Cardiovascular safety of celecoxib in rheumatoid arthritis and osteoarthritis patients: A systematic review and meta-analysis.

OBJECTIVE: To assess the cardiovascular safety of celecoxib compared to non-selective non-steroid anti-inflammatory drugs or placebo.
METHODS: We included randomized controlled trials of oral celecoxib compared with a non-selective NSAID or placebo in rheumatoid arthritis and osteoarthritis patients. We conducted searches in EMBASE, Cochrane CENTRAL, MEDLINE, China National Knowledge Infrastructure, VIP, Wanfang, and Chinese Biomedical Literature Database. Study selection and data extraction were done by two authors independently. The risk of bias was assessed using Cochrane's risk-of-bias Tool for Randomized Trials. The effect size was presented as a risk ratio with their 95% confidence interval.
RESULTS: Until July 22nd, 2021, our search identified 6279 records from which, after exclusions, 21 trials were included in the meta-analysis. The overall pooled risk ratio for Antiplatelet Trialists Collaboration cardiovascular events for celecoxib compared with any non-selective non-steroid anti-inflammatory drugs was 0.89 (95% confidence interval: 0.80-1.00). The pooled risk ratio for all-cause mortality for celecoxib compared with non-selective non-steroid anti-inflammatory drugs was 0.81 (95% confidence interval: 0.66-0.98). The cardiovascular mortality rate of celecoxib was lower than non-selective non-steroid anti-inflammatory drugs (risk ratio: 0.75, 95% confidence interval: 0.57-0.99). There was no significant difference between celecoxib and non-selective non-steroid anti-inflammatory drugs or placebo in the risk of other cardiovascular events.
CONCLUSION: Celecoxib is relatively safe in rheumatoid arthritis and osteoarthritis patients, independent of dose or duration. But it remains uncertain whether this would remain the same in patients treated with aspirin and patients with established cardiovascular diseases.

Introduction

Rheumatoid arthritis (RA) is a chronic, inflammatory disease of which pathological mechanism remains unclear [1]. Osteoarthritis (OA) is the most common joint disease worldwide [2]. Compared with the general population, the mortality rate among rheumatoid arthritis patients is higher, which is largely attributable to cardiovascular disease, particularly (fatal and non-fatal) myocardial infarction due to coronary atherosclerosis [3]. Risks of both myocardial infarctions and strokes are amplified in individuals with rheumatoid arthritis, which may be the result of inflammation-associated vascular damage [4, 5]. Likewise, the risks of heart failure and ischemic heart disease increase in osteoarthritis patients [6]. It is necessary to control cardiovascular events, especially fatal cardiovascular events for rheumatoid arthritis and osteoarthritis patients.

Nonsteroidal anti-inflammatory drugs (NSAIDs) are often prescribed to relieve arthritis symptoms. Cyclo-oxygenase (COX)-2 inhibitors (coxibs), which were developed as alternative analgesics to minimize upper gastrointestinal toxicity of non-selective NSAIDs (nsNSAIDs), were believed to reduce cardiovascular risks [7]. Celecoxib (Celebrex®) was the first coxib introduced into clinical practice. At its recommended doses of 200 or 400 mg/day, it is as effective for symptomatic treatment as conventional NSAIDs and some other coxibs [8] and can significantly reduce upper gastrointestinal events [9]. However, the subsequent coxib, rofecoxib, was found to increase cardiovascular events, which led to its worldwide withdrawal in 2004 [10]. Another coxib, valdecoxib (Bextra®), was also withdrawn from the market in 2005 for its cardiovascular toxicity and serious skin reactions [11]. The withdrawal raised concern about the cardiovascular safety of coxibs. As a result, the use of many coxibs was restricted and, all coxibs and nonselective NSAIDs were recommended to be used with caution in patients with older age or established cardiovascular disease [12, 13].

Cardiovascular safety on NSAIDs is highly controversial. Although it has been confirmed that some NSAIDs are associated with a higher risk of cardiovascular events, the cardiovascular safety profile varies widely. Coxibs were associated with increased risks of myocardial infarction when compared against placebo or non-selective NSAIDs [14]. Salpeter et al. suggested nonselective NSAIDs had no significant effect on cardiovascular events or death in trials of joint disease and Alzheimer’s disease, and there was no significant adverse or cardioprotective effect of naproxen [15]. Kearny et al. found diclofenac and ibuprofen were associated with higher cardiovascular risk, while naproxen was not [16]. A meta-analysis by Coxib and traditional NSAID Trialists’ Collaboration indicated that the vascular risks of high-dose diclofenac, and possibly ibuprofen, were comparable to coxibs, whereas high-dose naproxen was associated with less vascular risk than other NSAIDs [7]. In OA patients, the risk of heart failure in the coxib group remained significant even when rofecoxib was removed from the analysis [17].

