Connect to Protect Webinar
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Transcript of Connect to Protect Webinar
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, [email protected]