6 July 2010
A large cohort study found that individual NSAIDs have different levels of CV risk. In particular, this study found that diclofenac and rofecoxib were associated with a similar increase in CV mortality and morbidity in healthy individuals. Naproxen was found to have a safer CV risk profile. Although this observational study has important limitations, these findings are similar to previously published evidence. Diclofenac is still the most widely prescribed of all NSAIDs (39% of all NSAIDs in England). Therefore, this study re-emphasises the need for prescribers to continue to review their use of all NSAIDs, particularly diclofenac.
Level of evidence:
Level 2 (limited quality patient-oriented evidence) according to the SORT criteria.
Health professionals should assess both the cardiovascular (CV) and gastrointestinal (GI) risk on an individual patient basis and carefully consider the balance between benefit and risk before starting treatment with any NSAID. However, this study re-emphasises that even in healthy individuals, diclofenac appears to be associated with increased CV risk, which may be similar to that of rofecoxib, while naproxen appears to be associated with lower CV risk. Despite encouraging trends in NSAID prescribing over recent years, diclofenac is still the most widely prescribed of all the NSAIDs (39% of all NSAIDs in England). Some PCTs have been very effective in reducing diclofenac prescribing, whereas in other PCTs there has been little change. Prescribers should continue to follow our previous recommendations given in MeReC Extra 30 when considering the prescribing of NSAIDs:
- Where NSAIDs are required, prescribing should be based on the safety profiles of individual NSAIDs and on individual patient risk factors. All NSAIDs should generally be used at the lowest effective dose and for the shortest period of time necessary to control symptoms.
- The ideal anti-inflammatory prescribing choice will vary from patient to patient, depending on individual risk factors, therapeutic response, patient preference, and the patient’s attitude to the risk of adverse events.
- Low-dose ibuprofen (≤1200mg per day) is an appropriate first choice NSAID in view of its low risk of both GI and CV side effects.
- Low-dose ibuprofen or naproxen 1000mg per day would appear more appropriate than other NSAIDs for patients in whom CV risk is a significant consideration in decision making.
- Consider prescribing a proton pump inhibitor (PPI) with any NSAID to reduce the risk of adverse GI effects, particularly in those who are at high GI risk (includes anybody aged 65 years or older) and long-term NSAID users. PPIs should be prescribed routinely with NSAIDs for people with osteoarthritis or rheumatoid arthritis according to NICE clinical guidelines 59 and 79).
- Although coxibs are associated with a lower risk of GI side effects than traditional NSAIDs, there is still no high-quality evidence to support the use of coxibs alone ahead of traditional NSAIDs co-prescribed with a PPI. Coxibs also have a higher CV risk than ibuprofen ≤1200mg per day or naproxen 1000mg per day.
What is the background to this?
Following the worldwide withdrawal of rofecoxib in 2004, and a European-wide review, the CV risk associated with coxibs were well recognised. In June 2006, a meta-analysis of randomised controlled trials (RCTs) by Kearney, et al raised concerns about the CV safety of traditional (non-selective) NSAIDs. It suggested that high doses of diclofenac and ibuprofen, but not naproxen, were associated with an increased risk of CV events. In October 2006, a review of the CV safety of selective and non-selective NSAIDs, reported by the CHM, identified that diclofenac (especially 150mg per day) was associated with a small increased thrombotic risk similar to that of etoricoxib▼ and possibly other coxibs. High-dose ibuprofen (e.g. 2400mg per day) also appeared to be associated with a small increased thrombotic risk, whereas low-dose ibuprofen (e.g. ≤1200mg per day) and naproxen (1000mg per day) were not.
Two epidemiological studies, reviewed in the February 2009 edition of Drug Safety Update, provide further evidence that a thrombotic CV risk may apply to all NSAID users, regardless of their baseline risk, with the greatest concern being for chronic users of high doses (in particular coxibs and diclofenac).
In the second half of 2007, in view of the CV risks associated with the high prescribing volume of diclofenac, here at the NPC we initiated a number of activities to raise awareness of the safety issues around the use of NSAIDs, and to encourage the review of NSAID prescribing and more appropriate choice of NSAIDs for patients based on an assessment of their CV and GI risk. In September 2007 a programme of NPC funded workshops was initiated, supported by educational materials produced by the NPC and MeReC Extra 30 (November 2007).
