Connect to Protect is a collaboration between Horizon Pharma and the AGA to help physicians and patients better understand and manage non-steroidal anti-inflammatory drug (NSAID) risks. This Webinar was presented to physicians and media to demonstrate the risks associated with NSAID use and how physicians can address them.

1. 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,
Sucampo Ph
S Pharmaceuticals, P
ti l Pozen I Inc., and Pfi
d Pfizer I
Inc. and h
d has
been a consultant to PLx Pharma, Sucampo Pharmaceuticals,
Pozen Inc., Pfizer Inc., Horizon Therapeutics, Astra-Zeneca, NiCox
Inc., McNeil, Inc.
Inc McNeil Inc and Ritter Pharmaceuticals
Pharmaceuticals.

2. Connect to Protect
Management of Gastrointestinal Risks
of Non-Steroidal Anti-Inflammatory Drugs
Byron Cryer, M.D.
.
Chairman,
Chairman Connect to Protect Program
Program,
American Gastroenterological Association Institute
University of Texas Southwestern Medical School
& Dallas VA Medical Center

3. AGENDA
• Welcome and Introduction of Dr. Cryer
• The Current Impact of NSAID Use
• Reducing the Risk
• Problems with Adherence
• Summary
• Questions

4. CURRENT IMPACT OF NSAID USE

5. Prevalence of NSAID-Associated
GI Complications
• More than 60 million Americans are NSAID users1
– 1% to 2% of users have clinically significant upper GI events
• Endoscopic studies indicate that g
p gastric or duodenal ulcers develop in
p
approximately 15% to 30% of patients using NSAIDs2
• Estimates of mortality vary widely from 3200 to higher than 16 500
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.

6. Gastrointestinal Side Effects Induced by
Nonselective NSAIDs
Complications
1% t 2%
to
Ulcers
15% to 30%
Dyspepsia occurs in
25% to 50% of patients with
or without complications
No Lesion
70% t 85%
to
Graham DY, et al. Ann Intern Med. 1993;119:257 262.
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.

7. Mortality Associated With NSAID/Aspirin Use
500
443
450
Rate per million people
400
350
300 253
250
200
153
150
100
50
0
2005 2003 1999
Spain United Kingdom United States
Lanas A, et al. Am J Gastroenterol. 2005;100:1685-1693.

8. Peptic Ulcer Disease and NSAIDs
The major cause of peptic ulcer disease in Amsterdam has changed from H. pylori
to NSAIDs
Cause of Peptic
Ulcers
1990 2005
H. pylori 70% - 80% 47%
NSAIDs 20% - 30% 53%
Ramsoekh D, et al. Clin Gastroenterol Hepatol. 2005;3:859-864.

9. Risk Factors for Serious GI Adverse Events
with NSAIDs
Prior bleed
P i bl d 13.5 (10.3-17.7)
13 5 (10 3 17 7)
Anticoagulant / NSAID use 12.7 (6.3-25.7)
Corticosteroid use 4.4 (2.0-9.7)
Low-dose NSAID 2.9 (2.2-3.8)
High-dose NSAID 5.8 (4.0-8.6)
Age 70-80 5.6 (4.6-6.9)
Age 60-69 3.1 (2.5-3.7)
Age 50 59
50-59 1.6 (1.4-2.0)
1 6 (1 4 2 0)
1 5 10 15
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

10. Risk for GI Complications Begins at an
Earlier Age in Men
g
>84 7.4 5
80-84 5.8 5.6
75-79 6 7.8
70-74 4.5 7.7
65-69 3.1 6.9
60-64 2.2 5
55-59 1.8 4.5
50 54
50-54 1.3 4.6
45-49 1 3.5
Age 40-44 0.8 3
(years)
35-39 0.6 2.5
30-34
25-29
* Male patients had an onset of GI
complications at an earlier age
than women
0.5
05
0.4
1.8
18
1.5
* Females
0.3 1 Males
20-24
15-19 0.3 0.4
10 14
10-14 0.5 0.5
5-9 0.5 0.5
0-4 0.6 0.7
9 8 7 6 5 4 3 2 1 0 1 2 3 4 5 6 7 8 9
Patients with GI complications (%)
Adapted from
Lanas A, et al. Am J Gastroenterol. 2005;100:1685-1693.

