(NSAIDs) are medications used to alleviate pain and reduce inflammation. Recently a study published in “The BMJ” has revealed that a dose-response relationship between the use of non-steroidal anti-inflammatory drugs and extended risk of for heart attack.
            

Pain killers are of most selling medicine worldwide in modern world. Now days physicians use nonsteroidal anti-inflammatory drugs(NSAIDs) in any kind of simple to high inflammatory pain.Researchers have been studying on this medicine for long time to find out the side effects of its use.


Recently study published in “The BMJ” has revealed that a dose-response relationship between the use of non-steroidal anti-inflammatory drugs and extended risk of for heart attack.

            

Some common NSAIDs , used by the physicians

            

Nonsteroidal anti-inflammatory drugs (NSAIDs) are medications used to alleviate pain and reduce inflammation. They work by blocking the activity ofCOX-1 and COX-2 - enzymes that produce chemicals called prostaglandins, which promote inflammation.


According to the research team, led by Giovanni Corrao of the University of Milan-Bicocca in Italy, previous research has provided strong evidence that NSAIDs - including COX-2 inhibitors, a new generation of NSAIDs - can raise the risk of heart failure.


As such, clinical guidelines - such as those from the European Society of Cardiology - recommend limiting NSAID use among individuals who are already at increased risk of heart failure, while patients already diagnosed with heart failure should refrain from using NSAIDs completely.


"Nevertheless, there is still limited information on the risk of heart failure associated with the use of individual NSAIDs (both COX-2 inhibitors and traditional NSAIDs) in clinical practice, and especially on their dose-response associations,"the authors note.


With this in mind, Corrao and team decided to estimate how the use and dose of individual NSAIDs affect the risk of hospital admission for heart failure.

The new research cohort

The figure N3 shows the flowchart describing the attrition of eligible NSAIDs users after exclusion criteria were applied. Among nearly 10 million new users of NSAIDs identified across all databases,7 680 181 met the inclusion criteria and constituted the study cohort. Cohort members accumulated 24 555 063 person years of follow-up and generated 92 163cases of heart failure admitted to hospital (incident rate, 37.5 heart failure events per 10 000 person years). Cases were matched to 8 246 403 controls.


Mean age was 77 (standard deviation 11)years and 76 (10) years among cases and controls, respectively. About 45% of both cases and controls were men. Compared with controls, cases had more comorbidities (mainly cardiovascular disease, such as acute myocardial infarction, other ischaemic heart diseases, atrial fibrillation and flutter,and valvular disease and endocarditis) and received concomitant drug treatments more often (eg, anticoagulants, cardiac glycosides, nitrates, and cytochromeP450 2C9 inhibitors). We found 9.1% of cases and 2.5% of controls with a history of heart failure diagnosis, recorded as either an outpatient diagnosis or a secondary hospital diagnosis in the year before start of NSAID treatment(cohort entry).

The NSAIDs that are the culprit for increased heart attack risk

The researchers assessed data from five population-based healthcare databases across four European countries: Germany, Italy, the Netherlands, and the United Kingdom.


More than 10 million NSAID users were included in the data, and these were matched with more than 8 million controls. The analysis included a total of 27 NSAIDs, of which four were selective COX-2 inhibitors.

            

A total of 16 081 (17.4%) cases and 1 193 537(14.4%) matched controls were current users of NSAIDs. Figure N3 reports the distribution of current use of individual NSAIDs among all cases and controls. Among controls, the most frequently used traditional NSAIDs were diclofenac(2.9%), nimesulide (2.4%), and ibuprofen (1.7%), while the most frequently used COX 2 inhibitors were celecoxib (1.4%), rofecoxib (1.0%), and etoricoxib(0.6%).


According to the pooled analysis, current users of any NSAID had a 20% higher risk of heart failure than past users (odds ratio1.19; 95% confidence interval 1.17 to 1.22). Conversely, there was no evidence that recent use of any NSAID was associated with differences in heart failure risk with respect to past use (1.00; 0.99 to 1.02). We observed a statistically significantly higher risk of heart failure in association with current use of nine individual NSAIDs than with past use of any NSAIDs (fig N3). These NSAIDs were ketorolac, etoricoxib, indomethacin, rofecoxib, piroxicam, diclofenac,ibuprofen, nimesulide, and naproxen. Other less frequently used NSAIDs (eg, sulindac, acemethacin, and dexibuprofen) were also found to be associated with an increased risk of heart failure, although the 95% confidence intervals included the null value. All nine significant associations identified in this analysis were also identified as significant by the Bonferroni-Holm procedure(supplementary table S2).

Compared with current use of celecoxib,current use of other individual NSAIDs was not associated with a significant decrease in heart failure risk. Odds ratios ranged from 0.83 (95% confidence interval 0.57 to 1.20) for oxaprozin to 1.84 (1.67 to 2.04) for ketorolac (supplementary table S3).


For the nine individual NSAIDs significantly associated with heart failure risk, their association was also confirmed regardless of whether there was recorded evidence of a prior heart failure diagnosis and regardless of sex. The estimated risk of heart failure associated with current use of NSAIDs of nimesulide, etoricoxib, and indomethacin among women was lower in magnitude than among men, compared with past use of any NSAIDs.

            

Fig N3: Distribution of current use of individual NSAIDs among cases and controls and pooled associations between current use of individual NSAIDs and risk of hospital admission for heart failure, with past use of any NSAID as reference. Estimates obtained by pooling individual data from all available databases. Pooled odds ratios and 95% confidence intervals estimated by fitting a conditional logistic regression model after correcting for available covariates

            

Overall,the researchers found current NSAID users (defined as individuals who had used NSAIDs within the past 14 days) were 19 percent more likely to be admitted to the hospital with heart failure than past users (individuals who had not used NSAIDs for at least 183 days).


What is more, the researchers identified a dose-response relationship; at very highdoses, diclofenac, etoricoxib, indomethacin, piroxicam, and rofecoxib were associated with double the risk of hospital admission for heart failure.


Corrao and colleagues stress that their study is observational, so they are unable to confirm a causal link between NSAID use and heart failure.


Still,the researchers believe their findings have significant public health implications:


"Our study [...] provides evidence that current use of both COX-2 inhibitors and traditional individual NSAIDs are associated with increased risk of heart failure. Furthermore, the magnitude of the association varies between individual NSAIDs and according to the prescribed dose.


Because any potential increased risk could have a considerable impact on public health,the risk effect estimates provided by this study may help inform both clinical practices and regulatory activities."

Overview

The new study offers further evidence that the most frequently used individual traditional NSAIDs and selective COX 2inhibitors are associated with an increased risk of hospital admission for heart failure. Moreover, the risk seems to vary between drugs and according to the dose. For the individual NSAIDs less frequently used, we were not able to exclude a risk of low to moderate magnitude owing to the limited numbers of exposed cases identified in this study. Because any potential increased risk could have a considerable impact on public health, the risk effect estimates provided by this study may help inform both clinical practices and regulatory activities.

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