Nonselective Nonsteroidal Antiinflammatory Drugs and Cardiovascular Risk: Are They Safe?

Abstract

Spanish

French

Objective:

To assess possible cardiovascular risks associated with use of nonselective nonsteroidal antiinflammatory drugs (NSAIDs).

Data Sources:

Medline and Embase were searched from January 1985 through April 2007 and relevant studies were retrieved.

Study Selection and Data Extraction:

Peer-reviewed, prospective, double-blind, case–control, and cohort-design studies published in the English language literature were considered eligible for review. Previous meta-analyses and systematic reviews were also analyzed. In total, 17 case–control studies; 9 cohort studies; 1 prospective, double-blind study; 3 meta-analyses; and 1 systematic review of observational studies were identified.

Data Synthesis:

Three studies were prospective and the remainder consisted of observational, retrospective studies, with most reporting acute fatal or nonfatal myocardial infarction as the cardiovascular endpoint. Among the nonselective NSAIDs, diclofenac appears to pose the highest risk for cardiovascular toxicity; other agents trend toward a neutral effect with respect to cardiovascular risk. Although the data are suggestive, it remains unclear whether naproxen provides protective cardiovascular effects among patients on chronic therapy.

Conclusions:

Currently available data are insufficient for defining evidence-based clinical guidelines for the use of NSAIDs, and the need for additional research, specifically randomized controlled trials, is evident. Diclofenac demonstrates a significant risk while naproxen appears to pose the lowest, albeit nonsignificant, risk for cardiovascular morbidity. Although the current clinical evidence may not warrant recommending naproxen as the preferred NSAID treatment, it may be prudent to avoid diclofenac for patients with cardiovascular risk factors requiring NSAID treatment.

Keywords

nonsteroidal antiinflammatory drugs COX-2 inhibitors myocardial infarction

Get full access to this article

View all access options for this article.

References

Bombardier

, Laine

, Reicin

. Comparison of upper gastrointestinal toxicity of rofecoxib and naproxen in patients with rheumatoid arthritis. VIGOR Study Group. N Engl J Med 2000; 343:1520–8.

Silverstein

, Faich

, Goldstein

. Gastrointestinal toxicity with celecoxib vs nonsteroidal anti-inflammatory drugs for osteoarthritis and rheumatoid arthritis: the CLASS study: a randomized controlled trial. Celecoxib Long-term Arthritis Safety Study. JAMA 2000; 284:1247–55.

Lisse

, Perlman

, Johansson

. Gastrointestinal tolerability and effectiveness of rofecoxib versus naproxen in the treatment of osteoarthritis: a randomized, controlled trial. Ann Intern Med 2003; 139:539–46.

Bresalier

, Sandler

, Quan

. Cardiovascular events associated with rofecoxib in a colorectal adenoma chemoprevention trial. N Engl J Med 2005; 352:1092–102.

Ray

, Stein

, Daugherty

, Hall

, Arbogast

, Griffin

. COX-2 selective non-steroidal anti-inflammatory drugs and risk of serious coronary heart disease. Lancet 2002; 360:1071–3.

Solomon

, Goodson

. The cardiovascular system in rheumatic disease: the newest “extraarticular” manifestation? J Rheumatol 2005; 32:1415–7.

Topol

. Arthritis medicines and cardiovascular events—“house of coxibs.” JAMA 2005; 293:366–8.

FDA statement on naproxen. www.fda.gov/bbs/topics/news/2004/NEW01148.html (accessed 2007 May 15).

Howard

, Delafontaine

. Nonsteroidal anti-inflammatory drugs and cardiovascular risk. J Am Coll Cardiol 2004; 43:519–25.

10.

Juni

, Nartey

, Reichenbach

, Sterchi

, Dieppe

, Egger

. Risk of cardiovascular events and rofecoxib: cumulative meta-analysis. Lancet 2004; 364:2021–9.

11.

Stollberger

, Finsterer

. Nonsteroidal anti-inflammatory drugs in patients with cardio- or cerebrovascular disorders. Z Kardiol 2003; 92:721–9.

12.

Wong

, Wang

, Cheng

, Fitzgerald

. Cardiovascular hazard and non-steroidal anti-inflammatory drugs. Curr Opin Pharmacol 2005; 5:204–10.

13.