Also, the cardiovascular safety of celecoxib compared to other NSAIDs remains uncertain, especially among patients with established cardiovascular diseases [18]. One Cochrane review [19] suggested the risk of bias might be the reason for uncertainty about the rate of cardiovascular events between celecoxib and nsNSAIDs. Another factor was that most trials were small and short-term. It is also because mechanisms of the cardiovascular side effects are still controversial. One hypothesis is that coxibs have an impact on vasoactive endothelium-derived factors, particularly via inhibiting prostaglandin synthesis, which is important for the regulation of vascular tone and sodium excretion and may influence blood pressure, but it is not for certain yet. This systematic review and meta-analysis aimed to assess the cardiovascular safety of celecoxib compared to non-selective nonsteroidal anti-inflammatory drugs and placebo.

Methods

Our protocol was published on PROSPERO [CRD42020179936] with the title Cardiovascular Safety of Celecoxib for Rheumatoid Arthritis and Osteoarthritis: A Systematic Review and Meta-Analysis.

Search strategy

Publications were retrieved using computerized searches by EMBASE, CENTRAL, MEDLINE, CNKI, VIP, Wanfang, and the Chinese Biomedical Literature Database. No date or language limits were set. A re-run was done before the final analyses. The last search date was July 22nd, 2021.

Inclusion criteria

Patients with rheumatoid arthritis (diagnosed according to ACR 1987 criteria [20] or ACR/EULAR 2010 criteria [21]) or osteoarthritis (diagnosed according to ACR guidelines [22, 23]) were included, while patients with other rheumatic diseases such as systemic lupus erythematosus or Sjogren’s Syndromes were excluded. Only RCTs comparing celecoxib at any dose to non-selective NSAIDs or placebo were included.

Outcome measures

Primary outcomes: 1. all-cause mortality; 2. cardiovascular mortality; 3. fatal and non-fatal myocardial infarction; 4. fatal and non-fatal stroke. Secondary outcomes: 1. other cardiovascular events, including atrial fibrillation, arrhythmias, angina, revascularization, etc.; 2. total cholesterol (TC), triglycerides (TG), high-density lipoprotein (HDL), low-density lipoprotein (LDL); 3. systolic blood pressure (SBP) and diastolic blood pressure (DBP).

Study selection

Two reviewers (BR Cheng and JQ Chen) independently screened all titles and abstracts of the records. Full texts of potentially eligible studies were retrieved for further identification according to the eligibility criteria. Any uncertainty or discrepancy was resolved by discussion. We used Excel for recording decisions.

Data extraction

Two reviewers (BR Cheng and JQ Chen) independently extracted data following a predesigned data form using Excel (version Microsoft Excel 2016). Data were checked by an additional reviewer (XW Zhang). Disagreements were resolved by discussion.

Risk of bias assessment

Since only RCTs were included, the risk of bias was assessed through Cochrane’s risk-of-bias Tool for Randomized Trials (RoB 2) [24]. Two review authors (BR Cheng and QY Gao) independently assessed the risk of bias. Disagreements were resolved by discussion with an additional reviewer (XW Zhang). The risk of bias are assessed through the following five domains: (1) bias arising from the randomization process; (2) bias due to deviations from intended interventions; (3) bias due to missing outcome data; (4) bias in the measurement of the outcome; (5) bias in the selection of the reported result.

Data analysis and synthesis

A narrative synthesis of the findings from the included studies will be provided. We worked with the data within a meta-analysis, through Review Manager 5.3. Heterogeneity related to the results of the studies was assessed using both the chi-square test and the I2 statistic. If data were sufficiently homogenous, we would pool the results using a fixed-effect model, with standardized mean differences for continuous outcomes (in our review referring to TC, TG, HDL, LDL, systolic blood pressure, and diastolic blood pressure) and risk ratios for binary outcomes (in our review referring to all-cause mortality, cardiovascular mortality, fatal and non-fatal myocardial infarction, fatal and non-fatal stroke, and other cardiovascular events), and calculate 95% confidence intervals and two-sided P values for each outcome. We will provide summaries of intervention effects for each study by calculating risk ratios (for dichotomous outcomes) or standardized mean differences (for continuous outcomes). We considered an I2 value greater than 50% indicative of substantial heterogeneity. If there were high heterogeneity across included studies, we would use a random effect model or only provide a narrative synthesis of the findings from the included studies, structured around the type of intervention, target population characteristics, type of outcome, and intervention content.

Results

Database searches initially identified 6279 records in languages including English, Chinese, German, Russian, Turkish and Spanish. The last search date was July 22nd, 2021. After removing duplications, 4312 articles were screened by their titles and abstracts. 166 full-texts were assessed for eligibility, but we failed to find 5 of them, as 3 were anonymous and the other 2, written in Russian and Turkish respectively, had no available resources online. A flowchart (Fig 1) with the number of included studies at each step was established, including reasons for excluding studies. 21 studies were included in qualitative and 20 in the quantitative synthesis.

Fig 1

Flowchart of the study selection process.

Study characteristics

Table 1 presents the characteristics of the studies included through the systematic review process. Except for basic study information, we also paid attention to if patients with cardiovascular risk were excluded and if aspirin was allowed to use for cardiovascular protection, which may affect the result of adverse events.

Table 1

Characteristics of randomized controlled trials included in the qualitative synthesis.

