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Original Investigation |

Meta-analysis of Cyclooxygenase-2 Inhibitors and Their Effects on Blood Pressure FREE

Tai-Juan Aw, MBBS, FRACP; Steven Joseph Haas, BPharm, BPharmSci(Hons), MSHPA; Danny Liew, MBBS(Hons), FRACP; Henry Krum, MBBS, PhD, FRACP
[+] Author Affiliations

Author Affiliations: Department of Clinical Pharmacology (Drs Aw, Liew, and Krum) and National Health and Medical Research Council (NHMRC) of Australia Centre of Clinical Research Excellence in Therapeutics, Department of Epidemiology and Preventive Medicine and Department of Medicine (Mr Haas and Drs Liew and Krum), Monash University, Alfred Hospital, Melbourne, Australia.


Arch Intern Med. 2005;165(5):490-496. doi:10.1001/archinte.165.5.ioi50013.
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Published online

Background  Nonselective nonsteroidal anti-inflammatory drugs (NSAIDs) are widely prescribed and are associated with blood pressure (BP) elevation. The development of selective cyclooxygenase-2 inhibitors (coxibs) raises the issue of the magnitude of BP response compared with nonselective NSAIDs. We therefore performed a meta-analysis comparing the effects of coxibs with placebo, nonselective NSAIDs, and each other on BP elevation and hypertension.

Methods  Nineteen randomized controlled trials involving coxibs were published before May 2004, with a total of 45 451 participants in which BP data were available. The Cohen method statistically combined weighted mean difference (WMD). The Der Simonian and Laird method pooled results concerning the relative risk (RR) of developing hypertension and the RR of clinically important BP elevations.

Results  Among the trials analyzed, coxibs caused a WMD point estimate increase in systolic and diastolic BP compared with placebo (3.85/1.06 mm Hg) and nonselective NSAIDs (2.83/1.34 mm Hg). Cyclooxygenase-2 inhibitors were associated with a nonsignificantly higher RR of causing hypertension compared with placebo (RR, 1.61; 95% confidence interval [CI], 0.91-2.84; P = .10) and nonselective NSAIDs (RR, 1.25; 95% CI, 0.87-1.78; P = .23). Rofecoxib induced a WMD point estimate increase in systolic BP (2.83 mm Hg) and a nonsignificantly higher risk of developing clinically important systolic BP elevation (RR, 1.50; 95% CI, 1.00-2.26; P = .05) compared with celecoxib.

Conclusions  Cyclooxygenase-2 inhibitors were associated with a point-estimate BP elevation compared with placebo and nonselective NSAIDs. There was a nonsignificantly higher incidence of developing hypertension compared with nonselective NSAIDs, as was observed with rofecoxib compared with celecoxib. These BP elevations may be clinically significant in relation to increased cardiovascular risk.Published online February 14, 2005 (doi:10.1001/archinte.165.5.ioi50013).

Figures in this Article

Nonsteroidal anti-inflammatory drugs (NSAIDs) are among the most widely prescribed pharmacological agents.1 However, major limitations to their use have been associated with gastrointestinal toxic effects. This has resulted in a significant preference to prescribe cyclooxygenase-2 inhibitors (coxibs) over conventional NSAIDs because of their apparent lower toxicity profile,2,3 despite most patients not meeting specified criteria for treatment.4,5

Additional toxic effects extending beyond the gastrointestinal tract have been identified. For example, rofecoxib has been associated with an increased risk of cardiovascular events.2 Furthermore, coxibs may be associated with systemic hypertension,610 as are nonselective NSAIDs.11,12 However, it is unknown how the coxibs compare with nonselective NSAIDs with respect to blood pressure (BP) effects and hypertension risk.

Available data on the potential association of coxibs with hypertension are conflicting because they are drawn from heterogeneous studies not specifically designed to address this issue.10,13 Safety data from trials involving coxibs have alluded to an increased risk of BP elevation or development of hypertension.2,6,10,1418 However, the study population involved in previous trials was widely heterogeneous, the comorbidity of hypertension among participants remained elusive in trials involving arthritis patients, and the studies themselves varied in trial design. As such, it remains uncertain what magnitude of effect coxibs actually have on BP. To our knowledge, no long-term prospective study has attempted to specifically address this question to date.

Elevated systolic BP is closely associated with increased cardiovascular events including heart failure, myocardial infarction, and death.19,20 The BP effects of coxibs are a question of major clinical and public health significance owing to widespread and increasing use of these agents. In the United States, at least 20 million people are affected by osteoarthritis,21 many with comorbid hypertension.22,23

To determine if coxibs are associated with higher hypertension risk compared with nonselective NSAIDs, we performed a meta-analysis of available published data as of May 2004. We compared the effects of coxibs and nonselective NSAIDs on BP elevation and the risk of hypertension.

OUTCOME MEASURES AND APPLIED DEFINITIONS

The outcome measures analyzed were (1) weighted mean difference (WMD) for systolic and diastolic BP, (2) relative risk (RR) of patients developing hypertension (for trials comparing coxibs and placebo and those comparing coxibs and nonselective NSAIDs), and (3) RR of patients developing a clinically important elevation in systolic or diastolic BP (for trials comparing rofecoxib and celecoxib).

For trials comparing coxibs with placebo or nonselective NSAIDs, hypertension was not directly defined and only assessed as part of the safety data obtained during trial observations.2,3,6,14,15,17,18,2431

For the 3 trials comparing rofecoxib and celecoxib, a clinically important elevation in systolic BP was defined as an increase of 20 mm Hg with an absolute value higher than 140 mm Hg at any time during the trial, while a clinically important elevation in diastolic BP was defined as an increase of 15 mm Hg with an absolute value higher than 90 mm Hg at any time during the trial.8,9,32

CRITERIA FOR INCLUSION AND EXCLUSION OF STUDIES FOR META-ANALYSIS

Prospective randomized controlled trials of parallel design, published in English, were considered for inclusion in this meta-analysis. Studies were included if the BP effects of coxibs and comparator groups were described (available data were classified into appropriate treatment groups where necessary).

