Practical Approach in Managing NSAID Risks: GI and CV Prof. Chutima Pramoolsinsap Division of Gastroenterology and Tropical Medicine Ramathibodi Hospital 1 st Emergency Medicine Update 2550 สมาคมเวชศาสตร์ฉุกเฉินแห่งประเทศไทย 1 September 2007

Content Overview: Aspirin and NSAIDs GI adverse effects of NSAIDs Mechanism Risk factors Cardiovascular (CV) risks associated with NSAIDs Prevention strategy with NSAIDs based on GI and CV patient risk factors Summary

Overview: Aspirin and NSAIDs

GI adverse effects of NSAIDs

Mechanism

Risk factors

Cardiovascular (CV) risks associated with NSAIDs

Prevention strategy with NSAIDs based on GI and CV patient risk factors

Summary

Pharmacological Effects Analgesic Antipyretic Anti-inflammatory Anti-platelet Familial Adenomatous Polyposis Alzheimer’s Some are uricosuric Adverse effects Platelet dysfunction Gastritis / PUD + bleeding Cardiovascular Acute Renal Failure Sodium+ water retention Edema Analgesic nephropathy Prolongation of gestation and inhibition of labor Hypersenstivity Nonsteroidal Anti-inflammatory Drugs (NSAIDs)

Pharmacological Effects

Analgesic

Antipyretic

Anti-inflammatory

Anti-platelet

Familial Adenomatous Polyposis

Alzheimer’s

Some are uricosuric

Adverse effects

Platelet dysfunction

Gastritis / PUD + bleeding

Cardiovascular

Acute Renal Failure

Sodium+ water retention

Edema

Analgesic nephropathy

Prolongation of gestation

and inhibition of labor

Hypersenstivity

Major Diseases Attributable to Disability-Adjusted Life Years (DALYs) Lost of Thai People by Sex, 2002 Bureau of Policy and Strategy. Burden of Disease and Injuries in Thailand, 2002

Death and Injury Rates from Road Traffic Accidents, Thailand, 1984-2002 Police Information System Centre, Royal Thai Police.

Growing proportion of the Thai elderly M F M F M F M F Year 1960 1980 2000 2020 It is estimated that the number of Thai people > 60 years will increase from 4.02 million (7.36 % of total population) in 1990 to become 10.78 million (15.28%of the total population) in 2020 J Med Assoc Thai 2005; 88 (9): 1257-60

It is estimated that the number of Thai people > 60 years will increase from 4.02 million (7.36 % of total population) in 1990 to become 10.78 million (15.28%of the total population) in 2020

Proportion of Thai elders with most common diseases/symptoms by age group,2002 Surveys on Elderly People in Thailand 2002, National Statistical Office. Age (yrs) 17.7 22.3 27.5 34.4 34.1 42.8 72.7 60-64 20.3 26.5 31.1 35.6 38.1 46.7 74.7 65-69 21.9 33.2 37.3 38.7 42.0 49.8 77.8 70-74 21.6 20.0 Hyper/ hypotension 45.2 29.8 Dementia 42.8 33.2 Eye diseases 41.2 36.8 Vertigo 44.9 38.7 Insomnia 54.9 47.5 Joint pain (degeneration) 77.3 75.1 Body ache, backache > 75 Total Disease/Symptom of Thai Elders

Nonsteroidal Anti-Inflammatory Drugs (NSAIDs) WHO 2005: worldwide 10-50% suffer from musculoskeletal disorders P harmaceutical market value for pain relief = $23 billion in 2004. Worldwide: 70 million people/day prescribed NSAIDs 230 million people/day take OTC NSAIDs Inflammopharmacology. 2005;13(4):343-70.

WHO 2005: worldwide 10-50% suffer from musculoskeletal disorders

P harmaceutical market value for pain relief = $23 billion in 2004.

Worldwide: 70 million people/day prescribed NSAIDs

230 million people/day take OTC NSAIDs

Willow leaf extracts for musculoskeletal conditions Aspirin first synthesised NSAIDs – a Long History of Analgesia and Toxicity 4 00 B.C. Greek physician 1899 1938 1950 1970 1982 1992 1998 Hippocrates Non-selective NSAIDs identified and developed. COX-2 selective NSAIDs discovered First COX-2 selective NSAIDs approved first endoscopic evidence that aspirin caused gastric mucosal damage. Lancet 1938;ii:1222­5 M echanism of action for aspirin

NSAIDs inhibit the COX enzyme, which exists in two forms Arachidonic acid COX-1 (constitutive) COX-2 (induced by inflammatory stimuli) Non-selective NSAIDs Gastrointestinal cytoprotection Platelet activity Inflammation Pain Fever Prostaglandins Prostaglandins    COX-2 selective NSAIDs Vane & Botting 1995

Gastrointestinal cytoprotection

Platelet activity

Inflammation

Pain

Fever

The 9 chemical groupings of NSAIDs http://www.fda.gov/cder/drug/infopage/COX2/NSAIDmedguide.htm

Range of COX-1 and COX-2 selectivity of NSAIDs COX = cyclooxy-genase; IC50 = concentration of NSAID that inhibits COX by 50%,

Pharmacological Effects Analgesic Antipyretic Anti-inflammatory Anti-platelet Familial ddenomatous polyposis Alzheimer’s Some are uricosuric Adverse effects Platelet dysfunction Gastritis / PUD + bleeding Cardiovascular Acute Renal Failure Sodium+ water retention Edema Analgesic nephropathy Prolongation of gestation and inhibition of labor Hypersenstivity Nonsteroidal Anti-inflammatory Drugs (NSAIDs)

Pharmacological Effects

Analgesic

Antipyretic

Anti-inflammatory

Anti-platelet

Familial ddenomatous polyposis

Alzheimer’s

Some are uricosuric

Adverse effects

Platelet dysfunction

Gastritis / PUD + bleeding

Cardiovascular

Acute Renal Failure

Sodium+ water retention

Edema

Analgesic nephropathy

Prolongation of gestation

and inhibition of labor

Hypersenstivity

Gastrointestinal adverse effects and NSAIDs

GI Side effects of NSAIDs Dyspepsia E sophagitis E sophageal strictures Gastric and duodenal petechiae, erosions, ulceration, bleeding, and perforation Type C gastritis Small and large bowel ulceration, bleeding, and perforation Exacerbation of colitis