Study	Condition	Total Sample Size	Comparators	Celecoxib Doses and Frequency	Duration
Bingham 2007 (Trial 1) [25]	OA	599	Placebo	200mg Qd	26 weeks
Bingham 2007 (Trial 2) [25]	OA	608	Placebo	200mg Qd	26 weeks
Birbara 2006 (Trial 1) [26]	OA	395	Placebo	200mg Qd	6 weeks
Birbara 2006 (Trial 2) [26]	OA	413	Placebo	200mg Qd	6 weeks
Cannon 2008 [27]	OA	433	Placebo, Ibuprofen	200mg Bid	12 weeks
Clegg 2006 (GAIT) [28]	OA	1583	Placebo	200mg/day	24 weeks
Conaghan 2012 [29]	OA	1399	Placebo	100mg/day	12 weeks
Cryer 2012 (PROBE) [30]	OA	8067	(1)	(2)	6 months
Dahlberg 2009 [31]	OA	925	Diclofenac	200mg Qd	1 year
Essex 2012 [32]	OA	589	Naproxen	200mg Qd	6 months
Gibofsky 2003 [33]	OA	477	Placebo	200mg/day	6 weeks
Hawel 2003 [34]	OA	148	Dexiprofen	100mg/day	15 days
MacDonald 2017 (SCOT) [35]	OA&RA	7297	Diclofenac, Ibuprofen and Naproxen	169.8±80.6mg/day	(3)
McKenna 2001 [36]	OA	182	Placebo	200mg Qd	6 weeks
Nissen 2016 (PRECISION) [37]	OA&RA	24081	Naproxen and Ibuprofen	209±37mg/day	20 months (4)
Sampalis 2012 [38]	OA	60	Placebo	200mg/day	90 days
Sawitzke 2010 [39]	OA	662	Placebo	200mg/day	24 weeks
Schnitzer 2011 [40]	OA	1262	Placebo	200mg Qd	13 weeks
Simon 1999 [41]	RA	1149	Placebo and Naproxen	100mg, 200mg, or 400mg Bid	12 weeks
Smugar 2006 (Trial 1) [42]	OA	1521	Placebo	200mg Qd	6 weeks
Smugar 2006 (Trial 2) [42]	OA	1082	Placebo	200mg Qd	6 weeks
White 2002 (CLASS) [43]	OA&RA	7968	Diclofenac and Ibuprofen	100 mg Bid in patients with OA and up to 200 mg Bid in patients with RA	13 weeks
Williams 2001 [44]	OA	718	Placebo	100mg Bid or 200mg Qd	6 weeks
Wittenberg 2006 [45]	OA	364	Placebo	200mg Bid	1 week

(1): The nsNSAID in the comparator group was any nsNSAID of the investigator’s choice, prescribed within the dosages allowed in the United States package insert.

(2): Celecoxib dosage could be adjusted within the United States prescribing guidelines.

(3): The median intention-to-treat follow-up for the primary outcome was 3.0 years (maximum 6.3 years, total 22 600 person-years)

(4): The mean duration of treatment was 20.3±16.0 months for all patients.

OA: Osteoarthritis; RA: Rheumatoid Arthritis; Qd: once per day; Bid: twice per day; GAIT: Glucosamine/chondroitin Arthritis Intervention Trial; PROBE: Prospective, Randomized, Open-label, Blinded Endpoint; SCOT: Standard care vs. Celecoxib Outcome Trial; PRECISION: Prospective Randomized Evaluation of Celecoxib Integrated Safety versus Ibuprofen Or Naproxen; mg: milligram; nsNSAID: non-selective Non-Steroidal Anti-Inflammatory Drug.

Risk of bias of individual studies

Fig 2 and Fig 3 include a summary of the risk of bias assessed for each study included in this systematic review. Overall, most included studies were of low or unclear risks. Six studies were of high risk, which was mostly contributed by lack of specific randomization process or high withdrawal rates due to adverse events.

Fig 2

Risk of bias summary: A review of authors’ judgements about each risk of bias item for each included study.

Fig 3

Risk of bias graph: A review of authors’ judgements about each risk of bias item presented as percentages across all included studies.

Primary outcomes

All-cause mortality

A total of 9 trials reported this outcome. The risk of all-cause mortality was decreased statistically significantly in celecoxib groups, compared with nsNSAIDs groups (RR 0.81, 95% CI 0.66–0.98, I2 = 21%). As for celecoxib versus placebo, four trials reported all-cause mortality cases, which showed no significant differences between the two treatments (RR 0.92, 95% CI 0.26–3.27, I2 = 0%).

Cardiovascular mortality

The cardiovascular mortality rate of the celecoxib groups was also lower than nsNSAIDs groups (RR 0.75, 95% CI 0.57–0.99, I2 = 0%). When compared with placebo, the risk was not significantly different (RR 3.02, 95% CI 0.36–25.27, I2 = 0%).

