Websites Of Regulatory Agencies Research Articles

Interventions for adult Eustachian tube dysfunction: a systematic review.

Eustachian tube dysfunction (ETD) is the inability of the Eustachian tube (ET) to adequately perform at least one of its functions: to protect the middle ear from sources of disease, to ventilate the middle ear, and to help drain secretions away from the middle ear. There are a number of treatment options for ETD, but there is little consensus about management. To determine the clinical effectiveness of interventions for adult ETD and to identify gaps in the evidence to inform future research. Twelve databases were searched up to October 2012 for published and unpublished studies in English (e.g. MEDLINE from 1946, EMBASE from 1974, Biosis Previews from 1969 and Cumulative Index to Nursing and Allied Health Literature from inception). References of included studies, relevant systematic reviews and regulatory agency websites were checked. A systematic review was undertaken. Controlled studies evaluating prespecified treatments for adult patients diagnosed with ETD were eligible. Uncontrolled studies with at least 10 participants were included for interventions where no controlled studies were found. Outcomes included change in symptoms severity/frequency (primary outcome), quality of life, middle ear function, hearing, clearance of middle ear effusion, early ventilation tube extrusion, additional treatment, adverse events and complications. All aspects of the review process were performed using methods to reduce reviewer error and bias. Owing to heterogeneous data, a quantitative synthesis could not be performed, and results were reported in a narrative synthesis. Nineteen studies were included: three randomised controlled trials (RCTs) and two non-RCTs evaluating pharmacological interventions or mechanical devices for middle ear pressure equalisation; and 13 case series and one retrospective controlled before-and-after study evaluating surgical interventions. None was conducted in the UK. All studies were small (11 to 108 participants). Most non-surgical studies reported including mixed populations of adults and children. All except two studies were at high risk of bias, and subject to multiple limitations. Based on a single RCT, nasal steroids showed no improvement in symptoms or middle ear function for patients with otitis media with effusion and/or negative middle ear pressure. Very short-term improvements in middle ear function were observed in patients receiving directly applied topical decongestants or a combination of antihistamine and ephedrine. Single trials found two pressure equalisation devices were each associated with significant short-term improvements in symptoms, middle ear function and/or hearing. Eustachian tuboplasty (seven case series) and balloon dilatation (three case series) were associated with improved outcomes. Positive results were also reported for myringotomy (two case series), directly applied topical steroids (one case series) and laser point coagulation (one controlled before-and-after study). High rates of co-interventions were documented. Minor complications of surgery and pharmacological treatments but no serious adverse effects were reported. The evidence was limited in quantity and overall was of poor quality. No data were identified on several interventions despite extensive searches. It is not possible to draw conclusions regarding the effectiveness of any of the interventions for the treatment of adults with an ETD diagnosis, and there is insufficient evidence to recommend a trial of any particular intervention. Further research is needed to address lack of consensus on several issues, including the definition of ETD in adults, its relation to broader middle ear ventilation problems and clear diagnostic criteria. This study is registered as PROSPERO CRD42012003035. The National Institute for Health Research Health Technology Assessment programme.