Dyspepsia

E sophagitis

E sophageal strictures

Gastric and duodenal petechiae, erosions, ulceration, bleeding, and perforation

Type C gastritis

Small and large bowel ulceration, bleeding, and perforation

Exacerbation of colitis

Gastric acid plays a central role in NSAID-associated gastroduodenal damage Acidic environment Bicarbonate layer Ionic gradient Gastric acid NSAIDs Pepsin Surface epithelial cells Mucus layer Neutral environment Mucosal blood supply Alkaline environment Prostaglandin production Bicarbonate production Mucus production NSAIDs normal gastric mucosa 16 minutes after administration of aspirin Direct effect

Gastric acid plays a central role in NSAID-associated gastroduodenal damage Acidic environment Bicarbonate layer Ionic gradient Gastric acid NSAIDs Pepsin Surface epithelial cells Mucus layer Neutral environment Mucosal blood supply Alkaline environment Prostaglandin production Bicarbonate production Mucus production NSAIDs Systemic effect

NSAIDs increase neutrophil – endothelial adhesion NSAIDs Decreased prostaglandin, increased tumour necrosis factor Increased neutrophil– endothelial adhesion Ischaemic/hypoxic cell injury Endothelial and epithelial injury Mucosal ulceration Wallace et al 1997 Neutrophil release of proteases and oxygen-derived free radicals Capillary obstruction

NSAID induced GI damage 3 main types of GI lesions : Superficial damage i.e. mucosal hemorrhages and erosions Endoscopically documented non-symptomatic (‘silent’) ulcers Symptomatic ulcers causing complications i.e. GI hemorrhage .

3 main types of GI lesions :

Superficial damage i.e. mucosal hemorrhages and erosions

Endoscopically documented non-symptomatic (‘silent’) ulcers

Symptomatic ulcers causing complications i.e. GI hemorrhage .

NSAID ingestion and GI injury JIACM 2003; 4(4): 315-22

GI symptoms Endoscopic ulcers Clinical ulcers Serious GI events Relative severity Relative frequency NSAID-related GI Effects

Spectrum of lesions / side effects induced by NSAIDs Lesion / side effects Frequency Clinical Relevance Erosions > 50% Low Endoscopic Ulcers 10-30% Dyspepsia >30% Symptomatic Ulcers 2-4% UGI Complications 1-1.5% LGI Complications ≊ 0.8% High Lanas A, Hunt R, Ann Meds 2006.

Lesion / side effects Frequency Clinical Relevance

Erosions > 50% Low

Endoscopic Ulcers 10-30%

Dyspepsia >30%

Symptomatic Ulcers 2-4%

UGI Complications 1-1.5%

LGI Complications ≊ 0.8%

High

MUCOSA CLASS VIGOR TARGET (N=4439) (N=3981) (N=4029) (N=9127) Arthritis RA OA(73%); RA OA RA (27%) NSAID (N) 10 specified Ibuprofen naproxen Ibuprofen NSAIDs diclofenac naproxen Low-dose aspirin Not stated 20% 0 24% Median follow-up 6 mo 9 mo 9 mo 12 mo Upper GI complications 1.5% 1.0% 1.4% 1.3% (annualized incidence) Upper GI clinical events 2.7% 2.8% 4.5% 2.8% (annualized incidence) Incidences of Upper GI Complications and Clinical Events (Complications plus Symptomatic Ulcers) From NSAID-only Arms of GI Outcome Studies J Cardiovasc Pharmacol 2006; 47(1):S60-6

Clopidogrel in Unstable Angina to Prevent Recurrent Events (CURE) Trial Life-threatening or major bleeding 0 1 2 3 4 5 % of patients By aspirin dose, n=6293 <100 mg 1.9 n=990 100–150 mg 2.2 n=2857 151–300 mg 3.3 n=1385 >300 mg n=1061 3.8 Eur Heart J 2002;4:Suppl, 510

CURE: Aspirin plus clopidogrel All bleeding episodes 1.9 2.3 3.9 3.0 3.2 5.0 0 1 2 3 4 5  100 mg 110–162 mg  200 mg % of patients n=5259 n=3115 n=4172 Aspirin Clopidogrel + aspirin p < 0.001 Eur Heart J 2002;4:Suppl, 510

Relative risk (RR) and 95% confidence interval of upper GI bleeding for individual NSAIDs Non-use Reference Celecoxib 1.0 (0.4-2.1) Aceclofenac 2.6 (1.5-4.6) Diclofenac 3.1 (2.3-4.2) Ibuprofen 4.1 (3.1-5.3) Naproxen 7.3 (4.7-11.4) Lomoxicam 7.7 (2.4-24.4) Ketoprofen 8.6 (2.5-29.2) Indomethacin 9.0 (3.9-20.7) Meloxicam 9.8 (4.0-23.8) Piroxicam 12.6 (7.8-20.3) Ketorolac 14.1 (5.2-39.9) Low High Individual NSAID Relative Risk (95% CI) Lanas A et al. Gut (2006) *Adjusted for age, sex, calendar semester, ulcer history, nitrates, anticoagulants, antiplatelets, acid-suppressing drugs, coxib and aspirin use. Cases (n = 2777) and Controls (n = 5532)

Non-use Reference

Celecoxib 1.0 (0.4-2.1)

Aceclofenac 2.6 (1.5-4.6)

Diclofenac 3.1 (2.3-4.2)

Ibuprofen 4.1 (3.1-5.3)

Naproxen 7.3 (4.7-11.4)

Lomoxicam 7.7 (2.4-24.4)

Ketoprofen 8.6 (2.5-29.2)

Indomethacin 9.0 (3.9-20.7)

Meloxicam 9.8 (4.0-23.8)

Piroxicam 12.6 (7.8-20.3)

Ketorolac 14.1 (5.2-39.9)

*Adjusted for age, sex, calendar semester, ulcer history, nitrates, anticoagulants, antiplatelets, acid-suppressing drugs, coxib and aspirin use.

