Yamamoto et al[5
] examined the effects of gastroprotective drugs on aspirin-related gastroduodenal toxicity in 530 patients who had taken low-dose aspirin for 1 mo or more. Use of a PPI alone was significantly more protective against bleeding (9.3% vs
< 0.01) and mucosal injury (49.1% vs
< 0.01) than non-use of any gastroprotective medicine. Among the background characteristics, such as Helicobacter pylori
infection, concomitant use of anticoagulants, anti-platelet agents, NSAIDs and PPI, a bleeding history, age and gender, only the co-administration of a PPI was found significantly associated with reduced bleeding events. Patients taking any medicine PPI, H2RA, MP, PPI (or H2RA) plus MP showed significantly better outcomes with respect to mucosal injury as compared with the patients not receiving any gastroprotective medication.
Our study indicated that only 3.46% of the patients taking low-dose aspirin received concurrent therapy of PPI, H2RA and MPs. Thus it is imperative to enhance the awareness of preventing GI injury induced by low-dose aspirin among both physicians and patients.
The combined therapy of aspirin and PPI was more frequently used than that of aspirin and MPs (2.82% vs
< 0.05) and aspirin/H2RA (2.82% vs
< 0.05) in this hospital and it may be due to the more potent effects of PPIs in prevention of NSAIDS-related GI injuries[15
]. However, Nema et al[7
] observed that the healing rate of gastroduodenal ulcers during continuous use of low-dose aspirin was higher than 80% in both the PPI group and the H2RA group, with no significant difference between the two groups. Nakashima et al[16
] concluded that H2RA may be the most beneficial drug for both the prevention and treatment of low-dose aspirin-induced peptic ulcers, in which it has the similar anti-ulcer effects to PPIs, but with lower cost and fewer adverse effects as compared with PPIs and prostaglandins.
Concomitant use of NSAIDs, corticosteroids, clopidogrel or anticoagulants increases GI risk further in patients on low-dose aspirin[2-4
]. A meta-analysis by Lanas et al[4
] showed that the risk for GI bleeding in aspirin users increased with concomitant use of clopidogrel and anticoagulant therapies, but decreased in patients who took PPIs. Astoundingly, our investigation showed that 96.6% of patients on aspirin plus clopidogrel, 60.7% of patients on aspirin plus oral corticosteroids and 100% of patients on aspirin plus warfarin did not receive any GI protective medications.
The anti-platelet effect of clopidogrel was activated by biotransformation via
CYP2C19 and CYP3A4. Different PPIs have different effects on CYP2C19. It has been generally acknowledged that drug interaction between omeprazole and clopidogrel was of clinically significance and can reduce the efficacy of clopidogrel[17
]. Pantoprazole, esomeprazole and rabeprazole were alternatives[18-20
]. Coadministration of aspirin, clopidogrel and omeprazole was not observed in this study, indicating that this hospital is good at clopidogrel therapy management.
DDDs values of seven mucoprotective drugs were compared. Gefarnate’s DDDs ranked first and this result may be associated with its relatively low price. Teprenone’s DDDs ranked second. Murakami et al[21
] concluded that the effects of teprenone on aspirin-induced gastric ulcers in rats were more potent and more definite than those of gefarnate. Fang et al[14
] reported that teprenone (15.63 mg/kg daily) and gefarnate (31.25 mg/kg daily) can exert protective effects against the intestinal injury induced by NSAIDs in rats. Niwa et al[12
] found that teprenone (300 mg/d) reduced diclofenac-induced gastric and small intestinal injuries in 10 healthy volunteers (P
< 0.05). Shiotani et al[22
] reported that 1 wk administration of low-dose aspirin to 20 healthy volunteers was associated with visible small bowel damage in the majority of users whereas teprenone (150 mg/d) could not prevent aspirin-induced small bowel injury. The inconsistent findings about the preventive effects of teprenone against small intestinal injury may be associated with the dosage of teprenone, sample size of clinical trials and species differences. Although gefarnate used 50 mg twice daily was inferior to lansoprazole at 15 mg daily in reducing the risk of gastric or duodenal ulcer recurrence in patients with a definite history of gastric or duodenal ulcers who required long-term low-dose aspirin therapy[23
], the proven effects of gefarnate in prevention of small intestinal injury induced by NSAIDs in rats provoked further investigations on whether gefarnate could prevent small intestinal injury in aspirin users.
