Download NSAIDs Selective COX

cyclo-oxygenase 2 inhibitors
and cardiovascular risk
—where are we now?
Sung-Hwan Park M.D
Rheumatology, Internal Medicine
Kangnam St Mary’s hospital
The Catholic University of Korea
NSAIDs
Selective COX-2 inhibitors
Developed to avoid side effects of conventional NSAIDs,
including gastrointestinal and renal toxicity
COX-2 is constitutively expressed in the kidney.
regulated in response to alterations in intravascular volume
COX-2 metabolites :maintenance of renal blood flow,
mediation of renin release, and regulation of Na excretion
COX-2 inhibition transiently decrease urine sodium
excretion in some subjects
and induce mild to moderate elevation of BP
Cox1 / Cox2
ratio of NSAIDs
Clinically Significant Elevations in BP
Percent of Patients With Systolic Blood Pressure Increase From
Baseline >20 mm Hg and Absolute >140 mm Hg
Celecoxib 200 mg qd
Study 1:
Whelton et al
P=0.03
Rofecoxib 25 mg qd*
11.2%
(n=411)
16.5%
(n=399)
6.9%
(n=549)
14.9%
(n=543)
Study 2:
Whelton et al
P<0.001
Celecoxib vs Rofecoxib: Incidence of Edema1,2
Study 1: Whelton et al
10
% of Patients
10
P=0.01
P<0.05
9.5
8
6
4
Study 2: Whelton et al
8
7.7
6
4
4.9
2
4.7
2
0
CELEBREX®
(celecoxib capsules)
200 mg qd
(n=411)
Rofecoxib
25 mg qd
(n=399)
0
CELEBREX®
(celecoxib capsules)
200 mg qd
(n=549)
Rofecoxib
25 mg qd
(n=543)
Effects of celecoxib and rofecoxib on blood pressure
and edema in patients > or =65 years of age
with systemic hypertension and osteoarthritis.
Rofecoxib caused the greatest increase in systolic BP in
patients receiving ACE inhibitors or beta blockers,
whereas those on calcium channel antagonists
or diuretic monotherapy receiving either celecoxib or
rofecoxib showed no significant increases in BP.
Careful monitoring of BP is warranted after
the initiation of celecoxib or rofecoxib therapy.
Am J Cardiol. 2002 Nov 1;90(9):959-63
VIGOR(50mg): MI risk
x4
Inhibition of Platelet inhibitory
and vasodilator effect
Cardioprotective effect of COX-1,
Naproxen?, other NSAIDs
Cardioprotection and low dose aspirin
• Complete and irreversible inhibition of
platelet COX-1 : Inhibition of TXA2
mediated platelet aggregation
• Pharmacokinetics and phamacodynamics
--- different from low dose aspirin
Cardioprotection and low dose aspirin
COX-2 inhibitor and AMI
COX-2 inhibitor and AMI
•
•
•
•
Rofecoxib >25 mg; X 2 MI
First 90 days of exposure: risk
No elevation in AMI risk after 90 days
Similar RR of MI compared with no current
NSAIDs, naproxen, ibubrufen, other
NSAIDS
• Current rofecoxib(25mg) use was
associated with AMI risk compared with
celecoxib(200 mg).
Cardiovascular safety and NSAIDs
FDA News
FOR IMMEDIATE RELEASE
P05-16
April 7, 2005
Media Inquiries: Kathleen Quinn
301-827-6242
Consumer Inquiries: 888-INFO-FDA
FDA Announces Series of Changes to the Class of
Marketed Non-Steroidal Anti-Inflammatory Drugs (NSAIDs)
http://www.fda.gov/cder/drug/infopage/cox2/default.htm.
Inflammation, Atherosclerosis and Coronary artery disease
Selective COX-2 inhibition improves
endothelial function in coronary artery disease
The patients received celecoxib (200 mg BID)
or placebo for a duration of 2 weeks
in a double-blind, placebo-controlled,
crossover fashion.
selective COX-2 inhibition improves
endothelium-dependent vasodilation and
reduces low-grade chronic inflammation and
oxidative stress in coronary artery disease.
Circulation. 2003 Jan 28;107(3):405-9
Circulation. 2004 Jul 20;110(3):301-8
Association between carotid
atherosclerosis & markers of inflammation
in RA patients and healthy subjects
A significant linear trend for increased carotid
artery IMT was associated with increasing ESR
and CRP
Increased carotid artery IMT and the presence of
carotid plaque are associated with markers of
systemic inflammation in patients with RA
Drug insight: cyclo-oxygenase 2 inhibitors
and cardiovascular risk
Spektor G, Fuster V.
Zena and Michael A Wiener Cardiovascular Institute, Mount Sinai Medical Center,
Nat Clin Pract Cardiovasc Med. 2005 Jun;2(6):290-300.
New York, NY 10029, USA.
Cyclo-oxygenase (COX) 1 mediates the
production of thromboxane A2 in platelets, leading
to platelet aggregation and vasoconstriction.
Conversely, COX2 catalyzes endothelial
prostacyclin synthesis, which effectively counteracts
thromboxane A2, triggering vasodilation and
platelet inhibition. Selective COX2 inhibitors
decrease prostacyclin production, potentially
disrupting homeostasis and creating a
prothrombotic state.
Drug insight: cyclo-oxygenase 2 inhibitors
and cardiovascular risk
Spektor G, Fuster V.
Zena and Michael A Wiener Cardiovascular Institute, Mount Sinai Medical Center,
Nat Clin Pract Cardiovasc Med. 2005 Jun;2(6):290-300.
New York, NY 10029, USA.
