Introduction
Preventive effects of PPIs for NSAID-induced peptic ulcers in at-risk patients
References | Treatment (number of patients) | Control (number of patients) | NSAIDs | Patient characteristics | Scheduled endoscopy | Incidence of peptic ulcers | HR (95 % CI) |
---|---|---|---|---|---|---|---|
Japan | |||||||
Sugano et al. [21] | Lansoprazole 15 mg (n = 185) | Gefarnate 100 mg (n = 181) | Any | Having a history of peptic ulcers | 3, 6, 12 months | 3.3 % (LPZ) vs. 18.7 % (GN) (3 months) 5.9 % (LPZ) vs. 28.5 % (GN) (6 months) 12.7 % (LPZ) vs. 36.9 % (GN) (12 months) | 0.251 (0.1400–0.4499) |
Sugano et al. [22] | Esomeprazole 20 mg (n = 175) | Placebo (n = 168) | Any | Having a history of peptic ulcers | 1, 3, 6 months | 4.0 % (EPZ) vs. 35.6 % (placebo) (6 months) | 0.09 (0.04–0.20) |
Overseas | |||||||
Chan et al. [24] | Omeprazole 20 mg (n = 75) | HP eradication therapy followed by placebo (n = 75) | Naproxen 1,000 mg | Having a history of gastrointestinal bleeding with HP infection | None | 4.4 % (OPZ 20 mg) vs. 18.8 % (eradication) (6 months) (Upper-GI bleeding) | |
Graham et al. [26] | Lansoprazole 30 mg (n = 132) Lansoprazole 15 mg (n = 136) Misoprostol 800 μg (n = 134) | Placebo (n = 133) | Any | Having a history of gastric ulcers | 1, 2, 3 months | 17 % (LPZ 30 mg) vs. 21 % (LPZ 15 mg) vs. 12 % (Misoprostol) vs. 53 % (placebo) (3 months) | |
Chan et al. [27] | Omeprazole 20 mg (n = 143) | Celecoxib 400 mg (n = 144) | Diclofenac 150 mg (Omeprazole group) Celecoxib 400 mg (Celecoxib group) | Having a history of bleeding peptic ulcers | None | 6.4 % (OPZ + Diclofenac) vs. 4.9 % (Celecoxib) (6 months) (Upper-GI bleeding) | |
Lai et al. [25] | Lansoprazole 30 mg (n = 22) | None (n = 21) | Naproxen 750 mg | Having peptic ulcers with HP infection followed by ulcer healing and HP eradication | 2 months | 4.5 % (LPZ) vs. 42.9 % (control) (2 months) | |
Chan et al. [29] | Omeprazole 20 mg (n = 106) | Celecoxib 400 mg (n = 116) | Diclofenac 150 mg (Omeprazole group) Celecoxib 400 mg (Celecoxib group) | Having a history of bleeding peptic ulcers | 6 months | 32.3 % (OPZ + Diclofenac) vs. 24.1 % (Celecoxib) (6 months) (Bleeding and endoscopic ulcers) | |
Lai et al. [28] | Lansoprazole 30 mg (n = 122) | Celecoxib 200 mg (n = 120) | Naproxen 750 mg (Lansoprazole group) Celecoxib 200 mg (Celecoxib group) | Having a history of bleeding peptic ulcers | None | 6.3 % (LPZ + Naproxen) vs. 3.7 % (Celecoxib) (6 months) (Upper-GI bleeding) | |
Scheiman et al. [23] | Esomeprazole 40 mg (n = 467) Esomeprazole 20 mg (n = 459) | Placebo (n = 452) | nsNSAIDs or COX-2 inhibitor | Older age (≥60) and/or having a history of peptic ulcers | 1, 3, 6 months | 4.6 % (EPZ 40 mg) vs. 5.2 % (EPZ 20 mg) vs. 17.0 % (placebo) (6 months) | |
Chan et al. [30] | Esomeprazole 20 mg (n = 136) | Placebo (n = 137) | Celecoxib 400 mg | Having a history of bleeding peptic ulcers | None | 0 % (EPZ + Celecoxib) vs. 8.9 % (Celecoxib) (13 months) (Upper-GI bleeding) |
Preventive effects of antisecretory drugs for LDA-induced peptic ulcers
References | Treatment (number of patients) | Control (number of patients) | Patient characteristics | Scheduled endoscopy | Incidence of peptic ulcers | HR (95 % CI) |
---|---|---|---|---|---|---|
Japan | ||||||
