Disclosures

Connect to Protect is a program developed by the AGA Institute
whose independent medical advisor, Dr. Byron C...
Connect to Protect
  Management of Gastrointestinal Risks
of Non-Steroidal Anti-Inflammatory Drugs

                   Byr...
AGENDA

•   Welcome and Introduction of Dr. Cryer

•   The Current Impact of NSAID Use

•   Reducing the Risk

•   Problem...
CURRENT IMPACT OF NSAID USE
Prevalence of NSAID-Associated
                   GI Complications

•   More than 60 million Americans are NSAID users1
  ...
Gastrointestinal Side Effects Induced by
           Nonselective NSAIDs

            Complications
              1% t 2%
 ...
Mortality Associated With NSAID/Aspirin Use

                          500
                                               ...
Peptic Ulcer Disease and NSAIDs

The major cause of peptic ulcer disease in Amsterdam has changed from H. pylori
         ...
Risk Factors for Serious GI Adverse Events
                       with NSAIDs


               Prior bleed
               ...
Risk for GI Complications Begins at an
                       Earlier Age in Men
                                g
       ...
High Risk of Upper GI Bleeding Is
                     Maintained During NSAID Use

            11
                       ...
The Risk of NSAID-Associated Upper GI
                                      Complications Is Constant Over Time

         ...
Effect of Individual NSAIDs on
                                Peptic Ulcer Complications
                          Relati...
REDUCING THE RISK
Reducing the Risk of GI Complications
               with NSAIDs

• Identify risk factors
         y

• Use of gastroprote...
Options for Patients With GI Risk
            Who Need NSAIDs
• NSAID plus gastroprotective agent
   – Misoprostol
   – PP...
Relative GI Safety of Different
      Anti-Inflammatory Therapies: Overview
            Therapy                           ...
Gastroprotection

•   Use lowest effective NSAID dose

•   Misoprostol

•   Proton pump inhibitors

•   H2-Receptor Antago...
Gastroprotection:
               Misoprostol (MUCOSA trial)

% of patients with serious upper GI complications at 6 months...
Gastroprotection:
                 Proton Pump Inhibitors
                           p
% of patients with recurrent upper ...
H2-Receptor Antagonists in the Prevention of
              NSAID Ul
                     Ulcers
     35%

     30%

     2...
Endoscopic Ulcers and Ulcer Complications
                                Celecoxib vs NSAIDS
                            ...
PPI Co-therapy Reduces
                             Ulcer Development in
                       High-Risk
                ...
Prevention of Recurrent Ulcer Bleeding in
          High-Risk
          High Risk Patients**

    Initial Study Group1
   ...
Prevention of NSAID-induced Ulcers
              Systematic Review of Randomized
                      Controlled Trials:
...
PROBLEMS WITH ADHERENCE
Adherence to Evidence-Based Guidelines for
       Safe Prescription of NSAIDs in
             High-Risk* Patients
        ...
Utilization of Gastroprotective Strategies
                     Among New NSAID Users

                    1 GI Risk Facto...
Non-adherence is associated with
                  decreased relative effectiveness

Annualized       0.4
                ...
Gastric Ulcers After Six Months
                                  (Percentage and 95% CI)

                               ...
Gastroduodenal Ulcers After Six Months*
                                    (
                                    (Percent...
SUMMARY
Managing NSAID-Associated GI Conditions

• Treating symptoms
  – Manage dyspepsia with acid suppression

• Healing ulcers
...
Key Takeaways

• PPIs, high-dose H2RA, misoprostol and COX-2 selective inhibitors
  decrease upper GI ulcers due to tradit...
QUESTIONS?



For additional questions, please contact:
Molly Rabinovitz, mrabinovitz@wcgworld.com
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Connect to Protect Webinar

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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.

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Connect to Protect Webinar

  1. 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. 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. 3. AGENDA • Welcome and Introduction of Dr. Cryer • The Current Impact of NSAID Use • Reducing the Risk • Problems with Adherence • Summary • Questions
  4. 4. CURRENT IMPACT OF NSAID USE
  5. 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. 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. 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. 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. 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. 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. 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. 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. 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. 14. REDUCING THE RISK
  15. 15. Reducing the Risk of GI Complications with NSAIDs • Identify risk factors y • Use of gastroprotective drugs g g • Safer NSAIDs
  16. 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. 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. 18. Gastroprotection • Use lowest effective NSAID dose • Misoprostol • Proton pump inhibitors • H2-Receptor Antagonists (high dose) p g ( g )
  19. 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. 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. 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. 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. 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. 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. 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. 26. PROBLEMS WITH ADHERENCE
  27. 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. 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. 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. 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. 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. 32. SUMMARY
  33. 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. 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. 35. QUESTIONS? For additional questions, please contact: Molly Rabinovitz, mrabinovitz@wcgworld.com

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