Studies with fewer than 50 patients or involving treatment of less than 4 weeks’ duration were excluded. Trial participants with osteoarthritis and/or rheumatoid arthritis, with no restriction to age or sex, were considered for analysis. Studies with healthy volunteers were excluded. A flowchart detailing the reasons for exclusion of studies from consideration in this meta-analysis is provided, in accordance with the Quality of Reporting of Meta-analyses (QUOROM) statement33 (Figure 1).

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Figure 1.

Flow diagram of exclusions for trials under meta-analytic consideration. Coxib indicates cyclooxygenase-2 inhibitor; asterisk, search for randomized controlled trials (RCTs) were conducted via MEDLINE and Cochrane Database of Systematic Reviews; and dagger, 4 RCTs1618,32 were also identified through searches of conference abstracts of major rheumatology, cardiology, and gastroenterology in North America and Europe.

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SEARCH STRATEGY FOR STUDIES MEETING INCLUSION CRITERIA

We searched MEDLINE and the Cochrane Database of Systematic Reviews from date of inception through May 2004. Each search strategy included keywords related to trial design (meta-analysis, double blind, random allocation, randomized, clinical trial, placebo controlled) which were cross-linked with names of individual coxibs (celecoxib, rofecoxib, meloxicam, etoricoxib, and valdecoxib) and search terms of interest including NSAIDs, hypertension, blood pressure, and safety. Abstracts of major rheumatology, cardiology, and gastroenterology conferences from Europe and North America were reviewed, and bibliographies of all retrieved articles were consulted for additional publications. The Food and Drug Administration (FDA) Web site of currently licensed coxibs was reviewed for data concerning BP effects of coxibs.34,35 Data extraction was undertaken independently by one investigator (T.-J.A.). Formal quantitative data synthesis was undertaken in a blinded manner by another investigator (S.J.H.), in accordance with the QUOROM statement.33

TRIALS MEETING INCLUSION CRITERIA FOR ANALYSIS

Nineteen articles described random allocation of 1 or more coxibs and reported BP measurements.2,3,6,810,14,15,17,18,2432 Ten studies were randomized but not placebo-controlled, in which 2 or more NSAIDs were compared.2,3,8,9,17,18,24,25,28,32

Most studies did not have BP measurements as the primary outcome, since these were mainly gastrointestinal safety or arthritis efficacy studies. Twelve articles provided data concerning quantitative change in systolic BP,2,810,14,15,17,24,25,28,31,32 while 8 articles provided similar data regarding diastolic BP.2,10,14,17,24,25,31,32 Only 1 article provided uncertainty data (in the form of SE of the mean) for BP measurements.10 Sixteen articles provided actual numbers of patients who developed hypertension or experienced worsening of hypertension during the study.2,3,6,810,14,18,2532

All trials were categorized into 3 groups: (1) trials comparing coxibs with placebo (10 trials),6,10,14,15,26,27,2932 (2) trials comparing coxibs with conventional NSAIDs (13 trials),2,3,6,14,17,18,2429,31 and (3) trials comparing coxibs with another coxib (3 trials).8,9,32 Five studies involved arthritic patients with comorbid diabetes or hypertension.810,17,28 Because there were no apparent systematic differences between trials, we considered it clinically appropriate to pool their results.

STATISTICAL ANALYSIS

Available data were pooled using meta-analytical methods available in the STATA software program (version 7.0; Stata Corp, College Station, Tex). Weighted mean difference of both systolic and diastolic BP change was presented as a point estimate with no confidence interval of uncertainty (because uncertainty was not mentioned in most of the trials analyzed) using the Cohen method. Risk ratio estimates for the development of hypertension (the development of a clinically important elevation in either systolic or diastolic BP in the case of the rofecoxib vs celecoxib comparison) were presented as a point estimate, with 95% confidence intervals, using the Der Simonian and Laird (random effects) method.

STATA assigns relative weights to each individual study according to the contribution of each study to each meta-analysis performed.36,37 In the case of the Cohen method for continuous data, this is based on a function concerning the treatment group size. For the Der Simonian and Laird method concerning dichotomous data, this is based on a function concerning the treatment group size and the number of events observed.

Statistical significance was set at the α = .05 level on the basis of 2-way z tests implicitly related to the Der Simonian and Laird method only. Statistical significance could not be calculated for WMD calculated via the Cohen method because these results are point estimates only.

The meta-analysis included 45 451 patients from 19 trials (Table). In the trials providing sex stratification, there were overall more women studied, with a ratio of 2.5:1. Most patients had arthritis, of which 29 824 had osteoarthritis and 15 627 had rheumatoid arthritis. The number of patients in each category was (1) coxib vs placebo (n = 5786), (2) coxib vs NSAID (n = 40 888), and (3) rofecoxib vs celecoxib (n = 2833). The coxibs used in the trials were celecoxib, rofecoxib, and etoricoxib. Placebo was a comparator in 10 trials,6,10,14,15,26,27,2932 and the most commonly used nonselective NSAID comparator was naproxen, which was used in 9 trials.2,6,14,17,18,2629

Table Graphic Jump LocationTable. Characteristics of 19 Trials Meeting Inclusion Criteria for the Present Analysis

The WMD increases for systolic BP comparing coxibs with placebo, coxibs with a nonselective NSAID, and rofecoxib with celecoxib were 3.85 mm Hg, 2.83 mm Hg, and 2.83 mm Hg, respectively (Figure 2). The WMD increases for systolic BP comparing rofecoxib with placebo, rofecoxib with a nonselective NSAID, celecoxib with placebo, and celecoxib with a nonselective NSAID were 5.66 mm Hg, 3.32 mm Hg, 2.60 mm Hg, and 0.14 mm Hg, respectively (Figure 2).

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Figure 2.

Weighted mean difference (WMD) for systolic and diastolic blood pressure (BP). Coxib indicates cyclooxygenase-2 inhibitor; NSAID, nonsteroidal anti-inflammatory drug.

