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11/17/2010
NSAIDS Injury – How to Prevent it
H. Juergen Nord, MD, FACP, MACG
Professor of Medicine
University of South Florida
College of Medicine
Tampa, FL
11/17/2010
NSAIDS:
The size of the problem in the US
NSAID/ASA use common in Rx of pain, inflammation, fever
Low dose ASA used routinely for primary, second prophylaxis
of CV, cerebrovascular events
National prescription audit 2004
● NSAID prescriptions: 111,400,000
● Total cost: $4,800,000,000
Sales of OTC oral analgesics: $3 billion
● 60% NSAIDs including ASA
NSAID taking among people >65 years:
● 1 dose / week
70%
● Daily
34%
Shaheen,
Shaheen, AJG
AJG 2006;
2006; 101:2128
101:2128
11/17/2010
Scope of NSAID gastropathy
Dyspepsia in up to 50% of patients
(1.5- to 2-fold increment vs controls)
Results in discontinuation or change
of medication in 10% of patients
Gastric ulcers in 15–20%
Duodenal ulcers in 5–8%
Complications increased 4-fold
Risk of a complication is 1–4% per year
Graham, Ann Intern Med 1993; 119: 257
Langman et al, Lancet 1994; 343: 1075
Larkai et al, J Clin Gastroenterol 1989; 11: 158
Silverstein, Ann Intern Med 1995; 123: 241
11/17/2010
NSAID Healthcare Costs
Per $ spent on NSAID’s - $0.66 - $1.25 is
spent on managing side effects
30% of arthritis care costs are for GI adverse
events
> 100,000 hospitalizations and 16,700
deaths/year in US
Direct US cost: $ 4 billion/year
Rahme et al. Arthritis Rheum 2000; 43:917
Wolfe et al. N Engl J Med 1999; 340:1888
March et al. Baillieres Clin Rheumatol 1997; 11:817
11/17/2010
Mortality from NSAID-induced
GI complications vs other diseases in the US
● 25th most common cause of death, US
1 National
Center for Health Statistics, 1998
and Triadafilopoulos, J Rheum 1999; 26: 18
3 Johnson, Rev Cardiovasc Med 2005; 6:S15
2 Singh
11/17/2010
Risk factors for
NSAID-associated ulcer complications
Note! - Majority of patients who develop a serious GI adverse event on NSAIDs
are asymptomatic prior to event
- Risk is greatest in first three months of use
Gabriel et al, Ann Intern Med 1991; 115: 787
Garcia Rodriguez et al, Lancet 1994; 343: 769
Silverstein et al, Ann Intern Med 1995; 123: 241
11/17/2010
H. pylori and NSAID: Additive or
synergistic on gastric mucosal damage
11/17/2010
H. pylori, NSAID use,
and risk of peptic ulcer disease: Meta-analysis of
5 case control studies
Huang
Huang et
et al,
al, Lancet
Lancet 2002;
2002; 359:
359: 14
14
11/17/2010
Recommendation
Testing for and eradication of H. pylori in
patients with an ulcer Hx is recommended
before starting chronic antiplatelet
therapy.
