1. ARDITH DOMINGUEZ-TAN, MD, FPCC ARDITH DOMINGUEZ-TAN, MD, FPCC Diplomate and Fellow, Philippine College of Physicians Diplomate and Fellow, Philippine College of Cardiology Diplomate and Fellow, Philippine College of Physicians Diplomate and Fellow, Philippine College of Cardiology Assistant Professor, Dept. of Medicine, DLS-Health Sciences Institute College of Medicine Assistant Professor, Dept. of Medicine, DLS-Health Sciences Institute College of Medicine Consultant Cardiologist, De La Salle University Medical Center Consultant Cardiologist, De La Salle University Medical Center Unit Head, Dr. RP Ariniego Cardiovascular Laboratory- De La Salle University Medical Center Unit Head, Dr. RP Ariniego Cardiovascular Laboratory- De La Salle University Medical Center Cancer survivor (Non-Hodgkins Lymphoma) Cancer survivor (Non-Hodgkins Lymphoma)

2. “Statins and Aspirin for Primary Prevention? What are the current recommendations and risk stratification measures for its administration?” Ardith Dominguez-Tan, MD, FPCC

3. Disclosures: Currently lecture for Astra-Zeneca, Sanofi-Aventis, MSD, HospiraCurrently lecture for Astra-Zeneca, Sanofi-Aventis, MSD, Hospira

4. SESSION OBJECTIVES: 1.Review existing data on randomized trials on statins and aspirin in the primary prevention of CV events 2.Review current recommendations on the use of statins and aspirin in primary prevention 3.Propose risk stratification measures to adopt for the use of statins and aspirin in primary prevention

5. Cardiovascular Disease: Ranked as the number one cause of mortality and is a major cause of morbidity worldwideRanked as the number one cause of mortality and is a major cause of morbidity worldwide In the Philippines, heart disease is the number one cause of death among Filipinos (DOH, Phil. Health Statistics 2004)In the Philippines, heart disease is the number one cause of death among Filipinos (DOH, Phil. Health Statistics 2004) Important goal of medical treatment is to reduce high blood cholesterolImportant goal of medical treatment is to reduce high blood cholesterol Statins are the agents of first choiceStatins are the agents of first choice

6. STATINS

7. Adapted from Rosensen RS. Exp Opin Emerg Drugs 2004; 9 (2):269-279 LaRosa JC et al. N Engl J Med 2005; 352 :1425-1435 LDL-C achieved mg/dL (mmol/L) WOSCOPS – Placebo AFCAPS - Placebo ASCOT - Placebo AFCAPS - RxWOSCOPS - Rx ASCOT - Rx 4S - Rx HPS - Placebo LIPID - Rx 4S - Placebo CARE - Rx LIPID - Placebo CARE - Placebo HPS - Rx 0 5 10 15 20 25 30 40 (1.0) 60 (1.6) 80 (2.1) 100 (2.6) 120 (3.1) 140 (3.6) 160 (4.1) 180 (4.7) Event rate (%) 6 Secondary Prevention Primary Prevention Rx - Statin therapy PRA – pravastatin ATV - atorvastatin 200 (5.2) PROVE-IT - PRA PROVE-IT – ATV TNT – ATV10 TNT – ATV80 LDL-C is Closely Related to CHD Events in Statin Trials LDL-C is Closely Related to CHD Events in Statin Trials

8. Benefit of statins proven in secondary prevention trialsBenefit of statins proven in secondary prevention trials For people without a past history of cardiovascular disease (CVD) the evidence is less clearFor people without a past history of cardiovascular disease (CVD) the evidence is less clear Recommendations for statin use in primary prevention ? Clinical benefit in high vs. lower risk populations?Recommendations for statin use in primary prevention ? Clinical benefit in high vs. lower risk populations?

9. Framingham Heart Study Prediction Separate score sheets are used for men and women and the factors used to estimate risk includeSeparate score sheets are used for men and women and the factors used to estimate risk include age, blood cholesterol (or LDL cholesterol), HDL cholesterol, blood pressure, cigarette smoking, and diabetes mellitus.age, blood cholesterol (or LDL cholesterol), HDL cholesterol, blood pressure, cigarette smoking, and diabetes mellitus. Relative risk for CHD is estimated by comparison to low risk Framingham participantRelative risk for CHD is estimated by comparison to low risk Framingham participant

11. Users of this risk algorithm should be aware of several caveats: 1.The risk estimating score sheets are only for persons without known heart disease. 2.The Framingham Heart Study risk algorithm encompasses only coronary heart disease, not other heart and vascular diseases. 3.The Framingham Heart Study population is almost all Caucasian. The Framingham risk algorithm may not fit other populations quite as well. 4.For some of the sex-age groups in Framingham, the numbers of events are quite small. Therefore, the estimates of risk for those groups may lack precision. 5.Other organizations are considering how the information from the Framingham risk algorithm, as well as other assessments of risk, might best be incorporated into clinical practice. As new information and guidelines become available, they will be added.

