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Efficacy and safety of etoricoxib in the treatment of osteoarthritis Expert Rev. Clin. Pharmacol. 1(3), 345–355 (2008)

Anthony Sebba 36388 US Hwy 19 N, Palm Harbor, FL 34684, USA Tel.: +1 727 773 9793 Fax: +1 727 773 0674 [email protected]

Osteoarthritis is a progressive disease that affects millions of people worldwide, but for which there are no curative options and indeed a limited number of medical treatment options. The American College of Rheumatology recommendations suggest administering either a traditional NSAID or a COX-2-selective inhibitor for pain relief. Traditional NSAIDs, such as naproxen, may have a higher risk of gastrointestinal (GI) events, while COX-2-selective inhibitors may have a higher risk of thrombotic cardiovascular (CV) events (with traditional NSAIDs and COX-2-selective agents appearing to have a similar CV risk). Etoricoxib, introduced in 2002, has been approved in over 60 countries worldwide for osteoarthritis. Large-scale studies addressing the efficacy, GI tolerability and potential for CV events with etoricoxib have now been published. Several patient types appear to benefit from etoricoxib, including those with CV risk factors and those requiring gastroprotective agents. In patients with CV risk factors, the benefits and risks of all NSAIDs should be weighed carefully in each patient, balancing the potential risks of treatment against the potential relief for pain and disability. KEYWORDS: cardiovascular risk • COX-2-selective inhibitor • etoricoxib • gastrointestinal tolerability • nonsteroidal anti-inflammatory • NSAID

Osteoarthritis (OA) is the most common articular disorder, affecting millions of people worldwide [1,2]. The disease process is usually slowly progressive, causing reduced mobility and a negative impact on daily activities [2]. Radiographically, OA can be seen in the majority of adults by 40 years of age and, by the age of 60 years, 10% of all adults are disabled by OA [3]. The economic impact in the USA alone is greater than US$60 billion per year [3]. Options for therapy to reduce the pain induced by OA are limited and include nonselective NSAIDs, COX-2-selective inhibitors and, sometimes, opioids. The American College of Rheumatology (ACR) recommends administering either a traditional NSAID or a COX-2selective inhibitor for pain relief in patients with OA [4]. Responses vary among individual patients so that no single therapy is optimal for all patients. The major single issue regarding the use of traditional NSAIDs has been considered to be the risk of death or serious adverse effects due to gastrointestinal (GI) bleeding [5,6].

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10.1586/17512433.1.3.345

The COX-2 agents were introduced to reduce the risk of serious GI events, including death, and have been carefully evaluated in several studies (Celecoxib long-term Arthritis Safety Study [CLASS], Vioxx Outcomes Research [VIGOR], Therapeutic Research and Gastrointestinal Event Trial [TARGET], Multinational Etoricoxib and Diclofenac Arthritis Long-Term [MEDAL] and Etoricoxib Versus Diclofenac Sodium Gastrointestinal Tolerability and Effectiveness [EDGE]) in an attempt to address some of these GI issues [7–11]. It appears that traditional NSAIDs (e.g., diclofenac, ibuprofen and naproxen) will have a higher risk of GI events compared with placebo, while some COX-2-selective inhibitors in some studies have been associated with a higher risk of cardiovascular (CV) events. There is thus clinical tension in weighing the risk of serious GI and CV events with use of these agents. Etoricoxib was introduced in 2002 and is currently approved in 64 countries worldwide for multiple indications, including OA. This article will focus on the attributes of etoricoxib for

© 2008 Expert Reviews Ltd

ISSN 1751-2433

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patients with OA in the context of other treatment options against which it has been tested in comparative clinical trials (e.g., naproxen, diclofenac and ibuprofen).

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Pharmacokinetics

COX-1 is constitutively expressed and has an impact on platelet function, GI mucosa protection and renal hemodynamic regulation. COX-2 is inducible and affects prostaglandin production in response to inflammatory stimulation. COX-2-selective inhibitors were developed for improved GI tolerability. Etoricoxib, 5-chloro-6´-methyl-3-(4-(methylsulfonyl)phenyl)-2,3´-bipyridine, is a COX-2-selective inhibitor that does not contain the sulfonamide associated with hypersensitivity reactions (FIGURE 1). It is, rather, a sulfone (which may also be associated with hypersensitivity reactions). Etoricoxib is completely absorbed after oral administration (Tmax = 1 h), with 100% bioavailability [12]. Linear pharmacokinetics are observed up to 120 mg. The elimination half-life (∼22 h) supports once-daily dosing [13]. Steady-state levels are apparent after 7 days of treatment. Patients with creatinine clearance less than 30 ml/min should not be given etoricoxib; COX-2 is produced renally constitutively, thus all selective NSAIDs can have renal effects [14]. Patients with mild insufficiency may receive etoricoxib 60 mg/day, compared with every other day for those with moderate insufficiency [15]. Etoricoxib is extensively metabolized by the cytochrome P450 (CYP) system [16]. This may lead to a reduced potential for drug interactions with CYP inhibitors and an absence of interpatient pharmacokinetic differences [17]. Etoricoxib drug interactions have been studied and reviewed extensively [17–19]. Briefly, a 13% increase in prothrombin time was reported with warfarin, there is the potential for interaction with antihypertensives, a 65% decrease in etoricoxib concentrations occurred with rifampin and increased estradiol levels have occurred when etoricoxib and an oral contraceptive are administered concurrently [17]. Etoricoxib did not affect the antiplatelet activity of low-dose aspirin [19]. Pharmacotherapy for OA

