The authors have declared that no competing interests exist.
Conceived and designed the experiments: PMG DH. Analyzed the data: PMG DH. Wrote the first draft of the manuscript: PMG. Contributed to the writing of the manuscript: PMG DH.
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.
Data on the relative risk (RR) of cardiovascular events with individual NSAIDs were derived from meta-analyses of randomised trials and controlled observational studies. Listing of individual NSAIDs on Essential Medicines Lists (EMLs) was obtained from the World Health Organization. NSAID sales or prescription data for 15 low-, middle-, and high-income countries were obtained from Intercontinental Medical Statistics Health (IMS Health) or national prescription pricing audit (in the case of England and Canada). Three drugs (rofecoxib, diclofenac, etoricoxib) ranked consistently highest in terms of cardiovascular risk compared with nonuse. Naproxen was associated with a low risk. Diclofenac was listed on 74 national EMLs, naproxen on just 27. Rofecoxib use was not documented in any country. Diclofenac and etoricoxib accounted for one-third of total NSAID usage across the 15 countries (median 33.2%, range 14.7–58.7%). This proportion did not vary between low- and high-income countries. Diclofenac was by far the most commonly used NSAID, with a market share close to that of the next three most popular drugs combined. Naproxen had an average market share of less than 10%.
Listing of NSAIDs on national EMLs should take account of cardiovascular risk, with preference given to low risk drugs. Diclofenac has a risk very similar to rofecoxib, which was withdrawn from worldwide markets owing to cardiovascular toxicity. Diclofenac should be removed from EMLs.
Non-steroidal anti-inflammatory drugs (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.
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.
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.
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.
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Non-steroidal anti-inflammatory drugs (NSAIDs) are among the most widely used of therapeutic agents. Taken singly or in combination with other classes of drug, they relieve symptoms across multiple clinical indications, including short and long term pain states and a range of musculoskeletal disorders.
Serious adverse effects of NSAIDs are well understood, being related largely to their underlying mechanisms of action
Precise summary information on cardiovascular risk with NSAIDs has been available since 2006 and current evidence suggests that there are significant differences between commonly used members of the class
We ranked NSAIDs by cardiovascular risk (with non-use as reference) using relative risk (RR) values derived from published meta-analyses of randomised trials and controlled observational studies that reported RR for three or more individual drugs
Essential medicines are those satisfying the priority health care needs of the population. They are selected with due regard to public health relevance, evidence on efficacy and safety, and comparative cost-effectiveness. We determined the NSAIDs recommended by the World Health Organization (WHO) in its Model List of Essential Medicines
Intercontinental Medical Statistics Health (IMS Health) tracks over 80% of global pharmaceutical use by sampling individual country sales through multiple supply routes to retail pharmacies and hospitals (
Data on NSAID prescriptions dispensed in the community in England during 2011 were obtained from public prescription cost analysis reports
The meta-analyses were fairly constant in their findings (
NSAID | Serious Cardiovascular Events; RR (95% CI) Versus Non-use of NSAIDs | |||||
Observational Studies (Outcomes) | Randomised Studies (Outcomes) | |||||
Hernandez-Diaz et al., 2006 |
Singh et al., 2006 |
McGettigan and Henry, 2006 |
McGettigan and Henry, 2011 |
Trelle et al., 2011 |
Kearney et al., 2006 |
|
|
nr | nr | nr | 2.05 (1.45–2.88) | 1.53 (0.74–3.17) | nr |
|
nr | nr | nr | 1.55 (1.28–1.87) | nr | nr |
|
1.27 (1.12–1.44) | nr | 1.35 (1.15–1.59) | 1.45 (1.33–1.59) | 1.44 (1.00–1.99) | 1.42 (1.13–1.78) (with celecoxib) |
|
1.39 (1.18–1.64) | 1.38 (1.22–1.57) | 1.40 (1.16–1.70) | 1.40 (1.27–1.55) | 1.60 (0.85–2.99) | 1.63 (1.12–2.37) |
|
nr | nr | 1.30 (1.07–1.60) | 1.30 (1.19–1.41) | nr | nr |
|
nr | nr | 1.25 (1.00–1.55) | 1.20 (1.07–1.33) | nr | nr |
|
1.01 (0.89–1.15) | 1.11 (1.06–1.17) | 1.07 (0.97–1.18) | 1.18 (1.11–1.25) | 2.26 (1.11–4.89) | 1.51 (0.96–2.37) |
|
0.97 (0.86–1.08) | nr | 1.06 (0.91–1.23) | 1.17 (1.08–1.27) | 1.43 (0.94–2.16) | 1.42 (1.13–1.78)(with rofecoxib) |
|
0.98 (0.87–1.11) | 0.99 (0.88–1.11) | 0.97 (0.87–1.07) | 1.09 (1.02–1.16) | 1.22 (0.78–1.93) | 0.92 (0.67–1.26) |
|
nr | nr | 1.06 (0.70–1.59) | 1.08 (0.91–1.30) | nr | nr |
celecoxib and rofecoxib analysed together.
