NSAIDs in CAD Patients

NSAIDs in CAD Patients Mikhail Torosoff, MD, PhD, FACC Assistant Professor of Medicine Division of Cardiology Department of Medicine Albany Medical College

Cardiovascular Side Effects of NSAIDs Pathophysiology of Cyclooxygenase Inhibition

Pathophysiology: Effects of Cox-1 and Cox-2 Inhibition Cyclooxygenase-1 Arachidonic acid Prostaglandins Cyclooxygenase-2 Prostanoids TxA 2 PGE 2 PGI 2 Gastric Mucosa Platelets Kidney Vessels Endothelium Gastric ulceration Bleeding Na + retention BP edema Vasospasm Thrombosis Needeleman Proc Nat Acad Sci 1979; 76: 944; Marcus J Lipid Res 1984; 25: 151; Buerke Circulation 2004; 110: 2053; FitzGerald GA, Patrono C. Clin Exp Rheumatol. 2001;19(suppl 25):S31-S36; Robert A. Annu Rev Pharmacol Toxicol. 1998;38:97-120; Pairet M, Engelhardt G. Fundam Clin Pharmacol. 1996;10:1-15; Weksler BB et al. Proc Natl Acad Sci U S A. 1977;74:3922-3926; Whelton A. Am J Med. 2001;110(suppl 3A):33S-42S; Vane JR et al Annu Rev Pharmacol Toxicol. 1998;38:97-120; Fosslien E Ann Clin Lab 1998;28:67-81; Vane JR Nat New Biol. 1971;231:232-235; Gierse JK et al Biochem J. 1995;305:479-484; Robert A Gastroenterology. 1979;77:761-767; Pairet M, Engelhardt G Fundam Clin Pharmacol. 1996;10:1-15.

Cox-2 IC 50 ( mol/l) Pathophysiology: All NSAIDs inhibit Cox-1 and Cox-2 100 Fewer CV & Renal Complications 10 Ibuprofen Naproxen Acetaminophen 1.0 0.1 More CV & Renal Complications Indomethacin Diclofenac Meloxicam Celecoxib Nimesulide 0.01 0.01 0.1 1.0 10 100 More GI Complications Cox-1 IC 50 ( mol/l) Valdecoxib Rofecoxib Fewer GI Complications Patrignani P et al J Physiol Pharmacol 1997; 48:623-31; Chan C-C et al J Pharmacol Exp Ther 1999;290:551-60; Warner TD et al Proc Natl Acad Sci U S A 1999;96:7563-8. [Erratum, Proc Natl Acad Sci U S A 1999;96:9666.]; Cryer B et al Am J Med 1998;104:413-21; Gierse et al The Journal of Pharmacology And Experimental Therapeutics October 19, 2004; 10.1124

Cardiovascular Side Effects of NSAIDs Hypertension Congestive Heart Failure Stroke Myocardial Infarction

Medi-Cal: NSAIDs and Risk for AMI Medi-Cal Population (>18 Years) With Physician-Diagnosed Arthritis (1999-2004)* OR for AMI (95% CI) Remote use Indomethacin Sulindac Meloxicam Rofecoxib Ibuprofen Celecoxib Naproxen Valdecoxib Nabumetone 1.00 (reference) 1.71 (1.35-2.17); P<.0001 1.41 (1.01-1.96); P<.04 1.37 (1.05-1.78); P<.02 1.32 (1.22-1.42); P<.0001 1.11 (1.01-1.22); P<.02 1.09 (1.02-1.15); P<.008 1.08 (0.95-1.22); P=.22 0.99 (0.72-1.37); P=.97 0.83 (0.60-1.14); P=.26 0 0.2 0.4 0.6 0.8 1 1.2 1.4 1.6 1.8 *2,356,885 person-years of follow-up; 15,343 cases of AMI. Singh et al. Ann Rheum Dis. 2005;64(suppl III):85.

