Assessment of nonsteroidal anti-inflammatory drug-induced cardiotoxicity

1. Introduction

2. Pharmacologic effects of COX

inhibition on the CV system

3. Putative mechanism of COX

inhibitors to cause

cardiotoxicity

4. Assessment of CV toxicity

associated to NSAIDs

5. Conclusions

6. Expert opinion

Review

Assessment of nonsteroidalanti-inflammatory drug-inducedcardiotoxicityBhulan Kumar Singh†, Syed Ehtaishamul Haque & Krishna Kolappa Pillai†Department of Pharmacology, KIET School of Pharmacy, Uttar Pradesh, India

Introduction: Nonsteroidal anti-inflammatory drugs (NSAIDs), including selec-

tive cyclooxygenase-2 inhibitors (coxibs) and traditional NSAIDs (tNSAIDs),

have been widely used for the treatment of pain and rheumatic disease. The

use of NSAIDs has been linked to increased cardiovascular toxicity in both

healthy individuals and patients with established cardiovascular disease. Var-

ious recently published studies have raised concerns about the cardiovascular

safety of NSAIDs; this review is focused on the cardiotoxic effects of NSAIDs.

Areas covered: This review focuses on arthritis trials, placebo-controlled trials,

meta-analyses, preclinical and observational studies associated with the use of

NSAIDs-induced cardiotoxicity. It analyses the data given in these studies and

discusses the cardiotoxic risk of NSAIDs.

Expert opinion: Analysis of various clinical, preclinical, meta-analysis and

observational studies showed that coxibs and tNSAIDs increase the risk of car-

diotoxicity. Cardiotoxic risk depends on dose, duration and frequency of

NSAID administration. Most studies were based on large medical databases

with miscellaneous populations and pointed to an increase risk of cardiotox-

icity under NSAID medication. The cardiotoxicity associated with use of

NSAIDs might be due to inhibition of prostacyclin synthesis, oxidative stress,

increase in blood pressure and impaired endothelial function.

Keywords: adenomas, arthritis, cardiotoxicity, cyclooxygenase, nonsteroidal anti-inflammatory

drugs, prostacyclin, reactive oxygen species

Expert Opin. Drug Metab. Toxicol. (2014) 10(2):143-156

1. Introduction

Nonsteroidal anti-inflammatory drugs (NSAIDs) are commonly used in the generalpopulation. They are mainly used to treat pain but their long-term use is limited byserious gastrointestinal side-effects [1]. In view of this, selective cyclooxygenase(COX)-2 inhibitor drugs (collectively known as coxibs) were developed and early tri-als comparing coxibs versus traditional NSAIDs (tNSAIDs) seemed to confirm thatcoxibs at the doses with similar analgesic efficacy had less gastrointestinal toxicity [2,3].But, unfortunately, subsequent placebo-controlled trials showed that coxibs wereassociated with an increased risk of cardiovascular (CV) thrombotic events [4-6].

Soon after these studies were reported, meta-analysis of randomized trials com-paring a coxib versus placebo or a coxib versus tNSAID indicated that sometNSAIDs might also have adverse effects on CV thrombotic events but these hazardsmight depend on the degree, dose and duration of tNSAIDs administration [7,8].Similarly, other studies also reported that coxibs and most of the tNSAIDs wereassociated with CV risk events. However, CV thrombotic hazard among NSAIDswere different [9-14].

The focus of this review is to assess the effects of both coxibs and tNSAIDs oncardiotoxicity from several recent clinical and preclinical as well as from recentobservational studies.

10.1517/17425255.2014.856881 © 2014 Informa UK, Ltd. ISSN 1742-5255, e-ISSN 1744-7607 143All rights reserved: reproduction in whole or in part not permitted

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http://informahealthcare.com/journal/EMT

2. Pharmacologic effects of COX inhibition onthe CV system

The pharmacological effects of COX inhibition are shownin Figure 1. COX participates in numerous physiologic func-tions and human pathologic disorders. COX-1 is the constitu-tive enzyme present in mature platelets, expressed in thevascular endothelium, gastrointestinal epithelium, brain,spinal cord and kidney. COX-2 is the inducible enzymeexpressed in the atherosclerotic plaques, during angiogenesis,wound healing and in a variety of epithelial cell cancersas well as in the macula densa and renal medullaryinterstitium [15-17]. A clinical study reported that inhibitionof COX-2 reduces natriuresis and development of hyperten-sion in susceptible population. Numerous non-clinical studiesdemonstrated that inhibition of prostacyclin (PGI2) leads toboth platelet dependent and platelet independent inductionof thrombosis, plaque destabilization or atherogenesis [18-20].COX-2 has also been shown to be a cardioprotective in ische-mia reperfusion injury and is recognized as a key source ofPGI2 [21]. COX-2 inhibition decreases the level of antithrom-botic PGI2 made by arachidonate flux as well as enhances syn-thesis of leukotrienes (LTs) along with generation of reactiveoxygen species (ROS) and consumption of antithrombicnitric oxide (NO) [22]. A study conducted in animals reportedthat nonselective NSAID diclofenac sodium aggravatesdoxorubicin-induced cardiotoxicity [23]. This study suggestedthat diclofenac sodium increases risk of CV events due to oxi-dative stress. Another study showed an association betweenrofecoxib and its metabolism with mark degradation of aroticelastin through prevention of cross-linkages, a potential factorfor increased risk of CV events observed with this drug com-pared to other NSAIDs [24]. Inhibition of COX-2 also causesthe vascular endothelial dysfunction that is due to reduceavailability of NO and oxidative stress [25]. However,COX-2 inhibition with celecoxib led to reduce tissue factorexpression and activity in human endothelial cells that wasmediated by inhibition of c-Jun terminal NH2 kinase

phosphorylation [26]. These studies suggested that heterogene-ity responses of various coxibs might lead to different clinicaleffects, especially in patients with underlying atheroscleroticvascular diseases.

Acetaminophen, an indirect COX-2 selective inhibitor, actsvia a peroxidase site on prostaglandin H2 (PGH2) synthetase2 and reduces the conversion of arachidonic acid toPGH2 [27] as well as indirectly activates cannabinoid receptorsby N-arachidonoyl phenylamine, a metabolite of acetamino-phen [28]. Some study reported that acetaminophen increasedrisk of CV events which might be attributed due to theirblood pressure (BP) raising potential [29-31].

