1. Cardiovascular Risk Diabetes And Aspirin A Closer look into the evidence-base Howard Van IM2 Ahraaz Wyne IM1 The University of Western Ontario London Health Sciences Center

2. Contents 1.Cardiovascular Risks with Diabetes 2.Briefly review 9 trials of diabetes and aspirin 3.Briefly review 4 meta analyses on this topic 4.Current Guidelines from the CDA, ADA and AHA 5.Future Directions (ongoing Trials) 6.Conclusions and Summary

3. Diabetes Risks Individuals with diabetes are at 2-4X increased risk of cardiovascular events compared with individuals without diabetes. In Diabetic patients > 65 years, 68% of deaths are from coronary heart disease (CHD) and 16% are from stroke.

4. Framingham Heart Study 30-Year Follow-Up

5. Framingham Heart Study 30-Year Follow-Up: CVD Events in Patients With Diabetes (Ages 35-64) 10 9 20 11 9638 19 3* 30 0 2 4 6 8 10 Age-adjusted annual rate/1,000 MenWomen Total CVDCHDCardiac failure Intermittent claudication Stroke Risk ratio P<0.001 for all values except *P<0.05. Wilson PWF, Kannel WB. In: Hyperglycemia, Diabetes and Vascular Disease. Ruderman N et al, eds. Oxford; 1992.

6. THE EVIDENCE

7. British Medical Doctors (BMD) BMJ 1988 A 6 yr Randomized control trial of 5000 male physicians, on ASA 500mg daily vs. placebo Only n=101 diabetic males, NO significant reductions in CV outcomes reported in the diabetic group

8. Physician’s Health Study NEJM(1989) Randomized, double-blind, placebo-controlled trial of 22,071 physician all comers Average follow-up: 60 months Subgroup of n= 533 Male diabetics, assigned to 325mg ASA alternate days vs. placebo 41% reduction (RR 0.59, 95% CI 0.33-1.06) in fatal and non-fatal MI) in the ASA-group

9. Hypertension Optimal Treatment (HOT) 1998 Randomized multi-center trial of approx 18000 pts aged 50-80yo, with elevated dBP Objective: to determine optimal target dBP and effects of ASA 75mg daily vs. placebo Among the n= 1500 diabetics, reduction of 23% (RR 0.77, 95% CI 0.44–1.36) for CV events No effect on stroke or fatal bleeds At the expense of 2X as many non-fatal bleeds

10. Thrombosis Prevention Trial (TPT) Med Research Council 1998 A randomized trial of 5500 high-risk males aged 45- 69yo, followed for 7years Objective: to determine the role of warfarin and-or ASA 75mg daily in primary prevention of CHD Only N=68 diabetic males, No significant reduction in fatal CHD outcomes

11. Primary Prevention Project (PPP) 2003 Randomized, open trial of 4500 pts to determine role of ASA 100mg daily or Vit E vs. placebo, in prevention of CV outcomes in at-risk patients Subgroup of n= 1,031 diabetic pts In diabetics, ASA was associated with a non- significant reduction (RR 0.50, 95% CI 0.17–1.46) in combined MI end points (fatal + nonfatal MI)

12. Women's Health Study (WHS) NEJM 2005 RCT of 40,000 women aged ≥ 45yo, followed for 10yrs for first CV event. ASA 100 mg alternate days vs. placebo In Subgroup of n = 1,027 diabetics, NO reduction in risk for CHD with ASA; RR 1.34, 95% CI 0.85–2.12. There was, reduction in stroke with ASA in female diabetics; RR 0.45, 95% CI 0.25–0.82).

13. TRIALS DESIGNED FOR DIABETES

14. Trial Design with DM and Aspirin Three trials focused on the effect of aspirin exclusively among patients with diabetes.

