Individual Non-steroidal Anti-inflammatory Drugs Research Articles

A 2013 updated systematic review & meta‐analysis of 36 randomized controlled trials; no apparent effects of non steroidal anti‐inflammatory agents on the risk of bleeding after tonsillectomy

Although the literature suggests that non-steroidal anti-inflammatory drugs (NSAIDs) are effective in controlling post-operative pain in the paediatric population, physicians have been reluctant to utilise these medications after tonsillectomy due to concerns of increased bleeding rates. While many surgeons prescribe opioid analgesics postoperatively, these are associated with a number of potential adverse side-effects including nausea, vomiting, constipation, excessive sedation and respiratory compromise. To compare bleeding rates and severity between recipients of NSAIDs versus placebo or opioid analgesics for tonsillectomy. Two authors independently searched electronic databases including PubMed, OVID, EMBASE and Cochrane Review from inception to July 2012. The keywords used included: Adenotonsillectomy, Tonsillectomy, Analgesia, Bleeding, Perioperative and Postoperative. These were then combined in various combinations with specific NSAIDs. A systematic review and meta-analysis of all randomised control trials comparing bleeding rates and severity between NSAIDs versus placebo or opioids post-tonsillectomy. A total of 36 studies met our inclusion criteria including 1747 children and 1446 adults. When all of the studies were combined in a meta-analysis using the most severe outcome, there was no increased risk of bleeding in those using NSAIDs after tonsillectomy. Use of NSAIDs in general [1.30 (0.90-1.88)] or in children [1.06 (0.65-1.74)] was not associated with increased risk of bleeding in general, most severe bleeding, secondary haemorrhage, readmission or need of reoperation due to bleeding. Similarly, there was no increased bleeding risk for specific NSAIDs in adults. In the studies looking at paediatric subjects, the overall odds ratio of bleeding was even lower than in the general population and not significant. This result is based on 18 studies, six of which had zero outcomes in either treatment arm. Similar to the general population analysis, there was no significant difference in any of the subanalyses: bleeds treated with reoperation, readmission or bleeds in children that could be managed conservatively. There were also no significant differences in the subanalyses of individual NSAIDs. Similarly, there was no significant difference in rates of bleeding in the subanalysis of studies that gave NSAIDs multiple times, for instance, both before and after surgery. These results suggest that NSAIDs can be considered as a safe method of analgesia among children undergoing tonsillectomy.

Use of Non-Steroidal Anti-Inflammatory Drugs That Elevate Cardiovascular Risk: An Examination of Sales and Essential Medicines Lists in Low-, Middle-, and High-Income Countries

Certain non-steroidal anti-inflammatory drugs (NSAIDs) (e.g., rofecoxib [Vioxx]) increase the risk of heart attack and stroke and should be avoided in patients at high risk of cardiovascular events. Rates of cardiovascular disease are high and rising in many low- and middle-income countries. We studied the extent to which evidence on cardiovascular risk with NSAIDs has translated into guidance and sales in 15 countries. Data on the relative risk (RR) of cardiovascular events with individual NSAIDs were derived from meta-analyses of randomised trials and controlled observational studies. Listing of individual NSAIDs on Essential Medicines Lists (EMLs) was obtained from the World Health Organization. NSAID sales or prescription data for 15 low-, middle-, and high-income countries were obtained from Intercontinental Medical Statistics Health (IMS Health) or national prescription pricing audit (in the case of England and Canada). Three drugs (rofecoxib, diclofenac, etoricoxib) ranked consistently highest in terms of cardiovascular risk compared with nonuse. Naproxen was associated with a low risk. Diclofenac was listed on 74 national EMLs, naproxen on just 27. Rofecoxib use was not documented in any country. Diclofenac and etoricoxib accounted for one-third of total NSAID usage across the 15 countries (median 33.2%, range 14.7-58.7%). This proportion did not vary between low- and high-income countries. Diclofenac was by far the most commonly used NSAID, with a market share close to that of the next three most popular drugs combined. Naproxen had an average market share of less than 10%. Listing of NSAIDs on national EMLs should take account of cardiovascular risk, with preference given to low risk drugs. Diclofenac has a risk very similar to rofecoxib, which was withdrawn from worldwide markets owing to cardiovascular toxicity. Diclofenac should be removed from EMLs.

