Abstract
During the past 2 years, a great deal of evaluation has been conducted on the cardiovascular (CV) effects of nonsteroidal anti-inflammatory drugs (NSAIDs) and selective cyclooxygenase (COX)-2 inhibitors. This review focuses on the effects of the NSAIDs and COX-2 inhibitors on blood pressure and CV events. Clinical trial databases for NSAIDs and COX-2 inhibitors have shown varying levels of destabilization of blood pressure control in treated hypertensive patients as well as variable incident rates of the development of arrhythmias, congestive heart failure, myocardial infarction, and stroke. Nonselective and COX-2 selective NSAIDs can be used carefully in arthritis patients with hypertension and stable CV disorders (excluding congestive heart failure and moderate to severe kidney dysfunction) when the individual clinical benefit of anti-inflammatory therapy outweighs the CV and gastrointestinal risk.
Similar content being viewed by others
References and Recommended Reading
Silverstein FE, Faich G, Goldstein JL, et al.: Gastrointestinal toxicity with celecoxib vs nonsteroidal anti-inflammatory drugs for osteoarthritis and rheumatoid arthritis. The CLASS study: a randomized controlled trial. JAMA 2000, 284:1247–1255.
Bombardier C, Laine L, Reicin A, et al.: Comparison of upper gastrointestinal toxicity of rofecoxib and naproxen in patients with rheumatoid arthritis. N Engl J Med 2000, 343:1520–1528.
Mukherjee D, Nissen SE, Topol EJ: Risk of cardiovascular events associated with selective COX-2 inhibitors. JAMA 2001, 286:954–959.
Konstam MA, Weir MR, Reicin A, et al.: Cardiovascular thrombotic events in controlled, clinical trials of rofecoxib. Circulation 2001, 104:2280–2288.
Bresalier RS, Sandler RS, Quan H, et al.: Cardiovascular events associated with rofecoxib in a colorectal adenoma chemoprevention trial. N Engl J Med 2005, 352:1092–1102.
Nussmeier NA, Whelton AA, Brown MT, et al.: Complications of the COX-2 inhibitors parecoxib and valdecoxib after cardiac surgery. N Engl J Med 2005, 352:1081–1091.
Gilroy DW, Colville-Nash PR, Willis D, et al.: Inducible cyclooygenase may have anti-inflammatory properties. Nat Med 1999, 5:698–701.
Kiefer W, Dannhardt G: Novel insights and therapeutic applications in the field of inhibitors of COX-2. Curr Med Chem 2004, 11:3147–3161.
Fosslien E: Biochemistry of cyclooxygenase (COX)-2 inhibitors and molecular pathology of COX-2 in neoplasia. Crit Rev Clin Lab Sci 2000, 37:431–502.
Hao CM, Breyer MD: Hypertension and cyclooxygenase inhibitors. Target: The renal medulla. Hypertension 2004, 44:396–397.
Harris RC, Zhang MZ, Cheng HF: Cyclooxygenase-2 and the renal angiotensin system. Acta Physiol Scand 2004, 181:543–547.
Fries S, Grosser T: The cardiovascular pharmacology of COX-2 inhibition. Hematology Am Soc Hematol Educ Program 2005:445–51.
Rudic RD, Brinster D, Cheng Y, et al.: COX-2-derived prostacyclin modulates vascular remodeling. Circ Res 2005, 96:1240–1247.
Egan KM, Wang M, Lucin MB, et al.: Cyclooxygenases, thromboxane, and atherosclerosis: Plaque destabilization by cyclooxygenase-2 inhibition combined with thromboxane receptor antagonism. Circulation 2005, 111:334–342.
Francois H, Athirakul K, Howell D, et al.: Prostacyclin protects againsts elevated blood pressure and cardiac fibrosis. Cell Metab 2005, 2:201–207.
Rabausch K, Bretschneider E, Sarbia M, et al.: Regulation of thrombomodulin expression in human vascular smooth muscle cells by COX-2 derived prostaglandins. Circ Res 2005, 96:e1–e6.
