The non-selective non-steroidal anti-inflammatory drugs (nsNSAIDs) and cyclooxygenase-2 (COX-2) inhibitors are commonly utilized agents for musculoskeletal conditions. The harmful cardiorenal effects of some nsNSAIDs are well described and thought to be related to inhibition of prostanoid synthesis. Since the non-specific inhibition of both cyclooxygenase enzymes was associated with a higher incidence of gastrointestinal side effects, the selective targeting of the COX-2 enzymes with the COX-2 inhibitors promised and delivered a lower incidence of gastrointestinal side effects. However, the COX-2 inhibitors have not been found to be bereft of cardiorenal side effects. Indeed, some of these agents lead to increased blood pressure, an excessive risk of congestive heart failure and pro-thrombotic effects, especially in high risk populations. These deletrious effects, however, may not be class-specific and possibly related to pharmacokinetics, enzyme specificity and endothelium effects. This article also reviews the body of literature linking the nsNSAIDs and COX-2 inhibitors with important adverse cardiorenal effects and their putative mechanisms.
Baker, C.S., Hall, R.J., Evans, T.J., Pomerance, A., Maclouf, J., Creminon, C. et al. (1999) Cycloxygenase-1 is widely expressed in atherosclerotic lesions affecting native and transplanted human coronary arteries and colocalizes with inducible nitric oxide synthase and nitrotyrosine particularly in macrophages . Atheroscler Thromb Vasc Biol19: 646—655.
2.
Bertagnolli, M.M., Eagle, C.J., Zauber, A.G., Redston, M., Solomon, S.D., Kim, K. et al. (2006) APC Study Investigators. Celecoxib for the prevention of sporadic colorectal adenomas. N Engl J Med355: 873—884.
3.
Catella-Lawson, F., McAdam, B., Morrison, B.W., Kapoor, S., Kujubu, D., Antes, L. et al. (1999) Effects of specific inhibition of cyclooxygenase-2 on sodium balance, hemodynamics, and vasoactive eicosanoids. J Pharmacol Exp Ther289: 735—741.
4.
Chang, I.J. and Harris, R.C. (2005) Are all COX-2 inhibitors created equal? Hypertension45: 178—180.
5.
Cipollone, F., Toniato, E., Martinotti, S., Fazia, M., Iezzi, A., Cuccurullo, C. et al. (2004) A polymorphism in the cycloxygenase 2 gene an inherited protective factor against myocardial infarction and stroke. JAMA291: 2221—2228.
6.
Crofford, L.J., Breyer, M.D., Strand, C.V., Rushitzka, F., Brune, K., Farkouh, M.E. et al. (2006) Cardiovascular effects of selective COX-2 inhibition: is there a class effect? The International COX-2 Study Group. J Rheumatol33: 1403—1408.
7.
Curtis, S.P., Ng, J.,Yu, Q., Shingo, S., Bergman, G., McCormick, C.L. et al. (2004) Renal effects of etoricoxib and comparator nonsteroidal anti-inflammatory drugs in controlled clinical trials. Clin Ther26: 70—83.
8.
DeWitt, D.L. and Smith, W.L. (1988) Primary structure of prostaglandin G/H synthase from sheep vesicular gland determined from the complementary DNA sequence . Proc Natl Acad Sci USA85: 1412—1416.
9.
Farkouh, M.E., Greenberg, J.D., Jeger, R.V., Ramanathan, K., Verheugt, F.W., Chesebro, J.H. et al. (2007) Cardiovascular outcomes in high risk patients with osteoarthritis treated with ibuprofen, naproxen or lumiracoxib. Ann Rheum Dis66: 764—770.
10.
Feenstra, J., Heerdink, E.R., Grobbee, D.E., Stricker, B.H. (2002) Association of nonsteroidal anti-inflammatory drugs with first occurrence of heart failure and with relapsing heart failure: the Rotterdam Study. Arch Intern Med162: 265—270.
11.
FitzGerald, G.A. (2003) COX-2 and beyond: approaches to prostaglandin inhibition in human disease. Nat Rev Drug Discov2: 879—890.
12.
García Rodríguez, L.A. and Hernández-Díaz, S. (2003) Nonsteroidal antiinflammatory drugs as a trigger of clinical heart failure. Epidemiology14: 240—246.
13.
Guan,Y., Chang, M., Cho, W., Zhang,Y., Redha, R., Davis, L. et al. (1997) Cloning, expression, and regulation of rabbit cyclooxygenase-2 in renal medullary interstitial cells. Am J Physiol273: F18—F26.
14.
Hansson, L., Zanchetti, A., Carruthers, S.G., Dahlof, B., Elmfeldt, D., Julius, S. et al. (1998) Effects of intensive blood-pressure lowering and low-dose aspirin in patients with hypertension: principal results of the Hypertension Optimal Treatment (HOT) randomised trial. HOT Study Group. Lancet351: 1755—1762.