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The WMD increases for diastolic BP comparing coxibs with placebo and coxibs with a nonselective NSAID were 1.06 mm Hg and 1.34 mm Hg, respectively (Figure 2). The WMD increases for diastolic BP comparing rofecoxib with a nonselective NSAID, celecoxib with a nonselective NSAID, and celecoxib with placebo were 1.59 mm Hg, 0.15 mm Hg, and 0.99 mm Hg, respectively (Figure 2). The WMD for diastolic BP comparing rofecoxib vs celecoxib was not calculated because differences between the 2 agents have not been reported.8,9

The RR of developing hypertension for coxibs vs placebo (Figure 3) and coxibs vs nonselective NSAIDs (Figure 4) were 1.61 (95% confidence interval [CI], 0.91-2.84; P = .10) and 1.25 (95% CI, 0.87-1.78; P = .23), respectively. A breakdown of contribution for each individual coxib with respect to both of these RR calculations has also been provided (Figure 5 and Figure 6). In the trials comparing rofecoxib vs celecoxib, the RR of developing a clinically important elevation in systolic BP was 1.50 (95% CI, 1.00-2.26; P = .05), and the RR of developing a clinically important elevation in diastolic BP was 1.55 (95% CI, 0.91-2.63, P = .11).

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Figure 3.

Der Simonian and Laird relative risks (random effects) plot of developing hypertension for cyclooxygenase-2 inhibitors (coxibs) vs placebo. CI indicates confidence interval.

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Figure 4.

Der Simonian and Laird relative risks (random effects) plot of developing hypertension for cyclooxygenase-2 inhibitors (coxibs) vs nonselective nonsteroidal anti-inflammatory drugs.

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Figure 5.

Breakdown of contribution for each individual cyclooxygenase-2 inhibitor (coxib) with respect to the Der Simonian and Laird relative risks (random effects) plot of developing hypertension for coxibs vs placebo. CI indicates confidence interval.

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Figure 6.

Breakdown of contribution for each individual cyclooxygenase-2 inhibitor (coxib) with respect to the Der Simonian and Laird relative risks (random effects) plot of developing hypertension for coxibs vs nonselective nonsteroidal anti-inflammatory drugs (NSAIDs). CI indicates confidence interval.

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The development of coxibs, with their putative improved gastrointestinal safety profile, has led them to gain significant popularity as an alternative to nonselective NSAIDs for various musculoskeletal ailments.4,5,38 Our results demonstrate that coxibs cause both systolic and diastolic BP elevation compared with placebo and nonselective NSAIDs. Whether this elevation is clinically significant remains uncertain.

We note a disproportionate rise in systolic BP compared with diastolic BP, on average, with coxib use. This potential widened pulse pressure could have significant cardiovascular risk implications, as demonstrated in the Framingham study,39 which observed a very steep relationship between systolic BP and cardiovascular risk. Interestingly, for each defined level of systolic BP, the lower the diastolic BP, the greater the cardiovascular risk.39,40 The increase in systolic BP with a lesser change in diastolic BP observed, on average, among patients within these coxib studies over a relative short time may therefore be clinically significant in terms of potential cardiovascular risk.

Our analysis demonstrated a nonsignificantly increased risk of developing hypertension with coxib use compared with both placebo and nonselective NSAIDs. This risk was more pronounced when coxibs were compared with placebo (a 61% increase in RR) compared with nonselective NSAIDs (a 25% increase in RR). This is consistent with both coxibs and nonselective NSAIDs causing prostaglandin inhibition and possessing antinatriuretic and vasoconstrictor properties.12,41

The question that arises is whether these demonstrated changes are of clinical significance. Cyclooxygenase-2 inhibitors are increasingly used4,5,38 for musculoskeletal ailments, most commonly arthritis.42 The subgroup of patients most commonly afflicted are the elderly, often with cardiovascular comorbidities.23 These agents can potentially cause or exacerbate hypertension in this patient group. Although the incremental change in BP is small, the potential widening of pulse pressure39 and widespread use of these agents may have significant public health implications.

The other major observation of this investigation was that of a consistent increase in systolic and diastolic BP with rofecoxib in head-to-head trials vs celecoxib.8,9 There also appears to be a differential effect when reviewing the individual contributions of each coxib with respect to the development of hypertension (Figure 5 and Figure 6). These differential effects on BP by seemingly similar agents may relate to differences in pharmacokinetic and pharmacodynamic properties. Celecoxib has a shorter half-life than rofecoxib, with differential effects on BP still evident during 24-hour ambulatory BP monitoring.10,35,43 Rofecoxib is metabolized by cytosol reductase, which may (particularly at high doses) competitively inhibit the metabolism of aldosterone. This may further exacerbate fluid and sodium retention as well as vascular remodelling.44 Alternatively, celecoxib may also inhibit carbonic anhydrase, leading to a diuretic action that would offset some of the BP-elevating effect of cyclooxygenase-2 inhibition within the kidney.45

Analyses of this nature are subject to a variety of limitations. First, a number of studies have used a parallel study design, comparing 2 different NSAIDs (or doses) with a comparator. When combining the results, it was necessary to split the data into several classifications. For example, the study by Sower et al17 investigated 3 patient groups treated with different NSAIDs (rofecoxib, celecoxib, and naproxen). To conform to meta-analytical methods, the data were split into the following 2 comparisons: rofecoxib (25 mg/d) vs naproxen (1000 mg/d) and celecoxib (200 mg/d) vs naproxen (1000 mg/d). This has resulted in “double counting” of comparator group patients (in this example, naproxen, 1000 mg/d). Considering that the relative weights attributed to both comparisons within the context of the analysis were low (eg, a total of 4.6% of the total weight for the above example), this limitation is unlikely to impact greatly on interpretation of the results.

