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1.  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 
PLoS Medicine  2013;10(2):e1001388.
Patricia McGettigan and David Henry find that, although some non-steroidal anti-inflammatory drugs (NSAIDs) such as diclofenac are known to increase cardiovascular risk, diclofenac is included on 74 countries' essential medicine lists and was the most commonly used NSAID in the 15 countries they evaluated.
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.
Methods and Findings
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 Diclofenac has a risk very similar to rofecoxib, which was withdrawn from worldwide markets owing to cardiovascular toxicity.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.
Please see later in the article for the Editors' Summary
Editors' Summary
Non-steroidal anti-inflammatory drugs (NSAIDs) are among the most widely used drugs. Aspirin, the first NSAID, was developed in 1897 but there are now many different NSAIDs. Some can be bought over-the-counter but others are available only with prescription. NSAIDs can help relieve short- and long-term pain, reduce inflammation (redness and swelling), and reduce high fevers. Common conditions that are treated with NSAIDs include headaches, toothache, back ache, and arthritis. NSAIDs work by stopping a class of enzymes called cyclo-oxygenases (COXs) from making prostaglandins, some of which cause pain and inflammation. Like all drugs, NSAIDs have some unwanted side effects. Because certain prostaglandins protect the stomach lining from the stomach acid that helps to digest food, NSAID use can cause indigestion and stomach ulcers (gastrointestinal complications). In addition, NSAIDs increase the risk of heart attacks and stroke to varying degrees and therefore should be avoided by people at high risk of cardiovascular diseases—conditions that affect the heart and/or blood vessels.
Why Was This Study Done?
Different NSAIDs are associated with different levels of cardiovascular risk. Selective COX-2 inhibitors (e.g., rofecoxib, celecoxib, etoricoxib) generally have fewer stomach-related side effects than non-selective COX inhibitors (e.g., naproxen, ibuprofen, diclofenac). However, some NSAIDs (rofecoxib, diclofenac, etoricoxib) are more likely to cause cardiovascular events than others (e.g., naproxen). When doctors prescribe NSAIDs, they need to consider the patient's risk profile. Particularly for patients with higher risk of cardiovascular events, a doctor should either advise against NSAID use or recommend one that has a relatively low cardiovascular risk. Information on the cardiovascular risk associated with different NSAIDs has been available for several years, but have doctors changed their prescribing of NSAIDs based on the information? This question is of particular concern in low- and middle-income countries where cardiovascular disease is increasingly common. In this study, the researchers investigate the extent to which evidence on the cardiovascular risk associated with different NSAIDs has translated into guidance and sales in 15 low-, middle-, and high-income countries.
What Did the Researchers Do and Find?
The researchers derived data on the relative risk of cardiovascular events associated with individual NSAIDs compared to non-use of NSAIDs from published meta-analyses of randomized trials and observational studies. They obtained information on the NSAIDs recommended in 100 countries from national Essential Medicines Lists (EMLs; essential medicines are drugs that satisfy the priority health care needs of a population). Finally, they obtained information on NSAID sales for 13 countries in the South Asian, Southeast Asian, and Asian Pacific regions and NSAID prescription data for Canada and England. Rofecoxib, diclofenac, and etoricoxib consistently increased cardiovascular risk compared with no NSAIDs. All three had a higher relative risk of cardiovascular events than naproxen in pairwise analyses. Naproxen was associated with the lowest cardiovascular risk. No national EMLs recommended rofecoxib, which was withdrawn from world markets 8 years ago because of its cardiovascular risk. Seventy-four national EMLs listed diclofenac, but only 27 EMLs listed naproxen. Diclofenac was the most commonly used NSAID, with an average market share across the 15 countries of nearly 30%. By contrast, naproxen had an average market share of less than 10%. Finally, across both high- and low-/middle-income countries, diclofenac and etoricoxib accounted for one-third of total NSAID usage.
What Do These Findings Mean?
These findings show that NSAIDs with higher risk of cardiovascular events are widely used in low-/middle- as well as high-income countries. Diclofenac is the most popular NSAID, despite its higher relative risk of cardiovascular events, which is similar to that of rofecoxib. Diclofenac is also widely listed on EMLs even though information on its higher cardiovascular risk has been available since 2006. In contrast, naproxen, one of the safest in relative terms of the NSAIDs examined, was among the least popular and was listed on a minority of EMLs. Some aspects of the study's design may affect the accuracy of these findings. For example, the researchers did not look at the risk profiles of the patients actually taking NSAIDs. However, given the volume of use of high-risk NSAIDS, it is likely that these drugs are taken by many individuals at high risk of cardiovascular events. Overall, these findings have important implications for public health and, given the wide availability of safer alternatives, the researchers suggest that diclofenac should be removed from national EMLs and that its marketing authorizations should be revoked globally.
Additional Information
Please access these Web sites via the online version of this summary at 10.1371/journal.pmed.1001388.
This study is further discussed in a PLOS Medicine Perspective by K. Srinath Reddy and Ambuj Roy
The UK National Health Service Choices website provides detailed information on NSAIDS
MedlinePlus provides information about aspirin, ibuprofen, naproxen, and diclofenac; it also provides links to other information about pain relievers (in English and Spanish)
The American Heart Association has information on cardiovascular disease; Can Patients With Cardiovascular Disease Take Nonsteroidal Antiinflammatory Drugs? is a Cardiology Patient Page in the AHA journal Circulation
The British Heart Foundation also provides information about cardiovascular disease and has a factsheet on NSAIDs and cardiovascular disease
The World Health Organization has a fact sheet on essential medicines; the WHO Model List of Essential Medicines (in English and French), and national EMLs are available
PMCID: PMC3570554  PMID: 23424288
2.  Cardiovascular Risk with Non-Steroidal Anti-Inflammatory Drugs: Systematic Review of Population-Based Controlled Observational Studies 
PLoS Medicine  2011;8(9):e1001098.
David Henry and colleagues reevaluate the evidence from observational studies on the cardiovascular risk associated with non-steroidal anti-inflammatory drugs.
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.
Methods and Findings
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
Editors' Summary
The analgesic (pain relieving), anti-pyretic (fever reducing), and anti-inflammatory (inflammation reducing) properties of the class of drug called non-steroidal anti-inflammatory drugs (NSAIDs)—so called to distinguish this class of drug from steroids, which have similar but additional effects—make NSAIDs one of the most frequently used drugs for the symptomatic treatment of many common conditions. Some preparations of NSAIDs can be bought over the counter, and all are available on prescription, but this class of drug has well documented side effects and risks: people taking NSAIDs are on average four times more likely to develop gastrointestinal complications than people not taking these drugs (that is, the relative risk of gastrointestinal complications is 4), and the relative risk for associated cardiovascular complications—cardiovascular events during treatment with NSAIDs has been one of the most studied adverse drug reactions in history—ranges from 1.0 to 2.0.
Why Was This Study Done?
Several large systematic reviews, including one conducted by these researchers, have previously highlighted apparent differences in cardiovascular risk between individual drugs, but these reviews have provided limited information on dose effects and relevant patient characteristics and have not directly compared the cardiovascular risks of each drug. Furthermore, most of these analyses extensively investigated only a few drugs, with little information on some widely available compounds, such as etoricoxib, etodolac, meloxicam, indomethacin, and piroxicam. Therefore, the researchers conducted this study to update cardiovascular risk estimates for all currently available NSAIDs and to compare the risks between individual drugs. In order to investigate the likely effects of over-the-counter use of NSAIDS, the researchers also wanted to include in their review an analysis of the cardiovascular risk at low doses of relevant drugs, over short time periods, and in low risk populations.
