minerva medica copyright

MINERVA CARDIOANGIOL 2014;62:437-48

Cardiovascular risk associated with celecoxib or etoricoxib: a meta-analysis of randomized controlled trials which adopted comparison with placebo or naproxen

IN C ER O V P A Y R M IG E H DI T C ® A

R. DE VECCHIS 1, C. BALDI 2, G. DI BIASE 3, C. ARIANO 1 C. CIOPPA 1, A. GIASI 1, L. VALENTE 4, S. CANTATRIONE 1

Aim. The present meta-analysis attempted to assess whether an unfavourable cardiovascular risk profile could be identified in the case of two COX2 selective inhibitors (COXIBs), namely celecoxib and etoricoxib. Based on the data from the literature, our meta-analysis aimed to assess the probability of major cardiovascular events reported with the use of celecoxib or etoricoxib and compare this with the results seen in patients assigned to the placebo group. Furthermore, the risk of cardiovascular events found by using celecoxib or etoricoxib was also compared with that associated with the use of naproxen, a nonselective non-steroidal anti-inflammatory drug (NSAID) chosen as our reference drug. Methods. The studies had to be randomized controlled trials with at least 4-week duration. Studies were included if they compared celecoxib or etoricoxib against placebo or naproxen. Moreover, the selected studies had to have determined the risk, odds or incidence of myocardial infarction, stroke or cardiovascular death. For the comparisons versus placebo, the endpoints of interest were “serious vascular events”, “non-fatal myocardial infarction”, “non-fatal stroke” and “death from cardiovascular causes”, whereas “myocardial infarction” and “stroke” were the endpoints of interest concerning the comparison versus naproxen. Results. From the evaluation of 41 studies comparing celecoxib with placebo, we found a significantly higher incidence of serious vascular events in the celecoxib group compared to controls treated with placebo (rate

M

This document is protected by international copyright laws. No additional reproduction is authorized. It is permitted for personal use to download and save only one file and print only one copy of this Article. It is not permitted to make additional copies (either sporadically or systematically, either printed or electronic) of the Article for any purpose. It is not permitted to distribute the electronic copy of the article through online internet and/or intranet file sharing systems, electronic mailing or any other means which may allow access to the Article. The use of all or any part of the Article for any Commercial Use is not permitted. The creation of derivative works from the Article is not permitted. The production of reprints for personal or commercial use is not permitted. It is not permitted to remove, cover, overlay, obscure, block, or change any copyright notices or terms of use which the Publisher may post on the Article. It is not permitted to frame or use framing techniques to enclose any trademark, logo, or other proprietary information of the Publisher.

ORIGINAL ARTICLES

Corresponding author: R. De Vecchis, MD, via P. Gaurico 21, 80125 Naples, Italy. E-mail address: [email protected]

Vol. 62 - No. 6

1Cardiology Unit Presidio Sanitario Intermedio “Elena d’Aosta” Naples, Italy 2Heart Department, Interventional Cardiology “San Giovanni di Dio e Ruggi D’Aragona” Hospital, Salerno, Italy 3Neurorehabilitation Unit Clinica “S. Maria del Pozzo” Somma Vesuviana, Naples, Italy 4Orthopedic Outpatient Unit Presidio Sanitario Intermedio “Elena d’Aosta” Naples, Italy

ratio 1.598, 95% CI: 1.048 to 2.438; P=0.029). Furthermore, in patients allocated to treatment with celecoxib, we found an incidence rate of non-fatal acute myocardial infarction that was three times higher compared with the placebo group (rate ratio 3.074, 95% CI: 1.375-6.873, P=0.006). In contrast, we did not find any significant difference with regard to the incidence of nonfatal stroke and that of death from cardiovascular causes by comparing celecoxib and placebo. In addition, by examining cardiovascular outcomes that emerged from the 17 trials which compared etoricoxib with placebo, it was not possible to demonstrate statistically significant differences in incidence for each of the explored endpoints. With regard to the comparison of each coxib with the non-selective COX2 inhibitor naproxen, we did not find any significant difference for either the odds of myocardial infarction or that of stroke. Conclusion. On the basis of our meta-analysis, we can state that symptomatic benefits induced by the prolonged administration of celecoxib may be partially invalidated by a

MINERVA CARDIOANGIOLOGICA

437

Cardiovascular risk associated with celecoxib or etoricoxib

I

n the past years, various in-depth studies have been carried out regarding the alleged effect of triggering thrombogenesis and vasoconstriction exerted by some nonsteroidal anti-inflammatory drugs (NSAIDs), characterized by their selective inhibition of the enzyme cyclooxygenase-2.1-3 These drugs, which have the property of selectively interacting with cyclooxygenase 2, i.e., without impacting on cyclooxygenase 1, are commonly referred to as COXIBs (cyclo-oxygenase-2 inhibitors). The COXIBs were originally introduced on the market with the label of anti-inflammatory drugs free from significant acute gastrolesivity.4 However, a thrombogenic effect was subsequently shown for two of these drugs, namely rofecoxib and valdecoxib,5, 6 whose use was associated with an excess of myocardial infarctions and cardiovascular deaths. Therefore, rofecoxib and valdecoxib were withdrawn from the market in 2004 and 2005, respectively.2 Moreover, for non-selective NSAIDs, the well-known toxic effect on the gastric mucosa could effectively be antagonized by the concomitant administration of drugs that inhibit gastric acid secretion.7 Since myocardial infarction is a more serious side effect than gastritis or a gastroduodenal ulcer, and considering that the non-selective NSAIDs exert an anti-inflammatory effect as powerful as

