Helicobacter pylori eradication for primary prevention of peptic ulcer bleeding in older patients prescribed aspirin in primary care (HEAT): a randomised, double-blind, placebo-controlled trial.

BACKGROUND: Peptic ulcers in patients receiving aspirin are associated with Helicobacter pylori infection. We aimed to investigate whether H pylori eradication would protect against aspirin-associated ulcer bleeding. METHODS: We conducted a randomised, double-blind, placebo-controlled trial (Helicobacter Eradication Aspirin Trial [HEAT]) at 1208 primary care centres in the UK, using routinely collected clinical data. Eligible patients were aged 60 years or older who were receiving aspirin at a daily dose of 325 mg or less (with four or more 28-day prescriptions in the past year) and had a positive C13 urea breath test for H pylori at screening. Patients receiving ulcerogenic or gastroprotective medication were excluded. Participants were randomly assigned (1:1) to receive either a combination of oral clarithromycin 500 mg, metronidazole 400 mg, and lansoprazole 30 mg (active eradication), or oral placebo (control), twice daily for 1 week. Participants, their general practitioners and health-care providers, and the research nurses, trial team, adjudication committee, and analysis team were all masked to group allocation throughout the trial. Follow-up was by scrutiny of electronic data in primary and secondary care. The primary outcome was time to hospitalisation or death due to definite or probable peptic ulcer bleeding, and was analysed by Cox proportional hazards methods in the intention-to-treat population. This trial is registered with EudraCT, 2011-003425-96. FINDINGS: Between Sept 14, 2012, and Nov 22, 2017, 30 166 patients had breath testing for H pylori, 5367 had a positive result, and 5352 were randomly assigned to receive active eradication (n=2677) or placebo (n=2675) and were followed up for a median of 5·0 years (IQR 3·9-6·4). Analysis of the primary outcome showed a significant departure from proportional hazards assumptions (p=0·0068), requiring analysis over separate time periods. There was a significant reduction in incidence of the primary outcome in the active eradication group in the first 2·5 years of follow-up compared with the control group (six episodes adjudicated as definite or probable peptic ulcer bleeds, rate 0·92 [95% CI 0·41-2·04] per 1000 person-years vs 17 episodes, rate 2·61 [1·62-4·19] per 1000 person-years; hazard ratio [HR] 0·35 [95% CI 0·14-0·89]; p=0·028). This advantage remained significant after adjusting for the competing risk of death (p=0·028) but was lost with longer follow-up (HR 1·31 [95% CI 0·55-3·11] in the period after the first 2·5 years; p=0·54). Reports of adverse events were actively solicited; taste disturbance was the most common event (787 patients). INTERPRETATION: H pylori eradication protects against aspirin-associated peptic ulcer bleeding, but this might not be sustained in the long term. FUNDING: National Institute for Health and Care Research Health Technology Assessment.

Autologous stem cell transplantation in refractory Crohn's disease - low intensity therapy evaluation (ASTIClite): study protocols for a multicentre, randomised controlled trial and observational follow up study.