What Did the Researchers Do and Find?
The researchers included only controlled observational studies in their literature search and review (conducted by searching a wide range of databases for studies published from 1985 until November 2010) because randomized controlled trials have reported only small numbers of cardiovascular events that are insufficient for the purposes of this study. The researchers assessed the methodological quality of selected studies, analyzed adjustment variables (for example, age, sex, other medications), and summarized overall results for individual drugs across studies as pooled relative risk estimates. For the subsets of studies that provided relevant data, they pooled within-study relative risk estimates with high and low doses and in people at high and low risk of cardiovascular events, and performed a series of within-study (pair-wise) comparisons and for each pair of drugs, to estimate their comparative relative risks by using a validated online tool to give a ratio of relative risks.
Using this methodology, the researchers included 30 case-control studies and 21 cohort studies: the highest overall risks were with rofecoxib and diclofenac, and the lowest risks were with ibuprofen and naproxen, The researchers found that risk was elevated with low doses of rofecoxib, celecoxib, and diclofenac, and rose with higher doses. Ibuprofen risk was only evident with higher doses. Naproxen did not cause any additional risks at any dose. Of the less studied NSAIDs, etoricoxib, etodolac, and indomethacin had the highest risks. In the pair-wise comparisons, the researchers found that etoricoxib had a higher relative risk than ibuprofen and naproxen, etodolac was not significantly different from naproxen and ibuprofen, and naproxen had a significantly lower risk than ibuprofen. Finally, the researchers showed that relative risk estimates were constant with different background risks for cardiovascular disease and increased early the course of treatment.
What Do These Findings Mean?
This updated systematic review gives some new information on some familiar NSAIDs, and provides potentially important information on some little studied ones, which will help to inform clinical and regulatory decisions. The specific findings suggest that among widely used NSAIDs, naproxen and low-dose ibuprofen are least likely to increase cardiovascular risk, whereas diclofenac in doses available without prescription elevates risk. Based on sparse data, etoricoxib has a high risk of cardiovascular events and is similar to drugs that have been withdrawn because of safety concerns. Indomethacin is an older, rather toxic drug, and the new evidence on cardiovascular risk casts doubt on its continued clinical use.
Additional Information
Please access these websites via the online version of this summary at
Wikipedia defines and discusses NSAIDs
The UK National Health Service and MedicineNet have useful information on NSAIDs that is suitable for patients
The National Prescribing Service in Australia has a range of information on the use of NSAIDs
PMCID: PMC3181230  PMID: 21980265
3.  Associations between Aspirin and other non-steroidal anti-inflammatory drugs and aortic valve or coronary artery calcification: The Multi-Ethnic Study of Atherosclerosis and the Heinz Nixdorf Recall Study 
Atherosclerosis  2013;229(2):310-316.
The association between non-steroidal anti-inflammatory drugs (NSAIDs) and the incidence of valvular and arterial calcification is not well established despite known associations between these drugs and cardiovascular events.
To compare the association between the baseline use of aspirin with other NSAID class medications with the incidence and prevalence of aortic valve calcification (AVC) and coronary artery calcium (CAC).
The relationship of NSAID use to AVC and CAC detected by computed tomography was assessed in 6,814 participants within the Multi-Ethnic Study of Atherosclerosis (MESA) using regression modeling. Results were adjusted for age, sex, ethnicity, study site, anti-hypertensive medication use, education, income, health insurance status, diabetes, smoking, exercise, body mass index, blood pressure, serum lipids, inflammatory markers, fasting glucose, statin medication use, and a simple diet score. Medication use was assessed by medication inventory at baseline which includes the use of non-prescription NSAIDs. MESA collects information on both incident and prevalent calcification. The 4,814 participants of the Heinz Nixdorf Recall (HNR) Study, a German prospective cohort study with similar measures of calcification, were included in this analysis to enable replication.
Mean age of the MESA participants was 62 years (51% female). After adjustment for possible confounding factors, a possible association between aspirin use and incident AVC (Relative Risk(RR): 1.60; 95%Confidence Interval (CI): 1.19–2.15) did not replicate in the HNR cohort (RR: 1.06; 95%CI: 0.87–1.28). There was no significant association between aspirin use and incident CAC in the MESA cohort (RR 1.08; 95%CI: 0.91–1.29) or in the HNR cohort (RR 1.24; 95%CI: 0.87–1.77). Non-aspirin NSAID use was not associated with either AVC or CAC in either cohort. There were no associations between regular cardiac dose aspirin and incident calcification in either cohort.
Baseline NSAID use, as assessed by medication inventory, appears to have no protective effect regarding the onset of calcification in either coronary arteries or aortic valves.
PMCID: PMC3724227  PMID: 23880181
Non-steroidal anti-inflammatory drugs; aspirin; aortic valve calcification; coronary artery calcification; Multi-Ethnic Study of Atherosclerosis; Heinz Nixdorf Recall Study
4.  Potential of prescription registries to capture individual-level use of aspirin and other nonsteroidal anti-inflammatory drugs in Denmark: trends in utilization 1999–2012 
Clinical Epidemiology  2014;6:155-168.
Due to over-the-counter availability, no consensus exists on whether adequate information on nonsteroidal anti-inflammatory drug (NSAID) use can be obtained from prescription registries.
To examine utilization of aspirin and nonaspirin NSAIDs in Denmark between 1999 and 2012 and to quantify the proportion of total sales that was sold on prescription.
Based on nationwide data from the Danish Serum Institute and the Danish National Prescription Registry, we retrieved sales statistics for the Danish primary health care sector to calculate 1-year prevalences of prescription users of aspirin or nonaspirin NSAIDs, and to estimate the corresponding proportions of total sales dispensed on prescription.
Both low-dose aspirin and nonaspirin NSAIDs were commonly used in the Danish population between 1999 and 2012, particularly among elderly individuals. The 1-year prevalence of prescribed low-dose aspirin increased throughout the study period, notably among men. Nonaspirin NSAID use was frequent in all age groups above 15 years and showed a female preponderance. Overall, the prevalence of prescribed nonaspirin NSAIDs decreased moderately after 2004, but substantial variation according to NSAID subtype was observed; ibuprofen use increased, use of all newer selective cyclooxygenase-2 inhibitors nearly ceased after 2004, diclofenac use decreased by nearly 50% after 2008, and naproxen use remained stable. As of 2012, the prescribed proportion of individual-level NSAID sales was 92% for low-dose aspirin, 66% for ibuprofen, and 100% for all other NSAIDs.
The potential for identifying NSAID use from prescription registries in Denmark is high. Low-dose aspirin and nonaspirin NSAID use varied substantially between 1999 and 2012. Notably, use of cyclooxygenase-2 inhibitors nearly ceased, use of diclofenac decreased markedly, and naproxen use remained unaltered.