Inconsistencies in reporting styles among the studies analyzed necessitated some assumptions to be imputed regarding the data. For example, the study by Collantes et al14 reported a diastolic BP increase among their patients of <1.1 mm Hg, while the study by Emery et al25 reported a BP increase of 1-2 mm Hg. For the purposes of the present analysis, we used 1.1 mm Hg (worst case scenario) and 1.5 mm Hg (midpoint of the range), respectively, as the input data points for these particular studies.

The fact that BP was not a predetermined end point in the trials is another limitation of this analysis. Indeed, most outcomes concerning BP were ancillary considerations as part of the safety assessment for each compound and not part of the primary outcome measures. Most trials did not clearly define the term hypertension.2,3,6,810,14,15,17,18,24,25,28,3032 As such, it was difficult to determine if the definitions used in this meta-analysis were universally applied throughout the trials analyzed, which has potential impact on the accuracy of the data available.

Apart from the trials that looked at BP effects as an outcome measure, there was no clear description of techniques (or calibration of instruments) used to measure BP, particularly among the multicenter trials. Two trials used 24-hour ambulatory BP,10,34 whereas others presumably used clinic or office readings. There are limitations in regard to interpreting the analysis of such different methods of measuring BP.46

Similarly, some trials pooled for the analysis mention hypertension as an adverse event. Elevated BP could occur anywhere within each study and might not be related to NSAID effect. For example, a patient experiencing excessive pain during a study visit may have elevated BP and subsequently have been recorded as hypertensive. Given the generally similar analgesic efficacy of the active therapies, this would not be expected to make a significant difference to head-to-head comparisons.

Heterogeneity of the recruited study populations is another area of potential bias among the trials analyzed with respect to preexisting hypertension and use of antihypertensive medication. For instance, the proportion of patients in each study with hypertension at baseline was only noted in 5 of the studies analyzed.810,17,28 It is therefore difficult to determine whether these BP effects occurred in trial participants with preexisting hypertension or in those without (or in both categories). There was also a lack of information about whether the proportion of patients using different antihypertensive medications was evenly distributed. Normotensive patients usually have no significant BP increase when using anti-inflammatory agents,1 which may lead to an underestimate in our findings. Irrespective of the fact that these trials were randomized, the potential differences between hypertensive and normotensive patients increase the difficulty of establishing BP differences between treatment groups.

A further potential confounder to the individual trial data relates to the varying study designs used among trials, especially in regard to “wash-out” periods of previous NSAID therapy. Only 4 studies reported a “wash-out” period (mandatory in 3 studies9,14,30 and not specifically required in another25). It is possible that baseline BP and early subsequent measurements could be influenced by prior NSAID use, thereby affecting the relative BP changes during the study.

The possibility of sponsorship bias exists among the data available. Among the Pfizer/Pharmacia-sponsored trials,3,810,18 celecoxib was less likely to cause hypertension than rofecoxib, whereas in Merck Sharp Dohme–sponsored trials,2,6,15,24,28,30,32 the BP effects of the 2 agents appeared to be similar.

Finally, a meta-analysis is no substitute for a double-blind, randomized, placebo-controlled clinical trial that is adequately powered. However, it is difficult to design a trial that considers the copious number of different combinations and permutations of commercially available NSAIDs. Because such data are not yet available, we are reliant on retrospective analysis to guide us.

Despite the aforementioned caveats, this meta-analysis conforms to recommendations regarding size and careful searching to reduce publication bias.36,47 This enables these results to be, what we believe, the best possible summation of available information concerning the research question at hand.

The results of this meta-analysis demonstrate that, among the trials analyzed, there appears to be a somewhat greater BP elevation with coxibs compared with placebo and nonselective NSAIDs. Rofecoxib appears to confer a greater risk of developing hypertension and clinically important elevations in both systolic and diastolic BP compared with celecoxib. The effects observed may have most clinical significance in the elderly, in whom the prevalence of arthritis and hypertension is high.

Cyclooxygenase-2 inhibitors are a welcome addition to the therapeutic options in the treatment of arthritis, which remains a chronic, debilitating, and painful condition. However, their potential (and differential) effect on BP elevation requires caution in their use and warrants further investigation. Clinicians need to weigh the risks of improved gastrointestinal safety vs potential hazards of developing elevated BP when considering the use of these agents, especially in the elderly population.

Correspondence: Henry Krum, MBBS, PhD, FRACP, NHMRC Centre of Clinical Research Excellence in Therapeutics, Department of Epidemiology and Preventive Medicine and Department of Medicine, Monash University, Alfred Hospital, Melbourne, Victoria 3004, Australia (Henry.Krum@med.monash.edu.au).

Accepted for Publication: December 21, 2004; published online, February 14, 2005.

Financial Disclosure: Dr Liew has been a consultant to Pfizer, and Dr Krum has been a consultant to Pfizer, Merck, and Novartis regarding cyclooxygenase-2 inhibitors.

Funding/Support: Mr Haas currently receives assistance via a NHMRC Public Health Postgraduate Research Scholarship (scholarship application ID No. 237059). Dr Liew currently receives assistance via a Royal Australasian College of Physicians Postdoctoral Fellowship.