BACKGROUND: Intestinal inflammation in Crohn's disease (CD) is caused by mucosal immune system reactivity to luminal antigen and results in debilitating symptoms, reduced quality of life, impaired work productivity and significant health care costs. Not all patients respond to conventional and biologic therapies, with chronic inflammation ensuing. Although surgical resection may be required, disease frequently returns and surgery may not be an option, or may be declined. Case reports suggest potential benefit after haematopoietic stem cell transplant (HSCT) for patients with refractory CD. The ASTIC trial asked whether HSCT could cure CD. Few patients achieved the primary endpoint of clinical remission for 3 months, off all medication with no evidence of active disease, and there were a high number of adverse events (AEs) and serious adverse events (SAEs), including one patient death. However, beneficial effects were observed in some aspects of disease activity. The ASTIClite trial will investigate these potential benefits and safety using a lower intensity regimen than ASTIC. METHODS: Ninety-nine participants will be recruited from secondary care IBD centres in the UK into a multicentre, randomised controlled trial (RCT, ASTIClite) and an observational follow-up, and randomised to autologous HSCT versus standard care (ratio 2:1). The primary endpoint is treatment success at week 48, defined as mucosal healing without surgery or death. Secondary endpoints relating to efficacy, safety and mechanistic analyses will be evaluated at week 8, 14, 24, 32, 40 and 48. Long-term safety of the low intensity HSCT regimen forms the primary endpoint for the EBMT follow-up study and will be assessed annually for 4-7 years. DISCUSSION: ASTIClite will compare HSCTlite with standard care with respect to safety, efficacy and quality of life, and capture outcomes allowing findings to be generalised to current clinical practice in the UK. It will also provide significant mechanistic insights into the immunological consequences of HSCTlite and its impact on treatment outcomes. The observational follow-up will provide information, which is currently unavailable for this population. TRIAL REGISTRATION: The ASTIClite RCT was registered on 31st October 2017 ( ISRCTN17160440 ) and the EBMT follow-up study on 19th January 2018 ( ISRCTN31981313 ).

Autologous Haematopoietic Stem Cell Transplantation for Crohn's Disease: A Retrospective Survey of Long-term Outcomes From the European Society for Blood and Marrow Transplantation.

BACKGROUND AND AIMS: Autologous haematopoietic stem cell transplantation [AHSCT] is a therapeutic option for patients with severe, treatment-refractory Crohn's disease [CD]. The evidence base for AHSCT for CD is limited, with one randomised trial [ASTIC] suggesting benefit. The aim of this study was to evaluate safety and efficacy for patients undergoing AHSCT for CD in Europe, outside the ASTIC trial. METHODS: We identified 99 patients in the European Society for Blood and Marrow Transplantation [EBMT] registry, who were eligible for inclusion. Transplant and clinical outcomes were obtained for 82 patients from 19 centres in seven countries. RESULTS: Median patient age was 30 years [range 20-65]. Patients had failed or been intolerant to a median of six lines of drug therapy; 61/82 [74%] had had surgery. Following AHSCT, 53/78 [68%] experienced complete remission or significant improvement in symptoms at a median follow-up of 41 months [range 6-174]; 22/82 [27%] required no medical therapy at any point post-AHSCT. In patients who had re-started medical therapy at latest follow-up, 57% [24/42] achieved remission or significant symptomatic improvement with therapies to which they had previously lost response or been non-responsive. Treatment-free survival at 1 year was 54%. On multivariate analysis, perianal disease was associated with adverse treatment-free survival (hazard ratio 2.34, 95% confidence interval [CI] 1.14-4.83, p = 0.02). One patient died due to infectious complications [cytomegalovirus disease] at Day +56. CONCLUSIONS: In this multicentre retrospective analysis of European centres, AHSCT was relatively safe and appeared to be effective in controlling otherwise treatment-resistant Crohn's disease. Further prospective randomised controlled trials against standard of care are warranted.

Aspirin: 120 years of innovation. A report from the 2017 Scientific Conference of the International Aspirin Foundation, 14 September 2017, Charité, Berlin.

Acetylsalicylic acid was first synthesised by Dr FeIix Hoffman on 10th August 1897 and Aspirin was born. It quickly became the best-known pain killer in the world and in the 120 years since this event, aspirin has continued to attract interest, innovation and excitement. Set within the walls of the preserved ruins of Rudolf Virchow's lecture hall at Charité, within Berlin's Museum of Medical History, the International Aspirin Foundation's 28th Scientific Conference served to facilitate international, multi-disease, multidisciplinary discussion about the current understanding of aspirin's mechanisms of action and its utility in modern medicine as well as ideas for future research into its multifaceted applications to enhance global health. In addition to the delegates in Berlin, 300 medical doctors at the 19th Annual Scientific Congress of the Chinese Society of Cardiology were able to join the cardiology sessions from Taiyuan, Shangxi province via a live streaming link to and from China. This led to useful discussion and allowed a truly international perspective to the meeting.

