NSAIDs, Coxibs, and Cardio-Renal Physiology A Mechanism-Based Evaluation

NSAIDs, Coxibs, and Cardio-Renal Physiology

A Mechanism-Based Evaluation

COX-2 Hypothesis and GI Outcome Studies With Coxibs

Phospholipase A2

Membrane-bound phospholipids

Arachidonic acid

OO22

PGG2

PGH2

PGF2PGE2PGD2 PGI2 TxA2

COX-1

COX-2

COX = cyclooxygenase; coxibs = COX-2 inhibitors; PG = prostaglandin; TxA2 = thromboxane A2;

NSAID = nonsteroidal anti-inflammatory drug; ASA = aspirin.

NSAIDs, ASA

Coxibs

Tissue-specific isomerases

Prostaglandin and Thromboxane Biosynthesis

The COX-2 Hypothesis

PGsPGs

COX-1constitutive

COX-2inducible

Inflammation Fever Pain Headache

Carcinogenesis

GI cytoprotection Platelet aggregation Renal function

(blood flow)

Arachidonic acid

Caveats to COX-2 Hypothesis Constitutive COX-2 expression in kidney and brain Co-expression of COX-1 and COX-2 at sites of

inflammation Hemodynamic induction of COX-2

Testing the COX-2 Hypothesis At therapeutic plasma concentrations,

coxibs should

– Have no effect on COX-1 activity

– Spare the GI tract

In clinical studies of equally efficacious doses, coxibs should exhibit fewer GI adverse effects than NSAIDs

NSAIDs: COX-2 vs COX-1 Selectivity

FitzGerald and Patrono. N Engl J Med. 2001;345:433.

COX-1 IC50 (µM)

CO

X-2

IC50

(µ

M)

100.00

0.10

0.010.01 0.10 1.00 10.00 100.00

10.00

1.00

6-MNA

Acetaminophen

Rofecoxib

Nimesulide

Celecoxib

Meloxicam

Naproxen

Indomethacin

Diclofenac

Ibuprofen

6-MNA = 6-methoxy-2-naphthylacetic acid; IC50 = drug concentration at which the enzymatic activity is inhibited by 50%.

RofecoxibCelecoxib

Metabolism

Median Tmax = 2–3 hours

T1/2 = 17 hours

Steady state reached: 4 days

Tmax = 2.8 hours

T1/2 = 11.2 hours

Steady state reached: 5 days

KineticsAccumulation

Absorption time

In liver via P450 2C9

Linear No

60% in liver via cytosolic reductase40% in liver via P450 3A4

Nonlinear, saturable

Yes; accumulation factor: 1.67

Sulfonamide Sulfone

F

Vioxx® package insert, Merck & Co, Inc.; Celebrex® package insert, G.D. Searle & Co.

Oral bioavailability 22%–40% 92%–93%

Coxibs: Pharmacologic CharacteristicsO

O

NH2

CF3

N

S

N

CH3

F

OO

O

H3CS

O

Laine et al. Gastroenterology. 1999;117:776.

Patients: N=742, osteoarthritis

Cu

mu

lati

ve i

nci

den

ce o

f g

astr

od

uo

den

al u

lcer

s* (

%)

* ≥3 mm.† P<0.001 vs ibuprofen.

At doses 2- to 4-fold higher than the doses required to relieve symptoms of OA, rofecoxib caused significantly fewer gastroduodenal ulcers than ibuprofen

Upper GI Effect of Rofecoxib: Endoscopic Study

Placebo(n=158)

Ibuprofen 2400 mg(n=167)

Rofecoxib 25 mg(n=186)

Rofecoxib 50 mg(n=178)

Time of treatmentWeek 12 Week 24

0

10

20

30

40

50

†

†

Simon et al. JAMA. 1999;282:1921.