3. Putative mechanism of COX inhibitors tocause cardiotoxicity

Putative mechanism of COX inhibitors cause cardiotoxicity isshown in Figure 2. COX inhibition alters metabolism of eico-sanoids, which include prostaglandins (PGs), thromboxane(TX) and LTs that are derived from arachidonic acid, anomega-6 polyunsaturated acid. COX is rate-limiting for con-version of arachidonic acid to cyclic endoperoxides, which isconverted to the important vasoactive eicosanoids TXA2 andPGI2 as well as other PGs such as PGD2, PGE2 and PGF2aby specific synthases (Figure 1) [15,16].

Inhibition of COX-2 by tNSAIDs and coxibs can reduceendothelial cell PGI2 synthesis, a vital vasodilator and plateletinhibitor but not COX-1-derived TXA2, a vasoconstrictiveeicosanoid that promotes platelet aggregation and thrombusformation. This disrupts the normal balance between PGI2and TXA2, which lead to increase the risk of CV thromboticevents and atherosclerosis [19,20]. Inhibition of selectiveCOX-2 may also directly interfere with cardiac synthesis ofPGI2 and PGE2.

Furthermore, tNSAIDs and coxibs decrease synthesis ofPGI2 can cause arterial constriction and renal sodium aswell as potassium retention, may contribute to developmentof hypertension. Hypertension together with coxibs-inducedprothrombotic state increase the risk of myocardial infarction(MI) and thrombotic stroke [7,32].

Alteration in PG synthesis can affect cardiac mitochondriaand cardiomyocyte contraction. PGE2 enhances cardiac con-tractile function and increases cardiac output [21]. Most ofNSAIDs inhibits or uncouples cardiac mitochondrial oxida-tive phosphorylation and reduces membrane potential aswell as cardiac mitochondrial ATP production, which canleads to cardiac dysfunction [33].

Moreover, inhibition of COX by NSAIDs enhances accu-mulation of arachidonic acid which leads to inhibition of car-diac mitochondrial phosphorylation. As a result increasesgeneration of ROS and decreases antioxidant enzymes activitywhich leads to oxidative stress that induces cardiacdysfunction [23,34].

Acetaminophen and other NSAIDs have been shown toinhibit N-methyl-D-aspartic acid receptors, which play a

Article highlights.

. All non-aspirin NSAIDs increase risk of CV toxicity.

. Coxibs as a class are associated with increased risk ofatherothrombotic events.

. Cardiotoxicity risk depends on dose, duration andfrequency of NSAIDs administration.

. NSAIDs elevated BP in hypertensive population andantagonized BP lowering effect ofantihypertensive medication.

. All observational studies are based on large medicaldatabases of drugs with miscellaneous population.

. NSAIDs elevated cardiotoxicity due to inhibition of PGI2synthesis, oxidative stress and endothelial dysfunction.

This box summarizes key points contained in the article.

B. K. Singh et al.

144 Expert Opin. Drug Metab. Toxicol. (2014) 10(2)

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role in pain neurotransmission and in vasodilation [28].N-methyl-D-aspartic acid receptors release NO as a neurotrans-mitter in the spinal cord on stimulation that may modulatearachidonic acid metabolism by altering COX activity [28].There has been speculation that the novel mechanisms ofaction of acetaminophen could theoretically explain a pressoreffect in susceptible individuals.

4. Assessment of CV toxicity associated toNSAIDs

4.1 In hypertensive patientsArthritis and hypertension often co-exist in middle-aged andolder patients. Thus, co-administration of coxibs or tNSAIDswith antihypertensive agents has been fairly common in clin-ical practice [35]. A double-blind, randomized trial, the Cele-coxib Rofecoxib Efficacy and Safety in ComorbiditiesEvaluation Trial (CRESCENT) was conducted in patientswith type 2 diabetes, hypertension and osteoarthritis to assessthe effects of celecoxib (200 mg once daily), rofecoxib (25 mgonce daily) and naproxen (500 mg twice daily) on 24-h BP.The results of this trail showed that systolic BP was increasedsignificantly by rofecoxib (130.3 ± 1.2 to 134.5 ± 1.4 mmHg)but not by celecoxib (132.0 ± 1.3 to 131.9 ± 1.3 mmHg) ornaproxen (133.7 ± 1.5 to 133.0 ± 1.4 mmHg) [35].

Furthermore, meta-analyses of NSAID trials showed thatmany drugs within the class could elevate mean arterial pres-sure (MAP) by 5 -- 6 mmHg in hypertensive patients [36,37].The elevation of BP may be clinically significant in relationto increase CV risk events.

4.2 On BPInhibition of COX-2 decreases the synthesis of PG particu-larly PGE2 and PGI2 as well as is associated with both anti-natriuretic and vasoconstrictor effects [38,39]. Inhibition ofPGE2 may decrease excretion of urinary sodium 30 -- 50%[40]. These effects will tend to normalized in patients with nor-mal kidney function in order to maintain homeostasis ofsodium balance within few days [40,41]. However, this homeo-static process is impaired due to retention of salt and water inpatients with chronic kidney disease within 1 -- 2 weeks ofNSAIDs therapy. This may lead to oedema and hypertensionas well as in more severe cases, congestive heart failure(CHF) [42].

Coxibs and tNSAIDs may also impair systemic and renal vas-odilatory effects of PGI2. Loss of this effect in the face of numer-ous vasoconstrictors (e.g., angiotensin II, catecholamines andendothelin) may potentially lead to increase in systemic vascularresistance and subsequently to increase in MAP. An experimen-tal study reported that COX-1 inhibitors blunt the pressor effect

Vasoconstriction

Vasoconstriction

Vasodilatation

Vasodilatation Vasodilatation Vasodilatation

Increases natriuresis

Inhibits plateletaggregation

Inhibits plateletaggregation

Increases plateletaggregation

Inhibits gastricacid secretion

Decrease Na+/H2Oretention

Oxidative stress

Phospholipid

NSAIDS or selectiveCOX-2 inhibitors

Arachidonate

Endoperoxides

Synthase

LTs

OXPHOS

ROS≠

PGI2 PGD2 PGE2

PLA2

TXA2

LPO

COX-1 COX-2NMDA

NO

•

•

•

•

•

•

•

•

•

•

•

•

•

≠

≠ ≠ ≠ ≠

Figure 1. Schematic representation of the pharmacological effects related to cyclooxygenase inhibition.COX-1: Cyclooxygenase-1; COX-2: Cyclooxygenase-2; LPO: Lipoxygenase; LTs: Leukotrienes; NMDA: N-methyl-D-aspartic acid; NO: Nitric oxide; OXPHOS: Oxidative

phosphorylation; PGD2: Prostaglandin D2; PGE2: Prostaglandin E2; PGI2: Prostacyclin; PLA2: Phospholipase A2; ROS: Reactive oxygen species; TXA2: Thromboxane A2.

