Safe prescribing of non-steroidal anti-inflammatory drugs in patients with osteoarthritis – an expert consensus addressing benefits as well as gastrointestinal and cardiovascular risks

Presentation of the statements

Each statement is followed by the ‘grade’ of supporting evidence and the results of
the two votes: i) agreement with the statement and ii) agreement with the grade of
evidence followed by a brief summary. A consensus was considered reached when more
than 75% of participants voted a, b, or c (agree strongly, agree moderately, or agree
mildly).

NSAIDs: efficacy in OA and impact on quality of life (QoL)

Statement 1:OA impacts quality and quantity of life; it should therefore be treated appropriately.Level of Agreement: Strong Agreement (vote statement: a, 48.5%; b, 36.4%; c, 12.1%; d, 3%). Level of Evidence: B (vote grade: A, 42.4%; B, 48.5%; C, 9.1%).

Pain strongly and negatively impacts QoL, with increasing evidence that it may also
impact quantity of life. Chronic pain interferes with the domains of physical and
social functioning, emotional and mental health, energy, vitality, and general health
76]. In addition, it has been shown to be indirectly associated with a reduced cumulative
survival due to CV and respiratory causes 77].

QoL is adversely impacted by OA and this has been shown in large, comprehensive, cross-sectional,
or longitudinal studies 78], and this is supported by many other studies confirming the same conclusions. OA
patients suffer a spectrum of symptoms, which impair normal daily functions including
sleeping, walking, climbing stairs, opening containers, preparing food, or self-caring
to variable extents 78]. There is evidence that chronic musculoskeletal disorders, including OA, have an
overall greater adverse impact on QoL than other chronic diseases such as CV, respiratory,
cerebrovascular, and neurologic disorders, GI diseases, and cancer 79].

Three large, comprehensive, longitudinal studies confirm the effect of OA on longevity
77],80]-82]. Reduced physical function, especially walking disability, is a major risk factor
for mortality in OA patients 81]. Thus, physical activity is good for health 80]. The potential impact of disability on longevity has also been demonstrated in other
musculoskeletal inflammatory conditions. In a cohort of patients with ankylosing spondylitis
followed for up to 33 years, the highest mortality was associated with greater disability
and with non-use of NSAIDs 83].

Large observational studies and analyses of RCTs or pooled data confirm the important
benefits of treating OA 84]-86]. Treatment of OA improves physical performance and is beneficial to several domains
of arthritis function, including pain, stiffness, function, and global ratings of
performance. In addition, it improves the quality of sleep 87]-89].

Statement 2:Many OA patients requiring NSAID therapy are not being treated appropriately according
to their GI risk profile.Level of Agreement: Strong Agreement (vote statement: a, 75.0%; b, 21.9%; c, 3.1%). Level of Evidence: A (vote grade: A, 68.8%; B, 28.1%; C, 3.1%).

There is convincing evidence supporting the use of gastroprotective strategies in
at-risk patients treated with NSAIDs, which has been adopted by different guidelines
worldwide 90],91]. Patients at increased GI risk can be identified by a history of complicated or uncomplicated
ulcers, advancing age (patients older than 60 to 65 years, depending on guidelines),
use of concomitant medication (especially low-dose aspirin or anticoagulants), and
the presence of H. pylori infection 61]. NSAID-treated OA patients with risk factors can be exposed to inappropriate therapy
as a result of not receiving gastroprotective therapy, not being adherent to the prescribed
therapy, or getting non-indicated prevention strategies. Diverse studies with different
methodological approaches in different cohorts of patients have reported important
findings in this regard. Very low rates of prescription of gastroprotective therapies
according to national or international guidelines have been reported, although these
rates have increased progressively 92]-96]. In the Netherlands, correct prescription rose from 6.9% in 1996 to 39.4% in 2006
in high-risk NSAID users, whereas over-prescription rose from 2.9% to 12.3% 97].