Patients: N=1149, rheumatoid arthritis

0

5

10

15

20

25

30

Placebo (n=99)

Celecoxib 200 mg(n=148)

Celecoxib400 mg(n=145)

Celecoxib800 mg(n=130)

Naproxen1000 mg(n=137)

P<0.001 vs other groups

Gas

tro

du

od

enal

ulc

er

inci

den

ce*

ove

r 12

-wee

ktr

eatm

ent

per

iod

(%

)

Celecoxib produced significantly fewer visualized gastroduodenal ulcers than naproxen

Upper GI Effect of Celecoxib: Endoscopic Study

CLASS† (N=7982)VIGOR* (N=8076)

Bombardier et al. N Engl J Med. 2000;343:1520; Silverstein et al. JAMA. 2000;284:1247; FDA Advisory Committee Meeting, 2001, Gaithersburg, Md; FDA Arthritis Advisory Committee, 2001, Gaithersburg, Md.

Celecoxib 400 mg bid(2x max chronic dose)

Rofecoxib 50 mg qd(2x max chronic dose)

Drug

Yes (21%)NoASA (≤325 mg/d)

Ibuprofen 800 mg tidDiclofenac 75 mg bid

Naproxen 500 mg bidComparator

OA (72%), RA (28%)RAPatients

Duration Median 9 months Median 9 months

Symptomatic + complicated ulcersComplicated upper GI events2° end point

Complicated ulcersClinical upper GI events1° end point

* Vioxx Gastrointestinal Outcomes Research. † Celecoxib Long-Term Arthritis Safety Study.

GI Outcomes With Coxibs: Study Designs

Bombardier et al. N Engl J Med. 2000;343:1520; FDA Advisory Committee Meeting, 2001. Gaithersburg, Md.

1° End Point—Clinical UGI Event

Cu

mu

lati

ve in

cid

ence

(%

)

2° End Point—Complicated UGI Event

Cu

mu

lati

ve in

cid

ence

(%

)Months of follow-up

0

Rofecoxib

Naproxen

0.0

1.0

2.0

3.0

4.0

5.0

2 4 6 8 10 12

(RR=0.46; P<0.001)Rofecoxib

Naproxen

0

0.5

1.0

1.5

0 2 4 6 8 10 12

Months of follow-up

(RR=0.43; P=0.005)

GI Outcomes of VIGOR Study

2° End Point—Symptomatic Ulcers/Ulcer Complications

1° End Point—Ulcer Complications

Silverstein et al. JAMA. 2000;284:1247; FDA Arthritis Advisory Committee, 2001. Gaithersburg, Md.

4

3

2

1

0

0 100 200 300 380Days

Celecoxib 400 mg bidDiclofenac 75 mg bidIbuprofen 800 mg tid

0 3202001000

1

Days

2

% o

f p

atie

nts

GI Outcomes of CLASS

% o

f p

atie

nts

VIGOR– Compared with naproxen, rofecoxib significantly decreases the risk of

Clinical upper GI events

Complicated events

All GI bleeding

– Rofecoxib has similar efficacy to naproxen against RA CLASS

– No significant differences between celecoxib and nonspecific NSAID comparators for primary end point of complicated ulcers

– Celecoxib is associated with a lower rate of symptomatic and complicated ulcers compared with ibuprofen alone

Bombardier et al. N Engl J Med. 2000;343:1520; Silverstein et al. JAMA. 2000;284:1247;

FDA Arthritis Advisory Committee, 2001. Gaithersburg, Md.

GI Outcome Studies With Coxibs: Summary

NSAIDs and Coxibs: Renal Physiology

Arachidonic Acid

PGI2PGE2

Decreases Na+ reabsorption

Brater. Am J Med. 1999;107:65S.

Stimulates renin release secretion of aldosterone

K+ secretionVasodilation

- GFR- Renal blood flow

COX-1, COX-2

GFR = glomerular filtration rate.