438

that exhibited by COXIBs while showing a lower risk of cardiovascular disease (CVD), the grounds for using the latter would be relatively restricted, especially in the case of patients with chronic inflammatory disease with multiple concomitant CVD risk factors or overt ischemic heart disease.1, 3, 8 Due to these concerns surrounding cardiovascular safety, it is important to exercise adequate vigilance regarding the appropriate use of COXIBs, through the reporting of adverse events occurring during treatment. In order to acquire information about safety, retrospective case-control studies and metaanalyses concerning the cardiovascular outcomes related to these drugs are also useful. Using data from trials in the literature, the present meta-analysis aimed to assess the incidence of major cardiovascular events reported with the use of two COXIBs, namely celecoxib and etoricoxib, and to compare this with the results in patients assigned to the placebo group. Furthermore, the risk of cardiovascular events found by using each of these two molecules was also compared with that associated with the use of naproxen, a non-selective NSAID that was arbitrarily chosen as our reference drug.


concomitant increase in vascular risk, particularly the increased risk of myocardial infarction found in celecoxib-treated patients, compared to controls taking placebo. In contrast, treatment with etoricoxib proved not to result in an increased risk of serious vascular events when compared with both the placebo and naproxen. Our meta-analysis also denotes that the alternative to COXIBs, represented by naproxen, does not show significant benefit in terms of reduced cardiovascular risk. Therefore, considering that the increase in incidence rate of cardiovascular events associated with treatment with celecoxib is small in absolute terms, it is reasonable to state that celecoxib is still a drug whose benefits outweigh the potential adverse effects on the cardiovascular system. Key words: Cardiovascular diseases - Celecoxib Etoricoxib - Drug safety - Meta analysis.

M


DE VECCHIS

Materials and methods

Study selection

The studies assessed had to be randomized controlled trials of at least 4-weeks duration. Studies were included if they compared celecoxib or etoricoxib against placebo or the nonselective NSAID naproxen administered at equivalent analgesic doses. Moreover, the selected studies were required to have reported on the probability of experiencing serious vascular events, i.e. they should have determined the risk, odds or incidence of myocardial infarction, stroke or death from cardiovascular causes. In addition, the methodological quality of included trials had to score a minimum of two points using the Jadad scale.9 The endpoints that were specifically adopted in our meta-analysis were the following: for comparisons


December 2014

DE VECCHIS

etoricoxib versus naproxen. For these outcomes, the effect size was expressed by calculating the odds ratio (OR). Statistical analysis Statistical analyses were performed using Review Manager 5.0.4 software (available from the Cochrane Collaboration at: http// www.cochrane.org) and Stata version 10 (Stata Corp LP, College Station, Texas, USA). For comparing the effects of celecoxib or etoricoxib versus placebo on each of the four cardiovascular outcomes of interest, the pooled rate ratio was computed with a 95% confidence interval (CI), using a fixed effects model. Event numbers and person years of exposure were presented in the related forest plots for patients allocated to each COXIB and placebo group. For comparing the effects of celecoxib or etoricoxib versus naproxen on each of the two cardiovascular outcomes of interest, the pooled odds ratio was determined with a 95% confidence interval (CI), within a fixed-effect meta-analysis.


between COXIBs and placebo, the rate ratios, i.e. the ratios of the respective incidence rates, should have been calculated for the endpoints “non-fatal myocardial infarction”, “non-fatal stroke”, “cardiovascular death” and the composite endpoint “vascular events”, consisting of non-fatal myocardial infarction, non-fatal stroke and cardiovascular death; instead, for the comparison between COXIBs and naproxen, the odds ratio concerning each of the endpoints “myocardial infarction” and “stroke” should have been computed. We used 95% confidence intervals for all measures of dimension size. Search strategy

A systematic search was conducted by adopting the keywords “celecoxib” and “etoricoxib” as search terms in order to retrieve all of the relevant data from the PubMed and Embase electronic archives and the online Clinical Study Results Database (http://www. clinicalstudyresults.org). The search included publications up to March 2014 and no lower date limit was applied. All studies not written in English, duplicated studies, review articles, editorials, and expert opinions were excluded. Eligibility assessment and data extraction were carried out independently by two investigators (RDV and GDB) with any discrepancies resolved by consensus in consultation with a third author (CA). Titles and abstracts served to identify those studies that were suitable for further assessment of the full text.