Risk of Hospitalization for Upper GI Bleeding with COXIBs 3.0 4.0 1.9 1 2 3 4 5 6 7 Adjusted Rate Ratio 0 Non-use celecoxib rofecoxib diclo+miso NSAIDs Mamdani et al. BMJ 2002;325(7365):624-7 1.0 1.0 >55% women Mean age >75 yrs >1% with Hx of GI bleed >16% Use of gastroprotective agent >12% Use of aspirin 100,000 (2.2)* 18,908 (3.6)* 14,583 (7.3)* 5,087 (9.6)* 5,391 (12.6)* *n (no. upper GI bleeds per 1000 person-yrs)

Risk Factors for NSAID-Induced Gastropathy Definite: • Age • Prior history of ulcer • Duration of NSAID therapy • Concomitant corticosteroid therapy • Concomitant warfarin therapy • Concomitant ASA / NSAID • NSAID dose • Serious systemic illness (CHF, RA, CAD, others) Possible: • Concomitant H. Pylori infection? • Smoking • Alcohol

Risk Factors for NSAID-Associate d GI Complications NSAIDs, nonsteroidal antiinflammatory drugs; SSRIs, selective serotonin reuptake inhibitors. Dalton SO, et al. Arch Intern Med. 2003;163:59–64. Gabriel SE, et al. Ann Intern Med. 1991;115:787–796; Garcia Rodriguez LA, et al. Lancet. 1994;343:769–772. Silverstein FE, et al. Ann Intern Med. 1995;123:241–249.

Distribution of Patients with GI Complications From NSAIDs by Age and Sex Am J Gastroenterol 2005;100:1685–93

Risk of UGI Complication for NSAID Users Impact of Ulcer History 20-60 60-69 70-79 >=80 Men complic ulcer +NSAID Men ulcer + NSAIDs Men No ulcer +NSAIDs Incidence per 1,000 person-years Based on Hemandez & Garcia-Rodriguez, BMC Medicine 2006;4:22.

Rates of symptomatic ulcers and ulcer complications with naproxen in patients with rheumatoid arthritis Bombadlar C et al. N Engl J Med 343;1520-8(2000): Lenas A. Gastroenterol Gastro 2007. Number events x 100 patient-years No NSAID use <65 65-74 >74 Ulcer Hx Ulcer complications >65+Hx Ulcer >65+Hx Ulcer+sterolds Age

Annualized Incidence % Ulcer Complications Symptomatic Ulcers and Ulcer Complications 49 / 1384 30 / 1441 11 / 1441 20 / 1384 p = 0.02 p = 0.09 All Patients 32 / 1101 16 / 1143 5 / 1143 14 / 1101 p = 0.02 p = 0.04 Patients Not Taking Aspirin 17 / 283 14/ 298 6 / 298 6 / 283 p = 0.49 p = 0.92 Patients Taking Aspirin CLASS Trial: Upper GI Complications Alone and With Symptomatic Ulcers Silverstein et al. JAMA 2000; 284:1247-1255 = celecoxib = NSAIDs (ibuprofen + diclofenac)

Low-dose aspirin excluded

Cumulative Incidence (%) *P<0.001 vs placebo and vs aspirin ROF = Rofecoxib Gastroduodenal ulcers at 12 weeks in patients with OA Aspirin Negates the GI-sparing Effect of COX-2 Inhibitors Gastroenterology 2004; 127: 395-402. * * N=381 N=387 N=377 N=374 %

Low-Dose Aspirin Combined with NSAID or Coxib Drug R.R 95% CI Aspirin only 3.6 2.9-4.3 NSAID only 5.0 4.3-5.9 Combined 10.2 6.2-16.7 Aspirin only 3.3 2.8-4.0 Coxib only 1.1 0.7-1.9 Combined 9.5 2.5-36.2 Lanas et al. Gut 2006

Risk of UGI Complication for NSAID Users Impact of ASA use 20-60 60-69 70-79 >=80 Incidence per 1,000 person-years Based on Hermandez & Garcla-Rodriguez. BMC Medicine 2006;4:22

Non-aspirin antiplatelet agents combined with NSAIDs Drug R.R 95% CI Aspirin only 3.6 2.9-4.3 NSAID only 5.0 4.3-5.9 Combined 10.2 6.2-16.7 Clopidogrel/Ticlid only 3.1 2.2-4.4 NSAID only 5.0 4.3-5.8 Combined 15.5 4.7-50.4 Lanas et al. Gut 2006

NSAID-Induced Small Bowel Lesions Endoscopic photograph of terminal ileum, demonstrating inflamed diaphragm in patient receiving long-term NSAIDs

I ncrease in risk owing to NSAID use for upper GI and lower GI complications Lanas et al. 10.7 (95% CI,4.5–26.0) 18.4 (95% CI,4.7–51.4) Wilcox et al. 3.2 (95% CI,2.6 –4.0) 2.6 (95% CI,1.7–3.9) Lanas et al. 6.3 (95% CI,3.1– 12.9) 8.1 (95% CI,2.3–31.9) O dds ratios for use of NSAIDs in patients with upper GI bleeding lower GI bleeding O dds ratios for use of NSAIDs and GI perforation upper GI lower GI Gastroenterology 2003;124:288–92

Lanas et al. 10.7 (95% CI,4.5–26.0) 18.4 (95% CI,4.7–51.4)

Wilcox et al. 3.2 (95% CI,2.6 –4.0) 2.6 (95% CI,1.7–3.9)

Lanas et al. 6.3 (95% CI,3.1– 12.9) 8.1 (95% CI,2.3–31.9)

Liver Warning over L umiracoxib Australia, Aug. 11, 2007 Therapeutic Goods Administratio n ( TGA ) had received 8 reports of serious liver adverse reactions associated with use of lumiracoxib (prexige®) 2 deaths and 2 patients requiring liver transplants. All these reports have been received since March 2007 , with 6 reports received in the last 6 weeks.

Australia, Aug. 11, 2007

Therapeutic Goods Administratio n ( TGA ) had received 8 reports of serious liver adverse reactions associated with use of lumiracoxib (prexige®)

2 deaths and 2 patients requiring liver transplants.

All these reports have been received since March 2007 , with 6 reports received in the last 6 weeks.

Mortality Study ASA-attributed Complications and Deaths >5% of people take low-dose ASA (secondary CV prevention) Almost a third of all NSAID use detected in patients hospitalized with ulcer bleeding is low-dose ASA. 321 GI Bleedings per 100,000 users 18 Deaths per 100,000 users Lanas et al. Am J Gastroenterol 2005

>5% of people take low-dose ASA (secondary CV prevention)

Almost a third of all NSAID use detected in patients hospitalized with ulcer bleeding is low-dose ASA.