PMCID: PMC4026552  PMID: 24872722
drug utilization; NSAID; registries; over-the-counter
5.  Prescription of nonsteroidal anti-inflammatory drugs for elderly people in Alberta. 
OBJECTIVE: To examine the extent prescribed nonsteroidal anti-inflammatory drugs (NSAIDs) are used by elderly people in Alberta as well as the degree of concurrent use of multiple NSAIDs, of peptic ulcer medications and of certain medications known to have clinically significant adverse interactions with NSAIDs. DESIGN: Retrospective analysis of the Alberta Blue Cross database. SETTING: Alberta. PATIENTS: All people 65 years of age and older using the subsidized drug benefit plan for whom prescription claims were submitted for reimbursement between Jan. 1 and June 30, 1991. OUTCOME MEASURES: Number of people who received one or more prescriptions for NSAIDs, rates of prescribing peptic ulcer medications and drugs with the potential for clinically significant interactions with NSAIDs among NSAID users and non-NSAID users, and rate of prescribing more than one NSAID concurrently. RESULTS: Of the Albertan population 65 years of age and over 61,601 (26.7%) received at least one prescription for an NSAID during the study period. In decreasing order, the five most commonly prescribed NSAIDs were acetylsalicylic acid, diclofenac, naproxen, indomethacin and ibuprofen. The total cost of NSAID therapy was $5,415,974. Of the people prescribed an NSAID 25.8% were also prescribed a peptic ulcer medication, as compared with 10.5% of the non-NSAID users. There was a significant relation between the increasing number of NSAID prescriptions and the likelihood of receiving a peptic ulcer medication. Those who received a prescription for an NSAID were more likely than non-NSAID users to have been prescribed coumarin anticoagulants, diuretics, angiotensin-converting-enzyme inhibitors, beta-blockers, oral corticosteroids, methotrexate and lithium, all of which are known to have possible adverse interactions with NSAIDs. A total of 2,631 people had two or more prescriptions for NSAIDs filled on the same day. CONCLUSIONS: NSAIDs are prescribed frequently for elderly people and are associated with an increased likelihood of concurrent prescription of peptic ulcer medication and medications that could have adverse drug interactions with NSAIDs. Additional study is required to evaluate the appropriateness of NSAID use in elderly patients, to determine the degree of actual patient consumption of these medications, to document the true prevalence of clinically significant drug interactions and to formulate educational strategies to reach physicians with this information.
PMCID: PMC1336922  PMID: 8039085
6.  Non-steroidal anti-inflammatory drug (NSAID) related inhibition of aldosterone glucuronidation and arterial dysfunction in patients with rheumatoid arthritis: a cross-sectional clinical study 
BMJ Open  2011;1(1):e000076.
Patients with rheumatoid arthritis (RA) are at increased risk of cardiovascular (CV) disease and are also commonly prescribed non-selective non-steroidal anti-inflammatory drugs (ns-NSAIDs). New in vitro evidence suggests that this increased CV risk may be mediated through aldosterone glucuronidation inhibition (AGI), which differs between NSAIDs (diclofenac>naproxen>indomethacin>ibuprofen). Our aim was to explore the association between ns-NSAID-related AGI and arterial dysfunction.
The extent (augmentation index, AIX%) and timing (reflected wave transit time, RWT, ms) of aortic wave reflection (measured using radial applanation pulse wave analysis, PWA, SphygmoCor device) were assessed on a single occasion in 114 consecutive RA patients without overt CV disease aged 40–65 years. A higher AIX% and lower RWT indicate arterial dysfunction. Assessment included a fasting blood sample, patient questionnaire and medical record review. Multivariate analysis was used to adjust for age, sex, mean blood pressure, smoking, cumulative erythrocyte sedimentation rate (ESR-years) and Stanford disability score.
We identified 60 patients taking ns-NSAIDs and 25 non-users. Using a ns-NSAID with the highest AGI was associated with a higher AIX% (and lower RWT) versus treatment with a ns-NSAID with the lowest AGI (diclofenac AIX% 32.3, RWT 132.7 ms vs ibuprofen AIX% 23.8, RWT 150.9 ms): adjusted mean differences AIX% 6.5 (95% CI 1.0 to 11.9; p=0.02); RWT −14.2 ms (95% CI −22.2 to −6.3; p=0.001). Indomethacin demonstrated an intermediate level of arterial dysfunction. In relation to arterial dysfunction, both indomethacin and naproxen were more similar to diclofenac than to ibuprofen.
ns-NSAID-related AGI is associated with arterial dysfunction in patients with RA. These findings provide a potentially novel insight into the CV toxicity of commonly used ns-NSAIDs. However, the findings are limited by the small number of patients involved and require further replication in a much larger study.
Article summary
Article focus
Aldosterone glucuronidation inhibition (AGI) potentiates the adverse cardiovascular effects of aldosterone.
Recently published in vivo research suggests that such inhibition differs between non-selective non-steroidal anti-inflammatory drugs (ns-NSAIDs), with a ranked order of diclofenac>naproxen>indomethacin>ibuprofen, but no previous studies have assessed the relationship between ns-NSAID-related AGI and arterial dysfunction in chronic users.
This study assessed arterial dysfunction using pulse wave analysis.
Key messages
In patients with rheumatoid arthritis we found that chronic use (>3 months) of diclofenac (high AGI) was associated with greater arterial dysfunction compared to ibuprofen (lower AGI); this association was independent of other cardiovascular and rheumatological factors.
Indomethacin (intermediate AGI) was associated with an intermediate level of arterial dysfunction, although naproxen (intermediate AGI) did not fit the anticipated pattern.
Our findings support the concept that AGI may play a role in the cardiovascular toxicity of some ns-NSAIDs commonly used in routine clinical practice.
Strengths and limitations of this study
A single research nurse assessed rheumatoid arthritis patients who were recruited from a consecutive series attending a hospital rheumatology clinic. We adjusted for several important cardiovascular and rheumatological factors known to be independently associated with arterial function and our multivariate analysis explained a high proportion of the variability in arterial dysfunction among chronic ns-NSAID users. The observational cross-sectional design of our study means that we cannot assess causation, nor exclude residual confounding as an explanation for our findings. The small number of patients taking each NSAID meant that the confidence intervals are wide.
PMCID: PMC3191420  PMID: 22021751
7.  Traditional Nonsteroidal Anti-Inflammatory Drugs and Postmenopausal Hormone Therapy: A Drug–Drug Interaction? 
PLoS Medicine  2007;4(5):e157.
Suppression of prostacyclin (PGI2) is implicated in the cardiovascular hazard from inhibitors of cyclooxygenase (COX)-2. Furthermore, estrogen confers atheroprotection via COX-2–dependent PGI2 in mice, raising the possibility that COX inhibitors may undermine the cardioprotection, suggested by observational studies, of endogenous or exogenous estrogens.
Methods and Findings
To identify an interaction between hormone therapy (HT) and COX inhibition, we measured a priori the association between concomitant nonsteroidal anti-inflammatory drugs (NSAIDs), excluding aspirin, in peri- and postmenopausal women on HT and the incidence of myocardial infarction (MI) in a population-based epidemiological study. The odds ratio (OR) of MI in 1,673 individuals and 7,005 controls was increased from 0.66 (95% confidence interval [CI] 0.50–0.88) when taking HT in the absence of traditional (t)NSAIDs to 1.50 (95% CI 0.85–2.64) when taking the combination of HT and tNSAIDs, resulting in a significant (p < 0.002) interaction. The OR when taking aspirin at doses of 150 mg/d or more was 1.41 (95% CI 0.47–4.22). However, a similar interaction was not observed with other commonly used drugs, including lower doses of aspirin, which target preferentially COX-1.
Whether estrogens confer cardioprotection remains controversial. Such a benefit was observed only in perimenopausal women in the only large randomized trial designed to address this issue. Should such a benefit exist, these results raise the possibility that COX inhibitors may undermine the cardioprotective effects of HT.
It is controversial whether estrogens confer cardioprotection. This study suggests that even should such a benefit exist, COX inhibitors may undermine cardioprotective effects of hormone therapy.