Risk of CV Events with NSAIDs: The Nurses Health Study 121,701 female RNs; 12 years FU = 765,626 patient-years FU 2041 CV events: 814 MIs, 795 CVAs + 277 fatal MIs + 155 fatal CVAs 327 cases / 136700 patient-years after 1998 Days Per Week: None 1 2-3 4-5 6 Tabs Per Week: None 1-2 3-5 6-14 >14 More Events Chan et al. Circulation 2006 DOI 10.1161 0.5 1 1.5 2 2.5 3 3.5 Age-Adjusted Relative Risk (95% CI)

Risk of CV Events with Acetaminophen: The Nurses Health Study 121,701 female RNs; 12 years FU = 765,626 patient-years FU 2041 CV events: 814 MIs, 795 CVAs + 277 fatal MIs + 155 fatal CVAs 326 cases / 144389 patient-years after 1998 Days Per Week: None 1 2-3 4-5 6 Tabs Per Week: None 1-2 3-5 6-14 >14 More Events Chan et al. Circulation 2006 DOI 10.1161 0.5 1 1.5 2 2.5 3 3.5 Age-Adjusted Relative Risk (95% CI)

Distinguishing between Selective vs. Non-Selective Cox-2 Inhibitors ASA, Coxibs, NS-NSAIDs, and Myocardial Infarction

Acute Coronary Syndromes Unobstructed lumen Diseased Endothelium Platelet Rich Thrombus Ruptured plaque

Death or MI (%) Death or MI (%) ASA is Cardio-protective in Primary and Secondary Prevention 18 16 14 Placebo ASA In 2ry Prevention 5 4 Placebo ASA In 1ry Prevention 12 10 3 8 6 2 4 1 2 0 Lewis Cairns Theroux RISC 0 Anti-Platelet Trialists Braunwald et al. Heart Disease, 6 th Edition. pp.1244, 2117, 2119

Oral Antiplatelet Agents Mechanism of Action clopidogrel ticlopidine HCl ADP dipyridamole phosphodiesterase Integrillin Aggrastat Gp IIb/IIIa (Fibrinogen Receptor) COX-1 ADP Activation Collagen Thrombin TXA 2 aspirin TXA 2 ADP = adenosine diphosphate, TXA 2 = thromboxane A 2, COX = cyclooxygenase. Schafer AI. Am J Med. 1996;101:199 209.

Proportion Surviving (%) NSAIDs negate ASA Cardioprotection 100 90 80 70 7107 survivors of AMI ASA ASA+NSAID ASA+Ibuprofen 60 50 ASA vs ASA+Ibuprofen 1.9x risk of MI (1.3-2.9) P=0.001 40 30 20 0 2 4 6 8 10 Follow-Up (years) MacDonald T et Wei L Effect of ibuprofen on cardio-protective effect of aspirin Lancet 2003:361:573-574

April 2005 FDA statement on NSAIDs Boxed warning for increased risk of CV events and GI bleeding associated with all prescription NSAIDs For all prescription NSAIDs, FDA requested a contraindication for use in patients who have recently undergone CABG surgery The labeling for OTC NSAIDs has been revised to include more specific information about potential CV and GI risks and information to remind patients of the limited dose and duration of treatment of these products in accordance with the package instructions Lack of consistent evidence that concurrent use of aspirin mitigates the increased risk of serious CV thrombotic events associated with NSAID use. The concurrent use of aspirin and an NSAID does increase the risk of serious GI events OTC=over the counter. April 6, 2005. Public Health Advisory. Available at: http://www.fda.gov. Accessed September 15, 2005.