15.
Harris, R.C. and Breyer, M.D. (2001) Physiological regulation of cyclooxygenase-2 in the kidney. Am J Physiol Renal Physiol281: F1—F11.
16.
Harris, R.C., McKanna, J.A., Akai, Y., Jacobson, H.R., Dubois, R.N., Breyer, M.D. (1994) Cyclooxygenase-2 is associated with the macula densa of rat kidney and increases with salt restriction. J Clin Invest94: 2504—2510.
17.
Heerdink, E.R., Leufkens, H.G., Herings, R.M., Ottervanger, J.P., Stricker, B.H., Bakker, A. (1998) NSAIDs associated with increased risk of congestive heart failure in elderly patients taking diuretics. Arch Intern Med158: 1108—1112.
18.
Hermann, M., Camici, G., Fratton, A., Hurlimann, D., Tanner, F.C., Hellerman, J.P. et al. (2003) Differential effects of selective cycloxygenase—2 inhibitors on endothelial function in salt-induced hypertension. Circulation108: 2308—2311.
19.
Hudson, M., Rahme, E., Hughes, R., Pilote, L. (2007) Risk of Congestive Heart Failure with non-steroidal anti-inflammatory drugs and selective cyclooxygenase-2 inhibitors: A class effect? Arthritis and Rheumatism57: 516—523.
20.
Hudson, M., Richard, H., Pilote, L. (2005) Differences in outcomes of patients with congestive heart failure prescribed celecoxib, rofecoxib, or non-steroidal anti-inflammatory drugs: population based study. BMJ330: 1370—1375.
21.
Huerta, C., Varas-Lorenzo, C., Castellsague, J., García, Rodríguez L.A. (2006) Non-steroidal anti-inflammatory drugs and risk of first hospital admission for heart failure in the general population. Heart92: 610—615.
22.
Jassal, D.S., Howlett, J., Cox, J.L. (2003) Are COX-2 inhibitors safe in congestive heart failure? American Heart Association: scientific sessions. Orlando, FL: Nov 9—12, 2003. Circulation108: 665.
23.
Johnson, A.G., Nguyen, T.V., Day, R.O. (1994) Do nonsteroidal anti-inflammatory drugs affect blood pressure? A meta-analysis. Ann Intern Med121: 289—300.
24.
Komhoff, M., Grone, H.J., Kleinm T., Seyberth, H.W., Nusing, R.M. (1997) Localization of cyclooxygenase-1 and -2 in adult and fetal human kidney: implication for renal function. Am J Physiol272: F460—F468.
Mamdani, M., Juurlink, D.N., Lee, D.S., Rochon, P.A., Kopp, A., Naglie, G. et al. (2004) Cyclo-oxygenase-2 inhibitors versus non-selective non-steroidal anti-inflammatory drugs and congestive heart failure outcomes in elderly patients: a population-based cohort study. Lancet363: 1751—1756.
27.
Nantel, F., Meadows, E., Denis, D., Connolly, B., Metters, K.M., Giaid, A. (1999) Immunolocalization of cyclooxygenase-2 in the macula densa of human elderly. FEBS Lett457: 475—477.
28.
Nussmeier, N.A., Whelton, A.A., Brown, M.T., Langford, R.M., Hoeft, A., Parlow, J.L. et al. (2005) Complications of the COX-2 inhibitors parecoxib and valdecoxib after cardiac surgery. N Engl J Med352: 1081—1091.
29.
Page, J. and Henry, D. (2000) Consumption of NSAIDs and the development of congestive heart failure in elderly patients: an underrecognized public health problem . Arch Intern Med160: 777—784.
30.
Pitkala, K.H., Strandberg, T.E., Tilvis, R.S. (2002) Worsening heart failure associated with COX-2 inhibitors . Am J Med112: 424—426.
31.
Pope, J.E., Anderson, J.J., Felson, D.T. (1993) A meta-analysis of the effects of nonsteroidal anti-inflammatory drugs on blood pressure. Arch Intern Med153: 477—484.
32.
Rossat, J., Maillard, M., Nussberger, J., Brunner, H.R., Burnier, M. (1999) Renal effects of selective cyclooxygenase-2 inhibition in normotensive salt-depleted subjects. Clin Pharmacol Ther66: 76—84.
33.
Schonbeck, U., Sukhova, G.K., Graber, P., Coulter, S., Libby, P. (1999) Augmented expression of cycloxygenase-2 in human atherosclerotic lesions. Am J Pathol155: 1281—1291.
34.
