# Presentation: 164730

## RISKS of NSAIDS:	Focus on GI Risks of	Over-the-Counter NSAIDs

**Byron Cryer, M.D.**
**University of Texas Southwestern Medical School**

## List of Available NSAIDs:

**Prescription & OTC ********* ****	**

_**NON-SALICYLATES**__**	**__**            SALICYLATES              **__**	**__**COX-2 INHIBITORS**_

**Diclofenac (Voltaren)****	****	****Aspirin ****a,c**** (Zorprin, Easprin)****  **** ****	****Celecoxib (Celebrex)**
**Diclofenac/Misoprostol (Arthrotec)****	****	****Diflunisal (Dolobid)****	****	****   ****	****Rofecoxib (Vioxx)**
**Etodolac (Lodine)****	****	****Salsalate (Disalcid, Salflex)****	****   ****	****Valdecoxib (Bextra)**
**Fenoprofen (Nalfon)****	****	****Choline salicylate (Trilisate)****	**
**Flurbiprofen (Ansaid)****	****	****Magnesium salicylate (Magan)****	****   **
**Ibuprofen**** ****a,b,c ****(Motrin, Advil) ****	****	****	**
**Indomethacin (Indocin)****	****	****	**
**Ketoprofen**** ****a,b,c****(Orudis) ****	****	****	****     ****	**
**Ketorolac (Toradol)****c**
**Meclofenamate**
**Mefenamic acid (Ponstel)**
**Meloxicam (Mobic)**
**Nabumetone (Relafen)**
**Naproxen**** ****a,b,c****(Naprosyn, Anaprox)**
**Oxaprozin (Daypro)**
**Piroxicam (Feldene)**
**Sulindac (Clinoril)**
**Tolmetin (Tolectin)**

**a**** Also available as ****OTC**** preparations in U.S.**
**b**** ****OTC dose is usually ****half**** of prescribed dose**
**C ****All OTC NSAIDs are **_**non-selective**_** COX Inhibitors**

- * List of trade names is not exhaustive

**Comments on Over-the-Counter Preparations:**

## NSAIDs: What Are the Risks? Prescription & OTC 

**GI Tract****	**
**Ulcers, perforations, bleeding, obstruction strictures, enteropathy **
**Kidney**
**Sodium and fluid retention **
**Hyperkalemia**
**Acute renal failure **
**Hypertension**
**Platelet**
**Inhibition of aggregation leading to increased potential for bleeding**

## Peptic Ulcer Hospitalization Rates

**Kurata JH. *****Semin Gastrointest Dis***** 1993:4**

**Rate**
** ****per **
**100,000**

**Gastric Ulcer**

**Duodenal Ulcer**

**70**

**75**

**80**

**85**

**90**

**0**

**20**

**40**

**60**

**80**

**100**

**Uncomplicated **

** ****Hemorrhage**

**Perforation **

**70**

**75**

**80**

**85**

**90**

**0**

**20**

**40**

**Year**

**Year**

**30**

**10**

**Uncomplicated **

** ****Hemorrhage**

**Perforation **

## Endoscopic Photograph of Gastropathy

## Endoscopic Photographof Gastric Ulcer

**Endoscopic Photograph****of Gastric Ulcer**

## Prevalence of EndoscopicNSAID-Induced Ulceration

**	****	****	****	****	****	****	****Mean****	****	****Range**
**Gastric Ulcer****	**** 15 %****	****	****10 to 30%**
**Duodenal Ulcer****	****   5 %****	**** ****	**** 4 to 10 %**
**Clinically Significant Ulcers****	****    2%****	****  ****	**** 1 to 4%****	****	**

**Notes:**
What is the magnitude of the exposure?

## Risk Factors forSerious GI Adverse Events with NSAIDs: Relative Risks

**Risk Factors for****Serious GI Adverse Events with NSAIDs:**** ****Relative Risks**

- Rodriguez. *Lancet.* 1994; Guttham. *Epidemiology.* 1997; Shorr. *Arch Intern Med.* 1993; Piper. *Ann Intern Med.* 1991.