Editors' Summary
There is currently a great deal of uncertainty regarding the effect of postmenopausal hormone therapy on heart disease in women. Premenopausal women are much less likely to experience heart attacks and strokes than men, a difference that does not exist between postmenopausal women and men. One mechanism that might explain these observations relates to the effect of estrogen, which is thought to have a protective effect on the heart. Hormone replacement therapy (HT) consisting of replacement estrogen, and sometimes progesterone as well, is often taken by women experiencing symptoms of menopause. Evidence from observational studies and the Womens' Health Initiative (WHI) trial has suggested that HT protects against heart disease in perimenopausal women. However, researchers have suggested that any beneficial effect of hormone replacement therapy on the heart might be counteracted by the effects of certain types of painkillers also being taken by women involved in the studies. These painkillers, nonsteroidal anti inflammatory drugs ( NSAIDs), prevent production of a molecule called prostacyclin. Prostacyclin plays a role in preventing blood clotting and is therefore thought to be important in protecting the heart. Estrogen, however, acts to increase production of prostacyclin, and it is therefore theoretically possible that hormone replacement therapy does have a beneficial effect on heart health, but which is counteracted by the negative effects of NSAIDs.
Why Was This Study Done?
In this study, the researchers wanted to find out whether there was any evidence for an interaction between NSAID use, hormone replacement therapy, and heart disease. Such understanding in turn might help to identify more clearly whether hormone replacement therapy protects against heart disease in specific subgroups of postmenopausal women.
What Did the Researchers Do and Find?
This study was carried out using information from the UK's General Practice Research Database, which is the largest computer database of anonymous medical records from primary care anywhere in the world. It contains information entered by UK general practitioners on their patients' drug prescriptions, diagnoses, referrals to hospital, and other data. The researchers here searched for all individuals from the database who were aged between 50 and 84 years on 1 January 1997, and then followed them up through the database for four years, or until the individual died, reached 85 years of age, or was diagnosed with a heart attack or cancer. From this search, the researchers found 1,673 women who had heart attacks or who died from coronary heart disease; these were considered “cases.” Then, these 1,673 women were matched against 20,000 “control” women of similar age. Information was pulled out for each case or control on their use of hormone replacement therapy, NSAIDs (covering 21 different drugs, but most commonly diclofenac, ibuprofen, and naproxen), and various risk factors for heart disease. The researchers then compared use of hormone replacement therapy and NSAIDs between the cases and controls, while making statistical adjustments for other risk factors (such as diabetes and smoking, for example).
  The researchers found that current use of hormone replacement therapy was associated with a lower risk of heart attack than non-use. The odds ratio (chance of a heart attack among HT users compared to the chance among non-users of HT) was 0.78. However, when looking at women who used NSAIDs at the same time as hormone replacement therapy, the researchers found no suggestion of a reduction in risk of heart attack: the odds ratio for the chance of heart attack among this group of women, as compared to nonusers of both NSAIDs and hormone replacement therapy, was 1.50.
What Do These Findings Mean?
These findings suggest that hormone replacement therapy and NSAIDs might interact, with NSAIDs acting against a role for hormone replacement therapy in preventing heart attacks. At face value, these results are in conflict with the findings of one large trial, the WHI trial, which failed to find a benefit of HT in preventing heart attacks. However, a recent analysis of WHI suggests cardioprotective effects of HT in women close to the time of the menopause and this coincides with the younger age of women in the observational studies such as the present one rather than in the WHI overall. Observational research studies, such as the present one, are often difficult to interpret because the groups being compared are not necessarily equivalent. It's possible that women who take hormone replacement therapy, or NSAIDs, are in some way different from women who do not, which will bias the findings. Determination of the clinical implications of these findings would most appropriately be resolved in future trials, designed to address the question of interest.
Additional Information.
Please access these Web sites via the online version of this summary at
Resources from the US National Institutes of Health on menopausal hormone therapy, including links to information about the Women's Health Initiative trials, information about managing menopausal symptoms, and more
Resources from the US National Institutes of Health (MedlinePlus) about heart disease in women
Information from NHS Direct, the UK National Health Service, about hormone replacement therapy
The UK General Practice Research Database is the database utilized in this article
Wikipedia entry on nonsteroidal anti-inflammatory drugs (NSAIDs) (note: Wikipedia is an internet encyclopedia anyone can edit)
PMCID: PMC1872041  PMID: 17518513
8.  Individual NSAIDs and Upper Gastrointestinal Complications 
Drug Safety  2012;35:1127-1146.
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.
PMCID: PMC3714137  PMID: 23137151
9.  Accounting for the increase in NSAID expenditure: substitution or leakage? 
National Institute of Health and Clinical Excellence (NICE) guidance stated that a new form of non-steroidal anti-inflammatory drug (NSAID) (selective COX-2 inhibitors) should only be an option for arthritis patients at high risk of a gastro-intestinal (GI) event. Total expenditure on NSAIDs has risen by 57% over five years, to £247 million in 2004. We assess whether this expenditure increase can be accounted for by substitution – an increased prescribing of two (more expensive) selective COX-2 inhibitors (celecoxib and rofecoxib) and a simultaneous equivalent reduction in the prescribing volume of three (cheaper) older NSAIDs (diclofenac, ibuprofen and naproxen).
Quarterly prescription data was collated from January 1999 to September 2004. Over this period, the level of correlation between the total prescribing volumes for i) celecoxib and rofecoxib, and ii) diclofenac, ibuprofen, and naproxen were compared, the change in total expenditure on the five NSAIDs was also estimated. The latter was apportioned into that which was estimated to have arisen due to i) substitution, and ii) increased NSAID prescription volume.
Total prescription volumes for the two NSAID groups were negatively correlated (r = -0.97, p < 0.001). In the last quarter there were 1.23 million prescriptions for celecoxib and rofecoxib, and 0.46 million fewer prescriptions for naproxen, diclofenac, and ibuprofen (than in the first quarter, when celecoxib and rofecoxib were not prescribed). Total expenditure for the five NSAIDs was £32.7 million higher in the last quarter, than the first, £12.2 million of which was estimated to be due to substitution, and £20.4 million due to increased volume.
The introduction of celecoxib and rofecoxib was associated with a reduction in the prescription volume for naproxen, diclofenac, and ibuprofen. However, overall quarterly prescription volume for these five NSAIDs increased by 0.76 million, and we estimate that quarterly expenditure increased by £20.4 million more than would have been expected if overall NSAID volume had remained constant. This suggests that the prescription of both celecoxib and rofecoxib may have 'leaked' to population groups who would not previously have received an older NSAID.
PMCID: PMC1501056  PMID: 16737538
10.  Cardiovascular outcomes in high risk patients with osteoarthritis treated with ibuprofen, naproxen or lumiracoxib 
Annals of the Rheumatic Diseases  2007;66(6):764-770.
Evidence suggests that both selective cyclooxygenase (COX)‐2 inhibitors and non‐selective non‐steroidal anti‐inflammatory drugs (NSAIDs) increase the risk of cardiovascular events. However, evidence from prospective studies of currently available COX‐2 inhibitors and non‐selective NSAIDs is lacking in patients at high cardiovascular risk who are taking aspirin.
To determine the cardiovascular outcomes in high risk patients with osteoarthritis treated with ibuprofen, naproxen or lumiracoxib.
The Therapeutic Arthritis Research and Gastrointestinal Event Trial (TARGET) of 18 325 patients with osteoarthritis comprised two parallel substudies, comparing lumiracoxib (COX‐2 inhibitor) with either ibuprofen or naproxen. A post hoc analysis by baseline cardiovascular risk, treatment assignment, and low‐dose aspirin use was performed. The primary composite end point was cardiovascular mortality, non‐fatal myocardial infarction, and stroke at 1 year; a secondary end point was the development of congestive heart failure (CHF).