Similar rates were reported in a cross-sectional study of patients prescribed NSAIDs
in the United States of America, where only 27.2% of high-risk patients were prescribed
a gastroprotective compound according to guidelines. Among patients from VA hospitals
with at least two risk factors, adherence to guidelines was 39.7%; among those with
three risk factors, adherence was 41.8%. The likelihood of adherence was further decreased
if they were prescribed NSAIDs for ?90 days 98]. Review of medical charts in one large cross-sectional study (n?=?17,105) of OA patients
found that, in over half of the population examined, NSAID prescriptions did not follow
guidelines. Specific areas, where the recommendations were not followed or were overlooked,
were in patients with both high GI and CV history (74% inappropriate) and in those
with a high GI risk alone (49% inappropriate). However, other recommendations were
followed. The study showed high rates of PPI co-prescription with ns-NSAIDs in patients
with increased GI risk. However, half of patients with low GI risk and no CV history
were still treated with ns-NSAIDs plus a PPI or a COX-2 selective NSAID, contrary
to current guidelines 54]. A recent study in Canada has reported that concordance with guideline recommendations
increased for celecoxib and decreased for ns-NSAIDs after rofecoxib withdrawal, whereas
co-prescription of gastroprotective agents with ns-NSAIDs remained suboptimal, with
only 45.6% of at-risk patients receiving these drugs 99].

Adherence by patients to the prescribed drug is another problem. Early reports showed
that over one third of patients did not take the gastroprotective agents as prescribed
94]. More recent studies reported similar or better rates for prescription lasting 3 months
100],101], but others reported much lower adherence rates 92],93]. Appropriate prescription and optimal adherence are important for NSAID users; evidence
indicates that patients with risk factors who do not receive or follow appropriate
prevention strategies have an increased risk of GI complications 100],102]. A recent study involving three European databases found that, among NSAID treated
patients with low adherence (20% of the time with gastroprotection), the odds ratio
(OR) was 2.39 (95% CI, 1.66–3.44) for all upper GI events and 1.89 (95% CI, 1.09–3.28)
for upper GI bleeding alone when compared to patients who had high levels of adherence
(80% of the time on NSAIDs with gastroprotection) 96]. This increased risk among patients with low adherence was also found in high-risk
patients who received a COX-2 selective inhibitor alone whereas guidelines recommend
combination of a COX-2 selective inhibitor with a PPI 103].

Statement 3a:The efficacy of ns-NSAIDs and COX-2 selective inhibitors in pain is comparable in
patients with OA.Level of Agreement: Strong Agreement (vote statement: a, 87.5%; b, 12.5%). Level of Evidence: A (vote grade: A, 87.5%; B, 9.4%; C, 3.1%).

Statement 3b:The efficacy of ns-NSAIDs and COX-2 selective inhibitors in pain is comparable in
patients with rheumatoid arthritis (RA).Level of Agreement: Strong Agreement (vote statement: a, 84.4%; b, 9.4%; c, 6.3%). Level of Evidence: A (vote grade: A, 87.5%; B, 9.4%; C, 3.1%).

The discussion about whether ns-NSAIDs or COX-2 selective inhibitors should be preferred
in patients with RA or OA is usually dominated by the possible GI and CV events. Although
these adverse effects may have dramatic manifestations, they occur only in a minority
of patients. Other issues, like tolerability, adherence to therapy, and cost/price
of the drug, may also play a role. However, and perhaps of primary importance, the
analgesic and anti-inflammatory effect is crucial for patients suffering from pain
due to RA or OA.

In at least five high quality RCTs, a comparable effectiveness has been shown:

1. Different doses of celecoxib (100, 200, and 400 mg/day) were all comparable to
naproxen (1,000 mg/day), and superior to placebo, in a 12-week study in patients with
RA 104];

2. Celecoxib (200 mg/day) was as effective as diclofenac (150 mg/day) in the long-term
management of RA 105];

3. Etoricoxib (60 to 90 mg/day) was as effective as diclofenac (150 mg/day), in RA
and OA patients 106];

4. Celecoxib (200 mg/day) was as effective as naproxen 1,000 mg/day in patients with
knee OA 107];

5. In the Celecoxib versus Omeprazole and Diclofenac in Patients with Osteoarthritis
and Rheumatoid arthritis (CONDOR) study, no difference in effectiveness was found
between celecoxib (400 mg/day) and diclofenac (150 mg/day) in RA and OA patients 108].

