Recent Non-steroidal Anti-inflammatory Drugs Use Research Articles

Anti-Inflammatory Drug Use and Ovarian Cancer Risk by COX1/COX2 Expression and Infiltration of Tumor-Associated Macrophages.

Nonsteroidal anti-inflammatory drug (NSAID) use may affect ovarian cancer risk via prostaglandin synthesis and tumor-associated macrophage (TAM) infiltration. We evaluated if associations between aspirin or non-aspirin NSAID use and ovarian cancer risk differed by tumor expression of prostaglandin-related (COX1, COX2) and TAM-related (CD68, CD163) markers. We evaluated cases and matched controls from the Nurses' Health Study (NHS), NHSII, and New England Case-Control Study (NECC). Cases with IHC data on COX1 and COX2 (n = 532) or CD68 and CD163 (n = 530) were included. We used polytomous logistic regression, adjusted for ovarian cancer risk factors, to estimate OR for NSAID use and ovarian cancer risk by marker level. Recent aspirin use had a nonsignificant inverse association and recent non-aspirin NSAID use had no association with ovarian cancer risk. NSAID use was not differentially associated with ovarian cancer by COX1 or COX2 expression. However, recent aspirin use was associated with lower ovarian cancer risk for high [OR 0.54; 95% confidence interval (CI), 0.37-0.78], but not low (OR 1.50; 95% CI, 0.97-2.31), CD163 density (P heterogeneity < 0.001). Similar results were observed for aspirin duration and tablets and for recent non-aspirin NSAID use. Results were not clearly different by macrophage density defined by the less specific macrophage marker, CD68. NSAID use was inversely associated with risk of ovarian cancer with high density CD163, a marker for M2-type, immunosuppressive macrophages. However, the relationship did not differ by prostaglandin synthesis markers. Future research should explore prostaglandin-independent mechanisms for the association between NSAID use and ovarian cancer risk, including immune mechanisms.

Risk of myocardial infarction with use of selected non-steroidal anti-inflammatory drugs in patients with spondyloarthritis and osteoarthritis

ObjectivesSpondyloarthritis (SpA) is associated with an increased risk of myocardial infarction (MI) due to underlying inflammation and possibly due to medications such as certain non-steroidal anti-inflammatory drugs (NSAIDs). We sought...

Non-steroidal anti-inflammatory drugs and risk of cerebrovascular events in patients with osteoarthritis: a nested case-control study.

Recent studies show that the risk of cardiovascular adverse events for certain traditional non-steroidal anti-inflammatory drugs (NSAIDs) is similar to that of rofecoxib. While these results are focused on ischemic cardiomyopathy, there is little evidence concerning the risk of ischemic stroke/transient ischemic attack and hemorrhagic stroke. Additionally, there is no information on nimesulide and ketoprofen, the most frequently prescribed NSAIDs in Italy, along with diclofenac. This study aims to determine whether the use of NSAIDs is associated with an increased risk of cerebrovascular events in Italy. We performed a case-control analysis nested in a cohort of patients with osteoarthritis between 2002 and 2011 who were newly treated with NSAIDs. The patients were followed until December 31, 2012. Conditional logistic regression was used to estimate odds ratios (ORs) with 95% confidence intervals (95% CI) of cerebrovascular events (index date) associated with current (until 30 days before the index date), recent (31-365 days) and past (>365 days) use of NSAIDs. Within a cohort of 29,722 patients, 1566 cases (1546 matched with controls) were identified (incidence rate = 11.0/1000 person-years). The overall rate of cerebrovascular event was not elevated with current NSAIDs overall when compared with past use. Among individual NSAIDs, diclofenac and ketoprofen were the molecules significantly associated with an increased rate of cerebrovascular events (OR = 1.53; 95% CI 1.04-2.24; OR = 1.62; 95% CI 1.02-2.58, respectively). The most frequent event was hemorrhagic stroke following the use of ketoprofen (OR = 2.09; 95% CI 1.05-4.15). Diclofenac and ketoprofen seemed to increase the risk of cerebrovascular events. These findings might influence the choice of NSAIDs according to patient characteristics.

