Selective COX-2 Inhibitors Good or Bad Guys Nimmaanrat

Selective COX-2 Inhibitors: Good or Bad Guys? Nimmaanrat S, MD, FRCAT, MMed. PM (University of Sydney)

Basic Science

Pharmacology of Selective COX-2 Inhibitors (COXIBs) n Early 1990, cyclo-oxygenase (COX) existed in 2 distinct isoforms n While COX-1 and COX-2 are structurally similar n COX-2 contains a side pocket

Pharmacology of Selective COX-2 Inhibitors (COXIBs)

Pharmacology of Selective COX-2 Inhibitors (COXIBs) n Ratio of affinities to COX-1 and COX-2 determines how “selective” a compound is n NSAIDs inhibit COX-1 and COX-2 with different ratios n Differences in selectivity lead to some variability in Clinical action n Safety profiles n

Classification and Basic Differences of COXIBs Classification Drug Selectivity Chemical structure First generation Celecoxib Rofecoxib 30 272 Sulfonamide Sulfone Second generation Valdecoxib Etoricoxib Lumiracoxib 61 344 433 Sulfonamide Sulfone Phenylacetic acid derivative

COX-1 vs COX-2

Cyclo-oxygenase I (COX-1) n Constitutive enzyme n “House keeping” enzyme n Expresses ubiquitously n Mediates physiological responses

Cyclo-oxygenase I (COX-1) n Only isoenzyme found in platelets n n Thromboxane A 2 (TXA 2) formation Also plays a role in n Protection of GI mucosa n Renal hemodynamics n Platelet thrombogenesis

Cyclo-oxygenase II (COX-2) n Highly expressed by cells involved in inflammation (eg. macrophage, monocytes, synoviocytes) n Unregulated by bacterial lipopolysaccharides, cytokines, growth factors, tumor promoters

Cyclo-oxygenase II (COX-2) n “Inducible” n Primarily form responsible for synthesis of prostanoids involved in acute and chronic inflammatory states

COX-1 and COX-2 n However, this distinction is somewhat simplified n COX-2 also constitutively expressed under physiological conditions in severe tissues n n n Brain Spinal cord Kidney Vascular endothelium COX-1 also be unregulated to a certain degree in inflammation

Development of COXIBs

Development of COXIBS n Theoretically, selective inhibition of COX-2 would provide n Anti-inflammatory n Without effects disrupting gastric cytoprotection and platelet function

Development of COXIBS n Hypothesis: -2 will have selective inhibition of COX n Therapeutic n Without actions similar to NSAIDs GI side effects

Thromboxane A 2 (TXA 2) & Prostacyclin (PGI 2)

Thromboxane A 2 (TXA 2) n Synthesized by COX-1 in platelet Vasoconstriction n Smooth muscle proliferation n Platelet aggregation n

Prostacyclin (PGI 2) n In contrast, PGI 2, a product of arachidonic acid (AA) from COX-2 in vessel walls plays important role in homeostatic defense mechanism that promotes n Vasodilatation n Inhibition of platelet function

NSAIDS and COXIBs n NSAIDs block both COX-1 and COX-2 production to a similar extent n In contrast, COXIBs inhibits PGI 2 production n Thus, COXIBs may create an imbalance between TXA 2 and PGI 2 n This might be the dominant mechanism that can lead to increased risk of thrombosis

Therapeutic Use

Therapeutic Use Postoperative pain n Osteoarthritis (OA) n Rheumatoid arthritis (RA) n Acute gouty arthritis n n Chemoprevention Its role in carcinogenesis, apoptosis and angiogenesis n Celecoxib approved for Rx of familial adenomatous polyp (FAP) n

Therapeutic Use

Clinical Safety

Gastrointestinal (GI) Tract

Gastrointestinal (GI) Tract n Common reported adverse events (AEs) were related to GI tract n Dyspepsia n Diarrhea n Nausea n Abdominal pain n Flatulence

Gastrointestinal (GI) Tract n Upper GI complications have also occurred in pts treated with COXIBs n Perforation n Ulcers n Bleedings n PUBs

Gastrointestinal (GI) Tract n Many large RCTs n n COXIBs caused fewer GI AEs compared to NSAIDs However, most, if not all, of the GI benefits will be lost in pts who take low-dose aspirin

Comparison of Upper Gastrointestinal Toxicity of Rofecoxib and Naproxen in Patients with Rheumatoid Arthritis: Vioxx Gastrointestinal Outcome Research (VIGOR) study Group

VIGOR Study n 1 st large scale trial n Significantly fewer clinically important upper GI events (POBs) with rofecoxib compared to naproxen

