Clin J Gastroenterol (2013) 6:264–268 DOI 10.1007/s12328-013-0409-7
CLINICAL REVIEW
Upper gastrointestinal complications induced by anti-platelet agents Takashi Kawai • Hiroko Sugimoto • Mari Fukuzawa • Masakatsu Fukuzawa • Chika Kusano • Takuji Gotoda • Fuminori Moriyasu
Received: 13 June 2013 / Accepted: 23 June 2013 / Published online: 13 August 2013 Ó Springer Japan 2013
Abstract Low-dose aspirin and thienopyridine are associated with gastrointestinal (GI) complications such as petechiae, erosion, ulcer, bleeding, and perforation. The incidence of GI bleeding in aspirin study groups was 0.82 % in the hypertension optimal treatment (HOT) study and 0.76 % in the primary prevention project (PPP) study. On the other hand, the incidence of GI bleeding by endoscopic evaluation was higher than in an observational study. In a study of 187 patients receiving low-dose aspirin for prevention of cardiovascular disease, the prevalence of endoscopically detected GI ulcers was 11 % (95 % CI 6.3–15.1 %). Several risk factors for GI bleeding (history of peptic ulcer or GI bleeding, high aspirin dose, concomitant use of non-steroidal anti-inflammatory drugs and anti-platelet agents, advanced age and Helicobacter pylori infection) were reported for patients receiving aspirin. Prevention strategies for GI complications induced by antiplatelet agents are treatment with proton pump inhibitors, histamine-2 receptor antagonists, prostaglandin analogs, prostaglandin inducers and H. pylori eradication therapy. Further investigation is necessary to identify the strategies which are suitable for Japan. Keywords Low-dose aspirin H. pylori infection Gastrointestinal damage Proton pump inhibitor Adaptation
T. Kawai (&) H. Sugimoto M. Fukuzawa Endoscopy Center, Tokyo Medical University Hospital, Tokyo, Japan e-mail: [email protected] M. Fukuzawa C. Kusano T. Gotoda F. Moriyasu 4th Department of Internal Medicine, Tokyo Medical University, Tokyo, Japan
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Epidemiological data Despite clinical benefits, aspirin and thienopyridine are associated with gastrointestinal (GI) complications such as petechiae, erosion, ulcer, bleeding, and perforation [1, 2]. Although erosion and petechiae are not clinically relevant, some erosions may develop into ulcers and/or bleeding which in some cases can be fatal; however, it is not clear why some erosions progress to ulcers and others do not. Endoscopic observation of the stomach at short periodic intervals is necessary for confirmation. Furthermore, a poor correlation between the presence of symptoms and gastroduodenal ulcers and/or erosions [3] makes it difficult to clarify the developing frequency of ulcers without endoscopic testing. Several observational studies which reported frequencies of serious GI adverse events by hospitalization, as a clinical outcome, and for patients with chronic use of low-dose aspirin and/or thienopyridine are shown in Table 1. The incidence of GI bleeding in the aspirin group was 0.82 % in the hypertension optimal treatment (HOT) study and 0.76 % in the primary prevention project (PPP) study. On the other hand, the incidence in the placebo group was 0.39 % in the HOT study and 0.22 % in the PPP study [4, 5]. Recently, clopidogrel has been used with increased frequency. Two large studies evaluated the use of clopidogrel for patients with atherosclerotic vascular disease and acute coronary syndromes. In the CAPRIE study, the incidence of patients with GI bleeding was 0.49 % in the aspirin group and 0.71 % in the clopidogrel group [6]. The incidence of patients with GI bleeding using combination therapy, i.e., aspirin plus clopidogrel, was 1.33 % in the clopidogrel in unstable angina to prevent recurrent events (CURE) study [7]. These results showed that on three occasions aspirin induced GI bleeding compared with placebo by almost two-fold. The frequency of GI bleeding was
Clin J Gastroenterol (2013) 6:264–268
265
Table 1 Reported frequencies of GI bleeding in large randomized placebo-controlled trials with low-dose aspirin
Table 2 Risk factors for upper gastroduodenal serious damage in patients with low-dose aspirin
Source
Subjects (n)
Follow-up (months)
GI bleedings (%)
History of peptic ulcer or GI bleeding
