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

2. COX-2 Hypothesis and GI Outcome Studies With Coxibs

3. Prostaglandin and Thromboxane Biosynthesis
Membrane-bound phospholipids
Phospholipase A2
NSAIDs, ASA
Arachidonic acid O2
COX-1
COX-2
PGG2
Coxibs
PGH2
Arachidonic acid is mobilized from membrane-bound phospholipids in a reaction catalyzed by the enzyme phospholipase A2. The isozymes cyclooxygenase (COX)-1 and -2 convert arachidonic acid to unstable intermediate prostaglandins (PGs) G2 and H2. Then, tissue-specific isomerases are involved in the production of stable prostanoids such as PGD2, PGE2, PGF2, prostacyclin (PGI2), and thromboxane A2 (TxA2).
Prostanoids are bioactive lipids that act through specific cell-membrane receptors to mediate key cellular responses. Each class of prostanoids is involved in a specific set of functions.
Whereas aspirin irreversibly inhibits COX-1 in platelets, nonsteroidal anti-inflammatory drugs (NSAIDs) inhibit both COX-1 and COX-2 activity. Coxibs are selective COX-2 inhibitors.
Tissue-specific isomerases
PGD2
PGE2
PGF2
PGI2
TxA2
COX = cyclooxygenase; coxibs = COX-2 inhibitors; PG = prostaglandin; TxA2 = thromboxane A2;
NSAID = nonsteroidal anti-inflammatory drug; ASA = aspirin.

4. The COX-2 Hypothesis Arachidonic acid COX-1 constitutive COX-2
inducible
PGs
PGs
GI cytoprotection
Platelet aggregation
Renal function (blood flow)
Inflammation
Fever
Pain
Headache
Carcinogenesis
COX-1, considered a “housekeeping” enzyme, is expressed constitutively in almost all tissues, particularly in the GI tract, platelets, endothelial cells, and kidneys.
COX-1 appears to be responsible for the production of PGs that are important for homeostatic functions, such as maintaining the integrity of GI mucosa, mediating platelet function, and regulating renal blood flow.
COX-2 expression increases dramatically during inflammation and in carcinogenesis. For example, synovial tissue in patients with rheumatoid arthritis (RA) and osteoarthritis (OA), as well as colorectal carcinomas and adenomas, express increased amounts of COX-2.
NSAIDs are widely used drugs that nonselectively inhibit inducible COX-2, which results in a beneficial anti-inflammatory effect, and constitutive COX-1, which may cause GI toxicity. Therefore, it was hypothesized that selective COX-2 inhibition, such as that provided by coxibs, would maintain anti-inflammatory efficacy and avoid GI toxicity.

5. 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
Important evidence regarding COX-1 and COX-2 expression revealed the caveats of the COX-2 hypothesis.
Although COX-2 is an inducible enzyme, it is also present under basal conditions in the central nervous system and the kidney.
Expression of both COX-1 and COX-2 is up-regulated at inflammatory sites such as synovia of inflammed joints and atherosclerotic plaques.
COX-2 expression in the kidney is not only constitutive (macula densa [MD], cortical thick ascending limb [cTALH], and medullary interstitium) but is also subject to physiologic regulation. COX-2 expression is up-regulated in high renin states (salt restriction, angiotensin-converting enzyme inhibition, and renovascular hypertension) and is down- regulated in MD and cTALH by angiotensin II, glucocorticoids, and mineralocorticoids.

6. 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
The upper GI (UGI) complications related to NSAID treatment are a serious cause of concern because of their high incidence and potential severity. The hypothesis behind coxib development was that selective inhibition of COX-2 should ameliorate inflammation without affecting the gastroprotective COX-1 function. Thus, coxibs would be as efficacious as NSAIDs but better tolerated.
The hemorrhagic nature of GI lesions suggests an important role of COX-1 in platelets, as well as in the gastric mucosa. Thus, at therapeutic concentrations, coxibs should have efficacy comparable to that of conventional NSAIDs and no effect that can be attributed to COX-1 inhibition.
Based on these theoretical considerations, the UGI tolerability of coxibs should be significantly improved relative to that of NSAIDs. Several clinical studies examined the validity of this hypothesis.

7. NSAIDs: COX-2 vs COX-1 Selectivity
6-MNA
100.00
Naproxen
Acetaminophen
Ibuprofen
10.00
Meloxicam
COX-2 IC50 (µM)
1.00
Indomethacin
Nimesulide
Celecoxib
Rofecoxib
0.10
Diclofenac
Although the potencies of NSAIDs and coxibs against COX-1 and COX-2 have been analyzed in a wide range of assay systems, from purified enzymes to intact cells, whole blood assays are considered most accurate in determining the biochemical selectivity of these drugs.
The selectivity profiles of several NSAIDs and coxibs are summarized by plotting the drug concentrations necessary to inhibit the activity of each COX isoform by 50% in whole blood assays. The diagonal line indicates equivalent inhibition of COX-1 and COX-2. Drugs plotted under this line are more specific inhibitors of COX-2 than drugs plotted above the line.
The 2 currently available coxibs, rofecoxib and celecoxib, are both relatively selective for COX-2; celecoxib has a slightly lower affinity for the enzyme than rofecoxib.
0.01
0.01
0.10
1.00
10.00
100.00
COX-1 IC50 (µM)
6-MNA = 6-methoxy-2-naphthylacetic acid;
IC50 = drug concentration at which the enzymatic activity is inhibited by 50%.
FitzGerald and Patrono. N Engl J Med. 2001;345:433.
FitzGerald GA, Patrono C. The coxibs, selective inhibitors of cyclooxygenase-2. N Engl J Med. 2001;345:

8. Coxibs: Pharmacologic Characteristics
Sulfonamide
Sulfone O
NH2
CF3 N S
CH3 F O
H3C S F
Celecoxib
Rofecoxib
Absorption time
Tmax = 2.8 hours
T1/2 = 11.2 hours
Steady state reached: 5 days
Median Tmax = 2–3 hours
T1/2 = 17 hours
Steady state reached: 4 days
Metabolism
The potentially important pharmacologic differences between celecoxib and rofecoxib are related to chemical structure, oral bioavailability, half-life, and main pathways of hepatic metabolism.
Whereas rofecoxib contains a sulfone side chain, celecoxib has a sulfonamide. This is a clinically significant difference as celecoxib is contraindicated in patients with a history of allergic reaction to sulfonamides.
Rofecoxib has a significantly higher oral bioavailability compared with celecoxib (>90% vs 22%–40%, respectively).
In liver via P450 2C9
60% in liver via cytosolic reductase 40% in liver via P450 3A4
Kinetics
Linear
Nonlinear, saturable
Accumulation No
Yes; accumulation factor: 1.67
Oral bioavailability
22%–40%
92%–93%
Vioxx® package insert, Merck & Co, Inc.; Celebrex® package insert, G.D. Searle & Co.
Celebrex® (celecoxib). US prescribing information. G.D. Searle & Co
FitzGerald GA, Patrono C. The coxibs, selective inhibitors of cyclooxygenase-2. N Engl J Med. 2001;345:
Vioxx® (rofecoxib). US product information. Merck & Co., Inc