Autologous Haematopoietic Stem Cell Transplantation (AHSCT) in Severe Crohn's Disease: A Review on Behalf of ECCO and EBMT.

Despite the major recent progress in the treatment of Crohn's disease [CD], there is a subset of patients in whom the disease runs an aggressive course with progressive tissue damage requiring early and repeated surgical management. Increasing evidence supports sustained and profound improvement in gastrointestinal parameters and quality of life following high-dose immunosuppressive therapy and autologous haematopoietic stem cell transplantation [AHSCT] compared to standard therapy in this context. In addition, international transplant registry data reflect the use of AHSCT in CD outside of trials in selected patients. However, AHSCT may be associated with significant treatment-related complications with risk of transplant-related mortality. In a joint initiative, the European Crohn's and Colitis Organisation [ECCO] and the European Society for Blood and Marrow Transplantation [EBMT] have produced a state-of-the-art review of the rationale, evaluation, patient selection, stem cell mobilization and transplant procedures and long-term follow up. Given the unique spectrum of issues, we recommend that AHSCT should only be performed in experienced centres with expertise in both haematological and gastroenterological aspects of the procedure. Where possible, patients should be enrolled on clinical trials and data registered centrally. Future development should be coordinated at both national and international levels.

Research priority setting in Barrett's oesophagus and gastro-oesophageal reflux disease.

The incidence of gastro-oesophageal reflux disease and Barrett's oesophagus is increasing. Barrett's oesophagus is the main precursor to oesophageal adenocarcinoma, which has a poor prognosis. In view of the vast potential burden of these diseases on patients and health-care resources, there is a real need to define and focus research efforts. This priority setting exercise aimed to produce a list of the top ten uncertainties in the field that reflect the priorities of patients and health-care providers. We adopted the robust and transparent methodologies previously outlined by the James Lind Alliance. This qualitative approach firstly involves an ideas gathering survey that, once distilled, generates a longlist of research uncertainties. These uncertainties are then prioritised via an interim ranking survey and a final workshop to achieve consensus agreement. The initial 629 uncertainties, generated from a survey of 170 individual respondents (47% professional, 53% non-professional) and one workshop, were narrowed down to the final top ten uncertainties of priority for future research. These priorities covered a range of issues, including a need for improved patient risk stratification, alternative diagnostic and surveillance tests, efficacy of a dedicated service for Barrett's oesophagus, cost-effectiveness and appropriateness of current surveillance, advances in development of non-drug treatments for gastro-oesophageal reflux disease, safety of long-term drug treatment, and questions regarding the durability and role of different endoscopic therapies for dysplastic Barrett's oesophagus. This is the first patient-centred assessment of priorities for researchers in this chronic disease setting. We hope that recognition and dissemination of these results will shape the future direction of research and translate into meaningful gains for patients.

Exploring the genetic architecture of inflammatory bowel disease by whole-genome sequencing identifies association at ADCY7.

To further resolve the genetic architecture of the inflammatory bowel diseases ulcerative colitis and Crohn's disease, we sequenced the whole genomes of 4,280 patients at low coverage and compared them to 3,652 previously sequenced population controls across 73.5 million variants. We then imputed from these sequences into new and existing genome-wide association study cohorts and tested for association at ∼12 million variants in a total of 16,432 cases and 18,843 controls. We discovered a 0.6% frequency missense variant in ADCY7 that doubles the risk of ulcerative colitis. Despite good statistical power, we did not identify any other new low-frequency risk variants and found that such variants explained little heritability. We detected a burden of very rare, damaging missense variants in known Crohn's disease risk genes, suggesting that more comprehensive sequencing studies will continue to improve understanding of the biology of complex diseases.

Genome-wide association study implicates immune activation of multiple integrin genes in inflammatory bowel disease.