6. In other studies, rofecoxib was as effective as naproxen 109], and lumiracoxib as diclofenac 110]. However, neither rofecoxib nor lumiracoxib are now available. In fact, all these
studies clearly show that ns-NSAIDs and COX-2 selective inhibitors have comparable
efficacy, apparent in functioning and disability, as well as in pain.

It is worth emphasizing that, although these drugs seem to have – as a class and at
a population-based level – a comparable effect, individual treatment responses may
be variable and dose-dependent. Thus, in daily practice the choice between ns-NSAIDs
and COX-2 selective inhibitors will depend on the CV and GI risk profile, drug-tolerability,
clinical experience of the physician with the given drug, cost/price, and pharmaco-economic
considerations, as well as individual patient response.

GI risks of NSAIDs

Statement 4:NSAID use is associated with increased risk of adverse events throughout the entire
GI tract; this is associated with substantial mortality.Level of Agreement: Strong Agreement (vote statement: a, 75.0%; b, 21.9%; c, 3.1%). Level of Evidence: A (vote grade: A, 87.5%; B, 12.5%).

The GI adverse effects of NSAIDs have been well documented in several studies 111]-115], meta-analyses 116]-118], and Cochrane reviews 119]. The majority of these studies have reported adverse events in the upper GI tract.
The meta-analysis by Ofman et al. 118], which reviewed severe upper GI complications in almost 800,000 patients taking oral
NSAIDs for at least 4 days, showed an OR of 5.36 (95% CI, 1.79–16.1) from 16 RCTs
(versus placebo), RR of 2.7 (95% CI, 2.1–3.5) from 9 cohort studies, and OR of 3.0
(95% CI, 2.5–3.7) from 23 case control studies for severe upper GI complications,
which included perforations, clinically relevant ulcers, and bleeding 118].

Similarly, low-dose (?325 mg daily) aspirin is associated with major upper GI bleeding:
the RR was 2.1 (95% CI, 1.6–2.7) in the meta-analysis by McQuaid and Laine 120] and 2.6 (95% CI, 2.2–2.9) in the large Danish cohort study, carried out by Sørensen
et al.121]. Lanas et al. 122] recently reported an OR of 1.55 (95% CI, 1.27–1.90) and found that PPI use reduced
the risk of major GI bleeding (OR, 0.34; 95% CI, 0.21–0.57).

A predictable and consistent GI blood loss has been shown in healthy volunteers taking
ibuprofen (800 mg t.i.d.) 115]. Bleeding was observed in 27/31 subjects (87%) and averaged 4.5 to 5.0 mL/day (SD,
12; range, 0–65 mL/day) with an onset of 3 to 5 days after starting the drug 115].

In the recent CONDOR study, a large, prospective RCT (n?=?4,400), the cumulative proportion
of patients with adjudicated, clinically significant events throughout the GI tract
was significantly greater in those patients taking diclofenac in combination with
omeprazole, despite the partial protection provided by the PPI in the upper GI tract,
than in patients taking celecoxib 108].

The effect of NSAID use on mortality has been less well studied and a figure of 16,500
deaths in the US has been widely quoted since the original estimate was published
123]. However, in a more recent report of results from two concurrent Spanish studies
114], the incidence of hospital admission due to major GI events of the entire (upper
and lower) GI tract was 121.9 events/100,000 person/years and admissions for upper
GI complications were six-fold higher than for lower GI tract events. Mortality rates
attributed to NSAIDs/low-dose aspirin use were substantial, at 21.0 and 24.8 cases/million
people, respectively, and up to one-third of all NSAID/aspirin deaths could be attributed
to low-dose aspirin use. Mortality rates associated with either major upper or lower
GI events were similar, 5.57% (95% CI, 4.9–6.7) and 5.62% (95% CI, 4.8–6.8), respectively.
However, upper GI events were more frequent. Moreover, three further studies reported
mortality figures, which range from 3.8 to 11% in patients with peptic ulcer bleeding
associated with NSAID use 124]-126]. Furthermore, while the adverse events associated with NSAID use can lead to mortality,
this could be due to associated causes other than GI adverse events (e.g., CV events)
127].

