NSAIDs and Cardiovascular Diseases: Role of Reactive Oxygen Species

Table 2

Summary of results from clinical trials on the adverse effects of NSAIDs on cardiovascular diseases.

NSAID	Clinical trial name/location	Duration of study	Number of patients selected	Effect	References
Celecoxib, naproxen sodium, and placebo	Alzheimer's Disease Anti-Inflammatory Prevention Trial (ADAPT)/USA	4 years	2,528 patients with a family history of Alzheimer's Disease.	CVD/CBV death, MI, stroke, CHF, or TIA in the celecoxib-, naproxen-, and placebo-treated groups were 5.54%, 8.25%, and 5.68%, respectively. Death rates in the case of patients taking NSAIDs were higher but not statistically significant	[44]
Celecoxib, rofecoxib, valdecoxib, diclofenac, naproxen, ibuprofen, diflunisal, etodolac, fenoprofen, flurbiprofen, indomethacin, ketoprofen, ketoralac, meclofenamate, mefenamic acid, meloxicam, nabumetone, oxaprozin, piroxicam, sulindac, and tolmetin	None/USA	5 years	74,838 users of NSAIDs and 23,535 users of other drugs.	The adjusted rate ratio for Rofecoxib was 1.16 for MI and 1.15 for stroke which was the highest among all other NSAIDs including other coxibs. Naproxen modestly reduced the rate ratio (RR for MI 0.067 and RR for stroke 0.083) of cardiovascular events	[177]
Celecoxib, ibuprofen	None/Chieti, Chieti, Italy	3 months	24 patients undergoing aspirin treatment for cardioprotection	Ibuprofen interfered with the inhibition of platelet COX-1 necessary for cardioprotection by aspirin	[178]
Diclofenac, ibuprofen, indomethacin, ketoprofen, naproxen, mefenamic acid, piroxicam, tenoxicam, tolfenamic acid, aceclofenac, tiaprofenic acid, mefenamic acid, etodolac, nabumetone, nimesulide, and meloxicam, rofecoxib, celecoxib, valdecoxib, and etoricoxib	None/Finland	3 years	33,309 patients with first MI, 138,949 controls	Their results suggest that COX-selectivity do not determine the adverse effect of CVD by NSAIDs, at least concerning MI. No NSAID is MI-protective	[13]
Etoricoxib and diclofenac	Multinational Etoricoxib and Diclofenac Arthritis Long-term (MEDAL) Study Program/Multinational	18 months	34,701 patients (24,913 with osteoarthritis and 9,787 with rheumatoid arthritis)	Thrombotic cardiovascular events occurred in 320 patients in the etoricoxib group and 323 patients in the diclofenac group with event rates of 1.24 and 1.30 per 100 patient-years and a hazard ratio of 0.95 for etoricoxib compared to diclofenac. Long term usage of either of these NSAIDs had similar effects on the rates of thrombotic cardiovascular events	[179]
Etoricoxib and diclofenac	Etoricoxib versus Diclofenac Sodium Gastrointestinal Tolerability and Effectiveness (EDGE) trial/USA	9.3 months for etoricoxib and 8.9 months for diclofenac	7,111 patients; etoricoxib () or diclofenac sodium ()	The rate of thrombotic CV events was 1.30 and 1.24 in users of etoricoxib (90 mg) and diclofenac (150 mg), respectively, within 28 days	[180]
Ibuprofen, naproxen or lumiracoxib	The Therapeutic Arthritis Research and Gastrointestinal Event Trial (TARGET)/International	Extended report	18,325 patients with osteoarthritis	Ibuprofen increased risk of thrombosis and CHF compared to lumiracoxib (2.14% versus 0.25%) among aspirin users. Naproxen confers lower risk relative to lumiracoxib among nonaspirin users	[181]
Diclofenac, ibuprofen, and naproxen	None/USA	7 years	ND	Prolonged exposure to diclofenac increases the risk of AMI (relative ratio = 1.9–2.0) unlike ibuprofen or naproxen	[182]
Etoricoxib and diclofenac	EDGE II/USA	19.3 months for etoricoxib and 19.1 months for diclofenac	4,086 patients with rheumatoid arthritis etoricoxib ; diclofenac	The rate of occurrence of AMI was higher in diclofenac (0.68) treated patients than in etoricoxib users (0.43). Also an overall increase in cardiac events was observed in diclofenac treated group (1.14) versus the etoricoxib group (0.83)	[183]
Celecoxib (at 400 mg QD, 200 mg two times a day (BID), or 400 mg BID)	None/USA	3 years	7,950 patients (with arthritis and other conditions)	The hazard ratio for the CVD, MI, HF, or thromboembolic event was lowest for the 400 mg once a day (1.1), intermediate for the 200 mg-BID dose (1.8), and highest for the 400 mg-BID dose (3.1)	[184]
Ibuprofen, naproxen, diclofenac, meloxicam, indomethacin, piroxicam, and mefenamic acid	None/UK primary care	20 years	729,294 NSAID users; 443,047 controls	Increase in the relative rate for MI with cumulative and daily dose of ibuprofen and diclofenac. Higher risk of MI with diclofenac use (relative ratio = 1.21) than ibuprofen (relative ratio = 1.04) or naproxen (relative ratio = 1.03)	[185]
