Assessing Patients Who Take Blood-Altering Medications Ann Eshenaur Spolarich, RDH, PhD Herman Ostrow School of Dentistry of USC; Arizona School of Dentistry and Oral Health; University of Maryland Dental School Who uses these medications? At-risk cardiac groups stroke, MI, AF, artificial heart valves Cardiac stents Orthopedic surgical patients knee and hip prosthetics increased risk for DVT/PE Platelet-Related Fatalities More than half the people who died in the U.S. in 2009 were killed by platelets: stroke, MI Rationale for use of anti-platelet therapies in atherosclerosis and other diseases 200,000 cases of fatal sepsis in the U.S. every year Inflammatory over-reaction to microbes in blood Disseminated intravascular coagulation (half of all sepsis deaths) Bleeding and widespread clotting within blood vessels 3 Types of Acute Coronary Syndromes All caused by acute blood clots in coronary arteries Unstable angina Blockade not large enough or doesn t persist long enough No permanent damage to heart muscle Non-ST-elevated MI (NSTEMI) Incomplete blockage of a coronary artery Small amount of heart muscle damaged ST-elevated MI (STEMI) A coronary artery is completely blocked Muscle supplied by blocked artery damaged Large heart attack 1
Antiplatelet Medications Aspirin Most comprehensively studied and least expensive of all antiplatelet medications acetylsalicylic acid (ASA) causes irreversible platelet aggregation effects last for life of the platelet = 7-10 days Indications: prevention of thromboembolic conditions history of MI (lowers risk) history of stroke Little JW, Miller CS, Henry RG, McIntosh BA. Antithrombotic agents: implications in dentistry. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2002;93:544-551. Aspirin No need to discontinue low dose aspirin therapy prior to dental treatment Risk to patient for having a stroke is greater than the risk for the patient having an uncontrollable bleeding incident or bleeding to death in the dental chair Armstrong MJ, Gronseth G, Anderson DC, Biller J, Cucchiara B, Dafer R, Goldstein LB, Schneck M, Messé SR. Summary of evidence-based guideline: periprocedural management of antithrombotic medications in patients with ischemic cerebrovascular disease: report of the Guideline Development Subcommittee of the American Academy of Neurology. Neurology. 2013 May 28;80(22):2065-9. Sudden Discontinuation of Aspirin Discontinuing the use of aspirin increases mortality risk 1 Large clinical trial (n=1358) with hospitalized patients with an acute coronary syndrome 2 3 groups: never taken an oral antiplatelet agent (n=930), Hx of prior use (n=355), recently discontinued use (n=73) Among recently discontinued aspirin group, mostly due to physician recommendation prior to surgery, there was a higher 30 day rate of death or MI and adverse bleedings than among prior users No difference in the incidence of death or MI at 30 days between nonusers and prior users. Recent withdrawal displayed worse clinical outcomes than nonusers. 1. Ho PM, Spertus JA, Masoudi FA, et al. Impact of medication therapy discontinuation on mortality after myocardial infarction. Arch Intern Med. 2006 Sep 25;166(17):1842-7. 2. Collet JP, Montalscot G, Blanchet B, et al. Impact of prior use or recent withdrawal of oral antiplatelet agents on acute coronary syndromes. Circulation. 2004 Oct 19;110(16):2361-7. Epub 2004 Oct 11. 2
Sudden Discontinuation of Aspirin A meta-analysis reviewing data from over 50,000 patients showed that aspirin nonadherence/withdrawal was associated with a three-fold higher risk for major adverse cardiac events. 3 Risk was amplified by a factor of 89 in patients who had undergone stenting. 3. Biondi-Zoccai GG, Lotrionte M, Agostoni P, et al. A systematic review and meta-analysis on the hazards of discontinuing or not adhering to aspirin among 50,279 patients at risk for coronary artery disease. Eur Heart J. 2006 Nov;27(22):2667-74. Epub 2006 Oct 19. Indications for Antiplatelet Drugs Reduce risk of stroke and other adverse thromboembolic events Benefits improve when used in combination with aspirin Support improved outcomes with percutaneous coronary intervention (PCI) = stents More than 2 million people get a stent each year Antiplatelet Drugs Short-term and long-term dual antiplatelet therapy with aspirin and a thienopyridine is required to help ensure that stents remain patent and free from thrombosis these drugs cause irreversible effects on platelets King SB et al. American College of Cardiology/American Heart Association task force on practice guidelines. Circulation 2008;117:261-295. 3
