloxicam and esomeprazole, which is a known CYP 3A4 inhibitor and not recorded in Twosides. Furthermore, combined usage of proton pump inhibitors (esomeprazole) with NSAIDs (meloxicam) to allay potential GI bleeding is a common practice [64] and so the clinical relevance of this interaction is high. Still, validity of this complex interaction would require further clinical investigation. ...
Drug-drug interactions account for up to 30% of adverse drug reactions. Increasing prevalence of electronic health records (EHRs) offers a unique opportunity to build machine learning algorithms to identify drug-drug interactions that drive adverse events. In this study, we investigated hospitalizations’ data to study drug interactions with non-steroidal anti-inflammatory drugs (NSAIDS) that result in drug-induced liver injury (DILI). We propose a logistic regression based machine learning algorithm that unearths several known interactions from an EHR dataset of about 400,000 hospitalization. Our proposed modeling framework is successful in detecting 87.5% of the positive controls, which are defined by drugs known to interact with diclofenac causing an increased risk of DILI, and correctly ranks aggregate risk of DILI for eight commonly prescribed NSAIDs. We found that our modeling framework is particularly successful in inferring associations of drug-drug interactions from relatively small EHR datasets. Furthermore, we have identified a novel and potentially hepatotoxic interaction that might occur during concomitant use of meloxicam and esomeprazole, which are commonly prescribed together to allay NSAID-induced gastrointestinal (GI) bleeding. Empirically, we validate our approach against prior methods for signal detection on EHR datasets, in which our proposed approach outperforms all the compared methods across most metrics, such as area under the receiver operating characteristic curve (AUROC) and area under the precision-recall curve (AUPRC).
... COX1 is constitutive and is inhibited by most of the drugs currently available at the pharmaceutical market. Most of the adverse effects are due to the missing physiological effects of prostaglandins, such production of mucus at the gastrointestinal tract, vasodilatation, and regulation of platelet aggregation [10][11][12]. Thus, the patient must have an adequate therapeutic schedule and be proper advised about them. ...
... Gastroprotective drugs such as proton pump inhibitors are widely to prevent the main side effects of orally administrated NSAIDs [11]. Nevertheless, other important measures must be considered, such as avoiding administration of NSAIDs in fasting, or using citric juices [6]. ...
The pharmacoterapeutic treatment of pain is challenging for any health professional authorized to prescribed drugs. Nonsteroidal anti-inflammatory drugs (NSAIDs) are considered effective and safe to most patients with pain, and are prescribed as first choice for acute and some conditions of chronic pain. Notwithstanding their good clinical results, NSAIDs may cause several adverse reactions and have varied therapeutic schedules. Some of them can not be used in children, and interactions to other drugs must be observed prior to the prescription. Here we present a brief review on the clinical and molecular pharmacology of NSAIDs and present a summarized and updated guide for their prescription by authorized health professionals. This evidence-based paper aims to provide safe information for therapeutic decisions.
... e leakage rate of the Evans blue content is often used to reflect the degree of vascular injury [31]. erefore, Evans blue was used to investigate the effect of YQFM on small intestinal vascular leakage induced by continuous administration of 70 mg/kg dasatinib for 3 days in mice. ...
... Some components may be present that could inhibit the main components from working, or competitive inhibition might exist between different components in YQFM, so further improvement is needed. Other drugs currently in clinical use, such as nonsteroidal anti-inflammatory drugs (Aspirin), antithrombotic drugs (Dabigatran-etexilate), and some chemotherapy drugs (Methotrexate), have reported gastrointestinal bleeding [31,45,46]. e key molecules involved in the bleeding process include VEGF, COX1/2, NF -κB, ROCK, and MLC. ...
Dasatinib, as a second-generation broad-spectrum tyrosine kinase inhibitor, presents an antitumor effect by inhibiting tyrosine kinases. However, dasatinib causes serious side effects, such as gastrointestinal bleeding and liver toxicity, possibly through the activation of ROCK kinase and MLC phosphorylation. At present, there is no effective prevention and treatment method. Previous research studies have shown that YQFM (YiQiFuMai powder injection) protects the blood-brain barrier by inhibiting the ROCK/MLC signaling pathway; whether YQFM can alleviate the side effects of dasatinib is unknown. In this study, dasatinib was injected (i.p. 70 mg/kg) and YQFM (i.p. 0.336 g/kg, 0.672 g/kg, 1.342 g/kg) was given in advance for 3 days to mice, to explore the effect of YQFM on side effects induced by Dasatinib. The results confirmed that YQFM significantly decreased Evans blue leakage in the small intestine and increased intestinal blood flow, increased the expression of ZO-1, Occludin, and VE-cadherin, and reduced the contents of D-lactic acid, s-VE-cadherin, Alanine aminotransferase (ALT), and Aspartate aminotransferase (AST) in serum. Finally, YQFM inhibited the expression of ROCK-1 and phosphorylation of MLC induced by Dasatinib. These findings suggested that YQFM could improve the side effects caused by Dasatinib linked with the ROCK/MLC signaling pathway, as shown in the graphical abstract.
... Con el propósito de evaluar la efectividad comparativa de las distintas estrategias clínicas para prevenir la toxicidad gastrointestinal inducida por los AINE, investigadores chinos realizaron un metaanálisis pareado y bayesiano de red, en el cual se incluyeron 82 ECA que comparan el riesgo de eventos adversos gastrointestinales en pacientes consumidores de AINE-NS, inhibidores COX-2 selectivos o no a gastroprotección con IBP, ARH2 o misoprostol 95 . Para todos los criterios de evaluación de la eficacia, la prescripción concomitante de un inhibidor COX-2 selectivo + IBP se asoció con la menor probabilidad absoluta de evento adverso y el rango de seguridad más alto, seguido por los inhibidores COX-2 selectivos solos y, en tercer lugar, por los AINE-NS más IBP 95 . ...
... De entre los AINE no selectivos, el de mayor riesgo cardiovascular fue el diclofenaco, que presentó un riesgo similar al de los inhibidores COX-2 selectivos. Naproxeno, por su parte, a dosis de 500 mg cada 12 h, no se asoció a incremento del riesgo cardiovascular, a diferencia de ibuprofeno y diclofenaco, los AINE NS más estudiados 95 . Un caso particular es el de los pacientes que toman AAS, pues hay que tener en cuenta que los AINE como el naproxeno y, sobre todo, el ibuprofeno, interfieren con la actividad antiagregante del AAS 98 . ...
More than 30 million persons worldwide take nonsteroidal anti-inflammatory drugs (NSAIDs) on a daily basis, and annual consumption is increasing. In addition to their analgesic and anti-inflammatory properties, NSAIDs also produce well-known gastrointestinal adverse events. There is no consensus in Mexico on the diagnosis, treatment, and prevention of NSAID-induced gastropathy and enteropathy, and so the Asociación Mexicana de Gastroenterología brought together a group of experts to establish useful recommendations for the medical community. Thirty-three recommendations were formulated in the present consensus, highlighting the fact that the risk for NSAID-induced gastrointestinal toxicity varies according to the drug employed and its pharmacokinetics, which should be taken into account at the time of prescription. The risk factors for gastroduodenal complications due to NSAIDs are: a history of peptic ulcer, age above 65 years, high doses of NSAIDs, Helicobacter pylori infection, and the presence of severe comorbidities. The symptoms and gastroduodenal damage induced by NSAIDs vary, ranging from an asymptomatic course to the presentation of iron-deficiency anemia, bleeding, stricture, and perforation. Capsule endoscopy and enteroscopy are direct diagnostic methods in NSAID enteropathy. Regarding prevention, the minimum dose of an NSAID needed to achieve the desired effect, administered for the shortest period of time, is the recommendation. Finally, proton pump inhibitors are the gold standard for the prophylaxis and treatment of gastroduodenal effects, but they are not useful in enteropathy.
Copyright © 2020 Asociación Mexicana de Gastroenterología. Publicado por Masson Doyma México S.A. All rights reserved.
... The principal causes of PUD are Helicobacter pylori infection, which is present in approximately 42% of patients with PUD, and aspirin or nonsteroidal anti-inflammatory drug use, which are the etiologic factors in approximately 36% of patients with PUD [1][2][3][4]. Complications of peptic ulcers include hemorrhage (73%), perforation (9%), and pyloric obstruction (3%). Approximately two-thirds of the surgical procedures required for complications of PUD are because of hemorrhage, whereas approximately one-third are required because of perforation [5,6]. ...
... 22 En un análisis por diagnósticos reumatológicos, en un subgrupo de 104 adultos mayores, 53 de ellos recibieron AINEs, sin embargo, solo el 21% recibió gastroprotección con el inhibidor de bomba de protones (IBP) omeprazol; de los que recibieron gastroprotección, el 82% fue prescrito por médicos internistas y de los que no la recibieron, casi la mitad, 45,24%, fueron atendidos en medicina interna; al respecto se ha demostrado la reducción del riesgo de gastropatía por AINEs con el uso de IBPs con un RR de 0,28 (IC 95%: 0,18-0,41). 23 Berrospi y colaboradores, en 2 establecimientos de salud de Lima, usando los criterios STOPP START en pacientes ambulatorios, hallaron 39,5% de prescripción médica potencialmente inadecuada. 26 En un estudio en México, en pacientes ambulatorios se halló 59% de MPI según los criterios de Beers. ...
Objetivo: Identificar la frecuencia de prescripción de medicamentos potencialmente inapropiados (MPI) en adultos mayores según los criterios de Beers. Método: Se realizó un estudio observacional longitudinal retrospectivo en 14,517 historias de pacientes mayores de 65 años atendidos en el Hospital I Florencia de Mora Essalud. Se filtraron los MPI listados en los criterios de Beers incluidos en el Petitorio farmacológico de Essalud. Se determinó si los fármacos prescritos son potencialmente inapropiados según la tabla 2 de los criterios de Beers, que recomienda “evitarlos”. Resultados: Se identificaron 25 fármacos considerados como “evitar”, de los cuales se prescribieron 21 (84%). Los MPI señalados como “evitar” fueron hallados en 1,750 recetas (22.82%). Conclusión: La MPI ocurre en 23% de las prescripciones en adultos mayores según los criterios de Beers y, de los fármacos del petitorio calificados como evitar, se prescribe el 84% en el hospital Florencia de Mora Essalud.
... 60,61 Proton pump inhibitor (PPI) use mitigates the effects of NSAIDs on gastric mucosa integrity and concurrent use of these drugs reduces GI adverse events. 62 The long-term use of PPI therapy is generally well-tolerated by the general population, however it may be associated with malabsorption of calcium, 63 magnesium, 64 iron 65 and vitamin B12. 66 Furthermore PPIs may interfere with bone resorption processes 67,68 and long-term and/or high dose PPI use is associated with increased fracture risk. ...
... If the use of the NSAIDs is stopped, PPIs can treat more than 85% of PUD cases caused by NSAIDs or aspirin in 6 to 8 weeks. A combination of COX-2-selective NSAIDs and PPI is the most effective defence against PUD caused by NSAIDs [21]. Antiulcer medications' sites of action or modes of action can be used to categorize them. ...
Purpose of review: The management of Peptic Ulcer Disease (PUD) is achieved using pharmacological agents to counteract the aggressive factors or stimulate the mucosal defence. In recent years, plant-based bioactive products have gained popularity as an alternative management protocol due to the increased antibiotic resistance of Helicobacter pylori (H. pylori), lower cost, perceived effectiveness, availability, and little side effects. In this review, we summarized the conventional treatment methods, alternative bioactive compounds, and the dietotherapy of PUD.
Recent findings: The conventional management methods include antacids, gastric muscle stimulants, mucosal-increasing resistance agents, antisecretory medications (anticholinergic agents),
and Proton Pump Inhibitors (PPIs). Most of the plant’s bioactive compounds are alkaloids, terpenes, flavones, isoflavones, flavonols, chalcones, flavanones, xanthones, flavan-3-ols, anthocyanins, and capsaicinoids. These bioactive compounds work in a dose-dependent manner and express their therapeutic functions through pro-inflammatory cytokines such as Tumor Necrosis Factor-alpha (TNF-α), Interleukin-1 beta (IL-1β), and Interleukin-6 (IL-6), resulting in a reduction in prostaglandin E2. No food product has a history of causing the PUD, but some foods are prohibited or need to be taken with caution. Some of these food items, such as spicy foods, caffeine, and alcohol, can hinder healing and worsen the symptoms while fibres, vitamins C and A, zinc, iron, and selenium can promote healing.
