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Lessons in drug development

St Josephs Hospital, London, Canada, E-mail: ianicu{at}aol.com

To the Editor:

There are indeed many implications arising from the recent problems surrounding the use of cyclooxygenase (COX) 2 inhibitors. However, it is an over simplification to suggest that less selective non-steroidal anti-inflammatory drugs (NSAIDs) do not increase cardiovascular risk with long term use.¹

The literature is certainly complex and at times conflicting in its overall message - confounded by difficulties between studies of the patients’ baseline cardiovascular risk, age, drug dosage, concomitant use of low-dose aspirin, duration of dosing, possible use of over the counter analgesic remedies and different underlying pathologies. Nevertheless some (reasonably) firm conclusions can be made:

1. Many studies have shown increased cardiac events,^2,3 primarily thrombotic in nature, in patients taking COX 2 inhibitors compared to placebo or nonselective COX inhibitors.
   
2. Some studies have suggested that some COX 2 inhibitors are worse than others e.g., rofecoxib compared to celecoxib^4,5 perhaps related to their degree of COX selectivity. Lumiracoxib seems not to be associated with increased cardiac risk.⁶
   
3. Many studies also show increased cardiovascular risk with the COX 1 inhibitors^7–9 - at times comparable to the increased risk associated with COX 2 inhibitors.
   
4. Patients still die from gastrointestinal complications–more so with the less selective NSAIDs.
   

The imbalance created by the COX 2 mediated suppression of the vasodilator prostaglandin and the lack of suppression of the vasoconstrictor thromboxane A2 (the major COX 1 product of platelets causing platelet aggregration and vasoconstriction) has been suggested to explain the increased thrombotic complications, but this in itself does not explain the increased risk seen with non selective drugs. Other cardiac effects may do so. All NSAIDs are associated with worsening of hypertension control and probably increased risk of developing hypertension. In addition, fluid retention, renal dysfunction and increased edema will increase the likelihood of developing or worsening heart failure.

Lessons in drug development to be learned should include rigorous evaluation or reevaluation of the risks vs benefits of all NSAIDs, not just the COX 2 group. In the perioperative setting this should include sensible guidelines on duration of therapy, caution in elderly patients - especially those with heart disease, hypertension or heart failure, possible use of concomitant low-dose aspirin, and an understanding that nonselective COX inhibitors are not necessarily safer.

Footnotes

Accepted for publication October 16, 2006.

References

1 Stafford-Smith M. Hurry up and slow down: Lessons in drug development from the COX-2 inhibitors. Can J Anesth 2006; 53: 973–7.[Free Full Text]

2 Solomon SD, McMurray JJ, Pfeffer MA, et al.; Adenoma Prevention with Celecoxib (APC) Study Investigators Cardiovascular risk associated with celecoxib in a clinical trial for colorectal adenoma prevention. N Engl J Med 2005; 17: 1071–80.

3 Juni P, Nartey L, Reichenbach S, Sterchi R, Dieppe PA, Egger M. Risk of cardiovascular events and rofecoxib: cumulative meta-analysis. Lancet 2004; 364: 2021–9.[Medline]

4 Graham DJ, Campen D, Hui R, et al. Risk of acute myocardial infarction and sudden cardiac death in patients treated with cyclo-oxygenase 2 selective and non-selective non-steroidal anti-inflammatory drugs: nested case-control study. Lancet 2005; 365: 475–81.[Medline]

5 Solomon DH, Schneeweiss S, Glynn RJ, et al. Relationship between selective cyclooxygenase-2 inhibitors and acute myocardial infarction in older adults. Circulation 2004; 109: 2068–73.

6 Matchaba P, Gitton X, Krammer G, et al. Cardiovascular safety of lumiracoxib: a meta-analysis of all randomized controlled trials > or =1 week and up to 1 year in duration of patients with osteoarthritis and rheumatoid arthritis. Clin Ther 2005; 27: 1196–214.[Medline]

7 Helin-Salmivaara A, Virtanen A, Vesalainen R, et al. NSAID use and the risk of hospitalization for first myocardial infarction in the general population: a nationwide case-control study from Finland. Eur Heart J 2006; 27: 1657–63.[Abstract/Free Full Text]

8 Hernandez-Diaz S, Varas-Lorenzo C, Garcia Rodriguez LA. Non-steroidal antiinflammatory drugs and the risk of acute myocardial infarction. Basic Clin Pharmacol Toxicol 2006; 98: 266–74.[Medline]

9 Kearney PM, Baigent C, Godwin J, Halls H, Emberson JR, Patrono C. Do selective cyclo-oxygenase-2 inhibitors and traditional non-steroidal anti-inflammatory drugs increase the risk of atherothrombosis? Metaanalysis of randomised trials. BMJ 2006; 332: 1302–8.[Abstract/Free Full Text]

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