15. Early Treatment of Diabetic Retinopathy Study (ETDRS) The ETDRS trial examined the effect of 650 mg of aspirin daily versus placebo among 3,711 patients with type 1 or type 2 diabetes between ages 18 and 70 years who had some degree of retinopathy. Approximately one-half of participants reported some history of CVD, although it should be noted that the definition of CVD included the use of antihypertensive medication. Fewer than 10% had had a previous MI or stroke, and 9% had claudication. Intervention patients experienced a decreased risk of nonfatal or fatal MI (RR 0.85, 95% CI 0.73–1.00). In contrast, stroke occurred more frequently with aspirin, although the difference was not statistically significant (RR 1.18, 99% CI 0.88–1.58). Men appeared to derive more benefit from aspirin than women for prevention of MI (RR for men 0.74, 99% CI 0.54–1.00; RR for women 0.91, 99% CI 0.65–1.28), but this difference was not statistically significant and could represent a chance finding

16. Prevention of Progression of Arterial Disease and Diabetes (POPADAD) BMJ 2008). POPADAD trial studied whether aspirin and/or antioxidant therapy was more effective than placebo in reducing the incidence of cardiovascular events in patients with diabetes and asymptomatic peripheral arterial disease. This randomized, multicenter, double-blind, placebo- controlled trial involved 1,276 adults over age 40 years with either type 1 or type 2 diabetes. All subjects had an ankle brachial pressure index less than 0.99 but no symptomatic CVD.

17. POPADAD They were randomized in a 2×2 factorial design to aspirin 100 mg daily, an antioxidant supplement daily, both, or neither. Two composite primary end points were 1) death from CHD or stroke, nonfatal MI or stroke, or amputation above the ankle for critical limb ischemia; and 2) death from CHD or stroke.

18. POPADAD Study medication discontinuation rates were high: 14% at 1 year and 50% at 5 years. Overall, 116 of 638 (18.2%) primary events occurred in patients assigned to aspirin therapy versus 117 of 638 (18.3%) in those on placebo (HR 0.98, 95% CI 0.76–1.26). There were 43 CHD or stroke deaths in the aspirin group and 35 in the placebo group (6.7% vs. 5.5%; HR 1.23, 95% CI 0.79–1.93). The rates of a wide variety of secondary end points and adverse events also did not differ between groups. Outcomes were also similar with or without the antioxidants; there was no interaction between the two active therapies

19. POPADAD Conclusion This trial does not provide evidence to support the use of aspirin or antioxidants in primary prevention of cardiovascular events and mortality in the population with diabetes studied.

20. The Japanese Primary Prevention of Atherosclerosis with Aspirin for Diabetes (JPAD) In 2008, investigators examined the efficacy of low-dose aspirin for primary prevention of cardiovascular events in a randomized, open- label trial conducted in 2,539 Japanese patients with type 2 diabetes age (30-85) but no history of CVD.

21. JPAD Patients were assigned to either aspirin (81–100 mg daily) or no aspirin and were followed for an average of 4.4 years. The primary end point was a composite of fatal or nonfatal ischemic heart disease, fatal or nonfatal stroke, and peripheral arterial disease. A total of 154 events occurred: 68 (5.4%) in the aspirin group and 86 (6.7%) in the nonaspirin group (HR 0.80, 95% CI 0.58–1.10).

22. JPAD

23. The combined secondary end point of coronary and cerebrovascular mortality occurred in 1 patient (stroke) in the aspirin group and 10 patients (five fatal MIs and five fatal strokes) in the nonaspirin group (HR 0.10, 95% CI 0.01–0.79). Other secondary end points did not differ importantly between groups

24. JPAD Overall, mortality occurred in 34 patients in the aspirin group and 38 patients in the nonaspirin group (HR 0.90, 95% CI 0.57–1.14). According to prespecified subgroup analyses, however, in subjects over 65 years of age (n = 1,363), the incidence of the primary end point was lower with aspirin (HR 0.68, 95% CI 0.46–0.99). small increase in cases of serious GI bleeding (4 patients in the aspirin group had bleeding that required transfusion), but no excess of fatal GI or cerebral hemorrhages.