M



Outcomes of interest

“Serious vascular events”, “non-fatal myocardial infarction”, “non-fatal stroke” and “cardiovascular death” were the outcomes of interest for the comparison of celecoxib and etoricoxib versus placebo. For all of these outcomes, the effect size was expressed using the rate ratio, i.e., the ratio of incidence rates calculated for each outcome of interest in COXIB-treated and placebo groups, respectively. Instead, “myocardial infarction” and “stroke” were the outcomes of interest for comparison of celecoxib and

Vol. 62 - No. 6

Results

Figure 1 outlines the results of the trial selection process. We identified 116 studies, of which 92 RCTs met the inclusion criteria. Of these, 34 RCTs did not report any information about serious vascular events and the remaining 58 were included in our meta-analyses. Overall, the 58 RCTs included 62,634 patients with rheumatoid arthritis (8 trials), osteoarthritis (29 trials), osteoarthritis or rheumatoid arthritis (8 trials), Alzheimer’s disease (2 trials), colorectal adenomas (3 trials), low back pain (5 trials), and ankylosing spondylitis (3 trials). Some details of recruited studies are reported in Table I.13-51

Comparison of celecoxib or etoricoxib versus placebo Figures 2-5 show meta-analyses of each of the two considered selective COX2 inhibitors (celecoxib and etoricoxib) versus


439



Figure 1.—Flow diagram of study selection for meta-analysis. RCTs: double-blind randomized controlled clinical trials.

M


DE VECCHIS

placebo for each of the four analyzed outcomes (“serious vascular events”, “non-fatal myocardial infarction”, “non-fatal stroke” and “death from cardiovascular causes”). Indeed, in the setting of various inflammatory or degenerative disorders, we collated a total of 41 trials to compute respective incidences of serious vascular events in the group of patients treated with celecoxib and in that of controls taking placebo. Thus, 84 events were found during 8976 person

440

years of exposure to celecoxib (0.9%/year) compared to 29 events during 4953 person years of exposure to placebo (0.6%/year). Therefore, a significantly higher incidence of serious vascular events was evident in the celecoxib group compared to controls treated with placebo (rate ratio 1.598, 95% CI: 1.048 to 2.438; P=0.029). In patients allocated to treatment with celecoxib, we found an incidence rate of non-fatal acute myocardial infarction that was three times


December 2014

DE VECCHIS

Table I.—Summary characteristic of included trials. Author (Year) Celecoxib Simon (1998) 13

Disease Rheumatoid arthritis

Simon (1999) 15 Bensen (1999) 14

Osteoarthritis

Kivitz (2001) 20

Sample size

Scheduled duration, weeks

327

4

80/400/800

Yes

No

1148 1102 1092 1214 401 1059 684 715 13194

12 12 12 12 4 12 6 6 12

200/400/800 100/200/400 50/100/200 50/100/200 25/100/400 100/200/400 100/200 100/200 100/200

Yes Yes Yes Yes Yes Yes Yes Yes No

598 404 475 353 371 317 362 316 386 385

6 12 6 6 6 6 6 6 6 4

100 200 200 200 200 200 200 200 200 400

Yes No Yes Yes Yes Yes Yes Yes Yes Yes

83 2035 1561 68 245

24 156 156 6 6

200/800 400/800 400 200 100

Yes Yes Yes Yes Yes

Yes 500 mg bid Yes 500 mg bid Yes500 mg bid Yes 500 mg bid No Yes 500 mg bid No No Diclofenac 50 mg bid Yes 500 mg bid Diclofenac 50 mg bid Yes 500 mg bid No No No Yes 500 mg bid Yes 500 mg bid Yes 500 mg bid Ibuprofen 800 mg tid Nabumetone 1000 mg bid Ibuprofen 800 mg tid No No No Yes 500 mg bid Ketoprofen 100 mg bid

Celecoxib Placebo* dose, mg/day (Yes/No)

Naproxen comparator** (Yes/No)


Williams (2001) 21

McKenna (2001) 22 Sowers (2005) 43 Gibofsky (2003) 45 Pincus (2004) 23

Palmer (2003) 25

Phillips (2002) 26 Solomon (2005) 27 Levin (2005) 51 Ta (2004) 28 Dougados (2001) 29

Author (Year)

Etoricoxib Curtis (2003) 31

Osteoarthritis/ Rheumatoid arthritis FAP Polyps Polyps TMJ pain Ankylosing spondylitis Disease

Rheumatoid arthritis

Sample size 581

Matsuomoto (2002) 32

816

Collantes (2002) 33

891

Hunt (2003) 34 Tsoukas (2001) 35 Gottesdiener (2002) 36

560 102 617

Osteoarthritis

M



Reginster (2004) 37

496

Leung (2002) 38

501

Hunt (2003) 39

182 680 528 387

Wiessenhutter (2005) 40 Van der Heijde (2005) 41 Ankylosing spondylitis Back pain Pallay (2004) 42 Birbara (2003) 24 Hunt (2003) 39 Other DiBattiste (2004)30

325 319 62 433

Scheduled duration, weeks

Etoricoxib dose, mg/day Placebo*

174 (8 placebo) 121 (12 placebo) 121 (12 placebo) 12 6 190 (6 placebo) 138 (12 placebo) 138 (12 placebo) 12 12 12 52 (6 placebo) 12 12 4 12