Etoricoxib and diclofenac	The MEDAL Study/Multinational	19.4 to 20.8 months	Etoricoxib; 60 mg/d; 90 mg/d; Diclofenac	The thrombotic CV risk HR of etoricoxib to diclofenac = 0.96. Prolonged use of either NSAID resulted in an increased risk of thrombotic CV events	[186]
Naproxen, ibuprofen, diclofenac, celecoxib, and rofecoxib	None/USA	6 years	48,566 patients recently hospitalized for myocardial infarction, revascularization, or unstable angina pectoris	CVD risk increased with short term (<90 days) use for ibuprofen with incidence rate ratios of 1.67, diclofenac 1.86, celecoxib 1.37, and rofecoxib 1.46, but not for naproxen 0.88	[51]
Celecoxib, rofecoxib, valdecoxib, ibuprofen, naproxen, diclofenac, and indomethacin	None/USA	7 years	610,001 patients; without CVD ; with history of CVD	Rofecoxib (10.91 events/1000 person-years), valdecoxib (12.41 events/1000 person-years), and indomethacin (13.25 events/1000 person-years) increased CVD risk in patients with no history of CVD. Rofecoxib use increased risk of cardiovascular event in patients with CVD (30.28 events/1000 person-years)	[187]
Ibuprofen, diclofenac, rofecoxib, celecoxib, and naproxen	None/Danish population	9–34 days	153,465 healthy individuals	Dose dependent increase in cardiovascular events due to use of diclofenac (HR = 1.63), rofecoxib (HR = 2.13) and celecoxib (HR = 2.01) was observed	[188]
Celecoxib, ibuprofen, and naproxen	The Prospective Randomized Evaluation of Celecoxib Integrated Safety versus Ibuprofen Or Naproxen; (PRECISION) trial/Multinational	2009-ongoing	20,000 patients with symptomatic osteoarthritis or rheumatoid arthritis at high risk for or with established CVD	This trial will determine the cardiovascular safety of the NSAIDs	[189]
ND	None/Denmark	10 years	107,092 patients with first incidence of HF	The hazard ratio for death due to MI or HF was 1.70, 1.75, 1.31, 2.08, 1.22, and 1.28 for rofecoxib, celecoxib, ibuprofen, diclofenac, naproxen, and other NSAIDs, respectively	[190]
Ibuprofen, diclofenac, naproxen, rofecoxib, celecoxib, valdecoxib, and etoricoxib	None/The Netherlands	4 years	485,059 subjects with first hospitalisation for acute myocardial infarction, CV, and gastrointestinal events	AMI risk with celecoxib (OR 2.53), rofecoxib (OR 1.60), ibuprofen (OR 1.56), and diclofenac (OR 1.51) was significantly increased. Significant increase in CV risk with current use of individual COX-2 inhibitors and tNSAIDs (OR from 1.17 to 1.64). Significant decrease in AMI with current use of naproxen (OR 0.48)	[191]
Ibuprofen, naproxen, diclofenac, etodolac, celecoxib, rofecoxib	None/Northern Denmark	10 years	32,602 patients with first atrial fibrillation or flutter and 325,918 population controls	Increased risk of atrial fibrillation or flutter was 40–70% (lowest for non-selective NSAIDs and highest for COX-2 inhibitors).	[192]
ND	None/Denmark	10 years	83,677 patients of which 42.3% received NSAIDs	Death/recurrent MI due to NSAID treatment (even short term) was significantly higher. Diclofenac posed the highest risk of all NSAIDs	[193]
ND	INternational VErapamil Trandolapril STudy (INVEST)/Multinational	7 years	882 chronic NSAID users and 21,694 nonchronic NSAID users. Patients with hypertension and clinically stable coronary artery disease	Primary outcome like all-cause mortality, nonfatal MI, or nonfatal stroke and secondary individual outcomes like all-cause mortality, cardiovascular mortality, total MI, and total stroke occurred at a rate of 4.4 events per 100 patient-years in the chronic NSAID group, versus 3.7 events per 100 patient-years in the nonchronic NSAID group	[111]
Celecoxib, rofecoxib, ibuprofen, diclofenac, naproxen, and others	None/Denmark	13 years (with first MI)	128,418 patients (77% participated in the study)	Incidences of coronary death or nonfatal recurrent MI with NSAIDs use remain unchanged with the time elapsed even after 5 years	[194]
ND	None/data obtained from REduction of Atherothrombosis for Continued Health (REACH) registry which includes patients from Latin America, North America, Europe, Asia, the Middle East, and Australia	4 years	4,420 NSAID users; 39,675 NSAID nonusers	1.16-fold higher risk of CVD, MI in NSAID users	[41]

MI: myocardial infarction, HF: heart failure, CVD: cardiovascular diseases, CBV: cerebrovascular diseases, CHF: congestive heart failure, HR: hazard ratio, OR: odd ratio, ND: not defined, RR: rate ratio, and TIA: transient ischemic attack. Various clinical trials suggest the increased incidences of CVD in NSAID users. The table lists only the clinical trials reported between 2006 and 2014.