Genetic association studies have identified 215 risk loci for inflammatory bowel disease, thereby uncovering fundamental aspects of its molecular biology. We performed a genome-wide association study of 25,305 individuals and conducted a meta-analysis with published summary statistics, yielding a total sample size of 59,957 subjects. We identified 25 new susceptibility loci, 3 of which contain integrin genes that encode proteins in pathways that have been identified as important therapeutic targets in inflammatory bowel disease. The associated variants are correlated with expression changes in response to immune stimulus at two of these genes (ITGA4 and ITGB8) and at previously implicated loci (ITGAL and ICAM1). In all four cases, the expression-increasing allele also increases disease risk. We also identified likely causal missense variants in a gene implicated in primary immune deficiency, PLCG2, and a negative regulator of inflammation, SLAMF8. Our results demonstrate that new associations at common variants continue to identify genes relevant to therapeutic target identification and prioritization.

Randomized trial of switching from prescribed non-selective non-steroidal anti-inflammatory drugs to prescribed celecoxib: the Standard care vs. Celecoxib Outcome Trial (SCOT).

BACKGROUND: Selective cyclooxygenase-2 inhibitors and conventional non-selective non-steroidal anti-inflammatory drugs (nsNSAIDs) have been associated with adverse cardiovascular (CV) effects. We compared the CV safety of switching to celecoxib vs. continuing nsNSAID therapy in a European setting. METHOD: Patients aged 60 years and over with osteoarthritis or rheumatoid arthritis, free from established CV disease and taking chronic prescribed nsNSAIDs, were randomized to switch to celecoxib or to continue their previous nsNSAID. The primary endpoint was hospitalization for non-fatal myocardial infarction or other biomarker positive acute coronary syndrome, non-fatal stroke or CV death analysed using a Cox model with a pre-specified non-inferiority limit of 1.4 for the hazard ratio (HR). RESULTS: In total, 7297 participants were randomized. During a median 3-year follow-up, fewer subjects than expected developed an on-treatment (OT) primary CV event and the rate was similar for celecoxib, 0.95 per 100 patient-years, and nsNSAIDs, 0.86 per 100 patient-years (HR = 1.12, 95% confidence interval, 0.81-1.55; P = 0.50). Comparable intention-to-treat (ITT) rates were 1.14 per 100 patient-years with celecoxib and 1.10 per 100 patient-years with nsNSAIDs (HR = 1.04; 95% confidence interval, 0.81-1.33; P = 0.75). Pre-specified non-inferiority was achieved in the ITT analysis. The upper bound of the 95% confidence limit for the absolute increase in OT risk associated with celecoxib treatment was two primary events per 1000 patient-years exposure. There were only 15 adjudicated secondary upper gastrointestinal complication endpoints (0.078/100 patient-years on celecoxib vs. 0.053 on nsNSAIDs OT, 0.078 vs. 0.053 ITT). More gastrointestinal serious adverse reactions and haematological adverse reactions were reported on nsNSAIDs than celecoxib, but more patients withdrew from celecoxib than nsNSAIDs (50.9% patients vs. 30.2%; P < 0.0001). INTERPRETATION: In subjects 60 years and over, free from CV disease and taking prescribed chronic nsNSAIDs, CV events were infrequent and similar on celecoxib and nsNSAIDs. There was no advantage of a strategy of switching prescribed nsNSAIDs to prescribed celecoxib. This study excluded an increased risk of the primary endpoint of more than two events per 1000 patient-years associated with switching to prescribed celecoxib. CLINICAL TRIAL REGISTRATION: https://clinicaltrials.gov/show/NCT00447759; Unique identifier: NCT00447759.

Multicentre, prospective, randomised, open-label, blinded end point trial of the efficacy of allopurinol therapy in improving cardiovascular outcomes in patients with ischaemic heart disease: protocol of the ALL-HEART study.