Role of Prostaglandins in the Kidney

Constitutive Expression of COX-1 and COX-2 in the Kidney

Nantel et al. Nantel et al. FEBS LettersFEBS Letters. 1999;457:475; Schnermann et al. . 1999;457:475; Schnermann et al. J Clin InvestJ Clin Invest. 1999;104:1007.. 1999;104:1007.

Renin-secretingRenin-secretinggranular cellsgranular cells

Loop of HenleLoop of Henle

Efferent arteriole: COX-1, COX-2Efferent arteriole: COX-1, COX-2

Macula densa: Macula densa: COX-2COX-2

Distal tubuleDistal tubule

Afferent arteriole: Afferent arteriole: COX-1, COX-2COX-1, COX-2

ThickThickascendingascending

limb:limb:COX-2COX-2

Proximal Proximal convoluted tubuleconvoluted tubule

Glomerulus: Glomerulus: COX-1, COX-2COX-1, COX-2

Podocytes: COX-2Podocytes: COX-2

Harris and Breyer. Am J Physiol Renal Physiol. 2001;281:F1; Whelton. Am J Med. 2001;110(suppl 3A):33S.

Intrarenal Functional Roles of COX-2 and COX-1

COX-2 expression can be up-regulated– In the renal cortex by volume restriction – In the renal medulla by volume expansion – In high renin states (such as salt-restriction,

ACE inhibition, and renovascular hypertension) COX-2—dominant contributor to Na+, Cl–, and water

homeostasis under physiologic conditions COX-1—important role in hemodynamic regulation

under physiologic conditions

Potential Effects of NSAIDs on Renal Physiology

Brater. Am J Med. 1999;107:65S.

CHF = congestive heart failure.

PGI2

Hyperkalemia Acute renal failure

PGE2

Sodium retention• Peripheral edema• Blood pressure• Weight• CHF (rarely)

Arachidonic acid

COX-1

COX-2

NSAIDs

Ioh

exo

l cle

aran

ce*

(mL

/min

/1.7

3 m

2 )

P<0.05 vs rofecoxib

P<0.05 vs celecoxib

Celecoxib200 mg

bid

Naproxen500 mg

bid

Celecoxib400 mg

bid

Naproxen500 mg

bid

-8-8

-6-6

-4-4

-2-2

00

22

44Placebo Rofecoxib

50 mg qdIndomethacin

50 mg qd

-8-8

-6-6

-4-4

-2-2

00

22

44

Catella-Lawson et al. J Pharmacol Exp Ther. 1999;289:735; Whelton et al. Arch Intern Med. 2000;160:1465.

* Mean ± (SE) change from baseline GFR.

COX-1–Dependent Regulation of GFR in Healthy Elderly on a Sodium-Replete Diet

* P<0.05 vs placebo.† P=0.086 vs placebo.

% R

edu

ctio

n in

io

thal

amat

e cl

eara

nce

Swan et al. Ann Intern Med. 2000;133:1.

0.00

0.05

0.15

0.10

0.20

0.25

Placebo(n=15)

Rofecoxib12.5 mg qd

(n=15)

Rofecoxib25 mg qd

(n=15)

Indomethacin50 mg tid

(n=15)

* *†

COX-2–Dependent Regulation of GFR in Healthy Elderly

on a Sodium-Depleted Diet

* Investigator-reported.

1. Summary basis for approval, FDA. 2. FDA Advisory Committee Meeting, 2001.

% o

f p

atie

nts

3.8 3.4

Ibuprofen2400 mg

n=847

Diclofenac150 mgn=498

3.6 3.8

Rofecoxib25 mgn=1614

Rofecoxib12.5 mgn=1215

Phase II/III OA studies1 VIGOR study2


Naproxen1000 mgn=4029

5.4

3.6

Dose-Dependent Incidence of Lower-Extremity Edema*: Rofecoxib Trials

0.0

2.0

4.0

6.0

8.0

10.0

* Peripheral edema includes both upper- and lower-extremity edema (investigator-reported). † P<0.05 vs celecoxib; ‡ Naproxen, diclofenac.