**0**

**5**

**10**

**15**

**4.4 (2.0-9.7)**

**12.7 (6.3-25.7)**

**2.9**** (2.2-3.8)**

**5.8 (4.0-8.6)**

**5.6 (4.6-6.9)**

**3.1 (2.5-3.7)**

**1.6 (1.4-2.0)**

**13.5 (10.3-17.7)**

**Corticosteroid use**

**Anticoagulant use**

**Low dose NSAID**

**High dose NSAID**

**Age 70-80**

**Age 60-69**

**Age 50-59**

**Prior bleed**

**Relative Risk**

## OTC NSAIDs: What Are the GI Risks?

_**OTC NSAIDS / Low-Dose Aspirin**_**:**
**	**
**Non-Aspirin NSAIDs**
**Low Dose Aspirin **
**Non-Aspirin NSAIDs in combination with Low-Dose Aspirin **
**NSAIDs plus ETOH**
**Acetaminophen and Gastrointestinal Injury**
**Hepatotoxicity with NSAIDs **

## Prevalence of NSAID Use in Patients Presenting with Upper GI BleedingPatient History  (n = 411)

- Wilcox *et al*; *Arch Int Med *1994; 154:42

**0**

**10**

**20**

**30**

**40**

**50**

**Prescribed**

**OTC**

**Non-Aspirin**
**NSAIDs**

**Aspirin**

**Percent using**
**NSAIDs**

**14 %**

**7 %**

**9 %**

**35 %**

## Prevalence of OTC Analgesic Use in Patients Presenting with GI Bleeding

**Percent of Use**

*****

*****

*****

**UGI **= upper gastrointestinal;   **LGI **= lower gastrointestinal	 ******* p < 0.05**
- Peura DA et al. Am J Gastroenterol. 1997;92:924-928

**Notes:**
OTC NSAIDS suggested to have a 2-4 fold RR of GI bleeding compared to controls.

Does this risk with OTC NSAIDs differ from the risk associated with higher dose or prescribed NSAIDs?

## NSAID Dose andRelative Risk of Upper GI Complications

|  | Cases (n) | Controls (n) | Adjusted RR | 95% CI |
| --- | --- | --- | --- | --- |
|  |  |  |  |  |
| NSAID dose
  Low/medium
  High | 
92
311 | 
290
229 | 
2.4
4.9 | 
1.9-3.1
4.1-5.8 |

**Garcia Rodriguez, Hernandez-Diaz. Epidemiology. 2001;12:570-576.**

## Risks of GI Bleeding with Analgesics:Prescription & OTC  

- Blot WJ, Mclaughlin JK. *J Epidemiol Biostat.* 2000;5:137-142.

**Analgesic****	****Case****	****Control****	****Odds Ratio****	****95% CI ****	****n=627****	****n=590****	****(OR) ****	****	**
_**OTC use of**_**:****	****%****	****%**

**   ****Aspirin****	****27.0****	****12.0****	****2.7****	****1.9-3.8**
**   ****Ibuprofen****	****10.1****	****5.8****	****2.4****	****1.5-3.9**
**   ****Acetaminophen****	****4.5****	****6.3****	****0.9****	****0.5-1.6**
**Total ****OTC ****NSAIDs****	****36.2****	****17.5****	****3.0****	****2.2-4.1**
**Rx NSAIDs****	****9.3****	****5.9****	****2.1****	****1.2-3.4**
**Total NSAIDS****	****42.9****	****22.0****	****3.1****	****2.3-4.1**

## GI Bleeding According to Dose ofOTC Ibuprofen Use

**GI Bleeding According to Dose of****OTC Ibuprofen Use**

**0**

**1**

**2**

**3**

**4**

**<600 mg/d**

**600 to 1200 mg/d**

**>1200 mg/d**

**Odds Ratio**

- Blot WJ, McLaughlin J. *J Epidemiol Biostat.* 2000;5:137-142.