Osteoarthritis is often perceived as a relatively milder form of arthritis but, from the individual patient’s perspective, pain and disability can be profound. While there are nonpharmaceutical options for OA (e.g., physical therapy and total joint replacement), medical treatments are currently limited. Options include no treatment, acetaminophen, NSAIDs (both nonselective and COX-2-selective inhibitors) and the milder opioid analgesics. With currently available treatments, pain control is frequently suboptimal and many require surgical intervention for relief. The ACR guidelines advise administering a COX-2-selective inhibitor to patients with OA who have had inadequate response to nonpharmacologic therapy and acetaminophen, those who require greater pain relief or have inflammation, those who wish to continue acetaminophen therapy adjunctively and those at high risk of GI toxicity or bleeding [4]. However, owing to the

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Figure 1. Etoricoxib.

apparent increase in CV risk, ACR guidelines also advise that physicians weigh the relative risks and benefits of COX-2-selective inhibitors, which appear to be associated with a higher relative risk of CV events compared with placebo [1]. In the USA, labeling for all NSAIDs, both traditional and COX-2 selective, with the exception of aspirin, states that these agents carry an increased risk of CV events following long-term use [101]. The European League Against Rheumatism (EULAR) conducted a review of literature through 2002 and formulated ten recommendations for management of OA of the knee using an evidencebased approach and expert opinion [20]. EULAR recommended NSAIDs in patients unresponsive to acetaminophen, as well as nonselective NSAIDs and effective gastroprotective agents, or selective COX-2 inhibitors for patients with increased GI risk [20]. There are two types of NSAIDs: traditional (or nonselective) NSAIDs and the COX-2-selective inhibitors (which can perhaps be regarded as a subcategory). Traditional NSAIDs inhibit both the COX-1 and COX-2 enzyme isoforms, while COX-2-selective inhibitors are specific for the COX-2 isoform. Therapeutically, these appear similar in efficacy [1,21]. The important variation among all classes of NSAIDs resides in safety and tolerability issues, making this a key factor in treatment selection. Inhibition of the COX-1 isoform has been associated with gastroduodenal ulceration and bleeding [5,6]. COX-2-selective inhibitors carry a reduced relative risk of upper GI events, [10,11,22–25] serious and nonserious (as in TARGET and VIGOR), and, importantly, a lower risk of lower GI mucosal damage and adverse events [26–32]. The major concern for clinicians and patients with respect to COX-2-selective inhibitors has been the increased risk of CV events compared with placebo [32,33]. This led to the voluntary withdrawal of rofecoxib in 2004 due to CV adverse event data in the Adenomatous Polyp Prevention on Vioxx (APPROVe) trial [32]. The US FDA has requested revised labeling for all NSAIDs except aspirin to reflect a potentially increased risk of CV events with long-term use [5]. The EMEA has not required labeling changes for traditional NSAIDs with regard to CV events [102]. However, newer COX-2-selective

Expert Rev. Clin. Pharmacol. 1(3), (2008)

Etoricoxib in the treatment of osteoarthritis

Drug Profile

inhibitors are available that may provide the correct balance of efficacy and tolerability for certain patients with OA. Etoricoxib is one such option.

naproxen 500 mg twice daily (ACR 20 response 39%) or placebo (ACR 20 response 21%) in all primary end points, including swollen and tender joint counts, and patient and investigator assessment of disease activity (p < 0.05) [41].

Etoricoxib clinical trial results: efficacy

Etoricoxib versus diclofenac

Dosing

Patients were randomized to etoricoxib 30, 60 or 90 mg/day or diclofenac 50 mg three-times daily over 12 weeks [35]. The study was extended to 190 weeks with all patients receiving etoricoxib 60 mg/day or diclofenac. Etoricoxib efficacy was maintained for up to 190 weeks. Etoricoxib 60 mg had statistically comparable efficacy to diclofenac for all study end points. In a 6-week, randomized, double-blind, placebo-controlled study of etoricoxib 60 mg/day versus diclofenac 50 mg threetimes daily, etoricoxib was significantly more effective than diclofenac in terms of PGART within 4 h of dosing (p = 0.007) in patients with knee or hip OA (n = 516) [42]. By day 2, both agents exhibited comparable efficacy in terms of both WOMAC and PGART.

