Diclofenac: Similar CV Risk to Rofecoxib in Healthy People

June 09, 2010

June 9, 2010 (Copenhagen, Denmark) — The first study to examine the cardiovascular risk associated with nonsteroidal anti-inflammatory drugs (NSAIDs) in healthy individuals has found increased morbidity and mortality with diclofenac, rofecoxib (Vioxx, Merck), and high doses of ibuprofen [1]. Naproxen, in contrast, has a safer cardiovascular risk profile, say Dr Emil Loldrup Fosbøl and colleagues in their paper published online June 8, 2010 in Circulation: Cardiovascular Quality and Outcomes.

The increased cardiovascular morbidity and mortality seen with diclofenac, which is similar to that observed with rofecoxib--a drug that was withdrawn from the market in 2004 because of poor cardiovascular safety--is particularly concerning, Fosbøl told heartwire .

Patients and clinicians need to know that [diclofenac] increases the risk of cardiovascular adverse events.

"We've been so much focused on the newer COX-2 inhibitors, but the primary message concerns diclofenac, because there is so much evidence now that this is also a problem; it has been shown quite extensively in many reports. Diclofenac has been used for almost 50 years and is available over the counter [OTC] in many countries, which I think is irrational. This is a major public-health concern, and patients and clinicians need to know that this drug increases the risk of cardiovascular adverse events. "

Also worrying is the fact that the results were dose-dependent, and diclofenac is more often used in high doses compared with other NSAIDs, say Fosbøl and colleagues. "Our results suggest that naproxen could be a safer alternative when NSAID treatment is required," they state.

Large Study, Covering Entire Population of Denmark

The researchers used a nationwide cohort of healthy individuals over the age of 10 in Denmark, made possible by the fact that all residents have a unique personal number, which enables linkage of administrative registries on an individual level. They identified more than 2.5 million people who claimed at least one prescription for NSAIDs from 1997 to 2005; after applying selection criteria regarding comorbidity and concomitant pharmacotherapy, they included just over one million individuals in the analysis.

Ibuprofen was the only nonaspirin NSAID that could be purchased OTC in Denmark during the study period, but it was available only in low doses (200 mg) and in limited quantities, say the researchers. In addition, the system in Denmark would ensure that those requiring higher doses of ibuprofen would have financial incentive to obtain a prescription from their doctor, so OTC NSAID use is unlikely to have had a significant influence on the results, they point out.

Prescription use of the nonselective NSAID diclofenac and the selective COX-2 inhibitor rofecoxib was associated with an increased risk of cardiovascular death (odds ratio 1.91 and 1.66, respectively), with a dose-dependent increase in risk.

Our results further strengthen the association between NSAID use and cardiovascular risk by demonstrating effects on all cardiovascular outcomes.

There was a trend for an increased risk of fatal or nonfatal stroke associated with ibuprofen treatment (OR 1.29), but naproxen was not associated with increased cardiovascular risk (OR for cardiovascular death 0.84).

Although rofecoxib was withdrawn in 2004, another COX-2 inhibitor, celecoxib (Celebrex, Pfizer), is still available. But Fosbøl et al say they were unable to draw any firm conclusions about the cardiovascular safety of celecoxib in this study because the analysis is based on few events, especially at higher doses. The results of the ongoing Prospective Randomized Evaluation of Celecoxib Integrated Safety vs Ibuprofen and Naproxen (PRECISION) trial should shed more light on the risks and benefits of this drug, they say.

They also showed that all NSAIDs except for celecoxib were linked to a substantial increase in risk of serious bleeding, a well-known adverse effect of NSAIDs "that needs to be kept in mind."

Dr Florian Krötz (University Hospital Munich, Germany), who has recently published a review on the risk of MI associated with diclofenac [2] but was not involved with this study, told heartwire : "Concerning diclofenac and rofecoxib, I agree with the increased risk of CV death that the authors find."

However, a "major weakness" of such observational trials is the problem of correlating doctors' certificates on causes of death with numbers of prescriptions, he says. And it is unknown whether the individuals have actually taken these drugs or whether they had cardiovascular risk factors or even any history of CV disease. "As such, I think such studies must be interpreted with great caution," Krötz commented.

Fosbøl et al acknowledge these shortcomings of their trial but note that it also has its strengths, including the size and completeness of data, covering the entire population of Denmark, and the fact that two independent and different statistical approaches were employed to examine the relationship between exposure to NSAIDs and the chosen outcomes.

First Study to Show NSAIDs Affect All Cardiovascular Outcomes

The study was also the first to look at quite specific cardiovascular end points rather than just MI or MI and overall death, says Fosbøl. No previous study has reported results on specific end points such as fatal/nonfatal stroke or coronary death combined with nonfatal MI.

"Therefore, our results further strengthen the association between NSAID use and cardiovascular risk by demonstrating effects on all cardiovascular outcomes."

Population of NSAID Initiators and Sex-, Age- and Time-Matched Controls of Non-NSAID Initiators: Hazard Ratios for Specific Causes of Death Associated With Exposure Stratified According to Daily Dosagea

Drug (mg/day) CV death Coronary death or nonfatal MI Fatal or nonfatal stroke
Ibuprofen      
Any use 0.88b 1.31b 1.47b
<1200 0.79b 1.24b 1.39b
>1200 1.63b 1.94b 2.22b
Diclofenac      
Any use 1.20b 1.83b 2.00b
<100 0.80 1.39b 1.33c
>100 1.46b 2.10b 2.41b
Rofecoxib      
Any use 1.64b 1.84b 1.12
<25 1.60b 1.82b 1.10
>25 2.77c 2.36 1.79
Celecoxib      
Any use 1.24 1.44b 1.27
<200 1.19 1.44c 1.16
>200 1.51 1.49 1.95
Naproxen      
Any use 0.86 0.78 1.54b
<500 0.84 0.69c 1.55c
>500 0.92 1.22 1.48

a. Compared with no use (HR=1.00)

b. p<0.05

c. p<0.01

Fosbøl says the findings underline the fact that individual NSAIDs have different degrees of cardiovascular safety, so doctors should always make an individual assessment of cardiovascular risk and carefully consider the balance between benefit and risk before starting therapy with any NSAID.

Also, because adverse CV events observed were dose dependent, it is important that NSAIDs are prescribed at the lowest possible dose for the shortest period of time, he adds. He and his colleagues were not able to examine duration of use with regard to cardiovascular risk in this study, but will do so in a future analysis, he says.

The authors declare that they have no disclosures.

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