Measuring Progress in Neglected Disease Drug Development

BackgroundSince the late 1990s, funding for development of neglected disease drugs has increased with an influx of resources from product development partnerships (PDPs). Previous research showed modest gains in drug approvals and products in Phase III of clinical development in the period 2000–2008. ObjectiveWe assessed the 2009–2013 period in terms of numbers of products in Phase III development and numbers of approvals. Subsequently, we calculated the PDP share in terms of sponsorship of new approvals. We also identified the numbers of 2000–2013 approvals included in the World Health Organization’s Essential Drug List (EDL). MethodsWe identified new approvals and Phase III products targeting neglected diseases in the period 2009–2013 by searching ClinicalTrials.gov, IMS R&D Focus, and Investigational Drugs Database, as well as drug regulatory agency websites. Subsequently, we determined which products approved between 2000 and 2013 have been included in the most recent version of the EDL. ResultsWe found 20 new approvals targeting neglected diseases in the period 2009–2013. PDPs were the primary sponsor of 57% of new approvals in this time frame. Approvals included 1 new molecular entity, 5 vaccines, 2 new indications, 9 fixed-dose combinations, and 3 new formulations. HIV/AIDS (pediatric indications) and malaria accounted for 60% of approvals in 2009–2013. The average number of new approvals per year for neglected diseases rose from 2.6 in 2000–2008 to 4.9 in 2009–2013. The World Health Organization included 44% of 2000–2013 approved products on the EDL. We found 18 products currently in Phase III of clinical development. Products in Phase III testing included 3 new molecular entities, 6 vaccines, 2 fixed-dose combinations, 5 new indications, and 2 new formulations. ConclusionsIncreased funding through PDPs for neglected disease drug development seems to be producing results. Approvals and products in Phase III testing have shown a steady increase since 2000, with nearly a doubling of products in 2009–2013, compared with 2000–2008, in terms of the annual average yield. However, only 3 new molecular entities have been approved in 14 years. In addition, malaria and HIV (pediatric indications) seem to have benefited most from increased funding, whereas less success has occurred with other diseases. Inclusion of newly approved products on the EDL has been slow and limited, with only 44% of new approvals added to the list. Uneven progress suggests funding could be better targeted. In addition, PDPs could do more to facilitate access, in particular by working closely with the World Health Organization to assess the clinical effectiveness and cost-effectiveness of new approvals.

Systematic review and network meta-analysis comparing antithrombotic agents for the prevention of stroke and major bleeding in patients with atrial fibrillation

ObjectiveTo examine the comparative efficacy and safety of antithrombotic treatments (apixaban, dabigatran, edoxaban, rivaroxaban and vitamin K antagonists (VKA) at a standard adjusted dose (target international normalised ratio 2.0–3.0), acetylsalicylic...

HOW HEALTH TECHNOLOGY ASSESSMENT AGENCIES ADDRESS THE ISSUE OF UNPUBLISHED DATA

Reporting bias potentially threatens the validity of results in health technology assessment (HTA) reports. Our study aimed to explore policies and practices of HTA agencies regarding strategies to include previously unpublished data in their assessments, focusing on requests to industry for unpublished data. We included international HTA agencies with publicly available methods papers as well as HTA reports. From the methods papers and recent reports we extracted information on requests to industry and on searches in trial registries, regulatory authority Web sites and for conference abstracts. Eighteen HTA agencies and seventy-three reports were included. Agencies' methods papers showed variability regarding requests to industry (requests are routinely carried out in seven cases, not mentioned in six, at the discretion of HTA authors in three, and based on manufacturer applications in two), which were reflected in the reports investigated. As reporting of requests was limited, it often remained unclear whether unpublished data had been received. Searches in trial registries, at regulatory authorities or for conference abstracts are described as a routine or optional part of the search strategy in the methods papers of 9, 11, and 8 included agencies, respectively. A total of 52 percent, 39 percent, and 16 percent of reports described searches in trial registries, at regulatory agencies, and hand searching of conference proceedings. International HTA agencies currently differ considerably in their efforts to address the issue of unpublished data. Requests to industry may constitute one strategy to access and include unpublished data, while agencies can learn from each other concerning successful practice.

Dabigatran, Rivaroxaban, or Apixaban versus Warfarin in Patients with Nonvalvular Atrial Fibrillation: A Systematic Review and Meta-Analysis of Subgroups