9. Upper GI Effect of Rofecoxib: Endoscopic Study
Patients: N=742, osteoarthritis
Placebo
(n=158)
Ibuprofen 2400 mg
(n=167)
Rofecoxib 25 mg
(n=186)
Rofecoxib 50 mg
(n=178)
Time of treatment
Week 12
Week 24 10 20 30 40 50 †
Cumulative incidence of gastroduodenal ulcers* (%)
This randomized, double-blind, placebo-controlled, 6-month clinical trial compared the incidence of gastroduodenal ulcers as visualized by endoscopy in patients with OA (N=742) receiving rofecoxib (25 or 50 mg qd), ibuprofen (800 mg tid), or placebo.
To assess the potential for GI injury at doses higher than those required to relieve OA symptoms, in this study the rofecoxib doses were 2 to 4 times the therapeutic dose for OA.
The end point of this study was the cumulative incidence of gastroduodenal ulcers ≥3 mm visualized by endoscopy. Because symptoms often do not correlate with GI lesions, visualization of these lesions by endoscopy is a more accurate end point for GI tolerability studies. However, identification of lesions by endoscopy may not predict serious GI complications such as perforation, obstruction, and bleeding.
Cumulative incidence of gastroduodenal ulcers ≥3 mm with rofecoxib was significantly lower than with ibuprofen (P<0.001) at 12 and 24 weeks of treatment, and was similar to placebo at week 12.
At doses 2- to 4-fold higher than the doses required to relieve symptoms of OA, rofecoxib caused significantly fewer gastroduodenal ulcers than ibuprofen
* ≥3 mm. † P<0.001 vs ibuprofen.
Laine et al. Gastroenterology. 1999;117:776.
Laine L, Harper S, Simon T, et al. A randomized trial comparing the effect of rofecoxib, a cyclooxygenase 2-specific inhibitor, with that of ibuprofen on the gastroduodenal mucosa of patients with osteoarthritis. Gastroenterology. 1999;117:

10. Upper GI Effect of Celecoxib: Endoscopic Study
Patients: N=1149, rheumatoid arthritis
P<0.001
vs other groups 30 25
Gastroduodenal ulcer incidence* over 12-week treatment period (%) 20 15 10 5
In this prospective, randomized, double-blind, placebo-controlled, multicenter study, patients (N=1149) with RA were randomized to receive celecoxib (100, 200, or 400 mg bid), an NSAID (naproxen), or placebo. The recommended dose of celecoxib for treatment of RA is 100 or 200 mg bid.
During the 12 weeks of treatment, endoscopic analysis was performed at 2, 6, and 12 weeks to assess the incidence of gastroduodenal ulcer.
All dosages of celecoxib were efficacious and comparable to naproxen in the treatment of RA, as measured by the mean numbers of tender/painful joints and swollen joints.
The incidence of endoscopic ulcers was significantly reduced with celecoxib vs naproxen (P<0.001).
Placebo
(n=99)
Celecoxib
200 mg
Celecoxib
400 mg
Celecoxib
800 mg
Naproxen
1000 mg
(n=148)
(n=145)
(n=130)
(n=137)
Celecoxib produced significantly fewer visualized gastroduodenal ulcers than naproxen
Simon et al. JAMA. 1999;282:1921.
Simon LS, Weaver AL, Graham DY, et al. Anti-inflammatory and upper gastrointestinal effects of celecoxib in rheumatoid arthritis. JAMA. 1999;282:

11. GI Outcomes With Coxibs: Study Designs
VIGOR* (N=8076)
CLASS† (N=7982)
Celecoxib 400 mg bid
(2x max chronic dose)
Rofecoxib 50 mg qd
Drug
Yes (21%) No
ASA (≤325 mg/d)
Ibuprofen 800 mg tid
Diclofenac 75 mg bid
Naproxen 500 mg bid
Comparator
OA (72%), RA (28%) RA
Patients
Duration
Median 9 months
Symptomatic + complicated ulcers
Complicated upper GI events
2° end point
Complicated ulcers
Clinical upper GI events
1° end point
GI safety of the 2 currently available coxibs, rofecoxib and celecoxib, was evaluated in comparison with NSAIDs in 2 separate randomized clinical trials, VIGOR and CLASS, respectively. There are 4 major differences between the designs of these trials:
Characteristics of patient populations
Comparator NSAIDs
Use of concomitant medication
Choice of end point
Whereas all patients in VIGOR had RA, 72% of patients in CLASS had OA and only 28% had RA.
The GI tolerability of rofecoxib was compared with that of naproxen in VIGOR, while the CLASS trial used 2 other comparator NSAIDs, diclofenac and ibuprofen.
Patients with cardiovascular (CV) risk factors enrolled in CLASS were allowed to take aspirin (≤325 mg/d), while patients who required or who had been receiving aspirin were excluded from the VIGOR trial.
In VIGOR, the primary end point was confirmed clinical UGI events, including gastroduodenal perforation or obstruction, UGI bleeding, and symptomatic gastroduodenal ulcers.
Complicated UGI events (perforation, obstruction, and severe UGI bleeding) were included in the secondary end point of the VIGOR trial.
UGI ulcers and ulcer complications (perforation, gastric outlet obstruction, and bleeding) were the primary end point in CLASS. Symptomatic combined with complicated ulcers were chosen as the secondary end point in this trial.
Bombardier C, Laine L, Reicin A, et al. Comparison of upper gastrointestinal toxicity of rofecoxib and naproxen in patients with rheumatoid arthritis. N Engl J Med. 2000;343:
Food and Drug Administration. Celebrex: Arthritis Advisory Committee Meeting, Gaithersburg, Md; February 7,
Food and Drug Administration. Vioxx: Arthritis Advisory Committee Meeting, Gaithersburg, Md; February 8,
Silverstein FE, Faich G, Goldstein JL, et al. Gastrointestinal toxicity with celecoxib vs nonsteroidal anti-inflammatory drugs for osteoarthritis and rheumatoid arthritis: the CLASS study: a randomized controlled trial. Celecoxib Long-term Arthritis Safety Study. JAMA. 2000;284:
* Vioxx Gastrointestinal Outcomes Research. † Celecoxib Long-Term Arthritis Safety Study.
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.

