Cardiovascular and gastrointestinal effects of COX-2 inhibitors and NSAIDs: achieving a balance

Conventional 'nonselective' nonsteroidal anti-inflammatory drugs (NSAIDs) are widely used for the treatment of pain and inflammation; however, the potential gastrointestinal risks associated with their use can be a cause for concern. In response to the adverse effects that can accompany nonselective NSAID use, selective cyclo-oxygenase (COX)-2 inhibitors were developed to target the COX-2 isoenzyme, thus providing anti-inflammatory and analgesic benefits while theoretically sparing the gastroprotective activity of the COX-1 isoenzyme. Data from large-scale clinical trials have confirmed that the COX-2 inhibitors are associated with substantial reductions in gastrointestinal risk in the majority of patients who do not receive aspirin. However, some or all of the gastrointestinal benefit of COX-2 inhibitors may be lost in patients who receive low, cardioprotective doses of aspirin, and recent evidence suggests that some of these agents, at some doses, may be associated with an increased risk for cardiovascular adverse events compared with no therapy. The risks and benefits of conventional NSAIDs and of COX-2 inhibitors must be weighed carefully; in clinical practice many patients who might benefit from NSAID or COX-2 therapy are likely to be elderly and at relatively high risk for gastrointestinal and cardiovascular adverse events. These patients are also more likely to be taking low-dose aspirin for cardiovascular prophylaxis and over-the-counter NSAIDs for pain. Identifying therapies that provide relief from arthritis related symptoms, confer optimum cardioprotection, and preserve the gastrointestinal mucosa is complex. Factors to consider include the interference of certain NSAIDs with the antiplatelet effects of aspirin, differences in the adverse gastrointestinal event rates among nonselective NSAIDs and selective COX-2 inhibitors, emerging data regarding the relative risks for cardiovascular events associated with these drugs, and the feasibility and cost of co-therapy with proton pump inhibitors.     

Role of nitric oxide in the gastrointestinal tract

Worldwide osteoarthritis (OA) affects more than 9.6% of men and 18% of women older that 60 years. Treatment for OA often requires chronic use of selective or nonselective nonsteroidal anti-inflammatory drugs (NSAIDs), which have been associated with gastrointestinal and cardiovascular complications. An increased risk for upper gastrointestinal bleeding with NSAIDs alone and when combined with low-dose aspirin has been described in numerous studies. Although cyclo-oxygenase-2 inhibitors have been shown to carry a lower risk for gastrointestinal injury than nonselective NSAIDs, research continues to identify new treatments that not only are effective but also provide an improved benefit/risk profile, including better gastrointestinal tolerability. Nitric oxide (NO) is known to have a protective effect on the gastrointestinal tract. In preclinical studies NO was shown to help maintain gastric mucosal integrity, to inhibit leukocyte adherence to the endothelium, and to repair NSAID-induced damage. In addition, epidemiologic studies have shown that the use of NO-donating agents with NSAIDs or aspirin resulted in reduced risk for gastrointestinal bleeding. Recent studies have shown that cyclo-oxygenase inhibiting NO-donating drugs (CINODs), in which a NO molecule is chemically linked to an NSAID, are effective anti-inflammatory agents and may result in less gastrointestinal damage than is associated with NSAID use. Therefore, these agents provide a potential therapeutic option for patients with arthritis who require long-term NSAID therapy.     

Current state of therapy for pain and inflammation

Nonsteroidal anti-inflammatory drugs (NSAIDs), including both traditional nonselective NSAIDs and the selective cyclo-oxygenase (COX)-2 inhibitors, are among the most widely used medications in the USA. Traditional NSAIDs, although effective at relieving pain and inflammation, are associated with a significant increase in the risk for gastrointestinal adverse events. Throughout the 1990s these events were estimated to result in approximately 100,000 hospitalizations and 16,500 deaths each year nationally. Recent studies have indicated that the risk for serious NSAID gastropathy has declined substantially during the past decade as a result of a number of factors, including lower doses of NSAIDs, the use of gastroprotective agents such as proton pump inhibitors and misoprostol, and the introduction of the selective COX-2 inhibitors. One therapeutic approach that may reduce the risk for gastrointestinal side effects associated with traditional NSAIDs while retaining their efficacy is the inclusion of co-therapy with a proton pump inhibitor; these agents inhibit acid secretion and have been demonstrated to promote ulcer healing in patients with NSAID-related gastric ulcers. Alternatively, COX-2 selective agents have been used to treat patients at high risk for such events. Both nonselective and selective COX-2 inhibitors have now been shown to be associated with an increased risk for cardiovascular events. These studies, together with the outcomes of the recent US Food and Drug Administration decision to require 'black box' warnings regarding potential cardiovascular risks associated with NSAIDs, suggest that the use of COX-2 inhibitors as the sole strategy for gastroprotection in patients with arthritis and other pain syndromes must be reconsidered, particularly among those at risk for cardiovascular events.     