Non-steroidal anti-inflammatory drugs for heavy menstrual bleeding

Heavy menstrual bleeding (HMB) is an important cause of ill health in premenopausal women. Although surgery is often used as a treatment, a range of medical therapies are also available. Non-steroidal anti-inflammatory drugs (NSAIDs) reduce prostaglandin levels, which are elevated in women with excessive menstrual bleeding and also may have a beneficial effect on dysmenorrhoea. The primary objective of this review was to investigate the effectiveness of NSAIDs in achieving a reduction in menstrual blood loss in women of reproductive years with HMB. We searched the Cochrane Menstrual Disorders & Subfertility Group trials register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, and CINAHL in July 2012 and reference lists of articles. We also contacted manufacturers and researchers in the field. The inclusion criteria were randomised comparisons of individual NSAIDs or combined with other medical therapy with either each other, placebo or other medical treatments in women with regular heavy periods measured either objectively or subjectively and with no pathological or iatrogenic (treatment-induced) causes for their heavy menstrual blood loss. Eighteen RCTs were identified that fulfilled the inclusion criteria for this review and data were extracted independently. Odds ratios for dichotomous outcomes and weighted mean differences for continuous outcomes were estimated from the data of nine trials. The results of the remaining seven cross-over trials with data unsuitable for pooling, one trial with skewed data and one trial with missing variances were described in data tables. As a group, NSAIDs were more effective than placebo at reducing HMB but less effective than either tranexamic acid, danazol or the levonorgestrel-releasing intrauterine system (LNG IUS). Treatment with danazol caused a shorter duration of menstruation and more adverse events than NSAIDs but this did not appear to affect the acceptability of treatment. There were no statistically significant differences between NSAIDs and the other treatments (oral luteal progestogen, ethamsylate, an older progesterone-releasing intrauterine system (Progestasert), oral contraceptive pill (OCC)) but most studies were underpowered. There was no evidence of a difference between the individual NSAIDs (naproxen and mefenamic acid) in reducing HMB. NSAIDs reduce HMB when compared with placebo but are less effective than tranexamic acid, danazol or LNG IUS. However, adverse events are more severe with danazol therapy. In the limited number of small studies suitable for evaluation, no significant difference in efficacy was demonstrated between NSAIDs and other medical treatments such as oral luteal progestogen, ethamsylate, OCC or another type of intrauterine system, Progestasert.

Cause-Specific Cardiovascular Risk Associated with Nonsteroidal Anti-Inflammatory Drugs among Myocardial Infarction Patients - A Nationwide Study

BackgroundNon steroidal anti-inflammatory drugs (NSAIDs) increase mortality and morbidity after myocardial infarction (MI). We examined cause-specific mortality and morbidity associated with NSAIDs in a nationwide cohort of MI patients.Methods and ResultsBy individual-level linkage of nationwide registries of hospitalization and drug dispensing from pharmacies in Denmark, patients aged >30 years admitted with first-time MI during 1997–2009 and their subsequent NSAID use were identified. The risk of three cardiovascular specific endpoints: cardiovascular death, the composite of coronary death and nonfatal MI, and the composite of fatal and nonfatal stroke, associated with NSAID use was analyzed by Cox proportional hazard analyses. Of 97,698 patients included 44.0% received NSAIDs during follow-up. Overall use of NSAIDs was associated with an increased risk of cardiovascular death (hazard ratio [HR] 1.42, 95% confidence interval [CI] 1.36–1.49). In particular use of the nonselective NSAID diclofenac and the selective cyclooxygenase-2 inhibitor rofecoxib was associated with increased risk of cardiovascular death (HR 1.96 [1.79–2.15] and HR1.66 [1.44–1.91], respectively) with a dose dependent increase in risk. Use of ibuprofen was associated with increased risk of cardiovascular death (HR 1.34[1.26–1.44]), whereas naproxen was associated with the lowest risk of (e.g., HR 1.27[1.01–1.59].ConclusionUse of individual NSAIDs is associated with different cause-specific cardiovascular risk and in particular rofecoxib and diclofenac were associated with increased cardiovascular morbidity and mortality. These results support caution with use of all NSAIDs in patients with prior MI.

Risk of upper gastrointestinal complications in a cohort of users of nimesulide and other nonsteroidal anti‐inflammatory drugs in Friuli Venezia Giulia, Italy

Information on the risk of upper gastrointestinal complications (UGIC) in users of nimesulide, the most used nonsteroidal anti-inflammatory drug (NSAID) in Italy, is scarce. In the context of the European regulatory review on nimesulide, we estimated and compared the risk associated with nimesulide and other individual NSAIDs with the risk in nonusers. We used 2001-2008 data from regional health databases in Friuli Venezia Giulia (FVG), Italy, to conduct a cohort and nested case-control study of users of NSAIDs. Cases were identified by specific and nonspecific hospital discharge diagnoses in primary and secondary position and validated through hospital records. Ten controls per case were selected using density-based sampling from the cohort. Conditional logistic regression was used to estimate adjusted relative risks (RRs) and 95% confidence intervals (CIs). The cohort included 588,827 NSAIDs users and 3031 UGIC cases. Nonspecific codes contributed to 23% of cases and secondary codes to 5%. Among current users, IR per 1000 person-years decreased from 4.45 cases in 2001 to 2.21 cases in 2008. The RR (95%CI) for current use of NSAIDs was 3.28 (2.86, 3.76). RR was <2 for rofecoxib, celecoxib, and nimesulide; 2 to <5 for naproxen, ibuprofen, diclofenac, etoricoxib, and meloxicam; and ≥ 5 for ketoprofen, piroxicam, and ketorolac. IRs of UGIC in FVG decreased about 50% between 2001 and 2008. Nimesulide was in the low-medium range of RR. A complete ascertainment of UGIC cases in databases may require validation of nonspecific codes, secondary codes, and additional codes such as peritonitis and acute posthemorrhagic anemia.

