Oxidative Medicine and Cellular Longevity / 2015 / Article / Tab 2

Review Article

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.

NSAIDClinical trial name/locationDuration of studyNumber of patients selectedEffectReferences

Celecoxib, naproxen sodium, and placeboAlzheimer's Disease Anti-Inflammatory Prevention Trial (ADAPT)/USA 4 years2,528 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 tolmetinNone/USA5 years74,838 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, ibuprofenNone/Chieti, Chieti, Italy3 months24 patients undergoing aspirin treatment for cardioprotectionIbuprofen 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 etoricoxibNone/Finland3 years 33,309 patients with first MI, 138,949 controlsTheir 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 diclofenacMultinational Etoricoxib and Diclofenac Arthritis Long-term (MEDAL) Study Program/Multinational18 months34,701 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 diclofenacEtoricoxib versus Diclofenac Sodium Gastrointestinal Tolerability and Effectiveness (EDGE) trial/USA9.3 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 lumiracoxibThe Therapeutic Arthritis Research and Gastrointestinal Event Trial (TARGET)/InternationalExtended report18,325 patients with osteoarthritisIbuprofen 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 naproxenNone/USA7 yearsNDProlonged exposure to diclofenac increases the risk of AMI (relative ratio = 1.9–2.0) unlike ibuprofen or naproxen[182]

Etoricoxib and diclofenacEDGE II/USA19.3 months for etoricoxib and 19.1 months for diclofenac4,086 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/USA3 years7,950 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 acidNone/UK primary care20 years729,294 NSAID users; 443,047 controlsIncrease 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 diclofenacThe MEDAL Study/Multinational19.4 to 20.8 monthsEtoricoxib
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 rofecoxibNone/USA 6 years48,566 patients recently hospitalized for myocardial infarction, revascularization, or unstable angina pectorisCVD 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 indomethacinNone/USA7 years610,001 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 naproxenNone/Danish population9–34 days153,465 healthy individualsDose 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 naproxenThe Prospective Randomized Evaluation of Celecoxib Integrated Safety versus Ibuprofen Or Naproxen
(PRECISION) trial/Multinational
2009-ongoing20,000 patients with symptomatic osteoarthritis or rheumatoid arthritis at high risk for or with established CVDThis trial will determine the cardiovascular safety of the NSAIDs[189]

NDNone/Denmark10 years107,092 patients with first incidence of HFThe 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 Netherlands4 years485,059 subjects with first hospitalisation for acute myocardial infarction, CV, and gastrointestinal eventsAMI 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, rofecoxibNone/Northern Denmark10 years32,602 patients with first atrial fibrillation or flutter and 325,918 population controlsIncreased risk of atrial fibrillation or flutter was 40–70% (lowest for non-selective NSAIDs and highest for COX-2 inhibitors).[192]

NDNone/Denmark10 years83,677 patients of which 42.3% received NSAIDsDeath/recurrent MI due to NSAID treatment (even short term) was significantly higher. Diclofenac posed the highest risk of all NSAIDs[193]

NDINternational VErapamil Trandolapril STudy (INVEST)/Multinational7 years882 chronic NSAID users and 21,694 nonchronic NSAID users. Patients with hypertension and clinically stable coronary artery diseasePrimary 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 othersNone/Denmark13 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]

NDNone/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 Australia4 years4,420 NSAID users; 39,675 NSAID nonusers1.16-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.

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