Conclusion: While there are limited articles in the literature to elucidate the dietotherapy of PUD, a balanced diet should always be provided in this course to manage the pathology. The paucity of this information opens up more research opportunities in PUD dietotherapy.
... 3 Clinical guidelines categorize risk grade for NSAID-induced GI complications based on the number and profile of risk factors and recommend the concomitant use of gastroprotective agents (GPAs) with NSAIDs to reduce the risk of GI complications. [4][5][6][7][8] The American Gastroenterological Association (AGA) recommends proton-pump inhibitor (PPI) as the treatment of choice for the prevention of GI complications in patients with traditional NSAIDs (tNSAIDs) or high risk patients with selective cyclooxygenase-2 (COX-2) inhibitors. 4 A recently updated evidence-based clinical practice guideline by the Japanese Society of Gastroenterology recommends PPI with or without COX-2 inhibitors for patients with a previous history of GI complications and also strongly recommends the use of PPI as a GPA in elderly patients. ...
Purpose
The use of proton pump inhibitors (PPI) is recommended to prevent nonsteroidal anti-inflammatory drug (NSAID)-induced gastrointestinal (GI) complications. The incidence of several adverse effects during the long-term use of PPI prompts the search for other alternatives. Limited studies have evaluated the efficacy of rebamipide, a widely used mucoprotective drug, as a gastroprotective agent (GPA) compared to PPI, focusing on the elderly chronic NSAID users, nor with GI risk stratification. We aimed to determine the population who would get benefit from the use of rebamipide as an alternative to PPI to prevent traditional nonsteroidal anti-inflammatory drug (tNSAID)-associated GI complications.
Patients and Methods
We identified 41,889 and 35,708 elderly chronic tNSAID users with PPI and rebamipide co-therapy, respectively, from the national claims database. Outcome was defined as hospitalization or emergency department visits due to serious GI complications. Propensity score-matched cohorts were constructed and compared within risk strata.
Results
In high and moderate risk groups with two risk factors, rebamipide showed a higher risk of serious GI complication compared to PPI (aHR 2.63, 95% CI 1.24–5.59 and aHR 2.42, 95% CI 1.21–4.83, respectively). However, in elderly patients without risk factors, there was no significant difference in the risk of serious GI complications between PPI and rebamipide (aHR 0.69, 95% CI 0.27–1.76).
Conclusion
This study suggested that rebamipide can be considered as an alternative to PPI in elderly chronic tNSAID users without risk factors. However, elderly patients with other risk factors should use PPI rather than rebamipide. Therefore, the presence of GI risk factors needs to be evaluated in elderly chronic tNSAID users to prescribe the most suitable GPA in clinical practice.
... As a result, gastroprotective drugs are co-prescribed with them. 12,13 Analgesics were found to be co-prescribed with gastroprotective medicines in this study. And we observed that gastroprotective medicine is the second most prescribed drug. ...
... If this parameter fluctuates between 80 and 120% of its given value, ICERs from €−230.26 to €−372.18 per avoided persistent opioidinduced constipation were obtained, respectively. Total healthcare costs to 28 days of ketorolac-induced UGIB is the most influential parameter within the model of clinical rule B. Again, this parameter varied between 80 and 120% of its [35,36] No constipation (40%) [35,36] Macrogol (prophylactic) + Constipation (30%) [28,29] Macrogol (prophylactic) + No constipation (70%) [28,29] No constipation (40%) [ UGIB (0.27%) [37] UGIB (0.40%) [37] UGIB (0.025%) [31] No UGIB (99.73%) [37] No UGIB (99.6%) [37] No UGIB (99.975%) [ Sudden cardiac death (10%) [32] Need for additional care (90%) [32] TdP (0.01%) [16,20,21] No TdP (99.99%) [16,20,21] Sudden cardiac death (10%) [32] Need for additional care (90%) [32] TdP (0.01%) [16,20,21] No TdP (99.99%) [16,20,21] Sudden cardiac death (10%) [32] Need for additional care (90%) [32] TdP (0.20%) [16] No TdP (99.80%) [16] Sudden cardiac death (10%) [32] Need for additional care (90%) [32] a b c deterministic value, resulting in an ICER value fluctuating between €2983.62 and €4355.30 saved per avoided ketorolacinduced UGIB, respectively. ...
Background Adverse drug events following inappropriate prescribing in the hospital cause a substantial and avoidable medical and economic burden to hospitals, payers and patients alike. A clinical rule-based, pharmacist-led medication-review service, the ‘Check of Medication Appropriateness’ (CMA) was implemented in the University Hospitals Leuven. The CMA is shown to be effective in reducing potentially inappropriate prescriptions. Aim This study investigated whether this centralised clinical pharmacy service is cost-effective. Method We performed a cost-effectiveness analysis of three clinical rules of the CMA, targeting adverse drug events at three levels of severity: A) persistent opioid-induced constipation, B) ketorolac-induced gastrointestinal bleeding and C) drug-induced Torsade de Pointes. A decision tree was developed for each clinical rule. Both intervention costs as well as total costs associated with the occurrence of an adverse drug event were considered. The outcomes were reported in the form of an incremental cost-effectiveness ratio, expressed as an incremental cost per adverse drug event avoided. Results Applying clinical rules to avoid persistent opioid-induced constipation and ketorolac-induced gastrointestinal bleeding were cost-saving. Implementation of a medication check to avoid drug-induced Torsade de Pointes costed €8,846 per Torsade de Pointes avoided. Conclusion Our study provides strong indications that the CMA is worth its investment for clinical rules targeting (very) common adverse drug events, that can be avoided with limited expenses. Further research is required to assess the full CMA. The proposed model may be useful to perform cost-effectiveness analyses of other centralised clinical pharmacy services targeting inappropriate prescribing, at the level of individual adverse drug events.
... Undoubtedly, PPIs can be widely used in some indications beside NSAID-related gastropathies such as peptic ulcer, gastro-esophageal reflux. (Yuan et al., 2016;Sandhu & Fass, 2018). In our study, higher co-prescription of PPI in DIP compared to PIP reflects the tendency of physicians to gastroprotection with PPI when prescribing NSAIDs. ...
Introduction
The most frequently prescribed analgesic drugs in primary care centers in Turkey are diclofenac and paracetamol, respectively. In this study, we aimed to compare paracetamol-included prescriptions (PIP) and diclofenac-included prescriptions (DIP) generated for adult patients in primary care.
Methods
In this cross-sectional study, PIPs ( n = 280 488) and DIPs ( n = 337 935) created for adults by systematic sampling among primary care physicians working in Istanbul in 2016 ( n = 1431) were examined. The demographic characteristics, diagnoses, and additional drugs in PIPs and DIPs were compared.
Results
Women constituted the majority in both groups (69.8% and 67.9%, respectively; P < 0.05), and mean age at PIP (52.6 ± 18.8 years) was lower compared to DIP (56.3 ± 16.1 years), ( P < 0.05). In single-diagnosis prescriptions, 11 of the 15 most common diagnoses in PIP were respiratory tract infections (47.9%); three pain-related diagnoses formed 4.6% of all these prescriptions. In DIP, the number of pain-related diagnoses, mostly of musculoskeletal origin, was eight (28.5%); four diagnoses (7.8%) were upper respiratory tract infections. While hypertension was the third most common diagnosis in PIP (6.1%), it was ranked first in DIP (8.0%). The percentage of prescriptions with additional analgesic (14.0% versus 18.3%, P < 0.001), proton-pump inhibitor (13.8% versus 18.4%; P < 0.001), and antihypertensive (22.0% versus 24.8%, P < 0.001) was lower in PIP compared to DIP. However, the percentage of prescriptions with antibiotics (31.3% versus 14.7%, P < 0.001) was higher in PIP.
Conclusion
Paracetamol appears to be preferred mostly in upper respiratory tract infections compared to the preference of diclofenac rather in painful/inflammatory musculoskeletal conditions. The presence of hypertension among the most commonly encountered diagnoses for these analgesic drugs points to challenges in establishing the diagnosing-treatment match and indicates potential irrational prescribing practice, especially for interactions.
... • Рекомендуется назначение ингибиторов протонного насоса пациентам старше 60 лет с хронической болью при выборе НПВП в качестве обезболивающей терапии с целью профилактики развития НПВП-гастропатии и ее осложнений [205,206,207,208]. • Рекомендуется назначение противоэпилептических препаратов (прегабалин**, габапентин) пациентам старше 60 лет с нейропатической болью с целью купирования болевого синдрома [194,[209][210][211][212][213]. ...
The present document developed by the Russian Association of Gerontologists and Geriatricians represents the Clinical guidelines on chronic pain in older and senile patients. The Clinical guidelines were endorsed by Scientific Council of the Ministry of Health of the Russian Federation in December 2020.Clinical guidelines are focused on geriatricians providing medical care in outpatient and hospital settings, general practitioners, and physiotherapists.The document sets out the pain syndrom screening and diagnosis principles in older patients, management and treatment approaches in patients with chronic pain, as well as the prevention, rehabilitation, medical care organization issues and quality control criteria for its provision in this category of persons.
... Therefore, if misoprostol is not tolerated, the dose should be reduced to 100 µg 4 times daily, though this regimen is not approved by USFDA [16]. Despite these, a recent systematic review with network meta-analysis revealed that the prophylactic efficacy of COX-2 selective inhibitor plus PPIs is the best, followed by COX-2 selective inhibitor alone, the combination of nonselective NSAIDs and PPIs, and nonselective NSAIDs plus misoprostol [118]. Resultantly, to improve patient compliance, some manufacturers have provided several fixed-dose NSAIDs/gastroprotection formulations. ...
Introduction:
Although the incidence and prevalence of duodenal and gastric ulcers have been declining, it remains challenging for health care systems. Based on the underlying cause, history, and characteristics of ulcers, management is generally provided by administering proton pump inhibitors (PPIs) or antibiotics.
Areas covered:
This article is based on global guidelines and English language literature from the past decade obtained through searches using PubMed, Clinicaltrials.gov, the US FDA, and the Cochrane library. Using a stepwise approach, dose and duration of treatment, drug interactions, warnings and contraindications, adverse effects, and administration points were specified. New drug candidates that may get American and European approvals were also introduced.
Expert opinion:
Despite the wide use of PPIs, their development lags behind the clinical need. There is an absolute requirement to develop third-generation PPIs with higher potency and improved pharmacokinetic and safety profiles. Regarding the antibiotic resistance crisis, including those used against H. pylori, conducting more clinical trials and investigating regional antibiotic resistance are warranted. Potassium competitive acid blockers, ilaprazole, and an H. pylori vaccine all show promise for the future.
... • Рекомендуется назначение ингибиторов протонного насоса пациентам старше 60 лет с хронической болью при выборе НПВП в качестве обезболивающей терапии с целью профилактики развития НПВП-гастропатии и ее осложнений [205,206,207,208]. • Рекомендуется назначение противоэпилептических препаратов (прегабалин**, габапентин) пациентам старше 60 лет с нейропатической болью с целью купирования болевого синдрома [194,[209][210][211][212][213]. ...
Background : Falls in elderly–a multifactorial syndrome. One of the modifiable factors is polypharmacy. STOPP/START criteria are used for correction of polypharmacy in geriatrics.
Aim : Assessment of the prevalence of polypharmacy, analysis and correction of pharmacotherapy using STOPP/START criteria in patients with falls.
Materials and methods : The study included 655 patients hospitalized in the geriatric department over 60 years of age, who were divided into two groups. Group 1 (n=332, 50.7%)–patients with 1 or more falls, group 2 (n=323,49.3%)–patients without falls. The analysis of the received therapy before hospitalization was performed. After that, based on the indications, contraindications and STOPP/START criteria, drug therapy was corrected in patients with falls.
