Dr.ssa Allegra Ba/stoni. Proge7o Formazione Avanzata in Cardiologia nel Web Dire7ore: Prof. Massimo Volpe E- mail:

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1 Scuola di Specializzazione in Mala/e dell Apparato Cardiovascolare Dire7ore Prof. Massimo Volpe Facoltà di Medicina e Psicologia, Università di Roma Sapienza Anno Accademico Dr.ssa Allegra Ba/stoni Proge7o Formazione Avanzata in Cardiologia nel Web 2014 Scuola di Specializzazione in Mala/e dell Apparato Cardiovascolare Dire7ore: Prof. Massimo Volpe E- mail: massimo.volpe@uniroma1.it Coordinatore: Dr. Giuliano Tocci E- mail: giuliano.tocci@uniroma1.it

2 Aspirin Therapy in Primary Cardiovascular Disease Preven7on A PosiQon Paper by the European Society of Cardiology Working Group on Thrombosis..and more from the American Heart Associa1on 23 December 2014

3 Background The Global Burden of Disease study esqmated that 29.6% of all deaths worldwide ( million deaths) were caused by CVD in 2010, more than all communicable, maternal, neonatal and nutriqonal disorders combined, and about twice the number of deaths caused by cancers The most recent (2013) staqsqcs on heart disease and stroke from the American Heart AssociaQon (AHA) esqmate that the annual direct and indirect cost of CVD and stroke in the United States alone are $523 billion. From 2000 to 2010, the total number of inpaqent CV operaqons and procedures increased 28%, from 5,939,000 to 7,588,000. By 2030, 40.8% of the US populaqon is projected to have some form of CVD, and the annual cost will increase to $1.13 trillion. Despite the considerable improvements in the prognosis of CVD and the significant reducqon of CVD mortality obtained during the past half- century, paqents developing CVD even though saqsfactorily treated sqll carry coronary artery disease and remain at risk for advanced CVD. Thus the healthcare and socioeconomic burden linked to CVD remains high. As a result, the need for more effecqve CV prevenqon strategies remains crucial.. Lozano R, Naghavi M, Foreman K, Lim S, Shibuya K, Aboyans V, Abraham J et al. Global and regional mortality from 235 causes of death for 20 age groups in 1990 and 2010: a systemaqc analysis for the Global Burden of Disease Study Lancet 2012; 380: Go AS, Mozaffarian D, Roger VL, Benjamin EJ, Berry JD, et al. (2013) Heart disease and stroke staqsqcs 2013 update: a report from the American Heart AssociaQon. CirculaQon 127: e6 e245

4 2009 An7thrombo7c Trialists Collabora7on : Aspirin in secondary and primary preven7on..current guidelines largely ignore any differences in bleeding risk, and recommend that aspirin be used widely for primary preven1on in those at moderately raised risk of coronary heart disease (CHD) (2009 US Preven1ve Services Task Force; AHA Guidelines for primary preven1on of cardiovascular disease and stroke: 2002 update; 2005 Joint Bri1sh Socie1es' guidelines on preven1on of cardiovascular disease in clinical prac1ce)..it has also been suggested that, since age is a major determinant of the risk of CHD, daily aspirin should be started in all people above a specific age, either alone or in combina1on with other drugs 10- Year risk of a first CHD event in the six major trials of aspirin in primary preven7on of CVD. WHS ,876 pts 0%M 10yrs 54,6age 100mg alternate MI,stroke, CV death 2.5% HOT ,790pts 53%M 3.8yrs 61.5age 75 daily Major CV events 3.6% PPP ,495pts 42%M 3.6yrs 64.4age 100 daily MI, stroke, or CV death 4.3% PHS ,071pts 100%M 5.02yrs 53.8age 325 alternate MI, stroke, or CV death 4.8% BMD ,139pts 100%M 6.0yrs 63.6age 500/300 daily MI, stroke, or CV death 8.9% TPT ,085pts 100%M 6.4yrs 57.5age 75 daily Major coronary event 12.4% Hennekens et al. Trends in Cardiovascular Medicine 2014; 360

5 2009 An'thrombo'c Trialists Collabora'on : Ischemic Events Primary PrevenQon All serious vascular events Risk RaQos (95%CI) 0.88 ( ) Major coronary events Non- fatal MI 0.82 ( ) 0.77 ( ) Strokes 0.86 ( )