25. Limitations 6: population based trials and 3: specific diabetic trials In the 6 trials, proportions of pts with diabetes form subgroups within broader trials, ranging from: – TPT, BMD, PHS: 1-2% to, PPP: 22% TPT, BMD, PHS exclude women! WHS: only women! All trials excluded pts with prev GI Bleed. Only 2 of 9 reported on Statin use. ETDRS, BMD,PHS, TPT & HOT conducted prior to widespread Statin use NO single trial provides definitive results.

26. META-ANALYSES: A Need for Reconciliation

27. Meta-Analyses A total of 4 recent Meta-Analyses in an attempt to reconcile data: 1.Antithrombotic Trialists` Collaboration (ATTC)- Lancet 2009 (6 of 9 trials) 2.DeBerardis et al- BMJ 2009 (6 of 9 trials) 3.ADA, AHA and ACCF Consensus-Circulation 2010 (9 trials) 4.Zhang et al- Diab Clin Pract 2010 (7 of 9 trials)

28. Anti-thrombotic Trialists' Collaboration (ATTC) 2009 Patient level meta-analysis of 6 trials (excluded ETDRS, JPAD, POPADAD), of more than 95000 pts, with n= 4000 diabetics. ASA reduced risk of overall vascular events by 12% (RR 0.88, 95% CI 0.82-0.94) – Largest reduction for non-fatal MI: RR 0.77, 95% CI 0.67-0.89 NO EFFECT on total stroke (RR 0.95, 95% CI 0.85- 1.06) or CHD death (RR 0.95, 95% CI 0.78-1.15)

30. ATTC-Lancet 2009 Some evidence of a gender effect with ASA – ASA reduced CHD events in MEN (RR 0.77, 95% CI 0.67-0.89) but not in WOMEN RR 0.95, 95% CI 0.77-1.17) – ASA had no effect on stroke in MEN (RR 1.01, not sig) but reduced stroke in WOMEN (RR 0.77, sig) Effect of ASA on major vascular events was similar in patients WITH (RR 0.88, 95% CI 0.67-1.15) and WITHOUT diabetes (RR 0.87, 95% CI 0.79-0.96)

31. DeBerardis et al- BMJ 2009 6 RCTs included (excluded HOT, BMD, TPT), n=10 117 people with diabetes. No significant differences found with ASA: – MI: RR 0.86, 95% CI 0.61-1.21 – Stroke: RR 0.83, 95% CI 0.60-1.14 Moderately significant heterogeneity (I 2 =50%) Effect modification by Gender (reduced MI in Men RR 0.57 95% CI 0.34-0.94, vs not so in Women RR 1.08, 95% CI 0.71-1.65)

32. ©2009 by British Medical Journal Publishing Group

33. All 9 core trials of ASA and diabetes included in an Expert Consensus document by three large bodies ASA associated with the following outcomes: – CHD Events (fatal and non-fatal MI): NOT SIG- 9% reduction (RR 0.91, 95% CI 0.79-1.05) – Stroke: NOT SIGN- 15% reduction (RR 0.85 95% CI 0.66- 1.11) Not enough access to patient level data in diabetics to conclude whether there were effect modifications by gender, ASA dose, or other factors ADA, AHA and ACCF Consensus 2010

34. A)CHD Events B)Stroke

35. Total of 7 trials included (excluded BMD, TPT) ASA in diabetics NOT found to be sig assoc, – MI: RR 0.85, 95% CI 0.65-1.11 – Stroke: RR 0.83, 95% CI 0.63-1.10 Meta-regression analyses showed no effect modification by gender Interestingly, they showed that there was no publication bias (through funnel plots) Zhang et al. Diab Clin Pract 2010

36. Summary of META-ANALYSES METAANALYSISNo. Of Trials MIStroke ATTC (2009)6RR 0.77, 95% CI 0.67-0.89 RR 0.95, 95% CI 0.85-1.06 DeDerardis et al. (2009) 6RR 0.86, 95% CI 0.61-1.21 RR 0.83, 95% CI 0.60-1.14 ADA, AHA, ACCF (2010) 9RR 0.91, 95% CI 0.79-1.05 RR 0.85 95% CI 0.66-1.11 Zhang et al (2010)7RR 0.85, 95% CI 0.65-1.11 RR 0.83, 95% CI 0.63-1.10 Evidence may not be conclusive because too few events in available trials Garbage in = Garbage out for Meta-analyses (i.e. Subgroups within larger trials) Differences in men and women require further study...