Results : Patients of group 1 took 4.5±2.18 drugs, group 2–4.3±2.6. Polypharmacy was diagnosed in 150 (45.2%) patients with falls and in 122 (37.8%) patients without falls. Patients with falls were more likely to receive sleeping pills, NSAIDs. Univariate analysis showed that falls were associated with NSAIDs (OR 2.15, 95% CI 1.38–3.35, p=0.001) and sleeping pills (OR 2.03, 95% CI 1.02–4.02, p=0.047). An audit and correction of therapy was performed: in 108 (32.5%) patients the number of prescribed drugs was reduced. Patients with falls were prescribed statins, antidementia drugs, anticonvulsants and antidepressants as components of therapy for chronic pain syndrome, chondroitin sulfate and glucosamine sulfate for the treatment of osteoarthritis, calcium and antiresorbtive therapy, antianemic drugs, vitamin D. Antiplatelet agents, digoxin, sleeping pills and NSAIDs were less frequently prescribed. STOPP/START criteria and their frequency in patients with falls were analyzed. 141 cases of potentially non-recommended but prescribed medications were identified. STOPP criteria were for the administration of NSAIDs (n=53, 37.6%) and acetylsalicylic acid (n=62, 44%). There were 458 cases of potentially recommended but not prescribed medications. The most common START criteria were not for the administration of vitamin D and statins.
Conclusion . Half of elderly patients with falls have polypharmacy. These patients are more likely to take sleeping pills and NSAIDs. STOPP criteria most often concerned the appointment of NSAIDs and acetylsalicylic acid, and the START criteria revealed the absence of the appointment of vitamin D and statins.
... Overall, NSAIDs are superior to placebo for treating chronic low back pain with no significant difference in pain reduction between Cox-2 selective and traditional NSAID [6]. Unfortunately, their use can be limited by gastrointestinal and cardiac toxicity [7,8], although newer Cox-2 selective inhibitors (celecoxib, rofecoxib) are safer than traditional NSAIDs (naproxen, ibuprofen) [4]. A promising alternative to pharmacotherapy is the use of low-level laser therapy (LLLT). ...
Background: According to the World Health Organization, musculoskeletal conditions comprise more than 150 diagnoses affecting muscles, bones, joints and related tissues including tendons and ligaments. The use of 635nm red low-level laser has demonstrated beneficial effects for treating a range of painful musculoskeletal conditions including low back pain, plantar fasciitis, neck, and shoulder pain.
Methods: Data is compiled from six IRB-approved clinical trials which assessed the efficacy of 635 nm lasers for reducing pain arising from chronic conditions. These included five randomized, placebo-controlled studies and one randomized comparative study.
Results: Among subjects in the active treatment group, there was a 45.4% mean decrease in VAS scores compared to a 15.1% mean decrease among sham-treated subjects (p<0.0001). The active treatment group also documented significant improvement in range of motion, oswestry disability index, and foot function index.
Conclusion: Based on the data the Food and Drug Administration (FDA) cleared the first low-level laser for the indication as adjunctive use in providing temporary relief of nociceptive musculoskeletal pain.
... Recommendation: strong, 100% agreed, evidence level B. Comment: An MA revealed that the incidence of druginduced peptic ulcer development was similar between patients who received COX-2 selective inhibitors and placebos, suggesting that COX-2 selective inhibitors do not increase the risk of drug-induced peptic ulcers [60][61][62]. In a network MA, concomitant dosing of COX-2 selective inhibitors with PPIs effectively prevented the development of drug-induced peptic ulcer compared with COX-2 selective inhibitors alone [63]. However, patients with a history of peptic ulcers have a higher risk of developing drug-induced peptic ulcers. ...
The Japanese Society of Gastroenterology (JSGE) revised the third edition of evidence-based clinical practice guidelines for peptic ulcer disease in 2020 and created an English version. The revised guidelines consist of nine items: epidemiology, hemorrhagic gastric and duodenal ulcers, Helicobacter pylori ( H. pylori ) eradication therapy, non-eradication therapy, drug-induced ulcers, non -H. pylori, and nonsteroidal anti-inflammatory drug (NSAID) ulcers, remnant gastric ulcers, surgical treatment, and conservative therapy for perforation and stenosis. Therapeutic algorithms for the treatment of peptic ulcers differ based on ulcer complications. In patients with NSAID-induced ulcers, NSAIDs are discontinued and anti-ulcer therapy is administered. If NSAIDs cannot be discontinued, the ulcer is treated with proton pump inhibitors (PPIs). Vonoprazan (VPZ) with antibiotics is recommended as the first-line treatment for H. pylori eradication, and PPIs or VPZ with antibiotics is recommended as a second-line therapy. Patients who do not use NSAIDs and are H. pylori negative are considered to have idiopathic peptic ulcers. Algorithms for the prevention of NSAID- and low-dose aspirin (LDA)-related ulcers are presented in this guideline. These algorithms differ based on the concomitant use of LDA or NSAIDs and ulcer history or hemorrhagic ulcer history. In patients with a history of ulcers receiving NSAID therapy, PPIs with or without celecoxib are recommended and the administration of VPZ is suggested for the prevention of ulcer recurrence. In patients with a history of ulcers receiving LDA therapy, PPIs or VPZ are recommended and the administration of a histamine 2-receptor antagonist is suggested for the prevention of ulcer recurrence.
... Üst GİS kanama için risk faktörleri ve risk oranları Şekil 1 ve Grafik 1'de şematize edilmiştir. Genel olarak selektif COX-2 inhibitörleri artı PPI'ların kombine edilmesi en iyi Gİ korumayı, ardından selektif COX-2 inhibitörleri ve üçüncü olarakda non selektif NSA-İİ'lar ve PPI'ların kombinasyonu en iyi üst GİS korumasını sağlar (27).Risk faktörlerine göre kimlere proflaksi verilmesi gerektiği (Tablo 1) ve korunma önerileri (Tablo 2) tablolarda özetlenmiştir. ...
Non-steroid anti-inflamatuar ilaçları (NSAID) (Aspirin dahil) kullananlarda risk faktörlerine bağlı olarak; %3- 4.5 klinik gastrointestinal (GİS) sistem olayı, 1/70 semptomatik ülser, 1/5 endoskopik ülser, %1.5 (1-4) (major kanama, perforasyon, obstruksiyon vd.) ciddi komplikasyon, 1/150 kanayan ülser, 1/1200 ölüm gelişeceği tahmin edilmektedir. Non-steroid ani-inflamatuar ilaçlar (NSAID) (Aspirin dahil) gastrik ve düodenal ülserle ilişkili anlamlı derecede morbidite ve mortaliteye neden olurlar. Gastrointestinal olay gelişiminde NSAID’ların kendine ait özelliklerine göre risk 20 kata kadar, seçilen doza görede risk 3-7 kata kadar değişebilmektedir. Helicobacter pylori (H. Pylori) ve NSAID peptik ülser oluşumunda bağımsız iki risk faktörüdür. H.pylori eradikasyonu ülser komplikasyonlarını azaltmaktadır. NSAİD kullanan yüksek riskli hastalarda öncelikle misoprostol ( 600mg/gün ve üstü) veya PPI önerilmelidir.Bu derlemede NSAİ ilaç kullanan ve kullanmak zorunda olan hastalarda GİS proflaksisi gerekliliğinin değerlendirilmesi amaçlandı.
... Overall, the use of NSAID is unfortunately hampered by their gastrointestinal toxicity, ranging from light indigestion to serious complications including severe bleeding ulcers, as well as perforation and obstruction of the digestive tract [10]. It has been shown and proven in many studies that an endoscopically confirmed ulcer may develop in around 15% -30% of chronic NSAID users and serious complications may occur in approximately 2% -4% of developed ulcers [11,12]. ...
Objective:
The aim of this study is to assess the prevalence of gastroprotection and identify the main factors that influence the taking of protective drugs by the adult population treated with non-steroidal anti-inflammatory drugs (NSAID).
Methods:
This study was cross-sectional, conducted by including a contingent of 800 users of primary health care services (n=369, 46% males and n=431, 54% females). Included in the study were individuals of both genders aged 18+ who sought counselling or treatment during the three-month period. The data collection of this study was based on the completion of a structured questionnaire, which included questions related to the use of NSAIDs, the way these drugs were prescribed and administered and the simultaneous taking of gastroprotective drugs.
Results:
The prevalence of the gastroprotective drugs use was higher among the elderly, individuals living in urban areas, those with higher education, those with daily use of NSAID, individuals receiving prescriptions from their own doctors, and those suffering from side effects from the use of NSAID, as well as subjects that had a longer duration of NSAID use. Diclofenac was the most prescribed NSAID. Gastric pain and dizziness were the most experienced side effects.
Conclusion:
This paper demonstrates the need to improve the quality of primary health care service through informing and educating patients regarding the need to take gastro-protective drugs for those at high risk of adverse effects manifested by the use of NSAIDs.
... Especially in recent years, they have been shown to prevent and treat digestive tract tumours and Alzheimer's disease, which directly led to a blowout growth in the demand for clinical medication for NSAIDs. [1] According to WHO statistics, about 30 million people use NSAIDs every day in the world, and there are 0.7-1 billion NSAIDs prescriptions in the United States every year, and its use ranks second next to anti-infective drugs in China. [2] However, the high incidence of adverse reactions of NSAIDs should not be neglected, which alone account for 25% of current adverse drug reactions. ...
Objectives:
Our previous studies indicated that the triterpenes from the fruits of Chaenomeles speciosa (Sweet) Nakai (TCS) owned effectively therapeutic effects on gastric ulcer patients and animals, but its mechanisms have not been fully understood. The current study was to further investigate its protective effect on indomethacin (IND)-damaged RGM-1 cells and rats, as well as its mechanisms involved.
Methods:
The gastroprotection of TCS was evaluated with IND-induced gastric lesions model in RGM-1 cells and rats. In vitro, the proliferation, migration, mitochondrial viability and apoptosis were assessed. In vivo, ulcer index, ulcer inhibition rate, gastric juice acidity, gastric wall mucus (GWM) and histopathology of gastric mucosa were detected. The gastroprotective effects of TCS through the TFF1-mediated EGF/EGFR and apoptotic pathways were measured by qRT-PCR and Western blot assays.
Key findings:
The results demonstrated that TCS had gastroprotective function, which was related to the amelioration in promoting IND-damaged RGM-1 cell proliferation and migration, hoisting gastric juice acidity and GWM, improving ulcer index and ulcer inhibition rate, attenuating the haemorrhage, oedema, epithelial cell loss and inflammatory cell infiltration of gastric mucosa, upregulating PCNA, Bcl-2, Bcl-xl mRNA and TFF1, EGF, p-EGFR, p-Src, pro-caspase-3, pro-caspase-9 protein expressions, mitochondrial viability, mitochondrial cytochrome c concentration and p-EGFR/EGFR, p-Src/Src, Bcl-2/Bax, Bcl-xl/Bad ratioes, downregulating Bax, Bad, Apaf-1 mRNA and cleaved-caspase-3, cleaved-caspase-9, cleaved PARP-1 protein expressions and cytosol cytochrome c concentration.
Conclusions:
Our present study demonstrated that TCS's gastroprotective effect was closely connected with boosting TFF1 expression, activating TFF1-mediated EGF/EGFR pathway, thus restraining mitochondrial-dependent apoptosis, which provided new insights into interpreting its underlying mechanism and promised to act as a candidate drug to treat gastric mucosal injury.
... This was followed by NSAIDs either with or without serratiopeptidases which was a part of 83.14% of the prescriptions. NSAIDs are associated with the increased incidences of upper gastrointestinal complications [11][12][13] . Clinicians use several strategies to combat this adverse reaction and the use of antiulcer agents is one of the most common ones. ...
Importance
In the US, peptic ulcer disease affects 1% of the population and approximately 54 000 patients are admitted to the hospital annually for bleeding peptic ulcers.
Observations
Approximately 10% of patients presenting with upper abdominal pain in a primary care setting have a peptic ulcer as the cause of their symptoms. The principal causes of peptic ulcer disease are Helicobacter pylori infection, which affects approximately 42% of patients with peptic ulcer disease, and aspirin or nonsteroidal anti-inflammatory drug (NSAID) use, which are etiologic factors in approximately 36% of people with peptic ulcer disease. Complications of peptic ulcer include bleeding (73% of patients), perforation (9% of patients), and pyloric obstruction (3% of patients). Annually, 10 000 people die of peptic ulcer disease in the US. Endoscopy definitively diagnoses peptic ulcer disease. Acid blockers, such as omeprazole, can heal peptic ulcers in approximately 80% to 100% of patients within 4 weeks, but gastric ulcers larger than 2 cm may require 8 weeks of treatment. Eradication of H pylori decreases peptic ulcer recurrence rates from approximately 50% to 60% to 0% to 2%. Discontinuing NSAIDs heals 95% of ulcers identified on endoscopy and reduces recurrence from 40% to 9%. When discontinuing an NSAID is not desirable, changing the NSAID (eg, from ketorolac to ibuprofen), adding a proton pump inhibitor such as omeprazole or lansoprazole, and eradicating H pylori with treatment such as bismuth, metronidazole, and tetracycline combined with omeprazole can reduce recurrence rates.