Effects of prescription nonsteroidal antiinflammatory drugs on symptoms and disease progression among patients with knee osteoarthritis.

The effect of short-term and long-term use of nonsteroidal antiinflammatory drugs (NSAIDs) on structural change is equivocal. The aim of this study was to estimate the extent to which short- and long-term use of prescription NSAIDs relieve symptoms and delay structural progression among patients with radiographically confirmed osteoarthritis (OA) of the knee. We applied a new-user design among participants with confirmed OA not reporting NSAID use at the time of enrollment in the Osteoarthritis Initiative. Participants were evaluated for changes in the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) subscales (n = 1,846) and joint space width was measured using serial radiographs and a customized software tool (n = 1,116) over 4 years. We used marginal structural modeling to estimate the effect of NSAIDs. Compared to participants who never reported prescription NSAID use, those reporting use at 1 or 2 assessments had no clinically important changes, but those reporting prescription NSAID use at all 3 assessments had, on average, 0.88 point improvement over the followup period (95% confidence interval [95% CI] -0.46 to 2.22) in pain, 0.72 point improvement (95% CI -0.12 to 1.56) in stiffness, and 4.27 points improvement (95% CI -0.31 to 8.84) in function. The average change in joint space width was 0.28 mm less among those reporting NSAID use at 3 assessments relative to nonusers (95% CI -0.06 to 0.62). Recent NSAID use findings were not clinically or statistically significant. Long-term, but not short-term, NSAID use was associated with an a priori-defined minimally important clinical change in stiffness, physical function, and joint space width, but not pain. While showing modest clinical importance, the estimates did not reach statistical significance.

THU0090 Cardiovascular Morbidity in Patients with Ankylosing Spondylitis: A Population-Based Cohort Study

BackgroundIt is well recognized that rheumatoid arthritis is an independent risk factor for cardiovascular (CV) disease. For ankylosing spondylitis (AS), the literature on this risk is relatively scarce, and shows...

EComment. Atrial fibrillation in patients undergoing thoracic surgery

We have read with interest the article 'Lower preoperative fluctuation of heart rate variability is an independent risk factor for postoperative atrial fibrillation in patients undergoing major pulmonary resection' by Pawel Ciszewski and coworkers [1]. In that very well-designed study Ciszewski et al. concluded that preoperative lower fluctuation of heart rate variability (HRV) is an independent atrial fibrillation (AF) riskŦactor in the postoperative period in patients undergoing major pulmonary resection. Atrial fibrillation is responsible for considerable morbidity and mortality, making identification of modifiable risk factors a priority [2]. Chronic kidney disease (CKD) has been strongly associated with new-onset AF [3]. For this reason, kidney function is important in predicting mortality and morbidity in patients with AF. Serum creatinine level is the most common test for renal failure. On the other hand, elevated transaminase concentrations are related to increased risk of AF [4]. Furthermore, in the previous large population-based study, higher serum phosphorus and the related calcium-phosphorus product were also associated with a greater incidence of systemic embolism in patients with AF. Additionally, some medications may cause new-onset AF. The authors previously examined whether or not exposure to non-steroidal anti-inflammatory drugs (NSAIDs) was a risk factor for AF. They concluded that recent NSAID use may predispose patients to AF [3]. Bisphosphonate use was also associated with a significant increase in the risk of serious AF in postmenopausal women [5]. In conclusion, the link between AF and thoracic surgery was presented in the current study. However, AF may be affected by many conditions and it would have been better if these factors had been included in the paper. Finally, we believe that the pivotal roles of those risk factors deserve further large-scale prospective randomized clinical trials. Conflict of interest: none declared