Background. New oral anticoagulants (NOAC; rivaroxaban, dabigatran, apixaban) have become available as an alternative to warfarin anticoagulation in non-valvular atrial fibrillation (NVAF). Methods. MEDLINE and CENTRAL, regulatory agencies websites, clinical trials registers and conference proceedings were searched to identify randomised controlled trials of NOAC versus warfarin in NVAF. Two investigators reviewed all studies and extracted data on patient and study characteristics along with cardiovascular outcomes. Relative risks (RR) and 95% confidence intervals (CI) were estimated using a random effect meta-analysis. Results. Three clinical trials in 50,578 patients were included. The risk of non-hemorrhagic stroke and systemic embolic events (SEE) was similar with the NOAC and warfarin (RR = 0.93; 95% CI = 0.83–1.04), while the risk of intracranial bleeding (ICB) with the NOAC was lower than with warfarin (RR = 0.46; 95% CI = 0.33–0.65). We found differences in the effect size on all strokes and SEE depending on geographic region as well as on non-hemorrhagic stroke, SEE, bleeding and mortality depending on time in therapeutic range. Conclusion. The NOAC seem no more effective than warfarin for prevention of nonhemorrhagic stroke and SEE in the overall NVAF population, but are generally associated with a lower risk of ICB than warfarin.

Les médicaments de la vessie

To describe drugs targeting urinary bladder to treat bladder dysfunctions such as OAB, NDO and bladder pain syndrome. Pubmed search for efficacy, mode of action and side effects for each molecule. Additional data were searched from the French regulatory agencies web sites (HAS and ANSM). Anticholinergics antimuscarinics remain the first-line treatment option for both OAB and NDO. Beta-3 adrenergics emerges as a new therapeutic class for OAB. Post approval safety as well as association with other micturition cycle's drugs need to be evaluated. Phosphodiesterase 5 inhibitors are effective to treat BPH-related LUTS including storage symptoms. Botulinum toxin type A injections within the detrusor are effective and approved to treat NDO in MS and spinal cord injured patients voiding with clean intermittent catheterization. Evaluation of such approach to treat OAB is ongoing. Drug therapy for bladder pain syndrome has limited efficacy including pentosan polyphosphate despite it has a temporary autorisation. There is no drug treatment to restore or improve bladder contraction. Armamenterium to treat bladder dysfunction has recently increased. Three new therapeutic classes emerged. Careful post approval evaluation is mandatory and study of these drugs' combination is expected. Results should drive changes in bladder dysfunction treatment algorithms.

Les médicaments du cancer de vessie

To describe drugs used in bladder carcinoma.Pubmed search for efficacy, mode of action and side effects for each molecule. Additional data were searched from the French regulatory agencies web sites (HAS and ANSM).The drugs used in the treatment of bladder cancer are represented by the products referred to diagnosis (hexyl aminolevulinate), the intravesical instillations for the treatment of tumors not infiltrating the muscle and the infiltrating tumor chemotherapy (neo-adjuvant treatment or metastatic tumors). The hexyl aminolevulinate cystoscopy allows to identify a significantly greater number of lesions, including carcinoma in situ, compared to conventional white light cystoscopy. For intravesical instillations, BCG has a superior efficacy to mitomycin C with a lower tolerance. The chemotherapies for invasive tumors are effective in metastatic disease in 15-20% of cases with a mean survival of 12 to 14 months.Except the use of hexyl aminolevulinate for improving the diagnosis, there was no emergence in recent years of new drugs for the treatment of bladder cancer. Targeted therapies currently available for many neoplasms were ineffective for bladder cancer.

Les médicaments de l’urètre

To describe drugs targeting urethra and prostate to treat dysfunctions such LUTS related to BPH, primary bladder neck obstruction (PBNO), detrusor sphincter dyssynergia (DSD) or sphincter deficiency (SD). Pubmed search for efficacy, mode of action and side effects for each molecule. Additional data were searched from the French regulatory agencies web sites (HAS and ANSM). To treat LUTS related to BPH alpha-blockers (AB) and 5-alpha reductase inhibitors (5ARIs) have a clearer efficacy than plant extract. Daily Phosphodiesterase 5 inhibitors (PDE5Is) alone or in association with AB also demonstrate efficacy in this indication. AB are an option in PBNO and DSD related to multiple sclerosis. Although Botulinum toxin A derived molecules decrease urethral pressure in patient with DSD related to spinal cord injury or multiple sclerosis, efficiency remains to be demonstrated. Duloxetine a serotonin reuptake inhibitor increases urethral sphincter pressure and reduce stress urinary incontinence in women and men. Nevertheless, moderate efficacy combine with frequent side effects lead French regulation agency to reject its agreement. Armamenterium to treat urethral dysfunctions has recently increases. Two new therapeutic classes emerge: PDE5Is to treat LUTS related to BPH and an SRIs (Duloxetine) to treat stress urinary incontinence. Efficacy and safety evaluation of all the possible associations between drugs targeting urethra and/or bladder is needed to a subtler and more efficient pharmacologic modulation of lower urinary tract dysfunction.