Velentgas

, West

, Cannuscio

, Watson

, Walker

. Cardiovascular risk of selective cyclooxygenase-2 inhibitors and other non-aspirin or non-steroidal anti-inflammatory medications. Pharmacoepidemiol Drug Saf 2006; 15:641–52.

14.

Cannon

, Curtis

, FitzGerald

. Cardiovascular outcomes with etoricoxib and diclofenac in patients with osteoarthritis and rheumatoid arthritis in the Multinational Etoricoxib and Diclofenac Arthritis Long-term (MEDAL) programme: a randomised comparison. Lancet 2006; 368:1771–81.

15.

Hinz

, Dormann

, Brune

. 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; 54:282–91.

16.

Cox

, Frisse

, Behm

, Fairman

. Over-the-counter pain reliever and aspirin use within a sample of long-term cyclooxygenase 2 users. Arch Intern Med 2004; 164:1243–6.

17.

Singh

, Triadafilopoulos

. Epidemiology of NSAID induced gastrointestinal complications. J Rheumatol Suppl 1999; 56:18–24.

18.

Roberts

, Jackson

, Morrow

. Analgesic-antipyretic and antiinflammatory agents and drugs employed in the treatment of gout. In: Hardman

, Limbird

, Gilman

, eds. Goodman & Gilman's the pharmacological basis of therapeutics. 10th ed. New York: McGraw Hill, 2001: 687–731.

19.

Abramson

, Weissmann

. The mechanisms of action of nonsteroidal antiinflammatory drugs. Arthritis Rheum 1989; 32:1–9.

20.

Konttinen

, Kemppinen

, Segerberg

. Peripheral and spinal neural mechanisms in arthritis, with particular reference to treatment of inflammation and pain. Arthritis Rheum 1994; 37:965–82.

21.

Scheiman

. Nonsteroidal anti-inflammatory drugs, aspirin, and gastrointestinal prophylaxis: an ounce of prevention. Rev Gastroenterol Disord 2005; 5(suppl 2):39–49.

22.

Nielson

, Ainsworth

, Csillag

, Rask-Madsen

. Systematic review: coxibs, non-steroidal anti-inflammatory drugs or no cyclooxygenase inhibitors in gastroenterological high-risk patients? Aliment Pharmacol Ther 2006; 23:27–33.

23.

Warner

, Giuliano

, Vojnovic

, Bukasa

, Mitchell

, Vane

. Nonsteroid drug selectivities for cyclo-oxygenase-1 rather than cyclooxygenase-2 are associated with human gastrointestinal toxicity: a full in vitro analysis. Proc Natl Acad Sci U S A 1999; 96:7563–8.

24.

Rodondi

, Cornuz

, Bauer

. Aspirin for the primary prevention of cardiovascular disease: a comprehensive review. Compr Ther 2005; 31:186–93.

25.

Hennan

, Huang

, Barret

. Effects of selective cyclooxygenase-2 inhibition on vascular responses and thrombosis in canine coronary arteries. Circulation 2001; 104:820–5.

26.

Hermann

, Ruschitzka

. Coxibs, non-steroidal anti-inflammatory drugs and cardiovascular risk. Intern Med J 2006; 36:308–19.

27.

Chan

, Zhang

, Fernandez

. Effect of cyclooxygenase inhibition on cholesterol efflux proteins and atheromatous foam cell transformation in THP-1 human macrophages: a possible mechanism for increased cardiovascular risk. Arthritis Res Ther 2007; 9:R4.

28.

Prospective randomized evaluation of celecoxib integrated safety vs ibuprofen or naproxen (PRECISION) study. www.arthritisheartstudy.com (accessed 2007 Jun 15).

29.

Chan

, Manson

, Albert

. Nonsteroidal antiinflammatory drugs, acetaminophen, and the risk of cardiovascular events. Circulation 2006; 113:1578–87.

30.

Garcia Rodriguez

, Varas

, Patrono

. Differential effects of aspirin and non-aspirin nonsteroidal antiinflammatory drugs in the primary prevention of myocardial infarction in postmenopausal women. Epidemiology 2000; 11:382–7.

31.

Garcia Rodriguez

, Varas Lorenzo

, Maguire

, Gonzalez Perez

. Nonsteroidal antiinflammatory drugs and the risk of myocardial infarction in the general population. Circulation 2004; 109:3000–6.

32.