12. 6. The Framingham risk score estimates the risk of developing CHD within a 10-year time period. This risk score may not adequately reflect the long-term or lifetime CHD risk of young adults, which is: one in two for men and one in three for women. 7. The presence of any CHD risk factor requires appropriate attention because a single risk factor may confer a high risk for CHD in the long run, even if the 10-year risk does not appear to be high. 8. Since age is a prominent determinant of the CHD risk score, the 10-year hazards of CHD are, on average, high in older persons. This may over-identify candidates for aggressive interventions. Relative risk estimates (risk in comparison with low risk individuals) may be more useful than absolute risk estimates in the elderly. 9. The score derived from this algorithm should not be used in place of a medical examination.

13. Framingham Heart Study Prediction Limitations — Risk assessments that stratify patients according to the number of defined risk factors can identify high-risk persons, but they tend to falsely reassure persons deemed to be at low risk who may have multiple marginal abnormalities. Since the segment of the population with borderline abnormalities of blood pressure and lipids has most of the coronary events, it is important not to overlook these subjects.Limitations — Risk assessments that stratify patients according to the number of defined risk factors can identify high-risk persons, but they tend to falsely reassure persons deemed to be at low risk who may have multiple marginal abnormalities. Since the segment of the population with borderline abnormalities of blood pressure and lipids has most of the coronary events, it is important not to overlook these subjects.

14. SCORE-European High Risk Chart 10 year risk of fatal CVD in high risk regions of Europe

15. SCORE European High Risk Chart Cardiovascular Risk Estimation: 10 yr CV risk should be calculated and used as the basis to reduce the risk10 yr CV risk should be calculated and used as the basis to reduce the risk A total CVD risk of > 20% over 10 years is defined as HIGH RISKA total CVD risk of > 20% over 10 years is defined as HIGH RISK People with moderate to high risk more likely to be compliant w/ lifestyle changes and preventive medicationPeople with moderate to high risk more likely to be compliant w/ lifestyle changes and preventive medication Intermediate to low-risk ?Intermediate to low-risk ?

16. LDL Cholesterol Goals and Cutpoints for Therapeutic Lifestyle Changes (TLC) and Drug Therapy in Different Risk Categories NCEP ATP III Risk Category LDL Goal (mg/dL) LDL Level at Which to Initiate Therapeutic Lifestyle Changes (TLC) (mg/dL) LDL Level at Which to Consider Drug Therapy (mg/dL) CHD or CHD Risk Equivalents (10-year risk >20%) <100  100  130 (100–129: drug optional) 2+ Risk Factors (10-year risk  20%) <130  130 10-year risk 10– 20%:  130 10-year risk <10%:  160 0–1 Risk Factor<160  160  190 (160–189: LDL- lowering drug optional)

17. European guidelines on cardiovascular disease prevention in clinical practice: Fourth Joint Task Force of the European Society of Cardiology and Other Societies on Cardiovascular Disease Prevention in Clinical Practice

23. Trials on Primary Prevention “Statins for Primary prevention: At what coronary risk is safety assured?” ( Jackson et al B J Cl Pharm, Oct 2001) Methodology- Automated and manual literature searchMethodology- Automated and manual literature search Major placebo controlled statin outcome trialsMajor placebo controlled statin outcome trials Outcome measure - all cause mortality and baseline values of standard coronary risk factors abstracted for each trialOutcome measure - all cause mortality and baseline values of standard coronary risk factors abstracted for each trial Results:Results: Statin use could be associated with an increase in mortality of 1% in 10 yearsStatin use could be associated with an increase in mortality of 1% in 10 years Sufficiently large to negate statins beneficial effect on CHD mortality in patients w/ event risk < 13% over 10 yrsSufficiently large to negate statins beneficial effect on CHD mortality in patients w/ event risk < 13% over 10 yrs CONCLUSION: Absolute safety of statins not demonstrated for patients at LOW RISK of CHDCONCLUSION: Absolute safety of statins not demonstrated for patients at LOW RISK of CHD

24. “The Benefits of Statins in People without established Cardiovascular Disease but with Cardiovascular Risk Factors: Meta-analysis of Randomized Controlled Trials” (Brugts et al BMJ 2009) 10 RCTs, n= 70,388 persons ( women= 34%, DM=23% )10 RCTs, n= 70,388 persons ( women= 34%, DM=23% ) Mean ff-up= 4.1 yearsMean ff-up= 4.1 years Results: statins reduced the risk ofResults: statins reduced the risk of All cause mortality OR 0.88 (95% CI: 0.81 to 0.96)All cause mortality OR 0.88 (95% CI: 0.81 to 0.96) Major coronary events OR 0.70 (95% CI: 0.61 to 0.81)Major coronary events OR 0.70 (95% CI: 0.61 to 0.81) Major cerebrovascular events OR 0.81 (95% CI: 0.71-0.93)Major cerebrovascular events OR 0.81 (95% CI: 0.71-0.93) No significant heterogeneity in clinical subgroupsNo significant heterogeneity in clinical subgroups CONCLUSION: In patients WITHOUT established CVD but with cardiovascular risk factors, STATIN use was associated with significantly improved survival and large reductions in the risk of major CV eventsCONCLUSION: In patients WITHOUT established CVD but with cardiovascular risk factors, STATIN use was associated with significantly improved survival and large reductions in the risk of major CV events