_**DOSE**_

## OTC NSAID Usage Patterns (n=535 OTC NSAID Users)

**Fraction of Previous Month                               Respondents (%)**

**             ****< 50 ****	****	****	****	****	****          9.0**

**             ****50 – 75****	****	****	****                                  11.8**

**Having Used OTC**** ****NSAIDs (%)**

**            ****> 75****	****	****	****                                  79.2**

**Reason for Taking OTC NSAID****                            ****Respondents (%)***

**   ****Prevention of Cardiac Problems****	****                      43.2**

**    ****Other****	****	****	****	****                                     9.0**

**    ****Headache****	****	****	****	****                       12.3**

**   ****Arthritis****	****	****	****	****                      24.5**

**   ****General Aches & Pain****	****                                   29.9**

***Total exceeds 100 because multiple responses were allowed**

- Bloom BS et. al Am J Gastroenterol 2001 (abstract)

_**DURATION**_

**Notes:**
Respondents were considered to be users of OTC NSAIDs if they were taking and OTC NSAID on the day on survey as well as during 4 of the preceding 7 days

OTC NSAIDs were approved and are intended for short-term use.
However, the results of this survey indicates that many OTN NSAID users take these medications almost daily, and in quantity.

## Relative Risk of GI Problems in the Previous 30 Days with OTC NSAIDS

**Gastrointestinal**** ****	****   ****OTC NSAID****        ****(%)       Nonusers    (%)    Relative    (95% CI)**

**Any GI Problem****	****              105          ****(19.6)****	****      101          ****(9.4)****          ****2.1**** ****	****  (1.61-2.67)**

**Users (n=535)**

**(n=1,086)**

**Risk**

**Constipation****	****	****34            (6.3)****	****        16          (1.5)          4.5 ****	****  (2.36-7.62)**

**Stomach Cramps/Pain****	****18            (3.4)****	****        12          (1.1)          3.0 ****	****  (1.45-6.17)**

**Indigestion/Heartburn****	****11            (2.0)****	****        10          (0.9)          2.2 ****	****  (0.94-5.14)**

**Abdominal Bloating/Gas****	****  7            (1.3)****	****          7          (0.6)          2.0 ****	****  (0.70-5.66)**

**Diarrhea****	****	****	****17            (3.2)****	****        26          (2.4)          1.3 ****	****  (0.71-2.38)**

**Nausea/Vomiting****	****	****  4            (0.7)****	****          4          (0.4)          2.0 ****	****  (0.50-7.95)**

**GI Bleeding/Ulcer****	****	****  3            ****(0.6)****	****          3          ****(0.3)****          ****2.0****	****  (0.40-9.86)**

**Other Complaints****	****	****27            (5.0)****	****        33          (3.1)          1.6****	****  (0.99-2.69)**

**Complaint**

- Bloom BS et. Al Am J Gastroenterol 2001 (abstract)

_**DURATION**_

**Notes:**
Almost 20% of users reported having a GI symptom over previous month compared to only 10% of non-users.

If accept that there are 30 million user of OTC NSAIDs, this would equal 180,000 ulcers or GI bleeds over 1 month attributable to OTC NSAID use.

## Medications Taken in the Previous 30 Daysfor GI Problems by OTC NSAID Users

**Medications Used in****	****     OTC NSAID ****	****             ****	****	****Controls ****	****   *****P***** value**
**Previous Month **

**OTC GI Medication ****	****  ****	****24.3****	****               ****	**** 10.3****	****	****   0.001**

**Rx GI Medication****	****              9.5                      ****	****   5.2****	****	****   0.001**

**   ****Users (n=535)(%)**

**OTC and RX GI Medication****	**** 2.1                  ****	****	****   1.3****	****	****     NS**

- Bloom BS et. al Am J Gastroenterol 2001 (abstract)

** ****	**** ****(n=1,068)(%)**

**Notes:**
25% are self-medicating their GI symptoms.

Look more closely at data associating OTC NSAIDs with Risk for GI Bleeding.

