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NSAIDs, Coxibs, and Cardio-Renal Physiology

NSAIDs, Coxibs, and Cardio-Renal Physiology. A Mechanism-Based Evaluation. COX-2 Hypothesis and GI Outcome Studies With Coxibs. Prostaglandin and Thromboxane Biosynthesis. Membrane-bound phospholipids. Phospholipase A 2. NSAIDs, ASA. Arachidonic acid. COX-1. O 2. COX-2. PGG 2. Coxibs.

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NSAIDs, Coxibs, and Cardio-Renal Physiology

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  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 COX-1 O2 COX-2 PGG2 Coxibs PGH2 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

  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

  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

  7. NSAIDs: COX-2 vs COX-1 Selectivity 6-MNA 100.00 Naproxen Acetaminophen Ibuprofen 10.00 Meloxicam Nimesulide Indomethacin 1.00 COX-2 IC50 (µM) Celecoxib Rofecoxib 0.10 Diclofenac 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.

  8. NH2 O O O S S O H3C N N CF3 O F O CH3 Coxibs: Pharmacologic Characteristics Sulfonamide Sulfone F Celecoxib Rofecoxib Absorption time 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 60% in liver via cytosolic reductase40% in liver via P450 3A4 Metabolism In liver via P450 2C9 Kinetics Linear Nonlinear, saturable No Accumulation Yes; accumulation factor: 1.67 22%–40% Oral bioavailability 92%–93% Vioxx® package insert, Merck & Co, Inc.; Celebrex® package insert, G.D. Searle & Co.

  9. 50 † Placebo (n=158) 40 Rofecoxib 25 mg (n=186) † 30 Rofecoxib 50 mg (n=178) 20 10 Ibuprofen 2400 mg (n=167) 0 Week 12 Week 24 Time of treatment Upper GI Effect of Rofecoxib: Endoscopic Study Patients: N=742, osteoarthritis Cumulative incidence of gastroduodenal ulcers* (%) 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.

  10. Upper GI Effect of Celecoxib: Endoscopic Study Patients: N=1149, rheumatoid arthritis P<0.001 vs other groups 30 25 20 Gastroduodenal ulcer incidence* over 12-weektreatment period (%) 15 10 5 0 Placebo (n=99) Celecoxib 200 mg Celecoxib 400 mg Celecoxib 800 mg Naproxen 1000 mg (n=137) (n=148) (n=145) (n=130) Celecoxib produced significantly fewer visualized gastroduodenal ulcers than naproxen Simon et al. JAMA. 1999;282:1921.

  11. Drug Rofecoxib 50 mg qd (2x max chronic dose) Celecoxib 400 mg bid (2x max chronic dose) OA (72%), RA (28%) RA Patients Comparator Naproxen 500 mg bid Ibuprofen 800 mg tid Diclofenac 75 mg bid ASA (≤325 mg/d) No Yes (21%) Duration Median 9 months Median 9 months 1° end point Clinical upper GI events Complicated ulcers 2° end point Complicated upper GI events Symptomatic + complicated ulcers GI Outcomes With Coxibs: Study Designs CLASS† (N=7982) VIGOR* (N=8076) *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 1.0 (RR=0.46; P<0.001) (RR=0.43; P=0.005) 0 0.0 0 2 4 6 8 10 12 0 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, 2001. Gaithersburg, Md.

  13. GI Outcomes of CLASS 2° End Point—Symptomatic Ulcers/Ulcer Complications 1° End Point—Ulcer Complications 4 Celecoxib 400 mg bid Diclofenac 75 mg bid Ibuprofen 800 mg tid 2 3 % of patients % of patients 2 1 1 0 0 0 100 200 320 0 100 200 300 380 Days Days Silverstein et al. JAMA. 2000;284:1247; FDA Arthritis Advisory Committee, 2001. Gaithersburg, Md.

  14. 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 GI Outcome Studies With Coxibs: Summary Bombardier et al. N Engl J Med. 2000;343:1520; Silverstein et al. JAMA. 2000;284:1247; FDA Arthritis Advisory Committee, 2001. Gaithersburg, Md.

  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 Decreases Na+ reabsorption GFR = glomerular filtration rate. Brater. Am J Med. 1999;107:65S.

  17. Constitutive Expression of COX-1 and COX-2 in the Kidney Renin-secretinggranular cells Podocytes: COX-2 Afferent arteriole: COX-1, COX-2 Glomerulus: COX-1, COX-2 Distal tubule Proximal convoluted tubule Macula densa: COX-2 Thickascendinglimb: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.

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

  19. Potential Effects of NSAIDs on Renal Physiology Arachidonic acid NSAIDs COX-1 COX-2 PGE2 PGI2 Hyperkalemia Acute renal failure Sodium retention • Peripheral edema •  Blood pressure •  Weight • CHF (rarely) CHF = congestive heart failure. Brater. Am J Med. 1999;107:65S.

  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 0 0 Iohexol clearance* (mL/min/1.73 m2) -2 -2 -4 -4 -6 -6 P<0.05 vs rofecoxib -8 -8 P<0.05 vs celecoxib * Mean ± (SE) change from baseline GFR. Catella-Lawson et al. JPharmacol Exp Ther. 1999;289:735; Whelton et al. Arch Intern Med. 2000;160:1465.

  21. COX-2–Dependent Regulation of GFR in Healthy Elderly on a Sodium-Depleted Diet 0.25 * * 0.20 † 0.15 % Reduction in iothalamate clearance 0.10 0.05 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.