Cumulative MI Incidence (%) Risk of CV Events with NSAIDs: Physicians Health Study 22,071 healthy MDs randomized to ASA vs. placebo, 5 year f/u 378 MIs: 139 in ASA group vs. 239 in placebo group, p<0.00001 2.5 ASA group 2 Placebo Aspirin NSAIDs 1-60d/y NSAIDs >60d/y 1.5 1 0.5 Placebo group NSAIDs 1-60d/y NSAIDs >60d/y More MIs 0 6 12 24 36 48 60 72 Time (months) 0.1 1 10 Relative Risk of MI (times) Kurth T et al. Inhibition of Clinical Benefits of Aspirin on First Myocardial Infarction by Nonsteroidal Antiinflammatory Drugs. Circulation 2003, 108:1191-1195

Platelet Inhibition, ASA, NSAIDs, and Selective Cox-2 Inhibitors Platelet Aggregation Inhibition (%) 100 75 ASA before Ibuprofen Rofecoxib before ASA Ibuprofen Before ASA 50 25 0 2 6 8 12 16 20 24 Hours Catella Lawson - Vioxx Ibuprofen ASA vs Tx and Platelet Aggregation - NEJM 2001 345 25 1809-17

Patients were post-discharge after first CVD admission all on low-dose ASA N=7107 Ibuprofen Clinically Diminishes the Cardioprotective Effect of ASA All-cause Mortality 95% CI* ASA alone 1.00 NS ASA + ibuprofen 1.93 P=0.0011 CV Mortality 95% CI* ASA + ibuprofen 1.73 P=0.0305 *Adjusted for age; sex; Carstairs social deprivation score; previous admission for CVD, diabetes mellitus, RA, or OA; drug use for CVD or diabetes; disease-modifying antirheumatic drug use; lipid-lowering drug use at discharge; and interaction between length of ASA exposure and duration of ibuprofen, diclofenac, or other NSAID use MacDonald TM, et al. Lancet. 2003;361:573-574.

Sept 2006 FDA statement on NSAIDs

Ibuprofen and Aspirin Interaction: Attenuation of the Anti-Platelet Effect of Aspirin Healthcare professionals should be aware of an interaction between low dose aspirin (81 mg per day) and ibuprofen which might render aspirin less effective when used for its anti-platelet cardioprotective effect. Healthcare professionals should advise consumers and patients regarding the appropriate concomitant use of ibuprofen and aspirin. Other nonselective OTC NSAIDs should be viewed as having potential to interfere with the antiplatelet effect of low-dose aspirin unless proven otherwise. Analgesics that do not interfere with the antiplatelet effect of low dose aspirin should be considered for populations at high risk for cardiovascular events. FDA Scientific Statement 9/2006

Interaction of Naproxen with Aspirin Naproxen interfered with the inhibitory effect of aspirin on platelet COX-1 activity and function. This pharmacodynamic interaction might undermine the sustained inhibition of platelet COX-1 that is necessary for aspirin s cardioprotective effects. M. Capone et al. J Am Coll Cardiol 2005;45:1295.

Closure Time (sec) NSAID-ASA Interaction 400 350 300 250 200 150 Placebo Naproxen Celecoxib Ibuprofen Indomethacin 100 10 AM ASA 50 8 AM Dose 1 8 PM Dose 2 8 AM Dose 3 0 Day 1 Day 2 Day 3 Gladding NSAIDs and ASA Interaction AJC 2008 101 1060

NY Medicare P&T Committee Formulary Update Patients treated with ASA for CV Indications may be prescribed Celecoxib without prior authorization

AMCH Formulary Recommendations: With the exception of aspirin, all NSAID s are considered to be contraindicated in patients: Undergoing CABG in the immediate post operative period Undergoing PCI Acute Coronary Syndrome / AMI Orders for NSAID s, with the exception of aspirin, will be auto-discontinued in these patients. For patients receiving chronic maintenance aspirin therapy for CV indications ischemic stroke or TIA, atrial fibrillation, CAD, prosthetic heart valves, chronic extremity arterial insufficiency, following vascular surgery or PCI NSAID s are considered to be contraindicated. In these patients, acetaminophen or the selective COX-2 inhibitor, celecoxib (Celebrex ) not to exceed 200mg/day may be used. Orders for NSAID s, with the exception of celecoxib, will be auto-discontinued in these patients. For patients requiring an NSAID for analgesia, acetaminophen or celecoxib (Celebrex ) not to exceed 200mg/day may be used.