Statement 5:NSAID-induced adverse events in the lower GI tract are not prevented by PPIs.Level of Agreement: Strong Agreement (vote statement: a, 75.0%; b, 18.8%; c, 3.1%; d, 3.1%). Level of Evidence: B (vote grade: A, 43.8%; B, 56.3%).

While it is clear that PPIs reduce the development of peptic ulcer and ulcer complications
in patients taking NSAIDs and/or aspirin, their beneficial effect, which is related
to their antisecretory activity 128], is not expected beyond the duodenum 30]. The appreciation that NSAID-associated GI damage does extend beyond the duodenum
dates back to the early 90’s, when a few observational studies and the first large
RCT prevention study (i.e., the Misoprostol Ulcer Complication Outcomes Safety Assessment
(MUCOSA) trial) were published 129]. In the more recent Vioxxâ„¢ Gastrointestinal Outcomes Research (VIGOR) trial, more
than 40% of the NSAID-related events occurred in the lower (i.e., small bowel and
colon) GI tract 130]. A systematic review 131] of 47 studies (18 randomized, 14 case-control, 8 cohort, and 7 before/after studies)
found that patients taking ns-NSAIDs had significantly more adverse effects versus
no NSAID use in 20/22 lower GI integrity studies (dealing with permeability, inflammation,
and microscopic lesions), 5/7 visualization studies, 7/11 bleeding studies (OR, 1.9–18.4
in case-control studies), 2/2 perforation studies (OR, 2.5–8.1), and 5/7 diverticular
disease studies (OR, 1.5–11.2). As reported in the Spanish studies (described under
Statement 4), over the past decade there has been a progressive change in the overall
picture of GI events leading to hospitalization, with a clear decreasing trend in
upper GI events and a slight but significant increase in lower GI events 41].

The availability of video capsule endoscopy has allowed a precise quantification of
the incidence and characterization of small intestinal damage. Indeed, available studies
132],133] show that about 75% of NSAID users display intestinal mucosal injury, with most denuded
areas identified in the proximal part of the small bowel and all ulcers identified
in the distal part 134].

In healthy volunteers 133],135],136] and patients 132], omeprazole did not prevent NSAID-associated intestinal damage, evaluated by video
capsule and/or fecal calprotectin measurement. The failure of PPIs to protect the
small bowel is due to the fact that NSAID-enteropathy is not a pH-dependent phenomenon
30]. Indeed, although inhibition of mucosal prostaglandin synthesis with NSAID use occurs
along the entire digestive tract, there are significant differences between the distal
and proximal GI tract in the concurrence of other pathogenic factors that may add
to mucosal damage. Among the most evident are the absence of acid (which plays a pivotal
role in upper GI damage) and the presence of bacteria and bile in the intestine, which
may trigger specific NSAID-related pathogenic mechanisms in the distal GI tract 137]. Some recent experimental evidence 138] suggests that PPIs might actually worsen the NSAID intestinal damage by inducing
dysbiosis, an adverse event repeatedly described in humans 139],140].

Like non-selective compounds, COX-2 selective NSAIDs damage the small bowel, but the
frequency and severity of events are generally lower. Indeed, a systematic review
found that COX-2 selective inhibitors had significantly less effect versus ns-NSAIDs
in 3/4 GI integrity studies, one endoscopic study (RR mucosal breaks, 0.3), and two
randomized studies (RR lower GI clinical events, 0.5; hematochezia, 0.4) 131]. The better intestinal tolerability of the selective agent, celecoxib, persisted
even when the ns-NSAID was combined with a PPI 135],136]. In addition, switching RA patients on long-term ns-NSAIDs to celecoxib resulted
in a significant reduction of small bowel injury 141]. While two large outcome studies (the VIGOR and CONDOR trials) showed a reduced risk
of more serious events in the lower or the whole GI tract, for rofecoxib and celecoxib,
respectively 108],130], this benefit was not confirmed for etoricoxib in the Multinational Etoricoxib versus
Diclofenac Arthritis Long-term (MEDAL) program 142].

