Disclosures

Connect to Protect is a program developed by the AGA Institute whose independent medical advisor, Dr. Byron Cryer from the University of Texas Southwestern Medical Center, is responsible for the medical content. Funding for the program is provided through an unrestricted grant by Horizon Therapeutics.

Dr. Cryer has received research support from PLx Pharma, S Ph ti l P I d Pfi I d hSucampo Pharmaceuticals, Pozen Inc., and Pfizer Inc. and has been a consultant to PLx Pharma, Sucampo Pharmaceuticals, Pozen Inc., Pfizer Inc., Horizon Therapeutics, Astra-Zeneca, NiCox Inc McNeil Inc and Ritter PharmaceuticalsInc., McNeil, Inc. and Ritter Pharmaceuticals.

Connect to ProtectConnect to ProtectManagement of Gastrointestinal Risks

of Non-Steroidal Anti-Inflammatory Drugs

Byron Cryer, M.D..Chairman Connect to Protect ProgramChairman, Connect to Protect Program,

American Gastroenterological Association InstituteUniversity of Texas Southwestern Medical School

& Dallas VA Medical Center

AGENDA

• Welcome and Introduction of Dr. Cryer

• The Current Impact of NSAID Use

• Reducing the Risk• Reducing the Risk

• Problems with Adherence

• Summary

• Questions

CURRENT IMPACT OF NSAID USE

Prevalence of NSAID-Associated GI ComplicationsGI Complications

• More than 60 million Americans are NSAID users1

– 1% to 2% of users have clinically significant upper GI events

• Endoscopic studies indicate that gastric or duodenal ulcers develop in p g papproximately 15% to 30% of patients using NSAIDs2

• Estimates of mortality vary widely from 3200 to higher than 16 500• Estimates of mortality vary widely from 3200 to higher than 16,500 deaths per year in the United States1

1Cryer B. Am J Gastroenterol. 2005;100:1694-1695.

..

2Laine L. Gastroenterology. 2001;120:594-606.

Gastrointestinal Side Effects Induced by Nonselective NSAIDs

Complications1% t 2%

Complications1% t 2%

Nonselective NSAIDs

1% to 2%1% to 2%

Ulcers15% to 30%

Dyspepsia occurs inDyspepsia occurs in25% to 50% of patients with

or without complicationsNo Lesion70% t 85%

Graham DY, et al. Ann Intern Med. 1993;119:257-262.Graham DY, et al. Ann Intern Med. 1993;119:257-262.

70% to 85%

Graham DY, et al. Ann Intern Med. 1993;119:257 262. Langman MJ, et al. Lancet. 1994;343:1075-1078.

Larkai EN, et al. J Clin Gastroenterol. 1989;11:158-162. Silverstein FE, et al. Ann Intern Med. 1995;123:241-249.

Graham DY, et al. Ann Intern Med. 1993;119:257 262. Langman MJ, et al. Lancet. 1994;343:1075-1078.

Larkai EN, et al. J Clin Gastroenterol. 1989;11:158-162. Silverstein FE, et al. Ann Intern Med. 1995;123:241-249.

Mortality Associated With NSAID/Aspirin Use

450500

443

npe

ople

300350400450

253

per m

illio

150200250300

153

253

Rat

e

0050

100150

United StatesUnited KingdomSpain2005 2003 1999

Lanas A, et al. Am J Gastroenterol. 2005;100:1685-1693.Lanas A, et al. Am J Gastroenterol. 2005;100:1685-1693.

Peptic Ulcer Disease and NSAIDs

The major cause of peptic ulcer disease in Amsterdam has changed from H. pylorito NSAIDs

1990 2005Cause of Peptic Ulcers

47%70% - 80%H. pylori

NSAIDs 53%20% - 30%

Ramsoekh D, et al. Clin Gastroenterol Hepatol. 2005;3:859-864.

Risk Factors for Serious GI Adverse Events with NSAIDswith NSAIDs

13 5 (10 3 17 7)P i bl d

Anticoagulant / NSAID use

4.4 (2.0-9.7)

12.7 (6.3-25.7)

13.5 (10.3-17.7)

Corticosteroid use

Prior bleed

2.9 (2.2-3.8)

5.8 (4.0-8.6)

Low-dose NSAID

High-dose NSAID

5.6 (4.6-6.9)

3.1 (2.5-3.7)

1 6 (1 4 2 0)

Age 70-80

Age 60-69

Age 50 59

1 5 10 15

1.6 (1.4-2.0)Age 50-59

Relative risk. García-Rodriguez LA. Lancet. 1994;343:769-772.