25. “Statin prescription to men and women at cardiovascular risk: to whom and when?” ( Brugts, JJ and Deckers, JW Curr Op in Cardiol 2010) ( Brugts, JJ and Deckers, JW Curr Op in Cardiol 2010) Reviewed clinical trials of statins in patients at relatively low risk of cardiovascular disease but w/ CV risk factorsReviewed clinical trials of statins in patients at relatively low risk of cardiovascular disease but w/ CV risk factors WOSCOPS, AFCAPS, PROSPER, ALLHAT-LLT, ASCOT-LLA, HPS, CARDS, ASPEN, MEGA, JUPITERWOSCOPS, AFCAPS, PROSPER, ALLHAT-LLT, ASCOT-LLA, HPS, CARDS, ASPEN, MEGA, JUPITER CONCLUSION: Statins reduce the cardiovascular risk and mortality in low-risk patients without CVD. However, the overall ARR and cost-effectiveness of long-term statin prescription should be kept in mind before prescribing statins to relatively healthy individualsCONCLUSION: Statins reduce the cardiovascular risk and mortality in low-risk patients without CVD. However, the overall ARR and cost-effectiveness of long-term statin prescription should be kept in mind before prescribing statins to relatively healthy individuals

26. Odds ratios (95% confidence intervals) for all cause mortality, major coronary events, major cerebrovascular events, and incidence of cancer. Brugts J J et al. BMJ 2009;338:bmj.b2376 ©2009 by British Medical Journal Publishing Group

27. “Efficacy of statins for primary prevention in people at low cardiovascular risk : a meta-analysis ” (Tonelli M, Lloyd A et al CMAJ Nov 2011) MEDLINE and EMBASE registries (to Jan. 28 2011 ) Included trials of participants at low CV risk (10 yr risk of <20%) Statin vs. placebo or no statin Results: 29 eligible trials (n=80,711) Reduction in: -all-cause mortality RR 0.90 (95% CI: 0.84- 0.97) –10 yr risk <20% RR 0.83 (95% CI: 0.73-0.94)- 10 yr risk <10% -NFMI RR 0.64 (95% CI: 0.49-0.84) -Non-fatal stroke RR 0.81 (95% CI: 0.68-0.96) CONCLUSION: Statins efficacious in preventing death and CV morbidity in people at low CV riskCONCLUSION: Statins efficacious in preventing death and CV morbidity in people at low CV risk

28. “Primary Prevention of Cardiovascular Mortality and Events with statin treatments: a network meta- analysis involving more than 65,000 patients ” (JACC Nov. 2008) Comprehensive search of 10 electronic databases from inception to May 2008Comprehensive search of 10 electronic databases from inception to May 2008 RCTs of at least 12 month durationRCTs of at least 12 month duration Primary prevention populationPrimary prevention population Results: 20 RCTs- Reduction in:Results: 20 RCTs- Reduction in: 19 trials – all cause mortality RR 0.93 (95% CI: 0.87 to 0.99, p=0.03)19 trials – all cause mortality RR 0.93 (95% CI: 0.87 to 0.99, p=0.03) 18 trials - cardiovascular deaths RR 0.89 (95% CI: 0.81 to 0.9, p=0.01)18 trials - cardiovascular deaths RR 0.89 (95% CI: 0.81 to 0.9, p=0.01) 17 trials- major cardiovascular events RR 0.85 (95% CI: 0.77 to 0.95, p=0.004)17 trials- major cardiovascular events RR 0.85 (95% CI: 0.77 to 0.95, p=0.004) 17 trials- MI RR 0.77 (95% CI: 0.63 to 0.95, p=0.01)17 trials- MI RR 0.77 (95% CI: 0.63 to 0.95, p=0.01) CONCLUSION: Statins have a clear role in primary prevention of CVD mortality and major eventsCONCLUSION: Statins have a clear role in primary prevention of CVD mortality and major events

29. “Statins for the Primary Prevention of Cardiovascular Disease” (Taylor F, Ward K et al The Cochrane Library 2011) Cochrane Central Register of Controlled Trials (Issue 1, 2007), MEDLINE (2001 to March 2007) and EMBASE (2003 to March 2007)Cochrane Central Register of Controlled Trials (Issue 1, 2007), MEDLINE (2001 to March 2007) and EMBASE (2003 to March 2007) To avoid duplication- checked reference lists of previous systematic reviewsTo avoid duplication- checked reference lists of previous systematic reviews RCTs of statins with minimum duration of 1 yr and ff-up of 6 monthsRCTs of statins with minimum duration of 1 yr and ff-up of 6 months Adults w/ no restrictions on LDL or HDL levelsAdults w/ no restrictions on LDL or HDL levels History of CVD <10%History of CVD <10%

