Differences in the cardiovascular risk between NSAIDs and coxibs: the neglected role of pharmacokinetics and drug interactions

The study by Hudson et al (1) published recently in bmj indicates that celecoxib might be safer than rofecoxib and non-steroidal anti-inflammatory drugs (NSAIDs) in elderly patients with congestive heart failure (CHF). This is of great importance in a view of the evidence that NSAIDs could account for approximately 20% of hospitalizations for CHF. (2)
The authors rightly point out that inhibition of renal COX-2 may contribute to increased cardiovascular mortality associated with specific COX-2 inhibitors (coxibs). However, they fail to mention that differences in cardiorenal effects between individual coxibs and NSAIDs could be related to pharmacokinetics of a particular drug and their interactions with other cardiovascular drugs.
Indeed, results from many studies suggest that COX-2 rather than COX- 1 inhibition accounts for the renal effects of NSAIDs. Consequently, coxibs may be expected to have a similar renal adverse event profile as NSAIDs. The lower risk of celecoxib compared with rofecoxib corresponds with lower potency of celecoxib to inhibit COX-2. The dose-response relationship also suggests that this association may be causal. The pharmacodynamic effect is determined by the drug concentration at a receptor site.
Accumulation of conventional NSAIDs occurs particularly in acidic environment (in the stomach, kidneys and in inflamed tissues) which is where these drugs exert their therapeutic as well as adverse effects. In contrast, non-acidic coxibs are equally distributed throughout the body. The lower risk of celecoxib may be explained by its large distribution volume, which is several times higher then that of rofecoxib. Other pharmacokinetic differences that may contribute to higher cardiorenal toxicity of rofecoxib are longer half-life and non-linear kinetics.
Both NSAIDs and coxibs, in addition to the attenuation of therapeutic effects of many cardiovascular drugs, may also increase cardiovascular mortality due to potentiation of their side effects. For example, such interactions may increase the risk of bleeding in patients taking oral anticoagulants (3) or potentiate serious hyperkalemia associated with the use of spironolactone or an ACE inhibitor. (4) Finally, some NSAIDs my increase cardiovascular mortality by causing elevation of serum digoxin concentration. (5)
1. Hudson M, Richard H, Pilote L. Differences in outcomes of patients with congestive heart failure prescribed celecoxib, rofecoxib, or non-steroidal anti-inflammatory drugs: population based study. BMJ 2005;330:1370.
2. Page J, Henry D. Consumption of NSAIDs and the development of congestive heart failure in elderly patients: an underrecognized public health problem. Arch Intern Med 2000;160:777-84.
3. Pitt B, Zannad F, Remme WJ, Cody R, Castaigne A, Perez A, et al. The effect of spironolactone on morbidity and mortality in patients with severe heart failure. N Engl J Med 1999;341:709-17.
4. Battistella M, Mamdami MM, Juurlink DN, Rabeneck L, Laupacis A. Risk of upper gastrointestinal hemorrhage in warfarin users treated with nonselective NSAIDs or COX-2 inhibitors. Arch Intern Med 2005;165:189-92.
5. Rathore SS, Curtis JP, Wang Y, Bristow MR, Krumholz HM. Association of serum digoxin concentration and outcomes in patients with heart failure. JAMA 2003;289:871–8.