Myocardial infarction

The risk of myocardial infarction was not significant compared with both nsNSAIDs (RR 1.08, 95% CI = 0.88–1.33) and placebo (RR 1.87, 95% CI = 0.39–8.90) In the 4 trials which included placebo groups, the rate of myocardial infarction was zero, which could affect the result.

Stroke

The risk of stroke in the celecoxib group was also not significant compared with both nsNSAIDs and placebo (RR 0.94, 0.96, 95% CI = 0.71–1.24, 0.13–6.92).

Secondary outcomes

Secondary outcomes included dichotomous and continuous data. Dichotomous data were the numbers of atrial fibrillation, arrhythmias, angina, revascularization, and heart failure, of which some were only reported in single studies (atrial fibrillation, celecoxib versus nsNSAIDs and placebo; arrhythmias, celecoxib versus nsNSAIDs), some in no studies (arrhythmias, celecoxib versus placebo; revascularization, celecoxib versus placebo; heart failure, celecoxib versus placebo), and none of the results was statistically significant. More details are shown in Fig 4 and Fig 5.

Fig 4

Relative risk of dichotomous outcomes for celecoxib versus nsNSAIDs.

Fig 5

Relative risk of dichotomous outcomes for celecoxib versus placebo.

Continuous data included the levels of total cholesterol, triglycerides, high-density lipoprotein, low-density lipoprotein, systolic blood pressure, and diastolic blood pressure. Blood pressures were reported in 3 studies: Bingham 2007, Sampalis 2012, and Simon 1999, all of which compared the celecoxib and placebo groups. Sampalis 2012 did not present any data for meta-analysis, but in their study, no significant change of both systolic and diastolic blood pressures was seen in the celecoxib or placebo groups. Bingham 2007 reported the mean changes of systolic and diastolic blood pressures before and after the study, while Simon 1999 reported the average systolic and diastolic blood pressures before and after the study, so their data couldn’t be pooled, but their conclusions are the same: no differences were found between the celecoxib and placebo groups. As for the lipids and lipoproteins, only LDL-C levels were reported, in only one study [27], where the effects of celecoxib, placebo, and ibuprofen on LDL-C were comparable in patients with osteoarthritis.

Discussion

Overall, celecoxib does not significantly increase cardiovascular events compared with placebo and slightly decreases the risk of all-cause mortality and cardiovascular mortality compared with nsNSAIDs, which may prove it safe when used on rheumatoid arthritis and osteoarthritis patients. Our conclusion was basically in line with the result of the PRECISION trial, in which celecoxib was found to be non-inferior to naproxen or ibuprofen for cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke [37], and also in line with a prospective observational study in Japan assessing the cardiovascular risk between celecoxib and nsNSAIDs in patients with rheumatoid arthritis and osteoarthritis [46].

The all-cause mortality rate of celecoxib decreases significantly than that of nsNSAIDs but not that of placebo. However, since these causes include car accidents, suicide, and other irrelevant causes, it is not of much importance to this study.

The cardiovascular mortality rate comparing celecoxib and nsNSAIDs was reported in five studies, three of them excluded patients with cardiovascular risk (Cryer 2012, Dahlberg 2009 and MacDonald 2017), and aspirin was allowed in three studies (Dahlberg 2009, Nissen 2016 and White 2002), which may decrease the number of adverse cardiovascular events. In the secondary analysis of the CLASS study, the subgroup of patients not taking aspirin was analyzed separately and no differences were observed between celecoxib and the nsNSAID groups in terms of myocardial infarction or stroke with the exception that celecoxib was associated with a lower incidence of sudden cardiac death than diclofenac [47].

As only 2 studies (Schnitzer 2011 and Williams 2001) were included in this primary outcome analysis, although it reported no differences in cardiovascular mortality rate between celecoxib and placebo, it is not considered to be persuasive. In a study on the cardiovascular safety of NSAIDs (patients’ conditions unlimited), celecoxib was found to be related to a higher risk of cardiovascular death, as well as myocardial infarction, stroke, death from any cause, and APTC composite outcome, but none of them was statistically significant [48]. Our results did not present any significant differences either.

The use of celecoxib on blood pressure seems to be safe. Sampalis et al. found that both celecoxib and placebo did not influence systolic blood pressure or diastolic blood pressure. Curtis E et al. also found no significant increase in hypertension in celecoxib and etoricoxib compared with placebo, albeit an increase in the risk of heart failure and edema [17].

But it remains uncertain if celecoxib is more beneficial in patients with established cardiovascular risk (stroke history, hypertension, etc.). As the mechanism of elevated cardiovascular risk in RA and OA remains unveiled, there has been uncertainty about the nature and magnitude of these risks. Vitamin B-6 could be a possible factor, as its metabolism can be impaired by clinical use of cyclooxygenase inhibitors [49], and it is associated with higher cardiovascular risks [50, 51]. Still, we could not know if the cardiovascular safety profile of celecoxib is the same in all patients with different cardiovascular risks. Whether it is more beneficial or more dangerous in patients with specific cardiovascular risk is still nowhere to know.