12. GI Outcomes of VIGOR Study
1° End Point—Clinical UGI Event
2° End Point—Complicated UGI Event
1.5
5.0
Naproxen
Naproxen
4.0
1.0
3.0
Cumulative incidence (%)
Cumulative incidence (%)
2.0
0.5
Rofecoxib
Rofecoxib
The VIGOR trial was designed to evaluate the GI safety of rofecoxib (50 mg qd) compared with the NSAID naproxen (500 mg bid).
The cumulative incidence of perforation, symptomatic ulcers, and GI bleeding (PUBs) was 2.08 events per 100 patient-years with rofecoxib and 4.49 with naproxen.
The relative risk of sustaining a confirmed clinical UGI event with rofecoxib was significantly decreased compared with naproxen (RR=0.46; P<0.001). This difference corresponds to a 54% relative risk reduction (RRR).
Regarding the secondary end point of VIGOR, the cumulative incidence of complicated PUBs was 0.59 events per 100 patient-years with rofecoxib and 1.37 with naproxen, a difference that accounts for the 57% RRR with rofecoxib (RR=0.43; P=0.005).
In conclusion, in patients with RA, treatment with rofecoxib is associated with significantly fewer clinically important UGI events than treatment with naproxen, a nonselective NSAID.
1.0
(RR=0.46; P<0.001)
(RR=0.43; P=0.005)
0.0 2 4 6 8 10 12 2 4 6 8 10 12
Months of follow-up
Months of follow-up
Bombardier et al. N Engl J Med. 2000;343:1520; FDA Advisory Committee Meeting, Gaithersburg, Md.
Bombardier C, Laine L, Reicin A, et al. Comparison of upper gastrointestinal toxicity of rofecoxib and naproxen in patients with rheumatoid arthritis. N Engl J Med ;343:
Food and Drug Administration. Vioxx: Arthritis Advisory Committee Meeting, Gaithersburg, Md; February 8,

13. 2° End Point—Symptomatic Ulcers/ Ulcer Complications
GI Outcomes of CLASS
1° End Point—Ulcer Complications
2° End Point—Symptomatic Ulcers/ Ulcer Complications
Celecoxib 400 mg bid
Diclofenac 75 mg bid
Ibuprofen 800 mg tid 4 2 3
% of patients
% of patients 1 2
CLASS was designed to compare the UGI safety of celecoxib (400 mg bid) with 2 NSAIDs: diclofenac (75 mg bid) and ibuprofen (800 mg tid).
Although fewer serious UGI ulcer complications occurred with celecoxib than with NSAIDs, the differences between treatment groups did not achieve statistical significance (P=0.45 for celecoxib vs NSAIDs; P=0.64 for celecoxib vs diclofenac; P=0.414 for celecoxib vs ibuprofen).
Patients treated with celecoxib experienced significantly fewer serious UGI ulcer complications plus symptomatic gastroduodenal ulcers than patients receiving NSAIDs (P=0.04). When compared with each NSAID, the effect of celecoxib was significant vs ibuprofen (P=0.017) and not significant vs diclofenac (P=0.296). However, since only a small fraction of ulcers are thought to result in a clinically serious outcome, symptomatic ulcers do not represent the same severity of end point as complicated perforations, ulcers, and bleeding. 1
100
200
320
100
200
300
380
Days
Days
Silverstein et al. JAMA. 2000;284:1247; FDA Arthritis Advisory Committee, Gaithersburg, Md.
Food and Drug Administration. Celebrex: Arthritis Advisory Committee Meeting, Gaithersburg, Md; February 7, Silverstein FE, Faich G, Goldstein JL, et al. Gastrointestinal toxicity with celecoxib vs nonsteroidal anti-inflammatory drugs for osteoarthritis and rheumatoid arthritis: the CLASS study: a randomized controlled trial. Celecoxib Long-term Arthritis Safety Study. JAMA. 2000;284:

14. GI Outcome Studies With Coxibs: Summary
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
In the VIGOR study, rofecoxib and naproxen had similar efficacy in the treatment of RA, and withdrawals due to lack of efficacy were low in both groups (6.3% with rofecoxib, vs 6.5% with naproxen).
Rofecoxib (50 mg/d) significantly reduced the rates of clinically important UGI events and complicated UGI events compared with the standard naproxen dose (1000 mg/d).
The CLASS trial demonstrated that celecoxib does not significantly reduce the rate of complicated ulcers compared with NSAIDs (combined or individual rates). Celecoxib had significant impact on the rate of symptomatic ulcers combined with ulcer complications compared with ibuprofen only.
The FDA report of the CLASS trial states that “no conclusions regarding the safety of celecoxib compared to traditional less selective COX inhibitors as a group are possible.”
Based on the results from these clinical trials and other studies, the major risk factors for GI complications with NSAIDs are: age >60 years, history of ulcer disease or GI events, concomitant medication (steroid, anticoagulant), high-dose or multiple NSAIDs, presence of H. pylori, severity of RA, heart disease and other comorbidities (heart failure, diabetes), duration of NSAID exposure, and dyspepsia.
Bombardier et al. N Engl J Med. 2000;343:1520; Silverstein et al. JAMA. 2000;284:1247;
FDA Arthritis Advisory Committee, Gaithersburg, Md.
Bombardier C, Laine L, Reicin A, et al. Comparison of upper gastrointestinal toxicity of rofecoxib and naproxen in patients with rheumatoid arthritis. N Engl J Med. 2000;343:
Food and Drug Administration. Celebrex: Arthritis Advisory Committee Meeting, Gaithersburg, Md; February 7,
Food and Drug Administration. Vioxx: Arthritis Advisory Committee Meeting, Gaithersburg, Md; February 8,
Laine L. Approaches to nonsteroidal anti-inflammatory drug use in the high risk patient. Gastroenterology ;120:
Silverstein FE, Faich G, Goldstein JL, et al. Gastrointestinal toxicity with celecoxib vs nonsteroidal anti- inflammatory drugs for osteoarthritis and rheumatoid arthritis: the CLASS study: a randomized controlled trial. Celecoxib Long-term Arthritis Safety Study. JAMA. 2000;284:

15. NSAIDs and Coxibs: Renal Physiology

16. Role of Prostaglandins in the Kidney
Arachidonic Acid
COX-1, COX-2
PGE2
PGI2
Stimulates renin release
 secretion of aldosterone
 K+ secretion
Vasodilation
- GFR
- Renal blood flow
The 2 cyclooxygenase isoforms, COX-1 and COX-2, are main players in the formation of PGs from arachidonic acid. PGs are produced constitutively in many tissues in the body, including the brain, GI tract, and kidneys, and their synthesis is also induced at sites of inflammation.
In the kidneys, PGs act as modulators of physiologic functions such as microvascular hemodynamics, tubular salt and water reabsorption, and renin release.
The most important PGs in the kidneys are PGE2 and PGI2 (prostacyclin). PGE2 decreases tubular Na+ reabsorption. PGI2 stimulates renin release, which in turn stimulates secretion of aldosterone, and further leads to an increased K+ secretion at the distal nephron. PGI2 is also a potent vasodilator that preserves renal perfusion in conditions associated with decreased actual or effective circulating volume.
Decreases Na+
reabsorption
GFR = glomerular filtration rate.
Brater. Am J Med. 1999;107:65S.
Brater DC. Effects of nonsteroidal anti-inflammatory drugs on renal function: focus on cyclooxygenase-2-selective inhibition. Am J Med. 1999;107:65S-71S.

