NSAIDs FOR CARDIOVASCULAR CONDITIONS, MECHANISMS & EFFICACY

1. NSAIDs FOR CARDIOVASCULAR CONDITIONS, MECHANISMS & EFFICACY Kyle Acton, Ilana Richer, Alexandra Gilletz PHM142 Fall 2013 Coordinator: Dr. Jeffrey Henderson Instructor: Dr. David Hampson

2. NSAIDs • By definition, NSAIDs are Non-Steroidal Anti-Inflammatory Drugs • In contrast to steroids which are produced by the body (or through supplementation) to reduce inflammation • Eg. Glucocorticoids

3. Uses of NSAIDs Lower doses: analgesic, antipyretic (reduce fever) Higher doses: anti-inflammatory Non-addictive alternative to narcotics

4. List of NSAIDs Aspirin (Aspirin is a brand name; the chemical is called acetylsalicylic acid) Celecoxib (Celebrex) Dexdetoprofen (Keral) Diclofenac (Voltaren, Cataflam, Voltaren-XR) Diflunisal (Dolobid) Etodolac (Lodine, Lodine XL) Etoricoxib (Algix) Fenoprofen (Fenopron, Nalfron) Firocoxib (Equioxx, Previcox) Flurbiprofen (Urbifen, Ansaid, Flurwood, Froben) Ibuprofen (Advil, Brufen, Motrin, Nurofen, Medipren, Nuprin) Indomethacin (Indocin, Indocin SR, Indocin IV) Ketoprofen (Actron, Orudis, Oruvail, Ketoflam) Ketorolac (Toradol, Sprix, Toradol IV/IM, Toradol IM) Licofelone (under development) Lornoxicam (Xefo) Loxoprofen (Loxonin, Loxomac, Oxeno) Lumiracoxib (Prexige) Meclofenamic acid (Meclomen) Mefenamic acid (Ponstel) Meloxicam (Movalis, Melox, Recoxa, Mobic) Nabumetone (Relafen) Naproxen (Aleve, Anaprox, Midol Extended Relief, Naprosyn, Naprelan) Nimesulide (Sulide, Nimalox, Mesulid) Oxaporozin (Daypro, Dayrun, Duraprox) Parecoxib (Dynastat) Piroxicam (Feldene) Rofecoxib (Vioxx, Ceoxx, Ceeoxx) Salsalate (Mono-Gesic, Salflex, Disalcid, Salsitab) Sulindac (Clinoril) Tenoxicam (Mobiflex) Tolfenamic acid (Clotam Rapid, Tufnil) Valdecoxib (Bextra)

5. NSAIDs that require an Rx

6. Cardiac Conditions Myocardial infarction, stroke (up to 1%) Hypertension (0.7-3%) Edema (2-9%) Worsening of heat failure (<1%)

7. Aspirin’s Uses Reduction of inflammation Reduction of fever Relief of pain ***Prevention of clotting***

8. Cyclooxygenase (COX) Enzyme COX 1 and COX 2 isoforms COX 1  thromboxane synthesis  CLOTTING COX 2  prostaglandin synthesis  INFLAMMATION Aspirin inactivates the COX enzyme (weakly more selective for COX 1150-200 fold more)

9. How does Aspirin work? Irreversibly inhibits both forms of the COX enzyme It’s an acetylating agent! An acetyl group on aspirin covalently attaches to a serine residue (serine529) on COX 1, which is irreversibly inactivating Substrate Arachidonic acid can no longer get to catalytic site on enzyme (tyrosine 385) Thromboxane A2 synthesis is inhibited in platelets Platelet aggregation won’t occur

10. Mechanism of Aspirin

11. Platelet aggregation & Cardiovascular Therapy Platelets are small cells in the blood that bind together when they recognize damaged inner walls of blood vessels (endothelium) Forms a ‘plug’ over damaged vessel area (plaques or fatty deposits in cardiac patient) causing a blood clot (thrombus) Blood clot can be good if meant to stop bleeding, but if clot blocks blood flow to heart or the brain a heart attack or stroke can follow Low-dose, long-term Aspirin use irreversibly blocks the formation of Thromboxane A2  inhibitory effect on platelet aggregation  reduced clotting effect  blood can flow freely through narrow vessel wall decreased risk of heart attack (thrombosis treatment)

12. Recommended Use 40 mg Aspirin a day inhibits the production of large proportion of Thromboxane A2 without affecting Prostaglandin I2 synthesis too much! Prostaglandins used to form protective barrier in the stomach  peptic ulcers Why not another NSAID? Diclofenac/Ibuprofen are reversibleinhibitors of the COX enzyme

13. Difference between primary and secondary prevention • Primary: prevent onset of disease, reduce incidence of disease • Secondary: disease has already manifested, want to prevent symptoms and/or adverse events • Example: someone has been diagnosed with angina and takes 81 mg ASA qd to prevent blood clots and possible angina attack