37. CURRENT GUIDELINES & FUTURE DIRECTIONS

38. Guidelines FDA NOT approved ASA for primary prevention. The U.S. Preventive Services Task Force recently updated its recommendation about aspirin use for primary prevention. – The Task Force recommended encouraging aspirin use in men age 45–79 years and women age 55–79 years and not encouraging aspirin use in younger adults.

39. Guidelines In 2007, ADA, AHA jointly recommended that ASA therapy (75–162 mg/day) be used as a primary prevention strategy in those with diabetes at increased cardiovascular risk, including those who are over 40 years of age or who have additional risk factors (family history of CVD, hypertension, smoking, dyslipidemia, or albuminuria) – (These recommendations were derived from several older trials that included relatively small numbers of patients with diabetes.)

40. ADA Guidelines Recommendations in 2010 based on further data from ATT (Anti-Thrombotic Trialists') and JPAD and POPADAD. ADA AHA, and ACC have updated recommendation based on cardiac risk stratification.

41. ADA Guidelines Recommend ASA (75–162 mg/day) as a primary prevention strategy in those with type 1 or type 2 diabetes at increased cardiovascular risk (10-year risk >10%). men >50 years of age or women >60 years of age who have at least one additional major risk factor (family history of CVD, hypertension, smoking, dyslipidemia, or albuminuria).

42. ADA Guidelines No ASA for lower risk individuals – men <50 years of age or women <60 years of age without other major risk factors. For patients in these age-groups with multiple other risk factors, clinical judgment is required. Use ASA (75–162 mg/day) as a secondary prevention strategy in those with diabetes with a history of CVD.

43. CDA Guidelines In 2008 CDA guildlines, CDA suggest that we should recommend ASA to: Secondary prevention: DM patient and CVD. Primary prevention: individual clinical judgement due to lack of benefits vs long-term side effect of ASA. The recommendation is based on following trials. ( ETRDS, PPP,PHS,HOT,ATT)

44. Future: The Ongoing trials Two ongoing studies additional information on the role of low-dose ASA for prevention of cardiovascular events specifically in diabetics. – Aspirin and Simvastatin Combination for Cardiovascular Events Prevention Trial in Diabetes (ACCEPT-D) : open- label Italian primary prevention trial, ASA 100 mg daily vs. placebo in 5000 diabetic adults over 50yo who are also on simvastatin. – Plan to examine several apriori subgroups to detect differences, including men versus women, old vs. young

45. A Study of Cardiovascular Events in Diabetes (ASCEND): U.K. randomized double blind trial of ASA 100 mg daily vs. placebo among T1 and T2-diabetics over 40yo with no previous vascular events. Planned enrollment is 10,000, powered to detect a 20% reduction in major vascular events including MI and stroke.

46. SUMMARY & CONCLUSIONS

47. Conclusion ASA(75–162 mg/day) primary prevention is reasonable for adults with diabetes and high CVD risk – = 10 year risk of CVD events over 10% and no risk for bleeding (based on a history of previous gastrointestinal bleeding or peptic ulcer disease or concurrent use of other medications that increase bleeding risk, such as NSAIDS or warfarin).

48. Conclusion ASA should not be recommended for CVD prevention in adults with diabetes at low CVD risk – = 10-year CVD risk under 5%, Men under age 50 years and women under 60 years with no major additional CVD risk factors

49. Conclusion ASA use for prevention might be considered based on individualized clinical judgment for those with diabetes at intermediate CVD risk – 10-year CVD risk of 5–10%, Younger patients with one or more risk factors, or older patients with no risk factors, or patients with no history of GI bleeding or hemorrhagic stroke, until further research is available.

50. Thank you! Howard Van Ahraaz Wyne