Atrial fibrillation in patients with acute coronary syndromes

We have read with great enthusiasm the recently published article entitled “Incidence, treatment, and outcomes of atrial fibrillation complicating non-ST-segment elevation acute coronary syndromes” by Lopes and coworkers [1]. In that very well-designed and presented study, Lopes and coworkers tried to explain the incidence and timing of post-acute coronary syndrome (ACS) atrial fibrillation (AF) related and not related to coronary artery bypass grafting (CABG); described the use of antithrombotic therapy; and evaluated the association of AF with mortality. They concluded that AF was associated with a nearly 5-fold greater risk of death at 30 days, and both AF overall and post-CABG AFwere associated with amore than 2-fold greater 1year mortality rate. Their study highlights an unexplored area of antithrombotic therapy at hospital discharge in these high-risk patients. Atrial fibrillation, the most common cardiac arrhythmia in clinical practice, is expected to affect millions of people worldwide [2]. AF is responsible for considerable morbidity and mortality, making identification of modifiable risk factors a priority [3]. Chronic kidney disease (CKD) has recently been recognized to be a powerful predictor of cardiovascular morbidity and mortality. CKD was also strongly associated with new-onset AF [4]. For this reason, kidney function is important to predict mortality and morbidity in patients with AF. Serum creatinine level is the most common test for renal failure. The glomerular filtration rate (GFR) provides more sensitive information about renal function than the serum creatinine level. The GFR can be measured by the formula of modification of diet in renal disease (MDRD) and Cockcroft–Gault (CG) equation. However, MDRD formula may measure higher GFR in younger age groups in comparison with the Cockcroft–Gault equation, but it can measure lower GFR in older individuals compared to the Cockcroft–Gault equation [5]. Proteinuria was also apparently linked to the persistent form of AF [6]. Also in this case, if the authors had mentioned the proteinuria and the method of GFR measurements of the patients, the results of this study could contribute to the literature. On theotherhand, elevated transaminase concentrationsare related to increased risk of AF [7]. Also, hyperthyroidism is a relatively uncommon but important cause of atrial fibrillation [8]. Furthermore, in the previous large population-based study, greater levels of serumphosphorus and the related calcium–phosphorus product were also associated with a greater incidenceof systemic embolism inpatientswithAF [9]. Besides it has been proved that the people with a clinically recognized myocardial infarction (MI) are at increased risk for AF. Unfortunately a large proportion of all MI remains to be clinically unrecognized. Whether or not the subjects with electrocardiographic signs of an unrecognized MI were also at an increased risk of developing AF was not clearly elucidated. The presence of anunrecognizedMIwas associatedwithadouble increased risk of atrial fibrillation inmen, independent of known cardiovascular risk factors [10]. Another interesting study tried to examine whether or not exposure to non-steroidal anti-inflammatory drugs (NSAIDs) was a risk factor for AF. They found that recent NSAID use may predispose patients to AF [11]. Bisphosphonate use was also associated with a significant increase in the risk of serious AF in postmenopausal women [12]. In conclusion, AF was associated with a nearly 5-fold greater risk of death at 30 days, and both AF overall and post-CABG AF were associated with a more than 2-fold greater 1-year mortality rate as presented in the current study. However, AF may be affected by many conditions and the pivotal roles of those risk factors deserve further large-scale prospective randomized clinical trials.

Non‐steroidal anti‐inflammatory drug use and the risk of benign prostatic hyperplasia‐related outcomes and nocturia in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial

Study Type - Therapy (cohort) Level of Evidence 4. What's known on the subject? and What does the study add? Accumulating evidence suggests that inflammation may contribute to the development of BPH and LUTS. Therefore, it is plausible that anti-inflammatory agents, such as aspirin and other NSAIDs, may reduce the risk of BPH/LUTS, as was observed in a recent analysis of daily aspirin use and BPH/LUTS risk in the Olmsted County Study of Urinary Symptoms and Health Status in Men. The present study, conducted in the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial, found no association for recent aspirin or ibuprofen use with the risk of BPH/LUTS. To investigate the relationship between non-steroidal anti-inflammatory drug (NSAID) use and the incidence of benign prostatic hyperplasia (BPH)-related outcomes and nocturia, a lower urinary tract symptom (LUTS) of BPH, in light of accumulating evidence suggesting a role for inflammation in BPH/LUTS development. At baseline, participants in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial completed questions on recent, regular aspirin and ibuprofen use, BPH surgery, diagnosis of an enlarged prostate/BPH, and nocturia. Participants in the intervention arm also underwent a digital rectal examination (DRE), from which prostate dimensions were estimated, as well as a prostate-specific antigen (PSA) test. Only participants in the intervention arm without BPH/LUTS at baseline were included in the analysis (n= 4771). • During follow-up, participants underwent annual DREs and PSA tests, provided annual information on finasteride use, and completed a supplemental questionnaire in 2006-2008 that included additional questions on diagnosis of an enlarged prostate/BPH and nocturia. • Information collected was used to investigate regular aspirin or ibuprofen use in relation to the incidence of six BPH/LUTS definitions: diagnosis of an enlarged prostate/BPH, nocturia (waking two or more times per night to urinate), finasteride use, any self-reported BPH/LUTS, prostate enlargement (estimated prostate volume ≥30 mL on any follow-up DRE) and elevation in PSA level (>1.4 ng/mL on any follow-up PSA test). Generally, null results were observed for any recent, regular aspirin or ibuprofen use (risk ratio = 0.92-1.21, P= 0.043-0.91) and frequency of use (risk ratios for one category increase in NSAID use = 0.98-1.11, P-trends = 0.10-0.99) with incident BPH/LUTS. The findings obtained in the present study do not support a protective role for recent NSAID use in BPH/LUTS development.

Migraine History and Breast Cancer Risk Among Postmenopausal Women

PURPOSE Both migraine and breast cancer are hormonally mediated. Two recent reports indicate that women with a migraine history may have a lower risk of postmenopausal breast cancer than those who never suffered migraines. This finding requires confirmation; in particular, an assessment of the influence of use of nonsteroidal anti-inflammatory drugs (NSAID) is needed, because many studies indicate that NSAID use also may confer a reduction in breast cancer risk. METHODS We assessed the relationship between self-reported history of migraine and incidence of postmenopausal breast cancer in 91,116 women enrolled on the Women's Health Initiative Observational Study prospective cohort from 1993 to 1998 at ages 50 to 79 years. Through September 15, 2005, there were 4,006 eligible patients with breast cancer diagnosed. Results Women with a history of migraine had a lower risk of breast cancer (hazard ratio [HR], 0.89; 95% CI, 0.80 to 98) than women without a migraine history. This risk did not vary by recent NSAID use. The lower risk was somewhat more pronounced for invasive estrogen-receptor-positive and progesterone-receptor-positive tumors (HR, 0.83; 95% CI, 0.71 to 0.97), as no reduction in risk was observed for invasive ER-negative/PR-negative tumors (HR, 1.16; 95% CI, 0.86 to 1.57), and this difference in risk estimates was borderline statistically significant (P = .06). CONCLUSION This study supports the hypothesis that a history of migraine is associated with a lower risk of breast cancer and that this relationship is independent of recent NSAID use.

Aspirin, Nonsteroidal Anti-inflammatory Drugs, and the Risks of Cancers of the Esophagus

Frequent consumption of aspirin and nonsteroidal anti-inflammatory drugs (NSAID) has been associated with reduced occurrence of cancers of the esophagus, although potential modifying effects of other causal factors remain relatively unexplored. We compared nationwide samples of Australian patients with adenocarcinomas of the esophagus (EAC; n = 367) or esophagogastric junction (EGJAC; n = 426) or esophageal squamous cell carcinoma (ESCC; n = 309) with control participants sampled from a population register (n = 1,580). Intakes of aspirin, other NSAIDs, and acetaminophen (paracetamol) were assessed from self-reports. We calculated odds ratios (OR) and 95% confidence intervals (95% CI) using multivariable logistic regression. Compared with never-users of aspirin, those who used aspirin at least weekly had significantly lower risks of EAC (OR, 0.48; 95% CI, 0.32-0.72), EGJAC (OR, 0.71; 95% CI, 0.49-1.01), and ESCC (OR, 0.63; 95% CI, 0.40-0.98). At least weekly use of other NSAIDs was also associated with reduced risks of EAC (OR, 0.74; 95% CI, 0.51-1.08), EGJAC (OR, 0.53; 95% CI, 0.37-0.77), and ESCC (OR, 0.46; 95% CI, 0.30-0.73). No association was observed between frequent use of acetaminophen and esophageal cancer. Risk reductions for EAC among users of aspirin and NSAIDs were greater among those who experienced at least weekly symptoms of reflux (OR, 0.26; 95% CI, 0.12-0.55 and OR, 0.41; 95% CI, 0.21-0.77, respectively) than those who did not experience reflux (OR, 0.96; 95% CI, 0.46-2.00 and OR, 0.78; 95% CI, 0.35-1.72, respectively). Recent use of NSAIDs in the past 5 years was associated with greater risk reductions. Frequent use of aspirin and NSAIDs is associated with reduced occurrence of esophageal cancers, particularly among those with frequent symptoms of gastroesophageal reflux.