INTRODUCTION: Ischaemic heart disease (IHD) is one of the most common causes of death in the UK and treatment of patients with IHD costs the National Health System (NHS) billions of pounds each year. Allopurinol is a xanthine oxidase inhibitor used to prevent gout that also has several positive effects on the cardiovascular system. The ALL-HEART study aims to determine whether allopurinol improves cardiovascular outcomes in patients with IHD. METHODS AND ANALYSIS: The ALL-HEART study is a multicentre, controlled, prospective, randomised, open-label blinded end point (PROBE) trial of allopurinol (up to 600 mg daily) versus no treatment in a 1:1 ratio, added to usual care, in 5215 patients aged 60 years and over with IHD. Patients are followed up by electronic record linkage and annual questionnaires for an average of 4 years. The primary outcome is the composite of non-fatal myocardial infarction, non-fatal stroke or cardiovascular death. Secondary outcomes include all-cause mortality, quality of life and cost-effectiveness of allopurinol. The study will end when 631 adjudicated primary outcomes have occurred. The study is powered at 80% to detect a 20% reduction in the primary end point for the intervention. Patient recruitment to the ALL-HEART study started in February 2014. ETHICS AND DISSEMINATION: The study received ethical approval from the East of Scotland Research Ethics Service (EoSRES) REC 2 (13/ES/0104). The study is event-driven and results are expected after 2019. Results will be reported in peer-reviewed journals and at scientific meetings. Results will also be disseminated to guideline committees, NHS organisations and patient groups. TRIAL REGISTRATION NUMBER: 32017426, pre-results.

Mercaptopurine versus placebo to prevent recurrence of Crohn's disease after surgical resection (TOPPIC): a multicentre, double-blind, randomised controlled trial.

BACKGROUND: Up to 60% of patients with Crohn's disease need intestinal resection within the first 10 years of diagnosis, and postoperative recurrence is common. We investigated whether mercaptopurine can prevent or delay postoperative clinical recurrence of Crohn's disease. METHODS: We did a randomised, placebo-controlled, double-blind trial at 29 UK secondary and tertiary hospitals of patients (aged >16 years in Scotland or >18 years in England and Wales) who had a confirmed diagnosis of Crohn's disease and had undergone intestinal resection. Patients were randomly assigned (1:1) by a computer-generated web-based randomisation system to oral daily mercaptopurine at a dose of 1 mg/kg bodyweight rounded to the nearest 25 mg or placebo; patients with low thiopurine methyltransferase activity received half the normal dose. Patients and their carers and physicians were masked to the treatment allocation. Patients were followed up for 3 years. The primary endpoint was clinical recurrence of Crohn's disease (Crohn's Disease Activity Index >150 plus 100-point increase in score) and the need for anti-inflammatory rescue treatment or primary surgical intervention. Primary and safety analyses were by intention to treat. Subgroup analyses by smoking status, previous thiopurines, previous infliximab or methotrexate, previous surgery, duration of disease, or age at diagnosis were also done. This trial is registered with the International Standard Randomised Controlled Trial Register (ISRCTN89489788) and the European Clinical Trials Database (EudraCT number 2006-005800-15). FINDINGS: Between June 6, 2008, and April 23, 2012, 240 patients with Crohn's disease were randomly assigned: 128 to mercaptopurine and 112 to placebo. All patients received at least one dose of study drug, and no randomly assigned patients were excluded from the analysis. 16 (13%) of patients in the mercaptopurine group versus 26 (23%) patients in the placebo group had a clinical recurrence of Crohn's disease and needed anti-inflammatory rescue treatment or primary surgical intervention (adjusted hazard ratio [HR] 0·54, 95% CI 0·27-1·06; p=0·07; unadjusted HR 0·53, 95% CI 0·28-0·99; p=0·046). In a subgroup analysis, three (10%) of 29 smokers in the mercaptopurine group and 12 (46%) of 26 in the placebo group had a clinical recurrence that needed treatment (HR 0·13, 95% CI 0·04-0·46), compared with 13 (13%) of 99 non-smokers in the mercaptopurine group and 14 (16%) of 86 in the placebo group (0·90, 0·42-1·94; pinteraction=0·018). The effect of mercaptopurine did not significantly differ from placebo for any of the other planned subgroup analyses (previous thiopurines, previous infliximab or methotrexate, previous surgery, duration of disease, or age at diagnosis). The incidence and types of adverse events were similar in the mercaptopurine and placebo groups. One patient on placebo died of ischaemic heart disease. Adverse events caused discontinuation of treatment in 39 (30%) of 128 patients in the mercaptopurine group versus 41 (37%) of 112 in the placebo group. INTERPRETATION: Mercaptopurine is effective in preventing postoperative clinical recurrence of Crohn's disease, but only in patients who are smokers. Thus, in smokers, thiopurine treatment seems to be justified in the postoperative period, although smoking cessation should be strongly encouraged given that smoking increases the risk of recurrence. FUNDING: Medical Research Council.

