BALANCING RISK and BENEFIT on

NSAIDs for ARTHRITIS PATIENTS

WITH CVD RISK

FARIDIN HP
Rheumatology Division Internal Medicine
Department Medical Faculty of Hasanudin
University / Wahidin Sudirohusodo Hospital,
Makassar
What is pain?
Pain derived from Latin
(poena) signify a penalty or
punishment
Pain is a sensation that hurt
- discomfort
- distress
- agony

Nyeri adalah suatu perasaan

inderawi yang tidak
menyenangkan.
 Pain is unpleasant sensory
and emotional experience
associated with.
Potential tissue damage or
Actual tissue damage or
Described in term of such damage.
Pain is an POISONS alert to our body
Poisons
Mechanical Thermal Chemical

Tissue damage

Release of mediators
H , K , ATP, Prostaglandin, Bradikinin,
Serotonin, Substance P, Histamine. Cytocaines

Stimulation of nociceptors

Transmission to CNS ACUTE PAIN

via afferent pathways
4
 From neurobiological perspective pain
can be divided into 3 types

PAIN

Nociceptive Inflammatory Pathological

Pain Pain Pain
Neurophatic Pain
Dysfunctional Pain

Woolf CJ. What is this thing called pain? J Clin Invest 2010; 120(11): 3742-3744
 INFLAMATION PAIN
trauma
irritation infection

chemical INFLAMMATION
thermal
allergy etc.
COX-1 COX-2

PGE2

redness, pain, fever, edema and loss of function.

Inflammatory Pain

Central Inflammatory Mediators

sensitization
Histamine, Bradykinin
Leukotrienes, Cytokines,
Prostaglandins,
5-HT, H+/K+ions

NSAID
(Cox1 or Cox2)

Peripheral Sensitization of
sensitization Nociceptors
 Three Step Ladder of WHO

Nyeri Berat (VAS 8-10)

Nyeri Sedang (VAS 4-7)

Strong Opioid
Nyeri ringan VAS 1-3 nonopioid
Mild Opioid adjuvant
Nonopioid nonopioid
adjuvant Morphine
adjuvant - Rapid relies; tab or
Codein or Tramadol liquid
Acetaminophen Paracetamol - Slow relies MST
Ibuprofen or
Celecoxibe
Fentanyl Patch
NSAID or Coxib
 Target Point of Analgesics
Ketamin
Paracetamol
Gabapentin
Perception
Opioids
Gabapentinoids
Clonidine
Corticosteroids
NSAID
Modulation Transduction COXIB
Local Anesthetic

Transduction
DRG

Transmission
Modulation
Local anesthetics
Cryotherapy
COXIBs
Modify by AHT
 NSAIDs
COX 1 & COX 2 inhibitors Selective COX 2 inhibitors
ibuprofen (Motrin, Advil) celocoxib (Celebrex)
naproxen (Aleve)
rofecoxib (Vioxx)
diclofenac (Voltaren)
indomethacin (Indocin)
valdecoxib (Bextra)
ketorolac (Toradol) Parecoxib (dynastat)
sulindac (Clinoril)
mefanamic (Ponstel)
piroxicam (Feldene)
flurbiprofen (Ansaid)
ketoprofen (Orudis)

NSAIDs had many advantages but also many

disadvantages
 Are NSAIDs Safe?
NSAIDs are the cornerstone of arthritis pain and
inflammation management but there are GI & CV risks
that prevent a more generalized and effective use
Upper GI damage
Lower GI damage
Blood loss & Anemia
CV adverse event
 Cox-1 Selective Inhibitor vs Cox-2
More CV side effects
More GI side effects
Diclofenac Celecoxib
Acetosal Indomethacin Ibuprofen
Ketorolac Piroxicam Ketoprofen
Meloxicam COXIB
Rofecoxib
Nimesulide Valdecoxib

preferentially non- preferentially

COX-1 COX-1 COX-2 COX-2
selective
selective selective selective selective
COX
inhibitor inhibitor inhibitor inhibitor
inhibitor

anti-inflammatory
analgesic
 Celecoxib vs diclofenac: 6-week knee OA trial
Celecoxib and Diclofenac Significantly Reduced Pain

Patients assessment of pain (VAS):

Mean change at Week 6
*
40 * 36.8 *P=0.001
34.5
Mean Change (mm)

30
Less Pain

23.1
20

10

0
Placebo Celecoxib Diclofenac
(n=200) 100 mg BID 50 mg TID
(n=199) (n=199)

VAS = visual analogue scale.