Naproxen comparator** (Yes/No)

60/90/120

Yes

Diclofenac 50 mg tid

90/120

Yes

Yes 500 mg bid

90/120

Yes

Yes 500 mg bid

120 90 30/60/90

Yes Yes Yes

Yes 500 mg bid No Diclofenac 50 mg tid

60

Yes

Yes 500 mg bid

60

Yes

Yes 500 mg bid

120 120 30 90/120

Yes Yes Yes Yes

Yes 500 mg bid Ibuprofen 800 mg tid Ibuprofen 800 mg tid Yes 500 mg bid

60/90 60/90 120 90

Yes Yes Yes Yes

No No Ibuprofen 800 mg tid Ibuprofen 800 mg tid Celecoxib 200 mg bid

*Trials with a placebo arm are indicated by a yes; ** Trials with a naproxen arm are indicated by a yes followed by the naproxen dose.

Vol. 62 - No. 6


441


Discussion Some issues should be underscored. Firstly, our research only focused on two molecules, celecoxib and etoricoxib, as they are the only COXIBs currently approved for marketing in Europe (following the withdrawal of rofecoxib from the market in 2004 and valdecoxib in 2005). Therefore, the choice of limiting the metaanalysis by considering only those COXIBs that are used in current medical practice for calculations seemed appropriate in order to adhere to the “real world” of drug prescriptions. In addition, our research not only included studies comparing the two COXIBs and the placebo, but also those in which a COXIB (celecoxib or etoricoxib) was compared with the non-selective COX2 inhibitor naproxen. In fact, naproxen was chosen because it was frequently assumed as a representative molecule of the class of NSAIDs in several controlled clinical trials;10, 11 notably, it is the most widely used NSAID within trials that evaluate the COXIBs. Furthermore, unlike other NSAIDs, naproxen holds the well-recognized property of exerting nonselective action on the cyclo-oxygenase system which results in a well-balanced enzyme inhibition against both COX1 and COX2.12 Therefore, in our meta-analysis, naproxen was adopted as a reference drug of the NSAIDs class, as opposed to COXIBs, which, by definition, exert weak or no inhibitory action against COX1, due to their sole elective affinity for COX2. From our meta-analysis, it is plausible to infer that celecoxib but not etoricoxib is associated with an excess of cases of nonfatal myocardial infarction (Figures 2, 4) compared to placebo. In particular, the increased incidence rate of myocardial infarction in patients treated with celecoxib compared to those on placebo has been shown to decisively contribute to generating a pooled rate ratio indicating a significantly increased risk of serious vascular events (Figure 3) in the celecoxib group compared to placebo. We did not find any significant difference when comparing celecoxib to placebo with regard to the endpoints of nonfatal stroke


higher than that reported for the placebo group (rate ratio 3.074, 95% CI: 1.375-6.873, P=0.006). In contrast, we did not find any significant difference with regard to the incidence of nonfatal stroke and that of death from cardiovascular causes by comparing celecoxib and placebo. Therefore, we can say that the higher overall incidence of serious vascular events in the celecoxib group is largely due to the significantly increased incidence of nonfatal myocardial infarction in this group compared to placebo. In addition, by examining cardiovascular outcomes that emerged from the 17 trials which compared etoricoxib with placebo, it was not possible to demonstrate statistically significant incidence differences for each of the four explored endpoints (“serious vascular events”, “non-fatal myocardial infarction, “non-fatal stroke” and “death from cardiovascular causes”). By pooling the results of the 41 RCTs that compared celecoxib with placebo and 17 RCTs concerning comparison between etoricoxib and placebo, the pooled rate ratios appear to indicate an adverse effect of the two COXIBs with regard to serious vascular events and non-fatal myocardial infarction (Figures 2-4); in contrast, the rate ratios for nonfatal stroke and death from cardiovascular causes do not indicate any statistically significant difference with respect to placebo (Figures 2, 5, 6). Comparison of celecoxib or etoricoxib versus naproxen

Furthermore, a comparison was made between each of the two COXIBs and the non-selective NSAID naproxen. The cardiovascular outcomes that were chosen (myocardial infarction and stroke) were evaluated separately for celecoxib (6 RCTs for myocardial infarction and 4 for stroke) and for etoricoxib (2 RCTs for myocardial infarction and one for stroke). The relevant pooled odds ratios are reported in Figures 7 and 8. Overall, by comparing celecoxib with naproxen, as well as etoricoxib with naproxen, we did not find any significant difference regarding both the odds of myocardial infarction and that of stroke.