Gutthann SP, et al. Epidemiology. 1997;8:18-24.Shorr RI. Arch Intern Med. 1993;153:1665-1670.

Piper JM, et al. Ann Intern Med. 1991;114:735-740

Risk for GI Complications Begins at an Earlier Age in Men

7.85.6

5

75-79

>8480-84

g

65.8

7.4

4.64.5

56.9

7.7

55-59

65-6970-74

60-64

50-54 1.31.8

2.23.1

4.5

1 82.5

33.5

4.6

35-39

45-4950 54

40-44Age (years)Age

(years)

*0 5

11.3

0.6

0.8

0.50.4

11.5

1.830-3425-2920-2415-1910-14

FemalesFemales

MalesMales** Male patients had an onset of GI

complications at an earlier age than women

0.50.30.30.40.5

0.70.5

0 1 2 3 4 5 6 7 8 99

10 145-90-4

Patients with GI complications (%)

0.60.5

123456789

Adapted fromLanas A, et al. Am J Gastroenterol. 2005;100:1685-1693.

Patients with GI complications (%)

High Risk of Upper GI Bleeding Is Maintained During NSAID Use

11I d i k f h d i

Maintained During NSAID Use

9

Increased risk appears at start of therapy and ismaintained during use

5

7Relative riskRelative risk

15.13.7 4.15.7

3

11

Nonuse 1-30 31-90 91-180 181-365

Days of NSAID useDays of NSAID use

Hernández-Díaz S, et al. Arch Intern Med. 2000;160:2093-2099.Hernández-Díaz S, et al. Arch Intern Med. 2000;160:2093-2099.

The Risk of NSAID-Associated Upper GI Complications Is Constant Over TimeComplications Is Constant Over Time

MUCOSA Trial1NSAIDs (N = 4439)

VIGOR Trial2Naproxen (N = 4029)

mpl

icat

ion

NSAIDs (N = 4439)

nce

(%)

4.0

5.04.5

3.5

Naproxen (N = 4029)0.012

0.009

y of

UG

I Com

ulat

ive

inci

de

2.53.0

2.01 5

0.006

0 30 60 90 120 150 180

Pro

babi

lity

Cum

u 1.51.00.50.00

0.003

0 2 4 6 8 10 120 30 60 90 120 150 180 0 2 4 6 8 10 12

MonthsDays

1. Silverstein FE, et al. Ann Intern Med. 1995;123:241–249.2. Bombardier C, et al. N Engl J Med. 2000;343:1520–1528..

Effect of Individual NSAIDs on Peptic Ulcer Complications

Relative Risk: Current Use Versus Nonuse

6 37

6 37 NSAID risk varies

kk

4.6 4.6

6.3

4.65

6

4.6 4.6

6.3

4.655

66 • Aspirin and ibuprofen have higher risk than non-NSAIDs*

– Aspirin > Ibuprofen > Acetaminophen

elat

ive

risk

elat

ive

risk

2.7

3.43.8 4.0 4.1

3.63.43.3

3

4

2.7

3.43.8 4.0 4.1

3.63.43.3

33

44

Re

Re

1.1 1.3

2.21.9

2.2

11

21.1 1.3

2.22.21.9

2.2

111

22

111

García-Rodríguez LA, et al. Epidemiology. 2001;12:570-576.Hernández-Díaz S, et al. Arch Intern Med. 2000;160:2093-2099.

de Abajo FJ, et al. BMC Clin Pharmacol. 2001;1:1.

* Statistical significance was not reported

REDUCING THE RISKREDUCING THE RISK

Reducing the Risk of GI Complications with NSAIDs

• Identify risk factorsy

• Use of gastroprotective drugsg g

• Safer NSAIDs

Options for Patients With GI Risk Who Need NSAIDsWho Need NSAIDs

• NSAID plus gastroprotective agentMisoprostol– Misoprostol

– PPI– Histamine2-receptor antagonist (H2RA) - high dose

• COX-2 inhibitor

• Non-NSAID Pharmacologic TherapyAcetaminophen– Acetaminophen

– Tramadol– Narcotics

Relative GI Safety of DifferentAnti-Inflammatory Therapies: Overview

• All nonselective NSAIDs

Safety ProfileTherapy

• Increased risk of serious GI events• All nonselective NSAIDs

• Different formulations of nonselective NSAIDs

Increased risk of serious GI events

• No reduction in serious GI toxicity

N d ti i i• Different routes of NSAIDadministration

• Gastroprotection co-therapy

• No reduction in seriousGI toxicity

• Reduction in serious GI toxicity but

• NSAIDs that specifically inhibit COX-2

compliance issues

• Reduction in serious GI toxicity but possible increase in cardiovascular COX 2 padverse effects