Fischer

, Schlienger

, Matter

, Jick

, Meier

. Current use of nonsteroidal antiinflammatory drugs and the risk of acute myocardial infarction. Pharmacotherapy 2005; 25:503–10.

33.

Schlienger

, Jick

, Meier

. Use of nonsteroidal anti-inflammatory drugs and the risk of first-time acute myocardial infarction. Br J Clin Pharmacol 2002; 54:327–32.

34.

Jick

, Kaye

, Russmann

, Jick

. Nonsteroidal antiinflammatory drugs and acute myocardial infarction in patients with no major risk factors. Pharmacotherapy 2006; 26:1379–87.

35.

Watson

, Rhodes

, Cai

, Guess

. Lower risk of thromboembolic cardiovascular events with naproxen among patients with rheumatoid arthritis. Arch Intern Med 2002; 162:1105–10.

36.

Rahme

, Pilote

, LeLorier

. Association between naproxen use and protection against acute myocardial infarction. Arch Intern Med 2002; 162:1111–5.

37.

Kimmel

, Berlin

, Reilly

. Patients exposed to rofecoxib and celecoxib have different odds of nonfatal myocardial infarction. Ann Intern Med 2005; 142:157–64.

38.

Farkouh

, Kirshner

, Harrington

. Comparison of lumiracoxib with naproxen and ibuprofen in the Therapeutic Arthritis Research and Gastrointestinal Event Trial (TARGET), cardiovascular outcomes: randomised controlled trial. Lancet 2004; 364:675–84.

39.

Kimmel

, Berlin

, Kinman

. Parenteral ketorolac and risk of myocardial infarction. Pharmacoepidemiol Drug Saf 2002; 11:113–9.

40.

Kimmel

, Berlin

, Reilly

. The effects of nonselective non-aspirin non-steroidal anti-inflammatory medications on the risk of nonfatal myocardial infarction and their interaction with aspirin. J Am Coll Cardiol 2004; 43:985–90.

41.

Ray

, Stein

, Hall

, Daugherty

, Griffin

. Non-steroidal anti-inflammatory drugs and risk of serious coronary heart disease: an observational cohort study. Lancet 2002; 359:118–23.

42.

Solomon

, Glynn

, Levin

, Avorn

. Nonsteroidal anti-inflammatory drug use and acute myocardial infarction. Arch Intern Med 2002; 162:1099–104.

43.

Solomon

, Karlson

, Rimm

. Cardiovascular morbidity and mortality in women diagnosed with rheumatoid arthritis. Circulation 2003; 107:1303–7.

44.

Levesque

, Brophy

, Zhang

. The risk for myocardial infarction with cyclooxygenase-2 inhibitors: a population study of elderly adults. Ann Intern Med 2005; 142:481–9.

45.

Gislason

, Jacobsen

, Rasmussen

. Risk of death or reinfarction associated with the use of selective cyclooxygenase-2 inhibitors and nonselective nonsteroidal antiinflammatory drugs after acute myocardial infarction. Circulation 2006; 113:2906–13.

46.

Bak

, Andersen

, Tsiropoulos

. Risk of stroke associated with nonsteroidal anti-inflammatory drugs: a nested case-control study. Stroke 2003; 34:379–86.

47.

Ilkhanoff

, Lewis

, Hennessy

, Berlin

, Kimmel

. Potential limitations of electronic database studies of prescription non-aspirin nonsteroidal anti-inflammatory drugs (NANSAIDs) and risk of myocardial infarction (MI). Pharmacoepidemiol Drug Saf 2005; 14:513–22.

48.

McGettigan

, Han

, Henry

. Cyclooxygenase-2 inhibitors and coronary occlusion—exploring dose-response relationships. Br J Clin Pharmacol 2006; 62:358–65.

49.

Hawkey

, Hawkey

, Everitt

, Skelly

, Stack

, Gray

. Increased risk of myocardial infarction as first manifestation of ischaemic heart disease and nonselective nonsteroidal anti-inflammatory drugs. Br J Clin Pharmacol 2006; 61:730–7.

50.

Sajadieh

, Wendelboe

, Hansen

, Mortensen

. Nonsteroidal anti-inflammatory drugs after acute myocardial infarction. DAVIT Study Group. Danish Verapamil Infarction Trial. Am J Cardiol 1999; 83:1263–5.

51.