M


DE VECCHIS

442


December 2014


DE VECCHIS

M



Figure 2.—The figure shows the incidence of total vascular events, non-fatal myocardial infarction, non-fatal stroke and death from cardiovascular causes in patients treated with COX-2 selective inhibitors (Coxibs) compared with those receiving placebo. More precisely, for each of the 4 above mentioned endpoints, the corresponding ratio of incidence rates (rate ratio), derived by comparing Coxib and placebo groups, was calculated and reported in the provided column. Among the Coxibs, only celecoxib and etoricoxib were considered for the present meta-analysis. The incidence rates are reported as the “events/person-years” ratio in the relevant column. The overall rate ratio for each of the 4 endpoints is indicated by a diamond. Moreover, the rate ratio for the comparison between each Coxib and the placebo is indicated by a dark square. The horizontal lines represent the 95% confidence intervals for each value of the rate ratio. The data are derived from the pooling of 41 randomized trials for celecoxib and 17 randomized trials for etoricoxib. The incidence of vascular events on the whole, and especially that of non-fatal myocardial infarction is significantly higher in the Coxib group as a result of an increase in vascular events reported in the subset of patients treated with celecoxib.

Vol. 62 - No. 6


443


M


DE VECCHIS

444


Figure 3.—Rate ratios concerning the endpoint”serious vascular events” (that is, non-fatal myocardial infarction, nonfatal stroke, or vascular death) in patients treated with a coxib (celecoxib or etoricoxib) compared to patients taking placebo.

Figure 4.—Rate ratios concerning non-fatal myocardial infarction in patients treated with a coxib (celecoxib or etoricoxib) compared to patients taking placebo. A significantly higher incidence rate of non-fatal myocardial infarction in the celecoxib group compared to placebo group is noticeable (rate ratio=3.074, 95% CI: 1.375 to 6.873; P=0.006).

Figure 5.—Rate ratios concerning non-fatal stroke in patients treated with a coxib (celecoxib or etoricoxib) compared to patients taking placebo. There is no difference in the incidence of non-fatal stroke in the comparison between patients taking a Coxib (celecoxib or etoricoxib) and those receiving the placebo.


December 2014


M



Vol. 62 - No. 6


DE VECCHIS

Figure 6.—Rate ratios concerning death from cardiovascular causes in patients treated with a coxib (celecoxib or etoricoxib) compared to patients taking placebo. There is no difference in the incidence of cardiovascular death in the comparison between patients taking a Coxib (celecoxib or etoricoxib) and those receiving the placebo.

Figure 7.—Odds ratios concerning myocardial infarction in patients treated with a Coxib (celecoxib or etoricoxib) compared to those taking naproxen. The probability of myocardial infarction in patients treated with a Coxib is not significantly different from that found in patients taking naproxen.

Figure 8.—Odds ratios concerning stroke in patients treated with a Coxib (celecoxib or etoricoxib) compared to those taking naproxen. The probability of stroke in patients treated with a Coxib is not significantly different from that found in patients taking naproxen.

445


In fact, the current guidelines state that COXIBs are not safe for use in patients with known ischemic heart disease, but they accept their use in patients without any history of overt ischemic heart disease for the symptomatic treatment of painful inflammatory conditions, provided that clinicians have considered and carefully weighted the risk of coronary ischemic events that may result from prolonged COXIB administration (i.e., maintained for periods longer than 4 weeks), particularly in patients with one or more risk factors for ischemic heart disease.


and death from vascular causes (Figures 5, 6). In addition, celecoxib compared with naproxen showed a similar risk for the endpoints myocardial infarction and stroke (Figures 7, 8). With regard to etoricoxib, no significant differences versus both placebo and naproxen were detected for each of the endpoints of interest considered. The risk of nonfatal myocardial infarction appears to be the parameter that is most unfavourably influenced by celecoxib. In fact, our meta-analysis reported a rate ratio of 3, i.e. a triple incidence rate of non-fatal myocardial infarction in patients treated with celecoxib compared to controls randomized to placebo. This equates to an incidence of myocardial infarction of 0.43%/year in the celecoxib group compared with an incidence of 0.14%/year in the placebo group. In other words, the prolonged administration of celecoxib carried out to counteract the inflammation and pain of various osteoarticular diseases produces symptomatic benefits that could be outweighed or cancelled out by a concomitant increase in vascular risk, particularly the increased risk of myocardial infarction, compared to patients with the same diseases that are excluded from the analgesic-anti-inflammatory therapy with celecoxib. Nevertheless, our analysis also denotes that the alternative to COXIBs represented by naproxen does not show any significant benefit in terms of reduced vascular risk. Therefore, considering that the increase in the incidence rate of cardiovascular events with celecoxib is small in absolute terms, it is reasonable to state that celecoxib is still a drug whose benefits outweigh the adverse effects on the cardiovascular system. We did not identify any lower proportion of adverse vascular events (myocardial infarction and stroke) with the use of naproxen compared with celecoxib. Moreover, etoricoxib proved not to be burdened with an increased risk of serious vascular events versus both the placebo and naproxen. Therefore, on the basis of this meta-analysis, there is no reason to change the current guidelines for these two drugs.