Reference: 1. McKenna F et al. Scand J Rheumatol. 2001;30:11-18.
In OA, the recommended dose of CELEBREX is 200 mg administered as a single dose or as 100 mg twice per day. Safety has been demonstrated
for doses up to 400 mg twice per day.
 Knee or hip OA: Fewer OA flares with
continuous celecoxib vs PRN* celecoxib
Treatment of osteoarthritis with continuous versus intermittent celecoxib (22-week
double-blind treatment period)

P < 0.0001

PRN = celecoxib 200 mg once daily during a predefined flare episode. On average, subjects in the PRN group received celecoxib 200 mg
once daily for 10 days per month.

Strand et al. J Rheumatol 2011;38:2625-34

 Celecoxib vs diclofenac: 24-week RA trial
Celecoxib showed sustained anti-inflammatory and analgesic activity similar to
diclofenac
Number of Tender/Painful Joints Mean reduction in number of
tender/painful joints
*P<.012.
25

20

15
*
10
Celecoxib 200 mg BID (n=326)
5
Diclofenac SR 75 mg BID (n=329)
0
0 4 8 12 16 20 24
Week

Reference: 1. Emery P et al. Lancet. 1999;354:2106-2111.

In RA, the recommended dose of CELEBREX is 100 or 200 mg twice per day. Safety has been demonstrated for doses of up to 400 mg twice per
day.
 Why *ns-NSAIDs can cause GI damage?
Arachidonic Acid

Glucocorticoids
(block mRNA expression)

COX-1 COX-2
(Constitutive) (Cytokine inducible)

x nsNSAIDs x

GI tract Inflammatory site:

Kidney Macrophages
Platelet Synoviocytes
Endothelial cells

*ns = non-selective

nsNSAIDs: non selective Non Steroid Anti Inflammatory Drugs

Needleman P, and Isakson PC. J Rheumatol Suppl 1997;49:6-7; Flower RJ. Nat Rev Drug Discov 2003;2:179-191
 A new paradigm for COX biology: a specific COX-2
inhibitor is possible
Arachidonic Acid
Glucocorticoids
(block mRNA expression)

COX-1 COX-2
(Constitutive) (Cytokine inducible)

Purpose-designed COX-2 specific

inhibitor x
GI tract Disease models:
Kidney Osteoarthritis
Platelet Rheumatoid arthritis
Post-surgical pain

Needleman P, and Isakson PC. J Rheumatol Suppl 1997;49:6-7; Flower RJ. Nat Rev Drug Discov 2003;2:179-191
 Gastroprotective effect of a PPI does not
extend to the lower GI tract
Patients who take NSAIDs have an increased risk for lower GI clinical events1,2
Capsule endoscopy studies in healthy volunteers have increased the
understanding of the GI effects of NSAIDs3
Gastroprotective effect of a PPI does not extend to the lower GI tract4
35 55 healthy volunteers
# pa ents with small bowel lesions

23 ulcers received diclofenac

30
60% 75mg od + omeprazole
115
25 20mg od for 14 days.
denuded Small intestinal injury
20 areas was examined using
15 capsule endoscopy
p<0.0001 498 before and after
10
erosions treatment4
5
11%
0
Before A er At day 14, 32/53 patients
NSAID + PPI presented 636 small bowel
lesions.
1. Laine L et al., Gastroenterology 2003;124:288-292; 2. Allison MC et al., N Engl J Med 1992;327:749-754. 3. Maiden L et al., Gastroenterology
2005;128:1172-1178. 4. Adapted from Fujimori S et al., Eur J Clin Invest 2010;40(6):504-10.
 CONDOR Study: Celecoxib 200 mg BID causes significantly
fewer GI events than diclofenac + PPI
Study