Les médicaments du cancer du rein

To describe drugs used in renal cell carcinoma. Pubmed search for efficacy, mode of action and side effects for each molecule. Additional data were searched from the French regulatory agencies websites (HAS and ANSM). Since 2007, a total of three different therapeutic classes in the management of metastatic renal cell carcinoma are available. These three classes are tyrosine kinase inhibitors with sunitinib and sorafenib, the anti-VEGF antibodies (bevacizumab which is associated with alpha interferon in the treatment of advanced kidney cancer) and mTOR inhibitors with temsirolimus and everolimus. These targeted therapies are a major progress in the treatment of patients with metastatic kidney cancer. The side effects encountered with these molecules are numerous but serious side effects are less than 5% of all reported side effects. A better understanding of molecular mechanisms has enabled the development of new therapies for the treatment of metastatic renal cell carcinoma. In the future, a personalized approach taking into account the biology of each tumor could be created to provide a more targeted treatment.

Les médicaments de la médecine sexuelle

To describe drugs used in sexual medicine.Pubmed search for efficacy, mode of action and side effects for each molecule. Additional data were searched from the French regulatory agencies web sites (HAS and ANSM).5PDIs and intracavernous injection of alprostadil are first- and second-line therapies of erectile dysfunction. Dapoxetine is the first specific and approved treatment of premature ejaculation. Androgene supplementation improves sexual desire among patient with hypogonadism as much as initial serum testosterone levels are low. Female sexual dysfunctions pharmacology is to date less developed, although candidate drugs reach phase III clinical studies.Pharmacology is one but not the only therapeutic avenue in sexual medicine. Despite real breakthrough such as 5PDIs for erectile dysfunction, incomplete knowledge and understanding of physiology, pathophysiology and pharmacology of human sexual function reduces its development particularly for women.

The utility of prostate‐specific antigen in the management of advanced prostate cancer

To review current prostate-specific antigen (PSA) metrics used in monitoring treatment of advanced prostate cancer, with a specific focus on castration-resistant prostate cancer (CRPC) therapies. Explore what is known about the correlation between PSA and androgen levels as well as underlying reasons for persistent PSA expression and serum elevation in CRPC, and outline suggestions for use of PSA in managing patients with advanced prostate cancer. A comprehensive search of the PubMed database for English language articles through April 2012 was performed using the following Medical Subject Headings (MeSH) keywords or terms, alone or in combination: 'prostate cancer'; 'prostate cancer treatment'; 'prostate cancer outcomes'; 'prostate-specific antigen'; 'androgen receptor'; 'advanced prostate cancer'; 'castration-resistant prostate cancer'; 'biomarkers'. Bibliographies of relevant articles were searched for additional references. Relevant medical society and regulatory agency web sites from the USA and Europe were accessed for issued guidance on PSA use. PSA doubling time (PSADT) is a useful metric for determining which patients should be considered for androgen-deprivation therapy (ADT) after failing local treatment or for second-line therapies after failing ADT. However, it is not a validated surrogate for survival and no therapy has received regulatory approval based upon PSADT characteristics. PSA nadir and time-to-nadir have been identified as possible prognostic markers for patients receiving ADT. There is no universally accepted definition for PSA progression, nor is PSA progression a regulatory-approved surrogate for clinical progression in drug approval trials. PSA responses to second-line therapies can vary and are not considered by regulatory agencies as valid surrogates for clinical endpoints, so they must be assessed in the context of each individual therapy and trial design. PSA expression in CRPC is often a reflection of persistent androgen receptor activity. While we can provide guidance for use of PSA monitoring in managing patients with advanced prostate cancer based on the data at hand, there is an urgent need for prospective analyses of refined PSA metrics in conjunction with newer prostate cancer biomarkers in clinical trials to provide stronger evidence for their roles as surrogate endpoints.