46
77 (0.82)
Concomitant use of NSAIDs and corticosteroids
37 (0.39)
Concurrent use of anti-platelets and anti-coagulants
17 (0.76) 5 (0.22)
Advanced age
Lancet 1998 (HOT study)
Aspirin (9,399)
Lancet 2001 (PPP)
Aspirin (2,226) Placebo (2,269)
43
Lancet 1996 (CAPRIE study)
Aspirin (9,586)
22
N Engl J Med 2001 (CURE study)
Aspirin (6,303)
Placebo (9,391)
Clopidogrel (9,599)
Aspirin ? Clopidogrel (6,259)
High doses of aspirin
H. pylori infection
47 (0.49) 68 (0.71)
9
47 (0.75) 83 (1.33)
low, accounting for approximately 1 % of patients taking low-dose aspirin and thienopyridine. Slight bleeding in asymptomatic patients can be overlooked in an observational study; however, it may lead to serious bleeding which would require hospitalization. On the other hand, the incidence of GI bleeding by endoscopic evaluation was higher than in an observational study. Yeomans et al. [3], in a study of 187 patients receiving low-dose aspirin for cardiovascular (CV) disease prevention, found a prevalence of 11 % (95 % CI 6.3–15.1 %) for endoscopically detected GI ulcers. Although endoscopy has become the gold standard for assessing potential upper GI complications, there are some limitations such as cost performance, comfort, etc. Recently, transnasal upper GI endoscopy has become popular. Transnasal, unsedated, upper GI endoscopy has been developed as an alternative to transoral endoscopy to reduce the costs as well as the risks associated with conscious sedation [8, 9]. In addition, transnasal upper GI endoscopy is a comfortable and conventional test that, due to sedation, imposes less stress such as respiratory depression, hypotension, paradoxical agitation, and anaphylaxis [10] and, most importantly, imposes a decreased load on the CV pulmonary system [11]. In short-term trials of healthy subjects taking low-dose aspirin, all subjects had induced GI damage. Gastric mucosal changes occurred within 3 days after administration of low-dose aspirin [12]; however, these injuries recovered or reduced at 7 days. This process was presumably caused by the defensive reaction of the living body, such as inducing adaptation [13]. Therefore, periodic endoscopic observation is needed for patients with long-term use of aspirin and thienopyridine. Transnasal endoscopy is a useful modality for periodic monitoring.
Risk factors Several risk factors for GI bleeding in patients receiving aspirin have been reported (shown in Table 2).
History of peptic ulcer or GI bleeding A history of peptic ulcer or GI bleeding appears to be associated with a high risk of developing GI bleeding. Serrano et al. [14] conducted a study of 903 consecutive patients discharged on low-dose aspirin (73-325 mg/day), to study the prevention of CV diseases outside clinical trials. During a 45-month follow-up period, 4.5 % of patients presented with upper GI bleeding requiring hospitalization. Multivariate analysis showed a history of peptic ulcer or upper GI bleeding (risk ratio [RR] 3.1, 95 % CI 1.5–6.5). Aspirin dosage Several studies have suggested that the risk of GI bleeding is increased with higher doses of aspirin [15, 16]. Serebruany et al. [17], in a meta-analysis that compared the risk of hemorrhage due to low (\100 mg), moderate (100–200 mg), and high ([200 mg) doses of aspirin in 192,036 patients enrolled in 31 clinical trials, reported no significant relationship between aspirin dose and risk of upper GI bleeding. Concomitant use of non-steroidal anti-inflammatory drugs (NSAIDs), COX-2 selective NSAIDs, and corticosteroids The concomitant use of traditional NSAIDs, COX-2 selective NSAIDs, and corticosteroids is also an important risk factor. Lanas et al. [15] investigated a hospital-based, case–control study in Spain. The study included 2,777 consecutive patients with endoscopy-proved major upper GI bleeding because of peptic lesions and 5,532 controls matched by their background. Use of traditional NSAIDs increased the risk of upper GI bleeding (adjust RR 5.3, 95 % CI 4.5–6.2). Among traditional NSAIDs, aceclofenac (RR 3.1, 95 % CI 2.3–4.2) had the lowest RR, whereas ketorolac (RR 14.4, 95 % CI 5.2–39.9) had the highest. Rofecoxib treatment increased the risk of upper GI bleeding (RR 2.1, 95 % CI 1.1–4.0).