The impact of upper GI tract adverse effects can be mitigated by the use of PPIs.
The lack of efficacy of these agents in preventing lower GI tract damage is however
an unmet clinical need that requires addressing. The use of non acidic COX-2 selective
inhibitors, such as celecoxib, may help to reduce the risk of damage throughout the
entire GI tract, but much work is needed to define the best preventive strategy for
the lower GI tract in NSAID users.

Statement 6:Celecoxib is associated with fewer adverse events throughout the entire GI tract compared
to ns-NSAIDs.Level of Agreement: Strong Agreement (vote statement: a, 62.5%; b, 18.8%; c, 18.8%). Level of Evidence: A (vote grade: A, 46.9%; B, 43.8%; C, 9.4%).

A meta-analysis of RCTs showed that COX-2 selective inhibitors were associated with
significantly fewer gastro-duodenal ulcers (RR, 0.26; 95% CI, 0.23–0.30) and clinically
important ulcer complications (RR, 0.39; 95% CI, 0.31–0.50) than ns-NSAIDs 143]. Other studies have also shown that celecoxib is as safe to the upper GI tract as
ns-NSAIDs plus a PPI 144].

It is now well known that NSAIDs induce mucosal damage to the small and large bowel,
including inflammation, erosions, ulcers, bleeding, perforation, and obstruction 61],145]. Epidemiological studies have reported an increased risk of lower GI bleeding and
perforation with NSAID and aspirin use 146],147]. More recently, biochemical and endoscopy capsule studies have shown a high frequency
of mucosal inflammation and mucosal breaks in both healthy subjects 133] and patients taking NSAIDs 132]. Although PPIs are increasingly used to prevent NSAID-related GI adverse events,
they do not protect from lesions beyond the duodenum (see Statement 5). This may explain
the increasing number of hospitalizations due to complications of the lower GI tract,
seen in some studies, whereas the corresponding numbers for upper GI complications
are decreasing (see Statement 4) 41].

Capsule endoscopy studies 135],136] have demonstrated that, compared to ns-NSAIDs plus a PPI, celecoxib alone was associated
with less mucosal damage of the small bowel in healthy volunteers. In the 6-month,
double-blind, randomized CONDOR trial, in patients with OA or RA at increased GI risk
108], fewer (0.9%) subjects receiving celecoxib (200 mg b.i.d) met the criteria for the
primary endpoint (clinically significant upper and lower GI events) compared to those
receiving diclofenac (75 mg b.i.d.) plus omeprazole (3.8%; hazard ratio [HR]?=?4.3;
95% CI, 2.6–7.0). Also, fewer patients taking celecoxib withdrew early because of
GI adverse events compared to patients taking diclofenac plus omeprazole. Most of
the outcome events were a drop in hemoglobin ?2 g/dL attributed to identified lesions
from the upper GI tract or to presumed small bowel lesions. These data have been confirmed
in a recent 6-month randomized, open-label, blinded endpoint study that measured clinical
outcomes throughout the GI tract 148]. Celecoxib use was associated with a lower risk of clinically significant upper and
lower GI events than ns-NSAIDs (OR, 1.82; 95% CI, 1.31–2.55) 148]. However, a recent epidemiological study carried out in Taiwan has shown celecoxib
to be associated with an increased risk of complications in the lower GI tract, similar
to other NSAIDs 149]. These data need to be confirmed, since epidemiological studies are inevitably associated
with different biases and confounding factors that may be difficult to control.

A relevant question is whether data on the safety of celecoxib in the lower GI tract
can be extrapolated to other COX-2 selective inhibitors, since NSAID-associated mucosal
damage in the lower GI tract depends not only on COX-1/COX-2 inhibition, but also
on the physicochemical properties and the entero-hepatic circulation of individual
NSAIDs 30].