Conclusions and Relevance
Peptic ulcer disease is associated with increased hospitalization rates and mortality. Acid blocking with proton pump inhibitors, such as omeprazole or lansoprazole, is the primary treatment. Recurrence of ulcers can be prevented by eradicating H pylori if present and discontinuing aspirin or NSAIDs if applicable.
Objective
The frequency of small bowel (SB) injuries has increased due to the increased use of nonsteroidal anti-inflammatory drugs (NSAIDs) or aspirin. This study was a systematic review and meta-analysis to compare drugs effective for SB injuries caused by NSAIDs or aspirin use.
Methods
We searched MEDLINE, Embase, and Cochrane registries for randomized controlled trials through February 2023. The extracted data included changes in the number of erosions or ulcers in the jejunum or ileum observed through capsule endoscopy in patients taking NSAIDs or aspirin and administration of various mucoprotectants. We investigated the therapeutic or preventive efficacy of these drugs. The methodological bias was evaluated using Risk of Bias 2.0.
Results
Eighteen randomized controlled trials of drugs effective for NSAIDs or aspirin-induced SB injuries were included and analyzed. The agents used to treat or prevent SB injuries were rebamipide, misoprostol, geranylgeranylacetone, and probiotics. In the meta-analysis, the mucoprotectants that showed a significant effect in treating NSAID users, who developed SB injuries, were misoprostol (mean difference: −9.88; 95% CI: −13.26 to −6.50). Meanwhile, the mucoprotectant that can prevent SB injuries caused by NSAIDs or aspirin in the general population was rebamipide (mean difference: −1.85; 95% CI: −2.74 to −0.96).
Conclusions
Misoprostol was effective in treating SB injuries caused by NSAIDs or aspirin (CRD42023410946).
Celecoxib เป็นยาที่ได้รับความนิยมใช้อย่างแพร่หลายในข้อบ่งใช้ เพื่อบรรเทาปวดและลดการอักเสบ เฉียบพลันและเรื้อรัง โดยมีกลไกการออกฤทธิ์ยับยั้งเอนไซม์ cyclooxygenase 2 (COX-2) อย่างจำเพาะเจาะจง ดังนั้น celecoxib จึงมีประสิทธิภาพในการบรรเทาปวดและลดการอักเสบที่ดีในขณะที่มีอาการข้างเคียงต่อทางเดินอาหารน้อย กว่ายากลุ่ม traditional NSAIDs (tNSAIDs) ที่ออกฤทธิ์ไม่จำเพาะเจาะจง นอกจากนี้หลักฐานทางวิชาการจำนวนมาก ยังพบว่า celecoxib มีความปลอดภัยต่อระบบหัวใจและหลอดเลือดในระดับเดียวกับ tNSAIDs และมีประสิทธิภาพ เป็นที่น่าพอใจเมื่อใช้ในทางมะเร็งวิทยา จิตเวช และอาจรวมถึงการใช้ในโรคโควิด-19 บทความนี้เรียบเรียงขึ้น เพื่อรวบรวมและนำเสนอข้อมูลการใช้ในทางคลินิกในข้อบ่งใช้บรรเทาปวดลดการอักเสบ และข้อบ่งใช้อื่น ๆ ที่มีศักยภาพ ของ celecoxib
This study investigated a timeline of changes in the immunoreactivity of infiltrating macrophages during gastric ulcer healing. To this end, gastric tissue samples were obtained from an acetic acid-induced gastric ulcer model in rats on the 1st, 3rd, 7th, and 14th days of ulcer induction. Ulcerated gastric tissues were subjected to histologic and immunohistochemical evaluations for macrophage subtypes. The number of Iba-1+ macrophages in the gastric ulcer area significantly increased on day 3, reaching a maximum number on day 7, followed by a decrease on day 14. No Gal-3+ macrophages were seen in the gastric ulcer area until day 14. Interestingly,
CD68 reacted with macrophages, (myo)fibroblast-like spindle-shaped cells, and endothelial cells in the gastric ulcer area. There was a significant increase in the α-SMA+ myofibroblasts and desmin+ microvessels on days 7 and 14. The increase in the number of Iba-1+ macrophages was followed by the appearance of α-SMA+ myofibroblasts and desmin+ blood vessels. These results suggest that (i) different macrophage subtypes are involved in gastric ulcer healing, (ii) Iba-1+ macrophages, observed in the early stages of gastric healing, participate in proinflammatory and regenerative activities, (iii) Gal-3+ macrophages, seen in the late stages of healing,
contribute to proinflammatory response and tissue repair, and (iv) CD68 is not a macrophage-specific marker.
The aim of our study was to investigate the healing effect of propionyl-L-carnitine (PLC) on chronic gastric ulcers and its underlying mechanisms. This study included rats with gastric ulcers induced by applying serosal glacial acetic acid. These rats were then given either saline (vehicle) or PLC at doses of 60 and 120 mg/kg, administered orally 3 days after ulcer induction for 14 consecutive days. Our study found that treatment with PLC resulted in a reduction of the gastric ulcer area, a faster rate of ulcer healing, and stimulated mucosal restoration. Additionally, the treatment with PLC reduced the number of Iba-1+ M1 macrophages while increasing the number of galectin-3+ M2 macrophages, as well as desmin+ microvessels, and α-SMA+ myofibroblasts in the gastric ulcer bed. The mRNA expression of COX-2, eNOS, TGF-β1, VEGFA, and EGF in the ulcerated gastric mucosa was greater in the PLC-treated groups compared with the vehicle-treated rats. In conclusion, these findings suggest that PLC treatment may accelerate gastric ulcer healing by stimulating mucosal reconstruction, macrophage polarization, angiogenesis, and fibroblast proliferation, as well as fibroblast-myofibroblast transition. This process is associated with the upregulation of TGF-β1, VEGFA, and EGF, as well as modulation of the cyclooxygenase/nitric oxide synthase systems.
Objective
Nonsteroidal anti-inflammatory drugs (NSAIDs) are widely used to treat pain and rheumatic conditions. To facilitate patient management, we determined the predictive value of gastrointestinal (GI) symptoms and risk factors for the development of NSAID-associated GI injuries.
Methods
Post-hoc analysis of pooled data from naproxen treatment arms of two identical, randomized, double-blind, controlled phase 3 trials in arthritis patients at risk of GI adverse events. Endoscopic incidence of GI ulcers at baseline, and 1, 3, and 6 months was employed as a surrogate parameter for GI injury. For GI symptom analysis, Severity of Dyspepsia Assessment questionnaire was used. For GI risk factor analysis, the high risk factors: previous GI injury, concomitant selective serotonin reuptake inhibitors or corticosteroids, ulcer history, concomitant low-dose aspirin, and age >65 years were employed.
Results
Data of 426 naproxen patients were analyzed. Distribution of GI symptoms between patients with and without ulcer was similar; about one third of patients developing an ulcer reported no GI pain symptoms. GI symptoms experienced under naproxen treatment were thus not indicative of GI injury. The proportion of patients developing an ulcer increased with the number of risk factors present, however, about a quarter of patients without any of the analyzed risk factors still developed an ulcer.
Conclusion
GI symptoms and the number of risk factors are not reliable predictors of NSAID-induced GI injury to decide which patients need gastroprotection and will lead to a large group of patients with GI injuries. A preventive rather than reactive approach should be taken.
Peptic ulcer disease and complications of peptic ulcer disease are common in the geriatric population. We discuss the main causes of ulcer disease, their diagnosis, treatment, complications, and prevention. This chapter deals with the pathophysiology, diagnosis, manifestations, and therapy of peptic ulcers with special emphasis on the diagnosis and management of ulcers and ulcer disease related to Helicobacter pylori, nonsteroidal anti-inflammatory drug use, and stress ulcers. We provide detailed advice regarding the mechanistic and therapeutic role of acid suppression medication for the treatment of peptic ulcer disease and prevention of related complications, in particular proton pump inhibitors and H. pylori diagnosis and therapy. There is also an in depth discussion of ulcer complications of obstruction, perforation, and upper gastrointestinal bleeding, with a comprehensive overview of the risk factors and medical and endoscopic treatment options for the most common ulcer complication of hemorrhage. The chapter provides readers with both a historical and current perspective on peptic ulcer disease to help guide therapy and clinical decision-making.
Introduction:
Non-steroidal anti-inflammatory drugs (NSAIDs) are one of the most prescribed pharmacological groups, especially in elderly patients.Areas Covered: The main GI and CV adverse events associated with NSAID use are reviewed. Risk factors and prophylactic strategies are also covered.Expert Opinion: COX-2 selective agents are safer to the GI tract but have a worst CV profile. On the contrary, naproxen seems safer for CV system, but it is one of the NSAIDs with higher GI toxicity. Co-therapy with aspirin reduces the GI benefits of COX-2 selective agents, whereas ibuprofen and naproxen may neglect the antiplatelet effect of aspirin. NSAIDs increase the risk of both upper and lower GI complications. Co-therapy with PPI reduces the risk of upper but not lower GI complications, and seems to induce dysbiosis in the small bowel, which may be implicated in the damage induced by NSAIDs. Celecoxib, a COX-2 selective agent, seems safer for both the upper and the lower GI tract. Other potential alternatives to prevent the lower GI damage such as misoprostol, or modulation of the microbiota need further studies. Prescription of type and dose of NSAIDs must be individualized based on the stratification of the CV and GI risk of patients.
Introduction: Today there is a continuing search for an effective, affordable remedy that can be used to treat and prevent diseases of periodontal, stomach and duodenum during the use non-steroidal anti-inflammatory drugs ( NSAIDs ). Aim: To study the protective effect of phytopreparation (decoction of blueberry leaves) on an experimental model of gastric ulcer and periodontitis. Material and Methods: The study was performed on 30 rats, which were evenly divided into three groups: 1 – control animals, 2 – animals that were modeled with non-steroid gastric ulcer and periodontitis (7 mg/kg diclofenacum natrium intragastrically for 5 days) and 3 – group in the background experimental pathology was introduced decoction of blueberry leaves 1:10 2 ml intragastrically (30 minutes after the introduction of diclofenacum natrium). Results: Histological examination of the mucous membrane of rats, which used as a preventive agent decoction of blueberry leaves, showed that it is characterized only by single erosion, no fibrinosis and hemorrhagic plaque, lympho-macrophage infiltration. Conclusions: Simultaneous use of a decoction of blueberry leaves can be used as a preventive and curative agent to prevent the development of erosions and ulcers of the mucous membrane of the digestive system.
Introduction: Health treatment services in health resorts are a specific type of health care services in the Polish health protection system. In the context of performing the services, this specificity should be indicated in the rules for referring patients to treatment in health resorts. Referrals to treatment or rehabilitation in health resorts must be confirmed by the voivodeship branch office of the Fund, which is competent for the place of residence of the respective beneficiary. By confirming referrals, the voivodeship branch office of the National Health Fund specifies, inter alia, the type, place and date of the treatment. Therefore, it should be pointed out that the process in which the National Health Fund confirms referrals to treatment in health resorts is an important factor impacting the performance of treatment services in health resorts. Material: In order to inform about the performance of health care services in health resorts in 2019, the National Health Fund analysed the data by taking into account, inter alia, quantitative and value data (the value and number of registered medical referrals), medical data (the basis of the referrals, treatment profile, and scope of services), and statistical data (age and sex). Conclusions: From the analysis containing the above mentioned data, which is performed by the National Health Fund, results that the largest age group being treated in health resorts is the group aged from 56 to 65 years, which accounts for 41.03% of the total group of beneficiaries. On the other hand, the smallest groups is comprised of beneficiaries aged from 19 to 40 years, i.e. 1.39% of the total group of beneficiaries. This means that there is a significant disparity in the performance of treatment in health resorts between different age groups. Disparities may also be noticed in the performance of medical referrals to treatment in terms of sex, i.e. women account for 63.67% and men for just 36.33%.