Sugano et al. [31] | Lansoprazole 15 mg (n = 226) | Gefarnate 100 mg (n = 235) | Having a history of peptic ulcers | 3, 6, 12 months | 1.5 % (LPZ) vs. 15.2 % (GN) (3 months) 2.1 % (LPZ) vs. 24.0 % (GN) (6 months) 3.7 % (LPZ) vs. 31.7 % (GN) (12 months) | 0.099 (0.042–0.230) |
AstraZenecaa [32] | Esomeprazole 20 mg (n = 182) | Placebo (n = 182) | Having a history of peptic ulcers | 3, 6, 9, 12, 15, 18 months | 1.7 % (EPZ) vs. 18.8 % (placebo) (12 months) | 0.09 (0.02–0.41) |
Sanuki et al. [33] | Rabeprazole 20 mg (n = 89) Rabeprazole 10 mg (n = 87) | Gefarnate 100 mg (n = 85) | Having a history of peptic ulcers | 3 months | 5.5 % (RPZ) vs. 26.7 % (GN) (3 months) 3.7 % (RPZ 20 mg) 7.4 % (RPZ 10 mg) | 0.179 (0.082–0.394) |
Overseas | ||||||
Chan et al. [24] | Omeprazole 20 mg (n = 125) | HP eradication therapy followed by placebo (n = 125) | Having a history of gastrointestinal bleeding with HP infection | None | 0.9 % (OPZ 20 mg) vs. 1.9 % (eradication) (6 months) (Upper-GI bleeding) Statistically not significant | |
Lai et al. [37] | Lansoprazole 30 mg (n = 62) | Placebo (n = 61) | Having ulcer complications with HP infection followed by ulcer healing and HP eradication | None | 1.6 % (LPZ 30 mg) vs. 14.8 % (placebo) (12 months) (ulcer complications: bleeding, perforation, or obstruction) | |
Yeomans et al. [34] | Esomeprazole 20 mg (n = 493) | Placebo (n = 498) | Older age (≥60) | 2, 6.5 months | 1.8 % (EPZ) vs. 6.2 % (control) (6.5 months) | |
Taha et al. [36] | Famotidine 40 mg (n = 204) | Placebo (n = 200) | Aged ≥18 | 3 months | 3.4 % (Famotidine) vs. 15.0 % (placebo) (GU, 3 months) 0.5 % (Famotidine) vs. 8.5 % (placebo) (DU, 3 months) | 0.20 (0.09–0.47) (GU) 0.05 (0.01–0.40) (DU) |
Ng et al. [38] | Pantoprazole 20 mg (n = 65) | Famotidine 80 mg (n = 65) | Having a history of upper gastrointestinal bleeding or dyspepsia due to peptic ulcers/erosion | None | 0 % (PPZ) vs. 20.0 % (FAM) (12 months) (Dyspeptic or bleeding ulcers/erosion) | |
Bhatt et al. [40] | Omeprazole 20 mg (n = 1,876) | Placebo (n = 1,885) | Having acute coronary syndrome or percutaneous coronary intervention receiving aspirin and clopidogrel | None | 1.1 % (OPZ) vs. 2.9 % (placebo) (6 months) (GI events: overt or occult bleeding, symptomatic gastroduodenal ulcers or erosion, obstruction, or perforation) | 0.34 (0.18–0.63) |
Scheiman et al. [35] | Esomeprazole 40 mg (n = 817) Esomeprazole 20 mg (n = 804) | Placebo (n = 805) | Older age (≥65), older age (≥60) with one or more risk factors, aged ≥18 with a history of peptic ulcers | 2, 6.5 months | 1.5 % (EPZ 40 mg) vs. 1.1 % (EPZ 20 mg) vs. 7.4 % (control) (6.5 months) | 0.19 (0.10–0.37) (EPZ 40 mg) 0.14 (0.07–0.30) (EPZ 20 mg) |
Ng et al. [39] | Esomeprazole 20 mg (n = 163) | Famotidine 40 mg (n = 148) | Having acute coronary syndrome or ST elevation myocardial infarction receiving aspirin, clopidogrel, and enoxaparin or thrombolytics | None | 0.6 % (EPZ, 19.2 weeks) vs. 6.1 % (FAM, 17.6 weeks) | 0.095 (0.005–0.504) |
Definitions of high-risk NSAID users and recommended preventive strategies in recent guidelines
References | GI risk factors | Definition of GI risk | Definition of CV risk | Recommended preventive strategy |
---|---|---|---|---|