321 GI Bleedings per 100,000 users

18 Deaths per 100,000 users

Mortality Rate Attributed to NSAID/Aspirin-Associated GI Complications Am J Gastroenterol 2005;100:1685–93 Mortality rate per 1 million people Entire country population NSAID/aspirin users

Cardiovascular Risks Associated With COX-2–Selective Inhibitors and Nonselective NSAIDs

COX-2 Inhibitors: The “Promise” Lower incidence of GI side effects when compared to traditional NSAIDs Potentially attenuate intestinal tumor development COX-2 increased in atherosclerotic plaque COX-2 may play a role in inflammation that underlies cardiovascular risk

Lower incidence of GI side effects when compared to traditional NSAIDs

Potentially attenuate intestinal tumor development

COX-2 increased in atherosclerotic plaque

COX-2 may play a role in inflammation that underlies cardiovascular risk

NSAID Effects on Thromboxane and Prostacylin

Serious Thromboembolic Cardiovascular Adverse Events in Nonaspirin Users 1. Silverstein FE, et al. JAMA. 2000;284:1247–1255. 2. Bombardier C, et al. N Engl J Med. 2000;343:1520–1528.

APPROVe Trial: Confirmed Thrombotic Cardiovascular Events Over Time Bresalier RS, et al. N Engl J Med. 2005; 352: 1092-1102 . September 2004 , Vioxx (rofecoxib) withdrawal from worldwide market

April 7, 2005 , Bextra (valdecoxib) withdrawal Parecoxib/Valdecoxib: Cardiovascular Complications After Cardiac Surgery

Cardiovascular Risks in NSAID Users This black box warning statement now appears in the package insert (July 2005) for celecoxib

Black box warning for COX-2–selective drugs. This black box warning statement now appears in the package insert (July 2005 ) for celecoxib

APC Trial: Concomitant Aspirin Use Does Not Decrease Cardiovascular Risk of COX-2 Selective Inhibitors

MEDAL Program: Confirmed Thrombotic Cardiovascular Events Over Time Cannon CP, et al; MEDAL Steering Committee. Lancet. 2006;368:1771–1781.

BMJ 2006;332;1302-1308 Comparison of effects of different selective COX 2 inhibitors versus myocardial infarction

BMJ 2006;332;1302-1308 Comparison of effects of different selective COX 2 inhibitors versus placebo on stroke

Comparison of effects of different selective COX2 inhibitors versus placebo on vascular death. BMJ 2006;332;1302-1308

Is conventional NSAIDs safe for cardiovascular events?

Acute Myocardial Infarction NSAID Use: Case-Control Study of MediCal* FDA Advisory Committee Meeting. Rockville, MD; February 17, 2005. Singh G, et al. Ann Rheum Dis , 2005: 64 (Suppl 3 ) : 263.

Risk of Acute Myocardial Infarction Associated With Current NSAID Use *A d justed for other NSAID use, hypertension, congestive heart disease, cerebrovascular disease, hyperlipidemia, diabetes , rheumatoid arthritis, smoking and body mass index. Circulation. 2006; 113: 1950-1957.

*A d justed for other NSAID use, hypertension, congestive heart disease, cerebrovascular disease, hyperlipidemia, diabetes , rheumatoid arthritis, smoking and body mass index.

Meta-analysis : Cardiovascular Risk Associated With the Use of COX-2 Selective Inhibitors and Nonselective NSAIDs 17 case-control and 6 cohort studies reporting on CV events (mostly myocardial infarction) with COX-2 selective inhibitors, NSAIDs or both with nonuse/remote use of the agents as the reference exposure. JAMA. 2006; 296: 1633-1644 .

17 case-control and 6 cohort studies reporting on CV events (mostly myocardial infarction) with COX-2 selective inhibitors, NSAIDs or both with nonuse/remote use of the agents as the reference exposure.

Black Box Warning for A ll NSAIDs A ugust 1, 2005 FDA g ives b lack b ox w arning to all NSAIDs Cardiovascular r isk GI r isk

A ugust 1, 2005

FDA g ives b lack b ox w arning to all NSAIDs

Cardiovascular r isk

GI r isk

Black box warning for &quot;traditional&quot; NSAID group This example is from the package insert (January 2006 ) of diclofenac,

Comparison of effects of selective COX - 2 inhibitors versus traditional NSAIDs on myocardial infarction, BMJ 2006;332;1302-1308

BMJ 2006;332;1302-1308 Comparison of effects of selective COX - 2 inhibitors versus traditional NSAIDs on stroke

BMJ 2006;332;1302-1308 Comparison of effects of selective COX - 2 inhibitors versus traditional NSAIDs on vascular death.

Protective Strategies in Preventing NSAIDs-induced Ulcers and Ulcer Complications

Reduce the impact of risk factors Avoid inhibition or restore mucosal prostagladin levels Misoprostol (cytotec®) Coxibs Reduce acid H2-receptor antagonist (H2RA) Proton pump inhibitors (PPI) Protective Strategies in Preventing NSAIDs-induced Ulcers and Ulcer Complications

Reduce the impact of risk factors

Avoid inhibition or restore mucosal prostagladin levels

Misoprostol (cytotec®)

Coxibs

Reduce acid

H2-receptor antagonist (H2RA)

Proton pump inhibitors (PPI)

H2-receptor antagonist, (H2RA) B lock the action of histamine on parietal cells, decreasing acid production H2RA drugs cimetidine (Tagamet) ranitidine (Zantac) famotidine ( Famoc ) nizatidine (Axid)

B lock the action of histamine on parietal cells, decreasing acid production

H2RA drugs

cimetidine (Tagamet)

ranitidine (Zantac)

famotidine ( Famoc )

nizatidine (Axid)

Proton pump inhibitors (PP I s) Omeprazole (Losec®) Lansoprazole (Prevacid®) Pantoprazole ( Contro loc®) Rabeprazole (Pariet®) Esomeprazole (Nexium®) The cu rrently available 3 PPIs which have an IV formulation : Omeprazole , Pantoprazole , Esomeprazole

Omeprazole (Losec®)

Lansoprazole (Prevacid®)

Pantoprazole ( Contro loc®)

Rabeprazole (Pariet®)

Esomeprazole (Nexium®)

The cu rrently available 3 PPIs which have an IV formulation : Omeprazole , Pantoprazole , Esomeprazole

Misoprostol (cytotec®) PGE 1 analogue Stimulates increased mucus secretion Increases mucosal blood flow Side effects Diarrhea, abdominal pain, nausea, flatulence, headache, dyspepsia, vomiting, and constipation Contraindications: S hould not use in pregnant women because I ncreases uterine tone and contractions which may cause partial or complete abortions B irth defects

PGE 1 analogue

Stimulates increased mucus secretion

Increases mucosal blood flow

Side effects

Diarrhea, abdominal pain, nausea, flatulence, headache, dyspepsia, vomiting, and constipation

Contraindications: S hould not use in pregnant women because

I ncreases uterine tone and contractions which may cause partial or complete abortions

B irth defects

Di rectly targets COX-2, R educes risk of peptic ulceration D oes not seem to affect other adverse-effects of NSAIDs ( i.e. renal failure) I ncrease in the risk for heart attack, thrombosis and stroke by a relative increase in thromboxane. Selective COX-2 Inhibitors September 2004 , Vioxx (rofecoxib) withdrawal April 7, 2005, Bextra (valdecoxib) withdrawal

Di rectly targets COX-2,

R educes risk of peptic ulceration

D oes not seem to affect other adverse-effects of NSAIDs ( i.e. renal failure)

I ncrease in the risk for heart attack, thrombosis and stroke by a relative increase in thromboxane.