30. Results: 14 RCTs (16 trial arms; 34, 272 participants)Results: 14 RCTs (16 trial arms; 34, 272 participants) 11 RCTs- (raised lipids, diabetes, HPN, microalbuminuria) 11 RCTs- (raised lipids, diabetes, HPN, microalbuminuria) Reduction in:Reduction in: -all-cause mortality RR 0.84 (95% CI: 0.73-0.96) -all-cause mortality RR 0.84 (95% CI: 0.73-0.96) -combined fatal and nonfatal CVD endpoints -combined fatal and nonfatal CVD endpoints RR 0.70 (95% CI: 0.61-0.79) RR 0.70 (95% CI: 0.61-0.79) -revascularization rates RR 0.66 (95% CI: 0.53- 0.83) -revascularization rates RR 0.66 (95% CI: 0.53- 0.83) Reduction in TC and LDL in all trials with evidence of heterogeneity of effectsReduction in TC and LDL in all trials with evidence of heterogeneity of effects No clear evidence of any significant harm caused by statin prescription of effects on patient quality of lifeNo clear evidence of any significant harm caused by statin prescription of effects on patient quality of life

31. CONCLUSION: Reductions in all-cause mortality, major vascular events and revascularization were found with no excess of cancers or muscle pain among people without evidence of CV disease treated with statinsReductions in all-cause mortality, major vascular events and revascularization were found with no excess of cancers or muscle pain among people without evidence of CV disease treated with statins Only limited evidence showed that primary prevention with statins may be cost-effective and improve patient quality of lifeOnly limited evidence showed that primary prevention with statins may be cost-effective and improve patient quality of life Caution should be taken in prescribing statins for primary prevention among people at low cardiovascular riskCaution should be taken in prescribing statins for primary prevention among people at low cardiovascular risk

32. “Statins and All-Cause Mortality in High Risk Primary Prevention” A Meta-analysis of 11 RCTs involving 65, 229 Participants” (Ray et al Arch Intern Med June 2010) Computerized literature search of MEDLINE and Cochrane databases (January 1970- May 2009)Computerized literature search of MEDLINE and Cochrane databases (January 1970- May 2009) Prospective RCTs of statin therapy in individuals free from CVD at baseline with data on all-cause mortalityProspective RCTs of statin therapy in individuals free from CVD at baseline with data on all-cause mortality Results: 11 RCTs (n=65, 229) --244,000 person-yearsResults: 11 RCTs (n=65, 229) --244,000 person-years No statistically significant reduction inNo statistically significant reduction in All cause mortality RR 0.91 (95% CI: 0.83-1.01)All cause mortality RR 0.91 (95% CI: 0.83-1.01) No statistical evidence of heterogeneity among studiesNo statistical evidence of heterogeneity among studies CONCLUSION: This literature-based meta analysis did not find evidence for the benefit of statin therapy on all-cause mortality in a high-risk primary prevention set-upCONCLUSION: This literature-based meta analysis did not find evidence for the benefit of statin therapy on all-cause mortality in a high-risk primary prevention set-up

33. “Statins for the primary prevention of cardiovascular events in older adults: a review of the evidence” (Ali R, Am J Geriatr Pharmacother Mar 2007) Computerized literature search of PubMed database (Jan 1980 to June 2006)Computerized literature search of PubMed database (Jan 1980 to June 2006) Results: 6 published trials only 3 included subjects aged >75 yrsResults: 6 published trials only 3 included subjects aged >75 yrs Data suggests but does not confirm benefit in the elderly subgroup (i.e. >65 yrs old )Data suggests but does not confirm benefit in the elderly subgroup (i.e. >65 yrs old ) CONCLUSION: Prospective RCTs that better define tolerability, safety and efficacy of statin therapy in older adults w/ elevated cholesterol and intermediate CV risk are neededCONCLUSION: Prospective RCTs that better define tolerability, safety and efficacy of statin therapy in older adults w/ elevated cholesterol and intermediate CV risk are needed

34. “PROSPER: Pravastatin Reduces Cardiovascular Events in the Elderly” (Lancet 2002) N=5804 men and women, aged 70-82 yrsN=5804 men and women, aged 70-82 yrs History or risk factors for vascular dseHistory or risk factors for vascular dse Pravastatin 40 OD vs. placeboPravastatin 40 OD vs. placebo Ff-up : 3.5 yrsFf-up : 3.5 yrs Results: reduction inResults: reduction in coronary death, MI or stroke -15%coronary death, MI or stroke -15% Coronary mortality- 24%Coronary mortality- 24%