Individual NSAIDs and Upper Gastrointestinal Complications

Background: The risk of upper gastrointestinal (GI) complications associated with the use of NSAIDs is a serious public health concern. The risk varies between individual NSAIDs; however, there is little information on the risk associated with some NSAIDs and on the impact of risk factors. These data are necessary to evaluate the benefit-risk of individual NSAIDs for clinical and health policy decision making. Within the European Community’s Seventh Framework Programme, the Safety Of non-Steroidal anti-inflammatory drugs (NSAIDs) [SOS] project aims to develop decision models for regulatory and clinical use of individual NSAIDs according to their GI and cardiovascular safety.Objective: The aim of this study was to conduct a systematic review and meta-analysis of observational studies to provide summary relative risks (RR) of upper GI complications (UGIC) associated with the use of individual NSAIDs, including selective cyclooxygenase-2 inhibitors.Methods: We used the MEDLINE database to identify cohort and case-control studies published between 1 January 1980 and 31 May 2011, providing adjusted effect estimates for UGIC comparing individual NSAIDs with non-use of NSAIDs. We estimated pooled RR and 95% CIs of UGIC for individual NSAIDs overall and by dose using fixed- and random-effects methods. Subgroup analyses were conducted to evaluate methodological and clinical heterogeneity between studies.Results: A total of 2984 articles were identified and 59 were selected for data abstraction. After review of the abstracted information, 28 studies met the meta-analysis inclusion criteria. Pooled RR ranged from 1.43 (95% CI 0.65, 3.15) for aceclofenac to 18.45 (95% CI 10.99, 30.97) for azapropazone. RR was less than 2 for aceclofenac, celecoxib (RR 1.45; 95% CI 1.17, 1.81) and ibuprofen (RR 1.84; 95% CI 1.54, 2.20); 2 to less than 4 for rofecoxib (RR 2.32; 95% CI 1.89, 2.86), sulindac (RR 2.89; 95% CI 1.90, 4.42), diclofenac (RR 3.34; 95% CI 2.79, 3.99), meloxicam (RR 3.47; 95% CI 2.19, 5.50), nimesulide (RR 3.83; 95% CI 3.20, 4.60) and ketoprofen (RR 3.92; 95% CI 2.70, 5.69); 4–5 for tenoxicam (RR 4.10; 95% CI 2.16, 7.79), naproxen (RR 4.10; 95% CI 3.22, 5.23), indometacin (RR 4.14; 95% CI 2.91, 5.90) and diflunisal (RR 4.37; 95% CI 1.07, 17.81); and greater than 5 for piroxicam (RR 7.43; 95% CI 5.19, 10.63), ketorolac (RR 11.50; 95% CI 5.56, 23.78) and azapropazone. RRs for the use of high daily doses of NSAIDs versus non-use were 2-3 times higher than those associated with low daily doses.Conclusions: We confirmed variability in the risk of UGIC among individual NSAIDs as used in clinical practice. Factors influencing findings across studies (e.g. definition and validation of UGIC, exposure assessment, analysis of new vs prevalent users) and the scarce data on the effect of dose and duration of use of NSAIDs and on concurrent use of other medications need to be addressed in future studies, including SOS.

