Aspirin Dose for Cardiovascular Indications

PL Detail-Document #280901 This PL Detail-Document gives subscribers additional insight related to the Recommendations published in PHARMACIST S LETTER / PRESCRIBER S LETTER September 2012 Aspirin Dose for Cardiovascular Indications Aspirin s cardiovascular benefits stem from its permanent inactivation of platelet COX-1. 8 Inactivation of COX-1 inhibits the production of thromboxane A2, and therefore inhibits thromboxane A2-dependent platelet function and vasoconstriction. 8 Complete or nearly complete inhibition of COX-1 can be achieved with only 75 to 150 mg of aspirin. 8 Daily doses in the range of 50 to 160 mg have been shown to be effective for primary and secondary prevention of cardiovascular events, including prevention of stent restenosis and stroke. 8 In addition to efficacy at the lower doses, there is evidence that gastrointestinal side effects and major bleeding are directly related to aspirin dose. 8 Higher doses can double the risk of GI bleed. 19 These facts support the use of the lowest dose of aspirin that has been found effective in treating/preventing cardiovascular events. 8 This is reflected in the aspirin dosing recommendations in the chart below. The chart provides the aspirin dose for different cardiovascular indications per various guideline-promulgating organizations. (This chart does not include aspirin dosing for orthopedic indications. See our PL Detail-Document, Aspirin for VTE Prophylaxis After Hip or Knee Replacement.) Aspirin dosing recommendations in the guidelines may not reflect the aspirin dosage strengths available on the market. For practical purposes, 81 mg could be used if 75 to 100 mg is recommended, for example. Aspirin should be continued indefinitely for all indications unless otherwise noted. Abbreviations: ACC = American College of Cardiology; ACCF = American College of Cardiology Foundation; ACCP = American College of Chest Physicians; AHA = American Heart Association; ACS = acute coronary syndrome; BMS = bare metal stent; CABG = coronary artery bypass graft; CAD = coronary artery disease; CCS = Canadian Cardiovascular Society; CV = cardiovascular risk; DES = drug-eluting stent; LV = left ventricular; MI = myocardial infarction; NSTEMI = non-st-elevation MI; PCI = percutaneous coronary intervention; SCAI = Society for Cardiovascular Angiography and Interventions; STEMI = ST-elevation MI; UA = unstable angina; USPSTF = United States Preventive Services Task Force. (See footnotes for more details regarding appropriate use.) Indication Aspirin Dose (Adults) Primary prevention of cardiovascular events w USPSTF: 75 mg once daily 1,a ACCP: 75 to 100 mg once daily 5,d CCS: 75 to 162 mg once daily 14,m ADA/AHA/ACCF: 75 to 162 mg once daily 17,u Primary prevention of stroke in women AHA/American Stroke Association: 81 mg once daily or 100 mg every other day 2,b

(PL Detail-Document #280901: Page 2 of 8) Indication Aspirin Dose (Adults) Atrial fibrillation (to prevent stroke) ACCP: 75 to 325 mg once daily 4.c CCS: 75 to 325 mg once daily 18,v CAD ACCP: 75 to 100 mg once daily 5 AHA/ACCF: 75 to 162 mg once daily 10,L CCS: 75 to 162 mg once daily 14 Peripheral artery disease AHA/ACCF: 75 to 325 mg once daily 10,L CCS: 75 to 162 mg once daily 14 STEMI AHA/ACCF: chew 162 to 325 mg immediately for acute MI symptoms (unless patient already taking daily aspirin), then 75 to 162 mg once daily 11,e,k (see recommendations for PCI and CABG, as pertinent) ACCP: 75 to 100 mg once daily (maintenance) 5,e,k (see recommendations for PCI and CABG, as pertinent) CSS: 75 to 162 mg once daily (maintenance) 14,k,o (see recommendations for PCI and CABG, as pertinent) UA/NSTEMI AHA/ACCF: chew 162 to 325 mg immediately for ACS symptoms (unless patient already taking daily aspirin), then 75 to 162 mg once daily 7,e,k (see recommendations for PCI and CABG, as pertinent) ACCP: 75 to 100 mg once daily (maintenance) 5,e,k (see recommendations for PCI and CABG, as pertinent) CCS: 75 to 162 mg once daily (maintenance) 14,k,n (see recommendations for PCI and CABG, as pertinent)

