Antithrombotics 201: Aspirin and USPSTF. Presented by: Craig Williams, PharmD., BCPS., FNLA; November, Conflicts of Interest: None

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1 Antithrombotics 201: Aspirin and USPSTF Presented by: Craig Williams, PharmD., BCPS., FNLA; November, 2016 Conflicts of Interest: None 1

2 What percent of patients who die within 30 days of an MI die before reaching the hospital? 1. 10% Deaths within 30 days from MI* 2. 20% 3. 40% 4. 50% 5. 75% 8% 21% 19% 52% Prehospital 24-hours, in -hospital 48 hours, in-hospital 30 days *Guidelines 2006 for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. International Consensus on Science. Circulation 2006;102(8):I ; Part 7: The Era of Repurfusion. Section 1: Acute Coronary Syndromes (AMI) A patient walks into your office and says they just turned 60 years of age and wants your opinion on whether or not to start taking a daily ASA. What would you like to recommend? 2

3 Some background on aspirin and primary prevention Antithrombotic therapy 1. Anti-platelet therapy 2. anticoagulation 3. thrombolytic Aspirin Clopidogrel (Plavix) Prasugrel (Effient) Ticagrelor (Brilinta) Cangrelor (Kengreal) Aggrenox (ASA+dipyrid.) Vorapaxar (Zontivity) Warfarin (oral) Heparin (IV) LMWH (IV or SQ) Dabigatran (Pradaxa) oral Rivaroxaban (Xarelto) Apixaban (Eliquis) Edoxaban (Savaysa) tpa rpa streptokinase Acute MI Acute stroke Massive PE Prevention of arterial (high pressure) events: MI, stroke Prevention of venous (low pressure) thromboembolism (VTE) DVT, PE, Afib stroke prevention 3

4 What is the role of the platelet in vasculature? NEJM 2007;357: What is the role of the platelet in vasculature? NEJM 2007;357:

5 The initial platelet plug is important to facilitate endothelial repair and happens through a diverse array of both vascular and platelet receptors Circ 2009;120:2488 So, while still not fully understood, it does make pathophysiologic sense that antiplatelet therapy may benefit atherothrombosis long-term. 5

6 Key principle to decision making: greater risk=greater benefit The benefit of anti-platelet therapy is greater in higher risk patients and quite low in low risk patients Carlo Patrono, Barry Coller, Garret A. FitzGerald, Jack Hirsh, and Gerald Roth CHEST 2008;133: 1994S-233S. 5% ARR 2 Events prevented per 1000 treated in healthy population The debate in primary prevention: FDA

7 The debate in primary prevention: FDA 2003 FDA committee votes not to approve aspirin for the primary prevention of MI Tue, 09 Dec :00:00 Michael O'Riordan Gaithersburg, MD - The evidence supporting the use of aspirin for the primary prevention of MI failed to hold up to the scrutiny of the FDA's Cardiovascular and Renal Drugs Advisory Committee at its most recent December 8, 2003 meeting. The committee voted overwhelmingly 11 votes against and three votes for approval of the petition sought by Bayer Corp to approve aspirin for the reduction of the risk of a first MI in moderate-risk patients, those with a 10-year coronary heart disease risk of < 20% (annual risk ~ 2%) Despite the existing data, which consisted of five major clinical trials, the committee felt the evidence supporting the extended label for aspirin was inconsistent at best or lacking at worst. Why does the FDA say no : Vascular benefit about offset by major bleeding risk NEJM 2005;353:

8 So, any use of aspirin for primary prevention is off-label 8

9 CHEST guidelines ADA,

10 19 Pre-existing 2007/2009 USPSTF Aspirin Recommendations The USPSTF recommends the use of aspirin for men age 45 to 79 years when the potential benefit due to a reduction in myocardial infarctions outweighs the potential harm due to an increase in gastrointestinal hemorrhage. (A Recommendation) The USPSTF recommends the use of aspirin for women age 55 to 79 years when the potential benefit of a reduction in ischemic strokes outweighs the potential harm of an increase in gastrointestinal hemorrhage. (A Recommendation) The USPSTF concludes that the current evidence is insufficient to assess the balance of benefits and harms of aspirin for cardiovascular disease prevention in men and women 80 years or older. (I Statement) The USPSTF recommends against the use of aspirin for stroke prevention in women younger than 55 years and for myocardial infarction prevention in men younger than 45 years. (D recommendation) The USPSTF recommends against the routine use of aspirin and nonsteroidal antiinflammatory drugs (NSAIDS) to prevent colorectal cancer in individuals at average risk for colorectal cancer. (D recommendation) 2007 A patient walks into your office and says they just turned 60 years of age and wants your opinion on whether or not to start taking a daily ASA. What would you like to recommend? Answer in 2009: Let s check your CVD risk 10

11 ATP III: Framingham Point Scores Estimate of 10-Year Risk Age, y Points Systolic BP mm Hg If Untreated If Treated < HDL mg/dl Points <40 2 Total Cholesterol Age Age Age Age Age < Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA. 2001;285: Age Nonsmoker Smoker Point Total 10-Year Risk, % <0 < For men: Clinical decision-making with aspirin, 2009: Benefits exceed risks when below the shaded section USPSTF, Annals Int Med 2009;150:

12 For women: Clinical decision-making with aspirin, 2009: Benefits exceed risks when below the shaded section USPSTF, Annals Int Med 2009;150: So a man or woman needed a Framingham risk score ~ 8-10% for benefits to outweigh risks. Generally, with no major risk factors the 10% threshold was about age 60 for a man and 70 for a woman. But, with significant risk factors, therapy was recommended as young as 45 in men and 55 in women and stopped at age 80 12

13 Many patients are deciding to take aspirin Guidance was clearly needed and the 2009 guidelines were difficult to operationalize 13

14 N Engl J Med; March 6, at least 1 year N Engl J Med; March 6,

15 Lancet, Nov 20, 2010 Average duration of ASA use of 6.0 years Draft RS: For Adults years old at increased risk of CVD 30 The USPSTF recommends low-dose aspirin use for the primary prevention of cardiovascular disease (CVD) and colorectal cancer in adults ages 50 to 59 years who have a 10% or greater 10-year CVD risk, are not at increased risk for bleeding, have a life expectancy of at least 10 years, and are willing to take low-dose aspirin daily for at least 10 years. Grade B recommendation 15

16 Draft RS: For Adults years old at increased risk of CVD The decision to use low-dose aspirin to prevent CVD and colorectal cancer in adults ages 60 to 69 years who have a greater than 10% 10-year CVD risk should be an individual one. Persons who are not at increased risk for bleeding, have a life expectancy of at least 10 years, and are willing to take low-dose aspirin daily for at least 10 years are more likely to benefit. Persons who place a higher value on the potential benefits than the potential harms may choose to use low-dose aspirin. 31 Grade C recommendation 32 Draft I Statements The USPSTF concludes that current evidence is insufficient to assess the balance of benefits and harms of aspirin use in adults less than 50 years old. I Statement The USPSTF concludes that current evidence is insufficient to assess the balance of benefits and harms of aspirin use in adults age 70 years and older. I Statement 16

17 Differences between current recommendation and the draft recommendation Existing RS Age range Men: Women: Sex Sex specific recommendations CHD/CVD risk Men: 10 year CHD risk 45 59: > 4% 60 69: > 9 % 70 79: > 12% Women: 10 year stroke risk 55 59: >3 % 60 69: >8 % 70 79: >11 % Younger populations D rec: Men < 45, Women < 55 New Draft RS No differentiation 10% or greater 10 year CVD risk for y/o CHD Framingham Stroke Western Stroke CVD ACC/AHA I rec: Persons < 50 Older populations I rec: Persons > 80 I rec: Persons > 70 CRC Against use of ASA/NSAIDs Integrated into benefit Balancing benefits and harms Lifetime Events per 1,000 persons in Women Taking Aspirin CVD Risk MIs Prevented Ischemic Strokes Prevented CRC Cases Prevented Serious GI Bleeding Caused Hemorrhagic Strokes Caused Net Life Years Gained Quality Adjusted Life Years Gained Ages 50 to 59 years 10% % % Ages 60 to 69 years 10% % %

18 35 Balancing benefits and harms Lifetime Events per 1,000 persons in Men Taking Aspirin CVD Risk MIs Prevented Ischemic Strokes Prevented CRC Cases Prevented Serious GI Bleeding Caused Hemorrhagic Strokes Caused Net Life Years Gained Quality Adjusted Life Years Gained Ages 50 to 59 years 10% % % Ages 60 to 69 years 10% % % Guidance on Implementation The decision to start or continue taking aspirin is complex Key considerations: Age related to both benefits and harms, life expectancy needed to gain CRC benefit Baseline CVD risk higher CVD risk increases benefits, aided by using ACC/AHA risk calculator (despite its shortcomings) Risk for bleeding bleeding risk assessment based on patient history Preference for taking daily aspirin very preference sensitive choice 18

19 Conclusions: USPSTF 2016 A patient walks into your office and says they just turned 60 years of age and wants your opinion on whether or not to start taking a daily ASA. What would you like to recommend? If you have never had a GI bleeding event, let s calculate your 10-year ASCVD risk and: 1.If your 10-year risk of a vascular event is low, then you should not take aspirin 2.If your 10-year risk of a vascular event is > 10% then it is reasonable to take aspirin if you value the CVD benefit over the risk of a major bleed. Conclusions: Other general approaches A patient walks into your office and says they just turned 60 years of age and wants your opinion on whether or not to start taking a daily ASA. What would you like to recommend? 1.The FDA has evaluated the data and declined to give an indication for primary prevention so I m generally going to recommend against 2. Once most American men reach age 50 and women reach age 60, risk is high enough to consider aspirin and they should understand that bleeding risk about equals vascular benefit and that there is a small colon cancer benefit that begins after ~ 5 years 19

20 Questions Cumulative event rate* (%) Aspirin and thienopyridines are equal: Clopidogrel versus aspirin Patients with history of ischemic stroke or MI, or symptomatic PAD n=19,185 followed for 1.9 years ASA Clopidogrel 8.7% RRR (p=0.043) 0.5% ARR* Months of follow-up CAPRIE Steering Committee. Lancet 1996; 348: *events: stroke, MI or vascular death 20