In high risk patients among aspirin users, patients in the ibuprofen substudy had more primary events with ibuprofen than lumiracoxib (2.14% vs 0.25%, p = 0.038), whereas in the naproxen substudy rates were similar for naproxen and lumiracoxib (1.58% vs 1.48%, p = 0.899). High risk patients not taking aspirin had fewer primary events with naproxen than with lumiracoxib (0% vs 1.57%, p = 0.027), but not for ibuprofen versus lumiracoxib (0.92% vs 0.80%, p = 0.920). Overall, CHF developed more often with ibuprofen than lumiracoxib (1.28% vs 0.14%; p = 0.031), whereas no difference existed between naproxen and lumiracoxib.
These data suggest that ibuprofen may confer an increased risk of thrombotic and CHF events relative to lumiracoxib among aspirin users at high cardiovascular risk. The study indicates that naproxen may be associated with lower risk relative to lumiracoxib among non‐aspirin users. This study is subject to inherent limitations, and therefore should be interpreted as a hypothesis‐generating study.
PMCID: PMC1954641  PMID: 17412741
coronary disease; osteoarthritis; anti‐inflammatory agents, non‐steroidal anti‐inflammatory drugs; COX‐2 inhibitors; aspirin
11.  Comparative effects of non-steroidal anti-inflammatory drugs (NSAIDs) on blood pressure in patients with hypertension 
Nonsteroidal anti-inflammatory drugs (NSAIDs) may disrupt control of blood pressure in hypertensive patients and increase their risk of morbidity, mortality, and the costs of care. The objective of this study was to examine the association between incident use of NSAIDs and blood pressure in patients with hypertension.
We conducted a retrospective cohort study of adult hypertensive patients to determine the effects of their first prescription for NSAID on systolic blood pressure and antihypertensive drug intensification. Data were collected from an electronic medical record serving an academic general medicine practice in Indianapolis, Indiana, USA. Using propensity scores to minimize bias, we matched a cohort of 1,340 users of NSAIDs with 1,340 users of acetaminophen. Propensity score models included covariates likely to affect blood pressure or the use of NSAIDs. The study outcomes were the mean systolic blood pressure measurement after starting NSAIDs and changes in antihypertensive therapy.
Compared to patients using acetaminophen, NSAID users had a 2 mmHg increase in systolic blood pressure (95% CI, 0.7 to 3.3). Ibuprofen was associated with a 3 mmHg increase in systolic blood pressure compared to naproxen (95% CI, 0.5 to 4.6), and a 5 mmHg increase compared to celecoxib (95% CI, 0.4 to 10). The systolic blood pressure increase was 3 mmHg in a subgroup of patients concomitantly prescribed angiotensin converting enzyme inhibitors or calcium channel blockers and 6 mmHg among those prescribed a beta-adrenergic blocker. Blood pressure changes in patients prescribed diuretics or multiple antihypertensives were not statistically significant.
Compared to acetaminophen, incident use of NSAIDs, particularly ibuprofen, is associated with a small increase in systolic blood pressure in hypertensive patients. Effects in patients prescribed diuretics or multiple antihypertensives are negligible.
PMCID: PMC3502533  PMID: 23092442
NSAIDs; Hypertension; Blood pressure; Propensity score
12.  Use of Non-Steroidal Anti-Inflammatory Drugs and Prostate Cancer Risk: A Population-Based Nested Case-Control Study 
PLoS ONE  2011;6(1):e16412.
Despite strong laboratory evidence that non-steroidal anti-inflammatory drugs (NSAIDs) could prevent prostate cancer, epidemiological studies have so far reported conflicting results. Most studies were limited by lack of information on dosage and duration of use of the different classes of NSAIDs.
We conducted a nested case-control study using data from Saskatchewan Prescription Drug Plan (SPDP) and Cancer Registry to examine the effects of dose and duration of use of five classes of NSAIDs on prostate cancer risk. Cases (N = 9,007) were men aged ≥40 years diagnosed with prostatic carcinoma between 1985 and 2000, and were matched to four controls on age and duration of SPDP membership. Detailed histories of exposure to prescription NSAIDs and other drugs were obtained from the SPDP.
Any use of propionates (e.g., ibuprofen, naproxen) was associated with a modest reduction in prostate cancer risk (Odds ratio = 0.90; 95%CI 0.84-0.95), whereas use of other NSAIDs was not. In particular, we did not observe the hypothesized inverse association with aspirin use (1.01; 0.95–1.07). There was no clear evidence of dose-response or duration-response relationships for any of the examined NSAID classes.
Our findings suggest modest benefits of at least some NSAIDs in reducing prostate cancer risk.
PMCID: PMC3030588  PMID: 21297996
13.  Non-Steroidal Anti-Inflammatory Drugs and Antibiotics Prescription Trends at a Central West Bank Hospital 
We aimed to reliably describe the pattern of outpatient prescription of non-steroidal anti-inflammatory drugs (NSAIDs) and antibiotics (ATBs) at a central hospital in the West Bank, Palestine.
This was a retrospective, cross-sectional study investigating a cohort of 2,208 prescriptions ordered by outpatient clinics and the emergency room over one year in Beit Jala Hospital in Bethlehem, West Bank. The orders were analysed for the rate and types of NSAIDs and ATBs utilised, and the appropriateness of these drugs to the diagnosis.
Of the total prescriptions, 410 contained NSAIDs (18.6%), including diclofenac (40.2%), low dose aspirin (23.9%), ibuprofen (17.8%) and indomethacin (15.1%). A minority of these prescriptions contained a combination of these agents (2.5%). Only one prescription contained cyclooxyeganse-2 inhibitors (0.2%). The appropriateness of NSAID use to the diagnosis was as follows: appropriate (58.3%), inappropriate (14.4%) and difficult to tell (27.3%). The rate of ATB use was 30.3% (669 prescriptions). The ATBs prescribed were amoxicillin (23.3%), augmentin (14.3%), quinolones (12.7%), first and second generation cephalosporins (9.4% and 12.7%, respectively) and macrolides (7.2%). ATB combinations were identified in 9.4%, with the most common being second-generation cephalopsorins and metronidazole (4.3%). Regarding the appropriateness of prescribing ATBs according to the diagnosis, it was appropriate in 44.8%, inappropriate in 20.6% and difficult to tell in 34.6% of the prescriptions.
These findings revealed a relatively large number and inappropriate utilisation of ATBs and NSAIDs. An interventional programme needs to be adopted to reinforce physicians’ knowledge of the rational prescription of these agents.
PMCID: PMC3836647  PMID: 24273668
NSAIDs; Antibiotics; Prescription; Palestine
14.  Population-based analysis of non-steroidal anti-inflammatory drug use among children in four European countries in the SOS project: what size of data platforms and which study designs do we need to assess safety issues? 
BMC Pediatrics  2013;13:192.
Data on utilization patterns and safety of non-steroidal anti-inflammatory drugs (NSAIDs) in children are scarce. The purpose of this study was to investigate the utilization of NSAIDs among children in four European countries as part of the Safety Of non-Steroidal anti-inflammatory drugs (SOS) project.
We used longitudinal patient data from seven databases (GePaRD, IPCI, OSSIFF, Pedianet, PHARMO, SISR, and THIN) to calculate prevalence rates of NSAID use among children (0–18 years of age) from Germany, Italy, Netherlands, and United Kingdom. All databases contained a representative population sample and recorded demographics, diagnoses, and drug prescriptions. Prevalence rates of NSAID use were stratified by age, sex, and calendar time. The person-time of NSAID exposure was calculated by using the duration of the prescription supply. We calculated incidence rates for serious adverse events of interest. For these adverse events of interest, sample size calculations were conducted (alpha = 0.05; 1-beta = 0.8) to determine the amount of NSAID exposure time that would be required for safety studies in children.