A two-part dose-ranging study of etoricoxib (5–90 mg/day) began with a 14-week, double-blind, placebo-controlled period where etoricoxib 60 mg was found to provide the best efficacy according to the Western Ontario and McMaster’s University OA index (WOMAC) pain scale, patient global assessment of disease activity (PGART) and investigator global assessment of disease status [34]. Patients were then enrolled in the second portion of the study, where patients receiving etoricoxib 5 or 10 mg/day or placebo were randomized to etoricoxib 30, 60 or 90 mg/day or diclofenac 50 mg three-times daily over 12 weeks [35]. The study was extended to 190 weeks with all patients (n = 259) receiving etoricoxib 60 mg/day or diclofenac. Etoricoxib efficacy was maintained for up to 190 weeks. Etoricoxib 60 mg had statistically comparable efficacy to diclofenac for all study end points. Comparator trials

Of the 20 or more published clinical studies concerning etoricoxib, several early studies comparing etoricoxib with naproxen or diclofenac in patients with OA are of particular interest [34–40]. As a group, these studies found etoricoxib to have efficacy comparable to naproxen and diclofenac. Etoricoxib versus naproxen

Reginster et al. reported results of two 138-week, randomized, double-blind, parallel-group studies of etoricoxib 60 mg/day versus naproxen 500 mg/day in 997 patients with OA of the hip and knee [40]. Patients in both treatment groups demonstrated similar long-term efficacy based on patient global assessment of disease status and the WOMAC. The study was not powered to evaluate differences in GI or events. Etoricoxib 60 mg/day was found to have efficacy similar to naproxen 500 mg twice daily in two 12-week, randomized, multicenter, double-blind, placebo-controlled studies of adults (n = 501 and n = 496, respectively) with OA of the knee or hip in terms of WOMAC [36,37]. One of these studies allowed placebo-group patients to receive either etoricoxib or naproxen over 40 weeks [36,39,40]. The efficacy of each agent was maintained, with no changes in WOMAC subscales, and significant improvements in short form-36 subscales with both etoricoxib and naproxen compared with placebo [39,40]. It is perhaps of interest that etoricoxib has shown superior efficacy to naproxen in one trial in rheumatoid arthritis (RA). A 12-week, double-blind, placebo- and comparator-controlled trial reported that etoricoxib 90 mg/day (ACR 20 response 53%) provided significantly greater improvements than

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Etoricoxib versus celecoxib

Etoricoxib is used in most countries at a dose of 60 mg/day for OA. A study of low-dose etoricoxib (30 mg/day) was compared with celecoxib 200 mg/day in two identically designed multicenter, 26-week, double-blind, placebo-controlled studies of patients with OA of the knee and hip [43]. Each study was initiated with a 12-week placebo-controlled period followed by a 14-week period where all patients received either etoricoxib or celecoxib. Etoricoxib at this lower dose was noninferior to celecoxib for all primary end points, including WOMAC pain index and physical function subscales and Patient Global Assessment of Disease Status (PGADS), and there were fewer dropouts due to lack of effect due to etoricoxib. Etoricoxib clinical trial results: safety

The aforementioned studies indicate that etoricoxib is comparable to the traditional NSAIDs naproxen and diclofenac in treating OA. The initial clinical studies reported all three agents as being generally well tolerated, with a trend toward more GI symptoms with traditional NSAIDs than with COX-2-selective inhibitors. The in-depth studies now described have provided a clearer picture of the safety and tolerability of etoricoxib (TABLE 1). The MEDAL program

The MEDAL program is composed of three randomized, controlled, double-blind trials: Etoricoxib Versus Diclofenac Sodium Gastrointestinal Tolerability and Effectiveness (EDGE), EDGE II and Multinational Etoricoxib and Diclofenac Arthritis Long-term (MEDAL) [7]. The study was an attempt to evaluate the CV safety and compare the precise relative risk of CV events of etoricoxib with diclofenac in

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Table 1. Safety outcomes of etoricoxib and diclofenac in the MEDAL program. Safety outcome

Event rate (hazard ratio) Etoricoxib

Diclofenac

Thrombotic events

1.24

1.3 (0.95)

Arterial thrombotic events

1.05

1.1 (0.96)

APTC events

0.84

0.87 (0.96)

Cardiac events

0.71

0.78 (0.90)

Cerobrovascular events

0.34

0.32 (1.08)