M


DE VECCHIS

446

Conclusions

In patients with osteoarticular pain and inflammation (rheumatoid arthritis, osteoarthritis), symptomatic benefits obtained using celecoxib have been shown to be accompanied by a concomitant increase in vascular risk, particularly the increased risk of myocardial infarction found in celecoxib-treated patients, compared to controls treated with placebo. In contrast, etoricoxib did not entail an increased risk of serious vascular events versus both the placebo and naproxen. Moreover, naproxen, when given as an alternative to celecoxib, did not show any significant benefits in terms of reduced vascular risk. Therefore, considering that the increased incidence of cardiovascular events with celecoxib compared to placebo is small in absolute terms, it is reasonable to state that celecoxib is still a drug whose benefits outweigh the potential adverse effects on the cardiovascular system. References

1. Antman EM, Bennett JS, Daugherty A, Furberg C, Roberts H, Taubert KA; American Heart Association. Use of nonsteroidal antiinflammatory drugs: an update for clinicians: a scientific statement from the American Heart Association. Circulation 2007;115:1634-42. 2. Vardeny O, Solomon SD. Cyclooxygenase-2 inhibitors, nonsteroidal anti-inflammatory drugs, and cardiovascular risk. Cardiol Clin 2008;26:589-601. 3. Patrono C, Baigent C Nonsteroidal anti-inflammatory drugs and the heart. Circulation 2014;129:907-16. 4. Bombardier C. An evidence-based evaluation of


December 2014

DE VECCHIS

19. Solomon SD, McMurray JJ, Pfeffer MA, Wittes J, Fowler R, Finn P et al. Cardiovascular risk associated with celecoxib in a clinical trial for colorectal adenoma prevention. N Engl J Med 2005;352:1071-80. 20. Kivitz AJ, Moskowitz RW, Woods E, Hubbard RC, Verburg KM, Lefkowith JB et al. Comparative efficacy and safety of celecoxib and naproxen in the treatment of osteoarthritis of the hip. J Int Med Res 2001;29:467-79. 21. Williams GW, Hubbard RC, Yu SS, Zhao W, Geis GS. Comparison of once-daily and twice-daily administration of celecoxib for the treatment of osteoarthritis of the knee. Clin Ther 2001;23:213-27. 22. McKenna F, Borenstein D, Wendt H, Wallemark C, Lefkowith JB, Geis GS. Celecoxib versus diclofenac in the management of osteoarthritis of the knee. Scand J Rheumatol 2001;30:11-8. 23. Pincus T, Koch G, Lei H, Mangal B, Sokka T, Moskowitz R et al. Patient Preference for Placebo, Acetaminophen (paracetamol) or Celecoxib Efficacy Studies (PACES): two randomised, double blind, placebo controlled, crossover clinical trials in patients with knee or hip osteoarthritis. Ann Rheum Dis 2004;63:931-9. 24. Birbara CA, Puopolo AD, Munoz DR, Sheldon EA, Mangione A, Bohidar NR et al. Treatment of chronic low back pain with etoricoxib, a new cyclo-oxygenase-2 selective inhibitor: improvement in pain and disability--a randomized, placebo-controlled, 3-month trial. J Pain 2003;4:307-15. 25. Palmer R, Weiss R, Zusman RM, Haig A, Flavin S, MacDonald B. Effects of nabumetone, celecoxib, and ibuprofen on blood pressure control in hypertensive patients on angiotensin converting enzyme inhibitors. Am J Hypertens 2003;16:135-9. 26. Phillips RK, Wallace MH, Lynch PM, Hawk E, Gordon GB, Saunders BP et al. A randomised, double blind, placebo controlled study of celecoxib, a selective cyclooxygenase 2 inhibitor, on duodenal polyposis in familial adenomatous polyposis. Gut 2002;50:857-60. 27. Solomon SD, McMurray JJ, Pfeffer MA, Wittes J, Fowler R, Finn P et al. Cardiovascular risk associated with celecoxib in a clinical trial for colorectal adenoma prevention. N Engl J Med 2005;352:1071-80. 28. Ta LE, Dionne RA. Treatment of painful temporomandibular joints with a cyclooxygenase-2 inhibitor: a randomized placebo-controlled comparison of celecoxib to naproxen. Pain 2004;111:13-21. 29. Dougados M, Behier JM, Jolchine I, Calin A, van der Heijde D, Olivieri I et al. Efficacy of celecoxib, a cyclooxygenase 2-specific inhibitor, in the treatment of ankylosing spondylitis: a six-week controlled study with comparison against placebo and against a conventional nonsteroidal antiinflammatory drug. Arthritis Rheum 2001;44:180-5. 30. DiBattiste PM, Chen C, Viscusi J, Curtis SP, Cannon CP. Etoricoxib has no adverse effects on biomarkers of cardiovascular risk in patients with osteoarthritis. J Am Coll Cardiol 2004;43:511A. 31. Curtis SP, Losada B, Bosi-Ferraz M, Saenz R, Miller ER, Ray P et al. Etoricoxib and diclofenac demonstrate similar efficacy in a 174-week randomized study of rheumatoid arthritis patients. Arthritis Rheum 2003;48(9, Suppl.):S124-S5. 32. Matsumoto AK, Melian A, Mandel DR, McIlwain HH, Borenstein D, Zhao PL et al. A randomized, controlled, clinical trial of etoricoxib in the treatment of rheumatoid arthritis. J Rheumatol 2002;29:1623-30. 33. Collantes E, Curtis SP, Lee KW, Casas N, McCarthy T, Melian A et al. A multinational randomized, controlled, clinical trial of etoricoxib in the treatment of rheumatoid arthritis. BMC Fam Pract 2002;3:10.