In a 28-day trial conducted in healthy volunteers, Hunt et al. 150] found that fecal blood loss with etoricoxib (120 mg o.d.) was similar to placebo
and significantly lower than that found in patients treated with ibuprofen (800 mg t.d.s.).
However, the MEDAL program 142] did not confirm a decrease in lower GI complications with etoricoxib versus diclofenac.

Statement 7:The combination of celecoxib plus low-dose aspirin is associated with a lower risk
of adverse events in the upper GI tract, as compared with ns-NSAIDs plus low-dose
aspirin.Level of Agreement: Strong Agreement (vote statement: a, 43.8%; b, 28.1%; c, 6.3%; d, 9.4%; e, 3.1%;
f, 9.4%). Level of Evidence: B (vote grade: A, 25.0%; B, 40.6%; C, 25.0%; D, 3.1%; E, 6.3%).

It is well established that low-dose aspirin exerts a life-saving antithrombotic effect,
particularly in secondary prevention 151]. However, a large cohort study 121] and a meta-analysis of 35 RCTs, including 87,581 patients 122], have clearly shown that its use is associated with an increased risk of GI bleeding.
This risk is further increased when aspirin is combined with clopidogrel or anticoagulants
122] and appears to be independent of the formulation of aspirin used (e.g., buffered
or enteric coated) 152].

The well-known risk of upper GI events associated with the use of ns-NSAIDs is significantly
enhanced by concomitant use of low-dose aspirin, a quite frequent clinical situation
in older patients having both OA and CV co-morbidities 153],154]. A large, hospital-based, case-control study, performed in Spain, found that adding
low-dose aspirin to ns-NSAIDs, increased the risk of upper GI bleeding by more than
two-fold 155]. Similarly, a Canadian retrospective cohort study found a 62% increase in hazard
ratio of hospitalization for GI events in patients taking these combinations, although
the combination of celecoxib with low-dose aspirin was associated with a lower risk
(HR, 0.62; 95% CI, 0.48–0.80) than the association of ns-NSAIDs plus low-dose aspirin
156].

When COX-2 selective inhibitors were examined as a class, conflicting results were
reported by different studies. In the case of three epidemiological studies, one (a
hospital-based, case-control) found a similar RR of upper GI bleeding when low-dose
aspirin was combined with COX-2 selective inhibitors or ns-NSAIDs 155], while the others (nested case-control studies, performed in databases from the UK)
observed an increased RR of upper GI complications when ns-NSAIDs or COX-2 selective
agents were used together with an antiplatelet agent 157],158]. However, in a meta-analysis of four RCTs including 17,276 patients, the RR for perforation,
ulcer, and bleeding between the combination low-dose aspirin/COX-2 selective inhibitors
and low-dose aspirin/ns-NSAIDs was 0.72 (95% CI, 0.62–0.95) 143]. However, these were post hoc analyses and not randomised comparisons, which suggest a possible bias by patient
selection.

As expected, the analysis of the risk associated with the combination of low-dose
aspirin with individual COX-2 selective inhibitors also yielded different results.
Indeed, with the exception of the Celecoxib Long-Term Arthritis Safety Study (CLASS)
trial (where high doses, i.e., 800 mg/day, of the drug were employed) 159], all the available studies (be they epidemiological or RCTs) 156],160]-162], as well as a meta-analysis of 31 RCTs (n?=?39,605) 163], point to a lower upper GI risk of low-dose aspirin in combination with celecoxib
than with the same antiplatelet agent combined with an ns-NSAID. However, it must
be clear that low-dose aspirin potentiates the GI risk of either a selective COX-2
inhibitor or ns-NSAID and that, in patients with high GI risk, these combinations
may still be harmful and gastroprotection with a PPI seems appropriate and beneficial
31].