14. NSAIDs and cardiovascular disease • Aspirin is the only cardioprotective NSAID • In secondary prevention, reduces non-fatal CV events by 25-30%; fatal CV events by 15-20% • Ibuprofen, and possibly naproxen, interferes with the anti-platelet effect of low dose aspirin when coadministered • No interaction when ASA coadministered with weak inhibitors of platelet COX-1 (acetaminophen, diclofenac, and selective COX-2 inhibitors)

15. ASA for preventing CV disease • Meta-analysis from the Oxford Antithrombotic Trialists’ Collaboration • 287 trials with more than 200,000 patients • Compared ASA with a control (control outcome was serious vascular event) • Results: • Reduced risk of serious CV events by ¼ in patients at increased risk of occlusive vascular events (unstable angina, acute MI, transient ischemic attacks, peripheral arterial disease) • Non-fatal MI reduced by 1/3 • Non-fatal stroke reduced by ¼ • Vascular mortality reduced by 1/6

16. Con’t • Conclusion: • Benefits of antiplatelet use substantially outweighed risk • Analysis of ASA indicated that high doses (500-1500 mg qd) are no more effective than medium (160-325 mg qd) or low doses (75-150 mg qd) • *Unless a definite contraindication exists, antiplatelet therapy should be considered for all patients whose medical history suggests a significant risk of occlusive vascular disease*

17. Role of ASA in primary and secondary prevention of CV events • Primary prevention meta-analysis • 90,000 randomized men and women • ASA significantly reduced incidence of serious CV events (57%-->51%) • Increased rate of major GI and extracranial bleeds (0.07%-->0.1%) • In primary prevention, evidence shows conclusive benefits on first MI, but data on stroke and CVD death inconclusive

18. Con’t • Secondary prevention • Efficacy of low-dose ASA for secondary prevention of CV disease well documented. • Meta-analysis have found that it is effective for prevention of CV events in patients who have a history of coronary artery disease, stroke, and peripheral artery disease • In high risk patients, long term antiplatelet therapy reduced yearly risk of serious vascular events by ~25% • Benefit >>> Risk

19. Benefit vs. Risk

20. Role of Aspirin in Cardiovascular Prevention Aspirin is the most commonly prescribed drug for prevention of atherothrombotic events Aspirin is complementary to, and may potentiate, effects of other antiplatelet agents such as clopidogrel, dipyridamole, cilostazol Generally well tolerated by most patients

21. SUMMARY • Uses of NSAIDs: • Lower doses: analgesic, antipyretic (reduce fever) • Higher doses: anti-inflammatory • Non-addictive alternative to narcotics • By irreversibly inhibiting the COX enzyme, Aspirin inhibits thromboxane A2 formation in platelets and therefore inhibits platelet aggregation • There are two isoforms, COX 1=clotting and COX 2=pro-inflammation • With reduced platelet aggregation, clotting is reduced at narrow vessel walls (narrow due to fatty deposits/arterial plaque) and RBCs are able to move freely through vessels, hence reducing incidence of heart attack/stroke • Use of ASA in secondary prevention of CV events is much more effective than in primary prevention • Unless a definite contraindication exists, antiplatelet therapy should be considered for all patients whose medical history suggests a significant risk of occlusive vascular disease

22. REFERENCES Patrignani, P., M. L. Capone, and S. Tacconelli. "NSAIDs and Cardiovascular Disease." Heart 94.4 (2007): 395-97. Web. Gasparyan, Armen Yuri, Timothy Watson, and Gregory Y.H. Lip. "The Role of Aspirin in Cardiovascular Prevention Implications of Aspirin Resistance." Journal of the American College of Cardiology 51.19 (2008): 1829-843. Print. Canadian Public Health Association (CPHA). (2012). Compendium of Pharmaceuticals and Specialties. Canada, 2012 edition. Knowles, Sandra. “ASA for preventing cardiovascular disease.” Pharmacy Practice. May, 2002; Canada. Casad-Arroyo, R. et al. “Role of ASA in primary and secondary prevention of CV events.” Heart Rhythm Management Centre, Free University of Brussels; Belgium. ”How Aspirin Works." How Aspirin Works. Monash University, Department of Epidemiology and Preventive Medicine, 2010. Web. 14 Oct. 2013. http://www.aspree.org/AUS/aspree-content/aspirin/how-aspirin-works.aspx http://www.aspirin81.ca/247/utm_source=247+ROS&utm_medium=Banner&utm_content=Pump+ad&utm_campaign=Pump+ad+728x90 http://www.fda.gov/downloads/Drugs/DrugSafety/ucm089162.pdf http://www.nsaids-list.com/