Gastrointestinal Toxicity with Celecoxib vs Nonsteroidal Antiinflammatory Drugs for Osteoarthritis and Rheumatoid Arthritis: the CLASS Study: A Randomized Controlled Trial Celecoxib Long-term Arthritis Safety Study

CLASS Study n Celecoxib (greater dose 400 mg bid): a lower incidence of symptomatic ulcers and ulcers complications combined (diclofenac, ibuprofen) n No GI benefit if pts took low-dose aspirin concomitantly

Celecoxib versus Naproxen and diclofenac in Osteoarthritis Patients: Successive Celecoxib Efficacy and Safety Study I (SUCCESS-I)

SUCCESS - I n Successive Celecoxib Efficacy and Safety Study I (13, 274 OA pts) n Celecoxib: significantly fewer serious upper GI events n No statistical significance in pts taking aspirin concomitantly

SUCCESS- I

Gastrointestinal Side Effects of Etoricoxib in Patients with Osteoarthritis: Results of the Etoricoxib versus Diclofenac Sodium Gastrointestinal Tolerability and Effectiveness (EDGE) Trial

EDGE Trial n Cumulative discontinuation rate significantly lower with etoricoxib than diclofenac

Assessment of Upper Gastrointestinal Safety of Etoricoxib and Diclofenac in Patients with Osteoarthritis and Rheumatoid Arthritis in the Multinational Etoricoxib and Diclofenac Arthritis Long-term (MEDAL) programme: a randomised comparison

MEDAL Programme n Largest RCT: 34, 701 pts n Overall upper GI clinical events (POBs / ulcers) and uncomplicated GI events significantly less common with etoricoxib than diclofenac n Benefit maintained in pts taking PPI (proton pump inhibitor) or low-dose aspirin n But no difference in complicated GI events

High-risk Patients n High-risk pts with history of NSAID-related complicated peptic ulcers n Celecoxib as effective as NSAID plus PPI n However, significant proportion of pts still had recurrent ulcer complications over period of 24 wks n n Gastroenterology 2004; 127: 1038 -43. Am J Med 2005; 118: 1271 -8.

High-risk Patients n Celecoxib plus PPI more effective than celecoxib alone for prevention of ulcer bleeding in very high-risk pts n 13 -month cumulative incidence of recurrent ulcer bleeding 0% combined Rx n 8. 9% celecoxib n n Lancet 2007; 369: 1621 -6.

High-risk Patients n Addition of PPI to celecoxib conferred extra GI protection for pts aged 75 yrs or older n But did not seem to be necessary for pts aged 66 -74 n Arthritis Rheum 2007; 57: 748 -55.

GI AEs: Conclusions n Pts with risk factors are in need for “gastroprotective” PPI irrespective of the COX-2 selectivity of applied NSAID n Age > 70 n Past ulcerations n Multiple NSAIDs / aspirin taken esp. high dose n Anticoagulant n Steroid n Positive for Helicobacter pylori

Cardiovascular (CV) System

Cardiovascular (CV) System n n First evidence that COXIBs might increase CV risk emerged from VIGOR study Rofecoxib group: 5 -fold increase in thromboembolic events (primarily acute MI)

Cardiovascular Events Associated with Rofecoxib in a Colorectal Adenoma Chemoprevention Trial: Adenomatous Polyp Prevention on Vioxx (APPROVe)

Cardiovascular (CV) System 3 yr period of study in 2, 586 pts with history of colorectal adenomas n Rofecoxib 25 mg OD / placebo n Rofecoxib pts had greater risk of developing thrombotic events n Relative Risk (RR) n 95% CI n n 1. 92 1. 19 -3. 11 Withdrawal of rofecoxib

Cumulative Incidence of Confirmed Thrombotic Events

Cardiovascular (CV) System n High-risk pts with CABG n 3 -fold increased risk of CV events in pts initially received iv parecoxib followed by oral valdecoxib n n n J Thorac Cardiovasc Surg 2003; 125: 1481 -92. N Engl J Med 2005; 352: 1081 -91. In addition, case reports of severe skin reactions -> valdecoxib was withdrawn

Cardiovascular (CV) System n CLASS study (intake of low-dose aspirin allowed) n Incidence of serious CV events not significantly different between celecoxib and NSAID (ibuprofen / diclofenac)

Cardiovascular (CV) System n Celecoxib for the prevention of colorectal adenomatous polyps: Prevention of Spontaneous Adenomatous Polyps (Pre. SAP) Trial n 1, 561 pts with prior adenomatous polyps n No significant difference in CV risk between celecoxib (400 mg/day) vs placebo

Cardiovascular (CV) System n Celecoxib for the prevention of sporadic colorectal adenoma: Adenoma Prevention with Celecoxib (APC) n Celecoxib 200 / 400 mg bid vs placebo n Low-dose celecoxib 2. 3 X n High-dose celecoxib 3. 4 X n Early termination of trial