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Concomitant use of anti-platelets and coagulant agents In the CAPRIE study, reported adverse experiences in the clopidogrel and aspirin groups judged to be severe, included upper GI intracranial hemorrhage (0.33 vs 0.47 %), and GI hemorrhage (0.52 vs 0.72 %) [6]. On the other hand, Lanas et al. [15] who investigated upper GI bleeding risk of non-aspirin anti-platelet treatment, found that clopidogrel and/or ticlopidine had a similar risk of upper GI bleeding (RR 2.8, 95 % CI 1.9–4.2) to cardioprotective aspirin at a dose of 100 mg/day (RR 2.7, 95 % CI 2.0–3.6) or anticoagulants (RR 2.8, 95 % CI 2.1–3.7). Advanced age Advanced age may be thought of as an important risk factor. However, advanced age has several potential complications such as those attributed to an increase in the prevalence of Helicobacter pylori with age [18]. In addition, most patients with coronary and CV disease are older and also infected with H. pylori. H. pylori infection An ACCF/ACG/AHA expert consensus in 2008 suggested that ‘‘eradicating H. pylori in patients with a history of ulcer disease is recommended before starting chronic antiplatelet therapy’’ [19]. In a case–control study of 695 consecutive users of low-dose aspirin with upper GI bleeding, H. pylori infection was identified as an independent risk factor of upper GI bleeding (OR 4.7, 95 % CI 2.0–10.9) [20]. In a prospective cohort study, the incidences of ulcer bleeding were compared among 3 different cohorts of low-dose aspirin users—patients without prior ulcer history who just started using aspirin (n = 548), aspirin users with prior ulcer bleeding and H. pylori infection who had successful eradication of H. pylori (n = 250), and H. pylori-negative aspirin users who had prior ulcer bleeding (n = 118). All patients received lowdose aspirin. After a median follow-up of 48 months, the annual incidence of ulcer bleeding in the 3 groups was 0.5, 1.1, and 4.6 %, respectively [21]. This evidence suggested that confirmed eradication of H. pylori in aspirin users with prior ulcer bleeding reduced the risk of recurrent bleeding.
Prophylactic strategies for GI complications Prostaglandins (PGs) analogs and PG inducers Misoprostol, a PG analog and rebamipide, a PG inducer are cytoprotective agents. Misoprostol is well-known for reducing serious GI complications in patients with rheumatoid
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Clin J Gastroenterol (2013) 6:264–268
arthritis taking NSAIDs [22]. A randomized controlled trial which compared misoprostol and rebamipide for patients with NSAID-induced GI complications, found that the incidence of peptic ulcer was 4.4 % in the misoprostol group and 4.5 % in the rebamipide group [23]. Misoprostol and rebamipide also reduced development of GI injuries in healthy subjects with low-dose aspirin [12, 24]; however, it is well known that misoprostol is associated with serious side-effects, particularly diarrhea.