Bolli R, Shinmura K, Tang XL: Discovery of a new function of cyclooxygenase (COX)-2: COX-2 is a cardioprotective protein that alleviates ischemia/reperfusion injury and mediates the late phase of pre-conditioning. Cardiovasc Res 2002, 55:506–519.
Antman EM, DeMets D, Loscalzo J: Cyclooxygenase inhibition and CV risk. Circulation 2005, 112:759–770.
Virdis A, Colucci R, Fornai M, et al.: Cyclooxygenase-2 inhibition improves vascular endothelial dysfunction in a rat model of endotoxic shock: Role of inducible nitric-oxide synthase and oxidative stress. J Pharmacol Exp Ther 2005, 312:945–953.
Steffel J, Hermann M, Greutert H, et al.: Celecoxib decreases endothelial tissue factor expression through inhibition of c-Jun terminal NH2 kinase phosphorylation. Circulation 2005, 111:1685–1689.
Sowers JR, White WB, Pitt B, et al.: 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. Arch Intern Med 2005, 165:161–168.
Pope JE, Anderson JJ, Felson DT: A meta-analysis of the effects of nonsteroidal anti-inflammatory drugs on blood pressure. Arch Intern Med 1993, 153:477–484.
Johnson AG, Nguyen TV, Day RO: Do nonsteroidal anti-inflammatory drugs affect blood pressure? A meta-analysis. Ann Intern Med 1994, 121:289–300.
Grover SA, Coupal L, Zowall H: Treating osteoarthritis with cyclooxygenase-2 specific inhibitors: What are the benefits of avoiding blood pressure destabilization? Hypertension 2005, 45:92–97.
White WB: Benefits of antihypertensive therapy in older patients with hypertension. Arch Intern Med 2000, 160:149–150.
ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group. Major cardiovascular events in hypertensive patients randomized to doxazosin vs chlorthalidone: the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). JAMA 2000, 283:1967–1975.
Julius S, Kjeldsen SE, Weber M, et al.: Outcomes in hypertensive patients at high CV risk treated with regimens based on valsart an or amlodipine: the VALUE randomised trial. Lancet 2004, 363:2022–2031.
Morgan TO, Anderson A, Bertram D: Effect of indomethacin on blood pressure in elderly people with essential hypertension well controlled on amlodipine or enalapril. Am J Hypertens 2000, 13:1161–1167.
Schwartz JI, Vandormael K, Malice MP, et al.: Comparison of rofecoxib, celecoxib, and naproxen on renal function in elderly subjects receiving a normal-salt diet. Clin Pharmacol Ther 2002, 72:50–61.
Simon LS, Smolen JS, Abramson SB, et al.: Controversies in COX-2 selective inhibition. J Rheumatol 2002, 29:1501–1510.
Brater DC: Effects of nonsteroidal anti-inflammatory drugs on renal function: focus on cyclooxygenase-2-selective inhibition. Am J Med 1999, 107:65S–70S.
Whelton A, Schulman G, Wallemark C, et al.: Effects of celecoxib and naproxen on renal function in the elderly. Arch Intern Med 2000, 160:1465–1470.
Whelton A, White WB, Bello AE, et al.: Effects of celecoxib and rofecoxib on blood pressure and edema in patients > or = 65 years of age with systemic hypertension and osteoarthritis. Am J Cardiol 2002, 90:959–963.
Whelton A: Nephrotoxicity of nonsteroidal anti-inflammatory drugs: physiologic foundations and clinical implications. Am J Med 1999, 106(5B):13S–24S.
Qi Z, Hao CM, Langenbach RI, et al.: Opposite effects of cyclooxygenase-1 and-2 activity on the pressor response to angiotensin II. J Clin Invest 2002, 110:61–69.
Hermann M, Camici G, Fratton A, et al.: Differential effects of selective cyclooxygenase-2 inhibitors on endothelial function in salt-induced hypertension. Circulation 2003, 108:2308–2311.