Individual NSAIDs and Upper Gastrointestinal Complications

The risk of upper gastrointestinal (GI) complications associated with the use of NSAIDs is a serious public health concern. The risk varies between individual NSAIDs; however, there is little information on the risk associated with some NSAIDs and on the impact of risk factors. These data are necessary to evaluate the benefit-risk of individual NSAIDs for clinical and health policy decision making. Within the European Community's Seventh Framework Programme, the Safety Of non-Steroidal anti-inflammatory drugs (NSAIDs) [SOS] project aims to develop decision models for regulatory and clinical use of individual NSAIDs according to their GI and cardiovascular safety. The aim of this study was to conduct a systematic review and meta-analysis of observational studies to provide summary relative risks (RR) of upper GI complications (UGIC) associated with the use of individual NSAIDs, including selective cyclooxygenase-2 inhibitors. We used the MEDLINE database to identify cohort and case-control studies published between 1 January 1980 and 31 May 2011, providing adjusted effect estimates for UGIC comparing individual NSAIDs with non-use of NSAIDs. We estimated pooled RR and 95% CIs of UGIC for individual NSAIDs overall and by dose using fixed- and random-effects methods. Subgroup analyses were conducted to evaluate methodological and clinical heterogeneity between studies. A total of 2984 articles were identified and 59 were selected for data abstraction. After review of the abstracted information, 28 studies met the meta-analysis inclusion criteria. Pooled RR ranged from 1.43 (95% CI 0.65, 3.15) for aceclofenac to 18.45 (95% CI 10.99, 30.97) for azapropazone. RR was less than 2 for aceclofenac, celecoxib (RR 1.45; 95% CI 1.17, 1.81) and ibuprofen (RR 1.84; 95% CI 1.54, 2.20); 2 to less than 4 for rofecoxib (RR 2.32; 95% CI 1.89, 2.86), sulindac (RR 2.89; 95% CI 1.90, 4.42), diclofenac (RR 3.34; 95% CI 2.79, 3.99), meloxicam (RR 3.47; 95% CI 2.19, 5.50), nimesulide (RR 3.83; 95% CI 3.20, 4.60) and ketoprofen (RR 3.92; 95% CI 2.70, 5.69); 4-5 for tenoxicam (RR 4.10; 95% CI 2.16, 7.79), naproxen (RR 4.10; 95% CI 3.22, 5.23), indometacin (RR 4.14; 95% CI 2.91, 5.90) and diflunisal (RR 4.37; 95% CI 1.07, 17.81); and greater than 5 for piroxicam (RR 7.43; 95% CI 5.19, 10.63), ketorolac (RR 11.50; 95% CI 5.56, 23.78) and azapropazone. RRs for the use of high daily doses of NSAIDs versus non-use were 2-3 times higher than those associated with low daily doses. We confirmed variability in the risk of UGIC among individual NSAIDs as used in clinical practice. Factors influencing findings across studies (e.g. definition and validation of UGIC, exposure assessment, analysis of new vs prevalent users) and the scarce data on the effect of dose and duration of use of NSAIDs and on concurrent use of other medications need to be addressed in future studies, including SOS.

Choice of the denominator in case population studies: event rates for registration for liver transplantation after exposure to NSAIDs in the SALT study in France

The effect of denominator options on event rates was tested on the French part of the Study of Acute Liver Transplant (SALT). SALT is a case population study of acute liver failure registered for transplantation (ALFT), exposed to non-steroidal anti-inflammatory drugs (NSAIDs) or non-overdose paracetamol, from 2005 to 2007. Population exposure was computed from the Intercontinental Medical Services' (IMS) and the French national healthcare insurance system's data as the number of defined daily doses (DDDs) sold or dispensed and the number of exposed patients. Nine ALFT cases were exposed to 10 NSAIDs and 49 to non-overdose paracetamol. NSAID sales ranged from 0.04 billion (niflumic acid) to 0.5 billion (ibuprofen) DDDs, amounting to 2.5 billion DDDs for all NSAIDs. The mean per-person exposure ranged from 13.1 (niflumic acid) to 43.2 (ketoprofen) DDDs, reaching 60.5 DDDs for any NSAID. The number of users ranged from 2 million (niflumic acid) to 13 million (ibuprofen), which was 26.6 million for all NSAIDs. The ALFT rates per billion DDDs ranged from 0 to 26 for individual NSAIDs and amounted to 4.6 for all NSAIDs. The ALFT rates per billion DDDs were inversely correlated with the average per-patient exposure (R(2) = 0.935, p = 0.0016). The ALFT rates per million users ranged from 0.31 to 0.49, which was 0.41 for all NSAIDs, with no difference between drugs and no effect of mean per-patient exposure (R(2) = 0.01, p = 0.9). Whether measured per DDD or per user, the event rate with paracetamol was three to five times higher than with NSAIDs. ALFT risk with NSAID seems to be user dependent rather than person-time (exposure) dependent. Choosing the wrong denominator in case population studies might give erroneous results.