Antiplatelet Drugs ticlopidine (Ticlid) *Canadian clopidogrel (Plavix) prasugrel (Effient) ticagrelor (Brilinta) Approved for patients with acute coronary syndromes undergoing PCI Advisory Statement from AHA, ACC, ACS, ADA, ACP Prevention of premature discontinuation of dual antiplatelet therapy in patients with coronary artery stents: a science advisory from the American Heart Association, American College of Cardiology, Society for Cardiovascular Angiography and Interventions, American College of Surgeons, and American Dental Association, with representation from the American College of Physicians. Grines CL, Bonow RO, Casey DE Jr, Gardner TJ, Lockhart PB, Moliterno DJ, O'Gara P, Whitlow P; American Heart Association; American College of Cardiology; Society for Cardiovascular Angiography and Interventions; American College of Surgeons; American Dental Association; American College of Physicians. William Beaumont Hospital, Royal Oak, Michigan, USA. J Am Dent Assoc. 2007 May;138(5):652-5. 3 Recommendations from Advisory Statement Those concerned about peri/postprocedural bleeding must be aware of catastrophic risks of premature discontinuation Consult cardiologist to discuss optimal patient management strategies 3 Recommendations from Advisory Statement Elective procedures with significant risk of peri/postoperative bleeding should be deferred until patient has completed an appropriate course of thienopyridine therapy 12 months after DES implantation if they are not at high risk of bleeding Minimum of one month for bare-metal stent implantation 4
3 Recommendations from Advisory Statement Anticoagulant Medications Patients with DES who are to undergo subsequent procedures that mandate discontinuation of drug therapy, aspirin should be continued if at all possible Restart thienopyridine as soon as possible after the procedure because of concerns of late stent thrombosis Different Families of Anticoagulants Direct Thrombin Inhibitors (anticoagulants) Coumarin derivatives/vitamin K Antagonist warfarin Heparin (anticoagulant) Heparinoid (anticoagulant) danaparoid (Orgaran) *Canadian drug prevention of DVT following orthopedic surgery or in patients with non-hemorrhagic stroke Low Molecular Weight Heparin (anticoagulants) dalteparin (Fragmin) prevention and treatment of DVT/VTE; unstable angina enoxaparin (Lovenox) acute coronary syndromes; DVT prophylaxis nadroparin (Fraxiparine) *Canadian drug - acute coronary syndromes; DVT prophylaxis tinzaparin (Innohep) *Canadian drug treatment of DVT/PE; prevent DVT/PE following orthopedic surgery; prevent clotting in indwelling IV lines and circuit during hemodialysis argatroban px/tx of thrombosis with heparininduced thrombocytopenia (HIT); adjunct to PCI if at risk for HIT bivalirudin (Angiomax) with ASA for unstable angina receiving PCI; undergoing PCI with risk for HIT dabigatran etexilate (Pradaxa) prevention of stroke and systemic embolism with nonvalvular atrial fibrillation; postop thromboprophylaxis for hip/knee replacement desirudin (Iprivask) *US drug prophylaxis of DVT for hip replacement 5
Factor Xa Inhibitors (anticoagulants) apixaban (Eliquis) - thromboprophylaxis for hip/knee replacement; nonvalvular atrial fibrillation fondaparinux (Arixtra) thromboprophylaxis for hip/knee replacement; unstable angina; non-st segment elevation MI rivaroxaban (Xarelto) thromboprophylaxis for hip/knee replacement; treatment of DVT; nonvalvular atrial fibrillation; treatment of PE Heparin Naturally-produced anticoagulant (anti-thrombin) Synthetic version given by IV Indications: prevention and treatment of thromboembolic disorders Anticoagulant for dialysis procedures Heparin Lock flush used to clear IV lines Produces immediate anticoagulation effect Patient admitted to hospital is started on heparin and warfarin: heparin produces initial effect Low Molecular Weight Heparins warfarin (Coumadin, Jantoven) Use: prevention of DVT with or without PE; reduce risk for PE; acute unstable angina; non-q-wave MI Mechanism: Inhibit factor Xa and IIa (thrombin) dalteparin (Fragmin) enoxaparin (Lovenox) tinzaparin (Innohep) Indications: Prophylaxis and treatment of TE disorders (venous and pulmonary) and embolic complications that arise from atrial fibrillation or cardiac valve replacement Adjunct to reduce risk of systemic embolism (recurrent MI, stroke) after MI Investigational: prevention of recurrent TIA 6