Background The increasing use of antithrombotic therapies in older patients has led to an increased risk of gastrointestinal (GI) bleeding in chronic nonsteroidal anti-inflammatory drug (NSAID) users. Therefore, there is a pressing need for GI prophylaxis in these high-risk patients. Objective To analyze prescribing patterns and factors associated with the use of gastroprotective agents (GPAs) among high-risk, chronic NSAID users. Setting National claims database including 20% of the total Korean population aged ≥ 65 years. Method In this cross-sectional study, we identified older adults prescribed traditional NSAIDs for > 90 days and classified them into high- and ultra-high-risk groups if they had one or two or more GI risk factors, respectively. Proton pump inhibitors or misoprostol prescribed for more than 80% of traditional NSAID treatment days was regarded as appropriate GI prophylaxis. Main outcome measure Prevalence and associated factors with appropriate GI prophylaxis. Results Among 69,992 chronic traditional NSAID users, 38.8% and 9.4% belonged to the high and ultra-high-risk groups; 13.2% and 19.9% received appropriate GI prophylaxis, respectively. The most frequently used GPA was histamine H2 antagonists. Multiple NSAID use, concomitant antiplatelets and anticoagulants, and prior GI ulcer history increased the likelihood of receiving appropriate GI prophylaxis. Advanced age (≥ 85 years), indications other than arthritis, and neurology specialists negatively affected appropriate GI prophylaxis use. Conclusion Approximately one in five chronic NSAID users, considered ultra-high risk, are prescribed appropriate GI prophylaxis in Korea. Advanced age, indications, and specialties of the prescriber all need to be considered when selecting target populations for interventions.
Osteoarthritis (OA) is a degenerative disease of middle-aged and elderly people, contributed a higher burden of disease in China and the world. In 2017, under the support of the Rheumatology and Immunology Expert Committee of the Cross-Strait Medical and Health Exchange Association. The objective was to develop an evidence-based diagnosis and treatment guideline for OA in China based on emerging new evidence. The guideline was registered at International Practice Guidelines Registry Platform (IPGRP-2018CN028). The grading of recommendations assessment, development and evaluation (GRADE) approach was used to rate the quality of evidence and the strength of recommendations, and the RIGHT (Reporting Items for Practice Guidelines in Healthcare) checklist was followed to report the guideline. The guideline provides recommendations for the OA diagnosis, disease risks monitoring and evaluate, treatment purpose and physical, medical and surgical interventions. This guideline is intended to serve as a tool for Chinese clinicians for the best decisions-making on diagnosis and treatment of OA.
A quaternary carbon bears four other carbon substituents or combination of four non-hydrogen substituents at four vertices of a tetrahedron. The spirocyclic quaternary carbon positioned at the center of a bioactive molecule offers conformational rigidity which, in turn, reduces the penalty for conformational entropy. The quaternary carbon is a predominant feature of natural product structures and has been associated with more effectively and selectively binding to target proteins compared to planar compounds with a high sp2 count. The presence of a quaternary carbon stereocenter allows the exploration of novel chemical space to obtain new molecules with enhanced three-dimensionality. These characteristics, coupled to an increasing awareness to develop sp3-rich molecules, boosted utility of quaternary carbon stereocenters in bioactive compounds. It is hoped that this Perspective will inspire the chemist to utilize quaternary carbon stereocenters to enhance potency, selectivity, and other drug-like properties.
Background
Non-steroidal anti-inflammatory drugs (NSAIDs) are one of the most commonly prescribed medications, but they are associated with a number of serious adverse effects, including hypertension, cardiovascular disease, kidney injury and GI complications.
Objective
To develop a set of multidisciplinary recommendations for the safe prescription of NSAIDs.
Methods
Randomised control trials and observational studies published before January 2018 were reviewed, with 329 papers included for the synthesis of evidence-based recommendations.
Results
Whenever possible, a NSAID should be avoided in patients with treatment-resistant hypertension, high risk of cardiovascular disease and severe chronic kidney disease (CKD). Before treatment with a NSAID is started, blood pressure should be measured, unrecognised CKD should be screened in high risk cases, and unexplained iron-deficiency anaemia should be investigated. For patients with high cardiovascular risk, and if NSAID treatment cannot be avoided, naproxen or celecoxib are preferred. For patients with a moderate risk of peptic ulcer disease, monotherapy with a non-selective NSAID plus a proton pump inhibitor (PPI), or a selective cyclo-oxygenase-2 (COX-2) inhibitor should be used; for those with a high risk of peptic ulcer disease, a selective COX-2 inhibitor plus PPI are needed. For patients with pre-existing hypertension receiving renin-angiotensin system blockers, empirical addition (or increase in the dose) of an antihypertensive agent of a different class should be considered. Blood pressure and renal function should be monitored in most cases.
Conclusion
NSAIDs are a valuable armamentarium in clinical medicine, but appropriate recognition of high-risk cases, selection of a specific agent, choice of ulcer prophylaxis and monitoring after therapy are necessary to minimise the risk of adverse events.
Introduction
Irritable bowel syndrome (IBS) is a common chronic functional gastrointestinal disorder affecting approximately 10% to 25% of the adult population. A large number of clinical trials have been conducted to evaluate the efficacy of probiotics for IBS but the results were inconsistent. Previous meta-analyses have shown that probiotics are effective for IBS, but the comparative efficacy of individual species is unclear. In addition, evidence regarding the superiority of combination over single probiotic is still lacking. We, therefore, perform this study to evaluate the comparative efficacy and safety of various species of probiotics, and combination regimens for the treatment of IBS.
Methods and analysis
This study is a systematic review with network meta-analysis. We will search PubMed, Scopus, The Cochrane Central Register of Controlled Trials and CINAHL for randomised controlled trials comparing probiotics with placebo or comparing different probiotics for IBS, with no language restrictions. The primary outcomes will be treatment response and global IBS-symptom score. We will initially combine included studies with traditional pairwise meta-analysis and then with random-effects network meta-analysis. We will quantify the effect of potential effect modifiers by meta-regression if appropriate. We will check the consistency assumption by testing the absolute difference between direct and indirect estimates for comparisons in closed loops. The quality of evidence will be evaluated according to the GRADE framework.
Ethics and dissemination
Ethical approval is not required for literature-based studies. We will disseminate the findings through publications in peer-reviewed journals and relevant conferences.
PROSPERO registration number
CRD42018102101
Currently 2 difference classes of cyclooxygenase (COX)-2 inhibitors, coxibs and relatively selective COX-2 inhibitors, are available for patients requiring nonsteroidal anti-inflammatory drug (NSAID) therapy; their gastroprotective effect is hardly directly compared.
The aim of this study was to compare the gastroprotective effect of relatively selective COX-2 inhibitors with coxibs.
MEDLINE, EMBASE, and the Cochrane Library (from their inception to March 2015) were searched for potential eligible studies.
We included randomized controlled trials comparing coxibs (celecoxib, etoricoxib, parecoxib, and lumiracoxib), relatively selective COX-2 inhibitors (nabumetone, meloxicam, and etodolac), and nonselective NSAIDs with a study duration ≥4 weeks.
Comparative effectiveness and safety data were pooled by Bayesian network meta-analysis. The primary outcomes were ulcer complications and symptomatic ulcer. Summary effect-size was calculated as risk ratio (RR), together with the 95% confidence interval (CI).
This study included 36 trials with a total of 112,351 participants. Network meta-analyses indicated no significant difference between relatively selective COX-2 inhibitors and coxibs regarding ulcer complications (RR, 1.38; 95% CI, 0.47–3.27), symptomatic ulcer (RR, 1.02; 95% CI, 0.09–3.92), and endoscopic ulcer (RR, 1.18; 95% CI, 0.37–2.96). Network meta-analyses adjusting potential influential factors (age, sex, previous ulcer disease, and follow-up time), and sensitivity analyses did not reveal any major change to the main results. Network meta-analyses suggested that relatively selective COX-2 inhibitors and coxibs were associated with comparable incidences of total adverse events (AEs) (RR, 1.09; 95% CI, 0.93–1.31), gastrointestinal AEs (RR, 1.04; 95% CI, 0.87–1.25), total withdrawals (RR, 1.00; 95% CI, 0.74–1.33), and gastrointestinal AE-related withdrawals (RR, 1.02; 95% CI, 0.57–1.74).
Relatively selective COX-2 inhibitors appear to be associated with similar gastroprotective effect and tolerability as coxibs. Owing to the indirectness of the comparisons, future research is required to confirm the study conclusion.
Systematic reviews and meta-analyses are essential to summarize evidence relating to efficacy and safety of health care interventions accurately and reliably. The clarity and transparency of these reports, however, is not optimal. Poor reporting of systematic reviews diminishes their value to clinicians, policy makers, and other users.
Since the development of the QUOROM (QUality Of Reporting Of Meta-analysis) Statement—a reporting guideline published in 1999—there have been several conceptual, methodological, and practical advances regarding the conduct and reporting of systematic reviews and meta-analyses. Also, reviews of published systematic reviews have found that key information about these studies is often poorly reported. Realizing these issues, an international group that included experienced authors and methodologists developed PRISMA (Preferred Reporting Items for Systematic reviews and Meta-Analyses) as an evolution of the original QUOROM guideline for systematic reviews and meta-analyses of evaluations of health care interventions.
The PRISMA Statement consists of a 27-item checklist and a four-phase flow diagram. The checklist includes items deemed essential for transparent reporting of a systematic review. In this Explanation and Elaboration document, we explain the meaning and rationale for each checklist item. For each item, we include an example of good reporting and, where possible, references to relevant empirical studies and methodological literature. The PRISMA Statement, this document, and the associated Web site (http://www.prisma-statement.org/) should be helpful resources to improve reporting of systematic reviews and meta-analyses.
Network meta-analysis (NMA), combining direct and indirect comparisons, is increasingly being used to examine the comparative effectiveness of medical interventions. Minimal guidance exists on how to rate the quality of evidence supporting treatment effect estimates obtained from NMA. We present a four-step approach to rate the quality of evidence in each of the direct, indirect, and NMA estimates based on methods developed by the GRADE working group. Using an example of a published NMA, we show that the quality of evidence supporting NMA estimates varies from high to very low across comparisons, and that quality ratings given to a whole network are uninformative and likely to mislead.
Background:
A histamine-2 receptor antagonist (H2RA) is one of the common gastroprotective co-therapies used with non-steroidal anti-inflammatory drugs (NSAIDs) for the prevention or treatment of peptic ulcers (PUs). To date, no study has directly compared the prophylactic effectiveness between high-dose and low-dose H2RA.
Objective:
Our objective was to compare the effectiveness of high-dose versus low-dose H2RAs in the primary prophylaxis of PUs among short-term NSAID users.
Methods:
A retrospective cohort study was conducted using the Clinical Data Analysis and Reporting System (CDARS) in Hong Kong. Patients aged 18 years or above who received a single prescription of oral NSAID with oral H2RA were identified within the study period (1 January 2009-31 December 2012). Patients with a history of or risk factors for PU in the corresponding 2 years prior to the index date (of the first NSAID prescription) were excluded. Log binomial regression analysis was used to calculate the relative risk of PU among NSAID users with high-dose H2RA versus low-dose H2RA exposure.
Results:
Among the NSAID cohort (n = 102,042), 77,509 (76 %) were on low-dose H2RA and 24,533 (24 %) were on high-dose H2RA. Of the total 69 PU cases identified during the drug exposure period, 64 (0.08 %) received low-dose-H2RA and five (0.02 %) received high-dose H2RA. The overall absolute risk of PUs for NSAID users whilst on H2RA was approximately 1 per 1,479 patients. The adjusted relative risk for NSAID users receiving high-dose H2RA versus low-dose H2RA was 0.32 (95 % confidence interval [CI] 0.13-0.79). Patients aged ≥65 years, receiving a longer duration of treatment, or with concomitant use of antiplatelet agents were found to be at higher risk of PU.
Conclusion:
High-dose H2RA showed greater effectiveness than low-dose H2RA in the primary prophylaxis of NSAID-associated PUs in short-term new users.
A direct assessment of two interventions is available if a randomized controlled trial of the interventions has been conducted and the results of the study are available. However, many competing interventions have not been compared directly or such direct evidence is limited. The reasons for lack of direct comparisons vary; for drug interventions this is often related to commercial interests and the regulatory approval process. Head to head comparison of two active drugs is often not available since placebo controlled trials are usually sufficient for acquiring regulatory approval of a new drug and there is no motivation from the commercial sector to compare the new drug with existing active treatments. Indirect comparisons have been advocated when direct evidence is not available. Bucher et al. (1997) presented a model that evaluates the differences between treatment and placebo in two sets of clinical trials, while preserves the randomization of the originally assigned patient groups. Their model uses the odds ratio as the measure of treatment effect and was specifically designed for the simple indirect comparison of A vs B when direct evidence of A vs C and B vs C are available.