Pope  JEAnderson  JJFelson  DT A meta-analysis of the effects of nonsteroidal anti-inflammatory drugs on blood pressure. Arch Intern Med 1993;153477- 484
PubMed Link to Article
Bombardier  CLaine  LReicin  A  et al. VIGOR Study Group, Comparison of upper gastrointestinal toxicity of rofecoxib and naproxen in patients with rheumatoid arthritis. N Engl J Med 2000;3431520- 1528
PubMed Link to Article
Silverstein  FEFaich  GGoldstein  JL  et al.  Gastrointestinal toxicity with celecoxib vs nonsteroidal anti-inflammatory drugs for osteoarthritis and rheumatoid arthritis: the CLASS study: a randomized controlled trial: Celecoxib Long-term Arthritis Safety Study. JAMA 2000;2841247- 1255
PubMed Link to Article
Kerr  SJMant  AHorn  FEMcGeechan  KSayer  GP Lessons from early large-scale adoption of celecoxib and rofecoxib by Australian general practitioners. Med J Aust 2003;179403- 407
PubMed
 Pharmaceutical Benefits Schedule Item Statistics (last updated November 25, 2003) Health Insurance Commission (HIC). Available at: http://www.hic.gov.au/statistics/dyn_pbs/forms/pbs_tab1.shtml. Accessed June 2004
Hawkey  CJLaine  LSimon  TQuan  HShingo  SEvans  J Incidence of gastroduodenal ulcers in patients with rheumatoid arthritis after 12 weeks of rofecoxib, naproxen, or placebo: a multicentre, randomised, double blind study. Gut 2003;52820- 826
PubMed Link to Article
Konstam  MAWeir  MRReicin  A  et al.  Cardiovascular thrombotic events in controlled, clinical trials of rofecoxib. Circulation 2001;1042280- 2288
PubMed Link to Article
Whelton  AFort  JGPuma  JANormandin  DBello  AEVerburg  KM Cyclooxygenase-2–specific inhibitors and cardiorenal function: a randomized, controlled trial of celecoxib and rofecoxib in older hypertensive osteoarthritis patients—SUCCESS VI. Am J Ther 2001;885- 95
PubMed Link to Article
Whelton  AWhite  WBBello  AEPuma  JAFort  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;90959- 963
PubMed Link to Article
White  WBKent  JTaylor  AVerburg  KMLefkowith  JBWhelton  A Effects of celecoxib on ambulatory blood pressure in hypertensive patients on ACE inhibitors. Hypertension 2002;39929- 934
PubMed Link to Article
Johnson  AGNguyen  TVDay  RO Do nonsteroidal anti-inflammatory drugs affect blood pressure? a meta-analysis. Ann Intern Med 1994;121289- 300
PubMed Link to Article
Penning  TDTalley  JJBertenshaw  SR  et al.  Synthesis and biological evaluation of the 1,5-diarylpyrazole class of cyclooxygenase-2 inhibitors: identification of 4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benze nesulfonamide (SC-58635, celecoxib). J Med Chem 1997;401347- 1365
PubMed Link to Article
White  WBFaich  GWhelton  A  et al.  Comparison of thromboembolic events in patients treated with celecoxib, a cyclooxygenase-2 specific inhibitor, versus ibuprofen or diclofenac. Am J Cardiol 2002;89425- 430
PubMed Link to Article
Collantes  ECurtis  SPLee  KW  et al.  A multinational randomized, controlled, clinical trial of etoricoxib in the treatment of rheumatoid arthritis [ISRCTN25142273]. BMC Fam Pract 2002;310
PubMed Link to Article
Ehrich  EWSchnitzer  TJMcIlwain  H  et al. Rofecoxib Osteoarthritis Pilot Study Group, Effect of specific COX-2 inhibition in osteoarthritis of the knee: a 6 week double blind, placebo controlled pilot study of rofecoxib. J Rheumatol 1999;262438- 2447
PubMed
Geba  GP Hypertension and related adverse events among diabetic patients treated with rofecoxib or naproxen in the population of an osteroarthritis trial: ADVANTAGE.  Paper present at: American College of Rheumatology Annual Scientific Meeting October 24-28, 2003 Orlando, Fla.Abstract 1577
Sowers  JVanIngen  HWhite  WB  et al.  Rofecoxib, but not celecoxib, at doses providing equal OA efficacy, increases mean 24-hr systolic blood pressure in treated hypertensive patients with osteoarthritis and type 2 diabetes mellitus.  Paper presented at: Annual European Congress of Rheumatology, European League Against Rheumatism June 20, 2003 Lisbon, PortugalAbstract FRI0279
Whelton  A Celecoxib does not increase the risk of cardiac failure, edema, or hypertension compared to NSAIDs: results from SUCCESS I, a double blind, randomized trial in 13,274 OA patients.  Paper presented at: Annual European Congress of Rheumatology, European League Against Rheumatism June 16, 2001 Prague, Czech RepublicAbstract SAT0094
SHEP Cooperative Research Group, Prevention of stroke by antihypertensive drug treatment in older persons with isolated systolic hypertension: final results of the Systolic Hypertension in the Elderly Program (SHEP). JAMA 1991;2653255- 3264
PubMed Link to Article
Staessen  JAFagard  RThijs  L  et al. Systolic Hypertension in Europe (Syst-Eur) Trial Investigators, Randomised double-blind comparison of placebo and active treatment for older patients with isolated systolic hypertension. Lancet 1997;350757- 764
PubMed Link to Article
Lawrence  RCHelmick  CGArnett  FC  et al.  Estimates of the prevalence of arthritis and selected musculoskeletal disorders in the United States. Arthritis Rheum 1998;41778- 799
PubMed Link to Article
Harley  CWagner  S The prevalence of cardiorenal risk factors in patients prescribed nonsteroidal anti-inflammatory drugs: data from managed care. Clin Ther 2003;25139- 149
PubMed Link to Article
Houston  MC Nonsteroidal anti-inflammatory drugs and antihypertensives. Am J Med 1991;9042S- 47S
PubMed Link to Article
Cannon  GWCaldwell  JRHolt  P  et al. Rofecoxib Phase III Protocol 035 Study Group, Rofecoxib, a specific inhibitor of cyclooxygenase 2, with clinical efficacy comparable with that of diclofenac sodium: results of a one-year, randomized, clinical trial in patients with osteoarthritis of the knee and hip. Arthritis Rheum 2000;43978- 987
PubMed Link to Article
Emery  PZeidler  HKvien  TK  et al.  Celecoxib versus diclofenac in long-term management of rheumatoid arthritis: randomised double-blind comparison. Lancet 1999;3542106- 2111
PubMed Link to Article
Hunt  RHHarper  SCallegari  P  et al.  Complementary studies of the gastrointestinal safety of the cyclo-oxygenase-2–selective inhibitor etoricoxib. Aliment Pharmacol Ther 2003;17201- 210
PubMed Link to Article
Leung  ATMalmstrom  KGallacher  AE  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;1849- 58
PubMed Link to Article
Lisse  JRPerlman  MJohansson  G  et al.  Gastrointestinal tolerability and effectiveness of rofecoxib versus naproxen in the treatment of osteoarthritis: a randomized, controlled trial. Ann Intern Med 2003;139539- 546
PubMed Link to Article
Matsumoto  AKMelian  AMandel  DR  et al.  A randomized, controlled, clinical trial of etoricoxib in the treatment of rheumatoid arthritis. J Rheumatol 2002;291623- 1630
PubMed
Schnitzer  TJTruitt  KFleischmann  R  et al. Phase II Rofecoxib Rheumatoid Arthritis Study Group, The safety profile, tolerability, and effective dose range of rofecoxib in the treatment of rheumatoid arthritis. Clin Ther 1999;211688- 1702
PubMed Link to Article
Simon  LSWeaver  ALGraham  DY  et al.  Anti-inflammatory and upper gastrointestinal effects of celecoxib in rheumatoid arthritis: a randomized controlled trial. JAMA 1999;2821921- 1928
PubMed Link to Article
Geba  GP Comparative blood pressure effects of rofecoxib, celecoxib, and placebo in patients with osteoarthritis (OA): a randomized controlled trial.  Paper presented at: Annual European Congress of Rheumatology, European League Against Rheumatism June 16, 2001 Prague, Czech RepublicAbstract No. SAT0095
Moher  DCook  DJEastwood  SOlkin  IRennie  DStroup  DF Improving the quality of reports of meta-analyses of randomised controlled trials: the QUOROM statement: Quality of Reporting of Meta-analyses. Lancet 1999;3541896- 1900
PubMed Link to Article
 NDA 20-998/S-009 (Celecoxib): results from CLASS Medical officer review.  February2001;Available at: http://www.fda.gov/ohrms/dockets/ac/01/briefing/3677b1_03_med.pdf. Accessed June 2004
 NDA 21-042 and 21-052 (rofecoxib): results from VIGOR FDA Advisory Committee Background Information.  February2001;Available at: http://www.fda.gov/ohrms/dockets/ac/01/briefing/3677b2_01_merck.pdf. Accessed June 2004
Deeks  JJAltman  DGBradburn  MJ Statistical methods for examining heterogeneity and combining results from several studies in meta-analysis Egger  MSmith  GDAltman  DGeds.Systematic Reviews in Health Care: Meta-analysis in Context 2nd ed. London, England BMJ Publishing Group2001;285- 312
Sterne  JACBradburn  MJEgger  M Meta-analysis in Stata. Egger  MSmith  GDAltman  DGSystematic Reviews in Health Care: Meta-analysis in Context 2nd ed. London, England BMJ Publishing Group2001;347- 69
Landsberg  PGPillans  PIRadford  JM Evaluation of cyclooxygenase 2 inhibitor use in patients admitted to a large teaching hospital. Intern Med J 2003;33225- 228
PubMed Link to Article
Kannel  WB Fifty years of Framingham Study contributions to understanding hypertension. J Hum Hypertens 2000;1483- 90
PubMed Link to Article
Leonetti  GCuspidi  CFacchini  MStramba-Badiale  M Is systolic pressure a better target for antihypertensive treatment than diastolic pressure? J Hypertens Suppl 2000;18S13- S20
PubMed
Morgan  TOAnderson  ABertram  D Effect of indomethacin on blood pressure in elderly people with essential hypertension well controlled on amlodipine or enalapril. Am J Hypertens 2000;131161- 1167
PubMed Link to Article
Cutts  CLaCaze  ATett  S A clinical audit of the prescribing of celecoxib and rofecoxib in Australian rural general practice. Br J Clin Pharmacol 2002;54522- 527
PubMed Link to Article
 VIOXX (rofecoxib) [package insert].  West Point, Pa Merck and Co, Inc2001;
Liew  DKrum  H The role of aldosterone receptor blockade in the management of cardiovascular disease. Curr Opin Investig Drugs 2002;31468- 1473
PubMed
FitzGerald  GAPatrono  C The coxibs, selective inhibitors of cyclooxygenase-2. N Engl J Med 2001;345433- 442
PubMed Link to Article
Chobanian  AVBakris  GLBlack  HR  et al.  The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: the JNC 7 report. JAMA 2003;2892560- 2572
PubMed Link to Article
Flather  MDFarkouh  MEPogue  JMYusuf  S Strengths and limitations of meta-analysis: larger studies may be more reliable. Control Clin Trials 1997;18568- 579
PubMed Link to Article