(PL Detail-Document #280901: Page 3 of 8) Indication CABG Aspirin Dose (Adults) AHA/ACCF: 100 to 325 mg once daily for one year 10,L (see recommendations for CAD, UA/NSTEMI, and STEMI, as pertinent) CCS: 75 to 162 mg once daily (maintenance) 14,r Acute ischemic stroke/tia ACCP: 160 to 325 mg within 48 hours after onset 6 Secondary stroke/tia prevention ACCP: 75 to 100 mg once daily 6 AHA/American Stroke Association: 325 mg within 24 to 48 hours after onset 13 AHA/ACCF: 75 to 325 mg once daily 10,L CCS: 75 to 162 mg once daily 14 PCI, no stent ACCP: 75 to 325 mg once daily for the first month, then 75 to 100 mg once daily (elective, patient with CAD) 5,h,j,k ACCF/AHA/SCAI: continue aspirin indefinitely (see UA/NSTEMI, STEMI, CAD, as pertinent) 9,j,k CCS: 75 to 162 mg once daily 14,k,p PCI, elective, with stent ACCP: 75 to 325 mg once daily for the first month (BMS) or for three to six months (DES), then 75 to 100 mg once daily 5,g,j,k CCS: 75 to 162 mg once daily 14,k,q PCI with stent, post ACS ACCP: 75 to 100 mg once daily 5,e,j,k AHA/ACCF (UA/NSTEMI): 81 mg once daily 9,12.,i,j,k CCS: 75 to 162 mg once daily 14,k,q

(PL Detail-Document #280901: Page 4 of 8) Indication Anterior MI with LV thrombus, or at high risk of LV thrombus Aspirin Dose (Adults) ACCP: 75 to 100 mg once daily 5,f,k Mechanical Heart Valve ACCP: 50 to 100 mg once daily 16,t CCS: 75 to 162 mg once daily 14,s a. For men age 45 to 79 years of age and women 55 to 79 years of age if benefit outweighs risk. 1 The CV risk level varies with age and gender and is as follows, and applies only to patients not taking an NSAID who are free of upper GI pain and have no history of ulcer: 3 Men ages 45 to 59 years Women age 55 to 59 Men and women ages 60 to 69 years Men and women ages 70 to 79 years 4% or higher 3% or higher 9% or higher (men) 8% or higher (women) 12% or higher (men) 11% or higher (women) Risk calculators: CHD risk estimation tool (for men): http://hp2010.nhlbihin.net/atpiii/calculator.asp Stroke risk estimation tool (for women): http://www.westernstroke.org/index.php?header_name=stroke_tools.gif&main=stroke_tools.php Note: AHA/American Stroke Association guidelines also recommend aspirin (dose not specified) for people with a 10-year cardiovascular event risk of at least 6% to 10%. 2 b. For women whose stroke risk is high enough to justify risks. 2 c. Consider for patients with atrial fibrillation with low stroke risk (CHADS 2 score 0). 2,4 Also option for patients with moderate stroke risk (CHADS 2 score 1) as an alternative to anticoagulation if bleeding risk, patient preference, and patient access to high-quality anticoagulation monitoring makes anticoagulation unfeasible. 2,4 The CHADS 2 score is determined as follows: 1 point each for congestive heart failure, history of hypertension, age over 75 years, or diabetes, and two points for prior stroke or TIA. 2,4 d. Suggested for people 50 years of age and older without symptomatic heart disease. 5 e. Dual antiplatelet therapy is recommended for the first year post-acs. 5,12 f. Without stent placement: add warfarin for the first three months, then switch to dual antiplatelet therapy for up to 12 months. 5 With BMS placement: triple therapy (warfarin plus dual antiplatelet therapy) is suggested for the first month. Warfarin and single antiplatelet therapy is suggested for the second and third months. Thereafter, dual antiplatelet therapy is recommended for up to 12 months. 5