What’s more, there were discrepancies between real-world clinical practice and randomized clinical trials. Studies showed that the use of coxibs tended to be shorter, more variable, and at lower doses in clinical practice than in some clinical trials. As NSAIDs are always used as painkillers, so not every patient needs to take them every day at a specific dose. Therefore, most patients probably have been exposed to doses and duration sufficient to detect an increased cardiovascular risk [52]. This provided a basis for reconciling the apparent discrepancies between these trials and explained the findings from most non-experimental epidemiologic studies, which showed no increased risk with celecoxib, irrespective of dose [53].

Meanwhile, effective biomarkers to predict the cardiovascular risk associated with the use of anti-inflammatory drugs for RA and OA are in need to better provide cardiovascular protective prescriptions. NT-proBNP may be a useful marker for anticipating cardiovascular risk in OA patients [54].

Also, since valdecoxib is more selective for COX-2 than celecoxib in vitro, it is related to higher cardiovascular risk. However, there may well be some patients in whom celecoxib is the more selective inhibitor in vivo [55]. Therefore, better indications cannot be made until the mechanisms behind RA and OA patients’ elevated cardiovascular risk are unveiled.

Last, our research had some limitations. First, some of the studies included in this research were not intended to assess the cardiovascular risk of celecoxib, even though safety profiles were reported. Second, as the adverse cardiovascular events rate is relatively small, many studies included in full-text screening did not report any cardiovascular events. Some other studies that reported cardiovascular events were of small samples or of short duration, which may dilute the cardiovascular adverse effect of drugs. Also, publication bias couldn’t have been assessed properly due to the small number (most of them fewer than 5) of trials included in each meta-analysis, which added uncertainty to our conclusion.

However, despite a growing understanding of the mechanisms of RA and their interplay with cardiovascular risk factors, it also remains unclear the relationship between arthritis and increase cardiovascular events [56]. Discovering the mechanism is essential to pursue the specific treatment of this common comorbidity.

Conclusion

This meta-analysis found celecoxib does not increase the cardiovascular risk compared with common nsNSAIDs and placebo, and therefore confirmed celecoxib can be safely prescribed at approved doses in RA or OA patients as a first-line NSAID. But safety data are needed considering long duration or high dose usage. The result remains uncertain in patients treated with aspirin and patients with established cardiovascular diseases.

PRISMA 2020 flow diagram.

(DOCX)

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PRISMA 2020 checklist.

(DOCX)

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PROSPERO protocol.

(PDF)

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Search strategy.

(DOCX)

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Data extraction of study characteristics.

(XLS)

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Data extraction of outcomes.

(XLS)

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RoB assessment.

(XLSM)

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13 Sep 2021

PONE-D-21-23851Cardiovascular Safety of Celecoxib in Rheumatoid Arthritis and Osteoarthritis Patients: A Systematic Review and Meta-AnalysisPLOS ONE

Dear Dr. Liu,

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==============================The reviewers made several important points that should be addressed, particularly the statistics require attention. Please consider to to seek advice from a biostatistician (preferably also including him/her as an author.

Furthermore, the English needs substantial improvement.

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Reviewer #1: This is a timely manuscript which aims to provide some higher level of evidence in a relative arguable subject, namely the overall and in particular the cardiovascular safety profile of celecoxib and NSAIDs in patients with OA and/or RA. The authors performed a systematic review and a meta-analysis of available literature and found that celecoxib has a better CV profile than other NSAIDs in terms of all-cause mortality and CV mortality, whereas no differences have been observed for myocardial infarction and CVA. Similarly, no differences have been shown with respect to all analyzed outcomes when celecoxib has been compared to placebo. Some points could be made that should be addressed in order to improve the manuscript:

1. English language: please have the manuscript checked by a native English speaker or someone with highest qualifications in English language.

2. Methodologic issues/statistical issues: the study of Nissen (2016) and MacDonald (2017) are the largest studies and both of them provide data supporting a neutral/beneficial effect of celecoxib with respect to all-cause mortality and CV mortality. Likewise, it is of little surprise that the meta-analysis imbedding this two studies would come to the same conclusion, only now reaching statistical significance. My point is that we should still be caution when interpreting the results, because even this is a meta-analysis, it seems that these two studies are actually the ones determining the final outcome. Could the authors discuss this point?

3. Clinical relevance: from the clinician point of view it is of relevance to know if it is possible to safely prescribe NSAIDs to a patient, and which one fits the best with his clinical profile. Among the studies included in this meta-analysis a few investigated RA patients. Is it possible to perform separate analysis for the OA and RA patients respectively? While NSAIDs are often prescribed as painkillers in OA (where paracetamol represents an equally good alternative, given the low-inflammatory status in OA), their prescription in RA can sometimes be determined by an increasing of disease activity, thus working more as anti-inflammatory drugs, decreasing inflammation and consequently its detrimental cardiovascular effects. Therefore one may hypothesize that the same drug (celecoxib) might have different CV impact in RA and OA respectively because of different biological effects (more painkilling (OA) vs. more anti-inflammatory (RA)).