the gastrointestinal safety of coxibs. Am J Cardiol 2002;89:3D-9D. 5. Bresalier RS, Sandler RS, Quan H, Bolognese JA, Oxenius B, Horgan K et al. Adenomatous Polyp Prevention on Vioxx (APPROVe) Trial Investigators. Cardiovascular events associated with rofecoxib in a colorectal adenoma chemoprevention trial. N Engl J Med 2005;352:1092-102. 6. Nussmeier NA, Whelton AA, Brown MT, Langford RM, Hoeft A, Parlow JL et al. Complications of the COX-2 inhibitors parecoxib and valdecoxib after cardiac surgery. N Engl J Med 2005;352:1081-91. 7. Brooks J, Warburton R, Beales IL. Prevention of upper gastrointestinal haemorrhage: current controversies and clinical guidance. Ther Adv Chronic Dis 2013;4:206-22. 8. Hochberg MC, Altman RD, April KT, Benkhalti M, Guyatt G, McGowan J et al.; American College of Rheumatology. American College of Rheumatology 2012 recommendations for the use of nonpharmacologic and pharmacologic therapies in osteoarthritis of the hand, hip, and knee. Arthritis Care Res (Hoboken) 2012;64:465-74. 9. Jadad AR, Moore RA, Carroll D, Jenkinson C, Reynolds DJ, Gavaghan DJ, McQuay HJ. Assessing the quality of reports of randomized clinical trials: is blinding necessary? Control Clin Trials 1996;17:1-12. 10. Bombardier C, Laine L, Reicin A, Shapiro D, BurgosVargas R, Davis B et al. 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. 11. Lisse JR, Perlman M, Johansson G, Shoemaker JR, Schechtman J, Skalky CS et al. Gastrointestinal tolerability and effectiveness of rofecoxib versus naproxen in the treatment of osteoarthritis: a randomized, controlled trial. Ann Intern Med 2003;139:539-46. 12. Patrono C, Rocca B. Nonsteroidal antiinflammatory drugs: past, present and future. Pharmacol Res 2009;59:285-9. 13. Simon LS, Lanza FL, Lipsky PE, Hubbard RC, Talwalker S, Schwartz BD et al. Preliminary study of the safety and efficacy of SC-58635, a novel cyclooxygenase 2 inhibitor: efficacy and safety in two placebo-controlled trials in osteoarthritis and rheumatoid arthritis, and studies of gastrointestinal and platelet effects. Arthritis Rheum 1998;41:1591-602. 14. Bensen WG, Fiechtner JJ, McMillen JI, Zhao WW, Yu SS, Woods EM et al. Treatment of osteoarthritis with celecoxib, a cyclooxygenase-2 inhibitor: a randomized controlled trial. Mayo Clin Proc 1999;74:1095105. 15. Simon LS, Weaver AL, Graham DY, Kivitz AJ, Lipsky PE, Hubbard RC et al. Anti-inflammatory and upper gastrointestinal effects of celecoxib in rheumatoid arthritis: a randomized controlled trial. JAMA 1999;282:1921-8. 16. Goldstein JL, Correa P, Zhao WW, Burr AM, Hubbard RC, Verburg KM et al. Reduced incidence of gastroduodenal ulcers with celecoxib, a novel cyclooxygenase-2 inhibitor, compared to naproxen in patients with arthritis. Am J Gastroenterol 2001;96:1019-27. 17. Whelton A, White WB, Bello AE, Puma JA, Fort JG. Effects of celecoxib and rofecoxib on blood pressure and edema in patients ≤65 years of age with systemic hypertension and osteoarthritis. Am J Cardiol 2002;90:959-63. 18. Matsumoto AK, Melian A, Mandel DR, McIlwain HH, Borenstein D, Zhao PL et al. A randomized, controlled, clinical trial of etoricoxib in the treatment of rheumatoid arthritis. J Rheumatol 2002;29:1623-30.