Substandard and falsified medicines in the UK: a retrospective review of drug alerts (2001–2011)

ObjectiveTo determine the extent of substandard and falsified medicines in the UK.DesignA retrospective review of drug alerts and company-led recalls.SettingThe Medicines and Healthcare Products Regulatory Agency (MHRA) website search for...

First Generation E-Rulemaking: An Assessment of Regulatory Agency Websites

We examine 89 websites from federal regulatory agencies in order to evaluate their ease of use for those interested in commenting on or learning about their proposed regulations. We find that while there has been a lot of attention given to second and third generation e-rulemaking efforts, agency websites, a first generation innovation, still have considerable room for improvement. Notwithstanding legislative and executive branch efforts to enhance the accessibility of regulatory information on the Internet, our coding of regulatory agency websites reveals considerable variation in the quality of agency websites, with many websites still failing to provide relatively basic features.

Hepatotoxicidad en pacientes tratados con antagonistas del receptor de la endotelina: revisión sistemática y metaanálisis de ensayos clínicos aleatorizados

Background and objectiveWe evaluated the risk of hepatotoxicity associated to endothelin receptor antagonists. Patients and methodSystematic searches in PubMed/MEDLINE, the Cochrane Library as well as regulatory agencies websites were performed. Randomized controlled trials in patients receiving endothelin receptor antagonists (bosentan, sitaxentan or ambrisentan) in at least one treatment group were included. Prior to data extraction, definitions of hepatotoxicity were established. Effect sizes with 95% confidence intervals were calculated using random effects models. Heterogeneity was analysed using Cochran's Q and I2 tests. Publication bias was assessed using Egger's method and funnel plots were generated. ResultsTwenty-one trials met the inclusion criteria (3,644 patients). Bosentan was the evaluated drug in 1,689 (74%) patients who received endothelin receptor antagonists. Compared with controls, relative risk for any hepatic adverse reaction was 2.92 (1.85-4.62; I2=30.6%). When hepatotoxicity was defined as elevations of liver alanine or aspartate aminotransferases equal or greater than 3 times the upper limit of normal, relative risk was 2.98 (1.69-5.25; I2=40.9%). No evidence of publication bias was found (Egger's method: p=0.68). ConclusionsOur results suggest an increased risk of hepatotoxicity in patients receiving endothelin receptor antagonists. Given the limited data available for endothelin receptor antagonists other than bosentan, it is not possible to draw firm conclusions about the individual risk associated for the remaining endothelin receptor antagonists.

Risk of Malignancies in Patients With Rheumatoid Arthritis Treated With Biologic Therapy

Concerns exist regarding the potential development of malignancies in patients with rheumatoid arthritis (RA) who are receiving biologic response modifiers (BRMs). To assess the risk of malignancy in patients with RA enrolled in randomized controlled trials (RCTs) of BRMs. Electronic databases, conference proceedings, and websites of regulatory agencies were searched for RCTs evaluating abatacept, adalimumab, anakinra, certolizumab, etanercept, golimumab, infliximab, rituximab, and tocilizumab in RA from inception through July 9, 2012. Independent selection of studies included RCTs that compared the safety of any BRMs used in RA patients with placebo and/or any traditional disease-modifying antirheumatic drugs with a minimum of 24 weeks of follow-up. Independent reviewers selected studies and extracted data on quality and outcomes. Pooled estimates and 95% confidence intervals were calculated for each BRM. Sixty-three RCTs with 29,423 patients were analyzed. No statistically significant increased risk of developing malignancy was observed. Of the 29,423 patients, 211 developed a malignancy during the trial (118 solid tumors, 48 skin cancers, 14 lymphomas, 5 hematologic nonlymphomas, and 26 not specified). The incidence rate for any malignancy during the first year of therapy was very low in the BRM plus methotrexate group (0.77%; 95% CI, 0.65%-0.92%), the BRM monotherapy group (0.64%; 95% CI, 0.42%-0.95%), and the controls (0.66%; 95% CI, 0.52%-0.84%). Anakinra plus methotrexate showed lower odds compared with methotrexate alone (Peto odds ratio, 0.11; 95% CI, 0.03-0.45). No statistically significant risk was observed for specific cancer sites, although the Peto odds ratio for lymphoma was 2.1 (95% CI, 0.55-8.4) in patients receiving tumor necrosis factor inhibitors compared with controls. The use of BRMs among patients with RA included in RCTs of at least 6 months' duration was not significantly associated with an increased risk of malignancy compared with other disease-modifying antirheumatic drugs or with placebo.