The source population comprised 7.7 million children with a total of 29.6 million person-years of observation. Of those, 1.3 million children were exposed to at least one of 45 NSAIDs during observation time. Overall prevalence rates of NSAID use in children differed across countries, ranging from 4.4 (Italy) to 197 (Germany) per 1000 person-years in 2007. For Germany, United Kingdom, and Italian pediatricians, we observed high rates of NSAID use among children aged one to four years. For all four countries, NSAID use increased with older age categories for children older than 11. In this analysis, only for ibuprofen (the most frequently used NSAID), enough exposure was available to detect a weak association (relative risk of 2) between exposure and asthma exacerbation (the most common serious adverse event of interest).
Patterns of NSAID use in children were heterogeneous across four European countries. The SOS project platform captures data on more than 1.3 million children who were exposed to NSAIDs. Even larger data platforms and the use of advanced versions of case-only study designs may be needed to conclusively assess the safety of these drugs in children.
PMCID: PMC4225575  PMID: 24252465
Pharmacoepidemiology; Database; Drug utilization; Health resource utilization; Drug safety; Sample size; Asthma exacerbation; Self-controlled case series design; Case-crossover design
15.  Risk of myocardial infarction in patients taking cyclo-oxygenase-2 inhibitors or conventional non-steroidal anti-inflammatory drugs: population based nested case-control analysis 
BMJ : British Medical Journal  2005;330(7504):1366.
Aims To determine the comparative risk of myocardial infarction in patients taking cyclo-oxygenase-2 and other non-steroidal anti-inflammatory drugs (NSAIDs) in primary care between 2000 and 2004; to determine these risks in patients with and without pre-existing coronary heart disease and in those taking and not taking aspirin.
Design Nested case-control study.
Setting 367 general practices contributing to the UK QRESEARCH database and spread throughout every strategic health authority and health board in England, Wales, and Scotland.
Subjects 9218 cases with a first ever diagnosis of myocardial infarction during the four year study period; 86 349 controls matched for age, calendar year, sex, and practice.
Outcome measures Unadjusted and adjusted odds ratios with 95% confidence intervals for myocardial infarction associated with rofecoxib, celecoxib, naproxen, ibuprofen, diclofenac, and other selective and non-selective NSAIDS. Odds ratios were adjusted for smoking status, comorbidity, deprivation, and use of statins, aspirin, and antidepressants.
Results A significantly increased risk of myocardial infarction was associated with current use of rofecoxib (adjusted odds ratio 1.32, 95% confidence interval 1.09 to 1.61) compared with no use within the previous three years; with current use of diclofenac (1.55, 1.39 to 1.72); and with current use of ibuprofen (1.24, 1.11 to 1.39). Increased risks were associated with the other selective NSAIDs, with naproxen, and with non-selective NSAIDs; these risks were significant at < 0.05 rather than < 0.01 for current use but significant at < 0.01 in the tests for trend. No significant interactions occurred between any of the NSAIDs and either aspirin or coronary heart disease.
Conclusion These results suggest an increased risk of myocardial infarction associated with current use of rofecoxib, diclofenac, and ibuprofen despite adjustment for many potential confounders. No evidence was found to support a reduction in risk of myocardial infarction associated with current use of naproxen. This is an observational study and may be subject to residual confounding that cannot be fully corrected for. However, enough concerns may exist to warrant a reconsideration of the cardiovascular safety of all NSAIDs.
PMCID: PMC558288  PMID: 15947398
16.  Risk of acute myocardial infarction with nonselective non-steroidal anti-inflammatory drugs: a meta-analysis 
The use of cyclo-oxygenase 2 selective nonsteroidal anti-inflammatory drugs (NSAIDs) is associated with increased risk of acute myocardial infarction (AMI). The association between the risks of AMI with nonselective NSAIDs is less clear. We reviewed the published evidence and assessed the risk of AMI with nonselective NSAIDs. We performed a meta-analysis of all studies containing data from population databases that compared the risk of AMI in NSAID users with that in non-users or remote NSAID users. The primary outcome was objectively confirmed AMI. Fourteen studies met predefined criteria for inclusion in the meta-analysis. Nonselective NSAIDs as a class was associated with increased AMI risk (relative AMI risk 1.19, 95% confidence interval [CI] 1.08 to 1.31). Similar findings were found with diclofenac (relative AMI risk 1.38, 95% CI 1.22–1.57) and ibuprofen (relative AMI risk 1.11, 95% CI 1.06 to 1.17). However, this effect was not observed with naproxen (relative AMI risk 0.99, 95% CI 0.88–1.11). In conclusion, based on current evidence, there is a general direction of effect, which suggests that at least some nonselective NSAIDs increase AMI risk. Analysis based on the limited data available for individual NSAIDs, including diclofenac and ibuprofen, supported this finding; however, this was not the case for naproxen. Nonselective NSAIDs are frequently prescribed, and so further investigation into the risk of AMI is warranted because the potential for harm can be substantial.
PMCID: PMC1779447  PMID: 16995929
17.  Non-Steroidal Anti-Inflammatory Drugs and Prostate Cancer Risk in the VITamins And Lifestyle (VITAL) Cohort 
Chronic inflammation may be important in prostate carcinogenesis. Several epidemiologic studies have reported inverse associations between non-steroidal anti-inflammatory drugs (NSAIDs) and prostate cancer risk, although many studies are limited by assessment of short-term use only.
Participants were male members of the VITamins And Lifestyle cohort, comprised of 34,132 men, age 50-76 years, living in western Washington State. Cox proportional hazards models were used to estimate adjusted hazard ratios (HR) and 95% confidence intervals (95% CI) of 10-year average use of individual NSAIDs with total prostate cancer (n=1,550) and prostate cancer by grade.
Low-dose aspirin, regular-strength aspirin, ibuprofen, and any non-aspirin NSAID (ibuprofen, naproxen, and COX-2 inhibitors) were not associated with prostate cancer risk. There was a suggestion that regular-strength aspirin was inversely associated with risk of high-grade cancer (HR 0.73, 95% CI: 0.53-1.02).
NSAID use was not associated with prostate cancer risk in the VITAL cohort.
Our findings do not support the use of NSAIDs for chemoprevention of prostate cancer.
PMCID: PMC3005534  PMID: 20935064
18.  General practitioners' use of non-steroidal anti-inflammatory drugs in Tayside and Fife regions. 
The objectives of this study were to assess the prescribing of non-steroidal anti-inflammatory drugs (NSAIDs) by general practitioners and to determine their attitudes to problems caused by this class of drugs. The study consisted of two parts. The first was a questionnaire survey among general practitioners in Fife and Tayside, and the second was an analysis of NSAID prescribing over 12 months among the doctors in the Carnoustie Health Centre, using duplicate prescriptions. In the questionnaire survey 61% of the general practitioners responded. The three most preferred drugs were buprofen (56%), naproxen (20%) and mefenamic acid (7%); choice of drug was determined by efficacy and personal experience. Gastrointestinal side effects were most frequently encountered, although there was little consensus amongst respondents as to their management. The duplicate prescription study showed that 14% of patients (1607 individuals) received at least one NSAID prescription in the year of study. Ibuprofen (31%), naproxen (20%) and piroxicam (15%) were most frequently prescribed and up to 16% of the patients were co-prescribed a gastroprotective agent; ranitidine (75%) was the most commonly prescribed. Despite the introduction of newer NSAIDs, ibuprofen and naproxen are still the most commonly prescribed drugs. Furthermore, although gastrointestinal side effects are commonly encountered, there is some uncertainty about their management.