Histamine-2 receptor antagonists (H2RAs) H2RAs include ranitidine, cimetidine, famotidine and nizatidine, roxatidine acetate hydrochloride, lafutidine. They reduce gastric acid output as a result of H2RA blockade and are effective for prevention of low-dose aspirin-induced gastroduodenal ulcers [25].
Proton pump inhibitors (PPIs) PPIs include omeprazole, lansoprazole and esomeprazole. They inhibit the parietal cell proton pump and exert a strong suppressive effect on gastric acid compared with H2RAs. A study by Tamura et al. found a similar incidence between patients taking omeprazole plus low-dose aspirin for high number of GI complications and patients taking low-dose aspirin alone with non-high risk (1.2 %, 95 % CI: 0.3–3.5 %) [26]. Another study by Lanas et al. found the rate of gastric ulcer recurrence in patients with low-dose aspirin plus an NSAID was lower with lansoprazole than with placebo [27]. In a study by Chan et al, the cumulative incidence of recurrent bleeding during a 12-month period was 8.6 % in the clopidogrel alone group and 0.7 % in the aspirin plus esomeprazole group (difference 7.9 %, 95 % CI 3.4–12.4 %, p = 0.001) [28]. Rabeprazole also reduces the recurrence risk of peptic ulcers associated with low-dose aspirin in patients with CV or cerebrovascular disease [29]. Preventive treatment with PPIs for patients with lowdose aspirin and/or clopidogrel-induced GI complications is the most effective therapeutic strategy. However, not all patients taking aspirin may be indicated. PPIs may be prescribed according to the degree of risk because of cost performance. Fig. 1 shows a therapeutic strategy map according to risk. Risk groups are shown as risk factor groups A, B, and C. Group A is defined as patients with a history of GI ulcers and bleeding. Group B is defined as patients with at least
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Fig. 1 Therapeutic strategy map according to risk factors in patients with low-dose aspirin
one risk factor from the following (advanced age, use of high-dose aspirin, concomitant use of NSAIDs and anticoagulant agents). Group C is defined as patients with H. pylori-infection. Strategies 1-4 are therapeutic strategies. Strategy 1 is prevention therapy by use of anti-acid agents. Strategy 2 uses PGs, i.e., cytoprotective agents. Strategy 3 uses H. pylori eradication therapy. Strategy 4 uses no medication, however, patients in this category need periodic endoscopic observation. Conflict of interest of interest.
The authors declare that they have no conflict
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268 12. Kawai T, Yamagishi T, Goto S. Circadian variations of gastrointestinal mucosal damage detected with transnasal endoscopy in apparently healthy subjects treated with low-dose aspirin (ASA) for a short period. J Atheroscler Thromb. 2009;16:155–63. 13. Graham DY, Smith JL, Dobbs SM. Gastric adaptation occurs with aspirin administration in man. Dig Dis Sci. 1983;28:1–6. 14. Serrano P, Lanas A, Arroyo MT, Ferreira IJ. Risk of upper gastrointestinal bleeding in patients taking low-dose aspirin for the prevention of cardiovascular diseases. Aliment Pharmacol Ther. 2002;16:1945–53. 15. Lanas A, Garcı´a-Rodrı´guez LA, Arroyo MT, Gomollo´n F, Feu F, Gonza´lez-Pe´rez A, Zapata E, Ba´stida G, Rodrigo L, Santolaria S, Gu¨ell M, de Argila CM, Quintero E, Borda F, Pique´ JM, Asociacio´n Espan˜ola de Gastroenterologı´a. Risk of upper gastrointestinal ulcer bleeding associated with selective cyclo-oxygenase2 inhibitors, traditional non-aspirin non-steroidal anti-inflammatory drugs, aspirin and combinations. Gut. 2006;55:1731–8. 16. Mashita Y, Taniguchi M, Yokota A, Tanaka A, Takeuchi K. Oral but not parenteral aspirin upregulates COX-2 expression in rat stomachs. A relationship between COX-2 expression and PG deficiency. Digestion. 2006;73(2–3):124–32. 