  22. 10.0 8.0 6.0 4.0 2.0 0.0 Dose-Dependent Incidence of Lower-Extremity Edema*: Rofecoxib Trials 5.4 % of patients 3.8 3.8 3.6 3.6 3.4 Naproxen 1000 mg n=4029 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 VIGOR study2 Phase II/III OA studies1 * Investigator-reported. 1. Summary basis for approval, FDA. 2. FDA Advisory Committee Meeting, 2001.

  23. Dose-Dependent Incidence of Peripheral Edema*: Celecoxib Trials 10.0 8.0 † 6.0 5.2 % of patients 3.7 4.0 3.5 3.0 2.4 1.9 2.0 0.0 Celecoxib 200 mg n=1764 Celecoxib 400 mg n=1208 Ibuprofen 2400 mg n=1985 NSAID Comparator‡ n=1388 Celecoxib 800 mg n=3987 Diclofenac 150 mg n=1996 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.

  24. Hypertension* Reports: Rofecoxib 10.0 9.7 8.0 6.0 5.5 % of patients 4.0 4.0 2.9 2.8 1.6 2.0 0.0 Ibuprofen 2400 mg n=847 Diclofenac 150 mg n=498 Rofecoxib 12.5 mg n=1215 Rofecoxib 25 mg n=1614 Naproxen 1000 mg n=4029 Rofecoxib 50 mg n=4047 Phase II/III OA studies1 VIGOR study2 * Investigator-reported adverse experiences. 1. Summary basis for approval, FDA. 2. FDA Advisory Committee Meeting, 2001.

  25. Hypertension* Reports: Celecoxib 4.0 3.0 3.1 2.0 2.0 2.0 % of patients 1.2 0.9 1.0 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 studies1 CLASS2 * Investigator-reported.† Naproxen, diclofenac. 1. Summary basis for approval, FDA. 2. FDA Arthritis Advisory Committee Meeting, 2001.

  26. Effect of Naproxen and Coxibs onBlood Pressure in the Elderly 7 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 Systolic BP Diastolic BP -3 Schwartz et al. EULAR, 2001. 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

  28. NSAIDs and Coxibs: Cardiovascular Biology

  29. COX-1 COX-1 Coxibs Effects of NSAIDs on Platelets and Endothelium Endothelial cell Platelet Nonspecific NSAIDs/ASA COX-2 Thromboxane (TxA2) Prostacyclin (PGI2) Vasoconstrictor Promotes platelet aggregation Vasodilator Inhibitor of platelet aggregation Hemostasis Thrombosis McAdam et al. Proc Natl Acad Sci USA. 1999;96:272.

  30. Comparative Inhibitory Activity of NSAIDs on Platelet Aggregation P<0.01 vs placebo 100 90 80 70 60 Inhibition of platelet aggregation* (% change from baseline) 50 40 30 20 10 0 100 400 800 Placebo Celecoxib (mg) Ibuprofen *20 M arachidonate used as agonist. McAdam et al. Proc Natl Acad Sci USA. 1999;96:272.

  31. 0.36 0.73 0.17 0.42 0 1 2 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 28 (1.0) 10 (0.4) Cerebrovascular* 11 (0.4) 8 (0.3) Peripheral vascular 6 (0.2) 1 (0.04) Confirmed CV 45 (1.7) 19 (0.7) * Not including hemorrhagic stroke. FDA Advisory Committee Meeting, 2001.

  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) FDA Arthritis Advisory Committee Meeting, 2001.

  33. CV Biology and COX-2 Inhibition: Hypotheses Generated by VIGOR Results • Play of chance? • Thrombogenic risk with coxibs? • Is naproxen cardioprotective? FitzGerald and Patrono. N Engl J Med. 2001;345:433.

  34. CV Biology and COX-2 Inhibition: Hypotheses Generated by VIGOR Results(cont’d) • Play of chance? • Small number of events (<70, 1.7%) FitzGerald and Patrono. N Engl J Med. 2001;345:433.

  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

  36. Effect of Celecoxib and Rofecoxib on Prostacyclin Biosynthesis 200 200 160 160 120 120 Mean urinary PGI-M* ± SE (pg/mg creatinine) 80 80 ‡ † † † 40 40 † 0 0 Celecoxib 800 mg (n=7) Placebo (n=12) Rofecoxib50 mg qd(n=12) Indomethacin50 mg tid(n=10) Placebo (n=7) Celecoxib 400 mg (n=7) Ibuprofen 800 mg (n=7) * 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.

  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 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.

  38. MI and CV Death Adjusted Rate Ratios (95% CI) RA vs No Arthritis MI CV Death 1.43 (1.29, 1.58) 1.63 (1.50, 1.76) 1.55 (1.46, 1.65) Men* Women* Overall† 1.40 (1.22, 1.60) 1.49 (1.36, 1.63) 1.45 (1.35, 1.57) RA vs OA 1.26 (1.14, 1.40) 1.37 (1.26, 1.49) 1.32 (1.24, 1.41) Men* Women* Overall† 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, 2001. 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

  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 0 Placebo -20 0 2 4 8 Hours after dose FDA Advisory Committee Meeting, 2001.

  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; 1 patient had both hypertension and an MI 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.

  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 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.

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

  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

  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

  46. N Eng J Med 345:1809, 2001

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