Peripheral vascular events

0.20

0.22 (0.92)

GI: complicated events

0.30

0.32 (0.91)

Perforation

0.02

0.04

Obstruction

0.01

0.01

Bleeding

0.27

0.28

GI: uncomplicated events

0.37

0.65 (0.57)

Bleeding

0.02

0.02

Ulcer

0.35

0.63

CV

APTC: Anti-Platelet Trialists' Collaboration; CV: Cardiovascular; GI: Gastrointestinal; MEDAL: Multinational Etoricoxib and Diclofenac Arthritis Long-Term. Data from [7,9].

patients with OA and RA. Diclofenac was selected partly due to a wish to avoid interference with the antiplatelet effect of ASA (such as that which occurs with ibuprofen and naproxen). This study was designed to be a ‘real-world’ analysis and patients were encouraged to take aspirin appropriately for CV risk and proton pump inhibitors (PPIs) for GI risk. A total of 34,701 patients were enrolled (24,913 with OA) in MEDAL and received treatment for approximately 18 months. This study was easily the largest randomized, controlled trial in OA ever conducted. There were 320 patients with thrombotic events in the etoricoxib group compared with 323 in the diclofenac group, translating to event rates of 1.24 and 1.30 per 100 patient-years (hazard ratio [HR]: 0.95; 95% confidence interval [CI]: 0.81–1.11), respectively. Myocardial infarction was the most common event, with rates of 0.43 and 0.49 per 100 patientyears in the etoricoxib and diclofenac groups. Rates of fatal CV events were 0.17 per 100 patient-years in both groups. Longterm use of etoricoxib and diclofenac thus resulted in similar rates of CV events in MEDAL. In another study, the relative risk of CV events was less with etoricoxib than non-naproxen NSAIDs (FIGURE 2) [44]. The MEDAL program also evaluated upper GI events as a predefined end point [9]. Among the 34,701 patients enrolled, upper GI events, defined as bleeding, perforation, obstruction

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or ulcer diagnosed on clinical work-up, occurred significantly less frequently with etoricoxib than diclofenac (HR: 0.69; 95% CI: 0.57–0.83; p = 0.0001). This difference was due to a decrease in uncomplicated events (uncomplicated bleeding or uncomplicated ulcer) rather than a difference in serious complicated events (complicated bleeding or ulcer). The lower rate of uncomplicated events with etoricoxib was also shown in those patients who were receiving concurrent PPIs and in those who were taking low-dose aspirin. The EDGE portion of the MEDAL program reported that etoricoxib 90 mg was associated with significantly better GI tolerability compared with diclofenac 150 mg in patients with OA [8]. A similar rate of adjudicated CV events was observed with both treatments in the EDGE study, but the low overall number of events makes it difficult to draw conclusions. Concerns about the occurrence of CV events with COX-2selective inhibitors remain. The MEDAL program was powered to provide a precise estimate of CV events with etoricoxib versus the traditional NSAID diclofenac. There appeared to be no CV advantage or disadvantage to taking etoricoxib compared with diclofenac over the course of the study [7,8]. In patients at high risk of a CV event who were on concurrent aspirin and taking either etoricoxib or diclofenac, the CV risk was similar [7]. Additional safety studies

A pooled analysis of adjudicated CV event data from 12 clinical trials estimated the relative risk of CV events in patients with OA, RA, ankylosing spondylitis and chronic lower back pain (FIGURE 2) [44]. All trials were at least 4 weeks in duration and included data from approximately 6500 patient-years of drug exposure. The relative risk for CV events was 1.11 for etoricoxib versus placebo, 0.83 for etoricoxib versus the nonnaproxen NSAIDs diclofenac and ibuprofen, and 1.70 for etoricoxib versus naproxen. The authors concluded that there was no difference in the incidence of CV events between etoricoxib and non-naproxen traditional NSAIDs, although there was a trend toward more events with etoricoxib than naproxen. These data appear similar to data generated in TARGET, in which ibuprofen had similar CV event rates when compared with lumiricoxib, but naproxen had fewer CV events. The consistency of these results possibly suggests a true naproxen effect on reducing CV events, at least compared with COX-2 agents. Other data may also appear to support this concept [45]. Critical evaluation of trials

The two trials of etoricoxib, MEDAL and EDGE, together represent the largest cohort of patients ever studied in the arthritis field [7,8]. They were randomized, prospective and controlled studies, sponsored by the manufacturer of etoricoxib. Both studies enrolled patients to assess CV risk in an

Expert Rev. Clin. Pharmacol. 1(3), (2008)

Etoricoxib in the treatment of osteoarthritis

Favors etoricoxib Favors comparator Etoricoxib pooled analysis Etoricoxib vs placebo