17. Serebruany VL, Steinhubl SR, Berger PB, Malinin AI, Baggish JS, Bhatt DL, Topol EJ. Analysis of risk of bleeding complications after different doses of aspirin in 192,036 patients enrolled in 31 randomized controlled trials. Am J Cardiol. 2005;15(95): 1218–22. 18. Newton JL, Johns CE, May FE. Review article: the ageing bowel and intolerance to aspirin. Aliment Pharmacol Ther. 2004;1(19): 39–45. 19. Bhatt DL, Scheiman J, Abraham NS, Antman EM, Chan FK, Furberg CD, Johnson DA, Mahaffey KW, Quigley EM. ACCF/ ACG/AHA 2008 expert consensus document on reducing the gastrointestinal risks of antiplatelet therapy and NSAID use. Circulation. 2008;118:1894–909. 20. Lanas A, Fuentes J, Benito R, Serrano P, Bajador E, Sainz R. Helicobacter pylori increases the risk of upper gastrointestinal bleeding in patients taking low-dose aspirin. Aliment Pharmacol Ther. 2002;16:779–86. 21. Chan FK, Ching JY, Suen BY, Tse YK, Wu JC, Sung JJ. Effects of Helicobacter pylori infection on long-term risk of peptic ulcer bleeding in low-dose aspirin users. Gastroenterology. 2013;144(3): 528–35. 22. Silverstein FE, Graham DY, Senior JR, Davies HW, Struthers BJ, Bittman RM, Geis GS. Misoprostol reduces serious gastrointestinal complications in patients with rheumatoid arthritis receiving non-steroidal anti-inflammatory drugs. A randomized, double-
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CLINICAL REVIEW
Upper gastrointestinal complications induced by anti-platelet agents Takashi Kawai • Hiroko Sugimoto • Mari Fukuzawa • Masakatsu Fukuzawa • Chika Kusano • Takuji Gotoda • Fuminori Moriyasu
Received: 13 June 2013 / Accepted: 23 June 2013 / Published online: 13 August 2013 Ó Springer Japan 2013
Abstract Low-dose aspirin and thienopyridine are associated with gastrointestinal (GI) complications such as petechiae, erosion, ulcer, bleeding, and perforation. The incidence of GI bleeding in aspirin study groups was 0.82 % in the hypertension optimal treatment (HOT) study and 0.76 % in the primary prevention project (PPP) study. On the other hand, the incidence of GI bleeding by endoscopic evaluation was higher than in an observational study. In a study of 187 patients receiving low-dose aspirin for prevention of cardiovascular disease, the prevalence of endoscopically detected GI ulcers was 11 % (95 % CI 6.3–15.1 %). Several risk factors for GI bleeding (history of peptic ulcer or GI bleeding, high aspirin dose, concomitant use of non-steroidal anti-inflammatory drugs and anti-platelet agents, advanced age and Helicobacter pylori infection) were reported for patients receiving aspirin. Prevention strategies for GI complications induced by antiplatelet agents are treatment with proton pump inhibitors, histamine-2 receptor antagonists, prostaglandin analogs, prostaglandin inducers and H. pylori eradication therapy. Further investigation is necessary to identify the strategies which are suitable for Japan. Keywords Low-dose aspirin H. pylori infection Gastrointestinal damage Proton pump inhibitor Adaptation
T. Kawai (&) H. Sugimoto M. Fukuzawa Endoscopy Center, Tokyo Medical University Hospital, Tokyo, Japan e-mail: [email protected] M. Fukuzawa C. Kusano T. Gotoda F. Moriyasu 4th Department of Internal Medicine, Tokyo Medical University, Tokyo, Japan
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Epidemiological data Despite clinical benefits, aspirin and thienopyridine are associated with gastrointestinal (GI) complications such as petechiae, erosion, ulcer, bleeding, and perforation [1, 2]. Although erosion and petechiae are not clinically relevant, some erosions may develop into ulcers and/or bleeding which in some cases can be fatal; however, it is not clear why some erosions progress to ulcers and others do not. Endoscopic observation of the stomach at short periodic intervals is necessary for confirmation. Furthermore, a poor correlation between the presence of symptoms and gastroduodenal ulcers and/or erosions [3] makes it difficult