35. “Rosuvastatin to Prevent Vascular Events in Men and Women with Elevated CRP” JUPITER Trial (Ridker et al NEJM Nov 2008) n= 17,802n= 17,802 healthy men and womenhealthy men and women low LDL levels (<130 mg/dL/3.4 mmol/L) low LDL levels (<130 mg/dL/3.4 mmol/L) hs CRP > 2.0 mgs/Lhs CRP > 2.0 mgs/L Rosuvastatin 20 mgs vs placeboRosuvastatin 20 mgs vs placebo Trial stopped after 1.9 yearsTrial stopped after 1.9 years Results:Results: Rosuvastatin reduced LDL=50% and hs CRP=37%Rosuvastatin reduced LDL=50% and hs CRP=37%

36. Reduction inReduction in First major vascular event (NFMI, NF stroke, Hosp for UA, AR, or confirmed death fr cardiovasc causes)-First major vascular event (NFMI, NF stroke, Hosp for UA, AR, or confirmed death fr cardiovasc causes)- HR 0.56 (95% CI; 0.46-069; p<0.00001) HR 0.56 (95% CI; 0.46-069; p<0.00001) MI HR 0.46 (95% CI;0.3-0.7; p<0.00002)MI HR 0.46 (95% CI;0.3-0.7; p<0.00002) Stroke HR 0.52 (95% CI;0.34-0.79; p<0.002)Stroke HR 0.52 (95% CI;0.34-0.79; p<0.002) Revasc or UA HR 0.53 (95% CI; 0.4-0.7; p,0.00001)Revasc or UA HR 0.53 (95% CI; 0.4-0.7; p,0.00001) CONCLUSION: In apparently healthy persons without hyperlipidemia but with elevated hs CRP levels, rosuvastatin significantly reduced the incidence of major cardiovascular eventsCONCLUSION: In apparently healthy persons without hyperlipidemia but with elevated hs CRP levels, rosuvastatin significantly reduced the incidence of major cardiovascular events

37. Statins in Primary Prevention Summary 1.While there is conflicting evidence on the beneficial effect of the long-term use of statins in primary prevention we cannot ignore the fact that statins do play a role in the reduction of mortality and major events even in the low cardiovascular risk population 2.In estimating an individual/s risk for CHD we need to look beyond the lipid level 3.Additional markers for assessing overall CHD risk (e.g. hsCRP) may need to be put into guidelines especially when assessing the risk of seemingly “healthy” subjects

38. 4. The exact threshold of baseline risk of CVD has not been determined yet and is a challenge for emerging treatment guidelines in primary prevention 5. Despite the fact that scoring systems are available to estimate CHD risk, a thorough medical exam is still warranted

39. ASPIRIN

40. Aspirin is widely recognized and currently approved by BFAD : Aspirin is widely recognized and currently approved by BFAD : to reduce the risk of recurrent ischemic stroke and stroke after transient ischemic attack,to reduce the risk of recurrent ischemic stroke and stroke after transient ischemic attack, For suspected AMI, and prevention of recurrent MI,For suspected AMI, and prevention of recurrent MI, for unstable angina pectoris,for unstable angina pectoris, for chronic stable angina pectoris,for chronic stable angina pectoris, for revascularization procedures in selected patientsfor revascularization procedures in selected patients Primary prevention of CVD in patients with hypertension or diabetesPrimary prevention of CVD in patients with hypertension or diabetes In spite of these approvals, aspirin continues to be underutilized in many of these populations. *In spite of these approvals, aspirin continues to be underutilized in many of these populations. * One possible explanation for the underuse of aspirin by patients and physicians is concern regarding the potential for adverse effects and difficulty in assessing aspirin's benefit-to-risk relationship.One possible explanation for the underuse of aspirin by patients and physicians is concern regarding the potential for adverse effects and difficulty in assessing aspirin's benefit-to-risk relationship. 1.Stafford RS. Circulation. 2000;101:1097-1101.

41. PopulationNFMIVascular EventVascular Death SourceASAPlaceb o ASAPlaceb o ASAPlaceb o ASAPlaceb o PHS198811,03711,0341.2% 1.9% 2.8%3.4%0.7%0.8% BDT19913,4291,7102.3%2.4%8.4%8.5%4.3%4.6% TPT19982,5452,5403.7%5.4%9.0%10.2%4.0%3.2% HOT19989,3999,391NR 3.4%3.9%1.4%1.5% PPP20012,2262,2690.7%0.8%6.3%8.2%0.8%1.4% WHS 200519,93419,9420.92%0.90%2.4%2.6%0.6%0.63% JPAD 2008 1,2621,2771.0%0.7%2.2%2.5%0.08%0.8% POPADA D 2008 638 8.6%8.8%18.2%18.3%6.8%5.6% AAA 20101,675 3.7%4.1%10.8%10.5%2.1%1.8% Total50,86849,1701.0%1.3%3.6%4.0%1.2%1.1% Trials on Aspirin for Primary Prevention Am J Cardiol 2011;107:1796–1801