, Wang

, Berger

, Radford

, Krumholz

. Nonsteroidal antiinflammatory drugs after acute myocardial infarction. Am Heart J 2002; 143:475–81.

52.

Mamdani

, Rochon

, Juurlink

. Effect of selective cyclooxygenase 2 inhibitors and naproxen on short-term risk of acute myocardial infarction in the elderly. Arch Intern Med 2003; 163:481–6.

53.

Graham

, Campen

, Hui

. 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 control study. Lancet 2005; 365(9458):475–81.

54.

Fischer

, Schlienger

, Matter

, Jick

, Meier

. Discontinuation of nonsteroidal anti-inflammatory drug therapy and risk of acute myocardial infarction. Arch Intern Med 2004; 164:2472–6.

55.

Hippisley-Cox

, Coupland

. Risk of myocardial infarction in patients taking cyclo-oxygenase-2 inhibitors or conventional non-steroidal antiinflammatory drugs: population based nested case–control analysis. BMJ 2005; 330:1366.

56.

Johnsen

, Larsson

, Tarone

. Risk of hospitalization for myocardial infarction among users of rofecoxib, celecoxib, and other NSAIDs: a population-based case–control study. Arch Intern Med 2005; 165:978–84.

57.

Solomon

, Avorn

, Sturmer

, Glynn

, Mogun

, Schneeweiss

. Cardiovascular outcomes in new users of coxibs and nonsteroidal antiinflammatory drugs: high-risk subgroups and time course of risk. Arthritis Rheum 2006; 54:1378–89.

58.

Kearney

, Baigent

, Godwin

, Halls

, Emberson

, Patrono

. Do selective cyclo-oxygenase-2 inhibitors and traditional non-steroidal anti-inflammatory drugs increase the risk of atherothrombosis? Meta-analysis of randomised trials. BMJ 2006; 332:1302–8.

59.

Salpeter

, Gregor

, Ormiston

. Meta-analysis: cardiovascular events associated with nonsteroidal anti-inflammatory drugs. Am J Med 2006; 119:552–9.

60.

McGettigan

, Henry

. Cardiovascular risk and inhibition of cyclooxygenase: a systematic review of the observational studies of selective and nonselective inhibitors of cyclooxygenase 2. JAMA 2006; 296:1633–44.

61.

Singh

, Miller

, Lee

, Pettitt

, Russell

. Prevalence of cardiovascular disease risk factors among US adults with self-reported osteoarthritis: data from the Third National Health and Nutrition Examination Survey. Am J Manag Care 2002; 8:S383–91.

62.

de Maat

, Kluft

. The association between inflammation markers, coronary artery disease and smoking. Vascul Pharmacol 2002; 39:137–9.

63.

Patrono

, Coller

, FitzGerald

, Hirsh

, Roth

. Platelet-active drugs: the relationships among dose, effectiveness, and side effects: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest 2004; 126(3 suppl):234s–64s.

64.

Fornaro

, Rossi

, Mantica

. Indobufen in the prevention of thromboembolic complications in patients with heart disease. A randomized, placebo-controlled, double-blind study. Circulation 1993; 87:162–4.

65.

Brochier

. Evaluation of flurbiprofen for prevention of reinfarction and reocclusion after successful thrombolysis or angioplasty in acute myocardial infarction. The Flurbiprofen French Trial. Eur Heart J 1993; 14:951–7.

66.

Smith

, Lefer

. Stabilization of cardiac lysosomal and cellular membranes in protection of ischemic myocardium due to coronary occlusion:efficacy of the nonsteroidal anti-inflammatory agent, naproxen. Am Heart J 1981; 101:394–402.

67.

Van Hecken

, Schwartz

, Depre

. Comparative inhibitory activity of rofecoxib, meloxicam, diclofenac, ibuprofen, and naproxen on COX-2 versus COX-1 in healthy volunteers. J Clin Pharmacol 2000; 40:1109–20.

68.

Spalding

, Reeves

, Whelton

. Thromboembolic cardiovascular risk among arthritis patients using cyclooxygenase-2-selective inhibitor or nonselective cyclooxygenase inhibitor nonsteroidal anti-inflammatory drugs. Am J Ther 2007; 14:3–12.

69.

Mutru

, Laakso

, Isomäki

, Koota

. Cardiovascular mortality in patients with rheumatoid arthritis. Cardiology 1989; 76:71–7.