Non-steroidal anti-inflammatory drugs and endometrial cancer risk in the VITamins And Lifestyle (VITAL) cohort

ObjectiveChronic inflammation may be an important factor in the initiation and promotion of endometrial cancer. Use of non-steroidal anti-inflammatory drugs (NSAIDs), however, has been inconsistently associated with endometrial cancer risk. Methods22,268 female residents of western Washington State, ages 50–76, completed a baseline questionnaire in 2000–2002 and reported on their use of individual NSAIDs over the past 10years. Use was categorized as none, low (<4days/week or <4years), and high (≥4days/week and ≥4years). Over 9years of follow-up, 262 incident invasive endometrial cancers were identified. Multivariable proportional hazards models were used to estimate hazard ratios (HR) and 95% confidence intervals (CI). ResultsRelative to non-use, high use of aspirin was inversely associated with endometrial cancer risk (HR 0.64, 95% CI: 0.41–1.01; P trend=0.03). Findings were stronger for regular-strength than low-dose aspirin. High use of non-aspirin NSAIDs (HR 1.15, 95% CI: 0.68–1.95), including ibuprofen (HR 1.29, 95% CI: 0.73–2.28), and naproxen (HR 1.08, 95% CI: 0.39–2.95) was not associated with risk. In subgroup analyses, findings for aspirin were strongest for cancers of endometrioid histology and were restricted to non-smokers. ConclusionsThis study provides additional evidence that use of aspirin, but not non-aspirin NSAIDs, may reduce the risk of endometrial cancer, especially in estrogen-mediated cases; however additional prospective studies with high-quality measurement of NSAID use are needed. Aspirin should continue to be examined as a potential agent for cancer chemoprevention.

Prediagnostic Nonsteroidal Anti-Inflammatory Drug Use and Lung Cancer Survival in the VITAL Study

Inflammation is important for lung oncogenesis. Use of nonsteroidal anti-inflammatory drugs (NSAIDs) has been shown to improve colorectal cancer survival. However, few studies have examined the association in lung cancer patients. The VITamins And Lifestyle (VITAL) cohort includes Washington State residents, aged 50 to 76 years, who completed a baseline questionnaire between 2000 and 2002. Participants responded on the frequency and duration of use of individual NSAIDs in the previous 10 years. Subjects of this study were 785 members of the cohort, who were identified with incident lung cancer from baseline through 2007 through linkage to a population-based cancer registry. Participants were followed for lung cancer death through linkage to state records of death through 2009. Adjusted proportional hazards models estimated hazard ratios (HR) and 95% confidence intervals (CI) for the association between NSAIDs and lung cancer death. Five hundred and twenty-two participants (66%) died from lung cancer. Relative to nonuse, high (≥ 4 days/week and ≥ 4 years) prediagnostic use of regular-strength or low-dose aspirin (HR 0.99, 95% CI: 0.74-1.33 and HR 0.89, 95% CI: 0.67-1.17, respectively) or total nonaspirin NSAIDs (HR 1.20, 95% CI: 0.79-1.83) did not reduce lung cancer death. However, high use of ibuprofen was associated with a 62% increased risk of lung cancer death (HR 1.62, 95% CI: 1.01-2.58). Long-term, prediagnostic NSAID use does not improve lung cancer survival overall. Use of ibuprofen may reduce survival from lung cancer. Our results underscore the need for further study of the mechanisms of action for individual NSAIDs with regard to cancer survival.

Non-steroidal anti-inflammatory drugs and small cell lung cancer risk in the VITAL study

Few studies have examined the association between non-steroidal anti-inflammatory drug (NSAID) use and risk of small cell lung cancer (SCLC); among them, findings are mixed. Recently, we found that use of NSAIDs was differentially associated with lung cancer risk by histology. Here, we examine, more comprehensively, the association between individual NSAIDs and SCLC risk. 75,546 residents of western Washington State, ages 50–76, completed a baseline questionnaire in 2000–2002 and reported on their use of individual NSAIDs over the past 10 years. NSAID use was categorized as non-users, low (<4 days/week or <4 years), and high (≥4 days/week and ≥4 years). 111 SCLC were identified through linkage to a population-based cancer registry. Multivariable-adjusted Cox proportional hazards models including strong adjustment for smoking were used to estimate hazard ratios (HR) and 95% confidence intervals (95% CI). Compared to non-use, high use of regular-strength aspirin was associated with an elevated risk of SCLC (HR 1.78, 95% CI: 1.05–3.02; P-trend=0.03). Findings for low-dose aspirin were elevated but did not reach statistical significance. Use of non-aspirin NSAIDs was not associated with SCLC risk. Our findings provide further indication of heterogeneity in the association between aspirin and lung cancer morphologies. Large, prospective studies with comprehensive assessments of NSAID use and smoking history and data on both men and women, are needed in order to better understand the association between use of aspirin and SCLC.

Abstract 245: Cause specific Cardiovascular Risk Associated with use of Non Steroidal Anti-Inflammatory Drugs among Patients with Prior Myocardial Infarction - a Nationwide Cohort Study.