42. Results: Aspirin in primary prevention End pointOdds ratio (95% CI)p Total CHD 0.85 (0.69-1.06)0.154 Nonfatal MI 0.81 (0.67-0.99)0.042 Total CV events 0.86 (0.80-0.93)0.001 Stroke 0.92 (0.83-1.02)0.116 CV mortality 0.96 (0.80-1.14)0.619 All-cause mortality 0.94 (0.88-1.01)0.115 Bartolucci AA, Tendera M, and Howard G. Meta-analysis of multiple primary prevention trials of cardiovascular events using aspirin. Am J Cardiol 2011 0.5 0.8 1 2 5 9 randomized trials of aspirin in patients without CHD/CVD

43. Gastrointestinal Bleeding for the 9 study StudyAspirinControlAbsolute increase WHS 4.5%3.8%0.7% BMD 0.3%0.4%-0.1% PHS 4.0%3.8%0.2% HOT 0.8%0.4% PPP 0.8%0.2%0.6% TPT 1.4%0.9%0.5% AAAT 0.5% 0 JPAD 0.8%0.3%0.5% POPADAD 4.4%4.9%-0.5% Mean1.9%1.6%0.3% Modified from Am J Cardiol 2011;107:1796–1801

44. Benefit/risk ratio of antiplatelet prophylaxis with aspirin in different settings Clinical settingBenefit a Risk b Benefit/risk ratio Number of patients in whom a major vascular event is avoided per 1000/year Number of patients in whom a major GI bleeding event is caused per 1000/year Men and women at low-cardiovascular risk 1–2 1 Essential hypertension1–2 1 High risk for CHD101–25–10 Modified from Patrono et al., Chest 2008

45. Aspirin Primary Prevention Trials 1.Physician’s Health Study 1988 2.British Doctor’s Trial 1991 3.Thrombosis Prevention Trial 1998 4.Hypertension Optimal Treatment 1998 5.Primary Prevention Project 2001 6.Women’s Health Study 2005

46. PHS 1988 BDT 1991 TPT 1991 HOT 1998 PPP 2001 WHS 2005 Population 22,071 Men mean age 53 years; physicians No CHD, <2 risk factors 5,139 Men mean age 60 years; physicians No CHD, No stroke 5499 Men mean age 57.5 years at entry who were at increased risk of CHD 18,798 Men and women mean age 65 years w/ DBP =100 to 115 mm Hg 4, 495 Men and Women 60-79 years with >1 major risk factor for CHD 39,876 Women 45 years and older, No CHD/CVD Intervention 325 mg buffered ASA VS placebo 2/3 500mg ASA or 300mg ECA VS NO ASA 75 mg controlled release ASA vs Placebo 75 mg ASA VS Placebo 100 mg ASA VS No ASA 100 mg ASA EOD VS Placebo Outcome CV event MI and Stroke MI, Stroke, Death MI, CHD death, Stroke MI, Stroke, CV death CV death,MI, Stroke Method RCT; Double blind placebo controlled 2x2factorial; ITT analysis RCT, Open, 2:1 allocation; ITT analysis RCT, Double blind placebo controlled 2x2 factorial ITT analysis RCT, Double blind Placebo Controlled 2x2 factorial ITT analysis RCT, Open 2x2 factorial ITT analysis RCT, Double blind Placebo controlled 2x2 factorial ITT analysis Follow-up 60.2 months60 months81 months45 months43 months120 months

47. AspirinControl SourceNNFMIVasc Event Vasc Death NNFMIVasc Event Vasc Death PHS1988 11,037129 (1.2%) 307 (2.8%)81 (0.7%) 11,034213 (1.9%) 370 (3.4%) 83 (0.8%) BDT1991 3,42980 (2.3%)289 (8.4%)148 (4.3%) 1,71041 (2.4%)147 (8.5%) 79 (4.6%) TPT1998 2,54594 (3.7%)228 (9.0%)101 (4.0%) 2,540137 (5.4%) 260 (10.2%) 81 (3.2%) HOT1998 9,399NR315 (3.4%)133 (1.4%) 9,391NR368 (3.9%) 140 (1.5%) PPP2001 2,22615 (0.7%)141 (6.3%)17 (0.8%) 2,26918 (0.8%)187 (8.2%) 31 (1.4%) WHS 2005 19,934184 (0.92%) 477 (2.4%) 120 (0.6%) 19,942181 (0.90%) 522 (2.6%) 126 (0.63%) Total 48,870502 (1.0%) 1,757 (3.6%) 600 (1.2%) 46,886594 (1.3%) 1,854 (4.0%) 540 (1.1%) Trials on Aspirin for Primary Prevention