Long-term Outcome of Helicobacter pylori–Negative Idiopathic Bleeding Ulcers: A Prospective Cohort Study

Helicobacter pylori-negative idiopathic ulcers are increasingly recognized. The secular trend and long-term outcome of this condition are unknown. We prospectively studied consecutive patients with bleeding gastroduodenal ulcers from January to December 2000. The incidence and etiology of ulcers during this period were compared with that between September 1997 and August 1998. H. pylori-negative idiopathic ulcers were defined as negative tests for H. pylori, no exposure to analgesics within 4 weeks, and absence of other risk factors for ulcers. After the ulcers had healed, patients with H. pylori-negative idiopathic ulcers and patients with H. pylori ulcers who received eradication therapy were followed up for 12 months without anti-ulcer drugs. Six hundred thirty-eight patients had bleeding ulcers: 213 (33.4%) were H. pylori ulcers, and 120 (18.8%) were H. pylori-negative idiopathic ulcers (vs 480 [50.3%] H. pylori ulcers and 40 [4.2%] H. pylori-negative idiopathic ulcers in 1997-1998; P < .001). H. pylori-negative idiopathic ulcers accounted for 16.1% of patients who were admitted for bleeding and 42.4% of patients who bled while in the hospital (P < .0001); 28.3% of patients with H. pylori-negative idiopathic ulcers had histologic evidence of past H. pylori infection. The probability of recurrent ulcer complications in 12 months was 13.4% (95% CI: 7.3%-19.5%) in patients with H. pylori-negative idiopathic ulcers and 2.5% (95% CI: 0.4%-4.6%) in patients with H. pylori ulcers who received eradication therapy (P = .0002). The incidence of H. pylori-negative idiopathic bleeding ulcers is rising. These ulcers are prone to recurrent complications.

Effect of helicobacter pylori infection on the risk of upper gastrointestinal bleeding in users of nonsteroidal anti-inflammatory drugs

Purpose We evaluated whether infection with Helicobacter pylori, including specific cytotoxic-associated antigen (CagA)-positive strains, increase the risk of upper gastrointestinal bleeding in users of nonsteroidal anti-inflammatory drugs (NSAIDs). Methods Cases with upper gastrointestinal bleeding and recent NSAID use, including aspirin, who were admitted during 2001, were compared with age- and sex-matched outpatient controls who had recent NSAID use. H. pylori infection was diagnosed by serum antibodies or the 13C-urea breath test; and CagA seropositivity was diagnosed by enzyme-linked immunoassay. Results H. pylori was detected significantly more frequently in cases of bleeding than controls (79% [63/80] vs. 56% [45/80], P = 0.004). Cases of bleeding were more likely than controls to have a history of peptic ulcer (34% [n = 27] vs. 13% [n = 10], P = 0.003), previous upper gastrointestinal bleeding (19% [n = 15] vs. 6% [n = 5], P = 0.03), recent dyspepsia (29% [n = 23] vs. 15% [n = 12], P = 0.06), and <3 months of NSAID use (58% [n = 46] vs. 40% [n = 32], P = 0.04). CagA positivity was not associated with gastrointestinal bleeding. In a multivariate analysis, H. pylori infection was the only significant risk factor for upper gastrointestinal bleeding (odds ratio = 1.7; 95% confidence interval: 1.2 to 2.5; P = 0.004). Conclusion H. pylori infection almost doubles the risk of upper gastrointestinal bleeding among users of NSAIDs.