ACCF/ACG/AHA 2008 Expert Consensus Document
Am J Gastroenterol 2008; 103:2890
11/17/2010
ACG bleeding registry:
Risk factors for GI bleeding
Peura et al, Am J Gastroenterol 1997; 92: 924
11/17/2010
Key points
There is considerable morbidity and mortality
associated with NSAID use
Concurrent use of multiple NSAIDs (including
a non-aspirin NSAID with any dose of aspirin)
is a major risk factor for GI complications
H. pylori and alcohol increase the risk of upper GI
bleeding when taken with non-aspirin NSAIDs or
aspirin
11/17/2010
Dyspepsia
11/17/2010
NSAID-associated dyspepsia
Most common reason for stopping NSAID
Does not correlate with endoscopic findings
Not a clear risk factor for ulcer complications
COX-2 selective NSAIDs associated with
less dyspepsia but still more than placebo
Reduced or relieved by PPI co-therapy
11/17/2010
PPIs for GI side effects
in “at-risk” patients starting NSAID therapy
Non peptic ulcer patients
with mild dyspepsia
Cullen et al,
Aliment Pharmacol Ther 1998; 12: 135
Patients with history
of dyspepsia or PUD
Ekström et al,
Scand J Gastroenterol 1996; 31: 753
11/17/2010
Strategies for managing
NSAID-associated dyspepsia: Role of PPIs
Dyspepsia patients should be given
empiric PPI therapy
PPIs have shown benefit over H2RAs or
misoprostol in relieving dyspepsia1,2
Changing to another NSAID or COX-2
selective NSAID may still result in
dyspepsia
1Yeomans
et al, N Engl J Med 1998; 338: 719
2Hawkey et al, N Engl J Med 1998; 338: 727
11/17/2010
Healing and prevention of
NSAID associated ulcers
Healing of NSAID-associated GU and DU:
Comparison of omeprazole and ranitidine
(continuing NSAIDs)
11/17/2010
Yeomans et al, N Engl J Med 1998; 338: 719
11/17/2010
Gastric ulcer healing:
Comparison of lansoprazole and ranitidine
(continuing NSAIDs)
** p<0.01 vs either dose of lansoprazole
*** p<0.001 vs either dose of lansoprazole
Sontag et al, Am J Gastroenterol 1999; 94: 2620
Preventing ulcer relapse:
Placebo-controlled comparison
of lansoprazole and misoprostol
11/17/2010
357 patients:
H. pylori-negative,
long-term NSAID takers
p<0.001 lansoprazole, misoprostol vs placebo
Misoprostol associated
with significantly more
adverse events than
lansoprazole or
placebo, p<0.001
Graham
Graham et
et al,
al, Arch
Arch Intern
Intern Med
Med 2002;
2002; 162:
162: 169
169
11/17/2010
Healing and secondary prevention
of NSAID-associated ulcers: Summary
PPIs superior to H2-receptor antagonists
and sucralfate in healing
Only PPIs and misoprostol shown to be
effective for secondary prophylaxis
PPIs are the preferred agents for the
therapy and prophylaxis of NSAID and
ASA-associated GI injury
ACCF/ACG/AHA 2008 Expert Consensus Document
Am J Gastroenterol 2008; 103:2890
11/17/2010
COX-2 selective NSAIDs
A safer NSAID?
11/17/2010
Normal distribution
of COX isoenzymes
COX-1
COX-2
Digestive system
● esophagus
● stomach
● intestine
● liver
● pancreas
Brain
● neurons
Kidney
● interstitium
● medulla
● collecting ducts
Pancreas
● islet cells
Hematological system
● platelets
Bone
Kidney
● renal cortex
Female reproductive tract
● ovary
● uterus
Vascular endothelium
After Lipsky, Am J Med 1999; 106: 51s
11/17/2010
Does an Aspirin a Day Take the GI Benefit of
COX-2s Away?
Arachidonic acid
COX-1
Aspirin
COX-2
COXIB
Prostaglandins
Protection
of gastric mucosa
Prostaglandins
Hemostasis
Mediation of pain,
Inflammation, and
fever
Adapted from Cryer B. Chapter 23. In: Sleisenger & Fordtran’s
Gastrointestinal and Liver Disease. 7th ed. 2002:410.