Proton-pump inhibitors are associated with a reduced risk for bleeding and perforated gastroduodenal ulcers attributable to non-steroidal anti-inflammatory drugs: a nested case-control study

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.     

Balancing the gastrointestinal benefits and risks of nonselective NSAIDs

Nonselective nonsteroidal anti-inflammatory drugs (NSAIDs) are among the most widely used classes of medications to treat pain and inflammation. However, gastrointestinal complications associated with NSAIDs are prevalent, largely due to the frequent use of these agents. Adverse events associated with NSAIDs include minor side effects, such as dyspepsia, as well as serious complications, such as bleeding and perforation. Although the probability that any given individual user of an NSAID will suffer a serious gastrointestinal complication is fairly low, widespread patient exposure can translate into a major national health burden. The increasing use of aspirin in the prevention of cardiovascular events and the availability of select over-the-counter NSAIDs represent additional challenges to clinicians in their efforts to make the most appropriate therapeutic decisions while minimizing the potential gastrointestinal risks associated with the use of these agents. Side effects such as dyspepsia do not provide adequate warning of gastrointestinal complications, because most complications occur without the presence of antecedent symptoms. Therefore, accurate risk assessment and the management of controllable risk factors are crucial to the safe administration of NSAIDs. This review focuses on the gastrointestinal effects of aspirin, acetaminophen, and other nonselective NSAIDs, and discusses those factors that are associated with increased risk for adverse gastrointestinal events in certain individuals.     

New horizons and perspectives in the treatment of osteoarthritis

Osteoarthritis (OA) is increasingly prevalent worldwide and is associated with a significant economic burden. Despite the increasing number of patients with OA, treatments to manage the condition remain symptomatic, designed to control pain, and improve function and quality of life while limiting adverse events. Both the EULAR (European League Against Rheumatism) and the OARSI (Osteoarthritis Research Society International) issued new guidelines in 2007 and 2008 recommending a combination of nonpharmacological and pharmacological modalities to manage OA effectively. Because of gastrointestinal risks (including ulcer complications) and cardiovascular risks (including hypertension and thrombotic events associated with nonsteroidal anti-inflammatory drugs [NSAIDs]), these guidelines propose acetaminophen as the first choice anti-inflammatory agents. However, NSAIDs are considered to be more effective than acetaminophen for relief of pain. Given the efficacy, safety, and tolerability issues associated with NSAIDs, development of new agents to manage the pain associated with arthritis but without the cardiovascular and gastrointestinal adverse events remains a priority. This review considers current recommendations for the treatment of OA, the most recent evidence on the cardiovascular risks associated with current NSAID treatments, and the potential of newer anti-inflammatory agents with improved benefit-risk profiles.     

An evidence-based approach to prescribing NSAIDs in musculoskeletal disease: a Canadian consensus. Canadian NSAID Consensus Participants.

OBJECTIVE. To make recommendations for the long-term use of nonsteroidal anti-inflammatory drugs (NSAIDs) in primary care practice, particularly for patients at high risk for NSAID-induced complications. OPTIONS. The use of misoprostol to prevent gastrointestinal ulceration and other unwanted NSAIDs effects was considered. The role of cyclooxygenase-2 (COX-2) versus COX-1 inhibiting agents was also examined. OUTCOMES. Reduction of complications associated with long-term use of NSAIDs. EVIDENCE. Evidence was gathered in late 1995 from published research studies and reviews. Position papers were prepared by faculty and advisory board members and discussed at the Canadian NSAID Consensus Symposium in Cambridge, Ont., Jan. 26 and 27, 1996. VALUES. Recommendations were based on randomized, placebo-controlled clinical trials (level I evidence) and case-control studies (level II evidence) involving NSAID use when such evidence was available. When the scientific literature was incomplete or inconsistent in a particular area, recommendations reflect the consensus of the participants at the symposium (level III evidence). Physicians were recruited from across Canada for their expertise in rheumatology, gastroenterology, epidemiology, gerontology, family practice, and clinical and basic scientific research. BENEFITS, HARMS AND COSTS. Although a reduction in complications due to inappropriate NSAID use should reduce costs of additional investigations, admissions to hospital and time lost from work, definitive cost analysis studies are not yet available. RECOMMENDATIONS. Currently, no NSAID is available that lacks potential for serious toxicity; therefore, long-term use of NSAIDs should be avoided whenever possible, particularly in high-risk patients (e.g., those who are elderly, suffer from hypertension, congestive heart failure, renal or hepatic impairment or volume depletion, take certain concomitant medications or have a history of peptic ulcer disease) (level I evidence). If NSAIDs are to be used in patients with gastric or nephrotoxic risk factors, the lowest effective dose of NSAID should be used (level III evidence); NSAIDs that are weak COX-1 inhibitors may be preferred (level II evidence). In addition, concomitant administration of misoprostol is recommended in patients at increased risk for upper gastrointestinal complications (level I evidence). However, the clinical judgement of the practising clinician must always be part of any therapeutic decision. VALIDATION. These recommendations are based on the consensus of Canadian experts in rheumatology, gastroenterology and epidemiology, and have been subjected to external peer review.     