Assessment of NSAID-induced cardiotoxicity

Expert Opin. Drug Metab. Toxicol. (2014) 10(2) 145

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of angiotensin II whereas, COX-2 inhibitors reduce the renalmedullary blood flow, decrease the urine flow and enhance thepressor effect of angiotensin II [43]. Furthermore, aldosterone, akeyCVhormone, can induce deleterious effects, such asmyocar-dial fibrosis and vascular stiffening. NSAIDs inhibit the metab-olism of aldosterone which could lead to hypertension throughenhanced level of aldosterone [44].TheMultinational Etoricoxib andDiclofenac Arthritis Long-

term Program was a prospective randomized and double-blindin which patients were taken etoricoxib (60 or 90 mg daily) ordiclofenac (150 mg daily) for 18 months. The finding of thisstudy reported that BP observed was significantly higher andwas associated with risk of thrombotic CV events [45].

4.3 In patients taking antihypertensive medicationsA number of studies have been reported that tNSAIDs havethe potential to destabilize BP in hypertensive patients whoare receiving angiotensin converting enzyme (ACE) inhibi-tors, b-blockers, Ca2+-channel blockers or diuretics [46].A randomized, double-blind, placebo-controlled, parallel-group clinical trial studied in 178 patients who had essentialhypertension and received high dose of celecoxib (200 mgtwice a day) as well as ACE inhibitor therapy. Result analysisshown that high doses of celecoxib had no significant effect onthe antihypertensive effect of the ACE inhibitor lisinopril.The placebo-subtracted changes observed in 24-h BP

(1.6/1.2 mm Hg) were less than what had been reported forNSAIDs in ACE inhibitor-treated patients [46]. However, adouble-blind crossover trial studied the effects of celecoxiband diclofenac on ambulatory BP and glomerular filtrationrates (GFR), who had received ACE inhibitor at baseline.Result showed that mean 24-h systolic BP was significantlyincreased by diclofenac (+4.2 mmHg) compared to celecoxib(+0.6 mmHg) and GFR was significantly reduced by diclofe-nac but not by celecoxib [47].

Furthermore, a randomized, parallel-group, double-blindstudy using the systolic BP as the primary endpoint evaluatedthe effects of rofecoxib (25 mg/day) and celecoxib (200mg/day) in 1092 osteoarthritis patients (‡ 65 years age) whowere treated with fixed antihypertensive regimens [48]. Thistrial showed that rofecoxib significantly increases in systolicBP in patients who were receiving ACE inhibitors or b-block-ers, whereas those on Ca2+-channel antagonists or diureticmonotherapy receiving either celecoxib or rofecoxib showedno significant increase in BP. These results support the con-cept that Ca2+-channel antagonists do not depend on vascularPGI2 as part of their mechanism of action or are less affectedby accumulation of sodium compared to the other classes ofantihypertensive agents [48,49]. This finding was confirmedby a placebo-controlled multicenter study conducted in162 patients aged 18 -- 75 years with essential hypertensionfor 3 weeks, showed that neither ibuprofen nor naproxen

COX-1 COX-2

Vasoconstriction

Vasoconstriction

TXA2PGI2

Thrombotic risk events

Hypertension

LA

OXPHOS

CMMP

ATP

ROS

Platelet aggregationPlatelet aggregation

NSAIDS or selectiveCOX-2 inhibitors

LTs

Na+/H2O retention

Vasodilatation

Arachidonic acid

≠

Ø

Ø

Ø

Ø

≠

Cardiotoxicity risk≠

≠

Figure 2. Putative mechanism of cyclooxygenase inhibitors to cause cardiotoxicity.ATP: Adenosine triphosphate; CCMP: Cardiac mitochondrial membrane potential; COX-1: Cyclooxygenase-1; COX-2: Cyclooxygenase-2; LA: Leukocyte adhesion;

LTs: Leukotrienes; OXPHOS: Oxidative phosphorylation; PGI2: Prostacyclin; ROS: Reactive oxygen species; TXA2: Thromboxane A2.

B. K. Singh et al.


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significantly increased mean BP in patients treated withverapamil [49].

Recently, a study using an integrated safety analysis of threelarge osteoarthritis trials characterized the effects of naproxci-nod, a NO-donating COX inhibitor, on BP after 13 weeks oftherapy with naproxcinod, naproxen or placebo and includeda subgroup taking renin--angiotensin system (RAS) inhibi-tors [50]. This study demonstrated that naproxcinod had BPeffects similar to that of placebo. Naproxcinod would be lesslikely to alter systolic BP in patients with osteoarthritis thana tNSAID, particularly in those treated with RAS inhibitor.Moreover, a double-blind, crossover study conducted in131 hypertensive patients aged 50 -- 74 years for 8 week andreceived naproxcinod 750 mg twice daily or naproxen500 mg twice daily [51,52]. Result analysis suggested that nap-roxcinod had less effect on BP relative to naproxen in patientswith stable, treated hypertension who was not long-termNSAID users. Naproxcinod may be a beneficial alternativefor patients with osteoarthritis requiring NSAIDs. Another,double-blind, multicenter study conducted in 810 patientswith osteoarthritis of the hip for 13 week and received eithernaproxcinod 750 mg twice daily, placebo or naproxen500 mg twice daily [52,53]. This study analyzed that naproxci-nod was safe and well tolerated and had BP profile similarto placebo.