Consumption of NSAIDs and the Development of Congestive Heart Failure in Elderly Patients

Experimental studies have shown that administration of nonsteroidal anti-inflammatory drugs (NSAIDs) to susceptible individuals can lead to the development of congestive heart failure (CHF). There have been few epidemiological investigations of the importance of this adverse effect. To estimate the relative risk of first admission to a hospital with CHF in recent users of NSAIDs, compared with nonusers, and to determine whether the estimated relative risk was increased in those with a history of heart disease and the extent to which the level of risk varied with the dose and half-life of the drugs consumed. We conducted a matched case-control study of the relationship between recent use of NSAIDs and hospitalization with CHF. Cases (n = 365) were patients admitted to hospitals with a primary diagnosis of CHF. Controls (n = 658) were patients without CHF who were admitted to the same hospitals as case patients. Structured interviews were used to obtain information on several study factors, including recent use of aspirin and other NSAIDs. Use of NSAIDs (other than low-dose aspirin) in the previous week was associated with a doubling of the odds of a hospital admission with CHF (adjusted odds ratio, 2.1; 95% confidence interval, 1.2-3.3). Use of NSAIDs by patients with a history of heart disease was associated with an odds ratio of 10.5 (95% confidence interval, 2.5-44.9) for first admission with heart failure, compared with 1.6 (95% confidence interval, 0.7-3.7) in those without such a history. The odds of a first admission to a hospital with CHF was positively related to the dose of NSAID consumed in the previous week, and was increased to a greater extent with long half-life than with short half-life drugs. Assuming these relationships are causal, NSAIDs were responsible for approximately 19% of hospital admissions with CHF. The burden of illness resulting from NSAID-related CHF may exceed that resulting from gastrointestinal tract damage. NSAIDs should be used with caution in patients with a history of cardiovascular disease.

Recent nonsteroidal anti-inflammatory drug use increases the risk of early recurrence of bleeding in patients presenting with bleeding ulcer

Background: Nonsteroidal anti-inflammatory drug (NSAID) use is a well-known risk factor for ulcer formation and ulcer complications. The purpose of this study was to determine whether recent NSAID use increases the risk of early recurrence of bleeding in patients who present with bleeding ulcer. Methods: Clinical and endoscopic data were collected prospectively. Dose, frequency, and duration of recent NSAID use were quantified. Recent NSAID use was defined as consumption of over-the-counter or prescription NSAIDs or aspirin for at least 5 days of the 2-week period preceding the index episode of bleeding. Endoscopy was performed within 24 hours of admission to confirm the source of bleeding and endoscopic intervention was applied for stigmata of bleeding. Early recurrence of bleeding was defined as melena, hematochezia or blood per nasogastric tube with a 2 gm or greater decrease in hemoglobin during a period of 48 hours, occurring less than 2 weeks from index episode of bleeding. Results: One hundred twenty patients (52 NSAID users and 68 nonusers) were enrolled in the study; mean age was 56 years. NSAID users were older than nonusers ( p = 0.003); nonusers were more likely to have a history of ulcer disease ( p < 0.0005) and higher prevalence of Helicobacter pylori infection ( p = 0.05). Recent NSAID use was associated with a significantly higher frequency of early recurrence of bleeding and in-hospital recurrent bleeding compared with nonusers: 19% vs. 6%, p = 0.02, and 17% vs. 6%, p = 0.04, respectively. In multivariate logistic regression analysis, the significant association between recent NSAID use and early recurrence of bleeding persisted ( p = 0.0048) while controlling for age and other covariates. Conclusions: Recent NSAID use predisposes bleeding ulcer patients to early and in-hospital recurrent bleeding, probably via its effects on platelet function, mucosal prostaglandins, and ulcer healing. (Gastrointest Endosc 2000;51:146-51.)