Gastroprotection

• Use lowest effective NSAID dose

• Misoprostol

• Proton pump inhibitors

• H2-Receptor Antagonists (high dose)2 p g ( g )

Gastroprotection:Misoprostol (MUCOSA trial)Misoprostol (MUCOSA trial)

% of patients with serious upper GI complications at 6 months% of patients with serious upper GI complications at 6 monthsp pp pp pp pp=0.049

40% reduction in GI complications

Placebo + NSAID Misoprostol + NSAID

Silverstein et al. Ann Intern Med 1995;123:241–249

(n=4439) (n=4404)

Gastroprotection:Proton Pump Inhibitorsp

% of patients with recurrent upper GI bleeding at 6 monthsp=0.005p

76% reduction in upper GI bleeding

Omeprazole + NSAID(n=75)

H. pylori eradication+ NSAID(n=75)

Chan et al. N Engl J Med 2001;344:967–973

H2-Receptor Antagonists in the Prevention of NSAID UlNSAID Ulcers

35%

25%

30%

15%

20%

p = 0.003

0%

5%

10%

0%Placebo Fam 20 bid Fam 40 bid

Gastric ulcers Duodenal ulcersHigh dose

Taha AS. N Engl J Med. 1996;334:1435–9.Taha AS. N Engl J Med. 1996;334:1435–9.

Endoscopic Ulcers and Ulcer ComplicationsCelecoxib vs NSAIDS

Ulcer ComplicationsCLASS Study at 1 year

(Patient not taking aspirin)20

Endoscopic Ulcersat 6 months

Celecoxib

NSAIDS1.5

s)

P = 0.04

(Patient not taking aspirin)

15

20P < 0.001

1.0

s/ 1

00 p

t-yrs

10

15

denc

e (%

)

0.5

nce

(eve

nts

5

10

Ulc

er in

cid

0

Inci

den

0

5

P value by log-rank test0

Emery et al. Lancet 1999;354:2106-11.

Silverstein et al. JAMA. 2000;284:1247-55.

PPI Co-therapy Reduces Ulcer Development in

Hi h Ri k NSAID d COX 2 U *1,429 H. pylori-negative subjects

Age >60 years or ulcer history

High-Risk NSAID and COX-2 Users*

Age >60 years or ulcer history

s6

mon

ths

†p<0.01 vs. placebo‡p<0.001 vs. placebo

cers

at 6

†

‡

‡

* P ti t t k t diti l NSAID COX

% U

l

‡

* Patients took traditional NSAID or COX-2-selective inhibitor + ASA

Scheiman JM, et al. Am J Gastroenterology. 2006:1

01:701–710.

Prevention of Recurrent Ulcer Bleeding in High Risk Patients**High-Risk Patients**

I iti l St d G 1 F ll U St d GInitial Study Group1 Follow-Up Study Group2

P = NSCelecoxib 200 mg bid + placebo

Diclofenac 75 mg BID +

P = NSOmeprazole 20 mg QD

n = 143 n = 144 n = 116 n = 106

*Patients with prior ulcer bleed on NSAID; ulcer healed and H pylori-negative or eradicated prior to randomization. NS, not significant.

1. Chan FK, et al. N Engl J Med. 2002;347:2104–2110. 2. Chan FK, et al. Gastroenterology. 2004;127:1038–1043.

Prevention of NSAID-induced Ulcers Systematic Review of Randomized

Controlled Trials:Controlled Trials:Randomized Controlled Trials (n=40)

for the Prevention of NSAID-Induced Ulcers

Prevention of NSAID-induced Ulcers Relative Risk vs. Placebo (95% Confidence Interval)

0.17 (0.11-0.24)0.17 (0.11-0.24)Misoprostol 800 µg0.42 (0.28-0.67)0.42 (0.28-0.67)Misoprostol 400 µg

H2RA (standard dose) 0.73 (0.50-1.09)0.73 (0.50-1.09)

0.40 (0.32-0.51)0.40 (0.32-0.51)PPI

0.500.25 1.00.75 1.250.0

H2RA (double dose) 0.44 (0.26-0.74)0.44 (0.26-0.74)

Favors Co-TherapyRostom A, et al. Cochrane Database Systematic Review. 2002;4.Rostom A, et al. Cochrane Database Systematic Review. 2002;4.