4.4 In arthritis trialsCV toxicities have been evaluated among users of NSAIDs invarious types of study design, which are summarizedin Table 1. The first two studies that examined the CV toxic-ities in arthritis populations were the Vioxx GastrointestinalOutcomes Research (VIGOR) study [2] and the CelecoxibLong-term Arthritis Safety Study (CLASS) [1,54]. These stud-ies remain important with regard to outcomes as supra-therapeutic doses of coxibs were compared with maximaltherapeutic doses of tNSAID in their target treatment popula-tion of osteoarthritis and/or rheumatoid arthritis. The resultsof these studies were dissimilar. In the VIGOR trial, CV eventrates were substantial higher with rofecoxib (50 mg once aday) than with naproxen (500 mg twice a day) [2], whereasin the CLASS study, rates were similar for celecoxib(400 mg twice a day), ibuprofen (800 mg thrice a day) anddiclofenac (75 mg twice a day) [54]. The results of anotherstudy, the Therapeutic Arthritis Research and GastrointestinalEvent Trial (TARGET) were similar to CLASS but the cumu-lative incidence of Anti-Platelet Trialists’ Collaboration(APTC) events in TARGET was quite low and did not differbetween lumiracoxib (400 mg once a day) and naproxen(500 mg twice a day) or ibuprofen (800 mg thrice aday) [3,55]. There was no placebo in VIGOR, CLASS or TAR-GET since all of these patients suffered from arthritis andwould not have tolerated a long-term trial without anactive treatment.

CV event rates in the arthritis trials were about 0.7% in theTARGET [55], 1% in the CLASS [54] and 2% in the

VIGOR [2] treatment arms. Limitations of these trials werelack of power typically required for elucidating CV toxicityin a definitive fashion and a maximal treatment exposure of15 months. In addition, the VIGOR excluded patients takinglow-dose aspirin while in the CLASS and the TARGET thiswas allowed. Nevertheless, these controlled clinical trial datademonstrate that supra-therapeutic doses of celecoxib andmaximal doses of lumiracoxib have CV toxicity events similarto that of the nonselective NSAIDs.

Furthermore, the Multinational Etoricoxib and DiclofenacArthritis Long-term (MEDAL) program was a combinedanalysis of three trials randomized, double-blinded, controlledcomparing etoricoxib (60 or 90 mg daily) with diclofenac(150 mg daily) [56]. These drugs were taken to osteoarthritisor rheumatoid arthritis patients for 18 months. Long-termuse of etoricoxib in patient with arthritis produced the throm-botic CV event rates were seen similar to those produced bydiclofenac. This was the first clinical program designed toassess non-inferiority for the thrombotic CV events betweena coxibs and a tNSAIDs, and cannot be extrapolated otherselective and nonselective NSAIDs [56].

The celecoxib versus omeprazole and diclofenac in patientswith osteoarthritis and rheumatoid arthritis (CONDOR)trial [57] and the prospective, randomized, open-label, blindedendpoint (PROBE) study [58], both of which are parallel tothe CLASS and VIGOR trials, had a priori design CV adjudi-cation committees and considered all the faults that sufferedduring the CLASS and the VIGOR trial. In CONDOR trail,patients received celecoxib (200 mg twice a day) or diclofenacslow release (75 mg twice a day) plus omeprazole (20 mg oncea day) whereas, in PROBE study, patients received celecoxib(200 mg daily) or nonselective NSAIDs, for 6 months [57,58].Finding of these studies indicated that both coxibs andtNSAIDs increased the risk of CV thrombotic events.

4.5 In placebo-controlled COX inhibitor trialsPlacebo-controlled COX-2 inhibitor trials also raised concernregarding CV safety, which was conducted in non-arthritispopulation, summarized in Table 2. The Adenomatous PolypPrevention on Vioxx (APPROVe) trial was the first multicen-ter, randomized, placebo-controlled, double-blind trial, con-duced in the colorectal adenomas populations. Thethrombotic CV event was 1.50 events per 100 patient--yearsfor rofecoxib (25 mg daily) versus 0.78 events per100 patient--years for placebo. Finding of this trial indicatedthat rofecoxib increased CV toxicity risk in patients with ahistory of colorectal adenomas compared with placebo [4].Furthermore, the Adenoma Prevention with Celecoxib(APC) trial was conducted in the patients with a history ofcolorectal adenomas to review the serious CV toxicities. Thetwo doses of celecoxib (200 or 400 mg twice daily) was usedto compare with placebo for the prevention of colorectal ade-nomas. The results of this trail indicated that celecoxib wasassociated with an increased risk of CV toxicity comparedwith placebo [5,59]. Another study, the Prevention of



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Table

1.Cardiovasculartoxicityassociatedto

nonsteroidalanti-inflammatory

drugsin

arthritistrials.

Study

Studydisease

Age

(years)

Mean

follow-up

(years)

Exposu

reASA

use

(%)

Non-fatalmyocardial

infarction

Coronary

heart

disease

death

Tarm

N(%

)Carm

N(%

)Tarm

N(%

)Carm

N(%

)

VIGOR

[2]

Rheumatoid

arthritis

>40

0.57

Rofecoxib50mg(n

=4047)vs

naproxen500mgbid

(n=4029)

418(0.4)

4(0.1)

5(0.1)

4(0.1)

CLA

SS[54]

Rheumatoid

arthritis/

Osteoarthritis

>18

0.57

Celecoxib400mgbid

(n=3987)

vsdiclofenac75mgbid

(n=1996)oribuprofen800mg

tid(n

=1985)

22

12(0.3)

11(0.3)

9(0.2)

8(0.2)

TARGET[55]

Osteoarthitis

>50

0.74

Lumiracoxib400mg(n

=9156)vs

naproxen500mgbid

(n=4754)or

ibuprofen800mgtid(n

=4415)

24

18(0.2)

9(0.1)

2(0.02)

3(0.03)

MEDAL[56]

Rheumatoid

arthritis/

Osteoarthritis

>50

1.46

Etoricoxib60--90mg(n

=17,412)

vsdiclofenac150mg(n

=17289)

34

105(0.62)

105(0.64)

6(0.04)

17(0.10)

CONDOR*

[57]

Osteoarthritis/

Rheumatoid

arthritis

18--60

0.5

Celecoxib200mgbid

(n=2238)

vsdiclofenac75mgbid

plus

omeprazole

20mgonce

aday

(n=2246)

----

----

--

PROBE[58]

Osteoarthritis

‡55

0.5

Celecoxib200mgdaily

(n=4035)vs

nsN

SAIDs

(n=4032)

--11(0.4)

10(0.3)

5(0.1)

3(0.1)

*Cardiotoxicity

data

wasnotmention.