Clinical Features and HLA Association of 5-Aminosalicylate (5-ASA)-induced Nephrotoxicity in Inflammatory Bowel Disease.

BACKGROUND AND AIMS: Nephrotoxicity is a rare idiosyncratic reaction to 5-aminosalicylate (5-ASA) therapies. The aims of this study were to describe the clinical features of this complication and identify clinically useful genetic markers so that these drugs can be avoided or so that monitoring can be intensified in high-risk patients. METHODS: Inflammatory bowel disease patients were recruited from 89 sites around the world. Inclusion criteria included normal renal function prior to commencing 5-ASA, ≥50% rise in creatinine any time after starting 5-ASA, and physician opinion implicating 5-ASA strong enough to justify drug withdrawal. An adjudication panel identified definite and probable cases from structured case report forms. A genome-wide association study was then undertaken with these cases and 4109 disease controls. RESULTS: After adjudication, 151 cases of 5-ASA-induced nephrotoxicity were identified. Sixty-eight percent of cases were males, with nephrotoxicity occurring at a median age of 39.4 years (range 6-79 years). The median time for development of renal injury after commencing 5-ASA was 3.0 years (95% confidence interval [CI] 2.3-3.7). Only 30% of cases recovered completely after drug withdrawal, with 15 patients requiring permanent renal replacement therapy. A genome-wide association study identified a suggestive association in the HLA region (p = 1×10(-7)) with 5-ASA-induced nephrotoxicity. A sub-group analysis of patients who had a renal biopsy demonstrating interstitial nephritis (n = 55) significantly strengthened this association (p = 4×10(-9), odds ratio 3.1). CONCLUSIONS: This is the largest and most detailed study of 5-ASA-induced nephrotoxicity to date. It highlights the morbidity associated with this condition and identifies for the first time a significant genetic predisposition to drug-induced renal injury.

The Helicobacter Eradication Aspirin Trial (HEAT): A Large Simple Randomised Controlled Trial Using Novel Methodology in Primary Care.

BACKGROUND: Clinical trials measuring the effect of an intervention on clinical outcomes are more influential than those investigating surrogate measures but are costly. We developed methods to reduce costs substantially by using existing data in primary care systems, to ask whether Helicobacter pylori eradication would reduce the incidence of hospitalisation for ulcer bleeding in aspirin users. METHODS: The Helicobacter Eradication Aspirin Trial (HEAT) is a National Institute of Health Research-funded, double-blind placebo controlled randomised trial of the effects of H. pylori eradication on subsequent ulcer bleeding in infected individuals taking aspirin daily, conducted in practices across the whole of England, Wales and Northern Ireland. A bespoke web-based trial management system developed for the trial (and housed within the secure NHS Data Network) communicates directly with the HEAT Toolkit software downloaded at participating practices, which issues queries searching entry criteria (≥ 60 years, on chronic aspirin ≤ 325 mg daily, not on anti-ulcer therapy or non-steroidal anti-inflammatory drugs) for GP review of eligibility. Trial participation is invited using a highly secure automated online mail management system. Interested patients are seen once for consent and breath testing. Those with a positive test are randomised to eradication treatment (lansoprazole, clarithromycin, metronidazole) or placebo, with drug sent by post. Events are tracked by upload of accumulating information in the GP database, patient contact, review of National Hospital Episode Statistics and Office of National Statistics data. RESULTS: HEAT is the largest Clinical Research Network-supported drug trial, with 115,660 invitation letters sent from 850 practices, 22,922 volunteers, and 3038 H. pylori positive patients randomised to active or placebo treatment after 2.5 years of recruitment. 178 practices have performed their first follow-up data search to identify 21 potential endpoints to date. DISCUSSION: HEAT is important medically, because aspirin is so widely used, and methodologically, as a successful trial would show that large-scale studies of important clinical outcomes can be conducted at a fraction of the cost of those conducted by industry, which in turn will help to ensure that trials of primarily medical rather than commercial interest can be conducted successfully in the UK.