11/17/2010
NSAIDs, ASA, COXIBS, CLOPIDOGREL
ASA/NSAID effect on coxibs likely underappreciated
Increased CV risk of NSAIDs likely further increased
addition of ASA to anti-inflammation therapy
Clopidogrel decreases platelet-derived growth
factors/angiogenesis
Results in impaired ulcer healing
Clopidogrel in presence of acid, H. pylori may lead to
mucosal ulceration and its complications
MA, Natl Acad Sci USA 2001; 98:6470
11/17/2010
Cumulative probability of recurrent ulcer bleeding:
Omeprazole + NSAID vs celecoxib in the
high-risk patient (previous ulcer complication)
Chan
Chan et
et al,
al, N
N Engl
Engl JJ Med
Med 2002;
2002; 347:
347: 2104
2104
11/17/2010
Ulcer Recurrence
PPI (Eso) in High Risk NSAID Users
Eso 40 mg Eso 20 mg Placebo
0%
0%
19.1%
Cox 2 selective
NSAID
Non-selective
5.1%
5.9%
10.6%
NSAID
N – 585, international study, p < 0.05 vs. placebo
In high risk patients esomeprazole significantly reduced
ulcer recurrence @ 6 months
Scheiman, Am J Gastrointerol 2003; 98:S52
11/17/2010
Lack of long-term advantage of celecoxib
Adapted
Adapted from:
from: www.fda.gov/ohrms/dockets/ac/01/slides/3677s1_01_sponsor.pdf
www.fda.gov/ohrms/dockets/ac/01/slides/3677s1_01_sponsor.pdf
11/17/2010
Small bowel mucosal injury in
chronic NSAID users
Open label, endoscopist-blind, prevalence
study using capsule endoscopy
Non-selective NSAID users: 71%
Controls
: 10%
p < 0.001
Small bowel lesions are common in NSAID
users
Graham. Clin Gastroenterol. Hepatol 2005; 3:55
11/17/2010
Serious lower GI tract clinical events:
Comparison of rofecoxib and naproxen (VIGOR)
* Relative risk reduction 54%; p=0.03
Laine et al, Gastroenterology 2003; 124: 288
11/17/2010
Impact of aspirin co-therapy
on therapeutic choice
11/17/2010
Cardiovascular benefits of aspirin
15% reduced risk of stroke in patients with
previous TIAs1
15% reduced rate of cardiovascular events
in patients with coronary artery disease2
Anti-platelet effect may last for up to 10 days
because of irreversible acetylation of COX-1
Other non-selective NSAIDs are reversible
COX inhibitors and so effective period is shorter
and dependent on plasma half-life
1Sacco
et al, Arch Intern Med 2000; 16: 1579
2Sanmuganathan et al, Heart 2001; 85: 265
11/17/2010
Mechanism of
aspirin’s anti-thrombotic effect
Irreversible acetylation of serine in COX-1, completely inactivates COX-1
for life of platelet
Production of thromboxane A2 (platelet aggregation and vasoconstriction)
is inhibited, providing antithrombotic effect
Aspirin is a very potent COX-1 inhibitor but
a weak COX-2 inhibitor
All other NSAIDs are reversible, with varying degrees/ durations of
thromboxane inhibition
Aspirin + ibuprofen increases CV risk compared to aspirin alone or
aspirin + other NSAID (hazard ratio 1.93)
Naproxen vs. non-naproxen NSAIDs has a lower MI risk (RR 0.86)
NSAID of choice for card. risk patients (FDA 2005)
Awtry and Loscalzo, Circulation 2000; 101: 1206
Juni, Lancet 2004; 364:2021
11/17/2010
Cardiovascular Risk (MI, CVA) Associated with
NSAIDs in Healthy Individuals
Nationwide cohort study: 1,028.437 Danish individuals
OR
95% CI
Non-selective NSAID
BUT
Cox- 2 selective NSAID
diclofenac
ibuprofen
naproxen
refecoxib
1.91
1.29
0.84
1.91
(1.62-2.42)
(1.02-1.63)
(10.50-1.42)
(1.62-2.42)
Conclusion:
Individual NSAIDs: different, dose dependent CV safety
Diclofenac
: use with caution
Naproxen
: safer cardiovascular risk-profile
Fosbol. Cir Cardiovasc Qual Outcomes. June 8, 2010 (E pub)
11/17/2010
Aspirin dosing
Daily 75 mg dose completely inhibits COX-1
within a few days
Higher doses not more effective but may
increase risk of GI side effects
Low-dose aspirin may cause preferential
inhibition of platelet COX vs endothelial COX
(theoretical anti-thrombotic advantage)
Awtry and Loscalzo, Circulation 2000; 101: 1206
APTC, BMJ 1994; 308: 81
11/17/2010
Daily aspirin dose
and admission for ulcer bleeding
Aspirin dose
Odds ratio (95% CI)
75 mg
2.3 (1.2–4.4)
150 mg
3.2 (1.7–6.5)
300 mg
3.9 (2.5–6.3)
Bleeding risk is the same regardless of use of plain, buffered
or enteric-coated aspirin
Weil et al, BMJ 1995; 310: 827
Kelly et al, Lancet 1996; 348: 1413
11/17/2010
Who needs prophylactic ASA?