Heart Failure Hospitalizations Associated with Recent NSAID Use

Nonsteroidal anti-inflammatory drugs (NSAIDs) are known to raise systemic vascular resistance and to reduce renal perfusion through their inhibitory effects on prostaglandin synthesis. In addition, researchers have demonstrated deleterious hemodynamic effects of NSAIDs in patients with pre-existing congestive heart failure. In this retrospective, matched case-control study, Australian researchers examined the association between …

Consumption of non-steroidal anti-inflammatory drugs and the development of functional renal impairment in elderly subjects. Results of a case-control study.

The aim of the present study was to explore the level of risk associated with community use of non-steroidal anti-inflammatory drugs (NSAIDs). We carried out a matched case-control study of the relationship between recent use of NSAIDs and the presence of functional renal impairment present at the time of hospitalisation with a range of clinical problems. Cases (n = 110) were consecutive patients admitted acutely to hospital who had serum creatinine levels greater than or equal to 0.15 mmol l(-1) , which improved by 20% or more within the next 14 days, or prior to discharge from hospital. Controls (n= 189) were subjects of the same sex and age (to within 5 years) as the cases, who were admitted to the same hospital, who had normal serum creatinine levels (<0.12 mmol l(-1) throughout their hospital stay. Information on a number of study factors, including recent use of aspirin and other NSAIDs, was obtained by structured interview. Overall, there was a weak association between consumption of NSAIDs (including non-prophylactic aspirin) and the development of functional renal impairment-adjusted odds ratios (OR) with use of NSAIDs in the previous week or in the previous month: OR 1.5 (95% CI 0.80, 2.9) and 1.8 (95% CI 0.97, 3.4) respectively. In subjects with a previous history of renal disease the adjusted OR was 6.6 (0.75, 57.8) and in those with a history of gout or hyperuricaemia the OR was 7.2 (1.3, 40.2). There was a weak positive relationship between the dose of drug consumed in the previous week and the odds of functional renal impairment. The relationship between risk and published figures for drug half-lives (t1/2) was stronger. The odds ratio increased from 1.2 (95% CI 0.61, 2.4) with a t1/2 < or = 4 h, to 4.8 (1.5, 15.8) with a t1/2 of < or = 12 h (P=0.012, test for trend). This relationship remained statistically significant after adjustment for a number of clinical variables and the dose of drug ingested. NSAIDs are an important cause of functional renal impairment in subjects with renal disease or a history of gout or hyperuricemia. The half-life of the drug is more important than the ingested dose in determining the risk of this outcome. Long half-life drugs should be avoided in individuals who are at risk of developing renal impairment.

Urinary Leukotriene E4 Levels in High-Altitude Pulmonary Edema: A Possible Role for Inflammation

<h3>Study objectives</h3> Inflammation may contribute to the pathogenesis of high-altitude pulmonary edema (HAPE). This study was designed to determine whether a marker of inflammation, urinary leukotriene E4 (LTE4), is elevated in patients with HAPE. <h3>Design</h3> We conducted a case-control study to collect clinical data and urine samples from HAPE patients and healthy control subjects at moderate altitude (≥2727 m), and follow-up urine samples from HAPE patients following their return to low altitude (≤1,600 m). <h3>Setting</h3> Five medical clinics in Summit County, Colorado. <h3>Patients</h3> Questionnaire data were evaluated in 71 HAPE patients and 36 control subjects. Urinary LTE4 levels were determined from a random subset of 38 HAPE patients and 10 control subjects presenting at moderate altitude, and on 5 HAPE patients who had returned to low altitude. <h3>Measurements and Results</h3> Using an enzyme immunoassay technique, urinary LTE4 levels were found to be significantly higher in HAPE patients (123 [16 to 468] pg/mg creatinine, geometric mean [range]) than in control subjects (69 [38 to 135]), p=0.02. Following return to low altitude, urinary LTE4 levels fell significantly from 122 (41.8 to 309) to 53.6 (27.6 to 104) pg/mg creatinine (p=0.05). Urinary LTE4 levels were not related to age, sex, time at altitude, physical condition or habitual exercise, recent use of alcohol or nonsteroidal anti-inflammatory drugs (NSAIDs), or oxygen saturation. Clinical factors associated with HAPE included male sex, regular exercise, and recent use of NSAIDs. <h3>Conclusions</h3> We conclude that urinary LTE4 levels are elevated in patients with HAPE, supporting the view that HAPE involves inflammatory mechanisms.