The Effects of Cyclooxygenase-2 Inhibitors and Nonsteroidal Anti-inflammatory Therapy on 24 -hour Blood Pressure in Patients with Hypertension, Osteoarthritis, and Type 2 Diabetes Mellitus: Celecoxib Rofecoxib Efficacy and Safety in Comorbidities Evaluation Trial (CRESCENT)

CRESCENT n n n 24 -hr SBP (after 6 wks of Rx) HT, type 2 DM, OA Celecoxib / rofecoxib / naproxen Rofecoxib: significant increased SBP But not by celecoxib or naproxen Use of 3 drugs may result in different rates of CV events

EDGE Study n No significant differences between Etoricoxib n Diclofenac n n Same was true in pts taking aspirin n But in pts on etoricoxib, the non-aspirin group had more MIs

MEDAL Programme Cardiovascular Outcomes n Composite of major thrombotic CV events (at 18 months) similar with etoricoxib and diclofenac n Diclofenac (RR 1. 4)

Cardiovascular (CV) System n Nested case-control study in 486, 378 pts n Elevated risk of acute MI was a “class effect” of COXIBs n All COXIBs associated with higher MI risks compared to placebo / NSAIDs

Cardiovascular (CV) System n Health-register data suggested that increased mortality in pts with previous MI caused by n COXIBs in all dosages n NSAIDs in high dosages

Cardiovascular (CV) System n Meta-analyses of 17 case-control and 6 cohort studies calculated RR factors Rofecoxib (<25 mg/day) n Rofecoxib (>25 mg/day) n Celecoxib n Diclofenac n Naproxen n Piroxicam n Ibuprofen n 1. 33 2. 19 1. 06 1. 4 0. 97 1. 06 1. 07

CV System - Conclusions n Data from large-scale clinical trial and epidemiologic studies n COXIBs and NSAIDs (except naproxen) as a group can potentially increase the risk of CV events n And apparently there is a dose-dependent gradient among the various COXIBs and NSAIDs

Recommendations for the Use of NSAIDs according to Gastrointestinal and Cardiovascular Risks CV risk GI risk Low High NSAID Moderate High NSAID + PPI COXIB + PPI / misoprostol or COXIB NSAID + PPI / misoprostol Avoid NSAID or COXIB

Recommendations for the Use of NSAIDs according to Gastrointestinal and Cardiovascular Risks n a Gastrointestinal risk is arbitrarily defined as low (no risk factors), moderate (presence one or two risk factors), or high (more than two risk factors, previous ulcer complications, or concomitant use of corticosteroids or anticoagulants). All patients with a history of ulcers who require NSAIDs should be tested for H. pylori and if infection is present, eradication therapy should be given. n b High cardiovascular risk is arbitrarily defined as the requirement for low-dose aspirin for primary cardiovascular event prevention (calculated 10 -year cardiovascular risk >10%) or secondary prevention of serious cardiovascular events. n c Naproxen is the preferred NSAID in patients with a high cardiovascular risk. Abbreviation: COX 2, cyclo-oxygenase 2.

Kidney

Kidney n COX-2 also constitutively expressed in kidney n Is regulated in response to alterations in intravascular volume n COXIBs may transiently Decrease urinary Na+ excretion n Can induce mild to moderate BP elevation n

Kidney n COXIBs and NSAIDs n Similar effects for kidney damage n Renal n Na+ insufficiency retention with HT n Peripheral edema n Hyperkalemia n Papillary necrosis

Other Adverse Events (AEs)

Other (Common) Adverse Events n Dizziness n Fatigue n Headache n Anxiety n Flu-like symptoms n Insomnia

Other Adverse Events n As a sulfonamide, celecoxib can cause cutaneous adverse reactions without warning even in pts with no history of sulfonamide allergy n n Rash Urticaria Photoallergic dermatitis Serious and potentially fetal AEs n n n Exfoliative dermatitis Steven Johnson syndrome Toxic epidermal necrolysis

Other Adverse Events n Etoricoxib 30 -90 mg/day for up to 1 yr, the most frequently reported lab AEs Increased level of SGOT n Increased level of SGPT n 1 -2. 1% n n Hepatic dysfunction presents a contraindication n During long-term Rx with COXIBs, LFTs should be regularly monitored

Other Adverse Events n Lumiracoxib withdrawn due to severe liver damage

Conclusions

Conclusions n CV risks of COXIBs apparently increase with dose and duration of exposure n If COXIBs indicated The lowest effective dose n For a limited time n n BP as well as renal and hepatic function advisably monitored

Conclusions n COXIBs should not be prescribed in pts with n Ischemic heart disease n Cerebrovascular disorders (stroke) n Peripheral arterial disease

Thank You SN