## OTC NSAIDs: What Are the GI Risks?

_**OTC NSAIDS / Low-Dose Aspirin**_**:**
**	**
**Non-Aspirin NSAIDs**
**Low Dose Aspirin**** **
**Non-Aspirin NSAIDs in combination with Low-Dose Aspirin **
**NSAIDs plus ETOH**
**Acetaminophen and Gastrointestinal Injury**
**Hepatotoxicity with NSAIDs **

## Odds Ratio of Upper GI Bleeding

**In Patients Taking NSAIDS**

**FACTOR**
**History of gastrointestinal bleeding**
**History of ulcer**
**Aspirin at any dose**
**Nitrovasodilator**
**Antisecretory medication**

**Patients**
- (N=317)
- 37 (11.7)
- 69 (21.8)
- 73 (23.0)
- 11 (3.5)
- 29 (9.1)

**Controls**
- (N=187)
- 6 (3.4)
- 18 (9.6)
- 18 (9.6)
- 11 (5.9)
- 37 (19.8)

**Adjusted**
**Odds Ratio**
- (96% CI)
- 3.7 (1.2-1.1)
- 1.8 (0.9-3.6)
**3.1** (1.7-5.9)
- 0.3 (0.1-0.9)
- 0.4 (0.2-0.7)

**P**
**Value**
- 0.01
- 0.09
**<0.001**
- 0.04
- 0.001

**Number (%)**

- Lanas A., et al. N Engl J Med 2000; 343:834-839

## Prior Placebo-Controlled Study of Low Dose ASA for Prevention of Cerebrovascular Events

**0**

**10**

**20**

**30**

**40**

**13**

**21**

**38**

- **

- *

**Placebo**
**( n = 814 )**

**300 mg Q D**
**( n = 806 )**

**1200 mg Q D**
**( n = 815 )**

**Number of Patients with G.I. Bleeding**

**ASA Dose**

**BMJ 1988 ;296:316**

## Risk of Acute Major UGIB According to Use of Aspirin and Ibuprofen in the Week Before 

**Risk of Acute Major UGIB According to Use of Aspirin and Ibuprofen in the Week Before **

**Kaufman DW, Kelly JP, Wilholm BE, et al. *****Am J Gastroenterol*****. 1999;94:3189-3196.**

## Daily Aspirin Dose andAdmission for Ulcer Bleeding

**Aspirin Dose**
**75 mg (n=27)**
**150 mg (n=22)**
**300 mg (n=62)**

**Odds Ratio (95% Cl)**
**2.3 (1.2-4.4)**
**3.2 (1.7-6.5)**
**3.9 (2.5-6.3)**

- Weil J et al. *BMJ.* 1995;310:827-830.

## Mechanisms of NSAID/ Aspirin-induced Mucosal Injury

**Alterations in gastric mucosal barrier**
****** ****Prostaglandin synthesis**
****** ****Mucus and bicarbonate secretion**
****** ****Submucosal blood flow**
****** ****Mucosal ATP**
****** ****Cell turnover**
****** ****Platelet function (irreversible)**

- Ivey KJ. Am J Med. 1988;84:41-48.

