1. Aspirina e Prevenzione primaria Ci sono nuove evidenze ? Aspirina e Prevenzione primaria Ci sono nuove evidenze ? III Congresso Nazionale 17/19 Maggio 2013 Atlantic Hotel - Riccione Claudio Ferri Università dell’Aquila Cattedra e Scuola di Medicina Interna – Dipartimento MeSVA Divisione di Medicina Interna Universitaria – Ospedale San Salvatore

2. Antithrombotic therapy and prevention of CV disease Eur Heart J 2012, 33:1636-1701 SCA Sec.Pr. MI Sec.Pr. MI Sec.Pr. STROKE Sec.Pr. STROKE

3. Absolute risk difference in relation to placebo in primary prevention trials Absolute number of nontrivial bleedings caused versus nonfatal MIs averted Absolute number of nontrivial bleedings caused versus total CV events averted Seshasai SR et al, Arch Intern Med. 2012;172(3):209-216

4. 3.1.1-3.1.5. For patients with established coronary artery disease (CAD), defined as patients 1-year post-acute coronary syndrome (ACS), with prior revascularization, coronary stenoses > 50% by coronary angiogram, and/or evidence for cardiac ischemia on diagnostic testing, (including patients after the first year post-ACS and/or with prior coronary artery bypass graft [CABG] surgery): We recommend long-term single antiplatelet therapy with aspirin 75 to 100 mg daily or clopidogrel 75 mg daily over no antiplatelet therapy (Grade 1A). We suggest single over dual antiplatelet therapy with aspirin plus clopidogrel (Grade 2B). Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines Aspirina e Prevenzione cardiovascolare secondaria Copyright: American College of Chest Physicians 2012 © - Chest. 2012; 141(2 Suppl): e637S–e668S. Summary of Recommendations

5. 2.1.For persons aged 50 years or older without symptomatic cardiovascular disease, we suggest low-dose aspirin 75 to 100 mg daily over no aspirin therapy (Grade 2B). Remarks: Aspirin slightly reduces total mortality regardless of cardiovascular risk profile if taken over 10 years. In people at moderate to high risk of cardiovascular events, the reduction in myocardial infarction (MI) is closely balanced with an increase in major bleeds. Whatever their risk status, people who are averse to taking medication over a prolonged time period for very small benefits will be disinclined to use aspirin for primary prophylaxis. Individuals who value preventing an MI substantially higher than avoiding a GI bleed will be, if they are in the moderate or high cardiovascular risk group, more likely to choose aspirin. Copyright: American College of Chest Physicians 2012 © - Chest. 2012; 141(2 Suppl): e637S–e668S. Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines Aspirina e Prevenzione cardiovascolare primaria Summary of Recommendations

6. Variables Changes vs usual care HbA 1c 0·37% (95% CI 0·28—0·45; 120 trials) LDL cholesterol 0·10 mmol/L (0·05—0.14; 47 trials) Statin use (RR 1·12, 0·99—1·28, 10 trials) SBP 3·13 mm Hg (2·19—4·06, 65 trials) DBP 1·55 mm Hg (0·95—2·15, 61 trials) Hypertension control (RR 1·01, 0·96—1·07, 18 trials) Smoking cessation (RR 1·13, 0·99—1·29, 13 trials) Likelihood to receive: Aspirin (RR 1·33, 1·21—1·45,11 trials) Antihypertensive drugs (RR 1·17, 1·01—1·37, 10 trials) Screening for: Retinopathy (RR 1·22, 1·13—1·32, 23 trials) Renal function (RR 1.28, 1·13—1·44, 14 trials) Foot abnormalities (RR 1·27, 1·16—1·39, 22 trials) Tricco AC et al Lancet. 2012;379(9833):2252-61. Effectiveness of quality improvement strategies on the management of diabetes: a systematic review and meta-analysis – 48 cluster trials 84.865 patients

7. The Melbourne Colorectal Cancer Study Distribution of medication among cases and controls and relative risk estimates The Melbourne Colorectal Cancer Study Distribution of medication among cases and controls and relative risk estimates * 0,63 (0.50-0.78) p<0.001 after adjustment for arthritis * Kune GA, Kune S, Watson LF. Cancer Res. 1988;48(15):4399-404. Authors wrote about ASA-related decrements in cancer: “ consistent for both colon and rectal cancer and for both males and females ” *

8. Effect of allocation to aspirin versus placebo (A) and warfarin versus placebo (B) on the incidence of cancer during the Thrombosis Prevention Trial Rothwell PM et al Lancet 2012, 379, 9826: 1602–1612 Incidence of cancer

9. Aspirin Is Associated With Lower Melanoma Risk Among Postmenopausal Caucasian Women Gamba CA et al Cancer 2013 Hazard Ratio ASA users NSAID users (NON-ASA) NONE (ref) 1.0 Incidence per 100.000 person per year HR (fully adjusted, vs NSAID nonusers) ASA users69.8 0.79 (0.63-0.98) NSAID users (NON-ASA)87.9 1.05 (0.83-1.34) ASA users: p linear trend = 0.01 NSAID users: p linear trend = 0.8 ASAusersASAusers ASAusersASAusers ASAusersASAusers