Since November 2007 there has been a significant change in the prescribing rate of diclofenac (a decline of about 5% of total NSAID items per year) and naproxen (an increase of about 4% of total NSAID items per year). This change coincides with our initiatives to encourage medication review and more appropriate prescribing of NSAIDs, taking into account their CV and GI risks. More details are available here.
What does this study claim?
This was an observational cohort study assessing the CV safety of NSAIDs in a nationwide cohort of healthy individuals, estimated by cause-specific mortality and hospitalisations. Using Danish national databases, the authors identified a cohort of over 1 million healthy individuals aged >10 years. Over a 9-year period (1997–2005), the authors tracked the participants’ use of NSAIDs within 30 days of a major CV event. Outcomes were reported for ibuprofen, diclofenac, naproxen, rofecoxib and celecoxib only.
The results presented here are from the case-crossover analysis which represents the effects of short-term NSAID exposure. Similar differences in risk were identified using an alternative hazard analysis, which considers the rate of events occurring over time. See ‘Study details’ below for further information.
The use of diclofenac or rofecoxib was associated with a statistically significantly increased risk of CV death, whereas the use of ibuprofen, naproxen or celecoxib was not associated with a significant increase. The results for diclofenac show an almost two-fold increased risk (odds ratio [OR] 1.91, 95% confidence interval [CI] 1.62 to 2.42), compared with an OR of 1.66 for rofecoxib (95%CI 1.06 to 2.59), with a dose-dependent increase in risk. The composite of coronary death or non-fatal myocardial infarction (MI) was significantly increased with the use of all NSAIDs, except naproxen (OR 0.98, 95%CI 0.59 to 1.63) and rofecoxib (OR 1.72, 95%CI 0.95 to 3.12). Ibuprofen, naproxen and diclofenac showed an increased risk of fatal or non-fatal stroke, but there was no significant increase with rofecoxib or celecoxib.
Overall, diclofenac was the only NSAID that significantly increased the risk of all CV outcomes, which was only apparent at doses of >100mg daily. The authors suggest that diclofenac should “be used with caution in most individuals” and that naproxen is “probably the NSAID with the safest CV risk profile.” Acknowledging the limitations of their observational study, they conclude that their findings expose “a major public health issue.”
The risk of serious bleedings was also analysed and all NSAIDs, except celecoxib were significantly associated with an increased risk of fatal or non-fatal major bleedings. See ‘Study details ’ below for more detailed results.
This study suggests that diclofenac exerts a similar increase in risk for CV adverse events as rofecoxib (withdrawn from the market worldwide due to an increased risk of serious thrombotic events). However, it is important to remember that observational data has inherent limitations, which are discussed in detail by the authors in the published paper. Unlike an RCT, in ‘real life’ (on which observational studies are based), treatments are chosen, changed, or actively not chosen in the light of individual patients’ risk factors, preferences and tolerability or response to other drugs. Thus observed differences in outcomes may well be due to differences among the patients, not only the different treatments.
Despite its limitations, this was a very large, well conducted study, which supports the findings from RCTs and other observational studies. The MHRA have previously advised that diclofenac has a CV thrombotic risk profile similar to that of licensed doses of etoricoxib, and that naproxen is associated with a lower risk than coxibs. This study was conducted in otherwise healthy individuals with no co-morbidities. In addition, the median exposure time to NSAID was 14 days, which suggests that even short-term use increases CV risk. These findings also support the MHRA view that “some increase in thrombotic CV risk may apply to all NSAID users, irrespective of their baseline CV risk, and not only to chronic users.”
Over recent years there have been encouraging trends in NSAID prescribing showing a reduction in the overall volume of prescribing, a decline in diclofenac prescribing and an increase in naproxen prescribing. See Figure 1 below.
However, diclofenac is still the most commonly prescribed NSAID in England. This may potentially expose a substantial number of individuals to the risk of CV adverse events, as we have discussed previously. This study re-emphasises that even in healthy individuals, diclofenac appears to be associated with increased CV risk, which may be similar to that of rofecoxib, while naproxen appears to be associated with lower CV risk.