The use of proton pump inhibitors in treating and preventing NSAID-induced mucosal damage

NSAIDs are prescribed widely but have rare serious gastrointestinal side effects. More recently, adverse cardiovascular effects of these drugs have also been recognized, leading to the withdrawal of some agents and continuing uncertainty about the best approach for patients requiring NSAID therapy. Proton pump inhibitors (PPIs) provide potent and long-lasting inhibition of gastric acid secretion and have proven efficacy in healing NSAID-associated ulcers, including those with continued exposure to NSAIDs. PPIs have also shown efficacy in reducing the risk of ulcerations due to NSAID use compared with NSAIDs alone in randomized controlled trials (RCTs) where endoscopic ulcers are used as the primary endpoint, albeit a surrogate marker for clinical ulcers and complications. Large RCT outcome trials comparing patients exposed to NSAIDs with and without PPI co-therapy have not been performed, but adequately powered RCTs in high-risk patients demonstrate that PPI + nonselective NSAID provides similar rates of symptomatic ulcer recurrence rates as the use of a cyclooxygenase (COX)-2 selective inhibitor. A RCT in high-risk patients with previous ulcer complications supports the additive bene3 t of two risk-reducing strategies, as ulcer complication recurrence was eliminated in high-risk patients who were given a COX-2 selective agent with a PPI. Helicobacter pylori, an independent risk factor for ulcers, should be sought out and eradicated in patients at increased gastrointestinal risk, typically those with an ulcer history. Following H. pylori eradication, however, patients remain at risk and co-therapy with a PPI is recommended. NSAID medication selection should consider both the individual patients' gastrointestinal and cardiovascular risks.     

The effectiveness of five strategies for the prevention of gastrointestinal toxicity induced by non-steroidal anti-inflammatory drugs: systematic review

Objectives 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.Data sources 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.Review methods 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.Results 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).Conclusions 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.     

Fish oil: what the prescriber needs to know

There is a general belief among doctors, in part grounded in experience, that patients with arthritis need nonsteroidal anti-inflammatory drugs (NSAIDs). Implicit in this view is that these patients require the symptomatic relief provided by inhibiting synthesis of nociceptive prostaglandin E₂, a downstream product of the enzyme cyclo-oxygenase (COX), which is inhibited by NSAIDs. However, the concept of 'safe' NSAIDs has collapsed following a multiplicity of observations establishing increased risk for cardiovascular events associated with NSAID use, especially but not uniquely with the new COX-2-selective NSAIDs. This mandates greater parsimony in the use of these agents. Fish oils contain a natural inhibitor of COX, reduce reliance on NSAIDs, and reduce cardiovascular risk through multiple mechanisms. Fish oil thus warrants consideration as a component of therapy for arthritis, especially rheumatoid arthritis, in which its symptomatic benefits are well established. A major barrier to the therapeutic use of fish oil in inflammatory diseases is ignorance of its mechanism, range of beneficial effects, safety profile, availability of suitable products, effective dose, latency of effects and instructions for administration. This review provides an evidence-based resource for doctors and patients who may choose to prescribe or take fish oil.     