It would therefore be very useful if the authors would provide the readers with an answer to the following questions (based on their results):

a) Can I safely prescribe celecoxib in an OA patient? As a first NSAID? What if the patient has a history of CV events?

b) Can I safely prescribe celecoxib to an RA patient? As a first NSAID? What if the patient has a history of CV events?

Thank you.

Reviewer #2: Liu et al. have written a systematic review and meta-analysis about the use of celecoxib and its cardiovascular safety in patients with rheumatoid arthritis and osteoarthritis. This is a relevant topic for daily clinical practice. However, I have several concerns about the manuscript.

1. In the introduction, on page 2, line 47 and 48, the authors write about coronary atherosclerosis and non-fatal myocardial infarction. I think this sentence should be refrased. Now it reads as if coronary atherosclerosis and a myocardial infarction are different entities. It could be refrased to "particularly (fatal and non-fatal) myocardial infarction due to coronary atherosclerosis".

2. The authors write that there are no specific treatment strategies for CV disease in RA patients. However, the EULAR recommendations state that there is evidence (from mainly observational studies) that an optimal control of disease activity and treatment of CVD risk factors reduces the CVD risk in patients with an inflammatory joint disease.

3. Regarding the statistical analysis I would like to advise to discuss the methods with a statistician. Studies with zero events were included in the analyses. I wonder if this is the correct way to do these analyses. I wonder if you can conclude that all-cause mortality was decreased in the celecoxib group when there are 0-2 events in the studies included.

4. I could not find which non-selective NSAIDs the authors included in their search and comparison with celecoxib. I think this is relevant and should be added to the manuscript.

5. In general, I would advise to ask a native English speaker to review the manuscript.

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24 Oct 2021

Reviewer #1: This is a timely manuscript which aims to provide some higher level of evidence in a relative arguable subject, namely the overall and in particular the cardiovascular safety profile of celecoxib and NSAIDs in patients with OA and/or RA. The authors performed a systematic review and a meta-analysis of available literature and found that celecoxib has a better CV profile than other NSAIDs in terms of all-cause mortality and CV mortality, whereas no differences have been observed for myocardial infarction and CVA. Similarly, no differences have been shown with respect to all analyzed outcomes when celecoxib has been compared to placebo. Some points could be made that should be addressed in order to improve the manuscript:

1. English language: please have the manuscript checked by a native English speaker or someone with highest qualifications in English language.

Response: We apologize for the insufficient quality of the original manuscript. This issue has been highly recognized by our team, and multiple times of revisions with great scrutiny have been performed. Some grammatical errors and expressions have been checked. We hope we have presented a better version. Thank you.

2. Methodologic issues/statistical issues: the study of Nissen (2016) and MacDonald (2017) are the largest studies and both of them provide data supporting a neutral/beneficial effect of celecoxib with respect to all-cause mortality and CV mortality. Likewise, it is of little surprise that the meta-analysis imbedding this two studies would come to the same conclusion, only now reaching statistical significance. My point is that we should still be caution when interpreting the results, because even this is a meta-analysis, it seems that these two studies are actually the ones determining the final outcome. Could the authors discuss this point?

Response: Thank you for your question. If the amount of included literature meta-analysis is small, such as two studies as you mentioned, there is often a serious bias. In principle, we can see whether there is publication bias through the funnel chart for more than 9 documents. Publication bias is an important aspect which should be considered because in many cases, articles with negative results are less likely to be published. As for other biases, we can only find out based on the evaluation of the quality of the literature (criteria and methodology). The available literature should be included in the study according to the PRISMA guidelines.

3. Clinical relevance: from the clinician point of view it is of relevance to know if it is possible to safely prescribe NSAIDs to a patient, and which one fits the best with his clinical profile. Among the studies included in this meta-analysis a few investigated RA patients. Is it possible to perform separate analysis for the OA and RA patients respectively? While NSAIDs are often prescribed as painkillers in OA (where paracetamol represents an equally good alternative, given the low-inflammatory status in OA), their prescription in RA can sometimes be determined by an increasing of disease activity, thus working more as anti-inflammatory drugs, decreasing inflammation and consequently its detrimental cardiovascular effects. Therefore one may hypothesize that the same drug (celecoxib) might have different CV impact in RA and OA respectively because of different biological effects (more painkilling (OA) vs. more anti-inflammatory (RA)).

It would therefore be very useful if the authors would provide the readers with an answer to the following questions (based on their results):

a) Can I safely prescribe celecoxib in an OA patient? As a first NSAID? What if the patient has a history of CV events?

b) Can I safely prescribe celecoxib to an RA patient? As a first NSAID? What if the patient has a history of CV events?

Thank you.