Figure 1. The proportions of NSAIDs prescribed in general practice in England December 2005 to November 2006, compared with December 2008 to November 2009.
Figure prepared from data supplied by NHS Business Services Authority
Unlike diclofenac and rofecoxib, celecoxib was not significantly associated with an increased risk of CV death in this study. However, this was based on relatively few numbers of events. The results of this study do not rule out or confirm that celecoxib has a lesser CV risk than either diclofenac or rofecoxib. MHRA advice on the use of celecoxib (and other coxibs) should still be followed.
What about the GI risks?
Celecoxib was the only NSAID that did not significantly increase the risk of serious bleeding in this study. However, the use of a PPI with any NSAID significantly reduces the risk of GI side effects. There is no high-quality evidence that adding a PPI to a coxib is more beneficial, equivalent or a worse option than adding a PPI to a standard NSAID. The recent CONDOR study there is still no high-quality evidence to support the use of coxibs alone ahead of traditional NSAIDs co-prescribed with a PPI found that, while the incidence of anaemia was lower with celecoxib compared with diclofenac plus a PPI, the rates of serious upper GI events were identical.
Of the traditional NSAIDs, there is also a widely held view that naproxen is associated with a greater GI risk than diclofenac, but evidence supporting this assertion is not strong and there have been no comparative RCTs. This study appears to show a similar increased risk of serious bleeding with naproxen and diclofenac, although the confidence intervals were wide for naproxen. It doesn’t change what we know already about the GI risk of NSAIDs:
- coxibs, as a class, are associated with a lower GI risk than traditional NSAIDs However, their GI safety advantage is diminished when they are co-administered with aspirin
- of the traditional NSAIDs, low-dose ibuprofen is associated with a lower GI risk than either diclofenac or naproxen
- the benefits from gastroprotection with a PPI largely depend on the individual patient’s baseline risk of GI complications.
Fosbøl EL, et al. Cause-specific cardiovascular risk associated with nonsteroidal anti-inflammatory drugs among healthy individuals. Circ Cardiovasc Qual Outcomes. Published online 8th June 2010: doi: 10.1161/CIRCOUTCOMES.109.861104
Population-based historic cohort study from January 1st 1997 to December 31st 2005.
Entire Danish population (n=4,614,807) aged >10 years on January 1st 1997. 1,028,437 apparently healthy individuals (median age 39 years) who had claimed at least 1 NSAID prescription during 1997–2005 were included in the study after applying selection criteria of no co-morbidities and no ‘serious’ concomitant drugs. Co-morbidity was measured by prescription claims and hospitalisations. ‘Serious’ drug treatments included common CV medicines (e.g. ACE-inhibitors, antithrombotics), COPD treatments, glucose-lowering drugs, analgesics, chemotherapy, immunosuppressants, disease-modifying antirheumatic agents and anaesthetics.
- case-crossover analysis uses the same individual as its own control, but at a previous time point — almost all persisting confounders are excluded from the analysis
- cox proportional hazard analysis is designed for survival analysis, in which the exposure to NSAID, as well as confounders can change over time.
The authors suggest that the case-crossover analysis is the most suited statistical method for the purpose of this study, as the median exposure time to NSAID was 14 days, indicating short-time exposure in most individuals. The results of the hazard analysis were used to support the results of the case-crossover analysis.
- CV death
- a composite of coronary death of non-fatal MI
- a composite of fatal or non-fatal stroke
- a composite of fatal and non-fatal bleedings
The main results are shown below in Figures 2, 3 and 4 (Images from Fosbøl EL, et al. Circ Cardiovasc Qual Outcomes. Published online 8th June 2010). Point estimates and surrounding error bars (representing 95%CI) show the association between NSAID use and the listed end points. Where the horizontal error bar crosses the vertical dashed line at ‘1’, there is no statistically significant difference. Where the horizontal bar is to the right of the vertical dashed line, this shows a statistically significant increase in the listed end point. The hazard analysis was generally supportive of the case-crossover analysis.
Figure 2. Case-crossover analysis showing the association between NSAID use and the listed CV end points.
Figure 3. Cox proportional hazard analysis showing the association between NSAID use and the listed CV end points.
Figure 4. Case-crossover analysis showing the association between NSAID use and fatal or non-fatal major bleedings.
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