Sucralfate is proved to have protective effects against NSAID-associated ulcer due to the enhanced prostaglandin synthesis, increased mucus secretion, suppression of pro-inflammatory cytokines such as tumor necrosis factor-α (TNF-α), and induction of constitutive nitric oxide synthase as well as its antioxidant capability[24
]. Although it had the lowest daily expenditure, sucralfate chewable tablets had the lowest DDDs value. The DDDs value of sucralfate oral suspension was 16 times more than that of sucralfate chewable tablets, although oral suspension had a higher daily expenditure than chewable tablets. In this investigation, we observed that some patients swallowed the chewable tablets directly without chewing, and this implies that sucralfate suspension has a better medication compliance than chewable tablets.
Misoprostol exerts a protective effect on the gastrointestinal mucosa by increasing mucus and bicarbonate ion secretion as well as mucosal blood flow. In addition, it inhibits acid secretion. Watanabe et al[9
] reported that misoprostol 200 μg 4 times a day could effectively prevent aspirin-induced small intestinal injuries. However, drug compliance of misoprostol was not good due to its side effects and dosing frequency. In clinical trials, misoprostol-induced diarrhoea occurred in approximately one-tenth of the patients despite that it was usually mild and self-limiting. Donnelly et al[25
] conducted a double-blind placebo-controlled parallel group endoscopic study in 32 healthy volunteers over 28 d and concluded that low-dose misoprostol 100 μg daily can prevent the gastric mucosal injury induced by aspirin 300 mg daily without causing identifiable adverse effects. However, many physicians seem unaware of misoprostol use at such a low-dose. Off-label use of misoprostol (Cytotec®
, Piramal Healthcare Ltd., United Kingdom) is very common in China. In this investigation, all of Cytotec®
was prescribed for termination of early pregnancy in combination with mifepristone. Thus misoprostol was eliminated by the Drug and Therapeutics Committee of this hospital in September 2011.
Rebamipide provides mucoprotective effect by inducing the production of intracellular prostaglandins and epidermal growth factor, improving blood flow, suppressing increases in permeability, scavenging free radicals and exerting anti-infammatory effect[1
]. Yamamoto et al[5
] reported that in the patients taking rebamipide concomitantly with PPIs, aspirin-induced gastroduodenal mucosal injuries occurred less frequently than in those taking PPIs plus MPs other than rebamipide (14.8% vs
< 0.01). From this viewpoint, rebamipide had an obvious advantage over other MPs. Mizukami et al[1
] proved that rebamipide could prevent effectively aspirin-induced small bowel injury. If the exciting finding of this research can be applied to routine clinical practices, good clinical outcomes would be anticipated in patients taking low-dose aspirin.
Our investigation indicated a 0.25% incidence of upper GI bleeding in the low-dose aspirin users, a value nearly four times that of the documented baseline rate of 0.06% noted for the general population without medications or conditions predisposing to bleeding[26
], suggesting that low-dose aspirin users did have a relative higher risk of GI injury.
Physician education and computer alert were proved to improve targeted use of gastroprotection among NSAID users[27
]. The poor awareness of preventing aspirin-induced GI injury with combined protective medications has attracted the attention of the Drug and Therapeutics Committee of this hospital. Actions to address this issue include academic lectures and computer alert to encourage prescriptions of GI protecting agents, a multi-disciplinary team building and initiation of risk-benefit long-term study on the association between increase in expenditure of GI protecting agents and outcomes such as significant reduction in hospital admissions/stays related to GI bleeding.
In conclusion, the study of Mizukami et al[1
] inspired us to perform this retrospective drug utilization study on the prescribing pattern of low-dose aspirin from the perspective of combined therapy in a large university teaching hospital in China. The results of our survey indicated the poor awareness of preventing gastric and small intestinal injury in patients taking low-dose aspirin with combined protective medications. Good clinical outcomes would be anticipated in aspirin users, especially in patients with a high risk of GI injury, given that the importance of administration of gastroduodenal protective PPIs and intestinal protective rebamipide as well as other GI mucoprotectives is being recognized.