Aspirin, primary prevention and USPSTF Presented by: Craig Williams, PharmD., BCPS., FNLA; February 2017 Conflicts of Interest: None Primary prevention of ASCVD is important Myocardial Infarction Incidence and Recurrence (US, Annual) ACS First Event Recurrent Event Total Events 1,255,000 785,000 (2/3) 470,000 (1/3) AHA statistical update: Heart Disease and Stroke Statistics 2013 Update Circulation, January, 2015 1
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-172-203; 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? Some background on aspirin and primary prevention 2
Antithrombotic therapy 1. Anti-platelet therapy 2. anticoagulation 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) 3. thrombolytic 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 But why do antiplatelet agents prevent atherothrombotic events at all? What is the role of the platelet in vasculature? NEJM 2007;357:2482-94 3
What is the role of the platelet in vasculature? NEJM 2007;357:2482-94 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. But what is the magnitude of benefit and the magnitude of risk and how do we make decisions with that? 4
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 ASA for secondary prevention: No debate The SAPAT trial: Swedish Angina Pectoris Aspirin Trial (Lancet, 1992) 2,035 patients with stable CAD randomized to ASA 75mg vs. placebo for 4.2 years Results: 39% RRR in non-fatal MI (47 events vs. 78); 2.9% ARR (4.7% vs. 7.6%) NNT of 35 over 4.2 years 38% RRR in sudden death (19 events vs. 31); 1.1%ARR (1.9% vs. 3.0%) NNT of 91 over 4.2 years Combined CHD event reduction of 4.0% in 4.2 years or 1% per year in patients with stable CAD Aspirin and thienopyridines are clinicall equal in secondary prevention: CAPRIE trial Cumulative event rate* (%) 20 16 12 8 4 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* 0 0 3 6 9 12 15 18 21 24 27 30 33 36 Months of follow-up CAPRIE Steering Committee. Lancet 1996; 348: 1329 1339. *events: stroke, MI or vascular death 5
The debate in primary prevention: FDA 2014 The debate in primary prevention: FDA 2003 FDA committee votes not to approve aspirin for the primary prevention of MI Tue, 09 Dec 2003 21:00:00 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. www.theheart.org Why does the FDA say no : Vascular benefit about offset by major bleeding risk NEJM 2005;353:2373-83 1.0% per year = 10 yr CVD risk of 10% 6
So, any use of aspirin for primary prevention is off-label CHEST guidelines. 2012 7
ADA, 2016 What about AHA/ACC? 2003 guideline on primary prevention silent on ASA but www.americanheart.org People at high risk of heart attack should take a daily low-dose of aspirin (if told to by their healthcare provider). Many patients are confused but apparently deciding to take aspirin 8
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 25 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 ATP III: Framingham Point Scores Estimate of 10-Year Risk Age, y Points 20-34 -9 35-39 -4 40-44 0 45-49 3 50-54 6 55-59 8 60-64 10 65-69 11 70-74 12 75-79 13 Systolic BP If If Age mm Hg Untreated Treated 20-39 40-49 50-59 60-69 70-79 <120 0 0 Nonsmoker 0 0 0 0 0 120-129 0 1 Smoker 8 5 3 1 1 130-139 1 2 140-159 1 2 Point Total <0 10-Year <1 Risk, % 160 2 3 0 1 HDL mg/dl Points 1 1 60-1 2 1 3 1 50-59 0 4 1 40-49 1 5 2 <40 2 6 2 7 3 8 4 Total Cholesterol Age 20-39 Age 40-49 Age 50-59 Age 60-69 Age 70-79 <160 0 0 0 0 0 160-199 4 3 2 1 0 200-239 7 5 3 1 0 240-279 9 6 4 2 1 280 11 8 5 3 1 Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA. 2001;285:2486-2497. 9 5 10 6 11 8 12 10 13 12 14 16 15 20 16 25 17 30 9
For men: Clinical decision-making with aspirin, 2009: Benefits exceed risks when below the shaded section USPSTF, Annals Int Med 2009;150:396-404 For women: Clinical decision-making with aspirin, 2009: Benefits exceed risks when below the shaded section USPSTF, Annals Int Med 2009;150:396-404 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 10
So in 2016 - Guidance clearly needed as recommendations were confusing and often conflicting Plus, the data for colon cancer prevention was getting more robust USPSTF 2016. N Engl J Med; March 6, 2003..at least 1 year N Engl J Med; March 6, 2003 11
Lancet, Nov 20, 2010 Average duration of ASA use of 6.0 years So, including the colon cancer data and re-analysis of CVD data, what did the taskforce say? Ten trials met inclusion criteria for USPSTF analysis; all trials excluded patients with prior GI bleed; three were new since the 2009 guidance* *AAA trial: JAMA. 2010 Mar 3;303(9):841 8 JPAD: JAMA.2008 Nov 12;300(18):2134 41 POPADAD: BMJ.2008;337:a1840 36 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% 14.8 13.7 13.9 20.9 3.5 21.9 62.1 15% 15.0 14.3 13.5 20.0 3.4 33.4 71.6 20% 15.2 14.4 13.2 18.4 2.9 46.3 83.3 Ages 60 to 69 years 10% 10.1 11.6 10.5 23.0 3.2-1.2 28.4 15% 11.0 12.9 9.3 21.6 3.4 1.7 32.4 20% 11.1 13.0 9.7 21.7 3.3 4.8 36.0 12
37 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% 22.5 8.4 13.9 28.4 2.3 33.3 58.8 15% 26.7 8.6 12.1 26.0 2.8 39.5 64.4 20% 28.6 9.2 12.2 24.8 2.1 60.5 83.4 Ages 60 to 69 years 10% 15.9 6.6 11.2 31.4 3.1-2.0 18.0 15% 18.6 8.0 10.4 29.8 2.4 9.6 30.9 20% 20.1 8.4 9.1 26.7 2.7 11.6 31.8 Draft RS: For Adults 50-59 years old at increased risk of CVD 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 38 Draft RS: For Adults 60-69 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. Grade C recommendation 39 13
40 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 41 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 Differences between current recommendation and the draft recommendation Existing RS Age range Men: 45-79 Women: 55-79 Sex CHD/CVD risk Sex-specific recommendations 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 50-69 No differentiation 10% or greater 10 year CVD risk for 50-69 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 42 14
Conclusions: USPSTF application in 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 major 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 Americans with a major CVD risk factor (smoking, diabetes, HTN, hyperlipidemia) reach age 60, risk is high enough to consider aspirin therapy. They should understand: 1. Bleeding risk about equals vascular benefit Questions 15