● US Preventive Services Task Force Guideline
- 10-year risk of CV event is > 6%
● American Heart Association Guidelines
- 10 year risk of EV event is > 10%
● 50x106 Americans use ASA for CV prophylaxis daily
US Preventive Services Task Force. Ann Intern Med 2002; 136:157
Pearson T, et al. Circulation 2002; 106-338
Chan, Aliment Pharmacol Ther 2004; 19:1051
11/17/2010
How are the net benefits of low-dose
aspirin affected by cardiovascular risk?
Benefit:
Risk:
Prevents
Causes
5%
6–20 MIs
2–4 GI bleeds
0–2 hemorrhagic strokes
1%
1–4 MIs
2–4 GI bleeds
0–2 hemorrhagic strokes
Risk of coronary events in
1000 patients over 5 yrs
Calculator: http://hin/nhlbi.nih.gov/atpiii/cal culator.asp
Hayden et al, Ann Intern Med 2002; 136: 161
Multiple NSAID use:
The forgotten risk factor
When 2 rights make a wrong
11/17/2010
National cohort study in Denmark
27,694 people on aspirin 100–150 mg qd
Treatment regimen
Increased incidence
over general
population
95% CI
Low-dose aspirin
2.6
2.2–2.9
Low-dose aspirin +
traditional NSAID
5.6
4.4–7.0
Sørensen et al, Am J Gastroenterol 2000; 95: 2218
11/17/2010
Placebo-controlled trial of lansoprazole for prevention
of recurrent ulcer complications on low-dose aspirin
Lai et al, N Engl J Med 2002; 346: 2033
11/17/2010
Ulcers and ulcer complications in “CLASS”
at 12 months according to aspirin use
http://www.fda.gov/ohrms/dockets/ac/01/slides/3677s1_01_sponsor.pdf
11/17/2010
Recommendation
Substitution of clopipidogrel for ASA is
not a recommended strategy to reduce
the risk of recurrent ulcer bleed in high
risk individuals
It is inferior to the combination of ASA
plus PPI
ACCF/ACG/AHA 2008 Expert Consensus Document
Am J Gastroenterol 2008; 103:2890
11/17/2010
A Clinician’s Guide to
NSAID Therapy in 2010
Average GI Risk
Average
CV risk
(no aspirin)
High
CV risk
(consider
aspirin)
* Ibuprofen
Nonselective NSAID alone
High GI Risk
Coxib + PPI/misoprostol
or
Traditional NSAID + PPI
Naproxen
(if not on aspirin)
Avoid NSAIDs if possible
Naproxen +
PPI/misoprostol
(if on aspirin)
Naproxen + PPI/
misoprostol (irrespective
of concomitant ASA use)
should be used cautiously in individuals taking ASA
Chan, Am J Gastroenterol 2008; 103:2908
11/17/2010
Summary
Absolute benefits of aspirin outweigh risks
of major GI bleeding in patients at moderateto high-risk coronary heart disease
Aspirin may not be beneficial in patients with
low-risk of CHD due to increased GI bleeding
and hemorrhagic stroke
Coxibs increase CV risk (class effect) but have
greater GI safety (in absence of ASA)
NSAIDs may not be safer than coxibs (CV effect)
11/17/2010
Impact of NSAID gastropathy:
Summary
NSAIDs are recognized as a significant cause of
GI symptoms, ulcers and complications
Low dose aspirin should only be used in
patients in whom CV benefit outweighs GI risks
H. pylori is a cofactor for ulcer and
complications. Test and treat at risk groups
PPIs allow patients to get the most benefit from
their NSAID therapy by reducing GI risks