ASA:Acetylsalicylic

acid;C:Control;CI:Confidence

interval;

CLA

SS:TheCelecoxibLong-term

ArthritisSafety

Study;

CONDOR:Thecelecoxibversusomeprazole

anddiclofenacin

patients

withosteoarthritisand

rheumatoid

arthritistrail;

MEDAL:

TheMultinationalEtoricoxibandDiclofenacArthritisLong-term

program;nsN

SAIDs:

Nonselectivenonsteroidalanti-inflammatory

drugs;

PROBE:Theprospective,randomized,

open-label,blindedendpointstudy;

RR:Relative

risk;T:Treatm

ent;TARGET:TheTherapeuticArthritisResearchandGastrointestinalEventTrial;VIGOR:TheVioxx

GastrointestinalOutcomesResearchstudy.

B. K. Singh et al.


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Colorectal Sporadic Adenomatous Polyps (PreSAP) trial was arandomized, placebo-controlled, double-blind study of cele-coxib (400 mg once daily) conduced in the patients whohad adenomas. Celecoxib showed a nearly twofold increasedCV events compared with placebo [60,61]. Alzheimer’s DiseaseAnti-Inflammatory Prevention Trial (ADAPT) evaluated theinfluences of a tNSAID naproxen (220 mg twice daily) anda coxib celecoxib (200 mg twice daily) versus placebo for theprimary prevention of Alzheimer’s dementia. The trial wasterminated prematurely because data analysis indicated thatthese drugs increased CV toxicity events [62]. The Vioxx inColorectal Cancer Therapy: Definition of Optimal Regime(VICTOR) trial was a randomized, placebo-controlled trialof rofecoxib (25 mg daily), conducted in patients with StageII or III colorectal cancer and reported that rofecoxib therapywas associated with an increased frequency of CV toxicityevents among the patients with a median study treatment of7.4 months’ duration [63]. All these studies reported that cox-ibs have potential to increase the CV toxicity events amongthe users.

4.6 In preclinical studyVarious preclinical studies have been reported that NSAIDsincreases cardiotoxicity in experimental animals, which aresummarized in Table 3. Diclofenac, a tNSAID is commonlyused for the treatment of pain and inflammation. An experi-mental study reported that diclofenac sodium (2.5 and10 mg/kg/day, for 5 days), aggravates cardiotoxicity inducedby doxorubicin. The cardiotoxicity risk event of diclofenacsodium might be due to reduced antioxidant activity andincreased generation of free radical [23]. Another animal studyalso reported that naproxen (50 mg/kg/day) augments myo-cardial injury induced by doxorubicin [64]. A coxibSC236 studied in doxorubicin-induced myocardial injurymodel and suggested that SC236 augments CV toxicity riskdue to inhibition of PGI2 [65]. Furthermore, a coxib celecoxibincreases BP as well as accelerates thrombogenesis by increas-ing platelet aggregation and collagen-induced thrombocyto-penia [66]. Other study reported that inhibition of COX byNSAIDs enhance the expression of vascular and cardiacNADPH oxidases and reduces vascular NO bioavailability.Coxibs produce less oxidative stress than the tNSAIDs [67].The enhanced production of ROS in response to COX inhi-bition may be responsible, at least in part, for the adverseCV effects of NSAIDs observed in preclinical studies [23,67].Thus, all preclinical studies reported that NSAIDs augmentCV event risks in experimental animals.

4.7 In observational studiesCV event rates have been evaluated in patients takingNSAIDs in various observational studies during the pastdecade. These studies have some limitation that they all aregenerally retrospective and used either nested/matched case---control or cohort analysis based on drug use in a database.Therefore, they will always pose some methodologicalT

able

2.Cardiovasculartoxicityassociatedto

nonsteroidalanti-inflammatory

drugsin

placebo-controlledtrials.

Study

Studydisease

Age

(years)

Mean

follow-up

(years)

Exposu

reASA

use

(%)

Non-fatalmyocardial

infarction

Coronary

heart

disease

death

Tarm

N(%

)Carm

N(%

)Tarm

N(%

)Carm

N(%

)

APPROVe[4]Removedcolon

adenomas

>40

2.47

Rofecoxib25mg(n

=1287)vs

placebo(n

=1299)

17--16

19(1.5)

6(0.5)

2(0.2)

3(0.2)

APC

[5]

Removedcolon

adenomas

>30

3.01

Celecoxib200mgbid

(n=685)

orcelecoxib400mgbid

(n=671)vs

placebo(n

=679)

31

18(1.3)

3(0.4)

11(0.8)

1(0.1)

PreSAP[60]

Removedcolon

adenomas

>30

2.5

Celecoxib400mg(n

=933)vs

placebo(n

=628)

17

9(1.0)

4(0.6)

4(0.4)

4(0.6)

ADAPT[62]

Family

history

of

Alzheim

er’sdisease

>70

1.84

Celecoxib200mgbid

(n=726)vs

placebo(n

=1083)

56

8(1.1)

13(1.2)

4(0.6)

3(0.3)

VICTOR

[63]

StageII/III

colorectalcarcinoma

--0.79

Rofecoxib25mg(i=1167)vs

placebo(n

=1160)

8.7

--6.9

3(0.3)

1(0.1)

4(0.3)

2(0.2)

ADAPT:TheAlzheim

er’sDisease

Anti-Inflammatory

PreventionTrial;APC:TheAdenomaPreventionwithCelecoxibtrial;ASA:Acetylsalicylic

acid;APPROVe:TheAdenomatousPolypPreventiononVioxx

trial;

C:Control;CI:Confidence

interval;PreSAP:ThePreventionofColorectalSporadic

AdenomatousPolypstrial;RR:Relative

risk;T:Treatm

ent;VICTOR:TheVioxx

inColorectalCancerTherapy:

DefinitionofOptimal

Regim

etrial.



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concerns related to confounding, selection bias and lack ofinformation on non-prescription drugs, smoking status andaspirin use. However, the magnitude of the populations stud-ied and the number of CV events analyzed enhance their sci-entific and clinical value. Various observational studies utilizesimilar methods but do vary greatly with regards to samplesize, number of events and duration of exposure.