17. Constitutive Expression of COX-1 and COX-2 in the Kidney
Renin-secreting granular cells
Podocytes: COX-2
Glomerulus: COX-1, COX-2
Afferent arteriole: COX-1, COX-2
Distal tubule
Proximal convoluted tubule
Macula densa: COX-2
COX-1 is constitutively expressed in renal vasculature, glomerular mesangial cells, and collecting ducts (cortical and medullary).
Constitutive COX-2 expression has been detected in the renal cortex (MD and cTALH) and in the medulla (medullary interstitial cells).
The 2 COX isoforms exhibit differential compartmentalization in the medulla, with COX-1 predominantly in medullary collecting ducts and COX-2 in medullary interstitial cells.
Thick ascending limb: COX-2
Loop of Henle
Efferent arteriole: COX-1, COX-2
Nantel et al. FEBS Letters. 1999;457:475; Schnermann et al. J Clin Invest. 1999;104:1007.
Kömhoff M, Gröne H-J, Klein T, Seyberth HW, Nüsing RM. Localization of cyclooxygenase-1 and -2 in adult and fetal human kidney: implication for renal function. Am J Physiol. 1997;272:F460-F468.
Nantel F, Meadows E, Denis D, Connolly B, Metters KM, Giaid A. Immunolocalization of cyclooxygenase- 2 in the macula densa of human elderly. FEBS Letters. 1999;457:
Schnermann J, Briggs JP. The macula densa is worth its salt. J Clin Invest. 1999;104:

18. 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
Although functions of both COX isozymes appear to overlap under physiologic conditions, COX-1 may have a more dominant role in hemodynamic regulation, and COX-2 in salt and water homeostasis.
Accumulating evidence suggests that COX-2 also plays an important role in maintaining renal function in cases of physiologic stress, such as volume depletion and congestive heart failure (CHF).
COX-2 expression is up-regulated by salt and water intake and by high renin states. Negative regulation of COX-2 in macula densa (MD) and the cortical thick ascending limb of the loop of Henle (cTALH) is induced by angiotensin II and by glucocorticoids and mineralocorticoids.
Harris and Breyer. Am J Physiol Renal Physiol. 2001;281:F1; Whelton. Am J Med. 2001;110(suppl 3A):33S.
Harris RC, Breyer MD. Physiological regulation of cyclooxygenase-2 in the kidney. Am J Physiol Renal Physiol. 2001;281:F1-F11.
Whelton A. Renal aspects of treatment with conventional nonsteroidal anti-inflammatory drugs versus cyclooxygenase-2-specific inhibitors. Am J Med. 2001;110(suppl 3A):33S-42S.

19. Potential Effects of NSAIDs on Renal Physiology
Arachidonic acid
NSAIDs
COX-1
COX-2
PGE2
PGI2
Sodium retention
Peripheral edema
 Blood pressure
 Weight
CHF (rarely)
Hyperkalemia
Acute renal failure
PGE2 decreases Na+ reabsorption at the cortical thick ascending limb of the loop of Henle. Thus, COX inhibition by NSAIDs leads to increased Na+ reabsorption, decreased response to diuretics (15%–20%), weight gain, occasional edema, and potentially CHF. NSAIDs can also decrease the response to antihypertensive agents and thus cause an increase in blood pressure (BP) (≤5 mmHg).
PGI2 stimulates renin release and ultimately leads to an increase of K+ secretion by the distal nephron. Therapy with NSAIDs results in a hyporeninemic hypoaldosteronism that clinically manifests as type IV renal tubular acidosis and hyperkalemia. The decrease in K+ secretion can be fatal, especially in high-risk patients with renal insufficiency and diabetes.
PGI2, which is also a potent vasodilator, is synthesized by the kidneys to maintain renal perfusion when a decrease of actual or effective circulating volume occurs. Administration of NSAIDs can cause sharp decreases in renal blood flow and could lead to likely acute renal failure. The risk of acute renal failure associated with NSAIDs may be dose-related.
CHF = congestive heart failure.
Brater. Am J Med. 1999;107:65S.
Brater DC. Effects of nonsteroidal anti-inflammatory drugs on renal function: focus on cyclooxygenase-2-selective inhibition. Am J Med. 1999;107:65S-71S.

20. COX-1–Dependent Regulation of GFR in Healthy Elderly on a Sodium-Replete Diet
Placebo
Rofecoxib
50 mg qd
Indomethacin
50 mg qd
Celecoxib
200 mg
bid
Naproxen
500 mg
bid
Celecoxib
400 mg
bid
Naproxen
500 mg
bid 4 4 2 2
Iohexol clearance*
(mL/min/1.73 m2) -2 -2 -4 -4
The effect of rofecoxib vs a nonselective NSAID, indomethacin, on renal hemodynamics was studied in a healthy elderly population (N=36) placed on a fixed-sodium diet.
Indomethacin, but not rofecoxib, induced a significant decrease in glomerular filtration rate (GFR), as assessed by iohexol clearance (P<0.05). Both rofecoxib and indomethacin were associated with a transient but significant decline in urinary Na+ excretion during the first 72 hours of treatment.
These results suggest that acute Na+ retention by NSAIDs in healthy elderly subjects is mediated by COX-2 inhibition, whereas depression of GFR is due to inhibition of COX-1.
The effect of celecoxib vs naproxen on renal hemodynamics was studied in a separate study of an elderly population. During the 10-day treatment, a higher decrease in GFR was observed with naproxen than with celecoxib, a difference that became significant on day 6 (P=0.004).
Na+ excretion levels transiently decreased after initiation of treatment with celecoxib and naproxen, and returned to baseline by the end of study.
Together, these studies suggest a COX-1–dependent regulation of GFR in healthy elderly subjects. -6 -6
P<0.05
vs rofecoxib -8 -8
P<0.05
vs celecoxib
* Mean ± (SE) change from baseline GFR.
Catella-Lawson et al. J Pharmacol Exp Ther. 1999;289:735; Whelton et al. Arch Intern Med. 2000;160:1465.
Catella-Lawson F, McAdam B, Morrison B, et al. Effects of specific inhibition of cyclooxygenase-2 on sodium balance, hemodynamics, and vasoactive eicosanoids. J Pharmacol Exp Ther. 1999;289:
Whelton A, Schulman G, Wallemark C, et al. Effects of celecoxib and naproxen on renal function in the elderly. Arch Intern Med. 2000;160:

21. iothalamate clearance
COX-2–Dependent Regulation of GFR in Healthy Elderly on a Sodium-Depleted Diet
0.25 * *
0.20 †
0.15
iothalamate clearance
% Reduction in
0.10
0.05
The effect of rofecoxib on GFR was also analyzed in elderly subjects (N=75) on a sodium-depleted diet, which enhances renal dependence on prostaglandin production.
After 6 days of therapy, rofecoxib (12.5 or 25 mg/d) and indomethacin (50 mg tid) reduced iothalamate-determined GFR compared with placebo.
Compared with placebo, neither rofecoxib nor indomethacin significantly reduced urinary Na+ excretion.
These results suggest that predisposed subjects with low circulating volume (such as those with CHF, on diuretics, or with cirrhosis) may experience decreases in GFR with either NSAIDs or coxibs. COX-2 may have an essential function in GFR regulation in elderly subjects on a sodium-depleted diet.
0.00
Placebo
(n=15)
Rofecoxib
12.5 mg qd
(n=15)
Rofecoxib
25 mg qd
(n=15)
Indomethacin
50 mg tid
(n=15)
* P<0.05 vs placebo.
† P=0.086 vs placebo.
Swan et al. Ann Intern Med. 2000;133:1.
Swan SK, Rudy DW, Lasseter KC, et al. Effect of cyclooxygenase-2 inhibition on renal function in elderly persons receiving a low-salt diet. Ann Intern Med. 2000;133:1-9.