September 2004 , Vioxx (rofecoxib) withdrawal

April 7, 2005, Bextra (valdecoxib) withdrawal

Risk of adverse upper G.I. events associated with NSAIDs according to use of ulcer healing drugs. UK study: 9407 incident cases and 88,867 matched controls. BMJ 2005;331;1310-1316 Values are adjusted odds ratios* Not prescribed Prescribed Drug prescribed < 90 ulcer healing ulcer healing Interaction ratio ‡ P value for Days before index drugs in past drugs in past (95% Cl) interaction date † 90 days 90 days Celecoxib 1.44 1.06 0.73 (0.46 to 1.16) 0.18 Rofecoxib 2.33 1.06 0.45 (0.32 to 0.65) <0.001 Other selective 2.40 1.29 0.54 (0.36 to 0.81) <0.001 NSAIDs Ibuprofen 1.65 0.90 0.55 (0.43 to 0.70) <0.001 Diclofenac 2.17 1.49 0.69 (0.56 to 0.84) <0.001 Naproxen 2.73 0.83 0.31 (0.19 to 0.49) <0.001 Other non selective 2.03 1.16 0.57 (0.42 to 0.77) <0.001 NSAIDs Aspirin 1.87 0.81 0.43 (0.38 to 0.49) <0.001

Prevention of NSAID-induced ulcer Endoscopic remission rates for patients with endoscopically normal or hyperaemic gastric mucosa at baseline [a subset of patients with grade 0 of Lanza classification, who were treated with either pantoprazole 40 mg od or placebo for up to 12 weeks 0 4 8 12 P=0.036 92% 82% 75% 55% BIanchi Parro G, et a. Digest Liver Dis 2000 Endoscopic remission rate (%) Time (wks)

Efficacy of pantoprazole in the primary prevention of NSAID-induced gastroduodenal damage Patient population Treatment Treatment n Remission rate (%) duration Rheumatic 6 months Pantoprazole 20 mg od 257 89 disease; Continuous NSAID; Misoprostol 200 mg bid 258 70 high risk (p<0.001) Rheumatic 6 months Pantoprazole 20 mg od 196 90 Disease; Continuous NSAID; Pantoprazole 40 mg od 199 93 high risk Omeprazole 20 mg o.d. 200 89 (NS) SINGH, G. Int J Clin Pract 2005

112 RCTS ( 74,666 participants) 138 deaths and 248 serious GI events On comparing gastroprotective strategies vs placebo N o evidence of effectiveness of H2 receptor antagonists for any primary outcomes P roton pump inhibitors R educe risk of symptomatic ulcers ( RR 0.09, 95% CI 0.02 - 0.47 ) M isoprostol R educes risk of serious GI (RR 0.57, 95% CI 0.36 - 0.91 ) R educes symptomatic ulcers (RR 0.36, 95% CI 0.20 - 0.67 ) S ystematic review : E ffectiveness of five strategies for the prevention of GI toxicity induced by NSAIDs BMJ 2004; 329: 948

112 RCTS ( 74,666 participants)

138 deaths and 248 serious GI events

On comparing gastroprotective strategies vs placebo

N o evidence of effectiveness of H2 receptor antagonists for any primary outcomes

P roton pump inhibitors

R educe risk of symptomatic ulcers ( RR 0.09, 95% CI 0.02 - 0.47 )

M isoprostol

R educes risk of serious GI (RR 0.57, 95% CI 0.36 - 0.91 )

R educes symptomatic ulcers (RR 0.36, 95% CI 0.20 - 0.67 )

The effectiveness of five strategies for the prevention of gastrointestinal toxicity induced by NSAIDs : systematic review COX-2 selectives R educe risk of symptomatic ulcers ( 0.41, 95% CI; 0.26-0.65 ) No reduce the risk of endoscopic ulcers (at least 3 mm d iameter). COX-2 specifics R educe risk of symptomatic ulcers ( 0.49 , 95% CI; 0.38-0.62 ) R educe risk of serious GI complications ( 0.55 , 95% CI; 0.38-.80 ) BMJ 2004;329:948

COX-2 selectives

R educe risk of symptomatic ulcers ( 0.41, 95% CI; 0.26-0.65 )

No reduce the risk of endoscopic ulcers (at least 3 mm d iameter).

COX-2 specifics

R educe risk of symptomatic ulcers ( 0.49 , 95% CI; 0.38-0.62 )

R educe risk of serious GI complications ( 0.55 , 95% CI; 0.38-.80 )

Misoprostol All doses of misoprostol significantly reduced the risk of endoscopic ulcers. Misoprostol 800 ug/day was superior to 400 ug/day for prevention of endoscopic GU (RR= 0.17 , and RR= 0.39 respectively, p= 0.0055) A dose response relationship was not seen with DU Misoprostol caused diarrhea at all doses, although significantly more at 800 ug/day than 400 ug/day (p= 0012 ). Misoprostol was the only prophylactic agent documented to reduce ulcer complications. Prevention of NSAID-induced gastroduodenal ulcers ochrane Database of Systematic Reviews 2007 Issue 3

Misoprostol

All doses of misoprostol significantly reduced the risk of endoscopic ulcers.

Misoprostol 800 ug/day was superior to 400 ug/day for prevention of endoscopic GU (RR= 0.17 , and RR= 0.39 respectively, p= 0.0055)

A dose response relationship was not seen with DU

Misoprostol caused diarrhea at all doses, although significantly more at 800 ug/day than 400 ug/day (p= 0012 ).

Misoprostol was the only prophylactic agent documented to reduce ulcer complications.

