Following the worldwide voluntary withdrawal of rofecoxib (Vioxx®, Merck Sharp & Dohme) in October 2004 due to concerns of an increased cardiovascular (CV) risk, HSA and its Expert Advisory Committee reviewed the CV risks of the entire class of non-steroidal anti-inflammatory drugs (NSAIDs).

Based on the available data at that time, in April 2005, HSA concluded that the coxibs or the newer COX-2-selective inhibitors, namely rofecoxib, celecoxib, and etoroicoxib, were associated with an increased risk of CV events and that the risk increased with increased dose and duration of use. HSA also strengthened the local package inserts of these products to contraindicate the perioperative use of these drugs in patients who have recently undergone coronary artery bypass graft (CABG) surgery and revascularisation procedures. At that time, due to the lack of information on the CV risks for the older NSAIDs, HSA concluded that the possibility of similar CV risk could not be ruled out although there was insufficient data to show that the older NSAIDs pose similar CV risks as the coxibs.

Recently, the availability of several well conducted meta-analyses of randomised trials, case-control and cohort studies involving the older NSAIDs have provided regulators with a better means of assessing the safety profile of these drugs. HSA and its Pharmacovigilance Advisory Committee (PVAC) have reviewed these data and taking into account international regulatory developments, arrived at the following recommendations on the CV risks and the use of this class of drugs:

• Non-selective NSAIDs are important treatments for arthritis and other anti-inflammatory and painful conditions.
  
  
• Non-selective NSAIDs may be associated with a small increase in the absolute risk of cardiovascular events (e.g. myocardial infarction and stroke), especially when used at high doses for long-term treatment.
  
  
• All NSAIDs should be prescribed at the lowest effective dose and the duration of treatment should be periodically reviewed and kept as short as possible.
  
  
• All NSAIDs should not be used perioperatively in patients who have recently undergone coronary artery bypass graft (CABG) surgery and revascularisation procedures.

Unlike the placebo-controlled randomised clinical trials which have provided strong evidence of an increased CV risks for the newer coxibs, the new data on CV risks of the older NSAIDs were derived largely from pooled analysis of randomised trials, cohort studies and case control studies.^1-5 As it is unlikely that large placebo-controlled randomised clinical trials will be conducted on the older NSAIDs and given the potentially serious nature of the adverse events being considered, any evidence-based suggestion of increased risks should be considered to be the best available information. In this case, there was sufficient information from the pooled analyses to allow general conclusions to be made on the CV profile of the non-selective NSAIDs.

Overall, the data appear to suggest that older NSAIDs may be associated with a small but increased CV risks (e.g. myocardial infarction, stroke). With the exception of naproxen, other commonly used NSAIDs such as diclofenac, indomethacin, ibuprofen have consistently showed an unfavourable ratio in terms of CV thrombotic events when compared to placebo or when compared to the remote or nonuse of anti-inflammatory drugs (see table 1).

Two of the studies have individually concluded that the extent of NSAID use appears to be the critical determinant in the relation of most NSAIDs to myocardial infarction ⁴ and that there was close association of the proximity ⁵ of NSAID use to myocardial infarction – the longer the time from NSAID discontinuation, the weaker the association.

Whilst it was previously hypothesized that the mechanism of COX-2 selectivity is related to higher CV risk, the recent data did not demonstrate this.

Table 1*: Summary of results for diclofenac, indomethacin, ibuprofen & naproxen from 3 meta-analyses

HSA will be working with the relevant drug companies to strengthen the labelling information in the package inserts of the older NSAIDs to reflect the CV safety concerns.

1. BMJ 2006 Jun; 332:1302-08.
   
   
2. JAMA 2006 Oct; 296:E1-E12.
   
   
3. Basic Clinic Pharmacol Toxicol. 2006 Mar; 98(3):266-74.
   
   
4. Pharmacotherapy 2006 Oct; 26:1379–87.
   
   
5. Eur Heart J 2006 Jul; 27:1657-63.