Chan et al. [3] | Aged ≥70 Prior upper-GI event Concomitant use of aspirin Concomitant use of anticoagulants Concomitant use of corticosteroids | High: having any GI risk factor Average: no GI risk factors | High: established coronary artery disease, any CV disease that required prophylactic LDA, an estimated 10-year CV risk of greater than 20 % Average: no CV risk factors | High GI risk with High CV risk: avoid NSAID if possible, naproxen + PPI/misoprostol High GI risk with Average CV risk: nsNSAID + PPI/misoprostol or COX-2 inhibitor + PPI/misoprostol Average GI risk with High CV risk: naproxen (if not on aspirin) or naproxen + PPI/misoprostol (if on aspirin) Average GI risk with Low CV risk: nsNSAID alone |
Rostom et al. [4] | Aged ≥60–75 History of upper GI symptoms History of peptic ulcer History of GI bleeding High-dose NSAID Multiple NSAIDs Concomitant use of aspirin Concomitant use of anticoagulants Concomitant use of corticosteroids Concomitant use of SSRI Severe RA disability History of cardiovascular disease
Helicobacter pylori positive | Very High: having history of GI bleeding High: having any GI risk factor other than history of GI bleeding Low: no GI risk factors | High: requirement for prophylactic LDA Low: no requirement for prophylactic LDA | Very High GI risk: COX-2 inhibitor + PPI High GI risk with High CV risk: avoid NSAID if possible or naproxen + PPI High GI risk with Low CV risk: COX-2 inhibitor alone or nsNSAID + PPI Low GI risk with High CV risk: naproxen + (PPI) Low GI risk with Low CV risk: nsNSAID Eradication of Helicobacter pylori infection if positive |
Lanza et al. [5] | History of peptic ulcer complication History of peptic ulcer disease Aged >65 High-dose NSAID Concomitant use of aspirin, corticosteroids or anticoagulants
Helicobacter pylori positive | High: 1. history of peptic ulcer complication 2. concomitant use of corticosteroids or anticoagulants 3. multiple (≥3) GI risk factors Moderate: 1-2 GI risk factors Low: no GI risk factors | High: requirement for prophylactic LDA Low: no requirement for prophylactic LDA | High GI risk with High CV risk: avoid NSAID if possible High GI risk with Low CV risk: alternative therapy if possible or COX-2 inhibitor + PPI/misoprostol Moderate GI risk with High CV risk: naproxen + PPI/misoprostol Moderate GI risk with Low CV risk: NSAID + PPI/misoprostol Low GI risk with High CV risk: naproxen + PPI/misoprostol Low GI risk with Low CV risk: NSAID alone Eradication of Helicobacter pylori infection if positive |
Burmester et al. [6] | Previous upper-GI event Aged ≥65 Continuous NSAID use Concomitant use of aspirin, anticoagulants or corticosteroids | Increasing GI risk is related to the number of GI risk factors | High: 10-year risk of fatal CV event ≥10 % Low: 10-year risk of fatal CV event <10 % | High GI risk with High CV risk: avoid any NSAID if possible, if needed: diclofenac/naproxen + PPI or COX-2 inhibitor + PPI High GI risk with Low CV risk: ibuprofen/diclofenac + PPI or COX-2 inhibitor + PPI Moderate GI risk with High CV risk: naproxen + PPI Moderate GI risk with Low CV risk: COX-2 inhibitor or nsNSAID + PPI Low GI risk with High CV risk: naproxen + PPI Low GI risk with Low CV risk: nsNSAID alone |
Adherence to evidence-based guidelines for the safe prescription of NSAIDs
References | Database of patients | Number of NSAID users | Study design | Number of NSAID users with GI risk (%) | Adherence to guidelines |
---|---|---|---|---|---|