A randomised controlled trial of ibuprofen, paracetamol or a combination tablet of ibuprofen/paracetamol in community-derived people with knee pain.

OBJECTIVES: To compare the efficacy and safety of single versus combination non-prescription oral analgesics in community-derived people aged 40 years and older with chronic knee pain. METHODS: A randomised, double-blind, four-arm, parallel-group, active controlled trial investigating short-term (day 10) and long-term (week 13) benefits and side-effects of four regimens, each taken three times a day: ibuprofen (400 mg); paracetamol (1000 mg); one fixed-dose combination tablet (ibuprofen 200 mg/paracetamol 500 mg); two fixed-dose combination tablets (ibuprofen 400 mg/paracetamol 1000 mg). RESULTS: There were 892 participants (mean age 60.6, range 40-84 years); 63% had radiographic knee osteoarthritis and 85% fulfilled American College of Rheumatology criteria for osteoarthritis. At day 10, two combination tablets were superior to paracetamol (p<0.01) for pain relief (determined by mean change from baseline in WOMAC pain; n=786). At 13 weeks, significantly more participants taking one or two combination tablets rated their treatment as excellent/good compared with paracetamol (p=0.015, p=0.0002, respectively; n=615). The frequency of adverse events was comparable between groups. However, by 13 weeks, decreases in haemoglobin (≥1 g/dl) were observed in some participants in all groups. Twice as many participants taking two combination tablets had this decrease compared with those on monotherapy (p<0.001; paracetamol, 20.3%; ibuprofen, 19.6%; one or two combination tablets, 24.1%, 38.4%, respectively). CONCLUSIONS: Ibuprofen/paracetamol combination analgesia, at non-prescription doses, confers modest short-term benefits for knee pain/osteoarthritis. However, in this population, paracetamol 3 g/day may cause similar degrees of blood loss as ibuprofen 1200 mg/day, and the combination of the two appears to be additive. Study no ISRCTN77199439.

The appropriate use of non-steroidal anti-inflammatory drugs in rheumatic disease: opinions of a multidisciplinary European expert panel.

INTRODUCTION: Given the safety issues of non-steroidal anti-inflammatory drugs (NSAID) and the robustness of guidelines, making treatment choices in daily clinical practice is increasingly difficult. This study aimed systematically to analyse the opinions of a multidisciplinary European expert panel on the appropriateness of different NSAID, with or without the use of a proton pump inhibitor (PPI), in individual patients with chronic rheumatic disease. METHODS: /Using the Research and Development/University of California at Los Angeles appropriateness method, the appropriateness of five (non-)selective NSAID with or without a PPI was assessed for 144 hypothetical patient profiles, ie, unique combinations of cardiovascular and gastrointestinal risk factors. Appropriateness statements were calculated for all indications. RESULTS: All options without PPI were considered appropriate in patients with no gastrointestinal/cardiovascular risk factors. Cyclooxygenase-2 selective inhibitors (C2SI) alone and non-selective NSAID plus PPI were preferred for patients with elevated gastrointestinal risk and low cardiovascular risk. Naproxen plus PPI was favoured in patients with high cardiovascular risk. For the combination of high gastrointestinal/high cardiovascular risk the use of any NSAID was discouraged; if needed, naproxen plus PPI or a C2SI plus PPI could be considered. DISCUSSION: The panel results may support treatment considerations at the level of individual patients, according to their gastrointestinal/cardiovascular risk profile.