In contrast, in the MEDAL program, the pre-specified pooled intent-to-treat analysis
of the three RCTs (i.e., Etoricoxib versus Diclofenac sodium Gastrointestinal tolerability
and Effectiveness trial (EDGE)-I, EDGE-II, and MEDAL), comparing etoricoxib with diclofenac
in an overall population of 11,418 OA/RA patients taking low-dose aspirin the HR for
overall upper GI clinical events was 0.78 (95% CI, 0.60–1.1), indicating a lack of
significant difference between the two anti-inflammatory drugs 164]. Consistent with this finding, the cumulative rate of patient discontinuation due
to clinical and laboratory upper GI adverse events was also not statistically different
in the two treatment arms 165]. No formal studies have evaluated the GI risk of dual antiplatelet therapy in patients
taking either ns-NSAIDs or coxibs.

Recent video capsule studies have shown that low-dose aspirin is also harmful to the
small intestine 166]-168]. The combination of aspirin with ns-NSAIDs would likely be more damaging. However,
studies providing such evidence are lacking and, more importantly, the clinical relevance
of these mucosal lesions need to be defined in the context of serious and life-threatening
outcomes such as bleeding and perforation.

CV risk of NSAIDs

Statement 8:The risk of CV events associated with celecoxib use is similar to that associated
with the use of most ns-NSAIDs.Level of Evidence: Strong Agreement (vote statement: a, 68.8%; b, 15.6%; c, 9.4%; d, 6.3). Level of Evidence: A (vote grade: A, 53.1%; B, 40.6%; C, 6.3%).

Although OA is not apparently an independent risk factor for CV disease, many OA patients
are elderly and concomitant CV disease is not uncommon. In a nested case-control study
(n ?1,400,000) by Graham et al. 169], an increased CV risk was associated with rofecoxib as well as ns-NSAIDs. In RCTs,
rofecoxib demonstrated a higher incidence of CV adverse events than naproxen in non-aspirin
users with RA 109] or than placebo in patients with colorectal adenomas (Adenomatous Polyp Prevention
on Vioxxâ„¢ (APPROVe) trial) 170]. For celecoxib, an increase in CV events was noted in patients with colorectal cancer
when compared with placebo 171]. However, in these trials, the absolute numbers were low. In a RCT in Alzheimer’s
disease, CV events were higher with naproxen compared to celecoxib or placebo 172]. In the CLASS study performed in OA and RA patients, there was no difference in CV
events between celecoxib (400 mg b.i.d.) and ns-NSAIDs 173]. In the MEDAL trials, etoricoxib showed a similar cumulative incidence of thrombotic
CV events to diclofenac 106]. A large meta-analysis of cohort and nested case-control studies also found an increased
risk of CV events for all ns-NSAIDs and COX-2 selective inhibitors 46]. Other meta-analyses concluded that COX-2 selective agents and ns-NSAIDs have similar
CV risk 47],174],175]. A recent network meta-analysis, which aimed to compare the CV risk of ns-NSAIDs
and COX-2 selective inhibitors, found a similar CV risk between these two classes
of anti-inflammatory compounds 48]. Naproxen appeared to be the least harmful, but this advantage has to be weighed
against GI toxicity. It also must be considered that the absence of an increased CV
risk observed in RCTs and meta-analysis with naproxen, when compared to placebo, was
based on a high naproxen dose (500 mg b.i.d) 47].

Putting the CV risk in OA patients into context, the incidence of the GI risk is higher
than the CV risk, and COX-2 selective inhibitors have a lower GI risk than ns-NSAIDs.
Taking all the available data from clinical trials, meta-analyses, and cohort studies
into account, the overall CV risk is increased for both ns-NSAIDs and COX-2 selective
inhibitors. For each COX-2 selective inhibitor, however, the reduction of complicated
upper GI events was numerically greater than any increase in Antiplatelet Trialists’
Collaboration events (fatal or non-fatal myocardial infarction or stroke, or vascular
death) 176]. There is no evidence of major differences between ns-NSAIDs and COX-2 selective
inhibitors. Hitherto, there is no published RCT which has been specifically designed
to compare CV risk between ns-NSAIDs and COX-2 selective inhibitors. Results of the
Prospective Randomized Evaluation of Celecoxib Integrated Safety versus Ibuprofen
or Naproxen (PRECISION) study will provide important data on the comparative CV safety
of celecoxib, ibuprofen, and naproxen. It is worthwhile mentioning that this trial,
performed in a high CV risk population, is the first study specifically designed to
assess the CV safety of anti-inflammatory drugs 177]. Unfortunately, the trial has been delayed because of slow enrollment and full results
are not expected until 2016 178].