Nonsteroidal anti-inflammatory drugs and upper and lower gastrointestinal mucosal damage

NSAIDs are among the most commonly used drugs worldwide and their beneficial therapeutic properties are thoroughly accepted. However, they are also associated with gastrointestinal (GI) adverse events. NSAIDs can damage the whole GI tract including a wide spectrum of lesions. About 1 to 2% of NSAID users experienced a serious GI complication during treatment. The relative risk of upper GI complications among NSAID users depends on the presence of different risk factors, including older age (>65 years), history of complicated peptic ulcer, and concomitant aspirin or anticoagulant use, in addition to the type and dose of NSAID. Some authors recently reported a decreasing trend in hospitalizations due to upper GI complications and a significant increase in those from the lower GI tract, causing the rates of these two types of GI complications to converge. NSAID-induced enteropathy has gained much attention in the last few years and an increasing number of reports have been published on this issue. Current evidence suggests that NSAIDs increase the risk of lower GI bleeding and perforation to a similar extent as that seen in the upper GI tract. Selective cyclooxygenase-2 inhibitors have the same beneficial effects as nonselective NSAIDs but with less GI toxicity in the upper GI tract and probably in the lower GI tract. Overall, mortality due to these complications has also decreased, but the in-hospital case fatality for upper and lower GI complication events has remained constant despite the new therapeutic and prevention strategies.     

Fish oil: what the prescriber needs to know

There is a general belief among doctors, in part grounded in experience, that patients with arthritis need nonsteroidal anti-inflammatory drugs (NSAIDs). Implicit in this view is that these patients require the symptomatic relief provided by inhibiting synthesis of nociceptive prostaglandin E2, a downstream product of the enzyme cyclo-oxygenase (COX), which is inhibited by NSAIDs. However, the concept of 'safe' NSAIDs has collapsed following a multiplicity of observations establishing increased risk for cardiovascular events associated with NSAID use, especially but not uniquely with the new COX-2-selective NSAIDs. This mandates greater parsimony in the use of these agents. Fish oils contain a natural inhibitor of COX, reduce reliance on NSAIDs, and reduce cardiovascular risk through multiple mechanisms. Fish oil thus warrants consideration as a component of therapy for arthritis, especially rheumatoid arthritis, in which its symptomatic benefits are well established. A major barrier to the therapeutic use of fish oil in inflammatory diseases is ignorance of its mechanism, range of beneficial effects, safety profile, availability of suitable products, effective dose, latency of effects and instructions for administration. This review provides an evidence-based resource for doctors and patients who may choose to prescribe or take fish oil.     

The use of H2 antagonists in treating and preventing NSAID-induced mucosal damage

Pain affects the quality of life for millions of individuals and is a major reason for healthcare utilization. As populations age, medical personnel will need to manage more and more patients suffering from pain associated with degenerative and inflammatory musculoskeletal disorders. Nonsteroidal anti-inflammatory drugs (NSAIDs) are an effective treatment for both acute and chronic musculoskeletal pain; however, their use is associated with potentially significant gastrointestinal (GI) toxicity. Guidelines suggest various strategies to prevent problems in those at risk for NSAID-associated GI complications. In this article, we review the data supporting one such strategy - the use of histamine type-2 receptor antagonists (H2RAs) - for the prevention of GI adverse events in NSAID users. Older studies suggest that high-dose H2RAs are effective in preventing upper GI ulcers and dyspepsia. This suggestion was recently confirmed during clinical trials with a new ibuprofen/famotidine combination that reduced the risk of ulcers by 50% compared with ibuprofen alone.     

Glycemia Management and Cardiovascular Risk in Type 2 Diabetes: An Evolving Perspective

ObjectiveTo review recent glycemia trials focused on reducing cardiovascular disease (CVD) risk in patients with type 2 diabetes and to describe how the results of these studies have altered our approach to the management of glycemia in patients with diabetes.MethodsResults of some of the previous as well as recent trials, including the Action to Control Cardiovascular Risk in Diabetes (ACCORD), Action in Diabetes and Vascular Disease (ADVANCE), and Veterans Affairs Diabetes Trial (VADT), are reviewed.ResultsThe results demonstrate that the establishment of glycemia (hemoglobin A1c) goals in patients with type 2 diabetes aimed at reducing CVD events is complex, should be highly individualized, and should probably be varied depending on the duration of diabetes as well as the presence or absence of CVD and microvascular complications.ConclusionResults of the ACCORD, ADVANCE, and VADT studies have considerably increased our knowledge and refined our approach to establishing glycemia goals in patients with type 2 diabetes. In patients with recently recognized diabetes with no prior CVD events, glycemic control to normal or near-normal levels appears to be effective in preventing CVD events and mortality. In patients with established diabetes (8 to 10 or more years) and recognized CVD, however, glycemic control to normal or near-normal levels does not reduce the risk of further CVD events or mortality. Importantly, strict control of all known risk factors for CVD and microvascular complications by aggressive management of hypertension, dyslipidemia, and glycemia, use of aspirin, and cessation of smoking in patients with type 2 diabetes has proved to be highly beneficial. (Endocr Pract. 2008;14:639-643)     