4.7.1 Cohort studiesVarious cohort studies have used to assess CV toxicity ofNSAIDs and reported that most of the NSAIDs increasedCV toxicity. These studies are summarized in Table 4.NSAIDs are most commonly prescribing drugs over thecounter. A cohort analysis reported that treatment withNSAIDs increased risk of death/recurrent MI [hazard ratio,1.45; 95% confidence interval (CI), 1.29 -- 1.62] at the begin-ning of the treatment and the risk persisted throughout thetreatment course (hazard ratio, 1.55; 95% CI,1.46 -- 1.64 after 90 days). Even short-term treatment, mostof NSAIDs increased risk of death and recurrent MI inpatients with prior MI [68]. Diclofenac and rofecoxib arehighly effective drugs for treatment of pain and inflammation.Study reported that treatment with these drugs increased riskof CV death [odds ratio (OD), 1.91; 95% CI,1.62 -- 2.42 and OD, 1.66; 95% CI, 1.06 -- 2.59, respectively]in a dose-dependent manner. Treatment with ibuprofen alsoincreased risk of fatal or nonfatal stroke (OD, 1.29; 95%CI, 1.02 -- 1.63) but naproxen did not increase CV risk(OD for CV death, 0.84; 95% CI, 0.50 -- 1.42) [13,69]. Useof NSAIDs enhanced risk of death and CV morbidity inpatients who had CV disease [70]. Analysis of CV toxicity ofNSAIDs in patients who was hospitalized for serious coronaryheart disease (CHD) reported that naproxen showed betterCV safety than diclofenac, ibuprofen, rofecoxib indoses > 25 mg/day and celecoxib in doses > 200 mg/day [71].Furthermore, analysis of non-aspirin NSAIDs in patients

with or without cardiovascular disease (CVD) reported that

CV toxicity events were higher among all and new users ofrofecoxib, valdecoxib and indomethacin [72]. Another studyexamined the coxibs and tNSAIDs and incident of acute myo-cardial infarction (AMI). The result analysis reported the haz-ard ratio for AMI was elevated for both coxib (2.11, 95% CI,1.04 -- 4.26) and non-coxib (2.24, 95% CI, 1.13 -- 4.42)drugs. Thus, use of coxib and non-coxib COX-2 selectiveNSAIDs were associated with an increased risk of AMI [73].

A retrospective cohort analysis reported that use of diclofe-nac associated with higher risks of MI [relative ratio(RR) = 1.21] than ibuprofen (RR = 1.04) or naproxen(RR = 1.03) [74]. However, a prospective cohort study exam-ined the influence of NSAIDs and acetaminophen on risk ofmajor CV events (nonfatal MI, fatal CHD, nonfatal and fatalstroke). The patient who frequently used NSAIDs had aboutthe same elevated risk of CV event (RR 1.44; 95% CI,1.27 -- 1.65) as the patients who frequently consumed acet-aminophen (RR 1.35; 95% CI, 1.14 -- 1.59) compared withnonusers. Use of NSAIDs or acetaminophen at high fre-quency or dose elevated the risk of CV toxicity. This effectcould be due to increase in BP, inhibition of PG synthesisand impaired endothelial function [75]. Other cohort studyalso reported that naproxen and other NSAIDs did notshow cardioprotective effects on risk of CHD [76-78].

4.7.2 Nested/matched case--control studiesSeveral nested/matched case--control studies reported thatcoxibs and tNSAIDs increased risks of CV toxicity whichare summarized in Table 5. A case--control study analyzedthe patients who were first hospitalized for AMI and receivedcoxibs as well as tNSAIDs. AMI risk was increased amongcurrent users of coxibs combined (OR 1.73; 95% CI,1.37 -- 2.19) and tNSAIDs combined (OR 1.41; 95% CI,1.23 -- 1.61) compared to remote use. AMI risk event withcelecoxib (OR 2.53; 95% CI, 1.53 -- 4.18), rofecoxib (OR1.60; 95% CI, 1.22 -- 2.10), ibuprofen (OR 1.56; 95% CI,1.19 -- 2.05) and diclofenac (OR 1.51; 95% CI,

Table 3. Cardiotoxicity associated to nonsteroidal anti-inflammatory drugs in preclinical studies.

Study Animal Exposure Possible mechanism Findings

Singh et al. [23] Rats Diclofenac sodium (2.5 and 10 mg/kg/day), for 5 days " lipid peroxidation# antioxidant capacity" apoptosis

" cardiotoxicity

Pathan et al. [64] Rats Naproxen (50 mg/kg/day), for 5 days " lipid peroxidation# antioxidant enzymelevel

" cardiotoxiciy

Dowd et al. [65] Rats Selective COX-2 inhibitor SC236 (3 mg/kg), for 4 h " toponin T" PGI2" apoptosis

" myocardial injury

Zaitone et al. [66] Rats Celecoxib (20 mg/kg/day), for 6 weeks " blood pressure" platelet aggregation

" cardiovascular risk

Li et al. [67] Rats Rofecoxib (10 mg/kg/day), celecoxib (30 mg/kg/day),diclofenac (5 mg/kg/day), naproxen (50 mg/kg/day), for2 weeks

" ROS" NADPH oxidase!"O2˙

" cardiovascular risk

#: Decrease; ": Increase; COX-2: Cyclooxygenase-2; NADPH: Nicotinamide adenine diphonucleotide phosphate; PGI2: Prostacyclin; ROS: Reactive oxygen species.

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1.22 -- 1.87) were elevated. Cardiotoxicity risk with currentuse of individual coxibs and tNSAIDs were increased (OR1.17 -- 1.64). AMI and CV toxicity risk were similarly associ-ated with individual coxibs and tNSAIDs [79].

Furthermore, a nested case--control study analyzed thepatients with nonfatal MI and reported that the risk of MIwas increased with use of NSAIDs (RR, 1.35; 95% CI,1.23 -- 1.48) and associated with frequency, dose and durationof treatment [9]. However, other study reported that the exten-sive use of diclofenac substantially increased the risk of AMIbut not by ibuprofen or naproxen [80]. A nested case--controlstudy also reported that exposure of indomethacin and rofe-coxib were associated with greater risk of recurrent CHF com-pared with celecoxib [81]. Another study reported that currentuse of etoricoxib (RR, 2.09; 95% CI, 1.10 -- 3.97), rofecoxib(RR, 1.29; 95% CI, 1.02 -- 1.63), celecoxib (RR, 1.56; 95%CI, 1.22 -- 2.00), valdecoxib (RR, 4.60; 95% CI,0.61 -- 34.51) and diclofenac (RR, 1.37; 95% CI,1.17 -- 1.59) elevated the risk of AMI. The elevated risk ofAMI is a class effect of coxibs and increased in dose-dependent manner [82].