1. Summary basis for approval, FDA. 2. FDA Arthritis Advisory Committee Meeting, 1-year data, 2001.

Dose-Dependent Incidence of Peripheral Edema*: Celecoxib Trials

1.93.0

2.4

3.7 3.5

5.2

2.0

4.0

6.0

8.0

10.0

% o

f p

atie

nts

Celecoxib

400 mgn=1208

NSAID Comparator‡

n=1388

Ibuprofen 2400 mgn=1985

Diclofenac 150 mgn=1996

Celecoxib 200 mgn=1764

Phase II/III OA studies1 CLASS2

Celecoxib

800 mgn=3987

†

0.0

1. Summary basis for approval, FDA. 2. FDA Advisory Committee Meeting, 2001.

* Investigator-reported adverse experiences.

Hypertension* Reports: Rofecoxib

VIGOR study2

2.8

4.0

% o

f p

atie

nts


Rofecoxib12.5 mgn=1215

Phase II/III OA studies1

Rofecoxib 50 mg n=4047

Naproxen 1000 mg n=4029

9.7

5.5

2.9

1.6

Ibuprofen2400 mg

n=847

Diclofenac150 mgn=498

2.0

4.0

6.0

8.0

10.0

0.0

0.71.20.9

2.0 2.0

3.1

% o

f p

atie

nts


NSAID Comparator†

n=1388

Ibuprofen 2400 mgn=1985

Diclofenac 150 mgn=1996


Phase II/III OA studies1 CLASS2


1. Summary basis for approval, FDA.2. FDA Arthritis Advisory Committee Meeting, 2001.

* Investigator-reported.† Naproxen, diclofenac.

Hypertension* Reports: Celecoxib

0.0

1.0

2.0

3.0

4.0

-2

-1

0

1

2

3

4

5

Schwartz et al. EULAR, 2001. Abstract SAT0055.

Effect of Naproxen and Coxibs onBlood Pressure in the Elderly

Placebo (n=16)Naproxen 500 mg bid (n=17)

Celecoxib 200 mg bid (n=17)Rofecoxib 25 mg qd (n=17)

Systolic BP Diastolic BP

Changes in BP on Day 14 of Treatment

LS

mea

n c

han

ge

fro

m b

asel

ine

± S

E

-3

6

7

Renal Effects of Coxibs and NSAIDs: Summary

So far, the renal adverse event profile of coxibs resembles that of nonspecific NSAIDs

Limited information is available regarding the contribution of COX isoforms to function under conditions of renal stress and insufficiency

Clinically significant decline in renal function with coxibs is rare; however, few studies in susceptible populations have analyzed it

Comparative studies of coxibs and nonspecific NSAIDs in hypertension and edema, which adjust for pharmacologic differences, are required

NSAIDs and Coxibs: Cardiovascular Biology

Effects of NSAIDs on Platelets and Endothelium

McAdam et al. Proc Natl Acad Sci USA. 1999;96:272.

Thromboxane (TxA2)

Vasoconstrictor Promotes platelet aggregation

Platelet

Hemostasis Thrombosis

COX-1

VasodilatorInhibitor of platelet aggregation

Endothelial cell

Prostacyclin (PGI2)

COX-1

COX-2

Nonspecific NSAIDs/ASA

Coxibs

Comparative Inhibitory Activity of NSAIDs on Platelet Aggregation

McAdam et al. Proc Natl Acad Sci USA. 1999;96:272.

*20 M arachidonate used as agonist.