22. Dose-Dependent Incidence of Lower-Extremity Edema*: Rofecoxib Trials
0.0
2.0
4.0
6.0
8.0
10.0
5.4
% of patients
3.8
3.8
3.4
3.6
3.6
In the phase II/III OA studies, the incidences of lower extremity edema with 12.5 and 25 mg of rofecoxib were similar to those seen with the NSAID comparators, ibuprofen and diclofenac. In the VIGOR study, the incidence of lower-extremity edema with the 50-mg dose was higher than with 12.5 or 25 mg, or the NSAID comparator. This observation is not unexpected since these AEs are dose-related. Overall, in all treatment groups, discontinuation due to lower-extremity edema was rare, and most patients did not require a change in medication.
Definition of lower-extremity edema in these studies encompasses the majority of edema-related AEs reported by investigators.
Although the crude incidence rates shown here do not take into account the treatment duration, the VIGOR results were generally consistent with the results of the phase II/III OA studies.
Ibuprofen
2400 mg
n=847
Diclofenac
150 mg
n=498
Rofecoxib
12.5 mg
n=1215
Rofecoxib
25 mg
n=1614
Rofecoxib
50 mg
n=4047
Naproxen
1000 mg
n=4029
Phase II/III OA studies1
VIGOR study2
* Investigator-reported.
1. Summary basis for approval, FDA FDA Advisory Committee Meeting, 2001.
Food and Drug Administration. Vioxx: Arthritis Advisory Committee Meeting, Gaithersburg, Md; February 8,

23. Dose-Dependent Incidence of Peripheral Edema*: Celecoxib Trials
10.0
8.0 †
6.0
% of patients
5.2
4.0
3.7
3.5
3.0
2.4
1.9
2.0
0.0
NSAID Comparator‡
n=1388
Celecoxib 200 mg
n=1764
Celecoxib 400 mg
n=1208
Celecoxib 800 mg
n=3987
Diclofenac 150 mg
n=1996
Ibuprofen 2400 mg
n=1985
The incidence of edema in patients receiving celecoxib 200 or 400 mg/d in phase II/III OA studies and 800 mg/d in CLASS was similar to that seen with other NSAIDs (naproxen and diclofenac).
In these studies, the definition of peripheral edema included both upper- and lower-extremity edema, as reported by investigators.
Similar to rofecoxib, analysis of phase the II/III OA and CLASS results suggests that the incidence of peripheral edema with celecoxib is dose-dependent.
Phase II/III OA studies1
CLASS2
* 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.
Food and Drug Administration. Celebrex: Arthritis Advisory Committee Meeting, Gaithersburg, Md; February 7,

24. Hypertension* Reports: Rofecoxib
10.0
9.7
8.0
6.0
5.5
% of patients
4.0
4.0
2.9
2.8
2.0
1.6
0.0
In the phase II/III studies of rofecoxib in patients with OA, incidence of hypertension was similar with NSAIDs and rofecoxib at 12.5 and 25 mg/d. For 50 mg/d, which is 2 times the maximum recommended dose for osteoarthritis, an expected increase in hypertension incidence was observed, in agreement with the dose-dependent effect of NSAIDs.
Combined results from all these clinical trials suggest a dose-dependent effect of rofecoxib on blood pressure. Moreover, coxibs are likely to have similar effects to nonselective NSAIDs with respect to blood pressure and edema.
Ibuprofen
2400 mg
n=847
Diclofenac
150 mg
n=498
Rofecoxib
12.5 mg
n=1215
Rofecoxib
25 mg
n=1614
Rofecoxib 50 mg
n=4047
Naproxen 1000 mg
n=4029
Phase II/III OA studies1
VIGOR study2
* Investigator-reported adverse experiences.
1. Summary basis for approval, FDA.
2. FDA Advisory Committee Meeting, 2001.
Food and Drug Administration. Vioxx: Arthritis Advisory Committee Meeting, Gaithersburg, Md; February 8,

25. Hypertension* Reports: Celecoxib
4.0
3.0
3.1
% of patients
2.0
2.0
2.0
1.2
1.0
0.9
0.7
0.0
NSAID Comparator†
n=1388
Celecoxib
200 mg
n=1764
Celecoxib 400 mg
n=1208
Celecoxib 800 mg
n=3987
Diclofenac 150 mg
n=1996
Ibuprofen 2400 mg
n=1985
Phase II/III OA studies and CLASS demonstrate that, as with rofecoxib, there is a dose-dependent effect on the incidence of hypertension with celecoxib. These studies also show that hypertension with NSAIDs (naproxen and diclofenac) and with COX-2 selective inhibitors (celecoxib) occurs at similar rates.
In conclusion, studies of rofecoxib and celecoxib vs NSAIDs suggest that renal-related AEs such as edema and hypertension are dose-dependent, mechanism-based class effects.
Phase II/III OA studies1
CLASS2
* Investigator-reported. † Naproxen, diclofenac.
1. Summary basis for approval, FDA.
2. FDA Arthritis Advisory Committee Meeting, 2001.
Food and Drug Administration. Celebrex: Arthritis Advisory Committee Meeting, Gaithersburg, Md; February 7,

26. Effect of Naproxen and Coxibs on Blood Pressure in the Elderly7
Changes in BP on Day 14 of Treatment 6
Placebo (n=16)
Naproxen 500 mg bid (n=17)
Celecoxib 200 mg bid (n=17)
Rofecoxib 25 mg qd (n=17)
LS mean change from baseline ± SE
A double-blind, placebo-controlled, parallel-group study compared the effects of equipotent doses of rofecoxib (25 mg/d), celecoxib (200 mg bid), and naproxen (500 mg bid) with placebo on BP in 67 healthy elderly patients.
The study indicated that the effects of rofecoxib and celecoxib on systolic BP were not significantly different from that observed with the NSAID naproxen.
Coxibs and naproxen caused a significant increase of up to 5 mmHg in the systolic BP of elderly patients after 14 days of treatment. The change induced in diastolic BP was smaller.
Systolic BP
Diastolic BP -3
Schwartz et al. EULAR, Abstract SAT0055.
Schwartz JI, Malice MP, Lasseter KC, et al. Effect of rofecoxib, celecoxib, and naproxen on blood pressure and urinary sodium excretion in elderly volunteers. EULAR, Abstract SAT0055.