A population-based matched case--control study analyzedpatients who had taken tNSAIDs 1 -- 180 days or coxibs31 -- 90 days and reported that use of NSAIDs were associ-ated with increased risk of MI [83]. Analysis of another case---control study reported that some NSAIDs increased theCV toxicity events (particularly MI/unstable angina),whereas other did not compared to nonusers of NSAIDs [84].The CV toxicity rate was most notably seen with use ofrofecoxib and diclofenac but not with use of celecoxib andnaproxen [84,85].

Furthermore, the relative risk of a cardiac event wasincreased by most of the nonselective NSAIDs comparedwith the nonusers of NSAIDs. The increased risk of MI andsudden cardiac death were associated with the use of higherdose (> 25 mg daily) of rofecoxib but not with celecoxib [86].Various other nested case--control studies also reported that allthe nonaspirin NSAIDs were associated with increased risk ofCV toxicity which depends on dose and frequency of drugadministration [87-89].

4.8 CV toxicity associated to acetaminophen

(or paracetamol)Very little study reported the influences of acetaminophen (orparacetamol) on CV toxicity. This drug is one of the mostwidely prescribed pain analgesics in the world. Current guide-lines recommend acetaminophen as the first-line analgesic ofchoice on the assumption of its greater CV safety. But, arecent study reported that acetaminophen induces a signifi-cant increase in ambulatory BP (mean systolic pressuresfrom 122.4 ± 11.9 to 125.3 ± 12.0 mmHg and diastolic pres-sures from 73 ± 6.9 to 75.4 ± 7.9 mmHg) versus placebo inpatients with coronary artery disease [29]. The study was dou-ble-blind, placebo-controlled, crossover study evaluating theeffects of acetaminophen (1 g three times daily) on ambula-tory BP. It was administered for 2 weeks in 33 patients withknown coronary artery disease. A variety of serum biomarkersas well as platelet and vascular function were assessed. Resultanalysis was inconclusive [29,90]. The study was limited toonly 2 weeks and subjects had no pain indication. Hence,the trial results may not necessarily reflect the effects of the

Table 4. Cohort observation studies associated with nonsteroidal anti-inflammatory drugs-induced cardiotoxicity.

Study Source Age

(years)

Study period Exposure Findings

SchjerningOlsen et al. [68]

DNPR ‡ 30 1997 -- 2006 NSAIDs ‡ 90 days " risk of death and recurrent MI in patientswith prior MI

Fosbol et al. [13] DNPR ‡ 10 1997 -- 2005 NSAIDs ‡ 30 days Most of the NSAIDs " CV toxicity, naproxenis safer

Gislason et al. [70] DNPR 71 -- 76 1995 -- 2004 NSAIDs 40 -- 97 days " risk of death and CV morbidity in patientswith HF

Ray et al. [71] MedicaidSaskatchewanGPRD

40 -- 89 1999 -- 2004 NSAIDs 0 days Naproxen shows better CV safety than otherNSAIDs

Roumie et al. [72] Medicaid 35 -- 94 1999 -- 2005 NSAIDs ‡ 0 days " risk of CV toxicity among all and newcurrent users

Hammad et al. [73] GPRD 40 -- 84 1997 -- 2004 NSAIDs 30 days Coxib and non-coxib NSAIDs " risk of AMIvan Staa et al. [74] GPRD ‡ 40 1987 -- 2006 tNSAIDs ‡ 30 days Long term use of tNSAIDs " risk of MIChan et al. [75] Nurses Health 44 -- 69 1990 -- 2002 NSAIDs ‡ 22 days/month acetaminophen or NSAIDs at high frequency

or dose " risk of major CV eventsGislason et al. [76] DNPR ‡ 30 1995 -- 2002 NSAIDs ‡ 10 days Selective and nonselective NSAIDs " risk of

death in patients with prior MISolomon et al. [77] Medicare 65 -- 74 1999 -- 2003 NSAIDs ‡ 60 days " CV toxicity events rate among NSAIDs usersRay et al. [78] Medicaid 50 -- 84 1987 -- 1998 tNSAIDs 0 days Absence of protective effect on risk of CHD

": Increase; AMI: Acute myocardial infarction; CV: Cardiovascular; CHD: Coronary heart disease; DNPR: Danish National Patient Registry; GPRD: General Practice

Research Database; HR: Heart failure; MI: Myocardial infarction; tNSAIDs: Traditional nonsteroidal anti-inflammatory drugs.



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agent in a more typical clinical situation [29]. In fact, thechronic use of acetaminophen might induce more substantialincreases in BP than was observed in the study [90].Furthermore, a double-blind, crossover study analyzed the

effect of acetaminophen on BP and heart rate in hypertensivepatients with osteoarthritis who had under antihypertensivetherapy. This study reported that acetaminophen slightlybut significantly increased clinic and ambulatory systolic/diastolic BP as well as heart rate (+3.1, +3.3 and +3.4 b/minday-time heart rate values, for ramipril, valsartan and aliski-ren, respectively; p < 0.05) [31]. Cohort studies also reportedthat acetaminophen increased the risk of hypertension [91-94].

5. Conclusions

Reports from various clinical, preclinical, meta-analysis andobservational studies showed that coxibs and tNSAIDsincrease risk of cardiotoxicity. Risk events of CV toxicitydepend on dose, duration and frequency of NSAIDs adminis-tration. Analysis of various clinical trials studies showed thatcoxibs increase the risk of CV toxicity in the patients whohad taken for the treatment of inflammation/pain duringarthritis or adenomas. Studies of various NSAIDs on animalsshowed that coxibs and tNSAIDs augment doxorubicin-induced cardiotoxicity. A large number of observational stud-ies showed that use of nonaspirin NSAIDs or acetaminophenenhances risk of MI and CV toxicity. Most of these studies arebased on large medical databases with miscellaneous popula-tions. Very little prospective study also investigated the CVtoxicity profile of NSAIDs. However, most of these studies

pointed that coxibs as a class and most of the tNSAIDs areassociated to increase risk of thrombotic events. CV toxicityassociated with use of NSAIDs might be due to inhibitionof PGI2 synthesis, generation of free radicals, increase in BPand impaired endothelial dysfunction. Further study isneeded to unravel the mechanism by which these drugsenhanced risk of cardiotoxicity.