Clinically Significant Events Through the GI tract

10
population (ITT)
(n = 4484) 9
Celecoxib 200 mg bid (N=2238)

Cumulative Incidence of Adjudicated

8 Diclofenac SR 75 mg bid +
High 7
omeprazole 20 mg qd (N=2246)
GI
risk* 6

5 p<0.0001
H pylori OA/RA 4
negative diagnosis 3

1
Low
CV 0
risk 0 30 60 90 120 150 180 210 240

Days From First Dose

In moderate to high GI risk patients taking NSAIDs for arthritis pain:

Celecoxib demonstrated 4x lower risk of clinically significant GI AEs and lower
incidence of clinically significant anemia compare to Diclofenac + Omeprazole

1Chan et al. Lancet. Early Online Publication, 17 June 2010

So, Celecoxib safer for GI
than Conventional
NSAIDs + PPI

What about the effects

for CV both?
 COX-2 Inhibitors CV History
1998 1999 2000 2001

Nov 2000:
Dec 1998: May 1999: VIGOR trial published Nov 2001:
CELEBREX (celecoxib) Vioxx (rofecoxib) showing an increased CV Bextra (valdecoxib)
approved approved risk with Vioxx (rofecoxib) approved
vs. naproxen1

2004 2005 2006

Dec 2004:
Sep 2004: APC trial: CELEBREX Apr 2005: Jun 2005:
Merck (celecoxib 200mg BID or FDA recommends CHMP concludes
withdraws 400mg BID) associated boxed warnings for an increased risk
Vioxx with a significant all prescribed of CV events for
(rofecoxib) increase in CV events NSAIDs4,5 Oct 2006:
selective COX-2
vs. placebo2
inhibitors as a PRECISION
PreSAP trial: No class, with
significant
Pfizer withdraws increases in trial starts7
Bextra (valdecoxib) duration and dose
increase in CV events
because of increased
for CELEBREX Safety restrictions
risk of rare but
(celecoxib 400mg OD) introduced6
serious skin reactions
vs. placebo3

VIGOR=Vioxx Gastrointestinal Outcomes Research; APC=Adenoma Prevention with Celecoxib; PreSAP=Prevention of Colorectal Sporadic Adenomatous Polyps; FDA=Food and Drug
Administration; CHMP=Committee for Medicinal Products for Human Use.
1. Bombardier C et al., N Engl J Med 2000;343(21):1520-1528; 2. Bertagnolli MM et al., N Engl J Med 2006;355(9):873-884; 3. Arber N et al., N Engl J Med 2006;355(9):885-895; 4. FDA
Federal Register/Vol. 70, No. 12/Wednesday, January 19,2005/Notices. Accessed at www.fda.gov in August 2012; 5. Jenkins K et al., FDA NSAID decision memorandum, April 6, 2005.
Accessed at www.fda.gov in August 2012; 6. EMA Public Statement, London, 17 February 2005 EMEA/62838/2005; 7. https://clinicaltrials.gov/ct2/show/record/NCT00346216
(accessed Sept 2016).
 Why PRECISION?
CV Comorbidities are Common in Arthritis Patients

100 LOGICA study US National Center for

Health Statistics
OA patients Diabetes 11
80
% of patients with OA

Smoke 20
CV RISK 72.7%

60

40 High cholesterol 32

20
Hypertension 40
0
GI Risk CV Risk GI+CV 0 10 20 30 40 50
Risk % of arthritis patients

22
Singh G et al. Am J Manag Care 2002; 8: S38391. Lanas et al., Ann Rheum Dis 2010; 69: 1453-1458
 PRECISION Noninferiority for Primary APTC Endpoint
* P value for non-inferiority
Intention-To-Treat (ITT) On-Treatment (mITT)
Celecoxib vs. naproxen, HR 0.93 (0.76-1.12), P<0.001* Celecoxib vs. naproxen HR 0.90 (0.71-1.15), P<0.001*
100 Celecoxib vs. ibuprofen, HR 0.85 (0.70-1.04), P<0.001* Celecoxib vs. ibuprofen, HR 0.81 (0.65-1.02), P<0.001*
100
Ibuprofen vs. naproxen, HR 1.08 (0.90-1.31), P<0.02* Ibuprofen vs. naproxen HR 1.12 (0.89-1.4), P=0.025*
4
Patients with an Event (%)