6 2009 An'thrombo'c Trialists Collabora'on : Ischemic Events (2/2) ASA therapy was associated with 6 fewer MIs per 1,000 low- risk persons treated (5% CHD risk at 10 years according to the Framingham risk categories) 19 for persons at moderate (15%) and 31 for persons at high (25%) CHD risk. The downside was that the risk of bleeding events was also higher as a funcqon of CV risk. Thus, the overall reducqon of MIs was almost balanced by the increase in bleeding events throughout baseline risk categories. With respect to mortality, there was a small protecqve effect of aspirin therapy, with 0 to 6 fewer deaths per 1,000 persons treated over 10 years. This protecqve effect on mortality was found to be of similar magnitude in persons at low and at moderate- to- high risk for atherothromboqc events. Since bleeding risk appeared to be strongly related to the ischemic risk, the benefit of ASA was judged to be overshadowed by the bleeding hazard. If ASA were to be combined with other agents that would halve the risk of a major ischemic event, such as staqns, the potenqal benefit of ASA would be almost completely abolished.

7 Later on..meta- analysis un7l 2012 Four addiqonal meta- analyses have been performed by other groups, and published in 2011 to In all of them, 3 addiqonal trials were included: the JPAD (Japanese Primary PrevenQon of Atherosclerosis With Aspirin for Diabetes), POPADAD (PrevenQon of Progression of Arterial Disease and Diabetes), and AAA (Aspirin for AsymptomaQc Atherosclerosis) trials. These trials were somewhat nonhomogeneous with the previous ones, as they included individuals who, although asymptomaqc, were at higher risk because of pre- exisqng diabetes, asymptomaqc PAD, or both. In these meta- analyses, all- cause - but not vascular- mortality was slightly but consistently reduced, reiteraqng a risk raqo of 0.94 with uniform confidence limits (0.88 to 1.00), but without reaching formal significance. Ogawa H, et al. JAMA 2008;300: Fowkes FG, et al. JAMA 2010; 303: Belch J,, et al. BMJ 2008;337:a1840. Bartolucci AA, et al. Am J Cardiol 2011;107: Raju N, et al. Am J Med 2011;124: Berger JS, et al. Am Heart J 2011.

8 ASA and primary preven7on in Diabetes Three RCTs conducted specifically in paqents with diabetes and 6 RCTs in which paqents with diabetes were trackable subgroups (1% to 22%) failed to provide definiqve results on the effect of ASA in primary CVD prevenqon. A meta- analysis of these 9 RCTs found that ASA was associated with staqsqcally nonsignificant reducqons of CHD events (9%) and of cerebrovascular events (11%) Three other meta- analyses found similar esqmates Based on the overall negaqve results of these RCTs, it is generally assumed that aspirin is less effecqve in paqents with diabetes than in individuals without diabetes. However, the individual paqent- CV cardiovascular events was similar for parqcipants with and without diabetes (risk raqos: 0.88 [95% confidence interval (CI): 0.67 to 1.15] and 0.87 [95% CI: 0.79 to 0.96], respecqvely). Pignone M, et al. CirculaQon 2010;121: De Berardis G, et al. BMJ 2009;339:b4531. Zhang C, et al. Diabetes Res Clin Pract 2010;87: Calvin AD, et al. Diabetes Care 2009;32:

9 ASA end Adverse events : The Bleeding Risk The most common adverse effect associated with ASA is bleeding. The meta- analysis by the ATT CollaboraQon found that allocaqon to ASA increased major gastrointesqnal (GI) and other extracranial bleeds (defined as a bleed requiring transfusion or resulqng in death ) by about 50% (0.10%/year vs. 0.07%/year; risk raqo: 1.54 [95% CI: 1.30 to 1.82], p < ) The ATT CollaboraQon reported a staqsqcally significant 22% increased incidence of hemorrhagic stroke in paqents on anqplatelet treatment. A meta- analysis of 16 placebo- controlled RCTs, comprising a total of 55,462 paqents, showed that treatment with aspirin was associated with a relaqve risk of hemorrhagic stroke of 1.84 (p < 0.001) Recently, it has been emphasized that the bleeding risk is higher in individuals at higher CV risk over 10 years. Compared with placebo, this high- risk populaqon would experience 22 more bleeds per 1,000 persons treated with ASA versus 4 more bleeds per 1,000 persons treated with ASA in the low- risk populaqon (2009 ATT). He J, et al. JAMA 1998;280:

10 Interna7onal Guidelines (1/2) 2012 European Society of Cardiology 1. Aspirin is not recommended in individuals without cardiovascular or cerebrovascular disease due to the increased risk of major bleeding (Class III, Level of Evidence: B) American College of Chest Physician 1. Low- dose aspirin (75 to 100 mg) daily for persons age 50 years or older without symptomaqc CVD is suggested (Grade 2B) (similar for diabeqc paqents). Perk J, et al. Eur Heart J 2012;33: American College of Chest Physicians. Chest 2012;141:e637S 68S.

11 Interna7onal Guidelines (2/2) The American Diabetes Associa7on, the AHA, and the ACC : 1. Primary cardiovascular prevenqon with aspirin is reasonable in diabeqc paqents whose 10- year risk of events is >10% (men age >50 years and women age >60 years with at least 1 addiqonal risk factor: smoking, hypertension, dyslipidemia, albuminuria, or family history of premature CV events) and who are not at increased risk of bleeding (no history of GI bleeding or pepqc ulcer disease, no concurrent use of other medicaqons that increase bleeding risk). 2. Aspirin should not be recommended in diabetes paqents at low risk of CV events, because the potenqal adverse effects from bleeding offset the potenqal benefits. 3. Aspirin may be considered for diabetes paqents at intermediate risk of CV events (younger paqents with at least 1 risk factor, older paqents with no risk factors, or paqents with a 10- year risk of 5% to 10%). American College of Chest Physicians. Chest 2012;141:e637S 68S.

12 Aspirin and cancer preven7on Rothwell et al, 8 RCTs (not homogeneous as to the level of CV risk and aspirin doses [75 to 650 mg daily], in both primary and secondary CVD prevenqon) found that cumulaqve total mortality was 10.2% in aspirin users versus 11.1% in nonusers (odds raqo: 0.92, 95% CI: 0.85 to 1.00). The hazard raqo, which was calculated in a Qme- dependent analysis in 7 of the 8 trials, was 0.82, a significant total mortality reducqon (95% CI: 0.70 to 0.95). ReducQon in cancer mortality was a driving force for this, and became especially relevant auer 5 years (hazard raqo: 0.66) and persisted even auer 20 years for GI and other solid cancers (hazard raqo: 0.65). Regular, daily administraqon of aspirin for the enqre trial duraqon appeared to be necessary to confer the benefit. De Berardis G, et al. BMJ 2009;339:b4531.

13 The Net Clinical Benefit The net clinical benefit of giving aspirin to healthy individuals is made difficult to assess by the imprecision of esqmates of benefits and risks, especially for rare events, such as intracranial hemorrhage, and by the difficulty of weighing ischemic versus bleeding events. However, although the number of ischemic events averted (on average: 72 averted by treaqng 10,000 paqents for 10 years) was similar to the number of major bleeding events incurred (on average: 47 events), aspirin use would be associated with about 40 deaths averted against an average of 9 hemorrhagic strokes incurred, with an apparent overall benefit

14 2014 European Society of Cardiology Working Group on Thrombosis On February 2014 it was searched the electronic PubMed database for RCTs or meta- analyses of RCTs The authors criqcally evaluated the evidence, with an assessment of the risk/benefit raqo. The strength of recommendaqon and level of evidence of parqcular treatment opqons were weighed and graded according to the ESC system...it is hard to imagine that, going down the spectrum of CV risk from secondary to primary preven1on, there would be an immediate drop of the risk/benefit ra1o making aspirin use suddenly unappealing. Nature usually does not make jumps. Indeed, a graphical evalua1on of the benefit- risk balance, indicates a large area of CV risk in primary preven1on where data from trials are lacking, but in whom the benefit may s1ll outweigh the risk..