11. High Risk of Upper GI Bleeding Is
Maintained During NSAID Use
11
Increased risk appears at start of therapy and i
I d i k f h d is
maintained during use
9
Relative risk
7
5
3
5.7 3.7 4.1 5.1
1
1
Nonuse 1-30 31-90 91-180 181-365
Days of NSAID use
Hernández-Díaz S, et al. Arch Intern Med. 2000;160:2093-2099.

12. The Risk of NSAID-Associated Upper GI
Complications Is Constant Over Time
MUCOSA Trial1 VIGOR Trial2
NSAIDs (N = 4439) 5.0 Naproxen (N = 4029)
0.012
mplication
4.5
ulative incidence (%)
4.0
0.009 3.5
Probability of UGI Com
3.0
0.006 2.5
2.0
1.5
15
y
Cumu
0.003 1.0
0.5
0 0.0
0 30 60 90 120 150 180 0 2 4 6 8 10 12
Days Months
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.

13. Effect of Individual NSAIDs on
Peptic Ulcer Complications
Relative Risk: Current Use Versus Nonuse
7 NSAID risk varies 6.3
63
6
• Aspirin and ibuprofen have higher risk than
non-NSAIDs*
5 – Aspirin > Ibuprofen > Acetaminophen 4.6 4.6 4.6
elative risk
k
4.1
4 3.6 3.8 4.0
3.3 3.4 3.4
3 2.7
Re
2.2 2.2
1.9
2
1 1.3
1.1
1
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

14. REDUCING THE RISK

15. Reducing the Risk of GI Complications
with NSAIDs
• Identify risk factors
y
• Use of gastroprotective drugs
g g
• Safer NSAIDs

16. Options for Patients With GI Risk
Who Need NSAIDs
• NSAID plus gastroprotective agent
– Misoprostol
– PPI
– Histamine2-receptor antagonist (H2RA) - high dose
• COX-2 inhibitor
• Non-NSAID Pharmacologic Therapy
– Acetaminophen
– Tramadol
– Narcotics

17. Relative GI Safety of Different
Anti-Inflammatory Therapies: Overview
Therapy Safety Profile
• All nonselective NSAIDs • Increased risk of serious GI events
• Different formulations • No reduction in serious
of nonselective NSAIDs GI toxicity
• Different routes of NSAID • N reduction iin serious
No d ti i
administration GI toxicity
• Gastroprotection co-therapy • Reduction in serious GI toxicity but
compliance issues
• NSAIDs that specifically inhibit • Reduction in serious GI toxicity but
COX 2
COX-2 p
possible increase in cardiovascular
adverse effects

18. Gastroprotection
• Use lowest effective NSAID dose
• Misoprostol
• Proton pump inhibitors
• H2-Receptor Antagonists (high dose)
p g ( g )

19. Gastroprotection:
Misoprostol (MUCOSA trial)
% of patients with serious upper GI complications at 6 months
p pp p
p=0.049
40% reduction in
GI complications
Placebo + NSAID Misoprostol + NSAID
(n=4439) (n=4404)
Silverstein et al. Ann Intern Med 1995;123:241–249

20. Gastroprotection:
Proton Pump Inhibitors
p
% of patients with recurrent upper GI bleeding at 6 months
p
p=0.005
76% reduction in
upper GI bleeding
H. pylori eradication Omeprazole + NSAID
+ NSAID (n=75)
(n=75)
Chan et al. N Engl J Med 2001;344:967–973

21. H2-Receptor Antagonists in the Prevention of
NSAID Ul
Ulcers
35%
30%
25%
20%
15% p = 0.003
10%
5%
0%
Placebo Fam 20 bid Fam 40 bid
High dose
Gastric ulcers Duodenal ulcers
Taha AS. N Engl J Med. 1996;334:1435–9.