(PL Detail-Document #280901: Page 5 of 8) With DES placement: triple therapy (warfarin plus dual antiplatelet therapy) is suggested for the first three to six months. Thereafter, dual antiplatelet therapy is recommended for up to 12 months. 5 g. AHA/ACCF: Dual antiplatelet therapy is recommended for at least the first month after placement of a BMS, and for three to six months after placement of a DES. Continuation of dual antiplatelet therapy for up to 12 months is suggested. 5 AHA/ACCF/SCAI: Use dual antiplatelet therapy for at least 12 months after DES placement if the patient is not at high risk of bleeding. 9 After BMS placement, use dual antiplatelet therapy for at least the first month, and ideally for up to 12 months. If the patient is at increased risk of bleeding risk, then dual antiplatelet therapy should be given for at least two weeks after BMS placement. 9 h. Dual antiplatelet therapy is suggested for the first month. 5 i. With BMS placement: Provide dual antiplatelet therapy for up to 12 months. 12 Other guidelines recommend dual antiplatelet therapy for at least 12 months. 9 Consider earlier discontinuation of second agent if risk of bleeding outweighs anticipated benefits. 12 With DES placement: Provide dual antiplatelet therapy for at least 12 months. 12 Consider earlier discontinuation of second agent if risk of bleeding outweighs anticipated benefits. 12 j. Patients undergoing PCI who have not been taking aspirin should take nonenteric-coated aspirin 325 mg before PCI. Patients already taking aspirin should take 81 to 325 mg before PCI. Patients getting a stent will also receive a loading dose of a P2Y12 inhibitor (e.g., clopidogrel, etc). 9 k. Preference is given to 81 mg daily after PCI as opposed to higher doses. 9,10,12 Use an aspirin maintenance dose of 81 mg with ticagrelor (Brilinta). 12 Canadian ticagrelor labeling recommends an aspirin dose of 75 to 150 mg daily with ticagrelor. 15 L. Use aspirin 75 to 81 mg if the patient is also taking warfarin (e.g., for atrial fibrillation). 10 m. Consider aspirin for patients with: high cardiovascular risk (e.g., multiple risk factors, vascular disease on imaging, elevated CRP) and low bleeding risk; diabetes, other cardiovascular risk factors, and age over 40, with low bleeding risk; or end-stage renal disease with low bleeding risk. 14 n. Use dual antiplatelet therapy for at least one month. Dual antiplatelet therapy can be continued for 12 months in patients without excessive bleeding risk. 14 o. Use dual antiplatelet therapy for at least 14 days, and up to 12 months or longer if bleeding risk is low. 14 p. Post-ACS, use dual antiplatelet therapy for 12 months. Dual therapy may be continued beyond 12 months if thrombosis risk is high and bleeding risk is low. 14 q. BMS: use dual antiplatelet therapy for at least one month (at least two weeks with recent bleed or high bleeding risk), and up to 12 months if bleeding risk is not excessive. Consider dual therapy past one year if high risk of stent thrombosis and low bleeding risk. 14 DES: Use dual antiplatelet therapy for 12 months. Consider dual therapy past one year if high risk of stent thrombosis and low bleeding risk. 14 r. For Non-STEMI managed with CABG, dual antiplatelet therapy is recommended for at least one month, and up to 12 months. For CABG after PCI, use dual antiplatelet therapy for nine to 12 months unless stented vessel adequately bypassed. 14 s. Consider adding aspirin to warfarin, especially in patients with mechanical mitral valve or older caged-ball, tilting disk, or bileaflet mechanical aortic valve. 14 t. Aspirin is suggested as an add-on to warfarin for patients who have a mechanical mitral or aortic valve and low bleeding risk. 16

(PL Detail-Document #280901: Page 6 of 8) u. Aspirin is reasonable for patients with diabetes and a 10-year cardiovascular event risk over 10% (e.g., men over 50 years of age and women over 60 years of age with one additional major cardiovascular risk factor [e.g., smoking, hypertension, dyslipidemia, family history of early cardiovascular disease, or albuminuria]) who are not at increased risk of bleeding. 17 v. For patients with a CHADS 2 score (see footnote c) of 0 plus either female sex or vascular disease, or as an oral anticoagulant alternative in patients with a CHADS 2 score of 1, based on risk/benefit. 19 w. Not strongly recommended by most experts. Reserve for high risk patients after a careful benefit/risk assessment. Users of this PL Detail-Document are cautioned to use their own professional judgment and consult any other necessary or appropriate sources prior to making clinical judgments based on the content of this document. Our editors have researched the information with input from experts, government agencies, and national organizations. Information and internet links in this article were current as of the date of publication.