27. 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
Studies carried out so far indicate that the renal AE profile of coxibs resembles that of nonspecific NSAIDs.
In studies to date, clinically significant decline of renal function was rarely seen with coxibs. Incidences of edema and increased BP with coxibs are low and consistent with incidences of these AEs seen with nonselective NSAIDs. Rates of discontinuation due to these AEs are also low, and most cases resolve without discontinuation of therapy.
When prescribing NSAIDs or coxibs, it is important to take into consideration the risk factors present in patients, including hyperkalemia, volume depletion, renal insufficiency, CHF, and cirrhosis. Future studies should elucidate the contribution of each COX isoform to renal function under conditions of stress and insufficiency.
Edema and an increase in BP are renal mechanism–based, dose-dependent, class effects of all NSAIDs, which occur as a result of COX-2 inhibition in the kidney. However, definitive studies that adjust for pharmacologic differences among the coxibs and nonselective NSAIDs are required.

28. NSAIDs and Coxibs: Cardiovascular Biology

29. Effects of NSAIDs on Platelets and Endothelium
Endothelial cell
Coxibs
COX-1
Nonspecific NSAIDs/ASA
COX-1
COX-2
Thromboxane (TxA2)
Prostacyclin (PGI2)
COX-1 and COX-2 catalyze the conversion of arachidonic acid to prostanoids such as TxA2 and PGI2, which play an important role in platelet–vessel wall interactions. TxA2, the major product of platelet COX-1, is a vasoconstrictor and plays an important role in platelet aggregation. PGI2, mainly produced by the endothelium, is a potent vasodilator and antiplatelet factor.
Based on studies of vascular tissue, isolated cells, and immunohistochemistry, it was previously thought that COX-1 was responsible for PGI2 production in normal endothelial cells. However, recent studies demonstrated that the COX-2 inhibitors reduce the urinary excretion of a major metabolite of prostacyclin, which suggests that COX-2 also contributes to PGI2 biosynthesis in humans.
Aspirin is a more potent inhibitor of COX-1 than of COX-2, and its antithrombotic efficacy has been clearly demonstrated. Aspirin irreversibly inhibits TxA2 production by COX-1 in platelets. In contrast to aspirin, other NSAIDs reversibly inhibit both COX-1–derived TxA2 and COX-2–derived PGI2 biosynthesis. Coxibs, a new subclass of NSAIDs, suppress PGI2 production without concomitant inhibition of TxA2 biosynthesis.
Vasoconstrictor
Promotes platelet aggregation
Vasodilator
Inhibitor of platelet aggregation
Hemostasis
Thrombosis
McAdam et al. Proc Natl Acad Sci USA. 1999;96:272.
McAdam BF, Catella-Lawson F, Mardini IA, Kapoor S, Lawson JA, FitzGerald GA. Systemic biosynthesis of prostacyclin by cyclooxygenase (COX)-2: the human pharmacology of a selective inhibitor of COX-2. Proc Natl Acad Sci USA. 1999;96:

30. Comparative Inhibitory Activity of NSAIDs on Platelet Aggregation
100
P<0.01 vs placebo 90 80 70 60
Inhibition of platelet aggregation*
(% change from baseline) 50 40 30 20
The effect of celecoxib (100, 400, and 800 mg/d) compared with a nonselective NSAID (ibuprofen) and placebo on platelet function was analyzed in a group of healthy volunteers.
Whereas celecoxib at all doses did not have a significant effect on platelet aggregation relative to placebo, ibuprofen significantly inhibited platelet aggregation (P<0.01) in ex vivo assays.
These results suggest that celecoxib (100, 400, and 800 mg/d) has no COX-1–dependent antiplatelet effect compared with NSAIDs. 10
100
400
800
Placebo
Celecoxib (mg)
Ibuprofen
*20 M arachidonate used as agonist.
McAdam et al. Proc Natl Acad Sci USA. 1999;96:272.
McAdam BF, Catella-Lawson F, Mardini IA, Kapoor S, Lawson JA, FitzGerald GA. Systemic biosynthesis of prostacyclin by cyclooxygenase (COX)-2: the human pharmacology of a selective inhibitor of COX-2. Proc Natl Acad Sci USA. 1999;96:

31. CV Adverse Events: VIGOR
Patients: RA
Aspirin treatment: not allowed
Patients With Events
(Rates per 100 Patient-Years)
Rofecoxib
(n=4047)
Naproxen
(n=4029)
Relative Risk
(95% CI)
Event Category
Cardiac (1.0) (0.4)
Cerebrovascular* (0.4) (0.3)
Peripheral vascular (0.2) (0.0 4)
0.36
0.73
0.17
0.42 1 2
In the VIGOR study, there were 45 confirmed thrombotic events in the rofecoxib group and 19 in the naproxen group. The relative risk of sustaining a confirmed CV event on naproxen compared with rofecoxib was 0.42.
The majority of events occurring in VIGOR were cardiac events. The relative risk of sustaining such an event on naproxen compared with rofecoxib was Within the cardiac event category, most of the events were myocardial infarctions (MIs), and there was a significant reduction in MIs on naproxen compared with rofecoxib.
As expected, the patients who had thrombotic events were those at higher risk—older patients, males—and ~80% of these patients had 1 or more risk factors.
Confirmed CV
45 (1.7)
19 (0.7)
* Not including hemorrhagic stroke.
FDA Advisory Committee Meeting, 2001.
Food and Drug Administration. Vioxx: Arthritis Advisory Committee Meeting, Gaithersburg, Md; February 8,

32. CV Adverse Events: CLASS
Patients: 72% with OA and 28% with RA
Aspirin treatment: 21% of patients
% of Patients With Events Celecoxib Diclofenac Ibuprofen Event (n=3988) (n=1996) (n=1985) MI 20 (0.5) 6 (0.3) 10 (0.5) Angina 24 (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)
As with rofecoxib, the incidence of CV AEs in the celecoxib group of CLASS was very low (<1%).
The incidence of CV-related events was higher in patients taking aspirin, since they had more significant CV risk factors compared with the entire study population. However, no significant difference was observed in the incidence of CV AEs between celecoxib and the nonselective NSAID treatment groups.
FDA Arthritis Advisory Committee Meeting, 2001.
Food and Drug Administration. Celebrex: Arthritis Advisory Committee Meeting, Gaithersburg, Md; February 7,

33. CV Biology and COX-2 Inhibition: Hypotheses Generated by VIGOR Results
Play of chance?
Thrombogenic risk with coxibs?
Is naproxen cardioprotective?
Several hypotheses were generated in order to explain the difference in major CV events between the rofecoxib and naproxen groups in the VIGOR trial.
The higher incidence of CV events in the rofecoxib group may reflect the play of chance (low total number of events), a thrombogenic risk associated with coxib use (which would make patients with RA more susceptible because of their increased CV risk), or a cardioprotective effect associated with naproxen.
FitzGerald and Patrono. N Engl J Med. 2001;345:433.
FitzGerald GA, Patrono C. The coxibs, selective inhibitors of cyclooxygenase-2. N Engl J Med. 2001;345:

34. CV Biology and COX-2 Inhibition: Hypotheses Generated by VIGOR Results (cont’d)
Play of chance?
Small number of events (<70, 1.7%)
In VIGOR, the significant difference in major CV events seen between the rofecoxib (n=4047) and the naproxen (n=4029) groups may be the effect of chance, due to the very small number of events occurring: 45 with rofecoxib and 19 with naproxen.
FitzGerald and Patrono. N Engl J Med. 2001;345:433.
FitzGerald GA, Patrono C. The coxibs, selective inhibitors of cyclooxygenase-2. N Engl J Med. 2001;345:

35. CV Biology and COX-2 Inhibition: Hypotheses Generated by VIGOR Results (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
Because PGI2 is the major product of COX-2 in endothelial cells and TxA2 is the major product of COX-1 in platelets, it is hypothesized that coxibs abolish PGI2 biosynthesis without having any effect on TxA2 levels. This situation may favor thrombogenesis, and thus patients with CV risk could experience more events when treated with coxibs.
Deletion of the PGI2 receptor in mice, which is theoretically similar to complete COX-2 inhibition, increases their sensitivity to thrombotic stimuli.
Patients with RA, such as those in the VIGOR trial, have an increased risk of CV events, which is not shared by patients with OA. Most patients in the CLASS trial had OA.

36. Effect of Celecoxib and Rofecoxib on Prostacyclin Biosynthesis
200
200
160
160
Mean urinary PGI-M* ± SE (pg/mg creatinine)
120
120 80 ‡ 80 † † † 40 † 40
The effect of rofecoxib and celecoxib on prostacyclin metabolism was evaluated in 2 separate studies. A single dose of celecoxib 400 mg or 800 mg produces a significant decrease in the urinary excretion of PGI2 metabolite 2,3-dinor-6-keto-PGF1 (PGI-M), at 6 hours following the dose (P<0.01). PGI-M excretion is an indicator of systemic PGI2 biosynthesis. The reduction in PGI-M excretion was similar with celecoxib and ibuprofen 800 mg.
A separate study demonstrated that the effects of rofecoxib (50 mg/d) and indomethacin (150 mg/d) on urinary excretion of PGI-M after 14 days of treatment were similar (P=0.55). Both drugs significantly inhibited PGI-M excretion compared with placebo (P<0.05).
These results suggest that COX-2 is directly involved in PGI2 production under physiologic conditions, and thus coxibs may suppress PGI2 biosynthesis in vivo without having any effect on the concomitant TxA2 biosynthesis by COX-1.
Placebo
(n=7)
Celecoxib 400 mg
(n=7)
Celecoxib 800 mg
(n=7)
Ibuprofen 800 mg
(n=7)
Placebo
(n=12)
Rofecoxib 50 mg qd (n=12)
Indomethacin 50 mg tid (n=10)
* PGI-M = 2,3-dinor-6-keto-PGF1; † P<0.01 vs placebo; ‡ P<0.05 vs placebo.
McAdam et al. Proc Natl Acad Sci USA. 1999;96:272; Catella-Lawson et al. J Pharmacol Exp Ther. 1999;289:735.
Catella-Lawson F, McAdam B, Morrison B, et al. Effects of specific inhibition of cyclooxygenase-2 on sodium balance, hemodynamics, and vasoactive eicosanoids. J Pharmacol Exp Ther. 1999;289:
McAdam BF, Catella-Lawson F, Mardini IA, Kapoor S, Lawson JA, FitzGerald GA. Systemic biosynthesis of prostacyclin by cyclooxygenase (COX)-2: the human pharmacology of a selective inhibitor of COX-2. Proc Natl Acad Sci USA. 1999;96:

37. 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
Several studies demonstrate that inflammation plays an important role in coronary events and that RA is associated with increased mortality rates. These patients have a high mortality rate due to CV causes.
A recent study found that the overall risk of CV events in patients with RA vs patients with OA is 2.0.
Male sex, higher age at disease onset, inflammatory activity, and hypertension increase CV risk in patients with RA. Patients with RA also have increased levels of C-reactive protein, which also correlates with an increased CV risk.
1 Myllykangas-Luosujarvi et al. Semin Arthritis Rheum. 1995;25: 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.
Devlin J, Gough A, Huissoon A, et al. The acute phase and function in early rheumatoid arthritis. C-reactive protein levels correlate with functional outcome. J Rheumatol. 1997;24:9-13.
Doggen CJ, Berckmans RJ, Sturk A, Manger Cats V, Rosendaal FR. C-reactive protein, cardiovascular risk factors and the association with myocardial infarction in men. J Intern Med. 2000;248:
Myllykangas-Luosujarvi RA, Aho K, Isomaki HA. Mortality in rheumatoid arthritis. Semin Arthritis Rheum. 1995;25:
Wallberg-Jonsson S, Johansson H, Ohman ML, Rantapaa-Dahlqvist S. Extent of inflammation predicts cardiovascular disease and overall mortality in seropositive rheumatoid arthritis. A retrospective cohort study from disease onset. J Rheumatol ;26:
Wallberg-Jonsson S, Ohman ML, Dahlqvist SR. Cardiovascular morbidity and mortality in patients with seropositive rheumatoid arthritis in Northern Sweden. J Rheumatol ;24:
Wolfe F, Straus WL. Increased prevalence of cardiovascular and cerebrovascular disease in rheumatoid arthritis compared with osteoarthritis. Arthritis Rheum. 2000;43(9 suppl):S133.

38. MI and CV Death Adjusted Rate Ratios (95% CI) RA vs No Arthritis MI
Men*
Women*
Overall†
1.43 (1.29, 1.58)
1.63 (1.50, 1.76)
1.55 (1.46, 1.65)
1.40 (1.22, 1.60)
1.49 (1.36, 1.63)
1.45 (1.35, 1.57)
RA vs OA
Men*
Women*
Overall†
An analysis of thromboembolic events among patients with RA was performed using data collected in the General Practice Research Database (GPRD). The GPRD currently contains >35 million patient-years from the United Kingdom.
More than 6.5 million patients older than 40 years who did not have a history of MI or stroke prior to beginning of follow-up were included in the study. The incidence of RA was 0.68/1000 patient-years in men and 1.33/1000 patient-years in women.
In the end points of all-cause mortality, MI, cerebrovascular events, CV death, and all thromboembolic events, but not sudden death, age-adjusted rates were significantly increased in men and women with RA compared with those with OA but not RA, and similarly, in patients with RA compared with those with no arthritis.
In conclusion, patients with RA were 70% more likely to die and 30%–40% more likely to suffer an acute major thromboembolic event compared with patients with a diagnosis of OA but not RA.
1.26 (1.14, 1.40)
1.37 (1.26, 1.49)
1.32 (1.24, 1.41)
1.40 (1.22, 1.61)
1.49 (1.36, 1.69)
1.41 (1.24, 1.61)
* Adjusted for age. † Adjusted for age and gender.
Watson and Rhodes. EULAR, Abstract OP0109.
Watson DJ, Rhodes T. Higher incidence of thromboembolic events among patients with rheumatoid arthritis vs. osteoarthritis, and vs. no arthritis, in the General Practice Research Database (GPRD). EULAR, Abstract OP0109.