Response: Thank you for your question. Actually, before the submission, we tried to do this subgroup analysis you mentioned but failed because only 1 of the 24 trials included in our systematic review recruited only RA patients. 3 trials recruited both OA and RA patients, but data of OA and RA subgroups were not provided. Therefore, it is difficult to do this subgroup analysis. But based on the evidence we have so far, we consider it safe to prescribe celecoxib at an approved dose - 100, 200, and 400mg per day - in an OA patient, as a recommended NSAID. But we dare not say “a first NSAID” because naproxen also showed great safety and no statistical differences have been found between them in the study of Essex (2012)[1], MacDonald (2017)[2], Nissen (2016) [3] and Simon (1999)[4]. As for RA patients, although the participants were fewer, we still think it’s OK to draw the same conclusion because 1) any enhancement of CV risk with celecoxib or nsNSAID is modest[2]; and 2) trials with OA&RA patients presented the same results as those of trials with only OA patients. However, no subgroup analysis was reported considering patients with/without a history of CV events, so we cannot give a sound conclusion so far. We have added some related contents in the CONCLUSION.

Reviewer #2: Liu et al. have written a systematic review and meta-analysis about the use of celecoxib and its cardiovascular safety in patients with rheumatoid arthritis and osteoarthritis. This is a relevant topic for daily clinical practice. However, I have several concerns about the manuscript.

1. In the introduction, on page 2, line 47 and 48, the authors write about coronary atherosclerosis and non-fatal myocardial infarction. I think this sentence should be refrased. Now it reads as if coronary atherosclerosis and a myocardial infarction are different entities. It could be refrased to "particularly (fatal and non-fatal) myocardial infarction due to coronary atherosclerosis".

Response: Thank you for your advice and we apologize for the insufficient quality of the original manuscript. We value your opinion very much and have rephrased it as you suggested.

2. The authors write that there are no specific treatment strategies for CV disease in RA patients. However, the EULAR recommendations state that there is evidence (from mainly observational studies) that an optimal control of disease activity and treatment of CVD risk factors reduces the CVD risk in patients with an inflammatory joint disease.

Response: Thank you for your comments. Our purpose by saying “there were no specific treatment strategies” was that the relationship between RA and its raised CV risk remains unclear. Therefore, no specific treatments could have been found. We deeply agree with the EULAR recommendations that controlling disease activity and treatment of the risk factors reduces the CVD risk. To minimize misunderstanding, we deleted related lines.

3. Regarding the statistical analysis I would like to advise to discuss the methods with a statistician. Studies with zero events were included in the analyses. I wonder if this is the correct way to do these analyses. I wonder if you can conclude that all-cause mortality was decreased in the celecoxib group when there are 0-2 events in the studies included.

Response: Thanks for the advice. We discussed the methods with a statistician (Jingli Xing), and she found no mistakes in them. In a meta-analysis, when we want to calculate the rate of a specific event, the exact number of the event should be recorded, even though sometimes this event did not happen - meaning the rate is 0%. In Cochrane Handbook for Systematic Reviews of Interventions Version 6.2, Chapter 10.4.4.2: Studies with no events in either arm, it wrote: “Whilst the results of risk difference meta-analyses will be affected by non-reporting of outcomes with no events, odds and risk ratio based methods naturally exclude these data whether or not they are published, and are therefore unaffected”[5]. Therefore, we think it is appropriate to include studies with zero events.

4. I could not find which non-selective NSAIDs the authors included in their search and comparison with celecoxib. I think this is relevant and should be added to the manuscript.

Response: Thanks for your question. The details about which non-selective NSAIDs, if any, were included in each trial are concluded in “Table 1 Characteristics of randomized controlled trials included in qualitative synthesis”, which contains ibuprofen, diclofenac, naproxen, and dexiprofen. In the PROBE trial, the nsNSAID in the comparator group was any nsNSAID of the investigator’s choice, prescribed within the dosages allowed in the United States package insert. In most of the trials, celecoxib was compared with placebo. As the incidence of events decreases, the logarithmic conversion, logit conversion, and arcsine conversion methods can still maintain good performance.

5. In general, I would advise to ask a native English speaker to review the manuscript.

Response: We apologize for the insufficient quality of the original manuscript. This issue has been highly recognized by our team, and multiple times of revisions with great scrutiny have been performed this time. Some grammatical errors and expressions have been checked. We hope we have presented a better manuscript. Thank you.

References:

[1] ESSEX M N, BHADRA P, SANDS G H. Efficacy and tolerability of celecoxib versus naproxen in patients with osteoarthritis of the knee: a randomized, double-blind, double-dummy trial [J]. J Int Med Res, 2012, 40(4): 1357-70.

[2] MACDONALD T M, HAWKEY C J, FORD I, et al. Randomized trial of switching from prescribed non-selective non-steroidal anti-inflammatory drugs to prescribed celecoxib: the Standard care vs. Celecoxib Outcome Trial (SCOT) [J]. Eur Heart J, 2017, 38(23): 1843-50.

[3] NISSEN S E, YEOMANS N D, SOLOMON D H, et al. Cardiovascular Safety of Celecoxib, Naproxen, or Ibuprofen for Arthritis [J]. N Engl J Med, 2016, 375(26): 2519-29.

[4] SIMON L S, WEAVER A L, GRAHAM D Y, et al. Anti-inflammatory and upper gastrointestinal effects of celecoxib in rheumatoid arthritis: a randomized controlled trial [J]. JAMA, 1999, 282(20): 1921‐8.