Prevention of NSAID-induced gastroduodenal ulcers Standard doses of H2RAs E ffective at reducing the risk of endoscopic DU (RR= 0.36 ; 95% CI: 0.18-0.74) but not GU (RR= 0.73; 95% CI: 0.50-1.09) D ouble dose H2RAs and PPIs were effective at reducing the risk of endoscopic DU and GU (RR= 0.44 ; 95% CI: 0.26-0.74 and RR =0.40; 95% CI: 0.32-0.51 respectively for gastric ulcer, and were better tolerated than misoprostol. Cochrane Database of Systematic Reviews 2007 Issue 3

Standard doses of H2RAs

E ffective at reducing the risk of endoscopic DU (RR= 0.36 ; 95% CI: 0.18-0.74) but not GU (RR= 0.73; 95% CI: 0.50-1.09)

D ouble dose H2RAs and PPIs were effective at reducing the risk of endoscopic DU and GU (RR= 0.44 ; 95% CI: 0.26-0.74 and RR =0.40; 95% CI: 0.32-0.51 respectively for gastric ulcer, and were better tolerated than misoprostol.

PPIs reduce the relative risk of Ulcer bleeding in patients taking NSAIDs 0 0.5 1 2 3 4 5 6 7 8 9 10 27 Adjusted RR (95% IC) Non-ASA NSAIDs 5.0 +PPI ASA (>500 mg/day) +PPI Lanas et al. AJG 2007 > 70% GI risk reduction with PPI Reduction similar among different NSAIDs 8.7 0.30 0.14

> 70% GI risk reduction with PPI

Reduction similar among different NSAIDs

Effect of PPIs,H2-RA and nitrates on the RR of ulcer bleeding in patients taking Low-dose ASA or Clopidogrel 0 0.5 1 2 3 4 5 6 7 8 9 10 27 Adjusted RR (95% IC) Low dose ASA 3.6 +PPI 0.32 +H2-RA 0.40 +Nitrate 0.69 Clopidogrel 3.1 +PPI 0.19 +H2-RA 0.83 +Nitrate 0.88 Lanas et al. AJG 2007

PPI plus COX-2 inhibitor Ulcer incidence at 6 months by NSAID type ** P <.01, *** P <.001, **** P <.0001 vs . placebo. ** *** *** **** 134 141 125 318 326 334 n= Scheiman et al. DDW 2004

Coxibs versus standard-NSAIDs : Effect on serious upper GI events Adjusted relative risk (95% IC) 0 0.5 1 2 3 4 5 Type of event 51% reduction Symptomatic 0.49 (0.38-0.62) Ulcers Upper GI 45% reduction Complications 0.55 (0.38-0.80) Hooper L et al. BMJ 320:948-58 (2004)

M anagement of UGIB from NSAID-induced Ulcers

Approach to UGI Bleeding Assess severity Resuscitate Establish the site of bleeding Endoscopic intervention Reassess severity Medical treatment Indications for surgery

Assess severity

Resuscitate

Establish the site of bleeding

Endoscopic intervention

Reassess severity

Medical treatment

Indications for surgery

Assessing severity: Rockall criteria Criterion Score Age <60 years 0 60-79 yrs 1 >80 years 2 Shock None 0 Pulse & sBP >100 1 sBP <100 2 Co-morbidity None 0 Cardiac / any major 2 Renal / liver / malig. 3 Total initial score (max = 7) Mortality 50.0%

Criterion Score

Age <60 years 0

60-79 yrs 1

>80 years 2

Shock None 0

Pulse & sBP >100 1

sBP <100 2

Co-morbidity None 0

Cardiac / any major 2

Renal / liver / malig. 3

Total initial score (max = 7)

High risk Low risk Pharmacologic therapy Endoscopy feasible Yes Endoscopic Hemostasis Success No Consult surgeon or refer Fail Antisecretory therapy Refer Guideline of UGIB Management Endoscopy available Yes No Others Variceal bleeding Ulcer bleeding Pharmacological therapy and monitoring Rebleed Re-endoscopy Fail

Endoscopic Stigmata of Ulcer Hemorrhage Active arterial bleeding Visible Vessel Adherent clot Flat spot Clean base ulcer

Endoscopic Stigmata of Ulcer Hemorrhage: Prevalence, Risks of R ebleeding and Reduced Risk of Rebleeding following Endoscopic Therapy Endoscopy 1997; 29 : 827-33 Not available 3 32 Clean base ulcer Not available 7 10 Flat spot Not available 10 14 Oozong without stigmata 5 33 10 Adherent clot 15-30 50 22 Visible Vessel 15-30 90 12 Active arterial bleeding Rebleed Rate with Endoscopic treatment (%) Rebleed Rate Prevalence (%) Endoscopic Appearance

High risk Low risk Pharmacologic therapy Endoscopy feasible Yes Endoscopic Hemostasis Success No Consult surgeon or refer Fail Antisecretory therapy Refer Guideline of UGIB Management Endoscopy available Yes No Others Variceal bleeding Ulcer bleeding Pharmacological therapy and monitoring Rebleed Re-endoscopy Fail

Endoscopic modalities available for management of Non-variceal UGIB I njection Adrenaline (1:10,000) Fibrin glue Human thrombin Sclerosants Alcohol Thermal Heater probe Bicap probe Gold probe Argon plasma coagulation Laser therapy Mechanical Hemoclips Banding Endoloops Staples/sutures

I njection

Adrenaline (1:10,000)

Fibrin glue

Human thrombin

Sclerosants

Alcohol

Thermal

Heater probe

Bicap probe

Gold probe

Argon plasma coagulation

Laser therapy

Mechanical

Hemoclips

Banding

Endoloops

Staples/sutures

High risk Low risk Pharmacologic therapy Endoscopy feasible Yes Endoscopic Hemostasis Success No Consult surgeon or refer Fail Antisecretory therapy Refer Guideline of UGIB Management Endoscopy available Yes No Others Variceal bleeding Ulcer bleeding Pharmacological therapy and monitoring Rebleed Re-endoscopy Fail

Pharmacotherapy for Nonvariceal Bleeding 48-72 hrs after endoscopic therapy, patient should receive acid-suppressive drug to maintain gastric pH >6. In patients who do not require endoscopic therapy, oral PPI therapy is adequate. In patients with arterial spurt or visible vessel require endoscopic therapy and a continuous infusion of high -dose intravenous PPI therapy. Stop a spirin and NSAID . H pylori therapy should be test and treat if presented.

48-72 hrs after endoscopic therapy, patient should receive acid-suppressive drug to maintain gastric pH >6.

In patients who do not require endoscopic therapy, oral PPI therapy is adequate.