Statin use and the presence of microalbuminuria. Results from the ERICABEL trial: a non-interventional epidemiological cohort study

Background

Microalbuminuria (MAU) is considered as a predictor or marker of cardiovascular and renal events. Statins are widely prescribed to reduce cardiovascular risk and to slow down progression of kidney disease. But statins may also generate tubular MAU. The current observational study evaluated the impact of statin use on the interpretation of MAU as a predictor or marker of cardiovascular or renal disease.

Methodology/Principal Findings

We used cross-sectional data of ERICABEL, a cohort with 1,076 hypertensive patients. MAU was defined as albuminuria ≥20 mg/l. A propensity score was created to correct for “bias by indication” to receive a statin. As expected, subjects using statins vs. no statins had more cardiovascular risk factors, pointing to bias by indication. Statin users were more likely to have MAU (OR: 2.01, 95%CI: 1.34–3.01). The association between statin use and MAU remained significant after adjusting for the propensity to receive a statin based on cardiovascular risk factors (OR: 1.82, 95%CI: 1.14–2.91). Next to statin use, only diabetes (OR: 1.92, 95%CI: 1.00–3.66) and smoking (OR: 1.49, 95%CI: 0.99–2.26) were associated with MAU.

Conclusions

Use of statins is independently associated with MAU, even after adjusting for bias by indication to receive a statin. In the hypothesis that this MAU is of tubular origin, statin use can result in incorrect labeling of subjects as having a predictor or marker of cardiovascular or renal risk. In addition, statin use affected the association of established cardiovascular risk factors with MAU, blurring the interpretation of multivariable analyses.     

Helicobacter pylori and non-steroidal anti-inflammatory drugs: does infection affect the outcome of NSAID therapy?

1. H. pylori gastritis appears to increase the likelihood of developing dyspeptic symptoms on NSAID therapy. 2. There is preliminary evidence that the histologic severity of H. pylori gastritis may be adversely affected by NSAID therapy, with a consequent increase in the risk of developing a peptic ulcer, possibly with complications. Whether this results from an effect on the inflammatory process or results from a quantitative increase in H. pylori colonization is unknown. In these respects, ASA may differ from other NSAIDs. 3. Ulcers are more likely to develop during the course of NSAID therapy in those infected with H. pylori; eradication of the infection reduces ulcer recurrence in the face of continued NSAID therapy, and it seems likely that this must reduce but not abolish the risk of GI bleeding in those using NSAIDs. Eradication also reduces the damage (and possibly risks) of low-dose aspirin therapy. 4. While H. pylori and NSAID use are independent risk factors for GI bleeding, whether or not they are interactive remains unresolved. 5. The effect of H. pylori infection on the risk of perforation during NSAID therapy, or conversely, the contribution of NSAID therapy to the risk of perforation in H. pylori-infected subjects, is also unclear at the present time. 6. Only large outcome studies of accurately diagnosed patients (with regard to H. pylori gastritis), and with much more specific detail as to the type of NSAID, dose and duration of therapy, employing only well-defined end-points, such as significant hemorrhage, perforation or death, and avoiding all surrogate markers short of these end points can hope to unravel this tangled web.     

Use of NSAIDs in treating patients with arthritis

Patients with rheumatic diseases, including rheumatoid arthritis and osteoarthritis, almost universally describe pain and stiffness as important contributors to reduced health-related quality of life. Of the treatment options available, NSAIDs are the most widely used agents for symptomatic treatment. NSAIDs are effective anti-inflammatory and analgesic drugs by virtue of their ability to inhibit biosynthesis of prostaglandins at the level of the cyclooxygenase enzyme. However, many of the adverse effects of NSAIDs are also related to inhibition of prostaglandin production, making their use problematic in some patient populations. For the clinician, understanding the biology of prostaglandin as it relates to gastrointestinal, renal, and cardiovascular physiology and the pharmacologic properties of specific NSAIDs is key to using these drugs safely. Of particular importance is the recognition of co-morbid conditions and concomitant drugs that may increase the risk of NSAIDs in particular patients. In patients with risk factors for NSAID toxicity, using the lowest dose of a drug with a short half-life only when it is needed is likely to be the safest treatment option. For those patients whose symptoms cannot be managed with intermittent treatment, using protective strategies is essential.     