Figures

Place holder to copy figure label and caption
Figure 1.

Flow diagram of exclusions for trials under meta-analytic consideration. Coxib indicates cyclooxygenase-2 inhibitor; asterisk, search for randomized controlled trials (RCTs) were conducted via MEDLINE and Cochrane Database of Systematic Reviews; and dagger, 4 RCTs1618,32 were also identified through searches of conference abstracts of major rheumatology, cardiology, and gastroenterology in North America and Europe.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 2.

Weighted mean difference (WMD) for systolic and diastolic blood pressure (BP). Coxib indicates cyclooxygenase-2 inhibitor; NSAID, nonsteroidal anti-inflammatory drug.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 3.

Der Simonian and Laird relative risks (random effects) plot of developing hypertension for cyclooxygenase-2 inhibitors (coxibs) vs placebo. CI indicates confidence interval.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 4.

Der Simonian and Laird relative risks (random effects) plot of developing hypertension for cyclooxygenase-2 inhibitors (coxibs) vs nonselective nonsteroidal anti-inflammatory drugs.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 5.

Breakdown of contribution for each individual cyclooxygenase-2 inhibitor (coxib) with respect to the Der Simonian and Laird relative risks (random effects) plot of developing hypertension for coxibs vs placebo. CI indicates confidence interval.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 6.