[5] Deeks JJ, Higgins JPT, Altman DG (editors). Chapter 10: Analysing data and undertaking meta-analyses. In: Higgins JPT, Thomas J, Chandler J, Cumpston M, Li T, Page MJ, Welch VA (editors). Cochrane Handbook for Systematic Reviews of Interventions version 6.2 (updated February 2021). Cochrane, 2021. Available from www.training.cochrane.org/handbook.

Submitted filename: Response to Reviewers.docx

Click here for additional data file.

22 Nov 2021

PONE-D-21-23851R1Cardiovascular Safety of Celecoxib in Rheumatoid Arthritis and Osteoarthritis Patients: A Systematic Review and Meta-AnalysisPLOS ONE

Dear Dr. Jian-Ping Liu .

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

There are are some remaining methodological issues, raised by reviewer 1, that need to be addressed

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Reviewer #1: (No Response)

Reviewer #2: All comments have been addressed

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Reviewer #2: Yes

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Reviewer #2: Yes

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Reviewer #2: Yes

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Reviewer #1: I would like to ask the authors to address in the Discussion the issue of publication bias, as a important limitation to their meta-analysis.

Secondly, I would like to know if there is an explanation for the fact that 11 studies mentioned in Table 1 (references no. 25,26, 28, 29, 32, 34, 36, 38, 41, 42, 45) can not be found among the studies presented in the figures 4 - 8. Is the data from these 11 studies excluded from the meta-analysis?

Finally, I would like to ask the authors to sharpen their aim of the study at the end of the introduction and also to address in their discussion or conclusion the gain of knowledge for the scientific community resulting from their meta-analysis. Thank you.

Reviewer #2: (No Response)

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7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

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Reviewer #1: No

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24 Nov 2021

Reviewer #1:

Q1: I would like to ask the authors to address in the Discussion the issue of publication bias, as an important limitation to their meta-analysis.

Response: Thanks for your advice. As the number of trials included in each meta-analysis was small (fewer than 10 trials), publication bias could not have been assessed properly, which makes it an important limitation to our work. We have addressed this issue in the Discussion (Line 275-276).

Q2: Secondly, I would like to know if there is an explanation for the fact that 11 studies mentioned in Table 1 (references no. 25,26, 28, 29, 32, 34, 36, 38, 41, 42, 45) can not be found among the studies presented in the figures 4 - 8. Is the data from these 11 studies excluded from the meta-analysis?

Response: Thanks for your question. Figures 4-8 presented part of the pooled results of the primary outcomes, which are all-cause mortality, cardiovascular mortality, myocardial infarction, and stroke. Some negative results were only shown in the text because we were trying to reduce the number of pictures. As for the secondary outcomes, which are atrial fibrillation, arrhythmias, angina, revascularization, and heart failure, there were no figures in our last edition of the manuscript because some were only reported in single studies, some in no studies, and none of the results was statistically significant. We value your opinion very much and agree with you that it’s improper that we did not give more details about the 11 studies you mentioned, so we combined all the results of dichotomous outcomes into 2 figures (figure 4 and 5 in our latest manuscript), where 19 of the 21 studies included can be found except Sampalis 2012[1] and Simon 1999[2] for following reasons: 1. Sampalis 2012 did not present any data capable for analysis, so we only described their results in the text; 2. Simon 1999 was the only study that presented blood pressures in the celecoxib group and placebo group before and after the study, so the results couldn’t be pooled and also couldn’t be shown in Fig 5. Relative risk of dichotomous outcomes for celecoxib versus placebo as they were continuous data. Therefore, we only described their findings in the text.

Q3: Finally, I would like to ask the authors to sharpen their aim of the study at the end of the introduction and also to address in their discussion or conclusion the gain of knowledge for the scientific community resulting from their meta-analysis. Thank you.

Response: Thanks for your advice. We also think doing so helps readers to better find their take-home messages, so some changes were made in the text (Line 84-86, and Line294-295) to address the aim and findings clearer.

Thank you again for all your precious comments! They’ve been really helpful to us and this article.

References:

[1] SAMPALIS J S, BROWNELL L A. A randomized, double blind, placebo and active comparator controlled pilot study of UP446, a novel dual pathway inhibitor anti-inflammatory agent of botanical origin [J]. Nutr J, 2012, 11(21.

[2] SIMON L S, WEAVER A L, GRAHAM D Y, et al. Anti-inflammatory and upper gastrointestinal effects of celecoxib in rheumatoid arthritis: a randomized controlled trial [J]. JAMA, 1999, 282(20): 1921‐8.

Submitted filename: Response to Reviewers.docx

Click here for additional data file.

26 Nov 2021

Cardiovascular Safety of Celecoxib in Rheumatoid Arthritis and Osteoarthritis Patients: A Systematic Review and Meta-Analysis

PONE-D-21-23851R2

Dear Dr. Jian-Ping Liu,

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6 Dec 2021

PONE-D-21-23851R2

Cardiovascular Safety of Celecoxib in Rheumatoid Arthritis and Osteoarthritis Patients: A Systematic Review and Meta-Analysis

Dear Dr. Liu:

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