Page 10 - 53-Peptic ulcer diseases (Loét dạ dày)

814 PART VI Stomach and Duodenum

TABLE 53.2 Recommendations for Reducing the Risk of NSAID Ulcers as a Function of GI and Cardiovascular Risk
GI Risk*
Low Moderate High
Low CV risk NSAID at the lowest effective dose NSAID plus a PPI, or celecoxib alone Celecoxib plus a PPI
High CV risk † Naproxen or celecoxib, plus a PPI Naproxen or celecoxib, plus a PPI Celecoxib plus a PPI if simple analgesics failed

*Low GI risk denotes no risk factors (see Table 53.1); moderate GI risk denotes 1 or 2 risk factors; high GI risk denotes ≥3 risk factors, prior complicated
ulcer, or concomitant use of low-dose aspirin or anticoagulants. All patients with a history of ulcer who require NSAIDs should be tested for Hp, and if
infection is present, eradication therapy should be given (see Chapter 52).
† High CV risk denotes the requirement for prophylactic low-dose aspirin for primary or secondary prevention of serious CV events.
CV, cardiovascular.

Despite the improved gastric safety profile of COX-2 inhibi- (approximately 850 mg/day) with regard to cardiovascular safety.
tors, the cardiovascular risk associated with this new class of Patients treated with celecoxib had a significantly lower risk of
NSAIDs has been a subject of much concern. In the VIGOR adverse GI events than with naproxen or ibuprofen. The risk of
study, the incidence of acute myocardial events, although low, adverse renal events was also significantly lower with celecoxib
97
was 4 times higher among patients receiving rofecoxib than than with ibuprofen; however, the proportion of patients con-
among patients receiving naproxen. Whether this observed dif- tinued on concomitant low-dose aspirin during the study period
ference in myocardial infarction rates was related to an anti- was unclear and very few patients had a history of GI bleed-
platelet property of naproxen or to a pro-thrombotic effect of ing. It is, therefore, unclear whether the advantage of celecoxib
rofecoxib was debated. Further data regarding the cardiovascu- over naproxen or ibuprofen can be extrapolated to patients on
lar hazards of COX-2 inhibitors were derived from 2 long-term concomitant aspirin with high risk of GI bleeding. In another
studies of colon polyp prevention, using either rofecoxib (the 18-month randomized trial of patients at high risk of both cardio-
Adenomatous Polyp Prevention on Vioxx [APPROVE] study) vascular and GI adverse events who required concomitant low-
98
and celecoxib (the Adenoma Prevention with Celecoxib [APC] dose aspirin and an NSAID, celecoxib plus a PPI was found to be
study). In APPROVE, interim data at 18 months indicated that superior to naproxen plus a PPI in reducing the risk of recurrent
99
patients who had received 25 mg rofecoxib a day had twice the ulcer bleeding. 103, 108
risk of serious cardiovascular events compared with patients who
received placebo. In 2004, rofecoxib was voluntarily withdrawn Assessing Risk and Choice of Agent(s)
from worldwide markets in light of this unexpected finding. In
the APC study, interim data at 33 months showed that serious Safe prescription of NSAIDs should be based on assessment of an
cardiovascular events were significantly more frequent with cele- individual patient’s GI and cardiovascular risks. In patients with
coxib at the high dose of 400 mg twice a day (hazard ratio, 1.9; low cardiovascular risk, the therapeutic approach can be stratified
95% CI, 1 to 3.3). The MEDAL program was a pre-specified according to their levels of GI risk as follows (Table 53.2):
pooled analysis of cardiothrombotic events from 3 trials in which
• Low ulcer risk: no risk factors. Patients without risk factors
patients with osteoarthritis or rheumatoid arthritis were ran- (see Table 53.1) are at very low risk of ulcer complications
domly assigned to etoricoxib (60 mg or 90 mg daily) or diclofenac with NSAID use (≈1% per year). Rational use of NSAIDs,
(150 mg daily). After an average treatment of 18 months, rates of including avoidance of high doses of NSAIDs and use of a less
cardiothrombotic events were similar between the 2 treatment ulcerogenic NSAID (e.g., ibuprofen, diclofenac) at the lowest
groups. 100 effective dose is a cost-effective approach.
Current evidence suggests that not only COX-2 inhibitors
but also nonselective NSAIDs, with the exception of full-dose • Moderate ulcer risk: 1 or 2 risk factors. These patients should
receive combination therapy with an antiulcer agent (a PPI or
naproxen (1000 mg/day), increase cardiothrombotic risk. In a misoprostol) and an NSAID. Alternatively, substitution with
meta-analysis of randomized trials of COX-2 inhibitors (data celecoxib alone is as effective as the combination therapy men-
mostly derived from rofecoxib and celecoxib), all COX-2 inhibi- tioned earlier.
tors increased the cardiothrombotic risk compared with placebo
(risk ratio, 1.42; 95% CI, 1.13 to 1.78). This was largely attribut- High ulcer risk: 3 or more risk factors, history of ulcer compli-
able to an increased risk of myocardial infarction, with little dif- cations, or concomitant use of low-dose aspirin, glucocorticoids,
ference in other vascular outcomes. A dose-dependent increase or anticoagulant therapy. In general, NSAIDs should be avoided
in cardiothrombotic events was observed with celecoxib. Impor- in these patients, not only because of the high risk of ulcer com-
tantly, there was no significant difference in cardiothrombotic plications but also owing to the serious consequences of ulcer
risk between COX-2 inhibitors and nonselective NSAIDs, with complications in the presence of comorbidities. Glucocorticoid
naproxen (500 mg twice daily) the only exception. In a meta-anal- therapy (without NSAID) can be considered if short-term anti-
ysis of observational studies, high-dose rofecoxib (≥25 mg a day), inflammatory therapy is required for acute, self-limiting arthritis
diclofenac, and indomethacin were associated with an increase in (e.g., gout), because glucocorticoids alone do not increase the
cardiothrombotic events, whereas celecoxib did not significantly risk of ulcer. If regular anti-inflammatory therapy is required for
increase the cardiothrombotic risk, although an increased risk chronic arthritis, the combination of celecoxib and a PPI offers
could not be excluded with doses greater than 200 mg/day. 101 In the best GI protection.
a large-scale, randomized, noninferiority trial of celecoxib versus Defining patients with high cardiovascular risk remains arbi-
naproxen and ibuprofen in patients with arthritis (mostly osteo- trary. The American Heart Association recommends that aspirin
arthritis) and with increased cardiovascular risk, 102 more than should be considered in all apparently healthy men and women
24,000 patients were recruited with a mean treatment duration of whose 10-year risk for a cardiovascular event is 10% or above. 104
20 months and a mean follow-up period of 34 months. Celecoxib We consider patients with arthritis to have significant cardiovas-
(on average approximately 200 mg/day) was found to be nonin- cular risk if they are already on aspirin for secondary prophylaxis
ferior to ibuprofen (approximately 2000 mg/day) or naproxen or if they require aspirin for primary prophylaxis according to