1.11 (0.32–3.81) Patient-years = 895

Etoricoxib vs non-naproxen NSAIDs

0.83 (0.26–2.64) Patient-years = 2023

Etoricoxib vs naproxen

1.70 (0.91–3.18) Patient-years = 4207

0.1

0.2

0.5

1

2

5

10

Relative risk (etoricoxib/comparators)

Figure 2. The relative risk (95% confidence interval) of confirmed thrombotic events from a pooled analysis. Redrawn with permission from [44].

attempt to evaluate patients who were not specific to the study by imposing relatively few exclusion criteria; both studies managed patients as they would be in clinical practice, that is, with aspirin and PPIs appropriately. The decision to enrol patients with RA as well as those with OA, while allowing for later subgroup analysis, increased group heterogeneity and created some dilution of results. RA patients are known to be at higher risk of CV events. They are also younger, which may present demographic variability in this cohort. The decision to allow the use of aspirin and PPIs, while understandable from the ethical and real-world perspectives, makes signals of CV and GI risk much harder to detect. Due to the CV risk issues, it is possible that physicians knowingly or unknowingly avoided putting high-risk patients in the study, resulting in a generally lower risk group. While the study was controlled, perhaps the overall cohort in this case behaved differently from how a higher risk cohort would in practice. Similarly, a physician would have to be very confident in the safety of etoricoxib to allow a patient that was at high risk of a serious GI event to participate, with similar possible study distortion. These studies were large but of intermediate length. It is possible that some events are time related and that the hazard is not constant over time. Patients could conceivably take these medications for a long time and it is unclear that a study with a 2- or 3-year time horizon is adequate. In these studies, there are a few reasons, in addition to adverse events, why there would be a large number of patients discontinuing. In the CLASS trial for example (celecoxib vs ibuprofen or diclofenac), the discontinuation rate due to symptomatic ulcers appears to have been higher in the traditional NSAID group, making meaningful statistical comparison with celecoxib more difficult [46]. Approximately 50% of patients discontinued these studies, which is a fairly common rate for

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Drug Profile

an arthritis study, and these numbers were similar in both arms. The patients who discontinued the study were followed rigorously, with less than 1% loss to follow-up. The overall discontinuation rates in MEDAL were similar between agents. Selecting therapy based on GI tolerability

NSAID monotherapy has not proven to be highly successful with patients with respect to tolerability. For example, an analysis of 30,654 patients in the MediPlus database concluded that dissatisfaction with traditional NSAID therapy was common, and that the frequency of medication switching was due to the need for concurrent gastroprotective agents and GI intolerance [47]. With respect to etoricoxib, in MEDAL, patients had a lower discontinuation rate due to dyspepsia compared with diclofenac alone, whether or not they were on PPIs. This was shown again in a combined analysis from nine randomized, double-blind, controlled clinical trials of patients receiving etoricoxib for OA, RA, chronic low back pain or ankylosing spondylitis who reported significantly lower new use of gastroprotective agents with etoricoxib versus naproxen (9.1 vs 13/100 patient-years; p < 0.001) and significantly fewer discontinuations due to dyspepsia with etoricoxib (1.5 vs 2.7; p = 0.007) [48]. Other studies support this conclusion [49]. It seems reasonable to assume that taking etoricoxib rather than traditional NSAIDs (without a PPI) is less likely to result in GI distress and discontinuation. The option of taking an NSAID with a PPI remains but, in MEDAL, even in the group of patients taking a PPI, the discontinuation rate (although low) was higher in the diclofenac group with a PPI compared with etoricoxib with a PPI. In practice, prescription of concurrent gastroprotective therapy is carried out inconsistently. Specialists, who may be more aware of GI issues with anti-inflammatory therapies, prescribed COX-2-specific inhibitors twice as often as did primary-care physicians (44 vs 21%; p < 0.001) [50]. Even those patients who are indeed at higher risk are often likely not to be provided with a concurrent prescription of a cytoprotective agent. A retrospective observational study of a Dutch general practitioner patient record database reported that 87% of patients with one or more GI risk factors did not receive gastroprotective agents with an NSAID or a COX-2-selective inhibitor [51]. Similarly, a recent review confirmed that, although patients over 60 years of age receiving NSAIDs should receive GI-preventive treatment, at least half of patients with GI risk factors do not receive such concurrent therapy [52]. Even in those patients who are prescribed a protective PPI, it has been estimated that adherence is only 30% overall. It may be that, in study patients not offered concomitant PPIs, the GI effects of etoricoxib (without PPIs) are clearer than in MEDAL. In a meta-analysis of randomized, placebo-controlled