M



Vol. 62 - No. 6


447


celecoxib vs nonsteroidal anti-inflammatory drugs for osteoarthritis and rheumatoid arthritis: the CLASS study: A randomized controlled trial. Celecoxib Longterm Arthritis Safety Study. JAMA 2000;284:1247-55. 45. Gibofsky A, Williams GW, McKenna F, Fort JG. Comparing the efficacy of cyclooxygenase 2-specific inhibitors in treating osteoarthritis: appropriate trial design considerations and results of a randomized, placebocontrolled trial. Arthritis Rheum 2003;48:3102-11. 46. Geba GP, Weaver AL, Polis AB, Dixon ME, Schnitzer TJ. Efficacy of rofecoxib, celecoxib, and acetaminophen in osteoarthritis of the knee: a randomized trial. Journal of American Medical Association 2002;287:64-71. 47. Pfizer, Inc. Protocol N49-96-02-023: A double-blind, placebo controlled, randomized comparison study of the efficacy and safety of SC-58635 100mg, 200 mg and 400 mg BID and naproxen 500 mg BID in treating the signs and symptoms of rheumatoid arthritis; 1998. [cited 2014 October 8]. Available from: http:// www.clinicalstudyresults.org/documents/companystudy_79_19.pdf 48. Pfizer, Inc. Protocol N49-96-02-060: A multicenter, doubleblind, placebo controlled comparison study of the efficacy of SC-58635 200 mg QD versus SC-58635 100mg BID in treating the signs and symptoms of osteoarthritis of the knee; 1998. [cited 2014 October 8]. Available from: http://www.clinicalstudyresults.org/ documents/companystudy_ 79_14.pdf 49. Merck Research Laboratories. FDA Advisory Committee Meeting background information, ARCOXIA TM (Etoricoxib Tablets). [cited 2014 October 8]. Available from: 2005;http://origin.www.fda.gov/ ohrms/dockets/ac/05/brieﬁng/2005-4090B2_01_Merck-Etoricoxib.pdf 50. Pfizer, Inc. Protocol N49-97-02-071: A multicenter, doubleblind, parallel group study comparing the incidence of gastroduodenal ulcer associated with SC-58635 200mg BID with that of diclofenac 75 mg BID and ibuprofen 800mg TID, taken for 12 weeks in patients with osteoarthritis or rheumatoid arthritis; 1998. [cited 2014 October 8]. Available from: http:// www.clinicalstudyresults.org/ documents/companystudy_79_4.pdf 51. Levin B. Celecoxib in adenoma prevention – the PreSAP Trial. Slide presentation at: Meeting of the FDA Advisory Committee on COX-2 Inhibitors and NSAIDS; February 16-18, 2005; Gaithersburg, MD, USA. [cited 2014 October 8]. Available from: http:// www.fda.gov/ohrms/dockets/ac/05/slides/20054090S1_09_FDA-Levin.ppt


34. Hunt RH, Harper S, Callegari P, Yu C, Quan H, Evans J et al. Complementary studies of the gastrointestinal safety of the cyclo-oxygenase-2-selective inhibitor etoricoxib. Aliment Pharmacol Ther 2003;17:201-10. 35. Tsoukas C, Eyster E, Mukhpadhyay S, Giallells K. Efficacy of etoricoxib in the treatment of hemophilic arthropathy. Arthritis Rheum 2001;44:S124-S124. 36. Gottesdiener K, Schnitzer T, Fisher C, Bockow B, Markenson J, Ko A et al. Results of a randomized, dose-ranging trial of etoricoxib in patients with osteoarthritis. Rheumatology (Oxford) 2002;41:105261. 37. Reginster JY, Fischer CL, Beaulieu A, Malmstrom K, Curtis SP, Miller ER et al. Etoricoxib demonstrates similar efficacy and improved gastrointestinal safety compared to naproxen in two 138-week randomized studies of osteoarthritis patients. Ann Rheum Dis 2004;63:Abstract FRI0394. 38. Leung AT, Malmstrom K, Gallacher AE, Sarembock B, Poor G, Beaulieu A et al. Efficacy and tolerability profile of etoricoxib in patients with osteoarthritis: A randomized, double-blind, placebo and active-comparator controlled 12-week efficacy trial. Curr Med Res Opin 2002;18:49-58. 39. Hunt RH, Harper S, Watson DJ, Yu C, Quan H, Lee M et al. The gastrointestinal safety of the COX-2 selective inhibitor etoricoxib assessed by both endoscopy and analysis of upper gastrointestinal events. Am J Gastroenterol 2003;98:1725-33. 40. Wiesenhutter CW, Boice JA, Ko A, Sheldon EA, Murphy FT, Wittmer BA et al. Evaluation of the comparative efficacy of etoricoxib and ibuprofen for treatment of patients with osteoarthritis: A randomized, double-blind, placebo-controlled trial. Mayo Clin Proc 2005;80:470-9. 41. van der Heijde D, Baraf HS, Ramos-Remus C, Calin A, Weaver AL, Schiff M et al. Evaluation of the efficacy of etoricoxib in ankylosing spondylitis: results of a fifty-two-week, randomized, controlled study. Arthritis Rheum 2005;52:1205-15. 42. Pallay RM, Seger W, Adler JL, Ettlinger RE, Quaidoo EA, Lipetz R et al. Etoricoxib reduced pain and disability and improved quality of life in patients with chronic low back pain: a 3 month, randomized, controlled trial. Scand J Rheumatol 2004;33:257-66. 43. Sowers JR, White WB, Pitt B, Whelton A, Simon LS, Winer N 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 mellitus. Arch Intern Med 2005;165:161-8. 44. Silverstein FE, Faich G, Goldstein JL, Simon LS, Pincus T, Whelton A et al. Gastrointestinal toxicity with

M


DE VECCHIS

448

Epub ahead of print on July 16, 2014.


December 2014