Favors Placebo

PROBLEMS WITH ADHERENCE

Adherence to Evidence-Based Guidelines for Safe Prescription of NSAIDs inSafe Prescription of NSAIDs in

High-Risk* Patientsre

nce

(%)

Adh

er

N = 303,787 veterans prescribed NSAIDs in 2002.*Included age ≥65 years, concurrent corticosteroid or anticoagulant use, history of peptic ulcer, and high average daily dose of NSAIDs.

Abraham NS, et al. Gastroenterology. 2005;129:1171–1178.

Utilization of Gastroprotective Strategies Among New NSAID Users

≥ 2 GI Risk Factors1 GI Risk Factor

Among New NSAID Users

10.8%2.5%0.1% 14.7%4%0.2%

86.6% 81.2%

COX-2 Inhibitor alone NSAID + GPA Cox-2 Inhibitor + GPA No gastroprotection

GPA = gastroprotective agentGPA = gastroprotective agent

Sturkenboom MC, et al. Rheumatology. 2003;42(Suppl 3):iii23-iii31.Sturkenboom MC, et al. Rheumatology. 2003;42(Suppl 3):iii23-iii31.

GPA = gastroprotective agentGPA = gastroprotective agent

Non-adherence is associated with decreased relative effectivenessdecreased relative effectiveness

Annualized 0 4Annualized rates of upper GI events per patient-year 0.3

0.4

R2 = 0.30880.2

0 0

0.1

0.00 20 40 60 80 100

Adherence (%)

Goldstein JL et al. Clin Gastroenterol Hepatol 2006. 4 (11): 1337-45

Gastric Ulcers After Six Months(Percentage and 95% CI)(Percentage and 95% CI)

72% RR

e %

29.4%(22.9%-37.3%)

cum

ulat

ive

ic u

lcer

s, c

8.3%*(5.1%-13.5%)

Gas

tr

PPI/Naproxen (n=206) Naproxen (n=203)

Goldstein J L et al. Gastroenterology 2008, vol 134, A-19

Gastroduodenal Ulcers After Six Months*(Percentage and 95% CI)( g % )

29.1%23.0%- 36.5%

ve %

p=0.0002

cum

ulat

iv 14.7%11.4%- 18.8%

Ulc

ers,

Ibuprofen 800 mg/ Famotidine 26.6 mg TID(n=550)

Ibuprofen 800 mg TID (n=262)

*40 t 80 ld ti t t d t d NSAID ≥ 6 th (O t th iti

Laine L et al., Oral abstract presented at DDW 2009_____

*40 to 80 year old patients expected to need NSAIDs ≥ 6 months (Osteoarthritis, rheumatoid arthritis, chronic low back pain, chronic regional pain syndrome, and/or chronic soft tissue pain)

SUMMARY

Managing NSAID-Associated GI Conditions

• Treating symptoms– Manage dyspepsia with acid suppression

• Healing ulcers– Heal ulcer with a PPI: More effective than H2RA

• Preventing ulcers– Discontinue NSAID whenever possible and consider alternativeDiscontinue NSAID whenever possible and consider alternative

analgesic (e.g, acetaminophen)– Lower the dose of NSAID– Switch to COX-2 selective inhibitor or co-therapy with misoprostol, PPI py p ,

or high-dose H2RA– Compliance issues with a separately administered co-therapy may

reduce effectiveness

Wolfe MM, et al. N Engl J Med 1999;340:1888–1899.

Key Takeaways

• PPIs, high-dose H2RA, misoprostol and COX-2 selective inhibitors decrease upper GI ulcers due to traditional nonselective NSAIDsdecrease upper GI ulcers due to traditional, nonselective NSAIDs (RCT evidence)

• Fixed-dose combination therapy may increase patient compliance with GI risk reduction strategies

• Patients with the highest GI risk may require more than one risk-reducing strategy such as COX-2 selective inhibitor plus a PPI

• Clinicians must balance GI and CV issues when choosing NSAID therapy

RCT, randomized controlled trial.RCT, randomized controlled trial.

QUESTIONS?QUESTIONS?

For additional questions, please contact: Molly Rabinovitz, mrabinovitz@wcgworld.com