We expanded the indirect odds ratio approach by Bucher et al. (1997) for more complex webs of evidence involving k interventions (treatments), using the results of (k-1) pairwise direct comparisons of interventions. This generalized approach was then considered for the relative risk, hazard ratio, risk difference and mean difference. The effect estimates and tests of association for these different effect parameters were derived and their distributional and statistical properties assessed. Using empirical approaches the extent and direction of biases associated with indirect methods were explored, with the goal of developing specific guidelines for using these methods. In order to assess these biases, simulation methods were considered. Finally, a ‘reviewer-friendly’ program was developed and made available to facilitate the evaluation of indirect evidence for reviewers.
Inconsistency can be thought of as a conflict between "direct" evidence on a comparison between treatments B and C and "indirect" evidence gained from AC and AB trials. Like heterogeneity, inconsistency is caused by effect modifiers and specifically by an imbalance in the distribution of effect modifiers in the direct and indirect evidence. Defining inconsistency as a property of loops of evidence, the relation between inconsistency and heterogeneity and the difficulties created by multiarm trials are described. We set out an approach to assessing consistency in 3-treatment triangular networks and in larger circuit structures, its extension to certain special structures in which independent tests for inconsistencies can be created, and describe methods suitable for more complex networks. Sample WinBUGS code is given in an appendix. Steps that can be taken to minimize the risk of drawing incorrect conclusions from indirect comparisons and network meta-analysis are the same steps that will minimize heterogeneity in pairwise meta-analysis. Empirical indicators that can provide reassurance and the question of how to respond to inconsistency are also discussed.
In meta-analysis, between-study heterogeneity indicates the presence of effect-modifiers and has implications for the interpretation of results in cost-effectiveness analysis and decision making. A distinction is usually made between true variability in treatment effects due to variation in patient populations or settings and biases related to the way in which trials were conducted. Variability in relative treatment effects threatens the external validity of trial evidence and limits the ability to generalize from the results; imperfections in trial conduct represent threats to internal validity. We provide guidance on methods for meta-regression and bias-adjustment, in pairwise and network meta-analysis (including indirect comparisons), using illustrative examples. We argue that the predictive distribution of a treatment effect in a "new" trial may, in many cases, be more relevant to decision making than the distribution of the mean effect. Investigators should consider the relative contribution of true variability and random variation due to biases when considering their response to heterogeneity. In network meta-analyses, various types of meta-regression models are possible when trial-level effect-modifying covariates are present or suspected. We argue that a model with a single interaction term is the one most likely to be useful in a decision-making context. Illustrative examples of Bayesian meta-regression against a continuous covariate and meta-regression against "baseline" risk are provided. Annotated WinBUGS code is set out in an appendix.
Background:
There are conflicting and inconsistent data regarding the gastrointestinal (GI) protective effect of cyclooxygenase-2 (COX-2) inhibitors and of non-steroidal anti-inflammatory drugs (NSAIDs) plus proton-pump inhibitors (PPI).
Aim:
To compare the adverse GI effects between COX-2 inhibitors and NSAIDs plus PPI.
Methods:
We performed a systematic review of randomized trials comparing GI adverse effects between COX-2 inhibitors and NSAID plus PPI. Trials were identified in MEDLINE, EMBASE, and the Cochrane Library. Primary outcomes were major GI complications including hemorrhage, perforation, and obstruction.
Results:
A total of nine trials involving 7,616 participants from 2002 to 2011 were included. All trials were randomized, double blinded, and placebo-controlled with moderate to high quality. COX-2 inhibitors were found to have significantly reduced the risk of major GI events, including perforation, obstruction, and bleeding (relative risk or RR 0.38, 95 % confidence interval or CI 0.25-0.56, p < 0.001); however, the benefit was significant only for patients who were at high risk for NSAID-related GI complications and long-term users. Additionally, the risk of diarrhea (RR 0.56, 95 % CI 0.35-0.9, p 0.02) and withdrawal (RR 0.77, 95 % CI 0.62-0.94, p 0.01) was significantly lower in use of COX-2 inhibitors, while the rate of dyspepsia was higher (RR 1.58, 95 % CI 1.26-1.98, p < 0.001).
Conclusions:
COX-2 inhibitors significantly reduced the risk of perforation, obstruction, bleeding, diarrhea, and withdrawal due to GI adverse events, while the risk of dyspepsia was lower with NSAIDs plus PPI.
We set out a generalized linear model framework for the synthesis of data from randomized controlled trials. A common model is described, taking the form of a linear regression for both fixed and random effects synthesis, which can be implemented with normal, binomial, Poisson, and multinomial data. The familiar logistic model for meta-analysis with binomial data is a generalized linear model with a logit link function, which is appropriate for probability outcomes. The same linear regression framework can be applied to continuous outcomes, rate models, competing risks, or ordered category outcomes by using other link functions, such as identity, log, complementary log-log, and probit link functions. The common core model for the linear predictor can be applied to pairwise meta-analysis, indirect comparisons, synthesis of multiarm trials, and mixed treatment comparisons, also known as network meta-analysis, without distinction. We take a Bayesian approach to estimation and provide WinBUGS program code for a Bayesian analysis using Markov chain Monte Carlo simulation. An advantage of this approach is that it is straightforward to extend to shared parameter models where different randomized controlled trials report outcomes in different formats but from a common underlying model. Use of the generalized linear model framework allows us to present a unified account of how models can be compared using the deviance information criterion and how goodness of fit can be assessed using the residual deviance. The approach is illustrated through a range of worked examples for commonly encountered evidence formats.
Objective: Funnel plots (plots of effect estimates against sample size) may be useful to detect bias in meta-analyses that were later contradicted by large trials. We examined whether a simple test of asymmetry of funnel plots predicts discordance of results when meta-analyses are compared to large trials, and we assessed the prevalence of bias in published meta-analyses. Design: Medline search to identify pairs consisting of a meta-analysis and a single large trial (concordance of results was assumed if effects were in the same direction and the meta-analytic estimate was within 30
We performed two 24-week double-blind trials (REDUCE-1 and -2 (Registration Endoscopic Studies to Determine Ulcer Formation of HZT-501 Compared with Ibuprofen: Efficacy and Safety Studies)) to assess whether double-dose famotidine given in a single-tablet combination with ibuprofen (HZT-501) significantly reduces gastric and duodenal ulcers as compared with ibuprofen.
Patients (40-80 years) requiring daily non-steroidal anti-inflammatory drugs (NSAIDs) for ≥6 months with no prior ulcer complications, negative H. pylori stool test, and baseline endoscopy showing no ulcers and <5 erosions were randomly assigned in a 2:1 ratio to HZT-501 or identical-appearing ibuprofen 800 mg tablets thrice daily. Study endoscopies were done at 8, 16, and 24 weeks. After unblinding and initial analyses, 12 patients were found to be misclassified as having gastric ulcers based on the adjudication of endoscopy reports, and analyses were re-run.
In REDUCE-1, the primary end point analysis of gastric ulcers at 24 weeks with HZT-501 vs. ibuprofen was 12.7% vs. 22.9% (P=0.0044) in the post-adjudication analysis. In REDUCE-2, the primary end point analysis of upper gastrointestinal (GI) ulcers was 13.0% vs. 20.5% (P=0.0587) in the post-adjudication analysis. Prespecified pooled analyses showed significantly fewer gastric (12.5% vs. 20.7%) and duodenal ulcers (1.1% vs. 5.1%) with HZT-501 vs. ibuprofen. Proportional hazards analysis of multiple potential risk factors showed the risk ratio of upper GI ulcers with HZT-501 vs. ibuprofen was 0.46, 95% confidence interval was 0.34-0.61.
Combined results of the REDUCE studies indicate that double-dose famotidine plus ibuprofen, given as a combination tablet, decreases endoscopic upper GI ulcers as compared with ibuprofen alone.
To analyse the available evidence on cardiovascular safety of non-steroidal anti-inflammatory drugs.
Network meta-analysis.
Bibliographic databases, conference proceedings, study registers, the Food and Drug Administration website, reference lists of relevant articles, and reports citing relevant articles through the Science Citation Index (last update July 2009). Manufacturers of celecoxib and lumiracoxib provided additional data.
All large scale randomised controlled trials comparing any non-steroidal anti-inflammatory drug with other non-steroidal anti-inflammatory drugs or placebo. Two investigators independently assessed eligibility.
The primary outcome was myocardial infarction. Secondary outcomes included stroke, death from cardiovascular disease, and death from any cause. Two investigators independently extracted data.
31 trials in 116 429 patients with more than 115 000 patient years of follow-up were included. Patients were allocated to naproxen, ibuprofen, diclofenac, celecoxib, etoricoxib, rofecoxib, lumiracoxib, or placebo. Compared with placebo, rofecoxib was associated with the highest risk of myocardial infarction (rate ratio 2.12, 95% credibility interval 1.26 to 3.56), followed by lumiracoxib (2.00, 0.71 to 6.21). Ibuprofen was associated with the highest risk of stroke (3.36, 1.00 to 11.6), followed by diclofenac (2.86, 1.09 to 8.36). Etoricoxib (4.07, 1.23 to 15.7) and diclofenac (3.98, 1.48 to 12.7) were associated with the highest risk of cardiovascular death.
Although uncertainty remains, little evidence exists to suggest that any of the investigated drugs are safe in cardiovascular terms. Naproxen seemed least harmful. Cardiovascular risk needs to be taken into account when prescribing any non-steroidal anti-inflammatory drug.
Systematic reviews and meta-analyses are essential to summarise evidence relating to efficacy and safety of healthcare interventions accurately and reliably. The clarity and transparency of these reports, however, are not optimal. Poor reporting of systematic reviews diminishes their value to clinicians, policy makers, and other users.
Since the development of the QUOROM (quality of reporting of meta-analysis) statement—a reporting guideline published in 1999—there have been several conceptual, methodological, and practical advances regarding the conduct and reporting of systematic reviews and meta-analyses. Also, reviews of published systematic reviews have found that key information about these studies is often poorly reported. Realising these issues, an international group that included experienced authors and methodologists developed PRISMA (preferred reporting items for systematic reviews and meta-analyses) as an evolution of the original QUOROM guideline for systematic reviews and meta-analyses of evaluations of health care interventions.
The PRISMA statement consists of a 27-item checklist and a four-phase flow diagram. The checklist includes items deemed essential for transparent reporting of a systematic review. In this explanation and elaboration document, we explain the meaning and rationale for each checklist item. For each item, we include an example of good reporting and, where possible, references to relevant empirical studies and methodological literature. The PRISMA statement, this document, and the associated website (www.prisma-statement.org/) should be helpful resources to improve reporting of systematic reviews and meta-analyses.
To investigate basic assumptions and other methodological problems in the application of indirect comparison in systematic reviews of competing healthcare interventions.
Survey of published systematic reviews. Inclusion criteria Systematic reviews published between 2000 and 2007 in which an indirect approach had been explicitly used.
Identified reviews were assessed for comprehensiveness of the literature search, method for indirect comparison, and whether assumptions about similarity and consistency were explicitly mentioned.
The survey included 88 review reports. In 13 reviews, indirect comparison was informal. Results from different trials were naively compared without using a common control in six reviews. Adjusted indirect comparison was usually done using classic frequentist methods (n=49) or more complex methods (n=18). The key assumption of trial similarity was explicitly mentioned in only 40 of the 88 reviews. The consistency assumption was not explicit in most cases where direct and indirect evidence were compared or combined (18/30). Evidence from head to head comparison trials was not systematically searched for or not included in nine cases.
Identified methodological problems were an unclear understanding of underlying assumptions, inappropriate search and selection of relevant trials, use of inappropriate or flawed methods, lack of objective and validated methods to assess or improve trial similarity, and inadequate comparison or inappropriate combination of direct and indirect evidence. Adequate understanding of basic assumptions underlying indirect and mixed treatment comparison is crucial to resolve these methodological problems. APPENDIX 1: PubMed search strategy. APPENDIX 2: Characteristics of identified reports. APPENDIX 3: Identified studies. References of included studies.