Evidence of the depletion of susceptibles effect in non-experimental pharmacoepidemiologic research

Past experience with a drug may modify the risk of adverse event associated with current use of this drug. This effect was investigated empirically with a study on non-steroidal anti-inflammatory drugs (NSAIDs)-gastropathy. A hospital-based case-control study was conducted with 244 cases of upper gastrointestinal bleeding (UGIB) age 68 and over and 615 matched controls. Data on all medications dispensed to the study patients during the 3 years preceding admission were obtained from the Quebec universal prescription program automated database. Recent use (within 30 days prior to admission) of non-aspirin NSAIDs increased the risk of UGIB. The estimate of relative risk (RR) was 3.4 (CI, 2.1–5.5). Use of NSAIDs in the previous 3 years was associated with a lower risk of UGIB; the estimate of RR was 0.7 (CI, 0.4–1.0). The estimate of RR for first-time users was 22.7 (2.8–200.0) vs 3.0 (1.9–4.7) for those who had used the drugs at least once in the past 3 years. These results provide empirical evidence of a depletion of susceptibles effect whereby patients who remain on the drugs are those who can tolerate them while those who are susceptible select themselves out of the population at risk. Thus, past use should be considered as a potential risk modifier in non-experimental risk assessment of events associated with drug use.

Helicobacter pylori associated chronic gastritis and peptic ulceration in patients taking non‐steroidal anti‐inflammatory drugs

Helicobacter pylori is now recognized as a frequent cause of histological chronic gastritis, and this has radically changed our understanding of this common condition. In the light of these developments, the traditional view that non-steroidal anti-inflammatory drugs are one of the common 'environmental' causes of chronic gastritis has been re-examined. Gastric mucosal biopsies have been studied from 430 patients undergoing routine upper gastrointestinal endoscopy, 99 of whom had recently been taking non-steroidal anti-inflammatory drugs. No significant association was found between the use of these drugs and either the presence of chronic gastritis or the frequency of colonization with H. pylori, although there was a strong association (P less than 0.0001) between H. pylori and gastritis. Non-steroidal anti-inflammatory drugs appear, however, to modify the inflammatory process in the gastric body, leading to a lower frequency of atrophic gastritis (P less than 0.05). The majority of peptic ulcers were associated with H. pylori irrespective of non-steroidal anti-inflammatory drug use, but there was a higher frequency of H. pylori negative ulceration in the patients who had used these agents (P less than 0.04). Peptic ulceration was uncommon in the absence of either H. pylori or recent non-steroidal anti-inflammatory drug use.

Prostaglandin E1 Analogue Therapy in the Treatment of Refractory Gastric Ulcer in an Elderly Patient

An active 80-year-old woman without a history of peptic ulcer disease, recent nonsteroidal anti-inflammatory drug use, or smoking developed severe, symptomatic epigastric pain initially diagnosed as nonulcer dyspepsia secondary to esophagitis. Initial treatment consisted of 12 weeks of full-dose H2-receptor antagonist therapy. During this therapy the patient developed multiple gastric ulcers confirmed by endoscopy, and continued to have significant dyspeptic symptoms. An additional 16 weeks of combination therapy with ranitidine and sucralfate failed to ameliorate upper gastrointestinal symptoms, and there was significant increase in gastric ulcer size. Repeated ulcer biopsies showed no malignancy. Prior to scheduling elective gastric ulcer surgery, a trial of oral prostaglandin E1 analogue therapy was initiated with an investigational agent. Within the first three weeks of therapy, there was significant symptomatic improvement. Endoscopy of the upper gastrointestinal tract at 12 weeks revealed complete ulcer healing. This case report suggests that prostaglandin E1 analogue therapy should be considered as an alternative to elective gastric ulcer surgery for patients with refractory gastric ulcer.