6. Expert opinion

Analysis of numerous clinical, preclinical, meta-analysis andobservational studies showed that coxibs and tNSAIDsincrease the risk of cardiotoxicity. CV toxicity risks ofNSAIDs depend on dose, duration and frequency of adminis-tration. Most of the studies reported to increase risk of CVtoxicity are nested/matched case--control or cohort studybased on large medical databases of drugs with miscellaneouspopulation. Therefore, these observation studies will posesome methodological concerns related to confounding, selec-tion bias and lack of information on non-prescription drugsand aspirin use. However, the magnitude of the populationsstudied and the number of CV events analyzed enhance theirscientific and clinical value.

Experimental studies are very important for pharmacologi-cal evaluation of any drugs. Analysis of preclinical studiesreported that coxibs and tNSAIDs enhance risk of CV toxic-ity. However, these studies are conducted in the limitedexperimental models. Hence, more preclinical studies areneeded to conduct in different experimental models of CVdiseases. Results of preclinical studies will be useful for

Table 5. Nested/matched case-control studies associated with nonsteroidal anti-inflammatory drugs-induced

cardiotoxicity.

Study Source Age (years) Study period Exposure Findings

Van derLinden et al. [79]

NRD ‡ 30 2001 -- 2004 NSAIDs, 0 days AMI and CV toxicity " similarly with individualCOX-2 inhibitors and tNSAIDs

GarcıaRodrıguez et al. [9]

THIN 50 -- 84 2000 -- 2005 NSAIDs 0 -- 6 days " risk of MI

Jick et al. [80] GPRD 30 -- 79 1993 -- 2000 NSAIDs ‡ 1 days Diclofenac " risk of AMI, not by ibuprofen ornaproxen

Hudson et al. [81] QPD ‡ 66 1998 -- 2003 NSAIDs 7 days Indomethacin and rofecoxib " risk of recurrentCHF compared to celecoxib

Andersohn et al. [82] GPRD ‡ 40 2000 -- 2004 NSAIDs ‡ 14 days " risk of AMI, a class effects of COX-2 inhibitorsHelin-Salmivaara et al. [83]

FNR 35 -- 86 2000 -- 2003 NSAIDs ‡ 1 days Modest " risk of MI by all NSAIDs

McGettigan et al. [84] ADRA ‡ 50 2003 -- 2004 NSAIDs 7 days " risk of CV toxicityGraham et al. [86] Kaiser 18 -- 84 1999 -- 2001 NSAIDs ‡ 1 days Rofecoxib " risk of CHD, naproxen does notHippisley-Cox et al. [87]

QRESEARCH 25 -- 100 2000 -- 2004 NSAIDs 0 -- 90 days " risk of MI

Johnsen et al. [88] HDR 19 -- 101 2000 -- 2003 NSAIDs 0 -- 30 days All classes of non aspirin NSAIDs " risk of MIGarcıaRodrıguez et al. [89]

GPRD 50 -- 84 1997 -- 2000 tNSAIDs 0 -- 30 days Lack of protective effect against MI

ADRA: The Australian drug regulatory authority; AMI: Acute myocardial infarction; COX-2: Cyclooxygenase-2; CV: Cardiovascular; CHD: Coronary heart disease;

CHF: Congestive heart failure; FNR: The Finland national Registry; GPRD: General Practice Research Database; HDR: Hospital Discharge Registry; MI: Myocardial

infarction; NRD: The Netherland residents database; QPD: Que´bec Province Database; THIN: The Health Improvement Network; tNSAIDs: Traditional nonsteroidal

anti-inflammatory drugs.

B. K. Singh et al.


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analysis of CV risk profile of both coxibs and tNSAIDs. Thus,preclinical studies are more fruitful for evaluation of CVsafety/toxicity profile of NSAIDs.

Various clinical studies conducted in either adenomas orarthritis patients, not in patient with MI and/or other CV dis-orders. These trials were lack of power required for evaluatingCV toxicity in a definitive fashion. More clinical data’s areneeded to analyze CV safety of NSAIDs. Therefore, trialsshould be conducted in different populations to evaluate risksand benefits of NSAIDs. As we know that arthritis and hyper-tension often co-exist in middle and older age. Studiesreported that administration of selective and conventionalNSAIDs inhibit the synthesis of PGI2 that lead to decreaseexcretion of sodium salt and water. This effect may lead tooedema and hypertension as well as in more severe cases,CHF. Moreover, other studies reported that coxibs andtNSAIDs elevated BP in hypertensive patients and antago-nized the BP lowering effects of antihypertensive medication.Thus, these drugs elevated CV risk event. However, limitedstudies have been done in these areas. Therefore, more studiesare needed in these fields for analysis of CV safety of coxibsand convention NSAIDs.

Furthermore, a large number of studies reported that CVtoxicity associated with the use of coxibs and tNSAIDs mightbe due to inhibition of PGI2 and PGE2 synthesis, and gener-ation of free radicals as well as increase in BP and impairmentof endothelial function. However, the actual possible regionsthrough which non-aspirin NSAIDs increase the risk of CVtoxicity events are not known. Therefore, more molecularaspect-based studies are needed to find out the possible cellu-lar pathway through which selective COX-2 inhibitors andnonselective NSAIDs increase risk of CV toxicity events.

Acknowledgments

We are thankful to U Bajaj, Principal and V Kumar, AssistantProfessor, KIET School of Pharmacy, Ghaziabad for theirhelp during preparation of the manuscript.

Declaration of interest

The authors state no conflict of interest and have received nopayment in preparation of this manuscript.

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AffiliationBhulan Kumar Singh†1 MPharm,

Syed Ehtaishamul Haque2 MSc PhD &

Krishna Kolappa Pillai3 MPharm PhD†Author for correspondence1Assistant Professor,

Department of Pharmacology,

KIET School of Pharmacy,

Ghaziabad-Meerut Road,

Ghaziabad-201206, Uttar Pradesh, India

Tel: +01232 262057;

Fax: +0120 2675091;

E-mail: [email protected] Professor,


Faculty of Pharmacy, Hamdard University,

Hamdard Nagar, New Delhi-110062, India3Professor and Head,


Faculty of Pharmacy, Hamdard University,

Hamdard Nagar, New Delhi-110062, India

B. K. Singh et al.


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Assessment of nonsteroidal anti-inflammatory drug-induced cardiotoxicity