The VIGOR study findings of increased cardiovascular risk with
rofecoxib were subsequently confirmed by large metaanalyses, observational studies and recent APPROVe trial
publication. The APC trial findings of increased cardiovascular
risk with Celebrex (celecoxib) conflict with those in the ADAPT
trial, the upcoming PreSAP publication, a case-control study
by Graham et al. and prior large clinical trials, meta-analyses
and observational studies of this drug. Therefore, while an
adverse class effect is a possibility for COX2 inhibitors, the
published data are inconsistent.
Drug insight: cyclo-oxygenase 2 inhibitors
and cardiovascular risk
Spektor G, Fuster V.
Zena and Michael A Wiener Cardiovascular Institute, Mount Sinai Medical Center,
Nat Clin Pract Cardiovasc Med. 2005 Jun;2(6):290-300.
New York, NY 10029, USA.
Improved endothelial function has also been reported with
celecoxib, leading to endothelium-dependent vasodilation,
and associated decreases in C-reactive protein and LDL
cholesterol. The addition of meloxicam to low-dose aspirin and
heparin has improved clinical outcomes after acute coronary
syndromes. These are the first studies suggesting improvement
in endothelial function and reduction of inflammation with
COX2 inhibition. Thus, more randomized controlled trials are
needed to study the relative cardiovascular effects of
different COX2 inhibitors, alone and in combination with
aspirin.
Risk factors for peptic ulcer bleeding
NSAID use
Oral corticosteroid use
Warfarin use
Previous peptic ulcer
Dyspepsia in past year
Heart failure
Diabetes
Current smoking
0
1
2
3
4
Odds ratio
5
6
7
8
Rofecoxib carries a lower overall risk of
upper GI events than naproxen
Cumulative incidence of a
confirmed upper GI event† (%)
5
naproxen, 500 mg
twice daily
rofecoxib, 50 mg
once daily
4
3
n=8076
2
1
0
0
2
8
4
6
Duration of follow-up (months)
10
†Perforation,
obstruction, bleeding
or symptomatic peptic ulcer.
Bombardier et al 2000
12
Risk of ulcer complications with celecoxib
remains high among patients with other risk factors
Patients with ulcer complications
(%)
celecoxib, 400 mg
twice daily
2
ibuprofen, 800 mg
three times daily, or
diclofenac, 75 mg
twice daily
n=8059
1
0
No risk factor
More than one
risk factor
Hawkey & Skelly 2002
Risk of peptic ulceration is similar between non-selective and
COX-2 selective NSAIDs with concomitant low-dose aspirin
Cumulative incidence of ulcers
placebo
n=410
(%)
18
16
***
***
14
aspirin
n=406
rofecoxib + aspirin
n=399
12
ibuprofen
n=400
10
8
*** p<0.001 versus
placebo + aspirin
6
4
2
0
Laine et al 2004
Concomitant aspirin therapy increases the rate
of upper GI ulcer complications with celecoxib
Annualised incidence (6-month data) (%)
Upper GI ulcer
complications
Upper GI ulcer complications
+ symptomatic peptic ulcers
Celecoxib +aspirin
2.01
4.7
NSAID + aspirin
2.12
6.0
Celecoxib alone
0.44
NSAID alone
1.27
p<0.05
1.40
2.91
Silverstein et al 2000
p<0.05
H. pylori infection and NSAID use synergistically
increase the risk of peptic ulcer disease
Patients with peptic ulcer (%)
100
NSAID users
controls
80
60
40
20
0
H. pyloripositive
n=180
H. pylorinegative
n=205
H. pyloripositive
n=127
H. pylorinegative
n=149
Huang et al 2002
Risk factors for upper GI complications
occurring with NSAIDs
• Patient-related factors:
– age >60 years
– history of peptic ulcer disease/upper GI
complications.
• Drug-related factors
– use of a relatively toxic NSAID
– use of a high dose of NSAID (or two NSAIDs
used concurrently)
– concurrent use of an anticoagulant
– concurrent use of a corticosteroid.
NSAIDs induced gastropathy
Preventive measure
Dose reduction
Misoprostol, rebamipide
H2-blocker or PPI
Risk factor
Age > 65 yrs
Prior ulcer disease or Cx
High dose NSAIDs
Rofecoxib
Celecoxib
Multiple NSAIDs
Concomittent steroid Tx
Concomitant anticoagulation
Coxib
Cardioprotective Rationale
• Cardioprotection
– Inflammation plays an important role in
artherosclerotic disease
– COX-2 is highly expressed in artherosclerotic
plaques
– Pilot studies indicate that Celebrex improves
cardiovascular function in patients with
artherosclerotic disease
Thromboembolic Rationale
• Thromboembolic Events
– Includes CV death, myocardial infarction and stroke
– Current studies (mechanistic) suggest Vioxx/Arcoxia to be
pro-oxidant, leading to inflammation and thromboembolic events
– Current mechanistic studies suggest Celebrex
stimulates nitric oxide production leading to lower
thromboembolic events
– Major epidemiology study (Ray) and VIGOR demonstrate
Vioxx has higher thromboembolic events than NSAIDs
Cardiorenal Rationale
• Cardiorenal Events
– Includes hypertension and edema
– Vioxx induces significantly more hypertension
and edema in treated hypertensive patients vs
Celebrex (as seen in 2 clinical trials)
– Celebrex has a similar cardiorenal profile
compared to NSAIDs
Statins in rheumatoid arthritis--two birds with one stone?
Lancet. 2004 Jun 19;363(9426):2011-2.
Trial of Atorvastatin in Rheumatoid Arthritis (TARA):
double-blind, randomised placebo-controlled trial.
Lancet. 2004 Jun 19;363(9426):2015-21
Atorvastatin reduces arterial stiffness in patients
with rheumatoid arthritis. Ann Rheum Dis.
2004 Dec;63(12):1571-5