Breakdown of contribution for each individual cyclooxygenase-2 inhibitor (coxib) with respect to the Der Simonian and Laird relative risks (random effects) plot of developing hypertension for coxibs vs nonselective nonsteroidal anti-inflammatory drugs (NSAIDs). CI indicates confidence interval.

Graphic Jump Location

Tables

Table Graphic Jump LocationTable. Characteristics of 19 Trials Meeting Inclusion Criteria for the Present Analysis

References

Pope  JEAnderson  JJFelson  DT A meta-analysis of the effects of nonsteroidal anti-inflammatory drugs on blood pressure. Arch Intern Med 1993;153477- 484
PubMed Link to Article
Bombardier  CLaine  LReicin  A  et al. VIGOR Study Group, Comparison of upper gastrointestinal toxicity of rofecoxib and naproxen in patients with rheumatoid arthritis. N Engl J Med 2000;3431520- 1528
PubMed Link to Article
Silverstein  FEFaich  GGoldstein  JL  et al.  Gastrointestinal toxicity with celecoxib vs nonsteroidal anti-inflammatory drugs for osteoarthritis and rheumatoid arthritis: the CLASS study: a randomized controlled trial: Celecoxib Long-term Arthritis Safety Study. JAMA 2000;2841247- 1255
PubMed Link to Article
Kerr  SJMant  AHorn  FEMcGeechan  KSayer  GP Lessons from early large-scale adoption of celecoxib and rofecoxib by Australian general practitioners. Med J Aust 2003;179403- 407
PubMed
 Pharmaceutical Benefits Schedule Item Statistics (last updated November 25, 2003) Health Insurance Commission (HIC). Available at: http://www.hic.gov.au/statistics/dyn_pbs/forms/pbs_tab1.shtml. Accessed June 2004
Hawkey  CJLaine  LSimon  TQuan  HShingo  SEvans  J Incidence of gastroduodenal ulcers in patients with rheumatoid arthritis after 12 weeks of rofecoxib, naproxen, or placebo: a multicentre, randomised, double blind study. Gut 2003;52820- 826
PubMed Link to Article
Konstam  MAWeir  MRReicin  A  et al.  Cardiovascular thrombotic events in controlled, clinical trials of rofecoxib. Circulation 2001;1042280- 2288
PubMed Link to Article
Whelton  AFort  JGPuma  JANormandin  DBello  AEVerburg  KM Cyclooxygenase-2–specific inhibitors and cardiorenal function: a randomized, controlled trial of celecoxib and rofecoxib in older hypertensive osteoarthritis patients—SUCCESS VI. Am J Ther 2001;885- 95
PubMed Link to Article
Whelton  AWhite  WBBello  AEPuma  JAFort  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;90959- 963
PubMed Link to Article
White  WBKent  JTaylor  AVerburg  KMLefkowith  JBWhelton  A Effects of celecoxib on ambulatory blood pressure in hypertensive patients on ACE inhibitors. Hypertension 2002;39929- 934
PubMed Link to Article
Johnson  AGNguyen  TVDay  RO Do nonsteroidal anti-inflammatory drugs affect blood pressure? a meta-analysis. Ann Intern Med 1994;121289- 300
PubMed Link to Article
Penning  TDTalley  JJBertenshaw  SR  et al.  Synthesis and biological evaluation of the 1,5-diarylpyrazole class of cyclooxygenase-2 inhibitors: identification of 4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benze nesulfonamide (SC-58635, celecoxib). J Med Chem 1997;401347- 1365
PubMed Link to Article
White  WBFaich  GWhelton  A  et al.  Comparison of thromboembolic events in patients treated with celecoxib, a cyclooxygenase-2 specific inhibitor, versus ibuprofen or diclofenac. Am J Cardiol 2002;89425- 430
PubMed Link to Article
Collantes  ECurtis  SPLee  KW  et al.  A multinational randomized, controlled, clinical trial of etoricoxib in the treatment of rheumatoid arthritis [ISRCTN25142273]. BMC Fam Pract 2002;310
PubMed Link to Article
Ehrich  EWSchnitzer  TJMcIlwain  H  et al. Rofecoxib Osteoarthritis Pilot Study Group, Effect of specific COX-2 inhibition in osteoarthritis of the knee: a 6 week double blind, placebo controlled pilot study of rofecoxib. J Rheumatol 1999;262438- 2447
PubMed
Geba  GP Hypertension and related adverse events among diabetic patients treated with rofecoxib or naproxen in the population of an osteroarthritis trial: ADVANTAGE.  Paper present at: American College of Rheumatology Annual Scientific Meeting October 24-28, 2003 Orlando, Fla.Abstract 1577
Sowers  JVanIngen  HWhite  WB  et al.  Rofecoxib, but not celecoxib, at doses providing equal OA efficacy, increases mean 24-hr systolic blood pressure in treated hypertensive patients with osteoarthritis and type 2 diabetes mellitus.  Paper presented at: Annual European Congress of Rheumatology, European League Against Rheumatism June 20, 2003 Lisbon, PortugalAbstract FRI0279
Whelton  A Celecoxib does not increase the risk of cardiac failure, edema, or hypertension compared to NSAIDs: results from SUCCESS I, a double blind, randomized trial in 13,274 OA patients.  Paper presented at: Annual European Congress of Rheumatology, European League Against Rheumatism June 16, 2001 Prague, Czech RepublicAbstract SAT0094
SHEP Cooperative Research Group, Prevention of stroke by antihypertensive drug treatment in older persons with isolated systolic hypertension: final results of the Systolic Hypertension in the Elderly Program (SHEP). JAMA 1991;2653255- 3264
PubMed Link to Article
Staessen  JAFagard  RThijs  L  et al. Systolic Hypertension in Europe (Syst-Eur) Trial Investigators, Randomised double-blind comparison of placebo and active treatment for older patients with isolated systolic hypertension. Lancet 1997;350757- 764
PubMed Link to Article