A long-term "memory" of HIF induction in response to chronic mild decreased oxygen after oxygen normalization

Background

Cardiovascular diseases (CVD) are the leading cause of death and the third cause of disability in Europe. Prevention programmes should include interventions aimed at a reduction of medical risk factors (hypertension, hypercholesterol, hyperglycemia, overweight and obesity) as well as behavioural risk factors (sedentary lifestyle, high fat intake and low fruit and vegetable intake, smoking). The aim of this study is to investigate the effects of a multifaceted, multidisciplinary electronic prevention programme on cardiovascular risk factors.

Methods/Design

In a randomized controlled trial, one group will receive a maximal intervention (= intervention group). The intervention group will be compared to the control group receiving a minimal intervention. An inclusion of 350 patients in total, with a follow-up of 3 years is foreseen. The inclusion criteria are age between 25–65 and insured by the Onderlinge Ziekenkas, insuring for guaranteed income in case of illness for self-employed. The maximal intervention group receives several prevention consultations by their general practitioner (GP) using a new type of cardiovascular risk calculator with personalised feedback on behavioural risk factors. These patients receive a follow-up with intensive support of health behaviour change via different methods, i.e. a tailored website and personal advice of a multidisciplinary team (psychologist, physiotherapist and dietician). The aim of this strategy is to reduce cardiovascular risk factors according to the guidelines. The primary outcome measures will be cardiovascular risk factors. The secondary outcome measures are cardiovascular events, quality of life, costs and incremental cost effectiveness ratios. The control group receives prevention consultations using a new type of cardiovascular risk calculator and general feedback.

Discussion

This trial incorporates interventions by GPs and other health professionals aiming at a reduction of medical and behavioural cardiovascular risk factors. An assessment of clinical, psychological and economical outcome measures will be performed.

Trial registration

ISRCTN23940498     

Efficacy,tolerability, and upper gastrointestinal safety of celecoxib for treatment of osteoarthritis and rheumatoid arthritis: systematic review of randomised controlled trials

ObjectiveTo determine the efficacy, gastrointestinal safety, and tolerability of celecoxib (a cyclo-oxygenase 2 (COX 2) inhibitor) used in the treatment of osteoarthritis and rheumatoid arthritis.DesignSystematic review of randomised trials that compared at least 12 weeks'' celecoxib treatment with another non-steroidal anti-inflammatory drug (NSAID) or placebo and reported efficacy, tolerability, or safety. Trials identified from manufacturer and by searching electronic databases and evaluated according to predefined inclusion and quality criteria. Data combined through meta-analysis.Participants15 187 patients with osteoarthritis or rheumatoid arthritis.ResultsNine randomised controlled trials were included. Celecoxib and NSAIDS were equally effective for all efficacy outcomes. Compared with those taking other NSAIDs, in patients taking celecoxib the rate of withdrawals due to adverse gastrointestinal events was 46% lower (95% confidence interval 29% to 58%; NNT 35 at three months), the incidence of ulcers detectable by endoscopy was 71% lower (59% to 79%; NNT 6 at three months), and the incidence of symptoms of ulcers, perforations, bleeds, and obstructions was 39% lower (4% to 61%; NNT 208 at six months). Subgroup analysis of patients taking aspirin showed that the incidence of ulcers detected by endoscopy was reduced by 51% (14% to 72%) in those given celecoxib compared with other NSAIDs. The reduction was greater (73%, 52% to 84%) in those not taking aspirin.ConclusionCelecoxib is as effective as other NSAIDs for relief of symptoms of osteoarthritis and rheumatoid arthritis and has significantly improved gastrointestinal safety and tolerability.

What is already known on this topic

Long term NSAID use is associated with the development of peptic and duodenal ulcersCOX 2 specific inhibitors are claimed to cause fewer gastrointestinal complicationsThe National Institute for Clinical Excellence has recently recommended that COX 2 specific inhibitors are used in patients with arthritis who are at risk of gastrointestinal complications but not in those taking prophylactic aspirin

What this study adds

Systematic review of randomised trials shows that celecoxib is as effective as other NSAIDs for osteoarthritis and rheumatoid arthritisCelecoxib has significantly improved gastrointestinal safety and tolerability compared with standard NSAIDsAn improvement in gastrointestinal safety was still evident in patients who were also taking aspirin