Published online before print January 15, 2004, doi: 10.1161/01.STR.0000115533.05936.19
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(Stroke. 2004;35:e26.)
© 2004 American Heart Association, Inc.
Letters to the Editor |
Both Thrombotic and Nonthrombotic Cardiovascular and Cerebrovascular Side Effects of Nonsteroidal Anti-Inflammatory Drugs Should Be Considered
2nd Medical Department
Neurological Department, Krankenanstalt Rudolfstiftung, Wien, Austria
To the Editor:
Selective cyclooxygenase (COX)-2 inhibitors are increasingly used instead of "conventional" nonsteroidal anti-inflammatory drugs (NSAIDs). This is because they are just as effective as NSAIDs in relieving pain and less gastrotoxic.1–3 The cardiovascular safety of selective COX-2 inhibitors, however, has been questioned because they selectively reduce prostacyclin (PGI2) production without concomitant inhibition of platelet thromboxane A2 (TXA2), thus disrupting the normal homeostatic balance and promoting a prothrombotic state. This theory is supported by secondary analyses of clinical trials, which found an increased rate of thrombotic cardiovascular events (like myocardial infarction, unstable angina, ischemic stroke and transient ischemic attacks) in patients randomized to COX-2 inhibitors compared with conventional NSAIDs.1,4 On the contrary, emerging data from animal, experimental, and clinical studies suggest that COX-2 is atherogenic and thrombogenic and that selective COX-2 inhibitors may be cardioprotective, possibly due to their ability to improve endothelial function.5,6
Facing these controversies and uncertainties about COX-2 inhibitors, it has to be stressed that both conventional NSAIDs and COX-2 inhibitors share many side effects that may render them dangerous, especially to patients with cardiovascular or cerebrovascular diseases. All NSAIDs have cardiovascular, hematological, renal, central nervous system, and dermatological side effects. They may lead to uncontrolled hypertension and aggravation of heart failure by neurohumoral mechanisms and by attenuation of the effects of cardiac medications like ACE-inhibitors, AT-2 blockers, beta-blockers, and diuretics.7–9 They potentiate the effect of oral anticoagulants, thus leading to a higher bleeding risk.10 Whether these side effects occur as frequently during COX-2 inhibitor intake as during conventional NSAID intake is largely unknown. It has been shown, however, that rofecoxib leads to blood pressure increases in a similar proportion of patients (10.7%) like the conventional NSAID naproxen (9.3%).3 In a further study, comparing celecoxib with the conventional NSAID diclofenac, no differences in the incidence of hypertension (16.6%) and peripheral edema (5.2%) have been detected between both groups.2
These nonthrombotic cardiovascular side effects of NSAIDs, irrespective whether they are conventional or COX-2 selective, might be clinically relevant since it has been shown that (1) blood-pressure, even in the high-normal range may be associated with an increased risk of cardiovascular or cerebrovascular morbidity, and (2) there is a high coincidence of osteoarthritis with hypertension or heart failure, especially in elderly patients.11 Thus, we suggest to consider also nonthrombotic cardiovascular side effects, like blood pressure increases, precipitation or worsening of heart failure, as "hard" clinical outcome events when conducting trials of selective COX-2 inhibitors.
References
1. Bombardier C, Laine L, Reicin A, Shapiro D, Burgos-Vargas R, Davis B, Day R, Ferraz MB, Hawkey CJ, Hochberg MC, et al, for the VIGOR Study Group. Comparison of upper gastrointestinal toxicity of rofecoxib and naproxen in patients with rheumatoid arthritis. N Engl J Med. 2000; 343: 1520–1528.
2. Chan FKL, Hung LCT, Suen BY, Wu JCY, Lee KC, Leung VKS, Hui AJ, To KF, Leung WK, Wong VWS, et al. Celecoxib versus diclofenac and omeprazole in reducing the risk of recurrent ulcer bleeding in patients with arthritis. N Engl J Med. 2002; 347: 2104–2110.
3. Lisse JR, Perlman M, Johansson G, Shoemaker JR, Schechtman J, Skalky CS, Dixon ME, Polis AB, Mollen AJ, Geba GP. Gastrointestinal tolerability and effectiveness of rofecoxib versus naproxen in the treatment of osteoarthritis. Ann Intern Med. 2003; 139: 539–546.
4. Mukherjee D, Nissen SE, Topol EJ. Risk of cardiovascular events associated with selective COX-2 inhibitors. JAMA. 2001; 286: 954–959.
5. Hankey GJ, Eikelboom JW. Cyclooxygenase-2 inhibitors: are they really atherothrombotic, and if not, why not? Stroke. 2003; 34: 2736–2740.
6. Chenevard R, Hürlimann D, Béchir M, Enseleit F, Spieker L, Hermann M, Riesen W, Gay S, Gay RE, Neidhart M, et al. Selective COX-2 inhibition improves endothelial function in coronary artery disease. Circulation. 2003; 107: 405–409.
7. Curhan GC, Willett WC, Rosner B, Stampfer MJ. Frequency of analgesic use and risk of hypertension in younger women. Arch Intern Med. 2002; 162: 2204–2208.
8. 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: 777–784.
9. Stöllberger C, Finsterer J. Nonsteroidal anti-inflammatory drugs in patients with cardio- or cerebrovascular disorders. Z Kardiol. 2003; 92: 721–729.[CrossRef][Medline] [Order article via Infotrieve]
10. Knijff-Dutmer EA, Schut GA, Van de Laar MA. Concomitant coumarin-NSAID therapy and risk for bleeding. Ann Pharmacother. 2003; 37: 12–16.
11. Prospective Studies Collaboration. Age-specific relevance of usual blood pressure to vascular mortality: a meta-analysis of individual data for one million adults in 61 prospective studies. Lancet. 2002; 360: 1903–1913.[CrossRef][Medline] [Order article via Infotrieve]
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