Background: Non steroidal anti-inflammatory drugs(NSAIDs) utilization has been associated with worsened outcomes among patients with established cardiovascular disease.We analyzed the cause-specific cardiovascular risk associated with use of NSAIDs in a nationwide cohort of patients with prior myocardial infarction (MI). Methods: By individual-level linkage of nationwide registries of hospitalizations and drug dispenses from pharmacies in Denmark, patients aged &gt;30 years admitted with first-time MI during 1997-2009 and their subsequent NSAID use were identified. The risk of cardiovascular death, a composite of coronary death or nonfatal MI, and fatal or nonfatal stroke with NSAID use was analyzed by adjusted Cox proportional hazard models. Results: Of 97,698 patients included (mean age 69 years (SD 13.0), 63.0% men),44.0% received NSAIDs during follow-up. Relative to no NSAID use, overall NSAID was associated with an increased risk of cardiovascular death (hazard ratio [HR] 1.52 95% confidence interval [CI] 1.34-1.73). In particular, use of the nonselective NSAID diclofenac and the selective cyclooxygenase-2 (COX-2) inhibitor rofecoxib was associated with increased risk of cardiovascular death (HR 2.05 95% confidence interval CI 1.88-2.23) and HR 1.74(CI.1.53-1.98), respectively) with a dose dependent increase in risk. Use of ibuprofen was associated with increased risk of fatal/nonfatal stroke (HR 1.27(CI. 1.14-1.41)).Naproxen was associated with the lowest risk of all outcomes, although higher than no NSAID use. Conclusion: The cause specific cardiovascular risks associated with the use of individual NSAIDs found to differ and in particular rofecoxib and diclofenac were associated with increased cardiovascular morbidity and mortality. These results further support caution in use of NSAIDs in patients with prior MI.

What Is The “Safest” Non-Steroidal Anti-Inflammatory Drugs?

Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) which are widely used in clinical practice are also very well-known for their various adverse reactions. Each NSAID has its own unique safety profile and selecting an appropriate NSAID m ust be individualized for each patient based on his or her medical needs and risk factors. We reviewed literatures on NSAIDs, focusing on their adverse reaction profile. We reviewed and compared the inci dence of adverse reaction from individual NSAIDs according to organ systems. This review includes both selective COX-2 inhibitors and non- selective NSAIDs. Based on the most up-to-date evidence, ibuprofen appears to be the preferred NSAIDs based on its favorable GI and nephrotoxicity profiles. Naproxen might be considered in patients who have greater cardiac risk. Celecoxib, at the do se of less than or equal to 200 mg day -1 , might be an option in the patients who are at high risk for GI bleeding. Key word: Non-Steroidal Anti-Inflammatory Drugs (NSAIDs), COX-2 inhibitor, adverse drug reaction, adverse reactions, safety profile, clinic al practice, organ systems

Non‐steroidal anti‐inflammatory drugs use and risk of upper gastrointestinal adverse events in cirrhotic patients

The upper gastrointestinal (GI) toxicity associated with non-steroidal anti-inflammatory drugs (NSAID) use among cirrhotic patients remains unclear. The objective of this study was to evaluate the risk of upper GI adverse events associated with celecoxib and oral and parenteral non-selective NSAIDs in cirrhotic patients. All the patients aged ≥20years with a diagnosis of cirrhosis hospitalized for variceal bleeding and non-variceal upper GI adverse events (oesophageal, gastric, duodenal ulcer, bleeding; gastritis and duodenitis) in 2006 were identified using ICD-9-CM diagnosis codes from inpatient claims from the Taiwan National Health Insurance Database. In the case-crossover study design, the case period was defined as 1-30days and the control period as 31-60days before the date of hospitalization. The information for individual NSAID use was obtained from the outpatient pharmacy prescription database. Adjusted self-matched odds ratios (OR) and their 95% confidence intervals (CI) were estimated with a conditional logistic regression model. A total of 4876 cirrhotic patients were included. The adjusted OR (95% CI) was 1.44 (0.89-2.31) for celecoxib, 1.87 (1.66-2.11) for oral non-selective NSAIDs and 1.90 (1.55-2.32) for parenteral NSAIDs overall. Risks were similar for variceal and non-variceal events. Concomitant use of proton pump inhibitors and histamine-2 receptor antagonists tended to decrease the upper GI toxicity associated with non-selective NSAIDs and celecoxib. The use of nsNSAIDs but not celecoxib was associated with a two-fold increased risk of variceal and non-variceal upper GI events among cirrhotic patients.