Addendum

Effectiveness of Individual Therapies From Evidence-Based Trials Deaths caused Deaths prevented ACE Inhibitors in CHF Beta Blockers in CHF Aldosterone Blockers in CHF ASA in High Risk CAD Patients ASA in Low Risk CAD Patients NSAIDs in CAD Patients on ASA 20 10 0 10 20 30 40 Events per 1000 patient-years of Rx Remme WJ et al. Eur. Heart J. 2001;22:1527-1560., N Engl J Med 2003;348:1309-21 Antiplatelet Trialists Collaborative Group BMJ 1994 308 81

Rofecoxib, Celecoxib, and Valdecoxib: Not all medications are born equal Randomized Trials with Adverse Outcomes ROFECOXIB VALDECOXIB CELECOXIB Total number of patients enrolled 25,273 pts 14,372 pts 44,307 pts Trials with adverse trend 7 of 18 2 of 21 1 of 41 Patients with adverse events Any CABG Polyposis Dose of the drug Low: 25-50 qd IV dosing High: 400 bid FDA Panel Vote 2/18/2005 17-15 17-13 (2) 31-1 Pharmacokinetics, pharmacodynamics, and metabolism Oral bioavailability (%) 92 93 83 22 40 Elimination half-life (hr) 10 17 8-12 Appr. 11 Volume of distribution (liters) 86 91 55 455±166 Main pathway of metabolism Reduction Glucuronidation Oxidation Active Metabolites Present None None Metabolite-to-parent conversion Up to 20% None None Juni Vioxx Metaanalysis - Lancet 2004 364 2021 White Celebrex Metaanalysis AJC 2003 92 411 Nicoll - Bioorg Med Chem Letters 2000 10 2683; Halpin - Drug Met Disp - 2000 28 10 1244; Halpin - Drug Met Disp - 2002 30 684

Meta-analysis Cardiovascular Death, MI, and Stroke: Celecoxib vs ns-nsaids Celecoxib 200 mg daily (N=19,773) ns-nsaids (N=13,990) Patient-years 5651 4386 Mean exposure/patient (mo) 3.4 3.8 CV death, MI, stroke (n [%]) 57 (1.0) 54 (1.2) CV death 15 (0.3) 19 (0.4) MI 35 (0.6) 19 (0.4) Stroke 7 (0.1) 16 (0.4) Most common side effects were dyspepsia, diarrhea, and abdominal pain, and were generally mild to moderate. CELEBREX should be used in pregnancy only if the potential benefit outweighs the potential risk to the fetus. CELEBREX should be avoided during late pregnancy. Treatment with CELEBREX is not recommended in those patients with advanced renal disease. n=events per 100 patient-years. FDA Advisory Committee Meeting. February 16, 2005.

Adjusted Relative Risk of AMI Among Medicare Beneficiaries Selective COX-2 Inhibitor Reference Group Adjusted Odds Ratio (95% CI) Celecoxib No NSAID or coxib 0.93 (0.84-1.02) Celecoxib Naproxen 0.95 (0.74-1.21) Celecoxib Ibuprofen 0.98 (0.76-1.26) Celecoxib Other NSAIDs 0.95 (0.82-1.09) Rofecoxib Celecoxib 1.24 (1.05-1.46) Rofecoxib No NSAID or coxib 1.14 (1.00-1.31) Rofecoxib Naproxen 1.17 (0.90-1.52) Rofecoxib Ibuprofen 1.21 (0.92-1.58) Rofecoxib Other NSAIDs 1.17 (0.99-1.38) 0 0.5 1.0 1.5 2.0 Solomon et al. Circulation. 2004;109:2068-2073.