Schrör, K., Mehta, P., Mehta, J.L. (2005) Cardiovascular risk of selective cyclooxygenase-2 inhibitors. J Cardiovasc Pharmacol Ther10: 95—101.
35.
Schlondorff, D. (1993) Renal Complications of non-steroidal anti-inflammatory drugs. Kidney Int44: 643—653.
36.
Sowers, J.R., White, W.B., Pitt, B., Whelton, A., Simon, L.S., Winer, N. et al. (2005) Celecoxib Rofecoxib Efficacy and Safety in Comorbidities Evaluation Trial (CRESCENT) Investigators. The Effects of cyclooxygenase-2 inhibitors and nonsteroidal anti-inflammatory therapy on 24-hour blood pressure in patients with hypertension, osteoarthritis, and type 2 diabetes mellitus. Arch Intern Med165: 161—168. Erratum in Arch Intern Med165: 551.
37.
Sprangers, M.A., de Regt, E.B., Andries, F., van Agt, H.M., Bijl, R.V., de Boer, J.B. et al. (2000) Which chronic conditions are associated with better or poorer quality of life?J Clin Epidemiol53: 895—907.
38.
Staessen, J.A., Fagard, R., Thijs, L., Celis, H., Arabidze, G.G., Birkenhager, W.H. et al. (1997) Randomised double-blind comparison of placebo and active treatment for older patients with isolated systolic hypertension. The Systolic Hypertension in Europe (Syst-Eur) Trial Investigators. Lancet350: 757—764.
39.
Stichtenoth, D.O., Marhauer,V.,Tsikas, D., Gutzki, F.M., Frolich, J.C. (2005) Effects of specific COX-2-inhibition on renin release and renal and systemic prostanoid synthesis in healthy volunteers. Kidney Int68: 2197—2207.
40.
Swan, S.K., Rudy, D.W., Lasseter, K.C., Ryan, C.F., Buechelm K.L., Lambrecht, L.J. et al. (2000) Effect of cyclooxygenase-2 inhibition on renal function in elderly persons receiving a low-salt diet. A randomized, controlled trial. Ann Intern Med133: 1—9.
41.
Vane, J.R. (1971) Inhibition of prostaglandin synthesis as a mechanism of action for aspirin-like drugs. Nat New Biol231: 232—235.
42.
Warner, T.D., Giuliano, F., Vojnovic, I., Bukasa, A., Mitchell, J.A., Vane, J.R. (1999) Nonsteroid drug selectivities for cyclo-oxygenase-1 rather than cyclo-oxygenase-2 are associated with human gastrointestinal toxicity: a full in vitro analysis. Proc Natl Acad Sci USA96: 7563—7568.
43.
Whelton, A. (2001) Renal aspects of treatment with conventional nonsteroidal anti-inflammatory drugs versus cyclooxygenase-2-specific inhibitors. Am J Med110 Suppl 3A: 33S—42S.
44.
Whelton, A. and Hamilton, C.W. (1991) Nonsteroidal anti-inflammatory drugs: effects on kidney function. J Clin Pharmacol31: 588—598.
45.
Whelton, A., Fort, J.G., Puma, J.A., Normandin, D., Bello, A.E., Verburg, K.M. and the SUCCESS VI Study Group. ( 2001) Cyclooxygenase-2—specific inhibitors and cardiorenal function: a randomized, controlled trial of celecoxib and rofecoxib in older hypertensive osteoarthritis patients. Am J Ther8: 85—95. Erratum in Am J Ther8: 220.
46.
Whelton, A., Schulman, G., Wallemark, C., Drower, E.J., Isakson, P.C.,Verburg, K.M. et al. (2000) Effects of celecoxib and naproxen on renal function in the elderly. Arch Intern Med160: 1465—1470.
47.
Whelton, A., White, W.B., Bello, A.E., Puma, J.A., Fort, J.G., and the Success-Vii Investigators. (2002) Effects of celecoxib and rofecoxib on blood pressure and edema in patients ≥65 years of age with systemic hypertension and osteoarthritis. Am J Cardiol90: 959—963.
48.
White, W.B., Kent, J., Taylor, A., Verburg, K.M., Lefkowith, J.B., Whelton, A. (2002) Effects of celecoxib on ambulatory blood pressure in hypertensive patients on ACE inhibitors. Hypertension39: 929—934.
49.
Zhang, J., Ding, E.L., Song,Y. ( 2006) Adverse effects of cyclooxygenase 2 inhibitors on renal and arrhythmia events. Meta-analysis of randomized trials. JAMA296: 1619—1632.
50.
Zhao, S.Z., Burke, T.A., Whelton, A., von Allmen, H., Henderson, S.C. (2002) Cost of heart failure among hypertensive users of nonspecific NSAIDs and COX-2-specific inhibitors. Am J Manag Care8(15 Suppl): S414—S427.