Non-steroidal anti-inflammatory drugs and cancer incidence by sex in the VITamins And Lifestyle (VITAL) cohort

Use of non-steroidal anti-inflammatory drugs (NSAIDs) may reduce the incidence of several cancers. A recent meta-analysis of randomized trials of aspirin reported a reduction in cancer mortality; however, few studies have investigated whether aspirin or other NSAIDs reduce overall cancer risk. 64,847 residents of western Washington State, aged 50-76, completed a baseline questionnaire in 2000-2002 and reported on their use of individual NSAIDs over the past 10years. Behavior was categorized as non-use, low (<4days/week or <4years), and high (≥4days/week and ≥4years). Over 7years of follow-up, 5,946 incident invasive cancer cases were identified. Multivariable proportional hazards models were used to estimate hazard ratios (HR) and 95% confidence intervals (CI). Relative to non-use, high 10-year use of regular-strength NSAIDs was inversely associated with total cancer risk in men (HR 0.88, 95% CI: 0.79-0.97) and not associated with risk in women (HR 1.10, 95% CI: 0.96-1.25; p interaction<0.01). Use of regular-strength NSAIDs was strongly and inversely associated with colorectal cancer risk in men and women, but differentially associated with sex-specific risk of shared cancer sites other than colorectal cancer (men: HR 0.83, 95% CI: 0.71-0.97; women: HR 1.18, 95% CI: 0.97-1.44; p interaction<0.01). Long-term use of NSAIDs was associated with a reduced risk of total cancer among men and colorectal cancer among both sexes. Our findings do not support NSAID use for overall cancer prevention among women. Additional high-quality studies with long-term follow-up for cancer among women are needed before a public health recommendation can be made.

Endoscopic Hemostasis for Bleeding Gastric Ulcer Caused by Ibuprofen in a 16-month-old Infant

Gastric ulcers are rare in children and are typically seen in cases of Helicobacter pylori (H. pylori) infection, non-steroidal anti-inflammatory drugs (NSAIDs) use, and critical illnesses such as sepsis. The risk of a bleeding ulcer due to use of NSAIDs is dependent on the dose, duration, and the individual NSAIDs, but the bleeding may occur soon after the initiation of NSAID therapy. An experience is described of a 16-month-old infant with a bleeding gastric ulcer after taking the usual dosage of ibuprofen for 3 days. The infant was also successfully treated with endoscopic hemostasis. Even a small amount of ibuprofen may be associated with bleeding gastric ulcers in infant. (Pediatr Gastroenterol Hepatol Nutr 2012; 15: 105∼110)

Response to Letters Regarding Article, “Duration of Treatment With Nonsteroidal Anti-Inflammatory Drugs and Impact on Risk of Death and Recurrent Myocardial Infarction in Patients With Prior Myocardial Infarction: A Nationwide Cohort Study”

We appreciate the interest in our article in Circulation 1 and welcome further discussion on this important topic. Dr Naimer, Dr Alla, and colleagues comment on the influence that stress and rheumatic diseases have on risk in patients. We agree that confounding by indication may influence observational studies such as ours, and that lack of information on nonsteroidal anti-inflammatory drug (NSAID) treatment indication is a limitation of the study. However, our findings were consistent, and we found different degree of risk between the individual NSAIDs, which were probably all used for the same indications, a clear correlation between the degree of cyclooxygenase-2 inhibition (as reported in the literature) and risk, and a clear dose-dependent increase in …

Cardiovascular Risk with Non-Steroidal Anti-Inflammatory Drugs: Systematic Review of Population-Based Controlled Observational Studies

Randomised trials have highlighted the cardiovascular risks of non-steroidal anti-inflammatory drugs (NSAIDs) in high doses and sometimes atypical settings. Here, we provide estimates of the comparative risks with individual NSAIDs at typical doses in community settings. We performed a systematic review of community-based controlled observational studies. We conducted comprehensive literature searches, extracted adjusted relative risk (RR) estimates, and pooled the estimates for major cardiovascular events associated with use of individual NSAIDs, in different doses, and in populations with low and high background risks of cardiovascular events. We also compared individual drugs in pair-wise (within study) analyses, generating ratios of RRs (RRRs). Thirty case-control studies included 184,946 cardiovascular events, and 21 cohort studies described outcomes in >2.7 million exposed individuals. Of the extensively studied drugs (ten or more studies), the highest overall risks were seen with rofecoxib, 1.45 (95% CI 1.33, 1.59), and diclofenac, 1.40 (1.27, 1.55), and the lowest with ibuprofen, 1.18 (1.11, 1.25), and naproxen, 1.09 (1.02, 1.16). In a sub-set of studies, risk was elevated with low doses of rofecoxib, 1.37 (1.20, 1.57), celecoxib, 1.26 (1.09, 1.47), and diclofenac, 1.22 (1.12, 1.33), and rose in each case with higher doses. Ibuprofen risk was seen only with higher doses. Naproxen was risk-neutral at all doses. Of the less studied drugs etoricoxib, 2.05 (1.45, 2.88), etodolac, 1.55 (1.28, 1.87), and indomethacin, 1.30 (1.19, 1.41), had the highest risks. In pair-wise comparisons, etoricoxib had a higher RR than ibuprofen, RRR = 1.68 (99% CI 1.14, 2.49), and naproxen, RRR = 1.75 (1.16, 2.64); etodolac was not significantly different from naproxen and ibuprofen. Naproxen had a significantly lower risk than ibuprofen, RRR = 0.92 (0.87, 0.99). RR estimates were constant with different background risks for cardiovascular disease and rose early in the course of treatment. This review suggests that among widely used NSAIDs, naproxen and low-dose ibuprofen are least likely to increase cardiovascular risk. Diclofenac in doses available without prescription elevates risk. The data for etoricoxib were sparse, but in pair-wise comparisons this drug had a significantly higher RR than naproxen or ibuprofen. Indomethacin is an older, rather toxic drug, and the evidence on cardiovascular risk casts doubt on its continued clinical use. Please see later in the article for the Editors' Summary.