22. Endoscopic Ulcers and Ulcer Complications
Celecoxib vs NSAIDS
Ulcer Complications
Endoscopic Ulcers
CLASS Study at 1 year
at 6 months
(Patient not taking aspirin)
20 Celecoxib
P < 0.001 1.5 NSAIDS
P = 0.04
s)
15
Inciden (events 100 pt-yrs
dence (%)
1.0
10
Ulcer incid
s/
0.5
5 nce
0 0
Emery et al. Lancet 1999;354:2106-11. P value by log-rank test
Silverstein et al. JAMA. 2000;284:1247-55.

23. PPI Co-therapy Reduces
Ulcer Development in
High-Risk
Hi h Ri k NSAID and COX-2 U
d COX 2 Users*
*
1,429 H. pylori-negative subjects
Age >60 years or ulcer history
% Ulcers at 6 months
s
†p<0.01 vs. placebo
‡p<0.001 vs. placebo
‡
‡ †
‡
* P ti t t k t diti
Patients took traditional NSAID or COX
l COX- Scheiman JM, et al. Am J
2-selective inhibitor + ASA Gastroenterology. 2006:1
01:701–710.

24. Prevention of Recurrent Ulcer Bleeding in
High-Risk
High Risk Patients**
Initial Study Group1
I iti l St d G Follow-Up St d G
F ll U Study Group2
Celecoxib 200 mg bid + placebo P = NS
Diclofenac 75 mg BID +
Omeprazole 20 mg QD
P = NS
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.

25. Prevention of NSAID-induced Ulcers
Systematic Review of Randomized
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)
Misoprostol 800 µg 0.17 (0.11-0.24)
0.42 (0.28-0.67)
Misoprostol 400 µg
0.40 (0.32-0.51)
PPI
H2RA (standard dose) 0.73 (0.50-1.09)
H2RA (double dose) 0.44 (0.26-0.74)
0.0 0.25 0.50 0.75 1.0 1.25
Favors Co-Therapy Favors Placebo
Rostom A, et al. Cochrane Database Systematic Review. 2002;4.

26. PROBLEMS WITH ADHERENCE

27. Adherence to Evidence-Based Guidelines for
Safe Prescription of NSAIDs in
High-Risk* Patients
rence (%)
Adher
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.

28. Utilization of Gastroprotective Strategies
Among New NSAID Users
1 GI Risk Factor ≥ 2 GI Risk Factors
0.1% 2.5% 10.8% 0.2% 4% 14.7%
86.6% 81.2%
COX-2 Inhibitor alone NSAID + GPA Cox-2 Inhibitor + GPA No gastroprotection
GPA = gastroprotective agent
Sturkenboom MC, et al. Rheumatology. 2003;42(Suppl 3):iii23-iii31.

29. Non-adherence is associated with
decreased relative effectiveness
Annualized 0.4
04
rates of upper
GI events per
patient-year 0.3
R2 = 0.3088
0.2
0.1
0.0
00
0 20 40 60 80 100
Adherence (%)
Goldstein JL et al. Clin Gastroenterol Hepatol 2006. 4 (11): 1337-45

30. Gastric Ulcers After Six Months
(Percentage and 95% CI)
72% RR
29.4%
Gastric ulcers, cumulative %
(22.9%-37.3%)
c e
8.3%*
(5.1%-13.5%)
PPI/Naproxen (n=206) Naproxen (n=203)
Goldstein J L et al. Gastroenterology 2008, vol 134, A-19

31. Gastroduodenal Ulcers After Six Months*
(
(Percentage and 95% CI)
g % )
29.1%
23.0%- 36.5%
p=0.0002
Ulcers, cumulativ %
ve
14.7%
11.4%- 18.8%
Ibuprofen 800 mg/ Famotidine 26.6 mg TID Ibuprofen 800 mg TID
(n=550) (n=262)
*40 to 80 year old patients expected to need NSAIDs ≥ 6 months (O t
t ld ti t t dt d NSAID th (Osteoarthritis,
th iti
rheumatoid arthritis, chronic low back pain, chronic regional pain syndrome, and/or
chronic soft tissue pain)
Laine L et al., Oral abstract presented at DDW 2009_____

32. SUMMARY

33. 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 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.

34. Key Takeaways
• PPIs, high-dose H2RA, misoprostol and COX-2 selective inhibitors
decrease upper GI ulcers due to traditional, nonselective NSAIDs
traditional
(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.

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