Inh

ibit

ion

of

pla

tele

t ag

gre

gat

ion

*(%

ch

ang

e fr

om

bas

elin

e)

0

100

Placebo

20

IbuprofenCelecoxib (mg)

100 400 800

40

60

80

10

30

50

70

90

P<0.01 vs placebo

Event CategoryRofecoxib(n=4047)

Naproxen(n=4029)

Relative Risk(95% CI)

Cardiac 28 (1.0) 10 (0.4)

Cerebrovascular* 11 (0.4) 8 (0.3)

Peripheral vascular 6 (0.2) 1 (0.0 4)

Confirmed CV 45 (1.7) 19 (0.7)

Patients With Events (Rates per 100 Patient-Years)

0.36

0.73

0.17

0.420 1 2

Patients: RA Aspirin treatment: not allowed

* Not including hemorrhagic stroke.

FDA Advisory Committee Meeting, 2001.

CV Adverse Events: VIGOR

CV Adverse Events: CLASS

% of Patients With Events

Celecoxib Diclofenac Ibuprofen

Event (n=3988) (n=1996) (n=1985)

MI 20 (0.5) 6 (0.3) 10 (0.5)

Angina24 (0.6) 10 (0.5) 12 (0.6)

Unstable angina 12 (0.3) 4 (0.2) 2 (0.1)

Any event 100 (2.5) 42 (2.1) 44 (2.2)

Withdrawals 32 (0.8) 14 (0.7) 16 (0.8)

Patients: 72% with OA and 28% with RA Aspirin treatment: 21% of patients

FDA Arthritis Advisory Committee Meeting, 2001.


CV Biology and COX-2 Inhibition: Hypotheses Generated by VIGOR Results

Play of chance?

Thrombogenic risk with coxibs?

Is naproxen cardioprotective?



(cont’d)

Play of chance?

– Small number of events (<70, 1.7%)


(cont’d)

Thrombogenic risk with coxibs?– Coxibs inhibit PGI2, an antithrombotic agent

– Thromboxane formation is unopposed by concomitant generation of PGI2

– In mice, deletion of the PGI2 receptor increases the response to thrombogenic stimuli

– Patients with RA have an increased risk of thrombosis

Effect of Celecoxib and Rofecoxib on Prostacyclin Biosynthesis

* PGI-M = 2,3-dinor-6-keto-PGF1; † P<0.01 vs placebo; ‡ P<0.05 vs placebo.

0

40

80

120

160

200

Placebo(n=7)


Ibuprofen 800 mg(n=7)

Mea

n u

rin

ary

PG

I-M

* ±

SE

(p

g/m

g c

reat

inin

e)

†

‡

Placebo(n=12)

Rofecoxib50 mg qd

(n=12)

Indomethacin50 mg tid

(n=10)

†

†

0

40

80

120

160

200

McAdam et al. Proc Natl Acad Sci USA. 1999;96:272; Catella-Lawson et al. J Pharmacol Exp Ther. 1999;289:735.


†

1 Myllykangas-Luosujarvi et al. Semin Arthritis Rheum. 1995;25:193.2 Wolfe and Straus. Arthritis Rheum. 2000;43(9 suppl):S133.Doggen et al. J Intern Med. 2000;248:406; Devlin et al. J Rheumatol. 1997;24:9.

CV Morbidity and Mortality in RA Increasing evidence suggests a role of inflammation in coronary

events Most studies have shown that patients with RA have increased CV

mortality relative to patients of the same age and sex without RA1

– Standardized mortality ratios: 1.1:2.5

One recent study2 has shown increased CV risk (OR=2.0) in RA patients relative to OA patients, adjusting for age, gender, and other covariates

Patients with RA have increased plasma levels of C-reactive protein, which correlate with an increased CV risk

MI and CV Death

RA vs OA

Men*

Women*

Overall†

1.26 (1.14, 1.40)

1.37 (1.26, 1.49)

1.32 (1.24, 1.41)

RA vs No Arthritis

Men*

Women*

Overall†

1.43 (1.29, 1.58)

1.63 (1.50, 1.76)

1.55 (1.46, 1.65)

* Adjusted for age. † Adjusted for age and gender.