15 2014 European Society of Cardiology Working Group on Thrombosis

16 2014 European Society of Cardiology Working Group on Thrombosis

17 2014 European Society of Cardiology Working Group on Thrombosis The proposed threshold level is higher and more conservaqve than that proposed by the U.S. PrevenQve Task Force (0.6 per 100 paqent- years) and suggested by the AHA (>1 per 100 paqent- years). It is also significantly higher than the current recommendaqon from the ACCP, which suggests low- dose aspirin daily for all persons age >50 years without symptomaqc CVD. The proposed threshold risk level of 2 major CV events/100 paqent- years, corresponding approximately to a SCORE risk of 7% to 10% at 10 years, is sufficiently conservaqve to allow a net CV benefit to be achieved. 1. We recommend that aspirin use in the primary preven7on of acute MI and other atherothrombo7c CV events in subjects of both sexes is guided by an assessment of the underlying CV risk (Grade of Recommenda7on: I, Level of Evidence: B) 2. We suggest aspirin be considered in the primary preven7on of CVD in both sexes at a level of risk of major CV events (death, MI, and stroke) >2 per 100 subject- years, provided they have no clear evidence of increased risk of bleeding (GI bleeding or pep7c ulcer disease, no concurrent use of other medica7ons that increase bleeding risk) (Class of Recommenda7on: IIa, Level of Evidence: B). Ann Intern Med 2002;136: Pearson TA, et al. CirculaQon 2002;106:388-91

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19 Aspirin Use is Not Associated With Primary Preven7on of All- Cause, Cardiovascular, or Oncologic Mortality B. Doran; Y. Guo; J. Xu; S. Bangalore Using the NaQonal Health and NutriQon ExaminaQon Survey (NHANES III), it was examined the associaqon of ASA use and all- cause, CV, and oncologic mortality within 15,968 individuals. Auer weighqng, it was used a propensity score matching within parqcipants using an opqmal 1:4 matching technique to control for age, low density lipoprotein cholesterol, glomerular filtra1on rate, race, gender, use of cholesterol lowering medica1on, diabetes mellitus, high density lipoprotein, hypertension, elevated waist circumference, low socioeconomic status, and smoking. Were excluded those with pre- exisqng heart disease or missing informaqon on ASA use. All- cause, CV and oncologic mortality were assessed auer a mean of 14.0 (+/- 0.22) year follow- up. Auer matching there were 775 ASA users matched with 3,100 non- ASA users. There were no significant differences between both groups with respect to all- cause mortality (P=1.09, 95% CI ), CV mortality (P=1.14, 95% CI ), or oncologic mortality (P=1.04, 95% CI ).

20 Ongoing studies Most aspirin trials for primary CVD prevenqon have enrolled individuals at low CV risk, with esqmated coronary event rates <1% per person- years. To fill a missing gap, 5 ongoing RCTs are invesqgaqng the safety and efficacy of 100 mg aspirin daily versus placebo (or vs. no aspirin) in more than 60,000 men and women at a higher level of CV risk, that is, without known CVD but with esqmated rates of coronary events of 1% to 2% per person- years (or of total CV events 3% per person- years). In all 5 RCTs, the primary efficacy outcome includes vascular death, nonfatal MI, and nonfatal stroke to be weighed against major bleeding (mainly GI and intracranial) and other adverse events. The duraqon of follow- up is 4 to 7.5 years or driven by the number of accrued events. The Aspirin to Reduce Risk of IniQal Vascular Events (ARRIVE) trial is enrolling over 12,000 men and women with a 10- year risk of CHD over 15%; the Aspirin in Reducing Events in the Elderly (ASPREE) trial is enrolling elderly individuals aged >70 years and the JPPP elderly subject (age 60 to 85 years) with addiqonal risk factors; A Study of Cardiovascular Events in Diabetes (ASCEND) individuals with diabetes and the Aspirin and SimvastaQn CombinaQon for Cardiovascular Events PrevenQon Trials in Diabetes (ACCEPT- D) individuals with diabetes taking a staqn

21 Scuola di Specializzazione in Mala/e dell Apparato Cardiovascolare Dire7ore Prof. Massimo Volpe Facoltà di Medicina e Psicologia, Università di Roma Sapienza Anno Accademico Dr.ssa Allegra Ba/stoni Grazie per la Vostra A7enzione Proge7o Formazione Avanzata in Cardiologia nel Web 2014 Scuola di Specializzazione in Mala/e dell Apparato Cardiovascolare Dire7ore: Prof. Massimo Volpe E- mail: massimo.volpe@uniroma1.it Coordinatore: Dr. Giuliano Tocci E- mail: giuliano.tocci@uniroma1.it