Hermann M, Shaw S, Kiss E, et al.: Selective COX-2 inhibitors and renal injury in salt-sensitive hypertension. Hypertension 2005, 45:193–197.
Hinz B, Dormann H, Brune K: More pronounced inhibition of cyclooxygenase 2, increase in blood pressure, and reduction of heart rate by treatment with diclofenac compared with celecoxib and rofecoxib. Arthritis Rheum 2006, 54:282–291.
Winner LK, Elliot DJ, Miners JO, Knights KM: In vitro glucoronidation of aldosterone by human liver and kidney cortical microsomes and recombinant UDP-glucuronosyltransferase (UCT) 287: inhibition by non-steroidal anti-inflammatory drugs (NSAIDs). Proc Aust Soc Clin Exp Pharmacol Toxicol 2005, 11:P2–02.
Knights KM, Mangoni AA, Minors JO: Non-selective nonsteroidal anti-inflammatory drugs and cardiovascular events: is aldosterone the silent partner in crime? Br J Clin Pharmacol 2006, 61:738–740.
White WB, Kent J, Taylor A, et al.: Effects of celecoxib on ambulatory blood pressure in hypertensive patients on ACE inhibitors. Hypertension 2002, 39:929–934.
Izhar M, Alausa T, Folker A, et al.: Effects of COX-inhibition on blood pressure and kidney function in ACE inhibitor-treated blacks and hispanics. Hypertension 2004, 43:574–577.
Houston MC, Weir M, Gray J, et al.: The effects of nonsteroidal anti-inflammatory drugs on blood pressures of patients with hypertension controlled by verapamil. Arch Intern Med 1995, 155:1049–1054.
Mamdani M, Juurlink DN, Lee DS, et al.: 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. Lancet 2004, 363:1751–1756.
White WB, Faich G, Whelton A, et al.: Comparison of thromboembolic events in patients treated with celecoxib, a cyclooxygenase-2 specific inhibitor, versus ibuprofen or diclofenac. Am J Cardiol 2002, 89:425–430.
White WB, Faich G, Borer JS, Makuch RW: CV thrombotic events in arthritis trials of the cyclooxygenase-2 inhibitor celecoxib. Am J Cardiol 2003, 92:411–418.
White WB, West CR, Borer JS, et al.: Risk of CV events in patients receiving celecoxib. A metanalysis of randomized clinical trials. Am J Cardiol 2006, in press.
Collaborative overview of randomized trials of antiplatelet therapy: I: prevention of death, myocardial infarction, and stroke. Antiplatelet Trialists’ Collaboration. BMJ 1994, 308:81–106.
Farkouh ME, Kirshner H, Harrington RA, et al.: Comparison of lumiracoxib with naproxen and ibuprofen in the Therapeutic Arthritis Research and Gastrointestinal Event Trial (TARGET), cardiovascular outcomes: randomised controlled trial. Lancet 2004, 364:675–684.
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, 365:475–481.
Gislason GH, Jacobsen S, Rasmussen JN, et al.: Risk of death or reinfarction associated with the use of selective cyclooxygenase-2 inhibitors and nonselective non-steroidal antiinflammatory drugs after acute infarction. Circulation 2006, 113:2906–2913.
McGettigan P, Henry D: Cardiovascular risk and inhibition of cyclooxygenases: A systematic review of the observational studies of selective and nonselective inhibitors of cyclooxygenase-2. JAMA 2006, 296:1633–1644.
Chan AT, Manson JE, Albert CM, et al.: Nonsteroidal antiinflammatory drugs, acetaminophen, and the risk of cardiovascular events. Circulation 2006, 113:1578–1587.
Solomon SD, McMurray JJ, Pfeffer MA, et al.: Cardiovascular risk associated with celecoxib in a clinical trial for colorectal adenoma prevention. N Engl J Med 2005, 352:1071–1080.