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trials, etoricoxib alone was associated with a significantly lower risk of upper GI perforations, symptomatic gastroduodenal ulcer and upper GI bleeding (PUBs) than nonselective NSAIDs alone [53]. With respect to these GI risks in the MEDAL program, the patients on etoricoxib who were not taking PPIs, and thus presumably felt by their physicians to be at low GI risk, had approximately 50% fewer adjudicated peptic ulcers than those on diclofenac without a PPI [9]. No clear data exist on channeling of patients in this trial. However, in another analysis, patients with more GI risk and those with increased CV risk were preferentially treated with a COX-2-selective agent [54]. In this latter study, patients were enrolled in a real-world manner and it is unlikely that channeling occurred with respect to the comparator drugs. This was significant in those taking PPIs as well. To put it differently, etoricoxib was associated with a lower rate of uncomplicated bleeding events and ulcers in a group of ‘average’ patients not felt to be at higher risk of CV or serious GI events. Whereas, in MEDAL, the patients on etoricoxib and diclofenac who were not on PPIs had a similar rate of complicated events, in this meta-analysis, there were in fact differences favoring etoricoxib. This reduction in upper GI clinical events and dyspepsia is maintained in patients receiving low-dose aspirin [9]. Complicated GI events were an unmet end point in MEDAL. GI bleeding may require the initiation of mucosal damage and then an antiplatelet effect to initiate bleeding. Diclofenac does not cause sustained inhibition of COX-1derived thromboxane-dependent platelet function [55]. In patients on diclofenac, platelet function is initially affected following thromboxane inhibition greater than 95% [56]. However, after 6 h, diclofenac inhibits only 55% of platelet function and diclofenac thus does not inhibit platelet aggregation in a sustained manner [55] and appears dissimilar in this regard to most nonselective NSAIDs. These factors may therefore attenuate the effect on complicated events (which are mostly bleeding). Etoricoxib has no effect on COX-1 and thus no effect on platelet aggregation when administered at clinical doses [19]. It is worth bearing in mind, as referenced earlier, that patients in a more day-to-day environment may not be as compliant as study patients should be and that combined treatment imposes new compliance demands on the patient. These data suggest that patients at higher risk of GI problems – for example those over 65, those on concurrent steroids or aspirin and those who drink alcohol – would benefit from etoricoxib compared with nonselective NSAIDs alone with respect to reducing discontinuations and reducing ulcers. It is probable that patients would also experience a reduction in the complications of ulcers [9,53]. In addition, taking a PPI concurrently with an NSAID will not reduce the risk of lower GI bleeding, which is felt to account for approximately a third of all GI bleeding while on a traditional NSAID.

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The self-defined risk group of patients who require PPIs may therefore be good candidates for etoricoxib rather than traditional nonselective NSAIDs, such as diclofenac, but this depends on an individualized assessment of likely compliance with double therapy. Patients with OA tend to be older, and many have GI issues that could be obviated with etoricoxib. However, this older patient group may also tend to have CV issues. Selecting therapy based on CV safety

Increased CV event rates reported with earlier COX-2-selective inhibitors gave rise to concerns that this may be a class effect [32,33,57]. The MEDAL program provided data that have more precisely defined these issues for etoricoxib, at least with respect to diclofenac. The incidence of CV events in the general population in the MEDAL study, in those with specific risk factors and in those taking aspirin, was the same with etoricoxib as with diclofenac [7]. The pivotal question thus revolves around identifying the magnitude of risk associated with diclofenac use. The relative risk of diclofenac compared with placebo with regard to thromboembolic disease remains unclear, with conflicting data. Some data suggest that there is an increased CV risk with diclofenac and other data show no increased CV risk [58–66]. With respect to hypertension, MEDAL and EDGE reported more discontinuations with etoricoxib than diclofenac, and a greater overall incidence of hypertension with etoricoxib (2.2–2.5%) than diclofenac (0.7–1.6%) [7]. MEDAL included a heterogeneous population that included patients with CV and GI risk, giving a good approximation of the actual event rates. Many NSAIDs are of course approved and available in the USA and around the world, but data on the CV risk of NSAIDs are limited. The CV risk of most nonselective NSAIDs prescribed by physicians is in fact largely unknown. Recognizing this, the FDA has required a warning in the labeling of all NSAIDs to increase awareness of this issue. There is speculation regarding ways to reduce CV risk and further reduce GI risk but, to date, there are no data on intermittent dosing or other strategies. Conclusion

Overall, much of this debate centers around the question of patient needs. In a patient with significantly symptomatic OA who is dramatically better with an NSAID, the background risk of both CV and GI events needs to be evaluated. If the patient responds only to one particular COX-2-selective inhibitor, it may be reasonable to use such an agent. Such a case involves a personal decision between physician and patient. In the end, physicians must weigh the risks and benefits for the individual patients when selecting a treatment regimen for OA.