80 4
80

Patients with an Event (%)

3
3
60 60
2 2

40 Celecoxib 40 Celecoxib
1 1 Naproxen
Naproxen
Ibuprofen Ibuprofen
20 0 20 0
0 6 12 18 24 30 0 6 12 18 24 30 36 42

0.0 0.0
0 6 12 18 24 30 0 6 12 18 24 30 36 42
Months since Randomization Months since Randomization

Celecoxib demonstrated similar incidence of CV events compared to Naproxen and

Ibuprofen. Non-inferiority was demonstrated in all pairwise comparisons in both the ITT and MITT populations.
23
Nissen S et al. N Engl J Med. 2016 Dec 29;375(26):2519-29.
 PRECISION MACE (major adverse CV events)

Intention-To-Treat (ITT) On-Treatment (mITT)

Cel vs. Ibu, HR, 0.87 (0.751.01); P = 0.06 Cel vs. Ibu HR, 0.82 (0.69-0.97)
100 Cel vs. Nap, HR, 0.97 (0.831.12); P = 0.64 Cel vs. Nap HR, 0.95 (0.80-1.13)
Ibu vs. Nap, HR, 1.11 (0.971.29); P = 0.15 100 Ibu vs. Nap HR, 1.17 (0.99-1.38)

Patients with Event (%)

80 80
8.0
3
Patients with Event (%)

6.0
60 2 60
4.0

40 Celecoxib Celecoxib
1 40
Naproxen
2.0 Naproxen
Ibuprofen Ibuprofen
20
20 0 0.0
0 6 12 18 24 30 0 6 12 18 24 30 36 42

0
0.0
0 6 12 18 24 30 36 42
0 6 12 18 24 30
Months since Randomization Months since Randomization

No significant difference was found between celecoxib and naproxen (p=0.64)

The difference between celecoxib and ibuprofen was marginally non-significant in favour of
celecoxib (p=0.06)
MACE = APTC plus coronary revascularisation or hospitalisation for unstable angina or transient ischaemic attack; ITT, intention to treat; 24
Nissen S et al. N Engl J Med. 2016 Dec 29;375(26):2519-29.
 PRECISION Hospitalization for Hypertension or
Congestive Heart Failure (CHF)
Celecoxib Naproxen Ibuprofen

0.7

0.6
P=0.04

0.5
% of patients

0.4

0.3

0.2

0.1

0
Hypertension CHF Hypertension CHF
ITT mITT

The rate of hospitalization for hypertension was also significantly lower with
celecoxib compared to ibuprofen, HR 0.60 (0.360.99) p=0.04. 25
Nissen S et al. N Engl J Med. 2016 Dec 29;375(26):2519-29.
 PRECISION Renal outcomes (tertiary endpoint)
& Hypertension
Intention-To-Treat (ITT) On-Treatment (mITT)
1.5 Celecoxib vs. naproxen, HR 0.79 (0.56-1.12), P=0.19 Celecoxib vs. naproxen, HR 0.66 (0.44-0.97)
Celecoxib vs. ibuprofen, HR 0.61 (0.44-0.85), P=0.004
2.0
Celecoxib vs. ibuprofen, HR 0.54 (0.37-0.80)
Ibuprofen vs. naproxen, HR 1.29 (0.95-1.76), P=0.10 Ibuprofen vs. naproxen, HR 1.21 (0.86-1.70)
Patients with an Event (%)

1.5

Patients with an Event (%)

1.0
Celecoxib
Naproxen
1.0 Ibuprofen

0.5
Celecoxib
Naproxen 0.5
Ibuprofen

0.0 0
0 6 12 18 24 30 0 6 12 18 24 30 36 42
Months since Randomization Months since Randomization