Statement 9:COX-2 selective inhibitors do not interfere with the antiplatelet effect of low-dose
aspirin. Level of Agreement: Strong Agreement (vote statement: a, 65.6%; b, 21.9%; c, 6.3%; d, 6.3%). Level of Evidence: A (vote grade: A, 77.4%; B, 16.1; C, 3.2%; D, 3.2%).

The benefits of low-dose aspirin use in secondary prevention clearly outweigh the
risk 151]. However, this is not the case for primary prevention 179], where recommendations for aspirin use should be individualized, taking into account
the balance between benefits and risks, as well as individual patient values and preferences
180]. Given that aspirin is a life-saving drug, discontinuing it or not adhering to the
correct administration schedule enhances the risk of CV and cerebral events by more
than three-fold 181],182]. This risk was magnified by up to 90-fold in patients with intracoronary stents 182].

Ns-NSAIDs, being COX-1-inhibitors, all impair thromboxane A₂ synthesis and, as a consequence, platelet aggregation, although the magnitude and
duration of this effect varies amongst the different compounds 183]. With the exception of diclofenac 184],185] and meloxicam 186], almost all ns-NSAIDs can interfere with the anti-aggregant effect of aspirin 185],187]-189].

While the pharmacodynamic, negative interaction between ns-NSAIDs and low-dose aspirin
has been clearly established by studies in healthy volunteers and patients, the clinical
consequences of such interaction are still not definitely ascertained. Indeed, available
epidemiological studies provided conflicting results, with only three out of six reports
showing a reduction of the cardio-protective effect of aspirin 190]-195]. However, the few RCTs available are consistent in their findings that ns-NSAID use
does worsen the CV outcome in patients taking low-dose aspirin. Indeed, in the Physicians’
Health Study, the regular use of these agents was associated with an increased risk
(RR, 2.86; 95% CI, 1.25–6.56) of acute recurrent myocardial infarction 196]. Similarly, in the Therapeutic Arthritis Research and Gastrointestinal Event Trial
(TARGET), designed to assess the GI and CV safety of lumiracoxib versus naproxen and
ibuprofen, a post hoc subgroup analysis of high CV risk patients (n?=?3,042) taking low-dose aspirin (60%)
found a higher CV event rate in ibuprofen users compared to lumiracoxib users (1.48
versus 0.85 events per 100 patient/years) 197]. Besides the CV harm, concomitant administration of ns-NSAIDs and low-dose aspirin
can be followed by stroke recurrence in patients with prior cerebrovascular events
188].

COX-2 selective NSAIDs spare platelet COX-1 activity 198] and do not affect platelet aggregation 184],198]-201] or bleeding time 200]. Similarly, COX-2 selective inhibitors do not interfere with the anti-aggregant activity
of low-dose aspirin both in healthy subjects 184],186],187],198] and patients with coronary heart disease 202],203]. Consistent with these results, in vitro studies on human platelets have shown that a low affinity for COX-1 and a high degree
of COX-2 selectivity confers a low potential to block aspirin inhibition of platelet
COX-1 204].

Taking all the above lines of evidence into account, COX-2 selective inhibitors should
represent the anti-inflammatory drugs of choice for patients taking low-dose aspirin
for CV or cerebrovascular prevention 205], provided the anti-inflammatory therapy is deemed necessary and cannot be avoided
with alternative therapies. It should be emphasized, however, that the European Medicines
Agency’s (EMA) Committee for Medicinal Products for Human Use stated – in 2005 – that
“COX-2 inhibitors must not be used in patients with established ischemic heart disease
and/or cerebrovascular disease (stroke)” 206]. Therefore, the benefits (i.e., lack of blunting of aspirin protection and the anti-inflammatory/analgesic
activity) should be balanced against the possible CV risks, which ultimately depend
on individual patients’ clinical characteristics and co-medications.