to clarify the developing frequency of ulcers without endoscopic testing. Several observational studies which reported frequencies of serious GI adverse events by hospitalization, as a clinical outcome, and for patients with chronic use of low-dose aspirin and/or thienopyridine are shown in Table 1. The incidence of GI bleeding in the aspirin group was 0.82 % in the hypertension optimal treatment (HOT) study and 0.76 % in the primary prevention project (PPP) study. On the other hand, the incidence in the placebo group was 0.39 % in the HOT study and 0.22 % in the PPP study [4, 5]. Recently, clopidogrel has been used with increased frequency. Two large studies evaluated the use of clopidogrel for patients with atherosclerotic vascular disease and acute coronary syndromes. In the CAPRIE study, the incidence of patients with GI bleeding was 0.49 % in the aspirin group and 0.71 % in the clopidogrel group [6]. The incidence of patients with GI bleeding using combination therapy, i.e., aspirin plus clopidogrel, was 1.33 % in the clopidogrel in unstable angina to prevent recurrent events (CURE) study [7]. These results showed that on three occasions aspirin induced GI bleeding compared with placebo by almost two-fold. The frequency of GI bleeding was
Clin J Gastroenterol (2013) 6:264–268
265
Table 1 Reported frequencies of GI bleeding in large randomized placebo-controlled trials with low-dose aspirin
Table 2 Risk factors for upper gastroduodenal serious damage in patients with low-dose aspirin
Source
Subjects (n)
Follow-up (months)
GI bleedings (%)
History of peptic ulcer or GI bleeding
46
77 (0.82)
Concomitant use of NSAIDs and corticosteroids
37 (0.39)
Concurrent use of anti-platelets and anti-coagulants
17 (0.76) 5 (0.22)
Advanced age
Lancet 1998 (HOT study)
Aspirin (9,399)
Lancet 2001 (PPP)
Aspirin (2,226) Placebo (2,269)
43
Lancet 1996 (CAPRIE study)
Aspirin (9,586)
22
N Engl J Med 2001 (CURE study)
Aspirin (6,303)
Placebo (9,391)
Clopidogrel (9,599)
Aspirin ? Clopidogrel (6,259)
High doses of aspirin
H. pylori infection
47 (0.49) 68 (0.71)
9
47 (0.75) 83 (1.33)
low, accounting for approximately 1 % of patients taking low-dose aspirin and thienopyridine. Slight bleeding in asymptomatic patients can be overlooked in an observational study; however, it may lead to serious bleeding which would require hospitalization. On the other hand, the incidence of GI bleeding by endoscopic evaluation was higher than in an observational study. Yeomans et al. [3], in a study of 187 patients receiving low-dose aspirin for cardiovascular (CV) disease prevention, found a prevalence of 11 % (95 % CI 6.3–15.1 %) for endoscopically detected GI ulcers. Although endoscopy has become the gold standard for assessing potential upper GI complications, there are some limitations such as cost performance, comfort, etc. Recently, transnasal upper GI endoscopy has become popular. Transnasal, unsedated, upper GI endoscopy has been developed as an alternative to transoral endoscopy to reduce the costs as well as the risks associated with conscious sedation [8, 9]. In addition, transnasal upper GI endoscopy is a comfortable and conventional test that, due to sedation, imposes less stress such as respiratory depression, hypotension, paradoxical agitation, and anaphylaxis [10] and, most importantly, imposes a decreased load on the CV pulmonary system [11]. In short-term trials of healthy subjects taking low-dose aspirin, all subjects had induced GI damage. Gastric mucosal changes occurred within 3 days after administration of low-dose aspirin [12]; however, these injuries recovered or reduced at 7 days. This process was presumably caused by the defensive reaction of the living body, such as inducing adaptation [13]. Therefore, periodic endoscopic observation is needed for patients with long-term use of aspirin and thienopyridine. Transnasal endoscopy is a useful modality for periodic monitoring.