Renal outcomes included: Initiation of dialysis, Hospitalization for ARF, Creatinine rises
The rate of renal events was significantly lower with celecoxib than with ibuprofen (p=0.004),
and similar to naproxen

26
Nissen S et al. N Engl J Med. 2016 Dec 29;375(26):2519-29.
 PRECISION confirms celecoxib renal advantage seen
in healthy elderly (GFR) and in arthritis patients (CrCl)

Renal Function in healthy elderly1 Renal Function in arthritis patients2

Diclofenac Ibuprofen Celecoxib
Day 1 Day 6 75 mg BID 800 mg TID 400 mg BID
0.5
200mg BID

500mg BID

400mg BID

500mg BID
Naproxen

Naproxen
Celecoxib

Celecoxib
0.08
0

Change in CrCl, mL/min

Change in GFR, mL/m per 1.73m2

0 -0.5
-1
-0.8 -1.1 -1
-2 -0.96
-3 -1.5
-4
-2
-5
* P<0.05
-6 -5.3
-2.5
-7 * P=0.004
-8 -3 -2.82 *
-7.5 *

1. Healthy 65 y old received celecoxib 200mg BID 5 days 2. Patients with OA/RA received celecoxib or diclofenac or
+ celecoxib 400mg BID 5 days or naproxen BID 10 days ibuprofen for up to 6-9 months (CLASS study)

GFR - Glomerular filtration rate; CrCl - Creatinine clearance.

1. Whelton A, et al. Arch Intern Med 2000;160:1465-1470. 2. Whelton A et al., Kidney Int 2006;70:1495-1502.
 PRECISION All-Cause Mortality
Intention-to-treat (ITT ) On-treatment (mITT)
3.0 Celecoxib vs. naproxen, HR 0.80 (0.63-1.00), P=0.052 3.0 Celecoxib vs. naproxen, HR 0.65 (0.46-0.92)
Celecoxib vs. ibuprofen, HR 0.92 (0.73-1.17), P=0.49 Celecoxib vs. ibuprofen, HR 0.68 (0.48-0.97)
Patients with an Event (%)

Ibuprofen vs. naproxen, HR 0.87 (0.70-1.09), P=0.22 Ibuprofen vs. naproxen, HR 0.96 (0.70-1.31)

Patients with an Event (%)

2.5
2.0 2.0

1.5
1.0
Celecoxib 1.0
Naproxen Celecoxib
Ibuprofen 0.5 Naproxen
Ibuprofen
0.0 0.0
0 6 12 18 24 30 0 6 12 18 24 30 36 42
Months since Randomization Months since Randomization

Celecoxib was associated to less deaths from any cause (tertiary endpoint) than
naproxen in the ITT analysis, and significantly less deaths than naproxen and ibuprofen
in the mITT analysis.
28
Nissen S et al. N Engl J Med. 2016 Dec 29;375(26):2519-29.
 PRECISION:
Establishes the noninferior CV safety of celecoxib, vs
naproxen compared to ibuprofen in patients at CV
risk
Reaffirms the recognized better upper and lower GI
safety of celecoxib compared to naproxen &
ibuprofen

Defines celecoxib lower rates of renal outcomes

compared to naproxen and ibuprofen

Confirms celecoxib equivalence to naproxen &

ibuprofen to relieve arthritis pain and disability

Demystifies the class effect on CV safety attributed

to all selective COX-2 inhibitors

29
 THERE ARE NSAIDS, COXIBS
& THERE IS CELECOXIB.
Celecoxib is safer than ns-NSAIDs in the GI tract
With fewer GI events than ns-NSAIDS, even when they are
combined with a PPI
Celecoxib is effective on pain and inflammation
associated to OA, RA, AS. Dosage:
OA & AS 200 mg/ day
RA 200 400 mg/ day

Celecoxib is effective in reducing acute pain and

inflammation
Dosage: Loading dose 400 mg with additional dose 200 mg at first
day if needed, following with 200 mg bid

PRECISION trial has proven that CV risk is not COX-2

inhibitors class effect .. not all COX-2 inhibitors are same
Thank you for attention