Bertagnolli MM, Eagle CJ, Zauber AG, et al.: Celecoxib for the prevention of colorectal adenomas. N Engl J Med 2006, 355:873–884.
Arber N, Eagle CJ, Spicak J, et al.: Celecoxib for the prevention of colorectal adenomatous polyps. N Engl J Med 2006, 355:885–895.
Singh G, Mithal A, Triadafilopoulos G: Both selective COX-2 inhibitors and non-selective NSAIDs increase the risk of acute myocardial infarction in patients with arthritis: selectivity is with the patient not the drug class. Ann Rheum Dis 2005, 64(Suppl III):85.
Sturkenboom MC, Dieleman J, Verhamme K, et al.: Cardiovascular events during use of COX-2 selective and non-selective NSAIDs. Pharmacoepidemiol Drug Saf 2005, 14:S57.
Hippisley-Cox J, Coupland C: Risk of myocardial infarction in patients taking cyclooxygenase inhibitors or conventional non-steroidal anti-inflammatory drugs: population based nested case-control analysis. BMJ 2005, 330:1366–1372.
Johnsen SP, Larsson H, Tarone RE, et al.: Risk of hospitalisation for myocardial infarction among users of rofecoxib, celecoxib and other NSAIDs: a population based case control study. Arch Intern Med 2005, 165:978–984.
Levesque LE, Brophy JM, Zhang B: The risk for myocardial infarction with cyclooxygenase-2 inhibitors: a population study of elderly adults. Ann Intern Med 2005, 142:481–489.
Kimmel SE, Berlin JA, Reilly M, et al.: The effects of non-selective non-aspirin non-steroidal anti-inflammatory medications on the risk of non-fatal myocardial infarction and their interaction with aspirin. J Am Coll Cardiol 2004, 43:985–990.
Kimmel SE, Berlin JA, Reilly M, et al.: Patients exposed to rofecoxib and celecoxib have different odds of nonfatal myocardial infarction. Ann Intern Med 2005, 142:157–164.
Ray WA, Stein CM, Daugherty JR, et al.: Cyclo-oxygenase-2 selective non-steroidal anti-inflammatory drugs and risk of serious coronary heart disease. Lancet 2002, 360:1071–1073.
Ray WA, Stein CM, Hall K, et al.: Non-steroidal anti-inflammatory drugs and the risk of serious coronary heart disease: an observational cohort study. Lancet 2002, 359:118–123.
Fischer LM, Schlienger RG, Matter CM, et al.: Discontinuation of non-steroidal anti-inflammatory drug therapy and the risk of acute myocardial infarction. Arch Intern Med 2004, 164:2472–2476.
Garcia Rodriguez LA, Gonzalez-Perez A: Long-term use of traditional of non-steroidal anti-inflammatory drugs and the risk of myocardial infarction in the general population. BMC Med 2005, 3:17.
Bak S, Andersen M, Tsiropoulos I, et al.: Risk of stroke associated with non-steroidal anti-inflammatory drugs. Stroke 2003, 34:379–386.
Solomon DH, Glynn RJ, Levin R, Avorn J: Non-steroidal anti-inflammatory drug use and acute myocardial infarction. Arch Intern Med 2002, 162:1099–1104.
Schlienger RG, Jick H, Meier CR: Use of nonsteroidal anti-inflammatory drugs and the risk of first-time acute myocardial infarction. Br J Clin Pharmacol 2002, 54:327–332.
Watson DJ, Rhodes T, Cai B, Guess HA: Lower risk of thromboembolic cardiovascular events with naproxen among patients with rheumatoid arthritis. Arch Intern Med 2002, 162:1105–1110.
MacDonald TM, Wei L: Effect of ibuprofen on cardioprotective effect of aspirin. Lancet 2003, 361:573–574.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
White, W.B. Cardiovascular risk, hypertension, and NSAIDs. Curr Rheumatol Rep 9, 36–43 (2007). https://doi.org/10.1007/s11926-007-0020-3
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11926-007-0020-3