ASIAM V Congresso Nazionale Riccione - 15/17 maggio 2015 Aspirina a basso dosaggio in prevenzione primaria Claudio Ferri Università dell’Aquila Cattedra e Scuola di Medicina Interna – Dipartimento MeSVA Divisione di Medicina Interna e Nefrologia – Ospedale San Salvatore 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 Gai l / N ati o nal Cancer I n sti t ute Approach of Number the analysis. needed to treat and number needed to harm Number needed to treat and number needed to harm in person-years for primary prevention with lowTable 3B. Numberaspirin needed to treat number needed harm inage person-years for primary dose in and women for tofour categories in eperson-years for primary prevention with lowTabl s 5 and 6 show t h e absol u t e numbers of expect e d event s over 10 years without or with Table 3A. Number needed to treat and number needed to harm in person-years for primary dose aspirin in men for four age categories prevention for four with low-dose aspirin in women for four age categories low-dose with aspirlow-dose in for 1,000aspirin meninormenwomen, respectageicategories vely.65-74Take, for example,75-84men age 55 to 64 prevention Age category in 45-54 55-64 Age Category in 45-54 55-64 65-74 75-84 years years. The expected number of MIs per 1,000 untreated men over 10 years was 57. This was a years Benefit outcomes NNT (95% CI) Benefit outcomes NNT (95% CI) MI 1,786 [962 - NA] 1,153 [621 - NA] 769 [414 - NA] 511 [275 - NA] 5,953 [3,206 - NA] 2381 [1,283 - NA] 1,520 [819 - NA] 872 [470 - NA] lit le less than what would be calculated by simply multiplying the incidence rate of 6.2 MIs per MI ischemic 8,548 [NNT 4,116 - 3487 [NNT 1852 2,137 [NNT 1,029 - 1,026 [NNT 494 1,000ischemic person-years 10 years Table[NNT1) because consi[NNTdered662 -death as713a[NNTcompet343 -inNNHg risk Major Major * 6,411by[NNT 3,087 -(see 3,077 1,482 - we1,374 stroke* NNH 55,556] NNH 25,000] NNH 13,889] NNH 6,667] stroke NNH 41,667] NNH 20,000] NNH 8,929] 4,630] outcomes NNH [ 95% CI] that prevent MIs(95%fromCI)occurring in those who die early. As age increased, the impact of death Harm Harm outcomessNNH Major 28,572 [12,346 9,524 [4,116 5,715 [2,470 2,598 [1,123 Major 14,286 [6,173 7,143 [3087 3,572 [1,544 1,786 [772 - 62,501] hemorrhagic 1,000,001] 333,334] 200,000] 90,910] became larger. For500,001] example, the expect250,001]ed number of GI125,001 bleeds in untreated men age 75 to 84 stroke hemorrhagic stroke the number GI bl- 807]eeds (62 percent , excess GI bleedsof maj404or[250 202 [125RR - 404]increase, e.108g.[67 - 216] of 113 maj 68 [42or- GI 135]bleeds fo Major - 404] with deat 101h [63 34 [21 - l68] yearsGIwasbleeds285 over202 10[125years as -a202]competing ri54sk.[34Thi- 108]s is considerably ower than the Major * The 95% CIs for ischemic stroke (RR 0.87; 95% CI, 073 -1.02) include the possibilities of both benefit and harm and thus we CI = confidence interval; GI = gastrointestinal; MI = myocardial infarction; NA = not applicable because CIs for RR approximate men ageNNT65astwello 74as NNHyears)respectively. over 10Theyears.NNT is lower because it reflects the lower limit of the CI, and the NNH is higher reported 1;480 NNHthat = number needed toexpect harm; NNT =winumber needed todtreat; RR = relative risk woul d be e d t h out consi eri n g deat h as a compet i n g ri s k (Tabl e 1). events without andthewith aspirin Expected *TheExpected 95% CIs for ischemic stroke (RR 0.87; 95% CI, 073 -1.02) include possibilitieslow-dose of both benefit and harm and thus we because it reflects the upperevents limit of the CI. without and with low-dose aspirin report NNT as well as NNH respectively. The NNT is lowerinbecause it reflects the lower limit of the CI, and the NNH is higher men because it reflects the