AMI, acute myocardial infarction; APTC, Anti-Platelet Trialists Collaboration; CV, cardiovascular; nr, not reported.
The WHO Model List of Essential Medicines includes three drugs, paracetamol, acetyl salicylic acid (aspirin), and ibuprofen, in the category “non-opioids and non-steroidal anti-inflammatory medicines.” Of 100 countries with EMLs published on the WHO website, most included fewer than six agents in this class. The NSAIDs most commonly recommended were: aspirin (88 countries), ibuprofen (90 countries), diclofenac (74 countries), indometacin (56 countries), and naproxen (27 countries) (
Data reflect retail pharmacy and hospital sales in all countries except Bangladesh and Pakistan [retail pharmacy sales], China [hospital sales], and England and Canada [prescription sales only].
NSAID | Individual NSAID Use Expressed as Percent of Total NSAID Sales in All Countries in 2011 | ||
Median | Maximum | Minimum | |
|
27.80% | 43.40% | 8.30% |
|
11.00% | 26.60% | 3.30% |
|
9.40% | 28.20% | 0.00% |
|
9.10% | 34.70% | 0.00% |
|
7.20% | 21.20% | 0.20% |
|
3.60% | 21.00% | 0.30% |
|
3.10% | 23.60% | 0.00% |
|
2.80% | 27.60% | 0.20% |
|
3.67% | 7.20% | 0.00% |
|
1.10% | 9.50% | 0.20% |
|
33.20% | 58.69% | 14.65% |
HMIC | 31.10% | 58.70% | 15.80% |
LMIC | 37.30% | 57.50% | 14.70% |
Percentage refers to proportion of total NSAID sales in all countries studied. HMIC (high-/high middle-income countries): Australia, China, China (Hong Kong), Malaysia, New Zealand, Singapore, Taiwan, Thailand, UK/England, Canada; LMIC (low-/low middle-income countries): Bangladesh, Indonesia, Pakistan, Philippines, Vietnam.
Diclofenac, etoricoxib.
NSAIDs with a high risk of cardiovascular complications are widely used. Diclofenac and etoricoxib together account for approximately one-third of all sales of NSAIDs in the 15 countries included in our analysis. There was no difference between high- and low-income countries. Diclofenac was by far the most popular NSAID, despite having an RR identical to rofecoxib
Etoricoxib is the other high risk NSAID that features in this study. While there is limited information on its cardiovascular risk, an updated meta-analysis published by us in 2011 found a doubling of cardiovascular risk compared with non-use
Based on meta-analyses of randomised and non-randomised studies, the greatest amount of evidence supports naproxen as the safest choice to minimize cardiovascular risk. However, it was listed in only 27 out of 86 national EMLs published or updated since 2007. In contrast, diclofenac was included on 74 of these EMLs. On average, diclofenac was used three times as frequently as naproxen. In other words, evidence on the relative cardiovascular safety of this drug has failed to translate into appropriate selection for EMLs or usage. The WHO Model List of Essential Medicines provides limited guidance for selection of NSAIDs on EMLs
There are a number of limitations to this work. Most obviously, we do not have information on the risk profiles of patients taking NSAIDs. However, the large and consistent volumes of use of high risk NSAIDs make it very likely that these drugs are being taken by substantial numbers of individuals at high risk of serious cardiovascular events. We relied on sales data for 13 countries and prescription sales for England and Canada. Sales data provide the most comprehensive estimates capturing non-prescription and hospital use in addition to community prescribing, although coverage of all sectors was variable in our study. We could not analyse prevalence of use or dosage, and while it is possible that duration of treatment varies between individual drugs, we don't think this is likely to distort greatly the patterns we have observed in the overall sales data. Importantly, the increase in cardiovascular risk has been reported very early in the course of diclofenac treatment
The findings here have significant implications for public health. For instance, in China the age- and sex-standardised death rate from cardiovascular disease is estimated to be 312/100,000 for males and 260/100,000 for females
There is increasing regulatory concern about diclofenac. The European Medicines Agency has just commenced (as of October 2012) a new review of its cardiovascular safety
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Essential Medicines List
non-steroidal anti-inflammatory drug
relative risk
World Health Organization