Expert Rev. Clin. Pharmacol. 1(3), (2008)

Etoricoxib in the treatment of osteoarthritis

Expert commentary: selecting treatment for patients with OA

As stated previously, patients with OA frequently get inadequate relief with current medical options. Owing to these limitations, it is worth thinking carefully about the role of COX-2selective and -nonselective agents in OA before discarding these as options for the treatment of pain in a desperate patient. With this in mind, which individual patients in clinical practice might benefit from either the effectiveness or safety of etoricoxib? Attempts have been made to clarify a practical approach to the use of NSAIDs in general (TABLE 2) [64,65]. First, although not fully clear, at least it seems that significant risk of CV events associated with COX-2 agents in general take time to occur [32]. Despite the lack of clarity on this issue, it is difficult to see that the use of etoricoxib for a few days or weeks for acute pain represents a major risk. Thus, patients requiring short-term use of NSAIDs for symptomatic relief may be a reasonable group in which to consider this agent. Second, looking overall at the cumulative studies of etoricoxib, there is evidence of GI advantage in reducing GI symptoms and probably for reducing GI serious events, and increasing adherence. Thus, the patient with an unremarkable CV risk and higher GI risk would benefit. Etoricoxib should protect the entire bowel, rather than upper GI only, as with a PPI. Finally, the CV risk of etoricoxib is somewhat better defined than with nonselective NSAIDs in light of the aforementioned data. Whatever the precise numerical risk of a serious adverse CV outcome is for etoricoxib, we can be confident that it is not higher than it is with diclofenac. To put it differently, physicians who are comfortable with the CV risk of diclofenac and possibly other NSAIDs should, in theory, be comfortable with etoricoxib because the CV risk is similar. Since the GI risk is lower with etoricoxib, a case could be made that those patients already taking diclofenac could benefit from a shift to etoricoxib. In clinical practice, decisions are often made based on inadequate data. In an honest attempt to help the patient, the physician makes an assessment trying to balance risks and

Drug Profile

benefits. Many patients are treated for pain syndromes with medications that can have significant adverse effects, such as treating polymyalgia rheumatica with long-term prednisone. While patients with polymyalgia rheumatica are not treated to prevent death or even joint damage, but rather to make the patients feel better, they are exposed to a medicine for which there is a known risk (e.g., hypertension, blood glucose and cholesterol elevations, osteoporosis, skin thinning and cataracts). Many of these patients have identifiable baseline CV risks that can be impacted by corticosteroids use, yet we largely accept this risk, purely to try and make a patient who is in pain feel comfortable. Although the overall effect on a population of patients with NSAIDs is modest, there are many individuals who respond dramatically and preferentially to one over another and the existence of several alternate agents is helpful for physicians so that there are several options to try while attempting to find one to which a patient might respond. Patients with OA and an indeterminate risk of CV events who have not received symptomatic relief after having tried several other regimens are probably legitimate candidates to at least try etoricoxib. If there is no response in an appropriate period, 2 weeks for example, the drug would be discontinued and the risk issues are moot. If the patient does have a dramatic improvement, much depends on other risk factors. It is conceivable, for example, that even in a patient with known CV risk, the physician and a carefully informed patient together might elect to continue the chosen agent if the patient is substantially better with respect to pain, function and quality of life. This depends on the patient’s baseline tolerance for pain and the degree of improvement, as well as a precise evaluation of the individual risk of CV events. If indeed the patient is at a higher cardiac risk, all these factors would be addressed as they should be, irrespective of the addition of a new medication. In the situation in which the benefit that the patient derives is substantial, it would be prudent to follow the patient with care, and follow blood pressure, cholesterol and other risk factors.

Table 2. Clinicians’ guide to selecting anti-inflammatory therapy. Risk

No or low NSAID gastrointestinal risk

NSAID gastrointestinal risk

No cardiovascular risk (without aspirin)

Nonselective NSAID (cost consideration) COX-2-selective inhibitor or nonselective NSAID plus proton pump inhibitor COX-2-selective inhibitor plus proton pump inhibitor for those with prior gastrointestinal bleeding

Cardiovascular risk (with aspirin)

Naproxen* Addition of proton pump inhibitor if gastrointestinal risk of aspirin/NSAID combination warrants gastroprotection

Proton pump inhibitor irrespective of NSAID Naproxen if cardiovascular risk outweighs gastrointestinal risk COX-2-selective inhibitor plus proton pump inhibitor for those with previous gastrointestinal bleeding

* Nonselective or selective (low-dose) inhibitor without established aspirin interaction if naproxen is ineffective. Misoprostol at full dose (200 µg four-times daily) may be substituted for proton pump inhibitor. Adapted from [66]. Reproduced with permission from [65].