Smalley et al. [9] | Tennessee Medicaid program (from January 1999 to June 2000) | 76,765 (nsNSAIDs 71,839, Coxibs 4,926) | Retrospective cross-sectional study | Any single GI risk factor: 15,587 (20.3 %) Two or more GI risk factors: 1,692 (2.2 %) | Any single GI risk factor: 18 % (gastroprotectant 9 %, Coxibs 9 %) Two or more GI risk factors: 30 % (gastroprotectant 11 %, Coxibs 19 %) |
Abraham et al. [10] | Veterans Affairs database (from January 1999 to December 2002) | 707,244 | Retrospective cross-sectional study | At least 1 GI risk factors: 303,787 (43.0 %) At least 2 GI risk factors: 30,133 (4.3 %) Three or more GI risk factors: 1,503 (0.2 %) | At least 1 GI risk factor: 27.2 % (gastroprotectant 17.8 %, Coxibs 9.4 %) At least 2 GI risk factors: 39.7 % Three or more GI risk factors: 41.8 % |
Valkhoff et al. [11] | Integrated Primary Care Information database (from January 1996 to December 2006) | 50,126 | Retrospective cross-sectional study | At least 1 GI risk factor: 21,685 (43.3 %) | At least 1 GI risk factors: 21.9 % (gastroprotectant 14.6 %, Coxibs 7.3 %) Adherence to guidelines rose from 6.9 % in 1996 to 39.4 % in 2006 |
Lanas et al. [12] | Osteoarthritis patients that visited 1,760 doctors in the Spanish National Health System in a single day (25 March 2009) | 13,515 (nsNSAIDs 7,916, Coxibs 5,599) 17,105 OA patients | Prospective cross-sectional study | Moderate GI risk: 5,511 (32.2 %) OA patients High GI risk: 10,311 (60.3 %) OA patients CV history positive: 5,256 Low GI risk with CV history positive: 62 Low GI risk with CV history negative: 1,144 Moderate GI risk with CV history positive: 871 Moderate GI risk with CV history negative: 4,373 High GI risk with CV history positive: 4,323 High GI risk with CV history negative: 5,697 | Moderate GI risk: 88.7 % (nsNSAIDs + gastroprotectant 49.8 %, Coxibs 18.0 %, Coxib + gastroprotectant 20.9 %) High GI risk: 95.6 % (nsNSAIDs + gastroprotectant 52.0 %, Coxibs 10.3 %, Coxib + gastroprotectant 33.3 %) High GI risk with CV history positive: 25.6 % (no use of NSAIDs) High GI risk with CV history negative: 27.3 % (Coxib + gastroprotectant) |
Outcomes of adherence to preventive strategies for the safe prescription of NSAIDs
References | Database of patients | Number of NSAID users | Study design | Number of NSAID users receiving gastroprotectant | Upper-GI events | Outcome of adherence to gastroprotective therapy | Notes |
---|---|---|---|---|---|---|---|
Goldstein et al. [13] | PharMetrics Integrated Outcomes database (Information collected from approximately 75 commercial managed-care plans) (from January 2000 to December 2002) | 92,833 (nsNSAID) 51,370 (Coxibs) | Retrospective cross-sectional study | 1,312 (1.4 %) in nsNSAID users 1,322 (2.6 %) in Coxibs users | 161 (12.3 %) in nsNSAID users receiving gastroprotectant 302 (22.8 %) in Coxibs users receiving gastroprotectant | Higher risk of upper-GI events in nsNSAID users with adherence rate <80 % of PPI therapy | OR (95 % CI): 2.4 (1.0–5.6) (compared with nsNSAID users with adherence rates of 80 % or more) |
Van Soest et al. [14] | Integrated Primary Care Information database (from January 1996 to September 2005) | 31,944 (nsNSAID) 2,602 (Coxibs) 3,546 (Diclofenac/Misoprostol, fixed combination) | Nested case–control study | 2,735 (8.6 %) in nsNSAID users 359 (13.8 %) in Coxibs users 388 (10.9 %) in Diclofenac/Misoprostol, fixed combination | 169 cases in NSAID users (48,046 matched controls in NSAID users) | Strong inverse relationship between adherence to gastroprotectant and the risk of upper-GI complications | OR (95 % CI): 2.5 (1.0–6.7) in nsNSAID users receiving gastroprotectant with adherence 0.2–0.8 OR (95 % CI): 4.0 (1.2–13.0) in nsNSAID users receiving gastroprotectant with adherence <0.2 (compared with nsNSAID users receiving gastroprotectant with adherence rates of 80 % or more) |