Impact of Regulatory Guidances and Drug Regulation on Risk Minimization Interventions in Drug Safety

Therapeutic risk management has received growing interest in recent years, particularly since the publication of regulatory guidances in 2005 and 2006, paralleled with a change in drug regulation. The characteristics of risk minimization interventions (RMIs) that have been implemented or approved remain inadequately explored. The aim of this study was to review RMIs published in the literature or posted on regulatory agency websites over the past 10 years, and to assess whether publication of regulatory guidances on risk management is associated with changes in the number and types of interventions. Sources were searched for RMIs published/posted between 1 January 2000 and 31 December 2009. For the literature search, MEDLINE and EMBASE databases were used using key words related to drug safety (i.e. 'drug toxicity') and the individual RMI names. The website review involved searches of major regulatory authority websites such as the European Medicines Agency, US FDA, Health Canada, the UK's Medicines and Healthcare products Regulatory Agency, Japan's Pharmaceutical and Medical Devices Agency and Australia's Therapeutic Goods Administration. The following eligibility criteria were applied for inclusion in the review: published/posted between the years 2000 and 2009, inclusive; involving drug products; use in humans; and involving RMIs, or tools used to increase the reporting of adverse events (AEs). Natural healthcare products, devices, diagnostic chemicals, pregnancy registries without follow-up, medication errors and products not used as therapy for illness were not retained. For each source, the following characteristics were extracted: nature of the intervention, target population, therapeutic area, AE(s) of special interest, country/regulatory agency and year of publication. A total of 119 unique interventions were identified in the literature (54 published in 2000-4 and 65 published in 2005-9). Interventions included educational material (n = 37; 31%), black-box warnings (n = 22; 19%) and therapeutic drug monitoring (n = 11; 9%). The website review produced a total of 1112 interventions: 326 posted between the years 2000 and 2004, and 786 between the years 2005 and 2009. The main interventions observed were: educational material (n = 956; 86%), black-box warnings (n = 45; 4%) and withdrawals (n = 39; 4%). Additional regulatory resource websites were available in the post-guidances periods that were not available in the earlier years of the pre-guidances periods, and may bias the post-guidances results. Also, not all global regulatory websites were searched. Finally, only English-language websites were searched, limiting the variation of RMIs observed. Classification and categorizing for this particular review may not be consistent with future reviews by other researchers. The US is the sole region with a substantial increase in published RMIs during the post-guidances period, while the EU, Japan and the US all indicated an increase in the number of interventions on their websites.

Approval of antineoplastic agents in India: comparison with the US and EU regions

Background: The antineoplastic drugs are prescribed for the treatment of cancer, which is an important cause of mortality in India; therefore, a drug lag in the availability of antineoplastic drugs is a direct threat to life. The present study was undertaken to assess the drug lag for new antineoplastic agents in India compared with that in the United States (US) or European Union (EU). Methods: The new antineoplastic agents approved in the United States, European Union and India between 1999 and 2011 were identified and information was gathered primarily from the websites of regulatory agencies of the three regions. We assessed absolute and relative drug lag for new antineoplastic agents approved in the three regions. Results: Of the 70 new antineoplastic agents, 64 (91.42%) were approved in the United States, 54 (77.14%) in the European Union and 44 (62.85%) in India. The US was the first to approve 59 (84.28%) out of the 70 new antineoplastic agents, the EU was the first to approve 9 (12.85%) and India was the first to approve 2 (2.85%). The median approval lag for India (26.35 months) was higher as compared to the United States (0 month) and European Union (7.3 months). Conclusions: This study confirms that India’s drug lag in the case of new antineoplastic agents is higher as compared to the US and EU. Further detailed analyses are necessary to find the reasons and impacts of drug lag for antineoplastic agents in India.