****** ****Prostaglandin synthesis**

## Effect of Aspirin Doses on Gastrointestinal Prostaglandins

**Effect of Aspirin Doses on Gastrointestinal Prostaglandins**

**Percent of Baseline**

**(    p < 0.05 vs. Baseline )**

- *

**Stomach**

**Duodenum**

**Rectum**

- *

- *

- *

- *

- *

- *

**Baseline**

**0**

**2**

**0**

**4**

**0**

**6**

**0**

**8**

**0**

**1**

**0**

**0**

**1**

**2**

**0**

**1**

**0**

** **

**m**

**g**

** **

**A**

**S**

**A**

**8**

**1**

** **

**m**

**g**

** **

**A**

**S**

**A**

**3**

**2**

**5**

** **

**m**

**g**

** **

**A**

**S**

**A**

**Cryer, et al. Gastroenterology 1999;117:17-25.**

## Risk of UGI bleeding with Different Formulations of Low-Dose Aspirin (< 325mg)

**Risk of UGI bleeding with Different Formulations of Low-Dose Aspirin (< 325mg)**

**0**

**4**

**3.6**

**2.6**

**2.4**

**2.6**

**2.6**

**Relative Risk**

**Gastric bleeding**

**Duodenal bleeding**

**3.2**

**Plain ASA**

**Coated ASA**

**Buffered ASA**

**550 cases of UGIB admitted to hospital with melena or confirmed hematemesis**

***Kelley et al, Lancet 1996; 348; 1413***

##  Lansoprazole (30 mg QD) + aspirin (100 mg daily) or
   Aspirin alone (100 mg daily) for 12 months.

**   ****Aspirin alone (100 mg daily) for 12 months.**
**	****	****	****	**

***Lai et al, N Engl J Med 2002; 346: 2033***

**Effect of Proton Pump Inhibitor on Upper GI Injury with Low-Dose Aspirin**

## OTC NSAIDs: What Are the GI Risks?

_**OTC NSAIDS / Low-Dose Aspirin**_**:**
**	**
**Non-Aspirin NSAIDs**
**Low Dose Aspirin **
**Low-Dose Aspirin**** ****in combination with Non-Aspirin NSAIDs **
**NSAIDs plus ETOH**
**Acetaminophen and Gastrointestinal Injury**
**Hepatotoxicity with NSAIDs **

##  National cohort study in Denmark
 27,694 people on aspirin 100-150 mg qd

-  27,694 people on aspirin 100-150 mg qd

**Treatment regimen**

**Increased incidence**
**over general**
**population **

**95% CI**

**Low-dose aspirin**
**Low-dose aspirin + NSAIDs**

**2.6**

**5.6**

**2.2 - 2.9**

**4.4 - 7.0**

***Sorensen et al, Am J Gastroenterol 2000; 95; 2218***

**Risk of Combining Low-Dose Aspirin with NSAIDs**

## CLASS Trial: Upper GI Complications

**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)**

## OTC NSAIDs: What Are the GI Risks?

_**OTC NSAIDS / Low-Dose Aspirin**_**:**
**	**
**Non-Aspirin NSAIDs**
**Low Dose Aspirin **
**Non-Aspirin NSAIDs in combination with Low-Dose Aspirin **
**NSAIDs plus ETOH**
**Acetaminophen and Gastrointestinal Injury**
**Hepatotoxicity with NSAIDs **

## Risk Factors for GI Bleeding

| Risk Factor | Cases (n) | Controls (n) | OR (95% CI) |
| --- | --- | --- | --- |
| Neither factor | 284 | 411 |  |
| Alcohol | 107 | 75 | 2.07 (1.48-2.88) |
| OTC ASA/NSAID | 160 | 84 | 2.76 (2.03-3.74)  |
| OTC ASA/NSAID plus alcohol | 71 | 23 | 4.47 (2.73-7.32) |

- Peura DA et al. Am J Gastroenterol. 1997;92:924-928.

## Relative Risks of Upper Gastrointestinal Bleeding

-  Kaufmann et al.,  Am J Gastroenterol 1999;94:3189-3196.

## OTC NSAIDs: What Are the GI Risks?

_**OTC NSAIDS / Low-Dose Aspirin**_**:**
**	**
**Non-Aspirin NSAIDs**
**Low Dose Aspirin **
**Non-Aspirin NSAIDs in combination with Low-Dose Aspirin **
**NSAIDs plus ETOH**
**Acetaminophen and Gastrointestinal Injury**
**Hepatotoxicity with NSAIDs **

## Relative Risk of Upper GI Complications

|  | Cases (n) | Controls (n) | Adjusted RR | 95% CI |
| --- | --- | --- | --- | --- |
| Acetaminophen (mg)
   <1000
     1001-1999
     2000
     2001-3999
   4000 | 
142
59
84
78
13 | 
610
242
127
83
7 | 
1.0
0.8
1.9
3.4
6.5 | 
0.8-1.2
0.6-1.1
1.4-2.6
2.4-4.8
2.4-17.6 |
| NSAID dose
  Low/medium
  High | 
92
311 | 
290
229 | 
2.4
4.9 | 
1.9-3.1
4.1-5.8 |

**Garcia-Rodriguez, Hernandez-Diaz. Epidemiology. 2001;12:570-576.**

## GI Bleeding Associated with Analgesics 

- Blot WJ, Mclaughlin JK. *J Epidemiol Biostat.* 2000;5:137-142.