Risk factors Several risk factors for GI bleeding in patients receiving aspirin have been reported (shown in Table 2).
History of peptic ulcer or GI bleeding A history of peptic ulcer or GI bleeding appears to be associated with a high risk of developing GI bleeding. Serrano et al. [14] conducted a study of 903 consecutive patients discharged on low-dose aspirin (73-325 mg/day), to study the prevention of CV diseases outside clinical trials. During a 45-month follow-up period, 4.5 % of patients presented with upper GI bleeding requiring hospitalization. Multivariate analysis showed a history of peptic ulcer or upper GI bleeding (risk ratio [RR] 3.1, 95 % CI 1.5–6.5). Aspirin dosage Several studies have suggested that the risk of GI bleeding is increased with higher doses of aspirin [15, 16]. Serebruany et al. [17], in a meta-analysis that compared the risk of hemorrhage due to low (\100 mg), moderate (100–200 mg), and high ([200 mg) doses of aspirin in 192,036 patients enrolled in 31 clinical trials, reported no significant relationship between aspirin dose and risk of upper GI bleeding. Concomitant use of non-steroidal anti-inflammatory drugs (NSAIDs), COX-2 selective NSAIDs, and corticosteroids The concomitant use of traditional NSAIDs, COX-2 selective NSAIDs, and corticosteroids is also an important risk factor. Lanas et al. [15] investigated a hospital-based, case–control study in Spain. The study included 2,777 consecutive patients with endoscopy-proved major upper GI bleeding because of peptic lesions and 5,532 controls matched by their background. Use of traditional NSAIDs increased the risk of upper GI bleeding (adjust RR 5.3, 95 % CI 4.5–6.2). Among traditional NSAIDs, aceclofenac (RR 3.1, 95 % CI 2.3–4.2) had the lowest RR, whereas ketorolac (RR 14.4, 95 % CI 5.2–39.9) had the highest. Rofecoxib treatment increased the risk of upper GI bleeding (RR 2.1, 95 % CI 1.1–4.0).
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Concomitant use of anti-platelets and coagulant agents In the CAPRIE study, reported adverse experiences in the clopidogrel and aspirin groups judged to be severe, included upper GI intracranial hemorrhage (0.33 vs 0.47 %), and GI hemorrhage (0.52 vs 0.72 %) [6]. On the other hand, Lanas et al. [15] who investigated upper GI bleeding risk of non-aspirin anti-platelet treatment, found that clopidogrel and/or ticlopidine had a similar risk of upper GI bleeding (RR 2.8, 95 % CI 1.9–4.2) to cardioprotective aspirin at a dose of 100 mg/day (RR 2.7, 95 % CI 2.0–3.6) or anticoagulants (RR 2.8, 95 % CI 2.1–3.7). Advanced age Advanced age may be thought of as an important risk factor. However, advanced age has several potential complications such as those attributed to an increase in the prevalence of Helicobacter pylori with age [18]. In addition, most patients with coronary and CV disease are older and also infected with H. pylori. H. pylori infection An ACCF/ACG/AHA expert consensus in 2008 suggested that ‘‘eradicating H. pylori in patients with a history of ulcer disease is recommended before starting chronic antiplatelet therapy’’ [19]. In a case–control study of 695 consecutive users of low-dose aspirin with upper GI bleeding, H. pylori infection was identified as an independent risk factor of upper GI bleeding (OR 4.7, 95 % CI 2.0–10.9) [20]. In a prospective cohort study, the incidences of ulcer bleeding were compared among 3 different cohorts of low-dose aspirin users—patients without prior ulcer history who just started using aspirin (n = 548), aspirin users with prior ulcer bleeding and H. pylori infection who had successful eradication of H. pylori (n = 250), and H. pylori-negative aspirin users who had prior ulcer bleeding (n = 118). All patients received lowdose aspirin. After a median follow-up of 48 months, the annual incidence of ulcer bleeding in the 3 groups was 0.5, 1.1, and 4.6 %, respectively [21]. This evidence suggested that confirmed eradication of H. pylori in aspirin users with prior ulcer bleeding reduced the risk of recurrent bleeding.