PMCID: PMC1293583  PMID: 1404187
19.  A review of the benefits and risks of nonsteroidal anti-inflammatory drugs in the management of mild-to-moderate osteoarthritis 
This review is intended to provide physicians with an overview of the benefits and risks associated with the use of nonsteroidal anti-inflammatory drugs (NSAIDs) in the management of their patients with mild-to-moderate osteoarthritis (OA). New information on the inflammatory component of OA and the cardiovascular (CV) risk associated with cyclooxygenase (COX)-2-specific inhibitors has prompted efforts to revise the current recommendations for the use of NSAIDs in the treatment of patients with OA. Clinical studies have shown that naproxen and ibuprofen are significantly more effective at reducing OA pain than is acetaminophen, the traditional first-line therapy, which has no apparent anti-inflammatory activity in the joints. The theoretical advantage of COX-2-specific inhibitors in reducing gastrointestinal (GI) toxicity has been demonstrated by clinical studies. GI complications can be reduced by using lower NSAID doses for the shortest duration or with a concomitant proton-pump inhibitor. All prescription NSAIDs carry a black box warning regarding CV risks; these risks vary among the NSAIDs. While ibuprofen and diclofenac are associated with an increased CV risk, naproxen was associated with a neutral CV risk relative to placebo. Ibuprofen, but not naproxen, attenuates the antiplatelet effects of aspirin. An understanding of the risks and benefits is important when choosing an NSAID. An exhaustive search of the medical literature since 1990 was conducted using the words "ibuprofen," "naproxen," "COX-2-specific NSAIDs," "nonspecific NSAIDs," "low-dose aspirin," and "nonprescription dosage." Databases searched included MEDLINE, EMBASE, and SCISEARCH. This article provides primary care physicians with the information needed to assist them in making more informed decisions in managing patients experiencing mild-to-moderate OA pain.
PMCID: PMC2646740  PMID: 19126235
20.  Predicting NSAID related ulcers--assessment of clinical and pathological risk factors and importance of differences in NSAID. 
Gut  1994;35(7):891-895.
Although ulcers are often associated with non-steroidal anti-inflammatory drugs (NSAIDs) little is known about the feasibility of predicting their development in patients taking NSAIDs. In addition, the ulcerogenic potentials of the newer NSAIDs, taken on long term basis, have not been compared with those of more established preparations. The aim of this study was to identify the clinical and pathological characteristics of patients at a higher risk of NSAID induced ulcers, measure the ulcerogenic potential of a variety of NSAIDs, and test the effect of these potentials on the predictability of ulceration. Altogether 190 long term NSAID users were studied. The presence of abdominal complaints, previous history of ulcers, arthritis related physical disability, anaemia, gastritis, and Helicobacter pylori status were all assessed as possible risk factors. NSAIDs were classified into established drugs (group I), and newer agents (group II). Group I included naproxen, indomethacin, diclofenac, ketoprofen, piroxicam, and flurbiprofen. Group II included fenbufen, nabumetone, ibuprofen, etodolac, azapropazone, and tiaprofenic acid. Of 63 ulcers identified in the study group, 51 (81%) were seen in group I NSAID patients (51 of 132, 39%) compared with 12 ulcers in group II (12 of 58, 21%), p < 0.02; estimated relative risk (ERR): 2.41). In group I, 25 ulcers were found in 38 patients with abdominal pain (25 of 38, 66%, p < 0.01, ERR: 5.03); 18 in 25 (72%) patients with a previous history of ulcers (p < 0.001, ERR: 5.77), 26 in 44 (59%) patients with debilitating arthritis (p < 0.001, ERR 3.64), and 35 in 73 (48%) patients with H pylori associated gastritis (p < 0.01, ERR: 2.48). The presence of these factors in group II patients did not influence the risk of ulceration. Group I NSAIDs were more likely to be associated with chemical gastritis and to intensify H pylori related damage. Although silent ulcers are not uncommon in patients taking NSAIDs, recognition of the risk factors might helps predict a significant number (up to 81%), especially in those receiving group I NSAIDs.
PMCID: PMC1374834  PMID: 8063215
21.  The rate of prescribing gastrointestinal prophylaxis with either a proton pump inhibitor or an H2-receptor antagonist in Nova Scotia seniors starting nonsteroidal anti-inflammatory drug therapy 
Nonsteroidal anti-inflammatory drugs (NSAIDs) are widely used agents that can cause serious gastrointestinal (GI) side effects. For patients at increased risk of NSAID-related GI complications, prophylaxis with either a nonselective NSAID plus gastroprotective agent (GPA) or, alternatively, therapy with a cyclooxygenase-2 selective inhibitor with or without a GPA such as a proton pump inhibitor (PPI), is recommended.
To describe the rate, timing and duration of GI prophylaxis in Nova Scotia seniors receiving nonselective NSAIDs.
The Nova Scotia Seniors’ Pharmacare Program beneficiaries for the years 1998 to 2002 were studied. A cohort of incident NSAID and GPA users was selected from all nonselective NSAID users (no prescribed NSAID dispensed 12 months before the index month and no GPA dispensed two months before the index prescription). Monthly coprescribing rates were calculated by dividing the number of patients in the cohort using GPAs by the number of NSAID users. GI prophylactic coprescribing was defined as the coprescribing rate present at the first month (index month) of prescribing an NSAID.
The cohort consisted of 12,906 patients. Seventy-five per cent of the nonselective NSAID prescriptions dispensed were for up to two months duration, with only 2.3% longer than one year. GI prophylaxis was given to only 3.8% of patients starting NSAIDs who were not on a GPA in the two months before starting NSAIDs. Of this 3.8%, 92.7% of the patients received H2-receptor antagonists (H2RAs), and 7% received PPIs. The rate of H2RA coprescribing increased with the number of consecutive months on an NSAID from 3.5% in the first month to 24.1% at 48 months. For PPIs, the coprescribing rate increased from 0.3% to 1.9% of all NSAID users in the cohort. The rate of gastroprophylaxis coprescribing for patients receiving NSAIDs did not rise with increasing age.
In Nova Scotian seniors using nonselective NSAIDs, the rate of GI prophylaxis was low. Most patients received H2RAs as GPAs despite evidence that they offer insufficient protection.
PMCID: PMC2947001  PMID: 20711527
Cohort study; Cyclooxygenase-2 selective inhibitor; Drug utilization; Gastrointestinal prophylaxis; Histamine-2 receptor antagonist; Misoprostol; Nonsteroidal anti-inflammatory drugs; NSAIDs; Proton pump inhibitor; Prescribing; Seniors
22.  Non-steroidal anti-inflammatory drugs and Amyotrophic Lateral Sclerosis: Results from 5 prospective cohort studies 
Animal and pathological studies suggest that inflammation may contribute to amyotrophic lateral sclerosis (ALS) pathology and that non-steroidal anti-inflammatory drugs (NSAIDs) might be protective. However, there are no prospective data on the relation between NSAID use and ALS risk in humans.
The relation between NSAID use and ALS risk was explored in five large prospective cohort studies (the Nurses’ Health Study, the Health Professionals Follow-up Study, the Cancer Prevention Study II Nutrition Cohort, the Multiethnic Cohort Study, and the National Institutes of Health – AARP Diet and Health Study). Detailed NSAID information was sought from 780,000 participants, 708 of whom developed ALS during follow-up. Cox proportional hazards models were used within each cohort and cohort-specific estimates were pooled with random effects models.
Neither non-aspirin NSAID use, nor aspirin use was associated with ALS risk overall. The multivariable, pooled relative risk was 0.96 (95% CI 0.76-1.22) among non-aspirin NSAID users compared with non-users. Duration of NSAID use in years and frequency of NSAID use were not associated with ALS risk overall.