1.40 (1.22, 1.61) 1.49 (1.36, 1.69) 1.41 (1.24, 1.61)

1.40 (1.22, 1.60)1.49 (1.36, 1.63)1.45 (1.35, 1.57)

MI CV Death

Adjusted Rate Ratios (95% CI)

Watson and Rhodes. EULAR, 2001. Abstract OP0109.

CV Biology and COX-2 Inhibition: Hypotheses Generated by VIGOR Results (cont’d)

Is naproxen cardioprotective?

– Naproxen has a potent antiplatelet effect with an extended half-life

– No prospective evaluation of naproxen on CV outcome

Inhibition From Baseline During Dosing Interval

0 2 4 8

Hours after dose

Me

an

% in

hib

itio

n

SE Naproxen

500 mg bid

Placebo

Ibuprofen800 mg tid

100

80

60

40

20

0

-20

FDA Advisory Committee Meeting, 2001.

Effect of NSAIDs on Platelet Aggregation

Bombardier et al. N Engl J Med. 2000;343:1520.

CVA = cerebrovascular accident; TIA = transient ischemic attack; CABG = coronary artery bypass surgery;PTCA = percutaneous transluminal coronary angioplasty.

Importance of Antiplatelet Therapy in Patients With CV Risk: VIGOR

4% of enrolled patients met established criteria for secondary CV prophylaxis (prior MI, CVA, TIA, angina, CABG, PTCA)

– 47% of Mls occurred in this group

No correlation between hypertension and MIs; 1 patient had both hypertension and an MI

Baigent et al. BMJ. 1998;316:1337; Antiplatelet Trialists’ Collaboration. BMJ. 1994;308:81; Physicians’ Health Study Research Group. N Engl J Med. 1989;321:129; Patrono et al. Chest. 2001;119:39S.

Cardioprotective Properties of Aspirin

ASA is clearly indicated after heart attack and stroke– Acute MI (ISIS-2)

23% mortality 49% reinfarction

– Secondary prevention (APTC) 25% in nonfatal MI/stroke/vascular death

Evidence unclear in primary prevention

Rofecoxib50 mg qd (n=4047)

Naproxen500 mg bid

(n=4029)

VIGOR Study1

0.2

0.4

0.6

0.8

1.0

Ra

tes

pe

r 10

0 p

ati

ent-

ye

ars

Celecoxib400 mg bid

(n=3995)

Diclofenac75 mg tid(n=1999)

Ibuprofen800 mg bid

(n=1998)

CLASS Study2

0.2

0.4

0.6

0.8

1.0

1. FDA Advisory Committee Meeting, 2001. 2. FDA Arthritis Advisory Committee Meeting, 2001.

Incidence of MI in Rofecoxib and Celecoxib GI Outcome Studies

0.0 0.0

Nonspecific NSAIDs and Coxibs: CV Biology—Summary

The rate of CV events diverges between the 2 treatment groups in VIGOR; this may result from chance

Two mechanistic hypotheses may explain the distribution of CV events among the treatment groups; they are not mutually exclusive– Suppression of PGI2 (no ASA, RA population)

– Naproxen may have a cardioprotective effect There is no evidence that coxibs alone increase CV risk Patients at high risk for CV events should receive therapy

providing cardioprotection– Controlled clinical trials needed to examine whether patients receiving coxibs

+ ASA will experience fewer GI AEs compared with those receiving NSAIDs ± ASA

Summary

Rofecoxib, compared with naproxen at equally efficacious doses, significantly decreases the risk of upper GI events

Based on available evidence, the renal adverse event profile of coxibs resembles that of NSAIDs, to date

Distribution of CV events in VIGOR may be explained by chance; 2 possible mechanistic hypotheses proposed

Risk of CV and renal adverse events needs to be evaluated in patients prior to initiation of coxib therapy

N Eng J Med 345:1809, 2001

Documents

NSAIDs, Coxibs, and Cardio-Renal Physiology A Mechanism-Based Evaluation