Coumarin derivatives warfarin (Coumadin, Jantoven) interferes with liver synthesis of vitamin-k dependent clotting factors effects occurs in 4 to 5 days when patient is admitted to hospital with stroke, there is a 1 to 2 day overlap period with heparin following warfarin administration to prevent hypercoagulable state Heparin produces immediate effect Takes 4-5 days for effects of warfarin to occur warfarin (Coumadin, Jantoven) Many things can upset a patient s level of anticoagulation from warfarin: Fever Flu Diarrhea or vomiting Use of many drugs, including antibiotics Change in diet (consumption of green leafy vegetables increases vitamin K intake = promotes clotting) Need vitamin K to synthesize clotting factors in liver Warfarin shuts off production of these clotting factors Significant Dental Drug Interaction with Warfarin acetaminophen (Tylenol) and warfarin (Coumadin) Combination causes enhanced anticoagulation Dose and duration of acetaminophen should be as low as possible; individualize dose and monitor INR as necessary In patients who reported taking the equivalent of at least 4 regular strength (325 mg) acetaminophen for longer than a week, the odds of having an INR > 6.0 (toxic overdose level) increased 10 fold above those not taking acetaminophen. Hylek EM, Helman H, Skates SJ,e t al. Acetaminophen and other risk factors for excessive warfarin anticoagulation. JAMA 1998; 279(9):657-662. warfarin (Coumadin, Jantoven) Key messages:warfarin causes the greatest number of drug interactions Always check compatibility prior to issuing a prescription Always ask about the INR and monitor INR status across time to examine trends in anticoagulation control 7
Direct Antithrombins (Thrombin Inhibitors) dabigatran (Pradaxa) FDA approved October 2010 Thrombin inhibitor Prodrug = lacks anticoagulant activity converted in vivo to active dabigatran specific, reversible, direct thrombin inhibitor that inhibits both free and fibrin-bound thrombin prevents thrombin-mediated effects, and by inhibiting thrombin-induced platelet aggregation dabigatran (Pradaxa) Indications: Prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation Canadian labeling (not in U.S.): Postoperative thromboprophylaxis after total hip or knee replacement Knee replacement up to 10 days Hip replacement up to 35 days dabigatran (Pradaxa) compared to warfarin (Coumadin) advantages: no monthly monitoring; fewer drugdrug and drug-diet interactions disadvantages: very expensive; twice daily dosing in studies, patients who took Pradaxa had fewer strokes than those taking warfarin RE-LY trial = Randomized Evaluation of Long- Term Anticoagulation Therapy adverse effects: bleeding, GI effects 8
dabigatran (Pradaxa) No antidote Protamine and vitamin K do NOT reverse anticoagulant effects May be removed with dialysis ~ 60% removed over 2-3 hours Severe hemorrhage: transfusions of fresh frozen plasma, packed RBCs or surgical intervention when appropriate Prolongs aptt test Direct Thrombin Inhibitors (anticoagulants) argatroban px/tx of thrombosis with heparininduced thrombocytopenia (HIT); adjunct to PCI if at risk for HIT bivalirudin (Angiomax) with ASA for unstable angina receiving PCI; undergoing PCI with risk for HIT dabigatran etexilate (Pradaxa) prevention of stroke and systemic embolism with nonvalvular atrial fibrillation; postop thromboprophylaxis for hip/knee replacement desirudin (Iprivask) *US drug prophylaxis of DVT for hip replacement Direct Antithrombins (Thrombin Inhibitors; Factor Xa Inhibitors) Prevent/reduce ischemia with unstable angina Prevent DVT following hip replacement Prevent/treat thromboembolism Treatment of heparin-induced thrombocytopenia (HIT) Factor Xa Inhibitors (anticoagulants) apixaban (Eliquis) - thromboprophylaxis for hip/knee replacement; nonvalvular atrial fibrillation fondaparinux (Arixtra) thromboprophylaxis for hip/knee replacement; unstable angina; non-st segment elevation MI; treatment of DVT/PE rivaroxaban (Xarelto) thromboprophylaxis for hip/knee replacement; treatment of DVT; nonvalvular atrial fibrillation; treatment of PE 9
Factor Xa Inhibitors (anticoagulants) apixaban (Eliquis) best documented alternative to warfarin and aspirin for stroke prevention in the broad population with AF rivaroxaban (Xarelto) good alternative to warfarin in AF; most data in DVT and ACS No specific antidotes or reversal agents Overdose: orally administered activated charcoal; administration of coagulation factors (prothrombin complex concentrates) or activated factor VII if uncontrolled bleeding) De Caterina R, Husted S, Wallentin L, Andreotti F, Arnesen H, Bachmann F, Baigent C, Huber K, Jespersen J, Kristensen SD, Lip GY, Morais J, Rasmussen LH, Siegbahn A, Verheugt FW, Weitz JI; European Society of Cardiology Working Group on ThrombosisTask Force on Anticoagulants in Heart Disease. General mechanisms of coagulation and targets of anticoagulants (Section I). Position Paper of the ESC Working Group on Thrombosis Task Force on Anticoagulants in Heart Disease. Thromb Haemost. 2013 Apr;109(4):569-79. 10