**Analgesic****	****Case****	****Control****	****Odds Ratio****	****95% CI ****	****n=627****	****n=590****	****(OR) ****	****	**
**OTC use of:****	****%****	****%**

**Aspirin****	****27.0****	****12.0****	****2.7****	****1.9-3.8**
**Ibuprofen****	****10.1****	****5.8****	****2.4****	****1.5-3.9**
**Acetaminophen****	****4.5****	****6.3****	****0.9****	****0.5-1.6**
**Total OTC NSAIDs****	****36.2****	****17.5****	****3.0****	****2.2-4.1**
**Rx NSAIDs****	****9.3****	****5.9****	****2.1****	****1.2-3.4**
**Total NSAIDS****	****42.9****	****22.0****	****3.1****	****2.3-4.1**

## Effects of NSAIDs and Acetaminophen on Gastric Mucosa

**0**

**0.01**

**0.1**

**1**

**10**

**100**

**0**

**20**

**40**

**60**

**80**

**100**

**Acetaminophen**

**Rofecoxib**

**Celecoxib**

**Naproxen**

**Effects of NSAIDs and Acetaminophen on Gastric Mucosa**

**Cryer, B and Feldman, M. (Abstract in press Am J Gastro)**

## OTC NSAIDs: What Are the GI Risks?

_**OTC NSAIDS / Low-Dose Aspirin**_**:**
**	**
**Non-Aspirin NSAIDs**
**Low Dose Aspirin **
**Non-Aspirin NSAIDs in combination with Low-Dose Aspirin **
**NSAIDs plus ETOH**
**Acetaminophen and Gastrointestinal Injury**
**Hepatotoxicity with NSAIDs**** **

## Hepatotoxicity with NSAIDs

** ****Compared with other classes of drugs, hepatotoxicity with NSAIDs ****	****is uncommon.**
** ****Mild increases in liver tests**
**	******** ****1% (most NSAIDs)**
**	******** ****15% (diclofenac)**
** ****Clinically apparent hepatotoxicity is rare.**
** ****Exception = Bromfenac sodium (Duract ****TM****)**
** ****Mechanism of toxicity with NSAIDs is *****idiosyncratic reaction***** (not ****	****related to dose or duration) rather than intrinsic hepatotoxicity**
_**OTC NSAIDs**_**:**
**	****Ibuprofen:****	****rare**
**	****Naproxen:****	****rare**
**	****Ketoprofen:****	****rare**
**	****Aspirin:****	****rare but some intrinsic hepatotoxicity**

## Hepatotoxicity with NSAIDs

_**Aspirin**_**:**
** ****Some intrinsic hepatotoxicity**
** ****Injury related to:**
_**Dose**_**: rare at 325 mg/day or less**
_**Duration**_**:**
** ****Typically at least *****6 days***** duration of *****high doses***** in  ****	****patients with inflammatory conditions (eg., RA, SLE)**
** **_**Reye’s Syndrome**_**:**
** ****Dose-related:**
** ****Median Dose = 25 mg/kg**
** ****However, risk increases 7-fold at 15 mg/kg/day****	****	****(650 mg/day for 40 kg child)**
** ****Aspirin should be avoided in children with respiratory ****	****illness or varicella.**

## Summary

**OTC NSAIDs are associated with some GI risks**
**GI Risks of OTC NSAIDs include upper and lower GI bleeding**
**Risk appears to be related to NSAID dose.**
**Much of GI risks associated with OTC NSAIDs is related to aspirin, even at low-dose.**
**Low-dose aspirin combined with NSAID increases risks 2-4 fold.**
**Enteric-coated and buffered aspirin do not reduce risk.**
**Hepatotoxicity with OTC NSAIDs and Low-Dose Aspirin is rare.**