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Drug Profile

Sebba

Five-year view

The COX-2 field, which initially looked so promising, is now in disarray. The FDA recently declined to approve etoricoxib for use in the USA. The major issue in the background appears to have been the recent withdrawal of rofecoxib from the international market and the apprehension that members of the FDA advisory board felt regarding this drug category. Some of their concerns have been dealt with earlier. Other concerns included the need for safety data on the 30-mg strength, the generalizability of the studies and the wish for crossover trials. Robert Meyer, of the FDA’s Center for Drug Evaluation and Research, possibly summarized the advisory committee meeting when he stated that the message from the committee was that perhaps the FDA should no longer approve ‘just another product in a class if it has the same level of risk as existing products and does not offer a unique benefit’. In an official document, the FDA stated, ‘A new product that appears to have an increased overall risk profile for CV disease, particularly beyond that seen with other drugs in the class, would not be appropriate for marketing approval unless the product fills an unmet need for a particular patient population that has no relatively safer approved products available to them, and provides a reasonable risk to benefit balance for that patient population’ [101]. It is worth noting that lumiricoxib, another COX-2-selective agent, recently received a ‘nonapprovable’ letter from the FDA. Furthermore, in Australia, lumiricoxib has been withdrawn from the market due to hepatic issues. Taken together, this evidence suggests that regulatory authorities are not convinced that the benefits of additional COX-2 agents (at least from the population standpoint) outweigh the risks, and it seems improbable that further agents in this category will be developed. If COX-2 agents are to be further studied (or indeed if any new NSAIDs are to be), the CV risk with COX-2-selective agents must be clearly defined once and for all. Ideally, the investigational agent would be studied against a placebo or a mild analgesic (acetaminophen or a mild opioid) group for a period of at least 2 years, and preferably longer. The end point of such a study would be CV events. It would be interesting to include a naproxen arm and a diclofenac arm, which might illuminate issues pertaining to other COX-2-selective issues. Noninvasive techniques of evaluating arterial structure and function should be utilized for ongoing assessment in such a trial. To date, no NSAID has shown increased efficacy over others. A study of etoricoxib assessing efficacy in patients directly transferred to this agent from another was requested, where one arm would continue current therapy and one would switch to etoricoxib. Similarly, it might be useful to assess this agent in patients who had not responded to other agents in an attempt to document benefits relative to other agents. Research on the use of biochemical markers of cartilage in the assessment of OA is underway. Research also continues with respect to the genetic tendency to having the disease, to

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potential response to medication and to the potential risk. These markers may in time provide a clearer profile of patients in whom to use COX-2-selective agents. Further therapy in the OA field will require a change of direction. Current treatments are all variations of 100-year-old therapies. New therapies that are perhaps on the horizon include gene therapy, matrix metalloproteinase inhibition and the administration of IGF or bFGF for cartilage repair. Glucosamine continues to be of interest, although data supporting its use are inconsistent. Although there are many promising new investigational therapies in preclinical study for the treatment of OA, it appears that, over the near term, the concentration will be on analgesia rather than on anti-inflammatory medications. Information resources

• American College of Rheumatology www.rheumatology.org • Arthritis Research Campaign (UK) www.arc.org.uk • Australian/Canadian Hand Osteoarthritis Index www.auscan.org • British Society of Rheumatology www.rheumatology.org.uk • European League Against Rheumatism www.eular.org • Osteoarthritis Research Society International www.oarsi.org

Financial & competing interests disclosure

Funding for writing assistence was provided by Merck and Company. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. Writing assistance was utilized in the production of this manuscript. Writing assistance was provided by Wendy Horn, PhD.

Key issues • Options for the treatment of osteoarthritis are unsatisfactory. • There are concerns about serious gastrointestinal issues with NSAIDs and serious cardiovascular issues with COX-2 agents (and increasingly with NSAIDS in general with respect to these concerns). • Etoricoxib appears similar in effect to other NSAIDs and the cardiovascular risk of etoricoxib is known to be similar to diclofenac. • There is a small increase in the incidence of hypertension with the use of etoricoxib and this should be watched for. • Use of etoricoxib and all NSAIDs should be thoughtfully considered in each individual patient.

Expert Rev. Clin. Pharmacol. 1(3), (2008)

Etoricoxib in the treatment of osteoarthritis

Therapeutic Research and Gastrointestinal Event Trial (TARGET), reduction in ulcer complications: randomised controlled trial. Lancet 364, 665–674 (2004).

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Affiliation •

Anthony Sebba, MD, PA 36388 US Hwy 19 N, Palm Harbor, FL 34684, USA Tel.: +1 727 773 9793 Fax: +1 727 773 0674 [email protected]

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