Guidelines for clinical practice are intended to indicate preferred approaches to medical problems as established by scientifically valid research. Double-blind, placebo-controlled studies are preferable, but compassionate use reports and expert review articles are used in a thorough review of the literature conducted through Medline with the National Library of Medicine. Only when data that will not withstand objective scrutiny are available is a recommendation identified as a consensus of experts. Guidelines are applicable to all physicians who address the subject, without regard to specialty training or interests, and are intended to indicate the preferable, but not necessarily the only, acceptable approach to a specific problem. Guidelines are intended to be flexible and must be distinguished from standards of care, which are inflexible and rarely violated. Given the wide range of specifics in any health-care problem, the physician must always choose the course best suited to the individual patient and the variables in existence at the moment of decision. These guidelines were developed under the auspices of the American College of Gastroenterology by a committee of experts in the field, reviewed by its Practice Parameters Committee, and approved by the Board of Trustees. The recommendations of these guidelines are therefore considered valid at the time of production based on the data available. New developments in medical research and practice pertinent to each guideline will be reviewed at an established time and indicated at publication to assure continued validity. Owing to the volume of new data on the subject of non-steroidal anti-inflammatory drug (NSAID)-related injury to the upper gastrointestinal tract, i.e., the advent of cyclooxygenase (COX)-2 inhibitors, new data on interactions between these agents, as well as traditional NSAIDs, with aspirin and H. pylori, it was elected by the Committee to confine these guidelines to upper gastrointestinal (GI) injury and to leave post-duodenal injury as the subject of a separate guideline.
Funnel plots (plots of effect estimates against sample size) may be useful to detect bias in meta-analyses that were later contradicted by large trials. We examined whether a simple test of asymmetry of funnel plots predicts discordance of results when meta-analyses are compared to large trials, and we assessed the prevalence of bias in published meta-analyses.
Medline search to identify pairs consisting of a meta-analysis and a single large trial (concordance of results was assumed if effects were in the same direction and the meta-analytic estimate was within 30% of the trial); analysis of funnel plots from 37 meta-analyses identified from a hand search of four leading general medicine journals 1993-6 and 38 meta-analyses from the second 1996 issue of the Cochrane Database of Systematic Reviews.
Degree of funnel plot asymmetry as measured by the intercept from regression of standard normal deviates against precision.
In the eight pairs of meta-analysis and large trial that were identified (five from cardiovascular medicine, one from diabetic medicine, one from geriatric medicine, one from perinatal medicine) there were four concordant and four discordant pairs. In all cases discordance was due to meta-analyses showing larger effects. Funnel plot asymmetry was present in three out of four discordant pairs but in none of concordant pairs. In 14 (38%) journal meta-analyses and 5 (13%) Cochrane reviews, funnel plot asymmetry indicated that there was bias.
A simple analysis of funnel plots provides a useful test for the likely presence of bias in meta-analyses, but as the capacity to detect bias will be limited when meta-analyses are based on a limited number of small trials the results from such analyses should be treated with considerable caution.
One hundred years have passed since Felix Hoffman, working at Bayer Industries, reported the successful synthesis of acetylsalicylic acid as the first nonsteroidal antiinflammatory drug (NSAID).1,2 At the suggestion of Hermann Dreser, Bayer's chief pharmacologist at the time,3 the compound was called “aspirin” and was purported to represent a convenient mechanism for the delivery of salicylic acid in the treatment of rheumatic diseases, menstrual pain, and fever.2 Approximately 40 years elapsed before Douthwaite and Lintott4 provided endoscopic evidence that aspirin could cause gastric mucosal damage. Numerous reports have corroborated this observation,5–8 and the introduction of more potent agents . . .
To assess the effectiveness of five gastroprotective strategies for people taking non-steroidal anti-inflammatory drugs (NSAIDs)--H2 receptor antagonists plus non-selective (or cyclo-oxygenase-1) NSAIDs; proton pump inhibitors plus non-selective NSAIDs; misoprostol plus non-selective NSAIDs; COX-2 selective NSAIDs; or COX-2 specific NSAIDs--in reducing serious gastrointestinal complications, symptomatic ulcers, serious cardiovascular or renal disease, and deaths, and improving quality of life.
The Cochrane Library, Medline, Embase, Current Controlled Trials, and System for Information on Grey Literature in Europe (SIGLE) were searched to May 2002. Bibliographies and author contacts were used to identify further studies; non-English articles were included.
Trial selection, data extraction, and quality assessment were performed independently, in duplicate. Articles were rejected only if the study was not a randomised controlled trial; did not assess a gastroprotective strategy versus placebo; included exclusively children or healthy volunteers; lasted less than 21 days; or no review outcomes were measured. Quality assessment included allocation concealment and baseline similarity. Random effects meta-analysis, meta-regression and subgrouping were used to pool effects and analyse associations with length of follow up, mean age, and baseline gastrointestinal status. Heterogeneity was examined and sensitivity analyses performed.
Of 112 included randomised controlled trials (74 666 participants), five were judged to be at low risk of bias, and 138 deaths and 248 serious gastrointestinal events were reported overall. On comparing gastroprotective strategies versus placebo we found no evidence of effectiveness of H2 receptor antagonists for any primary outcomes (few events reported); proton pump inhibitors may reduce the risk of symptomatic ulcers (relative risk 0.09, 95% confidence interval 0.02 to 0.47); misoprostol reduces the risk of serious gastrointestinal complications (0.57, 0.36 to 0.91) and symptomatic ulcers (0.36, 0.20 to 0.67); COX-2 selectives reduce the risk of symptomatic ulcers (0.41, 0.26 to 0.65) and COX-2 specifics reduce the risk of symptomatic ulcers (0.49, 0.38 to 0.62) and possibly serious gastrointestinal complications (0.55, 0.38 to 0.80). All strategies except COX-2 selectives reduce the risk of endoscopic ulcers (at least 3 mm in diameter).
Misoprostol, COX-2 specific and selective NSAIDs, and probably proton pump inhibitors significantly reduce the risk of symptomatic ulcers, and misoprostol and probably COX-2 specifics significantly reduce the risk of serious gastrointestinal complications, but data quality is low. More data on H2 receptor antagonists and proton pump inhibitors are needed, as is better reporting of rare but important outcomes.
To assess the relative effectiveness, patient acceptability, costs and cost-effectiveness of four strategies for the prevention of non-steroidal anti-inflammatory drugs (NSAIDs)-induced gastrointestinal (GI) toxicity: (1) Cox-1 NSAIDs plus histamine-2 receptor antagonist (H2RA), (2) Cox-1 NSAIDs plus proton pump inhibitors (PPIs), (3) Cox-1 NSAIDs plus misoprostol, and (4) Cox-2 NSAIDs (later expanded to 4a Cox-2 coxibNSAIDs and 4b Cox-2 preferential NSAIDs).
Electronic databases up to May 2002.
Relevant studies were selected, assessed and analysed. Pooled relative risk ratios (RR) from the systematic review were combined with up-to-date UK resource use and unit costs data in an incremental economic analysis. A probabilistic decision-analytic model was designed and populated with data to carry out incremental economic analysis. Incremental cost-effectiveness ratios (ICERs) were generated for the outcome measure, endoscopic ulcer or serious GI event averted, against total cost, and non-parametric bootstrapping was used to simulate variance of these ICERs.
Of 118 selected trials, including 125 relevant comparisons (which included 76,322 participants) only 138 deaths and 248 serious GI events were reported. Seven comparisons were judged to be at low risk of bias. Comparing the gastroprotective strategies against placebo, there was no evidence of effectiveness of H2RAs against any primary outcomes (few events reported), PPIs may reduce the risk of symptomatic ulcers [RR 0.09, 95% confidence interval (CI) 0.02 to 0.47], misoprostol reduces the risk of serious GI complications (RR 0.57, 95% CI 0.36 to 0.91) and symptomatic ulcers (RR 0.36, 95% CI 0.20 to 0.67), Cox-2 'preferentials' reduce the risk of symptomatic ulcers (RR 0.41, 95% CI 0.26 to 0.65) and Cox-2 'coxibs' reduce the risk of symptomatic ulcers (RR 0.49, 95% CI 0.38 to 0.62) and possibly serious GI events (RR 0.55, 95% CI 0.38 to 0.80). All strategies except Cox-2 'preferentials' reduce the risk of endoscopic ulcers. There were only 12 direct comparisons between gastroprotective strategies. All they suggest is that Cox-2 preferentials are better than misoprostol for preventing GI complications. Indirect comparisons suggested that PPIs may prevent symptomatic ulcers better than Cox-2 coxibs, but this is very weak evidence. For prevention of endoscopic ulcers PPIs and misoprostol appear more successful than H2RAs and misoprostol is better than Cox-2 preferentials. There were no UK head-to-head published economic analyses with regard to the main gastroprotective strategies. There were generally insufficient data with regards to cardiac or renal outcomes, serious GI outcomes or life-years gained to populate the mode. Mean (2.5th and 97.5th percentile) costs per endoscopic ulcer averted compared with Cox-1 NSAIDs alone were as follows: Cox-1 plus H2RAs, -186 pounds (-555 to 804); Cox-1 plus PPIs, 454 pounds (251 to 877); Cox-1 plus misoprostol, 54 pounds (-112 to 238); Cox-2 selective NSAIDs, 263 pounds (-570 to 1280), or Cox-2 specific NSAIDs, 301 pounds (189 to 418). With regard to the prevention of endoscopic ulcers, Cox-1 NSAID plus H2RA is a dominant option. Cost-effectiveness acceptability analysis showed a 95% probability that this combination was less costly and more effective. Cost-effectiveness acceptability frontiers showed that if the decision-maker is willing to pay up to 750 pounds to avoid an endoscopic ulcer, then Cox-1 plus H2RA is the optimal strategy. If the decision-maker is willing to pay over 750 pounds, the optimal strategy is NSAID plus misoprostol. Between 1900 pounds and 3750 pounds, Cox-2 selective inhibitors are optimal, and over 3750 pounds, Cox-2 specific inhibitors become optimal. NSAID plus PPI is never the optimal strategy. Sensitivity and subgroup analyses suggest that Cox-1 NSAID plus H2RA and Cox-1 NSAID plus misoprostol become more cost-effective in the older age group. Some conclusions were associated with high levels of uncertainty.
Although there is a very large body of evidence comparing Cox-2 NSAIDs with Cox-1 NSAIDs, this is not matched by studies of the other types of gastroprotectors or by studies directly comparing active gastroprotective strategies. This lack of direct comparisons led to the use of indirect comparisons to help understand the relative efficacy of these strategies. Indirect evidence in itself is weak and was also hampered by lack of evidence in the underlying studies (where the gastroprotectors were compared with placebo). Economic modelling suggests that Cox-1 NSAID plus H2RA or Cox-1 NSAID plus PPI are the most cost-effective strategies for avoiding endoscopic ulcers in patients requiring long-term NSAID therapy. All strategies other than Cox-2 selective inhibitors reduce the rate of endoscopic ulcer compared with Cox-1 alone. The economic analysis suggests that there may be a case for prescribing H2RAs in all patients requiring NSAIDs. Misoprostol is more effective, but is associated with a greater cost and GI side-effects which may be unacceptable for patients. However, when assessing serious GI events, the economic analysis is sufficiently weakened by the data available as to render clear practice recommendations impossible. Further large, independent RCTs directly comparing various gastroprotective strategies are needed. These should report items such as major outcomes, primary data, adverse events, assessment of practice and patient preference.
Treatment with non-steroidal anti-inflammatory drugs (NSAIDs) is hampered by gastrointestinal ulcer complications, such as ulcer bleeding and perforation. The efficacy of proton-pump inhibitors in the primary prevention of ulcer complications arising from the use of NSAIDs remains unproven. Selective cyclooxygenase-2 (COX-2) inhibitors reduce the risk for ulcer complications, but not completely in high-risk patients. This study determines which patients are especially at risk for NSAID ulcer complications and investigates the effectiveness of different preventive strategies in daily clinical practice. With the use of a nested case-control design, a large cohort of NSAID users was followed for 26 months. Cases were patients with NSAID ulcer complications necessitating hospitalisation; matched controls were selected from the remaining cohort of NSAID users who did not have NSAID ulcer complications. During the observational period, 104 incident cases were identified from a cohort of 51,903 NSAID users with 10,402 patient years of NSAID exposure (incidence 1% per year of NSAID use, age at diagnosis 70.4 +/- 16.7 years (mean +/- SD), 55.8% women), and 284 matched controls. Cases were characterised by serious, especially cardiovascular, co-morbidity. In-hospital mortality associated with NSAID ulcer complications was 10.6% (incidence 21.2 per 100,000 NSAID users). Concomitant proton-pump inhibitors (but not selective COX-2 inhibitors) were associated with a reduced risk for NSAID ulcer complications (the adjusted odds ratio 0.33; 95% confidence interval 0.17 to 0.67; p = 0.002). Especially at risk for NSAID ulcer complications are elderly patients with cardiovascular co-morbidity. Proton-pump inhibitors are associated with a reduced risk for NSAID ulcer complications.
