16 June 2011
A Danish cohort study identified an increased risk of death or recurrent myocardial infarction (MI) with non-steroidal anti-inflammatory drugs (NSAIDs) in patients with prior MI. The risk was independent of the duration of treatment, and became apparent within the first weeks of treatment. Overall, the highest risk was associated with diclofenac, and the lowest risk was associated with naproxen.
Level of evidence:
Level 2 (limited quality patient-oriented evidence) according to the SORT criteria.
This study suggests that particular care is required when prescribing NSAIDs (including coxibs) for patients with prior MI, and reinforces previous advice (see MeReC Extra 30) regarding choice 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.
- Low-dose ibuprofen (≤1200mg per day) is an appropriate first choice NSAID in view of its low risk of gastrointestinal (GI) and cardiovascular (CV) side effects.
- Low-dose ibuprofen or naproxen 1000mg would appear more appropriate than other NSAIDs for patients in whom CV risk is a significant consideration in decision making.
- Consider prescribing a 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.
- Although coxibs are associated with a lower risk of GI side effects than traditional NSAIDs, there is no good 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.
Prescribers and prescribing managers should review local prescribing trends for NSAIDs as suggested in the document Key therapeutic topics 2010/11 – Medicines management options for local implementation, produced by the NPC as part of the QIPP programme.
What is the background to this?
There are long standing and well recognised safety concerns with all NSAIDs regarding GI and renal adverse effects, and increased risk CV events with many NSAIDs, including coxibs and some traditional NSAIDs. In October 2006, a review of the CV safety of selective and non-selective NSAIDs by the Commission on Human Medicines identified that traditional NSAIDs, including diclofenac, may be associated with a small increased risk of arterial thrombotic events. Diclofenac was associated with a similar risk to etoricoxib▼. This risk did not appear to be shared by ibuprofen at 1200mg per day or less, or naproxen 1000mg per day. The CV and GI safety of NSAIDs was reviewed in collaboration with the MHRA in MeReC Extra 30 in November 2007, and the recommendations given above were developed. Subsequently published data (see MeReC Rapid Reviews 1597 and 2451) support these recommendations and MHRA advice to use the lowest effective dose for the shortest duration. This present study evaluated the duration of NSAID treatment and CV risk in a large Danish cohort of patients with prior MI, and who were therefore at high risk of CV events.
What does this study claim?
The study found that, overall, NSAID treatment was associated with a significantly increased risk of death/recurrent MI (hazard ratio [HR] 1.45, 95% confidence interval [CI] 1.29 to 1.62) at the beginning of treatment (up to 7 days) and the risk persisted throughout the treatment course (>90 days, HR 1.55, 95%CI 1.46 to 1.64). Analyses of individual NSAIDs showed that diclofenac was associated with the highest risk of death/recurrent MI for most durations of treatment (up to 7 days: HR 3.26, 95%CI 2.75 to 3.86; >90 days 1.92, 95%CI 1.66 to 2.22). The authors claim that ibuprofen was associated with a lower risk than coxibs and diclofenac, and that naproxen was associated with the lowest CV risk overall.
How does this relate to other studies?
This study is consistent with many other studies (see MHRA webpage on NSAIDs and CV risk) that have demonstrated an increased risk of CV events with both coxibs (e.g. celecoxib, etoricoxib▼) and traditional NSAIDs (e.g. diclofenac, naproxen and ibuprofen). Among the traditional NSAIDs diclofenac is associated with the highest (and naproxen the lowest) risk of CV events. Although this study supports others that have shown that patients with established, or at high risk of CV disease, may be more vulnerable to CV toxicity, it is the first to report time-to-event analysis for patients with prior MI in a nationwide cohort.
It is now well recognised that both coxibs and many traditional NSAIDs increase the risk of CV events. Of the traditional NSAIDs, diclofenac 150mg/day appears to be associated with a similar excess risk to that of coxibs, whereas low-dose ibuprofen (≤1200mg/day) and naproxen 1000mg/day appear to be associated with a lower risk.
This study reinforces the view that, where considered necessary and CV risk is of concern, naproxen (with a PPI if appropriate) is a more appropriate choice than diclofenac or a coxib. Importantly, the present study demonstrates that the risks of MI/death are independent of treatment duration with risks becoming apparent for most NSAIDs during the first weeks of treatment. Although dose of NSAID was not evaluated, this study provides no evidence to change current advice to limit the use of NSAIDs to the lowest dose and the shortest time necessary to control symptoms.
The use of diclofenac is of particular concern because it is more frequently prescribed than naproxen or low dose ibuprofen. In 2007, the NPC initiated an educational programme to alert prescribers to these issues. Since then there appears to have been a significant and appropriate shift away from the prescribing of diclofenac to naproxen. However, from December 2010 to February 2011, diclofenac still accounted for approximately 1.3 million prescription items (33% of all NSAID items) in primary care in England, and there are still wide differences between localities with regard to the total proportion of NSAIDs prescribed which are ibuprofen or naproxen.
Although this study benefited from having data from a large nationwide cohort, it has a number of major limitations which need to be considered. As results are not stratified according to dose, we do not know whether the increased risk seen with ibuprofen would have been apparent at doses less than 1200mg — the dose generally recommended for first-line NSAID treatment. As this was an observational study, many confounding factors may have influenced the results. For instance, there was no information with which to adjust for important CV risk factors (e.g. blood pressure, smoking habit, lipid levels, body mass index), nor was it possible to adjust for the specific indication requiring the NSAID. Furthermore, the duration of treatment was estimated from prescription data, which provided only an indirect assessment of the dose and period over which the medicines were taken.
Schjerning Olsen A-M, Fosbøl EL, Lindhardsen J, et al. Duration of treatment with nonsteroidal anti-inflammatory drugs and impact on risk of death and recurrent myocardial infarction in patients with prior myocardial infarction. A nationwide cohort study. Circulation 2011;123:2226–35
Retrospective, nationwide Danish cohort study.
Patients 30 years of age (mean age 68 years) who were admitted with first-time MI during 1997 to 2006 and their subsequent NSAID use were identified by individual-level linkage of nationwide registries of hospitalisation and drug dispensing from pharmacies in Denmark.
Intervention and comparison
Risk of death and recurrent MI according to duration of NSAID treatment was analyzed by multivariable time-stratified Cox proportional-hazard models and by incidence rates per 1000 person-years.
Outcomes and results
Of the 83,677 patients included, 42.3% received NSAIDs during follow-up. There were 35,257 deaths/recurrent MIs. Overall, NSAID treatment was significantly associated with an increased risk of death/recurrent MI (HR 1.45, 95%CI 1.29 to 1.62) at the beginning of the treatment, and the risk persisted throughout the treatment course (HR1.55, 95%CI 1.46 to 1.64 after 90 days). Analyses of individual NSAIDs showed that the traditional NSAID diclofenac was associated with the highest risk (see Figure 1).
Figure 1. Time-dependent Cox proportional-hazard analysis of risk of death/recurrent MI according to duration of NSAID treatment in patients with prior MI
This figure has been reproduced with permission from Schjerning Olsen A-M, et al. Circulation 2011;123:2226–35. The HR CIs for naproxen >90 days (0.10 to 2.05) appears to be incorrect and inconsistent with the error bar on the figure. Clarification from the authors has been requested and we will update this Rapid Review accordingly
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