39. 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
Another possible explanation for the lower incidence of MIs with naproxen vs rofecoxib in the VIGOR study is that naproxen may have a cardioprotective effect.
Naproxen, a nonselective NSAID with an extended half-life, may have completely suppressed COX-1–derived TxA2 biosynthesis by the platelets throughout its dosing interval.
Although there is no convincing information supporting a cardioprotective effect of NSAIDs, future studies may evaluate the CV effect of coxibs and antiplatelet drugs.

40. Effect of NSAIDs on Platelet Aggregation
Inhibition From Baseline During Dosing Interval
100
Naproxen
500 mg bid 80 60
Ibuprofen
800 mg tid
Mean % inhibition  SE 40 20
The effects of ibuprofen and naproxen vs placebo on platelet aggregation were analyzed at varying times over the dosing interval at steady state, after 5 days of treatment. Time zero is the end of a dosing interval, which is 12 hours for naproxen and 8 hours for ibuprofen.
Naproxen 500 mg bid produces sustained platelet inhibition throughout its dosing interval, which is presumably related to its potent effects on COX-1 and its long half-life.
Ibuprofen 800 mg tid daily has the power to inhibit platelet aggregation nearly completely, but because of its relatively short half-life, inhibition is not sustained throughout the 8-hour dosing interval.
These results suggest that naproxen may have a stronger antiplatelet effect than other NSAIDs, and thus may exert a cardioprotective effect, which can be evaluated in future controlled clinical trials.
Placebo
-20 2 4 8
Hours after dose
FDA Advisory Committee Meeting, 2001.
Food and Drug Administration. Vioxx: Arthritis Advisory Committee Meeting, Gaithersburg, Md;
February 8,

41. 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; patient had both hypertension and an MI
In the VIGOR trial, MIs were less common with naproxen (0.1%) than with rofecoxib (0.5%). Although 4% of patients met FDA criteria for the use of aspirin for secondary CV prophylaxis, they were not allowed to take low-dose aspirin in this study.
At the end of the study period, these patients accounted for 47% of the patients who had had MIs. In the other patients, the difference in MI incidence with rofecoxib (0.2%) vs naproxen (0.1%) was not significant.
No correlation between hypertension and MIs was found in the VIGOR trial.
CVA = cerebrovascular accident; TIA = transient ischemic attack; CABG = coronary artery bypass surgery;
PTCA = percutaneous transluminal coronary angioplasty.
Bombardier et al. N Engl J Med. 2000;343:1520.
Bombardier C, Laine L, Reicin A, et al. Comparison of upper gastrointestinal toxicity of rofecoxib and naproxen in patients with rheumatoid arthritis. N Engl J Med. 2000;343:
Food and Drug Administration. Vioxx: Arthritis Advisory Committee Meeting, Gaithersburg, Md; February 8,

42. 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
Several prospective studies demonstrated the cardioprotective effect of aspirin, which is strongly recommended to patients who have suffered a heart attack or a thromboembolic stroke. In the ISIS-2 study, aspirin reduced mortality by 23% and reinfarction by 49% after an acute MI.
Although the effect of aspirin in primary prevention is unclear, the meta-analysis carried out by the Antiplatelet Trialists’ Collaboration (APTC) showed a clear benefit (25% reduction) of aspirin in secondary prevention of the combined end point of nonfatal MI, stroke, or vascular death.
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.
Antiplatelet Trialists' Collaboration. Collaborative overview of randomised trials of antiplatelet therapy--I: prevention of death, myocardial infarction, and stroke by prolonged antiplatelet therapy in various categories of patients. BMJ. 1994;308:
Baigent C, Collins R, Appleby P, Parish S, Sleight P, Peto R. ISIS-2: 10 year survival among patients with suspected acute myocardial infarction in randomised comparison of intravenous streptokinase, oral aspirin, both, or neither. The ISIS-2 (Second International Study of Infarct Survival) Collaborative Group. BMJ. 1998;316:
Patrono C, Coller B, Dalen JE, et al. Platelet-active drugs: the relationships among dose, effectiveness, and side effects. Chest. 2001;119:39S-63S.
Steering Committee of the Physicians' Health Study Research Group. Final report on the aspirin component of the ongoing Physicians' Health Study. N Engl J Med. 1989;321:

43. Incidence of MI in Rofecoxib and Celecoxib GI Outcome Studies
VIGOR Study1
CLASS Study2
1.0
1.0
0.8
0.8
0.6
0.6
Rates per 100 patient-years
0.4
0.4
In contrast to the VIGOR trial, CLASS showed no significant increase in CV event rates with celecoxib compared with NSAIDs.
Final data analysis from these rofecoxib and celecoxib GI outcome studies showed that the MI rate per 100 patient-years with rofecoxib in the VIGOR study is comparable to the MI rate seen with celecoxib in the CLASS trial.
The low incidence of MI in the naproxen group may be attributable to the possible cardioprotective effect of naproxen.
0.2
0.2
0.0
0.0
Rofecoxib
50 mg qd
(n=4047)
Naproxen
500 mg bid
(n=4029)
Celecoxib
400 mg bid
(n=3995)
Diclofenac
75 mg tid
(n=1999)
Ibuprofen
800 mg bid
(n=1998)
1. FDA Advisory Committee Meeting, FDA Arthritis Advisory Committee Meeting, 2001.
Food and Drug Administration. Celebrex: Arthritis Advisory Committee Meeting, Gaithersburg, Md; February 7,
Food and Drug Administration. Vioxx: Arthritis Advisory Committee Meeting, Gaithersburg, Md; February 8,

44. 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
The number of CV events occurring in the VIGOR trial was very low, and the event rates diverge between the 2 treatment groups. These findings may be taken as a play of chance.
The 2 independent hypotheses that may explain the incidence of CV events in VIGOR are the suppression of PGI2, which is characteristic of all coxibs, and the possible cardioprotective effect of naproxen.
Although coxibs were shown to decrease PGI2 biosynthesis, no evidence supports the hypothesis that coxibs alone increase CV risk.
A combination of low-dose aspirin and coxibs for patients with CV risk may cause fewer GI AEs than NSAID therapy; however, controlled clinical trials need to evaluate this hypothesis.

45. 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
The VIGOR trial demonstrated that rofecoxib at a dose 2 times higher than that required for treatment of RA has a significantly better GI safety profile than a nonselective NSAID (naproxen).
Several controlled clinical trials of celecoxib and rofecoxib showed that the renal AE profile of coxibs resembles that of NSAIDs.
The 2 mechanistic hypotheses that may explain the higher incidence of CV events seen with rofecoxib in the VIGOR trial take into consideration the suppression of PGI2 biosynthesis by coxibs and the possible cardioprotective effect of the NSAID comparator naproxen.
The risk of CV and renal AEs needs to be carefully evaluated in patients prior to initiation of coxib therapy.

47. N Eng J Med 345:1809, 2001