The aims of this review are four-fold: To undertake a systematic review of the clinical effectiveness and cost-effectiveness of cyclooxygenase-2 (COX-2) selective nonsteroidal anti-inflammatory drugs (NSAIDs), including etodolac, meloxicam celecoxib, rofecoxib, etoricoxib, valdecoxib and lumiracoxib, for osteoarthritis (OA) and rheumatoid arthritis (RA). To assess the cost-effectivenessof COX-2 selective NSAIDs from an NHS perspective. To explore the potential impact of concomitant gastroprotective agents, with either COX-2 selective NSAIDs, or other non-selective NSAIDs, on the incidence of symptomatic gastrointestinal (GI) ulcers and complications such as bleeding, perforation or gastric outlet obstruction. To explore the impact of low-dose aspirin (<= 325 mg/ day) used in conjunction with COX- 2 selective NSAIDs on the incidence of cardiovascular ( CV) adverse events and symptomatic upper gastrointestinal (UGI) ulcers and their complications.
. Objective : To investigate whether concurrent administration of misoprostol reduces the occurrence of serious upper gastrointestinal complications, such as perforation, gastric outlet obstruction, or bleeding, in patients with rheumatoid arthritis who are receiving nonsteroidal anti-inflammatory drugs (NSAIDs). . Design : 6-month randomized, double-blind, placebo-controlled trial. . Setting : 664 clinical practices of family medicine, internal medicine, or rheumatology in the United States and Canada. . Patients : 8843 men and women (mean age, 68 years) receiving continuous therapy with any of 10 specified NSAIDs for control of symptoms of rheumatoid arthritis. Patients were enrolled between July 1991 and August 1993. . Intervention : Patients were randomly assigned to receive 200 μg of misoprostol or placebo four times a day. . Measurements : Development of serious upper gastrointestinal complications detected by clinical symptoms or findings (not by scheduled endoscopy). . Results : Serious upper gastrointestinal complications were reduced by 40% (odds ratio, 0.598 [95% Cl, 0.364 to 0.982 ; P = 0.0491) among patients receiving misoprostol (25 of 4404 patients) compared with those receiving placebo (42 of 4439 patients). During the first month, more patients receiving misoprostol (20%) than placebo (15%) withdrew from the study, primarily because of diarrhea and related problems (P I 0.001). Risk factors for serious upper gastrointestinal complications were increasing age, history of peptic ulcer or bleeding, and cardiovascular disease. Patients with all four risk factors would have a 9% risk for a major complication in 6 months. . Conclusions : In older patients with rheumatoid arthritis, misoprostol reduced serious NSAID-induced upper gastrointestinal complications by 40% compared with placebo.
To evaluate if esomeprazole prevents recurrent peptic ulcer in adult patients with a history of peptic ulcer receiving low-dose acetylsalicylic acid (ASA, aspirin) for cardiovascular protection in East Asia.
In this prospective, randomised, double-blind, placebo-controlled trial conducted in Japan, Korea and Taiwan, eligible patients receiving low-dose ASA for cardiovascular protection (81-324 mg/day) were randomised to esomeprazole 20 mg/day or placebo for ≤72 weeks. All patients received concomitant mucosal protection (gefarnate 100 mg/day). The primary endpoint was time to ulcer recurrence (Kaplan-Meier analysis). Efficacy findings are presented up to week 48, as per a planned interim analysis within the study protocol.
A total of 364 patients (79.9% men; mean age, 67.1 years) comprised the full analysis set (esomeprazole, n=182; placebo, n=182). There was a statistically significant difference in the time to ulcer recurrence between esomeprazole and placebo (HR 0.09; 96.65% CI 0.02 to 0.41; p<0.001). The estimated ulcer-free rate at week 12 was 99.3% (esomeprazole) and 89.0% (placebo). The high estimated ulcer-free rate for esomeprazole was maintained through to week 48 (98.3% vs 81.2% of placebo-treated patients). No factors, other than female gender, reduced time to ulcer recurrence in addition to the effect of esomeprazole (p<0.001). Treatment with esomeprazole was generally well tolerated.
Daily esomeprazole 20 mg is efficacious and well tolerated in reducing the recurrence of peptic ulcer in East-Asian patients with a history of ulcers who are taking low-dose ASA for cardiovascular protection.
NCT01069939.
Non-steroidal anti-inflammatory drugs (NSAIDs) are important agents in the management of arthritic and inflammatory conditions, and are among the most frequently prescribed medications in North America and Europe. However, there is overwhelming evidence linking these agents to a variety of gastrointestinal (GI) toxicities.
To review the effectiveness of common interventions for the prevention of NSAID induced upper GI toxicity.
A literature search was conducted, according to the Cochrane methodology for identification of randomized controlled trials in electronic databases, including MEDLINE from 1966 to January 2000, Current Contents for 6 months prior to January 2000, Embase to Febuary 1999, and a search of the Cochrane Controlled Trials Register from 1973 to 1999. Recent conference proceedings were reviewed and content experts and companies were contacted.
Randomized controlled clinical trials (RCTs) of prostaglandin analogues (PA), H2-receptor antagonists (H2RA) or proton pump inhibitors (PPI) for the prevention of chronic NSAID induced upper GI toxicity were included.
Two independent reviewers extracted data regarding population characteristics, study design, methodological quality and number of patients with endoscopic ulcers, ulcer complications, symptoms, overall drop-outs, drop outs due to symptoms. Dichotomous data was pooled using Revman V3.1. Heterogeneity was evaluated using a chi square test.
Thirty-three RCTs met the inclusion criteria. All doses of misoprostol significantly reduced the risk of endoscopic ulcers. Misoprostol 800 ug/day was superior to 400 ug/day for the prevention of endoscopic gastric ulcers (RR=0.18, and RR=0.38 respectively, p=0.0055). A dose response relationship was not seen with duodenal ulcers. Misoprostol caused diarrhea at all doses, although significantly more at 800ug/day than 400ug/day (p=0.0012). Misoprostol was the only prophylactic agent documented to reduce ulcer complications. Standard doses of H2RAs were effective at reducing the risk of endoscopic duodenal (RR=0.24; 95% CI: 0.10-0.57) but not gastric ulcers(RR=0.73; 95% CI:0.50-1.09). Both double dose H2RAs and PPIs were effective at reducing the risk of endoscopic duodenal and gastric ulcers (RR=0.44; 95% CI:0.26-0.74 and RR=0.37;95% CI;0.27-0.51 respectively for gastric ulcer), and were better tolerated than misoprostol.
Misoprostol, PPIs, and double dose H2RAs are effective at preventing chronic NSAID related endoscopic gastric and duodenal ulcers. Lower doses of misoprostol are less effective and are still associated with diarrhea. Only Misoprostol 800ug/day has been directly shown to reduce the risk of ulcer complications.
Despite the great realized or potential value of network meta-analysis of randomized controlled trial evidence to inform health care decision making, many decision makers might not be familiar with these techniques. The Task Force developed a consensus-based 26-item questionnaire to help decision makers assess the relevance and credibility of indirect treatment comparisons and network meta-analysis to help inform health care decision making. The relevance domain of the questionnaire (4 questions) calls for assessments about the applicability of network meta-analysis results to the setting of interest to the decision maker. The remaining 22 questions belong to an overall credibility domain and pertain to assessments about whether the network meta-analysis results provide a valid answer to the question they are designed to answer by examining 1) the used evidence base, 2) analysis methods, 3) reporting quality and transparency, 4) interpretation of findings, and 5) conflicts of interest. The questionnaire aims to help readers of network meta-analysis opine about their confidence in the credibility and applicability of the results of a network meta-analysis, and help make decision makers aware of the subtleties involved in the analysis of networks of randomized trial evidence. It is anticipated that user feedback will permit periodic evaluation and modification of the questionnaire.
The characteristic of a biomarker that makes it a useful surrogate is the ability to identify a high risk of clinically important benefits or harms occurring in the future. A number of definitions or descriptions of surrogate definition have been put forward. Most recently the Institute of Medicine of the National Academy of Sciences in the USA has put forward an evaluation scheme for biomarkers, looking at validation (assay performance), qualification (assessment of evidence), and utilisation (the context in which the surrogate is to be used). This paper examines the example of endoscopy as a surrogate marker of NSAID-induced mucosal damage using the Institute of Medicine criteria. The article finds extensive evidence that the detection of endoscopic ulcers is a valid marker. The process of qualification documents abundant evidence showing that endoscopic ulcers and serious upper gastrointestinal damage are influenced in the same direction and much the same magnitude by a variety of risk factors and interventions. Criticisms of validation and qualification for endoscopic ulcers have been examined, and dismissed. Context is the key, and in the context of serious NSAID-induced upper gastrointestinal harm, endoscopic ulcers represent a useful surrogate. Generalisability beyond this context is not considered.
Cyclo-oxygenase (COX)-2-selective non-steroidal anti-inflammatory drugs (NSAIDs) and non-selective NSAIDs plus a proton-pump inhibitor (PPI) have similar upper gastrointestinal outcomes, but risk of clinical outcomes across the entire gastrointestinal tract might be lower with selective drugs than with non-selective drugs. We aimed to compare risk of gastrointestinal events associated with celecoxib versus diclofenac slow release plus omeprazole.
We undertook a 6-month, double-blind, randomised trial in patients with osteoarthritis or rheumatoid arthritis at increased gastrointestinal risk at 196 centres in 32 countries or territories. Patients tested negative for Helicobacter pylori and were aged 60 years and older or 18 years and older with previous gastroduodenal ulceration. We used a computer-generated randomisation schedule to assign patients in a 1:1 ratio to receive celecoxib 200 mg twice a day or diclofenac slow release 75 mg twice a day plus omeprazole 20 mg once a day. Patients and investigators were masked to treatment allocation. The primary endpoint was a composite of clinically significant upper or lower gastrointestinal events adjudicated by an independent committee. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00141102.
4484 patients were randomly allocated to treatment (2238 celecoxib; 2246 diclofenac plus omeprazole) and were included in intention-to-treat analyses. 20 (0.9%) patients receiving celecoxib and 81 (3.8%) receiving diclofenac plus omeprazole met criteria for the primary endpoint (hazard ratio 4.3, 95% CI 2.6-7.0; p<0.0001). 114 (6%) patients taking celecoxib versus 167 (8%) taking diclofenac plus omeprazole withdrew early because of gastrointestinal adverse events (p=0.0006).
Risk of clinical outcomes throughout the gastrointestinal tract was lower in patients treated with a COX-2-selective NSAID than in those receiving a non-selective NSAID plus a PPI. These findings should encourage review of approaches to reduce risk of NSAID treatment.
Pfizer Inc.
To propose methods for mixed treatment comparisons (MTC) based on pooled summaries of the type produced in overviews of reviews.
Overviews of reviews (umbrella reviews) summarize the results of multiple systematic reviews into a single document. They report the summary estimates from the original pairwise meta-analyses and discuss them in narrative form, with the intention of identifying the most effective treatment. We present methods for MTC synthesis, tailored for use with overviews of reviews. These generate a single internally consistent summary of all the relative treatment effects and assessments of whether the summary is consistent with the data. These methods are applied to a published overview of treatments for childhood nocturnal enuresis. We apply the methods to both fixed-effect (FE) and random-effects (RE) meta-analyses of the original trials.
The summary relative risks based on FE meta-analyses, as originally published, were highly inconsistent. Those based on RE meta-analyses were consistent and could, given standard assumptions on comparability of treatment effects in meta-analysis, form a basis for coherent decision making.
Along with the summaries from systematic reviews, MTC methods should be used in overviews to provide a single coherent analysis of all treatment comparisons and to check for evidence consistency.