Abraham et al. [15] | Veterans Affairs database (from January 2000 to December 2002) | 440,547 (nsNSAID) 41,433 (Coxibs) | Retrospective cross-sectional study | 53,031 (12.0 %) PPI therapy in nsNSAID users 33,124 (79.9 %) PPI therapy in Coxibs users | 2,753 upper-GI events in 220,662 person-years of follow-up | Higher risk of upper-GI events in NSAID users with no PPI therapy | OR (95 % CI): 1.8 (1.6–2.0) on NSAID alone OR (95 % CI): 1.8 (1.5–2.0) on Coxib alone OR (95 % CI): 1.1 (0.7–4.6) on NSAID + PPI OR (95 % CI): 1.1 (0.6–5.2) on Coxib + PPI (reference category is no exposure) OR (95 % CI): 3.0 (2.6–3.7) in NSAID users receiving PPI with adherence >0–20 % OR (95 % CI): 1.8 (1.5–2.3) in NSAID users receiving PPI with adherence 20–40 % OR (95 % CI): 1.8 (1.5–2.2) in NSAID users receiving PPI with adherence 40–60 % OR (95 % CI): 1.3 (1.1–1.6) in NSAID users receiving PPI with adherence 60–80 % OR (95 % CI): 1.1 (1.0–1.3) in NSAID users receiving PPI with adherence 80–100 % (reference category is no exposure to PPI) |
Tsumura et al. [16] | NSAID users who had undergone upper gastrointestinal endoscopy (from April 2006 to March 2007) | 254 (regular users 128, on-demand users 126) | Retrospective cross-sectional study | 25 (31.7 %) PPI or PA therapy in high risk regular NSAID users 16 (24.6 %) PPI or PA therapy in high risk on-demand NSAID users | 17 endoscopic GU in regular NSAID users 9 endoscopic GU in on-demand NSAID users | Higher incidence of endoscopic GU in NSAID users with non-adherence to guidelines for the prescription of NSAIDs | Incidence of GU: 29.6 % (non-adherence) vs. 4.0 % (adherence) in regular NSAID users |
Abraham et al. [17] | Veterans Affairs database (from January 2001 to December 2004) Veterans Affairs-Medicare dataset | Retrospective cohort study | 3,566 (nsNSAIDs 93.8 %, Coxib 6.2 %) (PPI + 41.8 %, PPI− 58.2 %) (Hospitalized for UGIE 47.5 %) | Higher risk of hospitalization due to upper-GI events, and higher medical cost in NSAID users with no PPI therapy | OR (95 % CI): 1.4 (1.1–1.7) (compared with NSAID users with PPI therapy) Medical cost: $9,948,738 (PPI +) vs. $18,686,081 (PPI−) (5-year medical costs) | ||
Van Soest et al. [18] | General Practice Research Database (UK 1998–2008) Integrated Primary Care Information database (the Netherlands 1996–2007) Health Search/CSD Longitudinal Patient Database (Italy 2000–2007) | 618,684 NSAID users 1,107,266 nsNSAID episodes | Nested case–control study | 117,307 nsNSAID episodes receiving gastroprotectants | 339 cases in nsNSAID plus gastroprotectant cohort (71,380 matched controls in nsNSAID plus gastroprotectant cohort) | Higher risk of upper-GI events in nsNSAID users with adherence rate <80 % of PPI therapy | OR (95 % CI): 1.35 (1.05–1.73) in nsNSAID users receiving gastroprotectant with adherence 0.2–0.8 OR (95 % CI): 2.39 (1.66–3.44) in nsNSAID users receiving gastroprotectant with adherence <0.2 (compared with nsNSAID users receiving gastroprotectant with adherence rates of 80 % or more) |