In patients with arterial spurt or visible vessel require endoscopic therapy and a continuous infusion of high -dose intravenous PPI therapy.

Stop a spirin and NSAID .

H pylori therapy should be test and treat if presented.

Brunner, et al. Aliment Pharmacol Ther 1995 Omeprazole 80 mg loading dose+ 40 mg q. 8 hours Omeprazole 80 mg loading dose + CI 4 mg/ hour Effective PPI Dosage & Administration Intermittent Bolus V.S. Continuous Infusion

0 8 6 4 2 0 8 16 24 32 40 48 Median Intragastric pH Time [h] Van Rensburg, et al. Gastroenterology 1997. (Abstract) 80 mg bolus then 8 mg/hour n = 14; median pH 6.3, 68% range IV Pantoprazole In Patients With UGI B After Endoscopic Hemostasis

Recommendation: An intravenous bolus followed by continuous-infusion proton-pump inhibitor is effective in decreasing rebleeding in patients who have undergone successful endoscopic therapy. Recommendation: A;Evidence: I Consensus Recommendations for Managing Patients with Nonvariceal UGIB . Consensus Recommendations for Managing Patients with Nonvariceal Upper Gastrointestinal Bleeding. Ann Intern Med 2003;139(10):843-57. A Canadian clinical practice algorithm for the management of patients with nonvariceal upper gastrointestinal bleeding. Can J Gastroenterol 2004;18(10):605-609.

Recommendation: An intravenous bolus followed by continuous-infusion proton-pump inhibitor is effective in decreasing rebleeding in patients who have undergone successful endoscopic therapy.

Recommendation: A;Evidence: I

Consensus Recommendations for Managing Patients with Nonvariceal Upper Gastrointestinal Bleeding. Ann Intern Med 2003;139(10):843-57.

A Canadian clinical practice algorithm for the management of patients with nonvariceal upper gastrointestinal bleeding. Can J Gastroenterol 2004;18(10):605-609.

High risk Low risk Pharmacologic therapy Endoscopy feasible Yes Endoscopic Hemostasis Success No Consult surgeon or refer Fail Antisecretory therapy Refer Guideline of UGIB Management Endoscopy available Yes No Others Variceal bleeding Ulcer bleeding Pharmacological therapy and monitoring Rebleed Re-endoscopy Fail

Proton pump inhibitor treatment for acute peptic ulcer bleeding No evidence to suggest that results on mortality and rebleeding were dependent on study quality, route of PPI administration, type of control treatment or application of initial endoscopic haemostatic treatment. PPIs significantly reduced surgery compared with placebo but not when compared with H2RA. Among patients with active bleeding or non-bleeding visible vessel, PPI treatment reduced mortality (OR 0.53; 95% CI 0.31 to 0.91), rebleeding and surgery. Cochrane Database of Systematic Reviews 2006 Issue 3

No evidence to suggest that results on mortality and rebleeding were dependent on study quality, route of PPI administration, type of control treatment or application of initial endoscopic haemostatic treatment.

PPIs significantly reduced surgery compared with placebo but not when compared with H2RA.

Among patients with active bleeding or non-bleeding visible vessel, PPI treatment reduced mortality (OR 0.53; 95% CI 0.31 to 0.91), rebleeding and surgery.

H . pylori and NSAIDs

H.pylori , NSAID Use and the Risk of PU Bleeding Prevalence (%) PU bleeding + - + - + - OR 1.79 95% CI; 0.97-3.32 OR 4.85 95% CI; 3.77-6.23 OR 6.13 95% CI; 3.93-9.56 Lancet 2002 HP+ NSAID uses HP+ NSAID use HP- No NSAID H pylori and NSAIDs independently and significantly increase risk of PU bleeding

Recommendations for H pylori eradication in Maastricht III Consensus 1b ; Individual RCT with narrow confidence interval Gut. 2006;55:1717-24 A Ib H. pylori eradication is of value in chronic NSAID users but is insufficient to prevent NSAID related ulcer disease completely A Ib In naı¨ve users of NSAIDs, H , pylori eradication may prevent PU and or bleeding A Ib In patients receiving long term NSAIDs and who have peptic ulcer and/or ulcer bleeding, PPI maintenance treatment is better than H. pylori eradication in preventing ulcer recurrence and/or bleeding Grade of recommendation Level of evidence Recommendations

H. pylori eradication is of value in chronic NSAID users but is insufficient to prevent NSAID related ulcer disease completely

In naı¨ve users of NSAIDs, H , pylori eradication may prevent PU and or bleeding

In patients receiving long term NSAIDs and who have peptic ulcer and/or ulcer bleeding, PPI maintenance treatment is better than H. pylori eradication in preventing ulcer recurrence and/or bleeding

H pylori and Low dose ASA H . pylori infection increases complications for patients taking low-dose aspirin. R isk for UGI bleeding with low-dose aspirin and H . pylori infection (OR = 4.7 ; 95 % CI, 2.0-10.9 ) compared with aspirin alone but much lower than previous ulcer history (OR = 15.2 ; 95 % CI, 3.8 - 60.1 ). Recommendation: Patients who are receiving long term aspirin who bleed should be tested for H . pylori and, if positive, receive eradication therapy.

H . pylori infection increases complications for patients taking low-dose aspirin.

R isk for UGI bleeding with low-dose aspirin and H . pylori infection (OR = 4.7 ; 95 % CI, 2.0-10.9 ) compared with aspirin alone but much lower than previous ulcer history (OR = 15.2 ; 95 % CI, 3.8 - 60.1 ).

Recommendation: Patients who are receiving long term aspirin who bleed should be tested for H . pylori and, if positive, receive eradication therapy.

Summary Practical Approach in Managing NSAID Risks: GI and CV

Strategy in patients who need NSAIDs Step 1 : Evaluate presence of risk factor : Estimate the GI & CV risk Step 2 : Minimize the risk according to these factors Step 3 : Use the most appropriate therapeutic strategy

Step 1 : Evaluate presence of risk factor :

Estimate the GI & CV risk

Step 2 : Minimize the risk according to these factors

Step 3 : Use the most appropriate therapeutic strategy

The most important risk factors Age Most Frequent Low-dose ASA >20% of patients Ulcer History Highest RR Factor Reason

Age Most Frequent

Low-dose ASA >20% of patients

Ulcer History Highest RR

Definition of GI risks GI risk Complication Rate NNT Cost of 100 pt-yrs prevention Low <1.5 >120 ≈ 120,000 ε Intermediate 2-10 10-100 3,000-20,000 ε High >20 <10 <3,000 ε Lanas et al. APT 2004;20:321-31.