Regulatory agencies, pharmaceutical information and the Internet: A European perspective

The Internet facilitates access to health information and can therefore support the effectiveness of healthcare provision and empower patients in healthcare decisions. In the field of pharmaceutical therapy the electronic provision of information can improve compliance and strengthen the general understanding of pharmaceutical risks and benefits. Current political developments in Europe encourage a stronger role of the pharmaceutical industry in this regard. In light of potential conflicts inherent to the private provision of information and given their public health mandate, regulatory bodies in the pharmaceutical sector may represent an important alternative source of information. The explorative analysis in this paper reviews the websites of European pharmaceutical regulatory agencies regarding the usability and provision of information from a Layman's perspective. It is found that while the majority of agencies do provide product-related information, the usability of websites from the lay perspective is subject to variation. The reluctant position of agencies can be attributed to sectoral path dependencies, the regulatory approach and a lack of regulatory resources.

Safety of non-steroidal anti-inflammatory drugs, including aspirin and paracetamol (acetaminophen) in people receiving methotrexate for inflammatory arthritis (rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, other spondyloarthritis)

Methotrexate is routinely used in the treatment of inflammatory arthritis. There have been concerns regarding the safety of using concurrent non-steroidal anti-inflammatory drugs (NSAIDs), including aspirin, or paracetamol (acetaminophen), or both, in these people. To systematically appraise and summarise the scientific evidence on the safety of using NSAIDs, including aspirin, or paracetamol, or both, with methotrexate in inflammatory arthritis; and to identify gaps in the current evidence, assess the implications of those gaps and to make recommendations for future research to address these deficiencies. We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library, second quarter 2010); MEDLINE (from 1950); EMBASE (from 1980); the Cochrane Database of Systematic Reviews (CDSR) and the Database of Abstracts of Reviews of Effects (DARE). We also handsearched the conference proceedings for the American College of Rheumatology (ACR) and European League against Rheumatism (EULAR) (2008 to 2009) and checked the websites of regulatory agencies for reported adverse events, labels and warnings. Randomised controlled trials and non-randomised studies comparing the safety of methotrexate alone to methotrexate with concurrent NSAIDs, including aspirin, or paracetamol, or both, in people with inflammatory arthritis. Two authors independently assessed the search results, extracted data and assessed the risk of bias of the included studies. Seventeen publications out of 8681 identified studies were included in the review, all of which included people with rheumatoid arthritis using various NSAIDs, including aspirin. There were no identified studies for other forms of inflammatory arthritis.For NSAIDs, 13 studies were included that used concurrent NSAIDs, of which nine studies examined unspecified NSAIDs. The mean number of participants was 150.4 (range 19 to 315), mean duration 2182.9 (range 183 to 5490) days, although the study duration was not always clearly defined, and the studies were mainly of low to moderate quality. Two of these studies reported no evidence for increased risk of methotrexate-induced pulmonary disease; one study assessed the effect of concurrent NSAIDs on renal function and found no adverse effect; one study identified no adverse effect on liver function; three studies demonstrated no increase in methotrexate withdrawal; and one study showed no increase in all adverse events, including major toxic reactions. However, transient thrombocytopenia was demonstrated in one study, specifically when NSAIDs were taken on the same week day as methotrexate. This study was a retrospective review that involved small numbers only and was of moderate quality; these finding have not been replicated since.Four studies looked at specific NSAIDs (etodolac, piroxicam, celecoxib and etoricoxib), with a mean number of participants of 25.8 (range 14 to 50) and mean study duration of 16.8 (range 14 to 23) days. These studies were mainly of moderate quality. The studies were primarily pharmacokinetic studies but also reported adverse events as secondary outcomes. There were no clinically significant adverse effects with concomitant piroxicam or etodolac; and only mild adverse events with celecoxib or etoricoxib, such as nausea and vomiting, and headaches.For aspirin, seven studies provided data on adverse events with the use of aspirin and methotrexate. These studies included a mean number of participants of 100 (range 11 to 232), had a mean duration of 1325 (range 8 to 2928) days and were mainly of low to moderate quality. Two of the studies reported no evidence for increased risk of methotrexate-induced pulmonary disease and two studies showed no increase in all adverse events including major toxic reactions; however, none of these studies specified the dose of aspirin that was used. One study demonstrated that concurrent aspirin adversely affected liver function at a mean dose of 6.84 tablets of aspirin per day, which is a possible daily dose of 2.1 g presuming that 300 mg aspirin tablets were given. A further study described a partially reversible decline in renal function with 2 g daily of aspirin. One study reported no increase in adverse events with 975 g aspirin daily, however the study duration was only one week.For paracetamol, no studies were identified for inclusion. In the management of rheumatoid arthritis, the concurrent use of NSAIDs with methotrexate appears to be safe provided appropriate monitoring is performed. The use of anti-inflammatory doses of aspirin should be avoided.