Lawrence  RCHelmick  CGArnett  FC  et al.  Estimates of the prevalence of arthritis and selected musculoskeletal disorders in the United States. Arthritis Rheum 1998;41778- 799
PubMed Link to Article
Harley  CWagner  S The prevalence of cardiorenal risk factors in patients prescribed nonsteroidal anti-inflammatory drugs: data from managed care. Clin Ther 2003;25139- 149
PubMed Link to Article
Houston  MC Nonsteroidal anti-inflammatory drugs and antihypertensives. Am J Med 1991;9042S- 47S
PubMed Link to Article
Cannon  GWCaldwell  JRHolt  P  et al. Rofecoxib Phase III Protocol 035 Study Group, Rofecoxib, a specific inhibitor of cyclooxygenase 2, with clinical efficacy comparable with that of diclofenac sodium: results of a one-year, randomized, clinical trial in patients with osteoarthritis of the knee and hip. Arthritis Rheum 2000;43978- 987
PubMed Link to Article
Emery  PZeidler  HKvien  TK  et al.  Celecoxib versus diclofenac in long-term management of rheumatoid arthritis: randomised double-blind comparison. Lancet 1999;3542106- 2111
PubMed Link to Article
Hunt  RHHarper  SCallegari  P  et al.  Complementary studies of the gastrointestinal safety of the cyclo-oxygenase-2–selective inhibitor etoricoxib. Aliment Pharmacol Ther 2003;17201- 210
PubMed Link to Article
Leung  ATMalmstrom  KGallacher  AE  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;1849- 58
PubMed Link to Article
Lisse  JRPerlman  MJohansson  G  et al.  Gastrointestinal tolerability and effectiveness of rofecoxib versus naproxen in the treatment of osteoarthritis: a randomized, controlled trial. Ann Intern Med 2003;139539- 546
PubMed Link to Article
Matsumoto  AKMelian  AMandel  DR  et al.  A randomized, controlled, clinical trial of etoricoxib in the treatment of rheumatoid arthritis. J Rheumatol 2002;291623- 1630
PubMed
Schnitzer  TJTruitt  KFleischmann  R  et al. Phase II Rofecoxib Rheumatoid Arthritis Study Group, The safety profile, tolerability, and effective dose range of rofecoxib in the treatment of rheumatoid arthritis. Clin Ther 1999;211688- 1702
PubMed Link to Article
Simon  LSWeaver  ALGraham  DY  et al.  Anti-inflammatory and upper gastrointestinal effects of celecoxib in rheumatoid arthritis: a randomized controlled trial. JAMA 1999;2821921- 1928
PubMed Link to Article
Geba  GP Comparative blood pressure effects of rofecoxib, celecoxib, and placebo in patients with osteoarthritis (OA): a randomized controlled trial.  Paper presented at: Annual European Congress of Rheumatology, European League Against Rheumatism June 16, 2001 Prague, Czech RepublicAbstract No. SAT0095
Moher  DCook  DJEastwood  SOlkin  IRennie  DStroup  DF Improving the quality of reports of meta-analyses of randomised controlled trials: the QUOROM statement: Quality of Reporting of Meta-analyses. Lancet 1999;3541896- 1900
PubMed Link to Article
 NDA 20-998/S-009 (Celecoxib): results from CLASS Medical officer review.  February2001;Available at: http://www.fda.gov/ohrms/dockets/ac/01/briefing/3677b1_03_med.pdf. Accessed June 2004
 NDA 21-042 and 21-052 (rofecoxib): results from VIGOR FDA Advisory Committee Background Information.  February2001;Available at: http://www.fda.gov/ohrms/dockets/ac/01/briefing/3677b2_01_merck.pdf. Accessed June 2004
Deeks  JJAltman  DGBradburn  MJ Statistical methods for examining heterogeneity and combining results from several studies in meta-analysis Egger  MSmith  GDAltman  DGeds.Systematic Reviews in Health Care: Meta-analysis in Context 2nd ed. London, England BMJ Publishing Group2001;285- 312
Sterne  JACBradburn  MJEgger  M Meta-analysis in Stata. Egger  MSmith  GDAltman  DGSystematic Reviews in Health Care: Meta-analysis in Context 2nd ed. London, England BMJ Publishing Group2001;347- 69
Landsberg  PGPillans  PIRadford  JM Evaluation of cyclooxygenase 2 inhibitor use in patients admitted to a large teaching hospital. Intern Med J 2003;33225- 228
PubMed Link to Article
Kannel  WB Fifty years of Framingham Study contributions to understanding hypertension. J Hum Hypertens 2000;1483- 90
PubMed Link to Article
Leonetti  GCuspidi  CFacchini  MStramba-Badiale  M Is systolic pressure a better target for antihypertensive treatment than diastolic pressure? J Hypertens Suppl 2000;18S13- S20
PubMed
Morgan  TOAnderson  ABertram  D Effect of indomethacin on blood pressure in elderly people with essential hypertension well controlled on amlodipine or enalapril. Am J Hypertens 2000;131161- 1167
PubMed Link to Article
Cutts  CLaCaze  ATett  S A clinical audit of the prescribing of celecoxib and rofecoxib in Australian rural general practice. Br J Clin Pharmacol 2002;54522- 527
PubMed Link to Article
 VIOXX (rofecoxib) [package insert].  West Point, Pa Merck and Co, Inc2001;
Liew  DKrum  H The role of aldosterone receptor blockade in the management of cardiovascular disease. Curr Opin Investig Drugs 2002;31468- 1473
PubMed
FitzGerald  GAPatrono  C The coxibs, selective inhibitors of cyclooxygenase-2. N Engl J Med 2001;345433- 442
PubMed Link to Article
Chobanian  AVBakris  GLBlack  HR  et al.  The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: the JNC 7 report. JAMA 2003;2892560- 2572
PubMed Link to Article
Flather  MDFarkouh  MEPogue  JMYusuf  S Strengths and limitations of meta-analysis: larger studies may be more reliable. Control Clin Trials 1997;18568- 579
PubMed Link to Article

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