upper limit of the CI. Table 5. Expected number of events without and with low-dose aspirin in men * Outcomes Number of Expected Events Over 10 Years Per 1,000 Men Without aspirin With aspirin Table 6. Expected events without and with low-dose aspirin in women * CI = confidence interval; GI = gastrointestinal; MI =in myocardial infarction; NA = not applicable because CIs for RR approximate women 1; NNH = number needed to harm; NNT = number needed to treat; RR = relative risk Outcomes Number of expected events over 10 years per 1,000 women Sensitivity AnalysisWifor Needed WitothTreat thoutthe aspirNumber in aspirin and Number Needed to Harm Approach Using Baseline Incidence Rates from the Age categories in years 45-54 55-64 65-74 75-84 45-54 55-64 65-74 75-84 Age categories in years 45-54 55-64 65-74 75-84 45-54 55-64 65-74 75-84 Trials MI MI 12 29 42 63 10 25 37 54 38 57 79 96 33 49 68 83 Major ischemic stroke 12 24 48 74 11 21 42 64 MajoBelow r ischemiwecpresent stroke the results 9 of the20 sensitivity 33 analysis 58 for the7 NNT 17and NNH29approach51 using baseline incident rates from the trials. Since the baseline incidence rates in the trials were Major hemorrhagic stroke 2 4 7 9 11 2 5 10 15 Major hemorrhagi strokeobservational 1 3studies (Appendix 5 9Table A-4), 2 the respective 4 7NNTs and12 lower than that ofc the Major GI bleeds 75 141 231 285 119 218 344 411 Major GIinblthiseedssensitivity analysis NNHs and women 39 were74 higher129for all four171outcomes 62 for both 117 men 200 260 Puhan No.:4A 12(14)-EHC149-EF. and 4B). GI = gastrMA ointestetinalal.; MIAgency = myocardiaforl infarctHealthcare ion; RR = relatiResearch ve risk and Quality (US); 2013 Nov. Report(Tables Association of NSAID Use With Risk of Bleeding during Antithrombotic Therapy Schjerning Olsen AM et al JAMA. 2015;313(8):805-814. ESC – CV prevention Guidelines 2012 Aspirin is not recommended in primary prevention Aspirin is recommended only in patients with established vascular disease or previous cardiovascular events Aspirina e Prevenzione cardiovascolare primaria Summary of Recommendations 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 ESC-EASD Diabetes and Prediabes Guidelines 2013 Low-dose aspirin for primary prevention may be considered in high risk patients with diabetes mellitus on an individual basis. High risk = all patients with diabetes mellitus Very high risk = patients with diabetes mellitus and >1 cardiovascular risk factor ESH-ESC Hypertension Guidelines 2013 Low-dose aspirin should be prescribed to controlled hypertensive patients with previous CV events and considered in hypertensive patients with reduced renal function or a high CV risk. Aspirin is not recommended in low-tomoderate risk hypertensive patients in whom absolute benefit and harm are equivalent. Lower incidences of cancer and mortality has been suggested in aspirin treated patients (primary prevention trials). If confirmed, this additional action of aspirin may lead to a more liberal reconsideration of its use. Low-dose aspirin may be considered in pre-eclampsia Effectiveness of quality improvement strategies on the management of diabetes: a systematic review and meta-analysis – 48 cluster trials 84.865 patients Variables HbA1c Changes vs usual care LDL cholesterol Statin use 0·10 mmol/L (0·05—0.14; 47 trials) (RR 1·12, 0·99—1·28, 10 trials) SBP 3·13 mm Hg (2·19—4·06, 65 trials) •DBP •Hypertension control 1·55 mm Hg (0·95—2·15, 61 trials) (RR 1·01, 0·96—1·07, 18 trials) Smoking cessation Likelihood to receive: Aspirin 0·37% (95% CI 0·28—0·45; 120 trials) (RR 1·13, 0·99—1·29, 13 trials) (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. The INTERHEART study 1000 2.9 2.4 1.9 3.3 13.0 42.3 68.5 182.9 333.7 334 (90.4 PAR) 1000 68.5 Odds ratio (99% CI) Odds ratio (99% CI) 100 2 (circa) 10 1 100 12.9 10 1 All RF s l l cia 1 oA cia oso ity ych be s 4 +Ps +O All /Ap s +3 oB N 1+ 2 Ap HT RF oso 1 oA DM ng ok i Sm All ity ych be s +Ps +O All4 /Ap +3 oB N 1+ 2 Ap HT DM ng ok i Sm Modificato da: Yusuf S et al Lancet 2004;364:937-52 Low dose Aspirin in Primary prevention – Position paper – ESC working Group on Thrombosis Magnitude of Antithrombotic Benefit and of Bleeding Risk Connected With the Use of Aspirin, and Absolute CV Risk, in Various A Proposed Practical Stepwise Approach to Subsets of Subjects in Primary Prevention the Use of Aspirin in Primary CV Prevention While awaiting the results of several ongoing studies, this document argues for a pragmatic approach to the use of low-dose aspirin in primary cardiovascular prevention, and suggests its use in patients at high cardiovascular risk, defined as ≥2 major cardiovascular events (death, myocardial infarction, or stroke) projected per 100 person-years, who are not at increased risk of bleeding. G Ital Cardiol 2014;15(7-8):442-451 Halvorsen S et al. Aspirin therapy in primary cardiovascular disease prevention: a position paper of the European Society of Cardiology Working Group on Thrombosis. J Am Coll Cardiol 2014;64:319-27 Low dose Aspirin in Primary prevention CV Cancer Bleeding Risk Risk Risk YES ASA Battistoni A et al Clin Cardiol. 2015 Apr 14. CV Cancer Bleeding Risk Risk Risk Clinical Judgement CV Cancer Bleeding Risk Risk Risk NO ASA Aspirin use and risk of cancer Algra AM and Rothwell PM Lancet Oncol. 2012;13(5):518-27. Ongoing trials in intermediate CV risk conditions Aspirin to Reduce Risk of Initial VascularEvents (ARRIVE) Aspirin in Reducing Events in the Elderly (ASPREE) Cardiovascular Events in Diabetes (ASCEND) Aspirin and Simvastatin Combination for Cardiovascular Events Prevention Trials in Diabetes (ACCEPT-D) Japanese Primary Prevention trial (JPPP) ENVIS-ion Elderly neurovascular imaging study (ASPREE substudy) ESH-ESC Hypertension Guidelines 2013 Low-dose aspirin should be prescribed to controlled hypertensive patients with previous CV events and considered in hypertensive patients with reduced renal function or a high CV risk. Aspirin is not recommended in low-tomoderate risk hypertensive patients in whom absolute benefit and harm are equivalent. Lower incidences of cancer and mortality has been suggested in aspirin treated patients (primary prevention trials). If confirmed, this additional action of aspirin may lead to a more liberal reconsideration of its use. Low-dose aspirin may be considered in pre-eclampsia Global Health Benefits from ASA: Number of Events Averted or Incurred Should 10,000 Persons Be Treated With Aspirin in Primary CVD Prevention and Followed-Up for 10 Years Events averted Deaths (any cause) MCE (CV death, MI, or stroke) Total CHD events CRC deaths Cancer deaths Events incurred Major bleeds GI bleeds Hemorrhagic strokes Sutcliffe P et al Health Technol Assess 2013;17:1–253. Range Mean 33–46 60–84 47–64 34–36 17–85 39.5 72.0 55.5 35.0 51.0 46–48 117–182 8–10 47.0 149.5 9.0 The role of aspirin in cancer prevention Females, age 50–59 years Females, age 65–74 years Males, age 50–59 years Males, age 65–74 years Michael J. Thun, Eric J. Jacobs and Carlo Patrono Nat. Rev. Clin. Oncol. 2012, 9, 259–267 Evidence That Acetylsalicylic Acid Attenuates Inflammation in the Walls of Human Cerebral Aneurysms Hasan DM et al J. Am. Heart Assoc. 