Comment on «Duration of treatment with nonsteroidal anti-inflammatory drugs and impact on risk of death and recurrent myocardial infarction in patients with prior myocardial infarction. A Nationwide Cohort Study»

BackgroundDespite the fact that nonsteroidal anti-inflammatory drugs (NSAIDs) are contraindicated among patients with established cardiovascular disease, many receive NSAID treatment for a short period of time. However, little is known about the association between NSAID treatment duration and risk of cardiovascular disease. We therefore studied the duration of NSAID treatment and cardiovascular risk in a nationwide cohort of patients with prior myocardial infarction (MI). Methods and resultsPatients ≥30 years of age who were admitted with first-time MI during 1997 to 2006 and their subsequent NSAID use were identified by individual-level linkage of nationwide registries of hospitalization and drug dispensing from pharmacies in Denmark. Risk of death and recurrent MI according to duration of NSAID treatment was analyzed by multivariable time-stratified Cox proportional-hazard models and by incidence rates per 1000 person-years. Of the 83 677 patients included, 42.3% received NSAIDs during follow-up. There were 35 257 deaths/recurrent MIs. Overall, NSAID treatment was significantly associated with an increased risk of death/recurrent MI (hazard ratio, 1.45; 95% confidence interval, 1.29 to 1.62) at the beginning of the treatment, and the risk persisted throughout the treatment course (hazard ratio, 1.55; 95% confidence interval, 1.46 to 1.64 after 90 days). Analyses of individual NSAIDs showed that the traditional NSAID diclofenac was associated with the highest risk (hazard ratio, 3.26; 95% confidence interval, 2.57 to 3.86 for death/MI at day 1 to 7 of treatment). ConclusionsEven short-term treatment with most NSAIDs was associated with increased risk of death and recurrent MI in patients with prior MI. Neither short- nor long-term treatment with NSAIDs is advised in this population, and any NSAID use should be limited from a cardiovascular safety point of view.

Comentário a «Duração do tratamento com anti-inflamatórios não esteroides e impacto no risco de morte e recorrência de enfarte do miocárdio em pacientes com enfarte do miocárdio prévio. Um estudo de coorte Nacional»

Background Despite the fact that nonsteroidal anti-inflammatory drugs (NSAIDs) are contraindicated among patients with established cardiovascular disease, many receive NSAID treatment for a short period of time. However, little is known about the association between NSAID treatment duration and risk of cardiovascular disease. We therefore studied the duration of NSAID treatment and cardiovascular risk in a nationwide cohort of patients with prior myocardial infarction (MI). Methods and results Patients ≥ 30 years of age who were admitted with first-time MI during 1997 to 2006 and their subsequent NSAID use were identified by individual-level linkage of nationwide registries of hospitalization and drug dispensing from pharmacies in Denmark. Risk of death and recurrent MI according to duration of NSAID treatment was analyzed by multivariable time-stratified Cox proportional-hazard models and by incidence rates per 1000 person-years. Of the 83 677 patients included, 42.3% received NSAIDs during follow-up. There were 35 257 deaths/recurrent MIs. Overall, NSAID treatment was significantly associated with an increased risk of death/recurrent MI (hazard ratio, 1.45; 95% confidence interval, 1.29 to 1.62) at the beginning of the treatment, and the risk persisted throughout the treatment course (hazard ratio, 1.55; 95% confidence interval, 1.46 to 1.64 after 90 days). Analyses of individual NSAIDs showed that the traditional NSAID diclofenac was associated with the highest risk (hazard ratio, 3.26; 95% confidence interval, 2.57 to 3.86 for death/MI at day 1 to 7 of treatment). Conclusions Even short-term treatment with most NSAIDs was associated with increased risk of death and recurrent MIin patients with prior MI. Neither short- nor long-term treatment with NSAIDs is advised in this population, and any NSAID use should be limited from a cardiovascular safety point of view.