48. Study AspirinControl n / N OR (95% CI Random) Weight % OR (95% CI Random) BMD169 / 342988 / 17105.50.96 [0.73, 1.24] PHS 163 / 11037266 / 1103423.80.61 [0.50, 0.74] TPT83 / 1268107 / 12722.730.76 [0.57, 1.03] HOT82 / 9399127 / 939120.20.64 [0.49, 0.85] PPP 26 / 222635 / 22694.80.75 [0.45, 1.26] WHS 198/19934193/19942 42.9 1.02 [0.841.25] Total (95 % CI) 721 / 47293 (1.5%) 816 /45618 (1.8%) 100.00.77 [0.60, 0.87] Test for heterogenecity chi-square = 5.38 d = 4 p = 0.25 125.2.2.5 Total Coronary Heart Disease Events Favors AspirinFavors Control

49. Study AspirinControl n / N OR (95% CI Random) Weight % OR (95% CI Random) BMD89 / 342847 / 171037.20.94 [0.66, 1.35] PHS 34 / 1103753 / 1103425.60.64 [0.42, 0.99] TPT36 / 126834 / 127221.11.06 [0.66, 1.71] HOT14 / 939914 / 93918.71.00 [0.48, 2.10] PPP 11 / 222613 / 22697.40.86 [0.39, 1.93] Total (95 % CI) 184 / 27359335 / 25676100.00.87 [ 0.70, 1.09] Test for heterogenecity chi-square = 5.38 d = 4 p = 0.25 125.2.5 Favors AspirinFavors Control Effect of Aspirin on Coronary Heart Disease Mortality

50. Study AspirinControl n / N OR (95% CI Random) Weight % OR (95% CI Random) BMD91 / 342839 / 17105.51.17 [0.80, 1.71] PHS 118 / 1103798 / 1103423.81.22 [0.93, 1.59] TPT18 / 126826 / 12722.730.69 [0.38, 1.27] HOT146 / 9399148 / 939120.20.99 [0.78, 1.24] PPP 16 / 222624 / 22694.80.68 [0.36, 1.28] WHS 221/19934266/19,942 42.9 0.83 [0.69,0.99] Total (95 % CI) 610 / 47293 (1.28%) 601 / 45618 (1.32%) 100.00.945 [ 0.84, 1.03] Test for heterogenecity chi-square = 5.38 d = 4 p = 0.25 Effect of Aspirin on Fatal and Nonfatal Stroke Events 125.2.5 Favors AspirinFavors Control

51. Hemorrhagic Stroke Secondary to Aspirin Usage AspirinControl SourceNHemorrhagic stroke N Physician’s Health Study11,0372311,03412 British Doctor’s Trial3,429131,7106 Thrombosis Prevention Trial 2,545122,5406 Hypertension Optimal Treatment NR Primary Prevention Project 2,22622,2693 Women’s Health Study19,9345119,94241 Total39,171101 (0.26%) 37,49568 (0.18%) Relative risk Ratio = 1.56 ( 95% CI 0.99-2.46)

52. Ulcer and GI Bleeding Trial Type of GI Adverse events Cumulative Incidence P Value Excess Bleeding Events per 1,000 Patients Treated per Year Fatal Gastrointestinal Bleeding Events Aspirin Group Control Group Aspirin Group Control Group BDT Self-reported peptic ulcer disease 2.6%1.6%<0.051.733 PHS Upper gastrointestinal ulcers 1.5%1.3%0.080.410 TPT Major or intermediate bleeding 1.7%0.8%NS1.301 HOT Fatal and nonfatal major gastrointestinal bleeding 0.8%0.4%NS1.153 PPP Gastrointestinal bleeding 0.8%0.2%NS1.500 WHS Gastrointestinal bleeding 4.6%3.8%<0.0011.0NR

53. Estimates of the Effect of Aspirin OutcomeOdds Ratio (95% CI) Benefits Myocardial Infarction0.72 (0.60 to 0.87) Coronary Heart Disease Death 0.87 (0.70 to 1.09) Total Stroke1.02 (0.85 to 1.23) All-Cause Mortality0.93 (0.84 to 1.02) Harms Odds Ratio (95% CI) Hemorrhagic Stroke**1.4 (0.9 to 2.0) Major Gastrointestinal Bleed**1.7 (1.4 to 2.1)

54. Likelihood of Help vs. Harm Estimated 5-Year Risk for CHD Events at Baseline Outcome1%3%5% Effect on all-cause mortalityNo change CHD events avoided, n3 (1 to 4)8 (4 to 12)14 (6 to 20) Ischemic strokes avoided, n000 Hemorrhagic strokes precipitated, n 1 (0 to 2) Major gastrointestinal bleeding events precipitated, 3 (2 to 4)

55. Patient application: If the patient meets all inclusion criteria and has violated none of the exclusion criteriaIf the patient meets all inclusion criteria and has violated none of the exclusion criteria the results can be applied with considerable confidence.the results can be applied with considerable confidence. Look at the baseline characteristicsLook at the baseline characteristics the patient before you may have different attributes or characteristics from those enrolled in the trial.the patient before you may have different attributes or characteristics from those enrolled in the trial. age, severity of disease, co morbid conditionage, severity of disease, co morbid condition health-seeking behavior, predicament, values and preferenceshealth-seeking behavior, predicament, values and preferences