Prophylactic strategies for GI complications Prostaglandins (PGs) analogs and PG inducers Misoprostol, a PG analog and rebamipide, a PG inducer are cytoprotective agents. Misoprostol is well-known for reducing serious GI complications in patients with rheumatoid
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arthritis taking NSAIDs [22]. A randomized controlled trial which compared misoprostol and rebamipide for patients with NSAID-induced GI complications, found that the incidence of peptic ulcer was 4.4 % in the misoprostol group and 4.5 % in the rebamipide group [23]. Misoprostol and rebamipide also reduced development of GI injuries in healthy subjects with low-dose aspirin [12, 24]; however, it is well known that misoprostol is associated with serious side-effects, particularly diarrhea.
Histamine-2 receptor antagonists (H2RAs) H2RAs include ranitidine, cimetidine, famotidine and nizatidine, roxatidine acetate hydrochloride, lafutidine. They reduce gastric acid output as a result of H2RA blockade and are effective for prevention of low-dose aspirin-induced gastroduodenal ulcers [25].
Proton pump inhibitors (PPIs) PPIs include omeprazole, lansoprazole and esomeprazole. They inhibit the parietal cell proton pump and exert a strong suppressive effect on gastric acid compared with H2RAs. A study by Tamura et al. found a similar incidence between patients taking omeprazole plus low-dose aspirin for high number of GI complications and patients taking low-dose aspirin alone with non-high risk (1.2 %, 95 % CI: 0.3–3.5 %) [26]. Another study by Lanas et al. found the rate of gastric ulcer recurrence in patients with low-dose aspirin plus an NSAID was lower with lansoprazole than with placebo [27]. In a study by Chan et al, the cumulative incidence of recurrent bleeding during a 12-month period was 8.6 % in the clopidogrel alone group and 0.7 % in the aspirin plus esomeprazole group (difference 7.9 %, 95 % CI 3.4–12.4 %, p = 0.001) [28]. Rabeprazole also reduces the recurrence risk of peptic ulcers associated with low-dose aspirin in patients with CV or cerebrovascular disease [29]. Preventive treatment with PPIs for patients with lowdose aspirin and/or clopidogrel-induced GI complications is the most effective therapeutic strategy. However, not all patients taking aspirin may be indicated. PPIs may be prescribed according to the degree of risk because of cost performance. Fig. 1 shows a therapeutic strategy map according to risk. Risk groups are shown as risk factor groups A, B, and C. Group A is defined as patients with a history of GI ulcers and bleeding. Group B is defined as patients with at least
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Fig. 1 Therapeutic strategy map according to risk factors in patients with low-dose aspirin
one risk factor from the following (advanced age, use of high-dose aspirin, concomitant use of NSAIDs and anticoagulant agents). Group C is defined as patients with H. pylori-infection. Strategies 1-4 are therapeutic strategies. Strategy 1 is prevention therapy by use of anti-acid agents. Strategy 2 uses PGs, i.e., cytoprotective agents. Strategy 3 uses H. pylori eradication therapy. Strategy 4 uses no medication, however, patients in this category need periodic endoscopic observation. Conflict of interest of interest.
The authors declare that they have no conflict
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