GI risk Complication Rate NNT Cost of

100 pt-yrs prevention

Low <1.5 >120 ≈ 120,000 ε

Intermediate 2-10 10-100 3,000-20,000 ε

High >20 <10 <3,000 ε

Assess Cardiac Risk First When choosing an NSAID Assess cardiac risk factors first because of concern about CV safety of COX-2 inhibitors Naproxen may have cardioprotective Consider whether patient would be benefit from aspirin therapy No GI benefit of COX-2 inhibitors for patients who take aspirin For patients with GI risk factors Consider non-NSAID therapies For patients requiring NSAIDs, consider adding a PPI

When choosing an NSAID

Assess cardiac risk factors first because of concern about CV safety of COX-2 inhibitors

Naproxen may have cardioprotective

Consider whether patient would be benefit from aspirin therapy

No GI benefit of COX-2 inhibitors for patients who take aspirin

For patients with GI risk factors

Consider non-NSAID therapies

For patients requiring NSAIDs, consider adding a PPI

Assess the presence of high-risk factors for serious NSAID-induced GI adverse events i.e elderly people,, if necessary, keep the dose as low as possible. Comorbidity (ie renal and hepatic disease) needs to be considered when prescribe NSAIDs. Prescribe with caution in patients with underlying GI disease or risk factors for CVS disease. Beware drug interactions of NSAIDs / COX-2 inhibitors Patients with history of chronic or allergic skin conditions, A standard NSAID may be preferred to a COXIB (rarely COXIBs reported to be associated with increased risk of serious skin reactions) Majority of cases occur in the first month of use Minimizing risk of NSAIDs users

Assess the presence of high-risk factors for serious NSAID-induced GI adverse events i.e elderly people,, if necessary, keep the dose as low as possible.

Comorbidity (ie renal and hepatic disease) needs to be considered when prescribe NSAIDs.

Prescribe with caution in patients with underlying GI disease or risk factors for CVS disease.

Beware drug interactions of NSAIDs / COX-2 inhibitors

Patients with history of chronic or allergic skin conditions,

A standard NSAID may be preferred to a COXIB (rarely COXIBs reported to be associated with increased risk of serious skin reactions)

Majority of cases occur in the first month of use

Coxibs are contraindicated in: ischemic heart disease cerebrovascular disease peripheral arterial disease moderate or severe heart failure. In people with risk factors for heart disease the balance of GI and CV risk should be considered before prescribing a coxib. People requiring low dose aspirin should generally not be prescribed a coxib because GI benefit has not been clearly demonstrated in this group. Practical Points for COX-2 selective NSAIDs Uses

Coxibs are contraindicated in:

ischemic heart disease

cerebrovascular disease

peripheral arterial disease

moderate or severe heart failure.

In people with risk factors for heart disease the balance of GI and CV risk should be considered before prescribing a coxib.

People requiring low dose aspirin should generally not be prescribed a coxib because GI benefit has not been clearly demonstrated in this group.

If high risk of NSAID-induced GI adverse effects and requires concomitant use of low-dose aspirin prophylaxis and an NSAID: Do not stop aspirin. Re-consider use paracetamol with or without codeine. If NSAID is considered necessary, cautious to prescribe an NSAID with less COX-2 selectivity (e.g. naproxen, but not ibuprofen) together with a gastroprotective agent. Avoid concomitant use of aspirin with ibuprofen. Low-dose Aspirin and NSAID

If high risk of NSAID-induced GI adverse effects and requires concomitant use of low-dose aspirin prophylaxis and an NSAID:

Do not stop aspirin.

Re-consider use paracetamol with or without codeine.

If NSAID is considered necessary, cautious to prescribe an NSAID with less COX-2 selectivity (e.g. naproxen, but not ibuprofen) together with a gastroprotective agent.

Avoid concomitant use of aspirin with ibuprofen.

Strategies to Reduce NSAID-induced Mucosal Injury and Platelet Dysfunction Avoid NSAIDs or minimize dosage Alternative COX-2 inhibitors Proton pump inhibitor s (PPIs) PPIs are more effective than H2RA in preventing NSAID-induced ulcer PPIs are better tolerate than misoprostol Prostaglandin analogue – misoprostol

Avoid NSAIDs or minimize dosage

Alternative COX-2 inhibitors

Proton pump inhibitor s (PPIs)

PPIs are more effective than H2RA in preventing NSAID-induced ulcer

PPIs are better tolerate than misoprostol

Prostaglandin analogue – misoprostol

NSAID required? High risk Low risk - No prophylaxis -Monitor clinical signs and symptoms -Use non-NSAIDs analgesic -Use low dose, short acting NSAIDs -Limit duration of therapy -Avoid using combination of NSAIDs -Avoid to combine with corticosteriod or anticoagulant Risk assessment for NSAID-induced ulcer -Cotherapy with Gastroprotective drugs -Selective COX-2 inhibitors Yes

Recommendations for the use of NSAIDs according to GI and cardiovascular risk. *High cardiovascular risk: requirement for low-dose aspirin for primary prevention (calculated 10-year cardiovascular risk >10%) or secondary prevention of serious cardiovascular events. **Gl risk: low (no risk factors), moderate (1-2 risk factors), or high (> 2 risk factors, previous ulcer complications, or concomitant use of corticosteroids or anticoagulants). All patients with a history of ulcers who require NSAIDs should be tested for H. pylori and if infection is present, eradication therapy should be given. *** Naproxen is preferred NSAID in patients with a high cardiovascular risk. Nat Clin Pract Gastroenterol Hepatol. 2006;3(10):563-73. Avoid NSAIDs or COX2 inhibitors NSAID***+ PPI or misoprostol NSAID *** + PPI or misoprostol High COX2 inhibitor + PPI NSAID + PPI/misoprostol or COX2 inhibitor NSAID Low Severe Moderate Low Gastrointestinal risk** Cardiovascular risk*

*High cardiovascular risk: requirement for low-dose aspirin for primary prevention (calculated 10-year cardiovascular risk >10%) or secondary prevention of serious cardiovascular events.

**Gl risk: low (no risk factors), moderate (1-2 risk factors), or high (> 2 risk factors, previous ulcer complications, or concomitant use of corticosteroids or anticoagulants). All patients with a history of ulcers who require NSAIDs should be tested for H. pylori and if infection is present, eradication therapy should be given.

*** Naproxen is preferred NSAID in patients with a high cardiovascular risk.

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