56. Patient characteristics in the trials TrialsPopulation PHS 1988 22,071 Men mean age 53 years; NO CHD, <2 risk factors HPN = 11.8%, DM2 = 2.3%, high cholesterol = 7.7%, smoking = 11% overweight =13.7%, hx of angina = 1.3% BDT 1991 5,139 Men mean age 60 years; physicians No CHD, No stroke; HPN= 10.2%, DM2= 2%, Hx of angina 2.2%, TIA = 2.7%, withdrawal rate = 44.3% stopped 1 st year (19.5%) stopped subsequent years (24.8%), Control group = 11% started aspirin. TPT 1991 5499 Men mean age 57.5 years at increased risk of CHD; HPN = 50%, Smoking = 41%, Family History of CAD = 15%, High cholesterol = 57%, Overweight and Obese = 10%, Top 20% risk score BUT NO CHD or STROKE HOT 1998 18,798 Men and women mean age 65 years w/ DBP =100 to 115 mm Hg HPN = 100%, DM = 8.0%, Smoking = 15.9%, previous MI = 1.6%, Previous Stroke = 1.2%, previous CHD = 5.9% PPP 2001 4, 495 Men and Women 60-79 years with >1 major risk factor for CHD HPN = 69%, DM= 17%, High cholesterol = 41%, Obese = 22%, Family history of premature CAD = 11%, Smoking = 15%, 2 risk factors= 39%; 3 risk factors = 30% WHS 2005 39,876 Women 45 years and older, No CHD/CVD HPN = 26%, Post-menopausal = 53%, Framingham risk score less than 5% = 85% 1.Smokers who do not want to quit 2.Hypertensives with > 1 additional risk factor 3.Diabetics with > 1 additional risk factor 4.Post-menopausal with > 1 additional risk factor 5.Multiple risk factors >3 (age > 55 men and >65 for women)

57. “Aspirin for primary prevention of cardiovascular events in people with diabetes: Meta-analysis of RCTs” (De Berardis BMJ 2009) Literature searchLiterature search 6 RCTs in DM with no known cardiovascular dse.6 RCTs in DM with no known cardiovascular dse. ASA vs. placebo/no aspirin ASA vs. placebo/no aspirin Results:Results: No statistically significant differences in the risk of major cardiovascular events, CV mortality, all- cause mortality, MI or stroke and “inconsistent” harm from aspirin use.No statistically significant differences in the risk of major cardiovascular events, CV mortality, all- cause mortality, MI or stroke and “inconsistent” harm from aspirin use. By sex, ASA appeared to significantly reduce the risk of MI by 43% but no significant reduction in MI seen in womenBy sex, ASA appeared to significantly reduce the risk of MI by 43% but no significant reduction in MI seen in women

58. Randomized trials are needed to answer the question about risk and benefit of aspirin in primary prevention in diabetic subjectsRandomized trials are needed to answer the question about risk and benefit of aspirin in primary prevention in diabetic subjects A Study of Cardiovascular Events in Diabetes (ASCEND)A Study of Cardiovascular Events in Diabetes (ASCEND) Aspirin and Simvastatin Combination for Cardiovascular Events Prevention Trial in Diabetes (ACCEPT-D)Aspirin and Simvastatin Combination for Cardiovascular Events Prevention Trial in Diabetes (ACCEPT-D)

59. Benefits of aspirin in cancer Review of an analyses of published clinical trials on aspirinReview of an analyses of published clinical trials on aspirin ASA user had a 38% reduction in the risk of colorectal and other GI cancers compared w/ non-usersASA user had a 38% reduction in the risk of colorectal and other GI cancers compared w/ non-users regular ASA users-15% lower CA mortality regular ASA users-15% lower CA mortality - 35-40% less metastasis - 35-40% less metastasis Jasmer R, MedPage Today March 21, 2012

60. However, did not include results from The Women’s Health Initiative and the Physicians Health Study- 2 largest clinical evaluations of ASA effect on cancer riskHowever, did not include results from The Women’s Health Initiative and the Physicians Health Study- 2 largest clinical evaluations of ASA effect on cancer risk did not demonstrate an effect of aspirin on cancer riskdid not demonstrate an effect of aspirin on cancer risk

61. Aspirin in Primary Prevention Summary 1.the widespread use of aspirin in primary prevention should be weighed carefully in terms of benefit vs. harm especially in the light of its possible beneficial effects in cancer

62. 2. The benefit of aspirin use in the diabetic population remains in question until large scale clinical trial results are in. In the meantime approaches known to minimize CV risk (e.g. avoidance of smoking, use of ACE-I and good glucose control) should be used

63. Thank You for your Attention!