(PL Detail-Document #280901: Page 7 of 8) Project Leader in preparation of this PL Detail- Document: Melanie Cupp, Pharm.D., BCPS References 1. U.S. Preventive Services Task Force. Aspirin for the prevention of cardiovascular disease: recommendation statement. AHRQ Publication No. 09-05129-EF-2. March 2009. http://www.uspreventiveservicestaskforce.org/uspstf0 9/aspirincvd/aspcvdrs.htm#clinical. (Accessed August 3, 2012). 2. Goldstein LB, Bushnell CD, Adams RJ, et al. Guidelines for the primary prevention of stroke: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke 2011;42:517-84. 3. U.S. Preventive Services Task Force. Aspirin for the prevention of cardiovascular disease: clinical summary. AHRQ Publication No.09-05129-EF-3. March 2009. http://www.uspreventiveservicestaskforce.org/uspstf0 9/aspirincvd/aspcvdsum.htm. (Accessed August 3, 12). 4. You JJ, Singer DE, Howard PA, et al. Antithrombotic therapy for atrial fibrillation: antithrombotic therapy and prevention of thrombosis, 9 th ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest 2012;141(Suppl 2):e531S-75S. 5. Vandvik PO, Lincoff AM, Gore JM, et al. Primary and secondary prevention of cardiovascular disease: antithrombotic therapy and prevention of thrombosis, 9 th ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest 2012;141(Suppl 2):e637S-68S. 6. Lansberg MG, O Donnell MJ, Khatri P, et al. Antithrombotic and thrombolytic therapy for ischemic stroke: antithrombotic therapy and prevention of thrombosis, 9 th ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest 2012;141(Suppl 2):e601-36S. 7. Wright RS, Anderson JL, Adams CD, et al. 2011 ACCF/AHA focused update incorporated into the ACC/AHA 2007 guidelines for the management of patients with unstable angina/non-st-elevation myocardial infarction. J Am Coll Cardiol 2011;57:e215-367. 8. Eikelboom JW, Hirsh J, Spencer FA, et al. Antiplatelet drugs: antithrombotic therapy and prevention of thrombosis, 9 th ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest 2012;141(Suppl 2):e89S-119S. 9. Levine GN, Bates ER, Blankenship JC, et al. 2011 ACCF/AHA/SCAI guidelines for percutaneous coronary intervention: a report of the American College of Cardiology Foundation/American Heart Association task force on practice guidelines and the Society for Cardiovascular Angiography and Interventions. Circulation 2011;124:e574-651. 10. Smith SC Jr, Benjamin EJ, Bonow RO, et al. AHA/ACCF secondary prevention and risk reduction therapy for patients with coronary and other atherosclerotic vascular disease: 2011 update: a guideline from the American Heart Association and American College of Cardiology Foundation. Circulation 2011;124:2458-73. 11. Antman EM, Anbe DT, Armstrong PW, et al. ACC/AHA guidelines for the management of patients with ST-segment myocardial infarction: a report of the American College of Cardiology/American Heart Association task force on practice guidelines (committee to revise the 1999 guidelines for the management of patients with acute myocardial infarction). Circulation 2004;110:e82-292. 12. Jneid H, Anderson JL, Wright S, et al. 2012 ACCF/AHA focused update of the guideline for the management of patients with unstable angina/non- ST-elevation myocardial infarction (updating the 2007 guideline and replacing the 2011 focused update): a report of the American College of Cardiology Foundation/American Heart Association task force on practice guidelines. Circulation 2012 July 16 [Epub ahead of print]. 13. Adams HP Jr, del Zoppo G, Alberts MJ, et al. Guidelines for the early management of adults with ischemic stroke: a guideline from the American Heart Association/American Stroke Association stroke council, clinical cardiology council, cardiovascular radiology and intervention council, and the atherosclerotic peripheral vascular disease and quality of care outcomes in research interdisciplinary working groups: the American Academy of Neurology affirms the value of this guideline as an educational tool for neurologists. Stroke 2007;38:1655-711. 14. Bell AD, Roussin A, Cartier R, et al. The use of antiplatelet therapy in the outpatient setting: Canadian Cardiovascular Society Guidelines. Can J Cardiol 2011;27(Suppl A):S1-59. 15. Product monograph for Brilinta. AstraZeneca Canada Inc. Mississauga, ON L4Y 1M4. May 2011. 16. Whitlock RP, Sun JC, Fremes SE, et al. Antithrombotic and thrombolytic therapy for valvular disease: antithrombotic therapy and prevention of thrombosis, 9 th ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest 2012;141(Suppl 2):e576S-e600S. 17. Pignone M, Alberts MJ, Colwell JA, et al. Aspirin for primary prevention of cardiovascular events in people with diabetes: a position statement of the American Diabetes Association, a scientific statement of the American Heart Association, and an expert consensus document of the American College of Cardiology Foundation. Circulation 2010;121:2694-701. 18. Skanes AC, Healey JS, Cairns JA, et al. 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(PL Detail-Document #280901: Page 8 of 8) 19. Serebruany VL, Steinhubl SR, Berger PB, et al. Analysis of risk of bleeding complications after different doses of aspirin in 192,036 patients enrolled in 31 randomized controlled trials. Am J Cardiol 2005;95:1218-22. Cite this document as follows: PL Detail-Document, Aspirin Dose for Cardiovascular Indications. Pharmacist s Letter/Prescriber s Letter. September 2012. Evidence and Recommendations You Can Trust 3120 West March Lane, P.O. Box 8190, Stockton, CA 95208 ~ TEL (209) 472-2240 ~ FAX (209) 472-2249 Subscribers to the Letter can get PL Detail-Documents, like this one, on any topic covered in any issue by going to www.pharmacistsletter.com, www.prescribersletter.com, or www.pharmacytechniciansletter.com