10. Figure 2 Pooled analysis of effect of allocation to aspirin on incidence of cancer during six randomised trials of daily low-dose (75?100mg daily) aspirin versus placebo in primary prevention of vascular events<ce:cross- refs refid="bib16 bib17 bi... Effect of aspirin on incidence of cancer during six randomised trials of daily low-dose (75–100mg daily) aspirin versus placebo in primary prevention of vascular events (A) All patients. (B) All patients with scheduled duration of trial treatment of at least 5 years. (C) Meta-analysis of the effect of aspirin on risk of non-vascular death during 12 randomised trials in primary prevention Rothwell PM et al Lancet 2012, 379, 9826: 1602–1612 C Incidence of cancer

11. Meta-analyses of the effect of aspirin on risks of incident cancer, major vascular events, and major extracranial bleeds during six randomised trials of daily low-dose aspirin versus control in primary prevention of vascular events stratified by period of trial follow-up Rothwell PM et al Lancet 2012, 379, 9826: 1602–1612

12. RR of colorectal cancer for highest vs lowest categories of ASA use Dose of ASA use and risk of colorectal cancer Frequency of ASA use and risk of colorectal cancer Years of ASA use and risk of colorectal cancer Ye X et al Plos One 2013; 8(2): e57578. 18% decreased risk for 10 years aspirin increment

13. Global Health Benefits from ASA: Pooled analyses of the six randomised trials of daily low-dose (75–100 mg daily) aspirin versus placebo in primary prevention (A) composite outcome of major vascular events, cancer, or fatal extracranial haemorrhage (B) major vascular events, cancer, or any extracranial haemorrhage Global Health Benefits from ASA: Pooled analyses of the six randomised trials of daily low-dose (75–100 mg daily) aspirin versus placebo in primary prevention (A) composite outcome of major vascular events, cancer, or fatal extracranial haemorrhage (B) major vascular events, cancer, or any extracranial haemorrhage Rothwell PM et al Lancet 2012, 379, 9826: 1602–1612

14. Aspirin use and risk of cancer Algra AM and Rothwell PM Lancet Oncol. 2012;13(5):518-27.

15. Aspirin use and risk of cancer metastasis Algra AM and Rothwell PM Lancet Oncol. 2012;13(5):518-27.

16. Gobal benefits from ASA: Reduction in CV events and cancer incidence 1) The time-dependent ability of ASA to reduce cancer incidence (not only colo-rectal and even metastatic) is evident 2) This cancer reduction modulates benefits and risk in favour of ASA use even in primary prevention 3) We need appropriate trials (?) 4) We need to understand

17. Hasan DM et al J. Am. Heart Assoc. 2013, 2 Evidence That Acetylsalicylic Acid Attenuates Inflammation in the Walls of Human Cerebral Aneurysms

18. Michael J. Thun, Eric J. Jacobs and Carlo Patrono Nat. Rev. Clin. Oncol. 2012, 9, 259–267 The role of aspirin in cancer prevention Females, age 50–59 years Females, age 65–74 years Males, age 65–74 years Males, age 50–59 years

19. Liao X et al. N Engl J Med 2012;367:1596-1606. Mortality among Patients with Colorectal Cancer, According to Regular Use or Nonuse of Aspirin after Diagnosis and PIK3CA Mutation Status. HR = 0.18 HR = 0.93

20. Gobal benefits from ASA: Reduction in CV events and cancer incidence 1) The time-dependent ability of ASA to reduce cancer incidence (not only colo-rectal and even metastatic) is evident 2) This cancer reduction modulates benefits and risk in favour of ASA use even in primary prevention 3) We need appropriate trials (?) 4) We need to understand 5) Future surprises from ASA ?

21. Change in MMSE by ASA in women followed from 2000 to 2005 Kern S et al BMJ, 2012 Oct 3;2(5) 1 – 0 – -1 – -2 – -3 – No ASA (n.338) ASA (n.66) P=0.04

22. Serum TXB 2 (ng/ml) 24222018161412 4 3 2 1 0 post-aspirin interval hr slope 0.07 [0.054-0.079] ng/ml hr -1 post-aspirin interval 24 hr222018161412 4 3 2 1 0 slope 0.14 [0.11-0.20] ng/ml hr -1 2422201816141 2 4 3 2 1 0 hr slope 0.02 [0.01-0.03] ng/ml hr -1 post-aspirin interval HS Rocca B. et al. J Thromb Haemost 2012;10:1220-30 Serum TXB2 recovery slopes according to tertile

23. Serum TXB 2 recovery slopes in diabetic patients in the upper tertile, before and after the randomized phase of the study Rocca B. et al. J Thromb Haemost 2012;10:1220-30