2013, 2 RR of colorectal cancer for highest vs lowest categories of ASA use Dose of ASA use and risk of colorectal cancer Years of ASA use and risk of colorectal cancer Frequency of ASA use and risk of colorectal cancer 18% decreased risk for 10 years aspirin increment Ye X et al Plos One 2013; 8(2): e57578. Mortality among Patients with known Colorectal Cancer, According to Regular Use or Nonuse of Aspirin after Diagnosis and PIK3CA Mutation Status. HR = 0.18 Liao X et al. N Engl J Med 2012;367:1596-1606. Regular Use of Aspirin and Incident Colorectal Cancer by PTGS2 Status and Combination of BRAF-PTGS2 Mutation Status HR = 0.93 Nishihara R et al JAMA. 2013;309(24):2563-2571. Aspirin Is Associated With Lower Melanoma Risk Among Postmenopausal Caucasian Women ASA users: p linear trend = 0.01 NSAID users: p linear trend = 0.8 1.2 1 1.0 Hazard Ratio 0.8 ASA users NSAID users (NON-ASA) 0.6 0.4 0.2 0 A S A A S A u s e r s u s e r s <1 year 1-4 years A S A NONE (ref) u s e r s ≥5 Incidence per 100.000 person per year HR (fully adjusted, vs NSAID nonusers) ASA users 69.8 0.79 (0.63-0.98) NSAID users (NON-ASA) 87.9 1.05 (0.83-1.34) Gamba CA et al Cancer 2013 Aspirin use and risk of cancer metastasis Algra AM and Rothwell PM Lancet Oncol. 2012;13(5):518-27. Platelet contribution to cancer progression PG-mediated lymphatic vessel dilation N. M. Bambace, Journal of Thrombosis and Haemostasis, 2011 9: 237–249 Conclusioni ASA a basso dosaggio sembra essere indicato anche in prevenzione cardiovascolare primaria La prescrizione consegue alla valutazione individuale ed al bilancio rischio emorragico / rischio cardiovascolare ASA a basso dosaggio sembra proteggere dal rischio oncologico (per diversi tipi di neoplasia ed anche nei confronti delle metastasi a distanza), paradossalmente in modo COX-2 mediato La rivalutazione delle evidenze in merito ad ASA e rischio oncologico porterà necessariamente ad una rivisitazione dei due punti precedenti Conclusioni ASA a basso dosaggio sembra essere indicato anche in prevenzione cardiovascolare primaria La prescrizione consegue alla valutazione individuale ed al bilancio rischio emorragico / rischio cardiovascolare ASA a basso dosaggio sembra proteggere dal rischio oncologico (per diversi tipi di neoplasia ed anche nei confronti delle metastasi a distanza), paradossalmente in modo COX-2 mediato La rivalutazione delle evidenze in merito ad ASA e rischio oncologico porterà necessariamente ad una rivisitazione dei due punti iniziali Conclusioni ASA a basso dosaggio sembra essere indicato anche in prevenzione cardiovascolare primaria La prescrizione consegue alla valutazione individuale ed al bilancio rischio emorragico / rischio cardiovascolare ASA a basso dosaggio sembra proteggere dal rischio oncologico (per diversi tipi di neoplasia ed anche nei confronti delle metastasi a distanza), paradossalmente in modo COX-2 mediato La rivalutazione delle evidenze in merito ad ASA e rischio oncologico porterà necessariamente ad una rivisitazione dei due punti iniziali Conclusioni ASA a basso dosaggio sembra essere indicato anche in prevenzione cardiovascolare primaria La prescrizione consegue alla valutazione individuale ed al bilancio rischio emorragico / rischio cardiovascolare ASA a basso dosaggio sembra proteggere dal rischio oncologico (per diversi tipi di neoplasia ed anche nei confronti delle metastasi a distanza), paradossalmente in modo COX-2 mediato La rivalutazione delle evidenze in merito ad ASA e rischio oncologico porterà necessariamente ad una rivisitazione dei due punti iniziali Conclusioni ASA a basso dosaggio sembra essere indicato anche in prevenzione cardiovascolare primaria La prescrizione consegue alla valutazione individuale ed al bilancio rischio emorragico / rischio cardiovascolare ASA a basso dosaggio sembra proteggere dal rischio oncologico (per diversi tipi di neoplasia ed anche nei confronti delle metastasi a distanza), paradossalmente in modo COX-2 mediato La rivalutazione delle evidenze in merito ad ASA e rischio oncologico porterà necessariamente ad una rivisitazione dei due punti iniziali