Pain management for rheumatoid arthritis and cardiovascular or renal comorbidity

Pain in rheumatoid arthritis is common, is often multi-factorial and many different pharmacotherapeutic agents are routinely used for pain management. There are concerns that some of the pain pharmacotherapies currently used may increase the risk of adverse events in people with rheumatoid arthritis and concurrent cardiovascular or renal disease. To systematically assess and collate the scientific evidence on the efficacy and safety of using pain pharmacotherapy in people with rheumatoid arthritis and cardiovascular or renal comorbidities. We searched the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library 2010, Issue 4); MEDLINE, from 1950; EMBASE, from 1980; the Cochrane Database of Systematic Reviews (CDSR) and the Database of Abstracts of Reviews of Effects (DARE). We also handsearched the conference proceedings for American College of Rheumatology (ACR) and European League against Rheumatism (EULAR) for 2008-09, and checked the websites of regulatory agencies for reported adverse events, labels and warnings. We considered randomised controlled trials and non-randomised studies comparing the efficacy and safety of pain pharmacotherapies in patients with rheumatoid arthritis, with and without comorbid cardiovascular or renal conditions.In addition, we also considered controlled before-after studies, interrupted time series, cohort and case control studies and case series (N ≥ 20) to assess safety.For the purpose of our review, pain pharmacotherapy was defined as including simple analgesics (such as paracetamol), non-steroidal anti-inflammatory drugs (NSAIDs), opioids or opioid-like drugs (such as tramadol), and neuromodulators (including anti-depressants, anti-convulsants, and muscle relaxants). Two review authors independently assessed the search results and planned to extract data and appraise the risk of bias of included studies. We did not identify any studies meeting our inclusion criteria. Many of the trials of NSAIDs explicitly excluded patients with cardiovascular or renal comorbidities.We did identify one trial that reported evidence in mixed populations (including both rheumatoid arthritis and osteoarthritis) taking either diclofenac or etoricoxib. In this study, the presence of cardiovascular disease increased the likelihood of a further cardiovascular event three-fold. Patients with two or more cardiovascular comorbidities showed a two-fold increased likelihood of adverse cardiovascular events. There were no trials that specifically compared the efficacy and safety of pain pharmacotherapies for patients with rheumatoid arthritis, with and without comorbid cardiovascular or renal conditions.In the absence of specific evidence in rheumatoid arthritis, current guidelines recommend that NSAIDs be used with caution in the general rheumatoid arthritis population while highlighting the added need for extra vigilance in patients with established cardiovascular disease or risk factors for its development. Current guidelines regarding the use of NSAIDs and opioids in moderate to severe renal impairment should also be applied to the rheumatoid arthritis population.Further research is required to guide clinicians when treating pain in rheumatoid arthritis.