The results do not support an overall effect of NSAIDs on ALS risk, but because NSAIDs have heterogeneous effects, a role of individual compounds cannot be excluded.
PMCID: PMC3474335  PMID: 22871075
ALS; NSAID; cohort; epidemiology
23.  How do people with knee osteoarthritis use osteoarthritis pain medications and does this change over time? Data from the Osteoarthritis Initiative 
Arthritis Research & Therapy  2013;15(5):R106.
The aim of this analysis was to describe comprehensively the cross-sectional and longitudinal patterns of analgesic and nutraceutical medication use for knee osteoarthritis (OA) in a contemporary US cohort and to investigate associated demographic and clinical factors.
Baseline, 12, 24 and 36 month data were obtained retrospectively from the National Institutes of Health Osteoarthritis Initiative. Participants had symptomatic radiographic knee OA. Multiple binary logistic regression models identified characteristics independently associated with the use of analgesics or nutraceuticals.
We included 987 subjects (55.9% female, mean age 61.5 years, 71.0% white). At baseline, 68.2% reported frequent use of a conventional analgesic or nutraceutical for joint pain (for more than half of the previous month). Non-prescription non-steroidal anti-inflammatory drugs (NSAIDs) were the most frequently reported medications (26.8%), even in those more than 75-years old. Multiple conventional analgesics were used by 11.9%. Frequent analgesic use was more likely in women (odds ratio (OR) 1.8 (95% confidence interval (CI) 1.3 to 2.3)) and people with more pain (moderate 1.7 (1.2 to 2.4); severe 3.1 (2.1 to 4.7)); nutraceutical use was less likely in non-whites (0.4 (0.3 to 0.6)), those more than 74-years old (0.6 (0.3 to 0.9)) and those with comorbidities (0.6 (0.5 to 0.9)) and more likely in people with Kellgren-Lawrence (KL) grade 4 (2.2 (1.5 to 3.3)). Overall there was no change in the proportion of participants frequently using prescription or over the counter (OTC) analgesics at 36 months, although most people had changed medication type; of those using a traditional analgesic at baseline approximately one third were still using the same type at 36 months (ranging from 26.2% of baseline prescription NSAID users to 40.6% of baseline acetaminophen users). All participants reporting baseline analgesic use also reported 36 month analgesic use. Female participants (OR 95% CI 1.2 to 3.2, P = 0.009), those with high body mass index (1.2 to 4.8, P = 0.010) and those with moderate (1.6 to 2.6, P = 0.090) or severe (1.8 to 12.0, P = 0.002) baseline pain were more likely to use pain medication during the 36 month follow-up period; participants more than 75-years old were less likely (0.2 to 1.0, P = 0.053).
Most people with knee OA used pharmacological therapies frequently, and use appeared to be according to American College of Rheumatology recommendations. Change in medication type used was common. Persistent non-prescription NSAID use in older people is an area of concern.
PMCID: PMC3978852  PMID: 24008023
Medications; knee osteoarthritis; Osteoarthritis Initiative
24.  Non-steroidal anti-inflammatory drugs: effects on mortality after colorectal cancer diagnosis 
Cancer  2009;115(24):5662-5671.
Non-steroidal anti-inflammatory drug (NSAID) use has been associated with decreased colorectal cancer (CRC) risk. However, NSAID effects on clinical outcomes after CRC diagnosis are not well-defined. We investigated the association of pre-diagnosis NSAID use and mortality after CRC diagnosis among women in the California Teachers Study (CTS) cohort.
Women under 85 years participating in the CTS, without prior CRC diagnosis at baseline (1995-1996), and diagnosed with CRC during follow-up through December 2005, were eligible for analysis of the association of pre-diagnosis NSAID use and mortality. NSAID use (including aspirin, and ibuprofen) was collected through a self-administered questionnaire. Cancer occurrence was identified through California Cancer Registry linkage. Multivariable Cox proportional hazards regression models were used to estimate hazard ratios (HR) for death and 95% confidence intervals (CI).
Among 621 CRC cases identified, 64% reported no pre-diagnosis regular NSAID use, 17% reported use 1-6 days/week, and 20% reported daily use; duration of NSAID use < 5 years was reported by 17% and ≥5 years reported by 18%. Regular pre-diagnosis NSAID use (1-3 days/week, 4-6 days/week, daily) vs. none was associated with improved overall survival (OS) (HR=0.71, 95% CI 0.53-0.95) and CRC-specific survival (CRC-SS) (HR=0.58, 95% CI 0.40-0.84) after adjustment for clinically relevant factors. Pre-diagnosis NSAID use ≥5 years (versus none) was associated with improved OS (HR=0.55, 95% CI 0.37-0.84) and CRC-SS (HR=0.40, 95% CI 0.23-0.71) in adjusted analyses.
When used regularly or over a prolonged duration prior to CRC diagnosis, NSAIDs are associated with decreased mortality among female CRC cases.
PMCID: PMC3008399  PMID: 19827153
Colon cancer; colorectal cancer; non-steroidal anti-inflammatory drugs; NSAIDs; rectal cancer; survival
25.  Cause for concern in the use of non-steroidal anti-inflammatory medications in the community -a population-based study 
BMC Family Practice  2011;12:70.
Non-steroidal anti-inflammatory (NSAID) medications are a common cause of reported adverse drug side-effects. This study describes the prevalence of non-steroidal anti-inflammatory (NSAID) use (other than low-dose aspirin) and the presence of co-existing relative contraindications to NSAID use and chronic conditions in a representative population sample.
Data were analysed from 3,206 adults attending first follow-up of the North West Adelaide Health Study (NWAHS) in 2004 - 2006, a longitudinal representative population study. Medications were brought into study clinic visits by participants. Clinical assessment included measured blood pressure, kidney function, serum cholesterol, blood glucose. Questionnaires assessed demographics, lifestyle risk factors, physician-diagnosed chronic conditions. Data were weighted to census measures by region, age group, gender, and probability of selection in the household, to provide population representative estimates. Pearson's Chi-square tests determined significant differences in proportions. Multiple logistic regression was used to examine associations of socio-demographic characteristics with use of NSAIDs.
Of 3,175 participants, 357 (11.2%), and 16% of those aged > 55 years, reported using either non-specific NSAIDs or COX-2 inhibitors, other than low-dose aspirin. Among people using NSAIDs, 60.8% had hypertension, 30.8% had Stage 3 or higher chronic kidney disease, 17.2% had a history of cardiovascular disease (CVD) and 20.7% had a > 15% 10-year CVD risk. The prevalence of NSAID use among people with hypertension was 16%, with kidney disease 15.9%, and a history of CVD 20.0%. Among people taking diuretics, 24.1% were also taking NSAIDs, and of those taking medications for gastro-esophageal reflux, 24.7% were on NSAIDs. Prescription-only COX-2 inhibitors, but not other NSAIDs, were used more by people > 75 years than by 35-54 year olds (OR 3.7, 95% CI 2.0, 6.7), and also were more commonly used by people with hypertension, cardiac and kidney disease.
There is a high prevalence of current NSAID use among groups at-risk for significant drug-related adverse events or who have major chronic conditions that are relative contraindications to NSAID use. Assessment of absolute risks regarding cardiovascular and kidney disease need to take into account use of medications such as NSAIDs. The potential to make a substantial impact on chronic disease burden via improved use of NSAIDs is considerable.
PMCID: PMC3166902  PMID: 21733195
COX-2 inhibitors; Non-steroidal anti-inflammatory; chronic disease; cardiovascular risk

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